CADTH Reimbursement Review

Caplacizumab (Cablivi)

Resubmission

Sponsor: Sanofi-Aventis Canada Inc.

Therapeutic area: Acquired thrombotic thrombocytopenic purpura

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the resubmission details for the drug under review is provided in Table 1.

Table 1: Resubmitted for Review

NOC = Notice of Compliance.

Source: Sponsor’s drug reimbursement review resubmission for caplacizumab.¹

Introduction

Thrombotic thrombocytopenic purpura (TTP) is an ultra-rare blood disorder caused by reduced enzymatic activity of the von Willebrand factor (vWF)-cleaving protease, a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13), resulting in an inability to cleave high molecular weight vWF multimers, and as a consequence, formation of platelet-rich blood clots in small vessels (thrombotic microangiopathy).² TTP is a medical emergency and acquired TTP (aTTP) (driven by autoantibodies against ADAMTS13) is the dominant form.^2-4 Mortality is estimated at approximately 10% to 20%;⁵ in addition, thrombotic complications and their sequelae contribute to persistent cognitive and physical difficulties that can be life-altering in some patients, compromising health-related quality of life (HRQoL).⁶ After the presenting episode, recurrence of aTTP (exacerbation: recurrence within 30 days of cessation of plasma exchange [PE]; relapse: recurrence after 30 days of cessation of PE) will occur in up to half of patients, while refractory aTTP (absence of platelet count increase following treatment) will occur in approximately 10% of patients.⁷

According to the clinical experts consulted by CADTH for this review, diagnosis of aTTP is based on clinical and laboratory findings and is made by a hematologist. The incidence of aTTP is estimated at approximately 2 to 4 cases per million population per year (approximately ||| cases per million adults);^8-10 approximately ||| |||||||| with TTP were treated in Canada in 2018.¹ According to the clinical experts consulted by CADTH for this review, current management of aTTP in Canada involves PE and immunosuppression with corticosteroids. The sponsor emphasized that the treatment burden associated with PE is significant as PE often requires a transfer to a PE centre, there is a need for surgery (vascular catheter insertion with a risk of infections), and there is potential for exposure to multiple donors (risk of PE reactions).¹ In Canada, rituximab is typically not used upfront and is administered to patients with aTTP exacerbations, relapsed aTTP, or refractory aTTP. The clinical experts stated the main goals of treatment are to prolong life and avoid mortality while preventing thrombotic complications and associated disabilities. Treatment goals are accomplished by replenishing ADAMTS13 and removing autoantibodies against ADAMTS13, allowing normalization of ADAMTS13 activity and consequently halting thrombotic microangiopathy.

Caplacizumab is a bivalent humanized nanobody that binds to the A1 domain of vWF, inhibiting the interaction between vWF and platelets, reducing vWF-mediated platelet activation and adhesion, and preventing the formation of ultra-large vWF-rich platelet microthrombi.¹¹ The drug is dosed at 11 mg (IV and subcutaneous [SC] injections on day 1 of PE followed by daily SC injections during PE and for a minimum of 30 days after cessation of PE).¹¹ The Health Canada indication for caplacizumab is “for the treatment of adults with aTTP in combination with PE and immunosuppressive therapy.”¹¹

Caplacizumab was initially reviewed by CADTH for the treatment of adults with aTTP in combination with PE and immunosuppressive therapy and received a negative funding recommendation from the CADTH Canadian Drug Expert Committee (CDEC) on September 1, 2020.¹² Key reasons for the recommendation included insufficient evidence of clinically important outcomes (e.g., survival, organ damage, health care use, or long-term aTTP recurrence), lack of long-term clinical outcome data, lack of an identifiable subpopulation most likely to benefit from treatment, generalizability to Canadian clinical practice, and absence of HRQoL data. The recommendation was based on evidence assessed in the CADTH Clinical Review Report for the initial submission of caplacizumab,¹³ the executive summary of which is reproduced as Appendix 2. The drug was resubmitted for review by the sponsor on the basis of the availability of new evidence on June 7, 2022.¹ The new evidence included a prospective long-term follow-up study of patients who completed the HERCULES trial (the post-HERCULES trial),^14,15 a variety of post hoc analyses including an integrated analysis of data from the HERCULES and TITAN studies,¹⁶ and several real-world evidence (RWE) studies including comparisons of patients treated with caplacizumab with historical controls who received standard of care (SOC) alone in France^17-19 and the UK.²⁰

The objective of this report was to perform a systematic review of the beneficial and harmful effects of caplacizumab (11 mg IV bolus plus 11 mg SC injection on day 1 of PE, followed by 11 mg SC injection daily) for the treatment of adults with aTTP in combination with PE and immunosuppressive therapy. This report is an update of the Clinical Review Report for the original submission of caplacizumab;¹³ new evidence provided by the sponsor or identified through a systematic literature search was included in the report if it addressed an evidence gap identified by CDEC in its final recommendation for the initial submission.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient groups who responded to CADTH’s call for patient input and from clinical experts consulted by CADTH for the purpose of this review.

Patient Input

One patient group, the Answering TTP Foundation, provided input for this review. The group conducted an online survey in May and June of 2022 (N = 49 respondents including 31 patients with aTTP, 16 family members, caregivers, or friends of patients with aTTP, 1 health care professional, and 1 researcher). Most (80%) survey respondents were women and most (90%) were people living in Canada. Approximately half of respondents (48%) had experienced at least 1 relapse. Patients highlighted delays in diagnosis and treatment as well as the negative impacts of serious and/or frequent symptoms of aTTP (e.g., bruising, fever, fatigue, migraine, confusion, abdominal pain, bleeding, shortness of breath, vision loss, and jaundice) which impose heavy burdens on mental health (e.g., anxiety, depression, and panic attacks). A subset of patients experienced incapacitating or life-threatening complications of aTTP including stroke, myocardial infarction, and kidney problems. Nearly all patients had experience with PE and corticosteroids while approximately two-thirds (65%) had experience with rituximab. Respondents described the challenges of current treatments including lengthy hospital stays, side effects of corticosteroids, and the inconvenience of daily PE; in addition, available treatments are costly, require time off from work, and may require travel to a major centre for access. Respondents identified an unmet need for treatments that can reduce the risk of death or disability from aTTP and ease the mental and emotional burdens of disease (e.g., continuous fear of relapse and impacts on social life and career goals). Specifically, respondents valued new treatments that enable patients to survive an aTTP crisis and thereby reduce the patient’s emotional uncertainty in the early stages of a TTP episode and improve peace of mind during remission. As well, respondents noted that a reduction in the number of PE treatments and ability to plan for the future were important when considering treatment options. Approximately one-third (34%) of respondents had experience with caplacizumab and felt that the drug had contributed to shorter hospitalization, faster remission, and prevention of further disease.

Clinician Input

Input From Clinical Experts Consulted by CADTH

Two clinical specialists with expertise in the diagnosis and management of aTTP provided input for this review. The clinical experts stated that while currently available treatments (PE plus immunosuppression with corticosteroids with or without rituximab) are effective in many patients, not all patients manifest durable responses and thus experience persistent or recurrent thrombotic microangiopathy, which can lead to thrombotic complications and, potentially, mortality. According to the clinical experts, there is an unmet need for additional treatment options especially for patients with aTTP recurrence or refractory aTTP. The clinical experts relayed that caplacizumab would be administered in combination with PE and immunosuppressive therapy. The clinical experts felt that because some patients respond well to PE and immunosuppressive therapy, caplacizumab may be a reasonable option to be reserved for patients with aTTP recurrence or refractory aTTP as these patients currently have limited treatment options. The clinical experts acknowledged that it is currently unclear if delaying access to caplacizumab may impact its efficacy. The HERCULES trial was designed to evaluate the upfront use of caplacizumab in combination with PE and immunosuppressive therapy. The clinical experts also felt that upfront treatment with caplacizumab would be considered in high-risk patients who have neurologic or cardiac abnormalities (including elevated troponin) or are otherwise critically ill. The clinical experts acknowledged that currently there is insufficient evidence to identify patients who are more likely to respond to caplacizumab in combination with PE plus immunosuppression.

The clinical experts stated that clinically meaningful responses to caplacizumab plus PE and immunosuppression would be defined by normalization of platelet count (complete blood count) and lactate dehydrogenase (LDH) level. Reticulocyte count, unconjugated bilirubin, hemoglobin, haptoglobin, creatinine, ADAMTS13 activity, and ADAMTS13 autoantibody levels should also normalize. The clinical experts relayed that although the ultimate mechanistic goal of therapy is to normalize ADAMTS13 activity, results of ADAMTS13 testing are generally not readily available in a timely manner, as compared to platelet count. According to the clinical experts, PE is typically discontinued after 5 days if platelet count, LDH, and other markers are normalized. Patients are then typically monitored for 1 to 2 days while in hospital to determine if their platelet counts decrease again or if the hemolytic markers show signs of aTTP recurrence. If there is no evidence of aTTP recurrence, patients are typically discharged from hospital with a corticosteroid taper plan and close outpatient follow-up. The clinical experts stated that in patients receiving caplacizumab who develop aTTP recurrence or refractory aTTP would be discontinued from therapy, as would patients with serious toxicities such as clinically significant bleeding. The clinical experts relayed that 1 of the challenges of using caplacizumab is that it directly increases platelets through its mechanism, potentially masking an indicator of aTTP disease activity, which would make it difficult to determine when it is time to taper PE.

Clinician Group Input

Clinician group input was received from the Canadian Apheresis Group (CAG), with 5 clinicians contributing to the submission. No major contrary views from those provided by the clinical experts consulted by CADTH for this review were presented. The clinician group echoed the inability of current treatments to accomplish the goals of therapy (avoid mortality and prevent thrombotic complications) in all patients and the unmet need for additional treatment options for patients with aTTP exacerbations, relapsed aTTP, and refractory aTTP as well as patients at high risk of mortality and/or organ damage. The clinician group also highlighted the unmet need for drugs that can rapidly inhibit platelet aggregation while waiting for PE and immunosuppression to take effect.

Drug Program Input

The Formulary Working Group identified the following jurisdictional implementation issues: considerations for initiation of therapy, considerations for continuation or renewal of therapy, considerations for discontinuation of therapy, considerations for prescribing of therapy, generalizability, care provision issues, and system and economic issues. The clinical experts consulted by CADTH for this review weighed evidence from the included study and other clinical considerations to provide responses to drug program implementation questions.

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Studies

One phase III, prospective, long-term follow-up study of adult patients with aTTP who completed the HERCULES study (post-HERCULES, N = 104)^14,15 contributed evidence to this review. The objectives of the post-HERCULES trial were to evaluate long-term safety and efficacy of caplacizumab, to evaluate the safety and efficacy of repeated use of caplacizumab in participants who experienced a recurrence of aTTP, and to characterize the long-term clinical impact of aTTP. Following the final 4-week follow-up visit in the HERCULES trial, adult patients with aTTP were invited to enrol in the post-HERCULES trial within 1 month. Patients who were not able or willing to comply with study protocol procedures or who enrolled in a clinical study with another investigational drug or device were excluded. Following enrolment at 43 centres in Europe, the US, Canada (3 centres), and Israel, patients were followed for a period of 3 years. Patients attended twice-yearly visits, starting with a baseline visit coinciding with or occurring within 1 month of the final 28-day follow-up visit in the HERCULES study. During the 3-year follow-up period, patients could receive open-label (OL) caplacizumab in combination with PE and immunosuppression (administered as in the HERCULES study, except that 1 PE could be given before initiation of caplacizumab) for aTTP recurrence (defined as recurrence of thrombocytopenia requiring initiation of daily PE).

The overall intent-to-observe (ITO) population was used for analysis of safety. The efficacy ITO population (patients within the overall ITO population who had not experienced aTTP recurrence in the HERCULES study or before the beginning of the post-HERCULES study) was used for analysis of efficacy based on twice-yearly follow-up visits. The recurrence population (patients within the overall ITO population who experienced at least 1 aTTP recurrence during the post-HERCULES study) was used for analysis of data collected during recurrence periods.

All patients who completed the HERCULES study (n = 108) were eligible for the post-HERCULES study, of whom 104 (96.3%) participated. ||||||||||||| ||| |||||| || |||||||||||| || ||||||||||||| |||| ||||| |||||||| ||||||||||||| ||| |||||| ||||||| |||| |||||| ||| ||| ||||||| ||| ||| |||| |||||| |||| |||| |||||||| |||| |||||||||||| || ||| ||||||||||||| |||||||| ||| |||| ||| ||||||| |||||||| |||||||| ||| ||||||

Efficacy Results

Key efficacy results of the post-HERCULES study are summarized in Table 2 In the efficacy ITO population, consisting of patients who completed the HERCULES study, enrolled in the post-HERCULES study, and had not experienced an aTTP recurrence in either the HERCULES study or before the beginning of the post-HERCULES study, aTTP-related events (aTTP-related death, recurrence of aTTP, or major thromboembolic events) occurred in 4 patients (8.2%) randomized to receive caplacizumab in the HERCULES study and in 11 patients (37.9%) randomized to receive SOC alone in the HERCULES study. No patients randomized to receive caplacizumab in the HERCULES study and 1 patient (3.4%) randomized to receive SOC in the HERCULES study died during the post-HERCULES study. Four patients (8.2%) randomized to receive caplacizumab in the HERCULES study and 8 patients (27.6%) randomized to receive SOC in the HERCULES study experienced recurrence of aTTP during the post-HERCULES study. Four patients (8.2%) randomized to receive caplacizumab in the HERCULES study and 11 patients (37.9%) randomized to receive SOC in the HERCULES study experienced major thromboembolic events during the post-HERCULES study; major thromboembolic events other than aTTP occurred in no patients randomized to receive caplacizumab in the HERCULES study and in 3 patients (10.2%) randomized to receive SOC in the HERCULES study.

Table 2: Summary of Key Results From the Post-HERCULES Study (Efficacy ITO Population)

aTTP = acquired thrombotic thrombocytopenic purpura; ITO = intent to observe; SOC = standard of care.

Source: Post-HERCULES Clinical Study Report (2021).¹⁴

Harms Results

Key harms results of the post-HERCULES study are summarized in Table 3. In the overall ITO population, 68 patients (90.7%) treated with caplacizumab in the HERCULES study and 26 patients (89.7%) treated with SOC only in the HERCULES study experienced adverse events (AEs) during the post-HERCULES study. Twenty-eight patients (37.3%) treated with caplacizumab in the HERCULES study and 16 patients (55.2%) treated with SOC only in the HERCULES study experienced serious AEs (SAEs) during the post-HERCULES study. No patients treated with caplacizumab, and 1 patient (3.4%) treated with SOC only in the HERCULES study died during the post-HERCULES study. Sixteen patients (21.3%) treated with caplacizumab in the HERCULES study and 9 patients (31.0%) treated with SOC only in the HERCULES study experienced at least 1 bleeding event during the post-HERCULES study (based on the Standardized Medical Dictionary for Regulatory Affairs [MedDRA] query “Haemorrhage” excluding the preferred term “aTTP”).

Table 3: Summary of Harms in Post-HERCULES (Overall ITO Population)

ADA = antidrug antibody; AE = adverse event; aTTP = acquired thrombotic thrombocytopenic purpura; ITO = intent to observe; MedDRA = Medical Dictionary for Regulatory Affairs; SAE = serious adverse event; TTP = thrombotic thrombocytopenic purpura.

^aBased on Standardized MedDRA query excluding TTP.

^bBased on investigator documentation of event indicating an increased bleeding tendency.

^cBased on specific preferred terms “drug hypersensitivity” and “hypersensitivity.”

Source: Post-HERCULES Clinical Study Report (2021).¹⁴

Critical Appraisal

Many of the internal validity issues of the HERCULES study affect the post-HERCULES study as well (refer to the Clinical Review Report for the initial submission of caplacizumab for details,¹³ the executive summary of which is reproduced as Appendix 2). Only patients who completed the HERCULES study (108 of 145, 74.5%) were eligible for the post-HERCULES study, and the study provides no information on patients who discontinued the HERCULES study. Higher proportions of caplacizumab-naive patients (n = 6, 20.7%) than patients who received caplacizumab in the HERCULES study (n = 5, 6.7%) discontinued the post-HERCULES study. The clinical experts consulted by CADTH for this review did not expect that any resulting biases would be directional in favour of caplacizumab. Due to variable rates of missing data, lack of formal statistical testing, potential for bias in patient-reported outcomes in an OL study, and uncertainty in the measurement properties of these instruments in patients for aTTP, changes in HRQoL over time and between the arms of the post-HERCULES efficacy ITO population could not be interpreted.

Many of the external validity issues of the HERCULES study affect the post-HERCULES study as well (refer to Appendix 2). The clinical experts consulted by CADTH felt that the post-HERCULES study population was generally reflective of adult patients with aTTP in Canada. Mortality rates in the HERCULES and post-HERCULES studies were lower than expected in routine clinical practice and patients may have been observed and followed by health care teams for aTTP recurrence and/or thromboembolic events more vigilantly compared to real-world practice. The clinical experts consulted by CADTH stated that the duration of follow-up in the post-HERCULES study was adequate to assess both early recurrence of aTTP (within the first month of presentation) and later recurrences (which often occur within the 2 years following cessation of PE). In the post-HERCULES study, caplacizumab could be administered following up to 1 administration of PE, but this was not a requirement as it was in the HERCULES study. Approximately half (6 of 13, 46.2%) of patients treated for their first recurrence in the post-HERCULES study with caplacizumab received rituximab. The clinical experts consulted by CADTH for this review noted that the proportion of patients living in Canada with aTTP who receive upfront rituximab in addition to PE and corticosteroids is not known with certainty but is likely lower than in the post-HERCULES trial. However, the proportion in clinical practice has increased in recent years due to improved access to rituximab.

Indirect Comparisons

No indirect evidence was identified for this review.

Other Relevant Evidence

Other Clinical Trials

The phase III HERCULES trial^21-23 and phase II TITAN trial^24-26 were reviewed in the CADTH Clinical Review Report for the initial caplacizumab submission¹³ (the executive summary of which is reproduced as Appendix 2). Both studies documented statistically significant differences in time to platelet count response that were viewed by the clinical experts consulted by CADTH for the initial review as too small to be clinically relevant. In the HERCULES study, the proportion of patients randomized to receive caplacizumab who experienced recurrence during the HERCULES overall study period was statistically significantly lower compared with patients randomized to receive SOC. The duration and volume of daily PE was shorter in the caplacizumab arm, which the clinical experts consulted by CADTH felt was encouraging and potentially clinically relevant. However, neither the HERCULES nor TITAN studies provided conclusive evidence showing that caplacizumab decreases mortality, minimizes organ damage, reduces health care utilization, or prevents long-term aTTP recurrence beyond the duration of the trials.

Post Hoc Analyses

Description of Studies

Peyvandi et al. (2021)¹⁶ conducted an integrated analysis of data from the HERCULES and TITAN trials as suggested by the FDA to increase statistical power for assessing treatment differences in efficacy and safety outcomes. The integrated analysis included all randomly assigned patients from the HERCULES and TITAN studies, which were described in detail in the Clinical Review Report for the initial review of caplacizumab¹³ (Appendix 2). This study provided an additional evaluation of the clinically important outcomes of mortality, organ damage, health care utilization, and refractory aTTP, but did not address long-term aTTP recurrence.

For the primary analysis of time to platelet count response, treatment groups were compared using a 2-sided log-rank test stratified by trial based on Kaplan-Meier analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using a Cox proportional hazards model with time to platelet count response as a dependent variable, treatment group as an independent variable, and study as a random effect. To compare secondary outcomes (time to normalization of organ damage markers, duration of PE, proportion of patients with aTTP-related death, aTTP recurrence, or major thromboembolic events, and aTTP recurrence) between treatment groups, a stratified Cochran-Mantel-Haenszel test was used as a stratification factor in the trials. Analysis of time to first normalization of organ damage markers was performed as for the primary analysis of time to platelet count response.

Efficacy Results

During blinded study drug treatment, no patients randomized to receive caplacizumab and 4 patients (3.6%) randomized to receive placebo died; during the overall study periods, 1 patient (0.9%) randomized to receive caplacizumab and 5 patients (4.5%) randomized to receive placebo died. The proportion of patients who experienced aTTP-related events (aTTP-related death, major thromboembolic events, or aTTP exacerbation) while receiving blinded study drug treatment was 13.0% in patients randomized to receive caplacizumab versus 47.3% among patients randomized to receive placebo. During blinded study drug treatment, no patients randomized to receive caplacizumab and 8 patients (7.1%) randomized to receive placebo had refractory aTTP. Consistent with the individual studies, treatment with caplacizumab resulted in a numerically faster time to normalization of LDH (HR = 1.43; 95% CI, 1.04 to 1.96), numerically faster time to normalization of troponin (HR = 1.32; 95% CI, 0.86 to 2.04), and numerically faster time to normalization of serum creatinine (HR = 1.68; 95% CI, 0.89 to 3.15). During the overall treatment periods, median duration of PE was numerically shorter in patients randomized to receive caplacizumab (5.0 days; range, 1 to 35 days) compared with patients randomized to receive placebo (7.5 days; range, 2 to 46 days). During the treatment-free follow-up periods, 14 patients (13.0%) randomized to receive caplacizumab and no patients randomized to receive placebo experienced aTTP relapses.

Harms Results

The safety data for the integrated safety population were consistent with the results of the individual studies and no new safety signals were identified. Bleeding excluding aTTP occurred in 58.5% of patients treated with caplacizumab and 42.7% of patients treated with placebo. Serious bleeding excluding aTTP occurred in 11.3% of patients treated with caplacizumab and 1.8% of patients treated with placebo.

Critical Appraisal

Overall, the results of the integrated analysis supported and reinforced the consistent numeric improvements in the clinically important outcomes of survival, refractory aTTP, and duration of PE observed in the clinical development program (phase II TITAN and phase III HERCULES studies). However, internal and external validity issues of the individual HERCULES and TITAN trials affect the integrated analysis as well (refer to the Clinical Review Report for the initial submission of caplacizumab¹³ for details, the executive summary of which is reproduced as Appendix 2). In particular, the clinical experts consulted by CADTH for this review were concerned that the higher proportion of patients in the placebo arm of the integrated population with recurrent rather than initial aTTP may have contributed to poorer outcomes, including higher mortality. In addition, there were several notable differences between the TITAN and HERCULES studies, including the time they were conducted (2010 to 2014 versus 2015 to 2017) and the administration of caplacizumab (requirement for 1 prior PE session in the HERCULES study and the possibility to extend treatment beyond the first 30 days post-PE in the HERCULES study). Thus, the clinical experts consulted by CADTH for this review relayed their uncertainty that the data from the 2 studies could be naively pooled. Statistical analyses of integrated data in the study by Peyvandi et al. (2021) were post hoc, not adjusted for multiple comparisons, and should be interpreted in descriptive and exploratory fashion.

Real-World Evidence

Description of Studies

Three studies of 2 RWE cohorts of patients treated with caplacizumab from France^17-19 and the UK²⁰ are summarized in this report. The RWE studies provided additional supportive evidence regarding the clinically important outcomes of mortality, health care use, and refractory aTTP, but did not address organ damage or long-term aTTP recurrence.

Coppo et al. (2021)¹⁸ prospectively analyzed outcome data for 90 patients with aTTP from France treated from September 2018 to December 2019 with a frontline triplet regimen consisting of PE, immunosuppression with corticosteroids and rituximab, and caplacizumab. Outcomes were compared with 180 historical control patients from the Centre National de Référence sur les Microangiopathies Thrombotiques (CNR-MAT) registry treated from June 2015 to September 2018 with standard frontline therapy (PE plus corticosteroids, with rituximab as salvage therapy). CEMKA and Sanofi^17,19 conducted an updated reanalysis of the data from this RWE cohort to include all historical controls available in the same registry, and to calculate a propensity score based on disease severity and mortality risk as an adjustment factor in multivariate modelling.

Dutt et al.²⁰ conducted a retrospective analysis of data from 85 patients with aTTP (including 4 children) who received caplacizumab in 22 UK hospitals from May 2018 and January 2020. Outcomes for these patients were compared with data from the HERCULES study and to a group of historical control patients consisting of 39 consecutive cases from the UK TTP registry who received standard treatment (PE plus immunosuppression with corticosteroids and rituximab) from 2014 to 2018.

Efficacy Results

In the RWE cohort of Coppo et al. (2021),¹⁸ the percentage of patients receiving the triplet regimen including caplacizumab with the composite primary outcome including death and refractoriness was 2.2% versus 12.2% in historical controls (HR = 6.2; 95% CI, 1.4 to 26.3). One patient (1.1%) treated with the triplet regimen died compared with 12 (6.7%) historical controls. One patient (1.1%) treated with the triplet regimen experienced refractory aTTP compared with 16 (18%) historical controls. Compared with historical controls, patients receiving the triplet regimen had numerically fewer PE sessions (median 5 sessions versus 10 sessions), required numerically lower overall PE volume until remission (median 24.2 L versus 44.2 L), and had numerically shorter duration of hospitalization (median 13 days versus 22 days).

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In the RWE cohort of Dutt et al. (2021),²⁰ 5 patients (6%) in the caplacizumab cohort died and no deaths were reported among historical control patients. aTTP recurrence and refractoriness were not compared between the 2 groups. In 4 of the patients who died, caplacizumab was introduced more than 48 hours after PE initiation (range, 3 to 21 days). Compared with historical controls, patients who received caplacizumab had numerically shorter duration of PE (median 7 days versus 9 days) and numerically shorter time from PE initiation to platelet count normalization (median 4 days versus 6 days). Duration of hospitalization was similar in the caplacizumab cohort (median = 12 days) and the historical control cohort (median = 14 days).

Harms Results

The safety data for the RWE cohorts were generally consistent with the clinical trial data from the HERCULES study. Bleeding events occurred in 12% to 18% of patients. In the RWE cohort of Dutt et al. (2021), 5 patients (5.9%) experienced venous thromboembolism.

Critical Appraisal

Comparisons between the RWE cohorts and historical controls or the HERCULES trial populations were limited by risk of bias in selection of participants and potential for confounding by measured and unmeasured variables including nonoverlapping time frames and differences in treatment, primarily use of rituximab, which was higher in the RWE cohorts. The impact of bias in selection of patients into RWE cohorts as well as selection of historical control groups could not be evaluated and contributed to a high level of uncertainty. Except for the reanalysis of Sanofi and CEMKA (2021),^17,19 all comparisons were naive and did not take into account baseline differences between populations, such as cardiac and organ involvement. The rationale for statistical hypothesis testing was not provided and it was unclear whether statistical tests were prespecified or conducted post hoc for some outcomes. Statistical tests were not adjusted for multiple comparisons and should be interpreted in descriptive and exploratory fashion.

Generalizability of the RWE to Canadian clinical practice was limited by high rates of rituximab use, including as upfront therapy. In addition, in the RWE cohort of Coppo et al. (2021),¹⁸ caplacizumab was administered upfront only, which may not be consistent with the anticipated use of the drug in Canadian clinical practice, according to the clinical experts consulted for this review. In the RWE cohort of Dutt et al. (2021),²⁰ the baseline characteristics suggested that some had severe disease and/or multiorgan involvement and may have been candidates for upfront therapy with caplacizumab in Canadian practice; however, in approximately half of patients caplacizumab was started 2 days or longer after PE initiation. In the RWE cohort of Dutt et al. (2021)²⁰ administration of caplacizumab was not aligned with the HERCULES study or the product monograph due to high rates of discontinuation before 30 days after PE.

Conclusions

Evidence from the HERCULES study suggested that administration of caplacizumab resulted in a statistically significant decrease in the frequency of aTTP recurrence during the HERCULES study period. In the long term follow-up study of the HERCULES study (the post-HERCULES study), there were no signs that treatment with caplacizumab during the HERCULES study resulted in increased frequency of aTTP relapse post PE discontinuation beyond the follow-up period of the HERCULES trial. A post hoc integrated analysis of data from the HERCULES and TITAN trials provided an additional evaluation of survival, health care use, organ damage, and refractory aTTP; however, due to naive pooling of the data and lack of formal statistical testing of prespecified hypotheses, including adjustment for multiple comparisons, its results supported but were unable to extend the conclusions regarding these outcomes drawn from the individual trials. Two RWE cohorts from France and the UK provided additional supportive evidence regarding the frequency of aTTP-related events, including mortality in patients receiving caplacizumab; however, due to potential for biased patient selection in observational studies, intergroup differences in measured and/or unmeasured confounders including treatments received that could not be accounted for, and absence of formal statistical testing, no conclusions could be drawn that go beyond the HERCULES, post-HERCULES, and TITAN trial data. The combined data from the HERCULES and post-HERCULES studies suggested that caplacizumab may decrease overall aTTP recurrence during treatment and immediately following treatment cessation (HERCULES) without producing an increased frequency of long-term aTTP relapse in the subsequent months and years (post-HERCULES).

Introduction

Disease Background

TTP is an ultra-rare blood disorder cause by reduced enzymatic activity of the vWF-cleaving protease, ADAMTS13, resulting in inability to cleave high molecular weight vWF multimers and as a consequence formation of platelet-rich blood clots in small vessels (thrombotic microangiopathy).² TTP is an acute, fulminant disorder that is a medical emergency occurring mainly among adults aged 30 to 50 years.^2,3 Congenital TTP (involving familial inheritance of ADAMTS13 gene mutations) makes up less than 5% of cases while aTTP, driven by autoantibodies against ADAMTS13), is the dominant form.⁴ Because there is no specific known cause of aTTP, it is sometimes known as immune TTP.

The incidence of aTTP is estimated at approximately 2 to 4 cases per million population (approximately ||| cases per million adults) per year.^8-10 In agreement with incidence estimates, data from the CAG registry indicated that approximately ||| patients with TTP were treated in Canada in 2018;¹ data for more recent years were not provided by the sponsor. When diagnosis is made immediately and current SOC treatments are administered rapidly, mortality has been estimated at approximately 10% to 20%.⁵ After the presenting episode, recurrence of aTTP (exacerbation: recurrence within 30 days of cessation of PE; relapse: recurrence after 30 days of cessation of PE) will occur in up to half of patients, while refractory aTTP (absence of platelet count increase following treatment) will occur in approximately 10% of patients.⁷ In addition, thrombotic complications and their sequelae (e.g., stroke, myocardial infarction, neurocognitive deficits, kidney injury) contribute to persistent cognitive and physical difficulties that can be life-altering in some patients, compromising HRQoL.⁶

According to the clinical experts consulted by CADTH for this review, diagnosis of aTTP is based on clinical and laboratory findings and is made by a hematologist, although treatment may also be managed by nephrologists and pathologists or transfusion medicine specialists. The clinical manifestations of aTTP are often nonspecific and may include skin discoloration (e.g., bruising), fatigue, dyspnea, fever, myalgia, arthralgia, and neurological symptoms.^2,4 aTTP is a microangiopathic hemolytic anemia and laboratory markers including findings of red blood cell fragments called schistocytes on peripheral blood smear, thrombocytopenia (typically platelets less than 30 × 10⁹/L), low ADAMTS13 activity (typically < 10% of normal), evidence of hemolytic anemia (low hemoglobin, elevated serum LDH, elevated unconjugated bilirubin, elevated reticulocyte count, and low to absent haptoglobin), and elevated creatinine.^2,4 Cardiac troponin may also be elevated. Due to the diverse clinical manifestations of aTTP, overlap in clinical presentation with other thrombotic microangiopathies, and limited availability of ADAMTS13 testing, diagnosis at immediate presentation to medication attention can be challenging. Therefore, patients who have a presentation concerning for aTTP (e.g., those who are identified as intermediate or high risk of having aTTP using the PLASMIC [platelets, lysis, active cancer, stem cell, or solid organ transplant, mean corpuscular volume, international normalized ratio, and creatinine] score²⁷) will be treated empirically for aTTP while awaiting the results of ADAMTS13 activity testing and inhibitor titres, which can take days. Empirical treatment for aTTP is initiated in these patients due to the potential consequences of a missed aTTP diagnosis.²

Standards of Therapy

According to the clinical experts consulted by CADTH for this review, current management of aTTP in Canada involves PE and immunosuppression. The sponsor emphasized that the treatment burden associated with PE is significant as PE often requires a transfer to a PE centre, there is a need for surgery (vascular catheter insertion with a risk of infections), and there is potential for exposure to multiple donors (risk of PE reactions).¹ PE is administered daily until platelet count and LDH normalize, with the goal of removing ADAMTS13 autoantibodies and ultra-large vWF multimers; if PE is not immediately available, plasma infusion can be used as a bridge while the patient is transferred to a centre that can perform PE. The goal of immunosuppression is to suppress production of ADAMTS13 autoantibodies via administration of corticosteroids (prednisone 1 mg/kg or methylprednisolone 1 g daily for 3 days, followed by prednisone 1 mg/kg; dosing is tapered once a patient is in remission) and, in some patients, rituximab (375 mg/m² weekly for 4 weeks). In Canada, rituximab is typically not used upfront and is administered to patients with aTTP exacerbations, relapsed aTTP, or refractory aTTP. Use of rituximab may decrease the risk of aTTP relapse.

The clinical experts consulted by CADTH for this review relayed that from a clinical standpoint, the main goals of treatment are to prolong life and avoid mortality while preventing thrombotic complications as well as their sequelae and associated disabilities (e.g., stroke, myocardial infarction, neurocognitive deficits, kidney injury). Treatment goals are accomplished by replenishing ADAMTS13 and removing autoantibodies against ADAMTS13, allowing normalization of ADAMTS13 activity and consequently halting thrombotic microangiopathy.

Drug

Key characteristics of caplacizumab are shown in Table 4. Caplacizumab is a bivalent humanized nanobody that is administered at a dose of 11 mg (IV and SC injections on day 1 of PE followed by daily SC injections during PE and for a minimum of 30 days after cessation of PE).¹¹ Its mechanism of action involves binding to the A1 domain of vWF, inhibition of the interaction between vWF and platelets, reduction of vWF-mediated platelet activation and adhesion, and prevention of the formation of ultra-large vWF-rich platelet microthrombi.¹¹ The Health Canada indication for caplacizumab is “for the treatment of adults with acquired thrombotic thrombocytopenic purpura (aTTP) in combination with plasma exchange (PE) and immunosuppressive therapy.”¹¹ The sponsor’s reimbursement request is the same as the approved Health Canada indication. Caplacizumab underwent priority review at Health Canada and received a Notice of Compliance on February 28, 2020.

Submission History

Caplacizumab was initially reviewed by CADTH for the treatment of adults with aTTP in combination with PE and immunosuppressive therapy and received a negative funding recommendation from CDEC on September 1, 2020.¹² The recommendation was based on evidence assessed in the CADTH Clinical Review Report for the initial submission of caplacizumab,¹³ the executive summary of which is reproduced as Appendix 2. Key reasons for the recommendation included:

• insufficient evidence of clinically important outcomes (e.g., survival, organ damage, health care use, or long-term aTTP recurrence), and given caplacizumab’s mechanism of action, uncertainty in the correlation between time to normalization of platelet count and these outcomes

• lack of long-term clinical outcome data, including on aTTP recurrence, beyond the relatively short durations of the trials

• lack of an identifiable subpopulation most likely to benefit from treatment with caplacizumab, given the variability in the natural history of aTTP

• unclear generalizability of the trial results, primarily due to higher rates of rituximab use compared with Canadian clinical practice

• absence of HRQoL data.

In response to the draft CDEC recommendation, the sponsor submitted a request for reconsideration in which the potential role caplacizumab might play in reducing aTTP mortality and microvascular thrombosis was emphasized, as was the potential clinical importance of consistent numerical improvements achieved with caplacizumab across many outcomes. In addition, to better align with the views of clinical experts consulted by CADTH, the sponsor’s reimbursement request was narrowed to patients with multiorgan involvement indicating more severe disease as well as patients with refractory aTTP who do not respond well to SOC treatment for a given time period. However, CDEC maintained its initial position that direct evidence showing an advantage for caplacizumab in clinically relevant outcomes was not currently available and that subgroup analyses justifying use of caplacizumab in patients with severe or refractory aTTP were unavailable.

The drug was resubmitted for review by the sponsor on the basis of the availability of new evidence on June 7, 2022.¹ The new evidence included a prospective long-term follow-up study of patients who completed the HERCULES study (post-HERCULES),^14,15 a variety of post hoc analyses of clinical trial data including an integrated analysis of data from the HERCULES and TITAN studies,¹⁶ and several RWE studies including comparisons of patients treated with caplacizumab from France^17-19 and the UK²⁰ with historical controls who received SOC alone. The sponsor suggested that the post-HERCULES study addressed CDEC concerns 2 and 5 (lack of long-term clinical outcome data and absence of HRQoL data), while the post hoc analyses addressed CDEC concerns 1 to 4 (insufficient evidence of clinically important outcomes, lack of long-term clinical outcome data, lack of an identifiable subpopulation most likely to benefit, and generalizability to Canadian practice) and the RWE studies addressed CDEC concerns 1 to 3 (insufficient evidence of clinically important outcomes, lack of long-term clinical outcome data, and lack of an identifiable subpopulation most likely to benefit).

The objective of this report was to perform a systematic review of the beneficial and harmful effects of caplacizumab (11 mg IV bolus plus 11 mg SC injection on day 1 of PE, followed by 11 mg SC injection daily) for the treatment of adults with aTTP in combination with PE and immunosuppressive therapy. This report is an update of the Clinical Review Report for the original submission of caplacizumab;¹³ any new evidence provided by the sponsor or identified through a systematic literature search was included in the report if it addressed an evidence gap identified by CDEC in its final recommendation for the initial submission.

Table 4: Key Characteristics of Caplacizumab, PE, and Immunosuppressive Therapy for Treatment of aTTP

ADAMTS13 = a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13; aTTP = acquired thrombotic thrombocytopenic purpura; IST = immunosuppressive therapy; NA = not applicable; PE = plasma exchange; SC = subcutaneous; vWF = von Willebrand factor.

^aHealth Canada–approved indication. Note that rituximab is used off label to treat aTTP.

^bThere is some variation in clinical practice related to administration and dosing of corticosteroids and rituximab for treatment of aTTP.

Source: Sponsor’s drug reimbursement review resubmission¹ and product monograph for caplacizumab.¹¹

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by a patient group. The original patient group submission can be found at the end of this report.

One patient group, the Answering TTP Foundation, provided input for this review. The group conducted an online survey in May and June of 2022 (N = 49 respondents including 31 patients with aTTP, 16 family members, caregivers, or friends of patients with aTTP, 1 health care professional, and 1 researcher). Most (80%) survey respondents were women and most (90%) were living in Canada. Approximately half of respondents (48%) had experienced at least 1 relapse. Patients highlighted delays in diagnosis and treatment as well as the negative impacts of serious and/or frequent symptoms of aTTP (e.g., bruising, fever, fatigue, migraine, confusion, abdominal pain, bleeding, shortness of breath, vision loss, and jaundice) which impose heavy burdens on mental health (e.g., anxiety, depression, and panic attacks). A subset of patients experienced incapacitating or life-threatening complications of aTTP including stroke, myocardial infarction, and kidney problems. Nearly all patients had experience with PE and corticosteroids while approximately two-thirds (65%) had experience with rituximab. Respondents described the challenges of current treatments including lengthy hospital stays, side effects of corticosteroids, and the inconvenience of daily PE; in addition, available treatments are costly, require time off from work, and may require travel to a major centre for access. Respondents identified an unmet need for treatments that can reduce the risk of death or disability from aTTP and ease the mental and emotional burdens of disease (e.g., continuous fear of relapse and impacts on social life and career goals). Specifically, respondents valued new treatments that enable patients to survive an aTTP crisis and thereby reduce the patient’s emotional uncertainty in the early stages of an aTTP episode and improve peace of mind during remission. As well, respondents noted that a reduction in the number of PE treatments and ability to plan for the future were important when considering treatment options. Approximately one-third (34%) of respondents had experience with caplacizumab and felt that the drug had contributed to shorter hospitalization, faster remission, and prevention of further disease.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of aTTP.

Unmet Needs

The clinical experts consulted by CADTH for this review stated that while currently available treatments are effective in many patients, not all patients manifest durable responses to the current SOC (PE plus immunosuppression with corticosteroids with or without rituximab) and thus experience persistent or recurrent thrombotic microangiopathy, which can lead to thrombotic complications and, potentially, mortality (in 10% to 20% of patients). The clinical experts emphasized that both currently available therapies (PE and immunosuppression) as well as caplacizumab aim to correct the dysfunctions of aTTP (PE removes ADAMTS13 autoantibodies and replaces ADAMTS13, immunosuppression aims to suppress production of ADAMTS13 autoantibodies, and caplacizumab blocks platelet aggregation), but these treatments do not modify the underlying disease mechanism involving loss of self-tolerance and generation of autoantibodies to ADAMTS13. However, the clinical experts relayed that immunosuppression can limit or stop autoantibody production for sustained periods.

According to the clinical experts, there is an unmet need for additional treatment options that improve survival and prevent thrombotic complications and their sequelae (e.g., stroke, myocardial infarction, neurocognitive deficits), especially for patients with aTTP recurrence or refractory aTTP. It is not currently possible to identify which patients will experience these outcomes at the time of presentation. Patients with refractory aTTP are continued on PE (sometimes with increased frequency) and typically receive rituximab if it was not administered upfront. For patients with aTTP recurrence, PE is restarted, doses of corticosteroids are increased (if on a taper) and rituximab is typically administered. Less commonly, other immunosuppressive agents may be used in patients with aTTP recurrence or refractory aTTP such as cyclophosphamide, vincristine, and cyclosporine as well as IV immunoglobulin and splenectomy.

Place in Therapy

The clinical experts relayed that the mechanism of action of caplacizumab (disruption of the interaction between vWF and platelets) differs from that of PE and immunosuppressive therapy. Therefore, caplacizumab would be administered in combination with PE and immunosuppressive therapy. The clinical experts felt that because some patients respond well to PE and immunosuppressive therapy, caplacizumab may be a reasonable option to be reserved for patients with aTTP recurrence or refractory aTTP as these patients currently have limited treatment options. The clinical experts acknowledged that it is currently unclear if delaying access to caplacizumab may impact its efficacy. The HERCULES trial was designed to evaluate the upfront use of caplacizumab in combination with PE and immunosuppressive therapy. According to the clinical experts, upfront treatment with caplacizumab could also be considered in high-risk patients who have neurologic or cardiac abnormalities (including elevated troponin) or are otherwise critically ill. The clinical experts acknowledged that currently there is insufficient evidence to identify patients who are more likely to respond to caplacizumab in combination with PE plus immunosuppression. The clinical experts did not expect that use of caplacizumab would cause a shift in the treatment paradigm for aTTP; PE plus immunosuppression would still be initiated immediately and response to treatment monitored using the same markers.

Patient Population

According to the clinical experts consulted by CADTH, high-risk patients (those with neurologic or cardiac abnormalities or who are otherwise critically ill) would be best suited for caplacizumab. Patients with aTTP recurrence or refractory aTTP (regardless of the presence of high-risk features) would also benefit from the addition of caplacizumab to standard therapy (PE plus immunosuppression). These patients would be identified by the treating hematologist. Low-risk patients (defined by the absence of high-risk features described previously), patients who have responded to PE plus immunosuppression, and patients in clinical remission (clinical response of 1 month or longer) would be least suitable for treatment with caplacizumab. The clinical experts noted that currently it is not possible to identify patients who are more likely to respond to caplacizumab in combination with PE plus immunosuppression.

The clinical experts relayed that misdiagnosis of aTTP is relatively common (overdiagnosis) due to the potential consequences of a missed diagnosis, and that at present there is some uncertainty in diagnostic testing of ADAMTS13 due to lack of standardized testing methods. However, these diagnostic challenges would not affect selection of patients to receive caplacizumab.

Assessing Response to Treatment

The clinical experts consulted by CADTH for this review stated that response to caplacizumab plus PE and immunosuppression would be based on normalization of platelet count (complete blood count) and LDH. Reticulocyte count, unconjugated bilirubin, hemoglobin, haptoglobin, ADAMTS13 activity, and ADAMTS13 autoantibody levels should also normalize. Some clinicians also monitor creatinine, although acute kidney injury in patients with aTTP is typically mild. A clinically meaningful response to treatment would be defined by normalization of platelet count and LDH. During acute aTTP episodes, complete blood count (platelets, hemoglobin), unconjugated bilirubin, LDH, reticulocyte count, and creatinine are monitored daily. Haptoglobin, ADAMTS13 activity, and ADAMTS13 autoantibody levels are typically monitored after completion of 5 days of PE as well as following cessation of PE.

The clinical experts relayed that the ultimate mechanistic goal of therapy is to normalize ADAMTS13 activity. It is possible to use ADAMTS13 levels to monitor response, but these results will not be as available in a timely manner, as compared to platelet count. More typically, if a patient is not demonstrating a clinical response to standard therapy, ADAMTS13 activity may be measured.

Discontinuing Treatment

According to the clinical experts, PE is typically discontinued after 5 days if platelet count, LDH, reticulocyte count, unconjugated bilirubin, and hemoglobin are normalized. Patients are then typically monitored for 1 to 2 days to determine if their platelet counts drop again or if hemolytic or other markers (e.g., LDH, reticulocytes, unconjugated bilirubin) show signs of aTTP recurrence. If there is no evidence of recurrence, patients are typically discharged from hospital and doses of corticosteroids are tapered with close outpatient follow-up. If there is evidence of recurrence, PE is reinitiated and additional treatments such as rituximab are ordered.

The clinical experts stated that in patients receiving caplacizumab who develop aTTP recurrence or refractory aTTP would be discontinued from therapy, as would patients with serious toxicities such as clinically significant bleeding. The clinical experts relayed that 1 of the challenges of using caplacizumab is that it directly increases platelets through its mechanism, potentially masking an indicator of aTTP disease activity, which would make it difficult to determine when it is time to taper PE.

Prescribing Conditions

The clinical experts emphasized that PE is only offered in certain hospitals and therefore patients with aTTP are typically transferred urgently to major centres. Patients are typically managed by a hematologist (either as the admitting or consulting service). Caplacizumab would be administered in centres that have both PE capacity and a hematology service.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by a clinician group. The original clinician group submission can be found at the end of this report.

Clinician group input was received from the CAG, with 5 clinicians contributing to the submission. No major contrary views from those provided by the clinical experts consulted by CADTH for this review were presented. The clinician group echoed the inability of current treatments to accomplish the goals of therapy (avoid mortality and prevent thrombotic complications) in all patients and the unmet need for additional treatment options for patients with aTTP exacerbations, relapsed aTTP, and refractory aTTP as well as patients at high risk of mortality and/or organ damage. The clinician group also highlighted the unmet need for drugs that can rapidly inhibit platelet aggregation while waiting for PE and immunosuppression to take effect.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 5.

Table 5: Summary of Drug Plan Input and Clinical Expert Response

ADAMTS13 = a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13; aTTP = acquired thrombotic thrombocytopenic purpura; CDEC = CADTH Canadian Drug Expert Committee; FWG = Formulary Working Group; LDH = lactate dehydrogenase; PE = plasma exchange; SC = subcutaneous.

Clinical Evidence

The clinical evidence included in the review of caplacizumab is presented in 2 sections. The first section, the Systematic Review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol. No indirect evidence was submitted by the sponsor and no indirect evidence was selected from the literature that met the selection criteria specified in the review. The second section includes additional relevant studies that were considered to address important gaps in the evidence included in the systematic review.

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of caplacizumab (11 mg IV bolus plus 11 mg SC injection on day 1 of PE, followed by 11 mg SC injection daily) for the treatment of adults with aTTP in combination with PE and immunosuppressive therapy.

Methods

Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s resubmission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 6. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

Table 6: Inclusion Criteria for the Systematic Review

ADAMTS13 = a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13; AE = adverse event; aTTP = acquired thrombotic thrombocytopenic purpura; DVT = deep vein thrombosis; HRQoL = health-related quality of life; LDH = lactate dehydrogenase; MI = myocardial infarction; PE = plasma exchange; RCT = randomized controlled trial; SAE = serious adverse event; SC = subcutaneous; WDAE = withdrawal due to adverse event.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.²⁸ Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946—) via Ovid and Embase (1974—) via Ovid. All Ovid searches were run simultaneously as a multifile search. Duplicates were removed using Ovid deduplication for multifile searches, followed by manual deduplication in EndNote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concept was Cablivi (caplacizumab). Clinical trials registries were searched: the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform (ICTRP) search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. Refer to Appendix 1 for the detailed search strategies. The initial search was completed on July 6, 2022. Regular alerts updated the search until the meeting of CDEC on October 26, 2022.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist.²⁹ Included in this search were the websites of regulatory agencies (FDA and European Medicines Agency). Google was used to search for additional internet-based materials. Refer to Appendix 1 for more information on the grey literature search strategy.

These searches were supplemented by reviewing bibliographies of key papers and through contacts with appropriate experts. In addition, the manufacturer of the drug was contacted for information regarding unpublished studies.

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

Findings From the Literature

Two reports of a single study^14,15 were identified for inclusion in the systematic review (Figure 1). In the previous CADTH Clinical Review Report for the initial submission of caplacizumab,¹³ the pivotal HERCULES trial was identified and evaluated; therefore, this study was excluded from the systematic review section for the resubmission, as was the CADTH Clinical Review Report for the initial submission of caplacizumab¹³ itself (the executive summary of which is reproduced as Appendix 2). A table of included and excluded studies is presented in Appendix 3.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

The included study (post-HERCULES) is summarized in Table 7. For ease of reference, the HERCULES study^21-23 is summarized alongside the post-HERCULES study, although the evidence from the HERCULES study was previously evaluated by CADTH and is not presented further in the systematic review section of this report.

Description of Studies

Key characteristics of the post-HERCULES study^14,15 are summarized in Table 7. The post-HERCULES study was a phase III, prospective, long-term follow-up study (N = 104) of patients who completed the HERCULES study (N = 145, n = 108 completed). The objectives of the post-HERCULES study were to evaluate long-term safety and efficacy of caplacizumab, to evaluate the safety and efficacy of repeated use of caplacizumab in participants who experienced a recurrence of aTTP, and to characterize the long-term clinical impact of aTTP. Following the final 4-week follow-up visit in the HERCULES study, adult patients with aTTP were invited to enrol in the post-HERCULES study within 1 month. Patients who were not able or willing to comply with study protocol procedures or who enrolled in a clinical study with another investigational drug or device were excluded.

The design of the post-HERCULES study is illustrated in Figure 2. Following enrolment at 43 centres in Europe, the US, Canada (3 centres), and Israel, patients were followed for a period of 3 years. Patients attended twice-yearly visits, starting with a baseline visit coinciding with or occurring within 1 month of the final 28-day follow-up visit in the HERCULES study. At each twice-yearly visit, patients completed patient-reported outcome measures and underwent clinical and safety assessments. During the 3-year follow-up period, patients could receive OL caplacizumab in combination with PE and immunosuppression (administered as in the HERCULES study, except that 1 administration of PE was optional before initiation of caplacizumab) for aTTP recurrence (defined as recurrence of thrombocytopenia requiring initiation of daily PE). Patients receiving caplacizumab followed a scheduled of visits including at presentation, day 3 of treatment with caplacizumab, weekly visits during treatment with caplacizumab, and a follow-up visit 1 week after the end of treatment of caplacizumab. At each of these visits, information on the aTTP recurrence and treatment was collected and patients underwent clinical and safety assessments. The study is complete (data cut-off October 2020) and was funded by Ablynx (acquired by the sponsor in 2018) and the sponsor.

Figure 2: Design of the Post-HERCULES Trial

Note: In case of recurrent thrombocytopenia requiring reinitiation of daily plasma exchange during an ongoing recurrence period, a new visit cycle was started, with a recurrence visit on the day of the new recurrence followed by all subsequent visits. All remaining visits of the original schedule were no longer applicable and were not to be performed. Twice-yearly visits that were scheduled within a recurrence period were not held, as assessments at such visits would be confounded by the concurrent recurrence.

Source: Post-HERCULES Clinical Study Report (2021).¹⁴

Populations

Inclusion and Exclusion Criteria

All patients who completed the HERCULES study were eligible for the post-HERCULES study. Patients who participated in the HERCULES study but did not complete the study were not eligible. Patients who completed the HERCULES study but were not able or willing to comply with post-HERCULES study protocol procedures or who enrolled in a clinical study with another investigational drug or device were excluded.

Baseline Characteristics

The baseline characteristics of patients in the overall ITO population (refer to the Statistical Analysis section for descriptions of analysis sets) in the post-HERCULES study are shown in Table 8. ||||||||||||| ||| |||||| || |||||||| ||| |||||||||||| || ||||||||||||| |||| |||||| |||||||| ||||||||||||| ||| |||||| ||||||| |||| |||||| ||| ||| ||||||| ||| ||| |||| |||||| No significant imbalances were observed between study groups in the overall ITO population. In general demographic baseline characteristics corresponded with those described for the intention-to-treat (ITT) population of the HERCULES trial. Note that patients were disease-free at the baseline of the post-HERCULES study and thus the average ADAMTS13 activity was |||||.

Separate demographic and TTP disease characteristics for the efficacy ITO population were not provided. The efficacy ITO population included the same patients in the group of “SOC-treated in HERCULES” as the overall ITO population (n = 29) and 60% (n = 49) of patients in the group of “Caplacizumab-Treated in HERCULES” of the overall ITO population.

Table 8: Summary of Baseline Characteristics in Post-HERCULES (Overall ITO Population)

ADAMTS13 = a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13; IQR = interquartile range; ITO = intent to observe; SD = standard deviation; SOC = standard of care.

^aADAMTS13 activity was measured in 28 of 29 patients treated with SOC in the HERCULES study.

Source: Post-HERCULES Clinical Study Report (2021).¹⁴

Interventions

There were no scheduled interventions in the post-HERCULES study. In the event of aTTP recurrence (defined as recurrence of thrombocytopenia requiring initiation of daily PE), patients received daily PE and immunosuppression. Immunosuppression with corticosteroids and other immunosuppressive agents (e.g., rituximab) was as per standard practice at each study site. In addition, an IV loading dose of OL caplacizumab (11 mg bolus) could be administered before initiation of daily PE followed by daily SC administration of caplacizumab (11 mg) for the duration of daily PE and for 30 days thereafter. Of note, up to 1 PE could be given before initiation of treatment with caplacizumab as long as it was considered part of the treatment of the presenting aTTP episode. Treatment with caplacizumab could be extended for a maximum of 4 weeks in case of persistent signs and symptoms of underlying disease activity (e.g., ADAMTS13 activity less than 10% based on weekly measurements). The decision to extend caplacizumab treatment with additional 1-week periods was made by the investigator based on ADAMTS13 activity, as well as other signs and symptoms of continued underlying disease activity, such as presence of inhibitors if measured as routine practice by the site. Caplacizumab was stopped when ADAMTS13 activity showed a sustained upward trend above 10% or was stable and there were no other signs and symptoms of disease activity. For recurrences during an existing recurrence period, an IV loading dose of caplacizumab needed to be administered before reinitiation of PE.

Treatment with caplacizumab was not permitted for patients who were pregnant or intended to get pregnant in the near future or for patients with a history of severe or serious hypersensitivity reactions to caplacizumab observed in either the HERCULES or post-HERCULES studies. These patients would receive SOC (PE plus immunosuppression) only.

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trial included in this review is provided in Table 9. These end points are further summarized subsequently. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 5.

Table 9: Summary of Outcomes of Interest Identified in the CADTH Review Protocol

aTTP = acquired thrombotic thrombocytopenic purpura; CVA = cerebrovascular accident; DVT = deep vein thrombosis; HIT-6 = Headache Impact Test 6; HRQoL = health-related quality of life; MI = myocardial infarction; NA = not applicable; RBANS = Repeatable Battery for the Assessment of Neuropsychological Status; SMQ = Standardized MedDRA query; SF-36 = Short Form (36) Health Survey.

Source: Post-HERCULES Clinical Study Report (2021).¹⁴

Outcomes related to aTTP recurrence were assessed both as a composite outcome (aTTP-related events) and the individual components of this outcome (aTTP-related death, recurrence of aTTP, and major thromboembolic events). For Kaplan-Meier analyses of aTTP-related events, time to event was calculated with reference to the post-HERCULES study baseline visit.

Cognitive status was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)³⁰ at baseline and at study completion. Higher RBANS total scores reflect improvement in cognitive symptoms. HRQoL was assessed using the Headache Impact Test (HIT-6, a 6-item questionnaire used to assess the impact of headache on HRQoL)³¹ and the Short Form (36) Health Survey (SF-36)³² at baseline, at twice-yearly visits, at study completion, and after the end of caplacizumab treatment for patients who experienced aTTP recurrence. For the SF-36, higher subscale scores reflect better HRQoL. For the HIT-6, higher scores reflect worse HRQoL due to a greater impact of headache. The RBANS, SF-36, and HIT-6 are all patient-reported outcome measures. Note that the measurement properties of these instruments in patients with aTTP have not been studied and no minimal important difference (MID) has been identified. Refer to Appendix 5 for more details.

In the subset of patients who experienced aTTP recurrence, duration of aTTP (defined as time to initial platelet count initial platelet count of ≥ 150 × 10⁹/L with subsequent stop of daily PE within 5 days), time to platelet count of 150 × 10⁹/L or greater, duration of daily PE, and durations of hospitalization and intensive care unit (ICU) stay were also calculated.

Harms outcomes included treatment-emergent AEs, SAEs, AEs requiring dose interruption, withdrawal due to AEs, and deaths. AEs were considered for the overall ITO population during the overall study period. For patients with aTTP recurrence who were treated with caplacizumab during the post-HERCULES study, AEs that began or worsened on or after the start of protocol therapy until 30 days after the last dose of study drug were captured. AEs were defined as any untoward medical occurrence and were coded according to MedDRA version 22.0³³ and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.³⁴

Statistical Analysis

||||||||||| |||||||| || |||||||| |||||||| || ||||||||||||| || |||||||||| || ||||||||| ||| |||||| |||| ||| ||| ||||| || ||||||||||| |||||||||||||| ||| || ||||| |||||||||||| |||| |||||||||| ||||| |||| || ||||||| ||||||||| ||||||||||| |||||||| ||| ||| |||||||| |||||||| ||||||||||| ||| ||||||| ||||||||||| || ||||||||| ||| |||||||| || |||||||||||| |||||| ||| | ||||||||| ||||||| || |||| || ||| |||||||||| ||||||||||| |||||||||||| |||||| |||||||||| || ||||| ||| ||||| |||||||||||||| |||||||| |||||||| ||||||||| |||| ||||||||| ||||| ||| |||||||||||| ||||||| ||||| |||||| ||| ||||||||| ||||||||||| ||||| ||||| |||| |||||||||||| ||||||||| ||||| ||||||||| |||||||| || ||| |||| || |||| ||||||| || ||| ||||| ||| ||| ||||||||| |||| |||| ||| ||||||| ||| ||| |||||||| |||| |||| |||||||| || ||||||||| || |||||||| || || |||||| ||||||||||| |||||||| ||||| |||||||||| || ||||||||||| ||||||||| ||| || ||||||| |||||||| |||||||| |||| |||||||||

Table 10: Statistical Analysis of Efficacy End Points

aTTP = acquired thrombotic thrombocytopenic purpura; CCA = complete case analysis; HIT-6 = Headache Impact Test 6; HRQoL = health-related quality of life; MTE = major thromboembolic event; RBANS = Repeatable Battery for the Assessment of Neuropsychological Status; SF-36 = Short Form (36) Health Survey.

Source: Post-HERCULES Clinical Study Report (2021).¹⁴

Analysis Populations

Analysis sets in the post-HERCULES study are described in Table 11. The overall ITO population was used for analysis of safety. The efficacy ITO population (patients within the overall ITO population who had not experienced aTTP recurrence in the HERCULES study or before the beginning of the post-HERCULES study) was used for analysis of efficacy based on twice-yearly follow-up visits. The recurrence population (patients within the overall ITO population who experienced at least 1 aTTP recurrence during the post-HERCULES study) was used for analysis of data collected during recurrence periods. A diagram of patient flow is shown in Figure 3 (refer to Patient Disposition section).

Table 11: Analysis Populations in Post-HERCULES

aTTP = acquired thrombotic thrombocytopenic purpura; ITO = intent to observe.

Source: Post-HERCULES Clinical Study Report (2021).¹⁴

Results

Patient Disposition

Patient disposition in the post-HERCULES study is summarized in Table 12. A diagram of patient flow is shown in Figure 3. Of 108 patients who completed the HERCULES study, 104 (96.3%) enrolled in the post-HERCULES study. Among post-HERCULES study participants, 29 patients (27.9%) had received only PE plus immunosuppression in the HERCULES study while 75 patients (72.1%) had received caplacizumab in addition to SOC in the HERCULES study (including 55 patients randomized to receive caplacizumab and 20 patients randomized to received placebo who received OL caplacizumab). Twenty-three patients who received only SOC in the HERCULES study (79.3%) and 70 patients who received caplacizumab in addition to SOC in the HERCULES study (93.3%) completed the post-HERCULES study. Among patients who received only SOC in the HERCULES study (n = 29), the most common reason for discontinuation was loss to follow-up (13.8%). Among patients who received SOC plus caplacizumab in the HERCULES study (n = 75), the most common reason for discontinuation was physician decision (4.0%).

Table 12: Patient Disposition in the Post-HERCULES Study (Overall ITO Population)

ICF = informed consent form; IRB = institutional review board; ITO = intent to observe; ITT = intention to treat; SOC = standard of care.

Note: Definitive treatment discontinuation is defined as the discontinuation of all study drugs. When all study drugs are not discontinued at the same time, the reason for definitive discontinuation is the reason for discontinuation of the last study drug stopped.

^aOf the 6 patients who did not receive caplacizumab for recurrence during the post-HERCULES study, 2 discontinued the study upon the recurrence event. Reasons for not receiving caplacizumab included pregnancy, investigator’s decision due to pending IRB approval for latest ICF, patient withdrawal due to neurological deterioration on commencing plasma exchange and transferred to palliative care, receiving more than 1 plasma exchange before initiation of caplacizumab at recurrence.

Source: Post-HERCULES Clinical Study Report (2021).¹⁴

Figure 3: Patient Flow in the Post-HERCULES Trial

DB = double blind; capla = caplacizumab; C301 = Study ALX0681-C301/HERCULES; C302 = Study ALX0681-C302/Post-HERCULES/LTS16371; IMP = investigational medicinal product; OL = open label; SoC = standard of care.

Source: Post-HERCULES Clinical Study Report (2021).¹⁴

|||||||| || ||||| |||||||| |||||||||| || ||| ||||||||||||| ||||| |||||| |||| ||||||||||| |||||||| |||||||| ||||||||| ||||||||||||||| ||||||||||||||| ||| ||||| ||||| || |||||||| |||||||||| || ||| ||||||||| || |||||||||||||| ||| |||||||||| || ||||||||| ||||| ||||||||||||| ||||||||||||| || |||||||| ||||||| ||| |||||||| |||| || |||| ||||||||||||||||| || |||||||| ||||||||||| ||||| || |||||||| |||||||| |||||||||| ||||| || |||||||| ||||||| ||| |||||||| |||||||||||| || |||||||| || ||| || |||||||| ||||||||||| ||||| || |||||||| |||||||| ||||||||||| ||| |||| |||||||| |||||||| |||||||| || |||||||| || ||||| |||||||| |||||||||| ||| |||||||| ||| ||||| |||| ||||||||| ||| || |||||||||| |||||||||||||||| ||||||| |||||||| ||||||| |||||| |||||| ||||||| |||| ||||||||| || |||| ||| |||||||| |||| |||||||| ||||||| ||||||||||

Table 13: Critical or Major Protocol Deviations in the Post-HERCULES Trial (Overall ITO Population)

ITO = intent to observe; SOC = standard of care.

Note: A patient can be counted in multiple deviation categories.

Source: Post-HERCULES Clinical Study Report (2021).¹⁴

Exposure to Study Treatments

Among participants in the post-HERCULES study, 5 patients (17.2%) who received only PE plus immunosuppression in the HERCULES study experienced at least 1 recurrence during the post-HERCULES study and were treated with caplacizumab plus SOC while 8 patients (10.7%) who received caplacizumab in addition to SOC in the HERCULES study experienced at least 1 recurrence during the post-HERCULES study and were treated with caplacizumab plus SOC. Three patients (10.3%) who received only PE plus immunosuppression in the HERCULES study experienced at least 1 recurrence during the post-HERCULES study and were not treated with caplacizumab while 3 patients (4.0%) who received caplacizumab in addition to SOC in HERCULES experienced at least 1 recurrence during the post-HERCULES study and were not treated with caplacizumab.

Treatments administered for aTTP recurrence during the post-HERCULES study are summarized in Figure 4. Overall, 13 patients had a first recurrence during the post-HERCULES study that was treated with caplacizumab and 6 patients had a second recurrence of aTTP that was treated with caplacizumab. Only 1 participant had more than 2 recurrences; this patient experienced 8 recurrences, of which 7 were treated with caplacizumab and 1 (recurrence 6) was treated with PE plus immunosuppression alone. For the first recurrence in the post-HERCULES study, the median duration of caplacizumab treatment was 56 days and mean compliance with caplacizumab was ||| during daily PE and ||||| after daily PE. Six patients had a recurrence during the post-HERCULES study and were not treated with caplacizumab. Reasons for not receiving caplacizumab included pregnancy, patient withdrawal due to neurological deterioration on commencing PE and transfer to palliative care, investigator decision due to absence of informed consent, and administration of more than 1 PE before initiation of caplacizumab; 2 patients discontinued the study upon recurrence.

For treatment of the first aTTP recurrence in the post-HERCULES study, 3 of 4 patients (75%) who were treated without caplacizumab received rituximab while 6 of 13 patients (46.2%) who were treated with caplacizumab received rituximab.

Figure 4: Treatment of Patients With Recurrence During the Post-HERCULES Study

Capla = caplacizumab; IMP = investigational medicinal product; N = number of participants; SoC = standard of care.

Source: Post-HERCULES Clinical Study Report (2021).¹⁴

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported subsequently. Refer to Appendix 4 for detailed efficacy data.

aTTP-Related Death, Recurrence of aTTP, and Major Thromboembolic Events

aTTP-related death, recurrence of aTTP, and major thromboembolic events were analyzed both as a composite end point and its individual components in the efficacy ITO population. aTTP-related events during the post-HERCULES study are summarized in Table 14. aTTP-related events (TTP-related death, recurrence of aTTP, or major thromboembolic events) occurred in 11 patients (37.9%) randomized to receive SOC in the HERCULES study and in 4 patients (8.2%) randomized to receive caplacizumab in the HERCULES study. One patient (3.4%), who was randomized to receive SOC in the HERCULES study, died during the post-HERCULES study. Eight patients (27.6%) who were randomized to receive SOC in the HERCULES study and 4 patients (8.2%) who were randomized to receive caplacizumab in the HERCULES study experienced recurrence of aTTP during the post-HERCULES study. Eleven patients (37.9%) who were randomized to receive SOC in the HERCULES study and 4 patients (8.2%) who were randomized to receive caplacizumab in the HERCULES study experienced major thromboembolic events during the post-HERCULES study. Major thromboembolic events other than aTTP occurred in 3 patients who were randomized to receive SOC in the HERCULES study.

Table 14: aTTP-Related Events in the Post-HERCULES Trial (Efficacy ITO Population)

aTTP = acquired thrombotic thrombocytopenic purpura; ITO = intent to observe; SOC = standard of care.

Source: Post-HERCULES Clinical Study Report (2021).¹⁴

Kaplan-Meier analyses of time to first aTTP-related event and time to first aTTP relapse during the post-HERCULES study are shown in Figure 5 and Figure 6. Median time to first aTTP-related event and time to first aTTP relapse was not reached in either patients randomized to receive caplacizumab in the HERCULES study or in patients randomized to receive SOC alone in HERCULES study. No formal statistical analysis was performed.

Figure 5: Kaplan-Meier Analysis of Time to First aTTP-Related Event in the Post-HERCULES Trial (Efficacy ITO Population) — Redacted

aTTP = acquired thrombotic thrombocytopenic purpura; C301 = HERCULES study; C302 = post-HERCULES study; Capla = caplacizumab; ITO = intent to observe; SOC = standard of care.

Notes: Figure redacted based on the sponsor request.

Time to event calculated from screening/baseline.

Participants with a recurrence of aTTP in the post-HERCULES study were analyzed up to their first recurrence in the post-HERCULES study. Participants without a recurrence of aTTP in the post-HERCULES study were analyzed up to the end of the study.

Source: Post-HERCULES Clinical Study Report (2021).¹⁴

Figure 6: Kaplan-Meier Analysis of Time to First aTTP Relapse in the Post-HERCULES Trial (Efficacy ITO Population) — Redacted

aTTP = acquired thrombotic thrombocytopenic purpura; C301 = HERCULES study; C302 = post-HERCULES study; Capla = caplacizumab; SOC = standard of care.

Notes: Figure redacted based on the sponsor request.

Time to event calculated from screening/baseline.

Participants with a recurrence of aTTP in the post-HERCULES study were analyzed up to their first recurrence in the post-HERCULES study. Participants without a recurrence of aTTP in the post-HERCULES study were analyzed up to the end of the study.

Source: Post-HERCULES Clinical Study Report (2021).¹⁴

Reduction in Use of PE

The duration of PE in the recurrence population in the post-HERCULES study (n = 19) is shown in Table 15. Among patients experiencing a first recurrence in the post-HERCULES study who were treated with PE plus immunosuppression only (n = 4), the mean duration of PE was ||| |||| ||| ||| |||||| Among patients experiencing a first recurrence in the post-HERCULES study who were treated with caplacizumab (n = 13), the mean duration of PE was ||| |||| ||| ||| |||||| Among patients experiencing a second recurrence in the post-HERCULES study who were treated with caplacizumab (n = 6), the mean duration of PE was ||| |||| ||| ||| ||||||

Table 15: Duration of PE in the Post-HERCULES Trial (Recurrence Population)

NA = not applicable; NC = not calculable; PE = plasma exchange; SD = standard deviation.

Source: Post-HERCULES Clinical Study Report (2021).¹⁴

Health-Related Quality of Life

Total HIT-6 scores in a post-HERCULES study efficacy ITO population are summarized in Table 16. At the post-HERCULES study baseline, all patients completed the HIT-6. The mean total HIT-6 score was 45.0 (standard deviation [SD] = 10.0) in patients randomized to receive SOC alone in the HERCULES study and 48.2 (SD = 9.9) in patients randomized to receive caplacizumab in the HERCULES study. At the 36-month follow-up visit, 14 of 29 patients randomized to receive SOC only in the HERCULES study and 43 of 49 randomized to receive caplacizumab in the HERCULES study completed the HIT-6. The mean total HIT-6 score was 44.1 (SD = 10.1) in patients randomized to receive SOC alone in the HERCULES study and 49.4 (SD = 10.2) in patients randomized to receive caplacizumab in the HERCULES study.

Table 16: Total HIT-6 Score in the Post-HERCULES Trial (Efficacy ITO Population)

HIT-6 = Headache Impact Test 6; ITO = intent to observe; SD = standard deviation; SOC = standard of care.

Source: Post-HERCULES Clinical Study Report (2021).¹⁴

SF-36 physical functioning scores in the post-HERCULES study efficacy ITO population are summarized in Table 17. At the post-HERCULES study baseline, all patients completed the SF-36. The mean SF-36 physical functioning score was 68.3 (SD = 28.9) in patients randomized to receive SOC alone in the HERCULES study and 74.1 (SD = 23.6) in patients randomized to receive caplacizumab in the HERCULES study. At the 36-month follow-up visit, 15 of 29 patients randomized to receive SOC only in the HERCULES study and 43 of 49 randomized to receive caplacizumab in the HERCULES study completed the SF-36. The mean SF-36 physical functioning score was 82.0 (SD = 22.9) in patients randomized to receive SOC alone in the HERCULES study and 80.7 (SD = 22.3) in patients randomized to receive caplacizumab in the HERCULES study.

Table 17: Total SF-36 Physical Functioning Score in the Post-HERCULES Trial (Efficacy ITO Population)

ITO = intent to observe; SD = standard deviation; SF-36 = Short Form (36) Health Survey; SOC = standard of care.

Source: Post-HERCULES Clinical Study Report (2021).¹⁴

Productivity

Productivity was not evaluated as an efficacy outcome in the post-HERCULES study.

Organ Damage Markers

Levels of organ damage markers were not evaluated as an efficacy outcome in the post-HERCULES study.

Refractory aTTP

Refractory aTTP was not evaluated as an efficacy outcome in the post-HERCULES study.

Response to Treatment and Change in Platelet Count

Time to platelet count response (defined as initial platelet count of ≥ 150 × 10⁹/L with subsequent stop of daily PE within 5 days) in the post-HERCULES study recurrence population is shown in Table 18. Among patients experiencing a first recurrence in the post-HERCULES study who were treated with PE plus immunosuppression only (n = 5), the mean time to platelet count response was 9.8 days (SD = 4.0 days). Among patients experiencing a first recurrence in the post-HERCULES study who were treated with caplacizumab (n = 13), the mean time to platelet count response was ||| |||| ||| ||| |||||| Among patients experiencing a second recurrence in the post-HERCULES study who were treated with caplacizumab (n = 6), the mean time to platelet count response was ||| |||| ||| ||| ||||||

Table 18: Time to Platelet Count Response in the Post-HERCULES Trial (Recurrence Population)

NA = not applicable; NC = not calculable; SD = standard deviation.

Note: Platelet count response was defined as defined as initial platelet count ≥ 150 × 10⁹/L with subsequent stop of daily plasma exchange within 5 days.

Source: Post-HERCULES Clinical Study Report (2021).¹⁴

aTTP Exacerbation

Exacerbation of aTTP was not evaluated as an efficacy outcome in the post-HERCULES study.

Cognitive and Neurological Assessment (RBANS)

Total RBANS scores in the post-HERCULES study efficacy ITO population are summarized in Table 19. At the post-HERCULES study baseline, 26 of 29 patients randomized to receive SOC only in the HERCULES study and 38 of 49 randomized to receive caplacizumab in the HERCULES study completed the RBANS. The mean total RBANS score was 89.7 (SD = 20.3) in patients randomized to receive SOC alone in the HERCULES study and 92.7 (SD = 14.9) in patients randomized to receive caplacizumab in the HERCULES study. At the 36-month follow-up visit, 12 of 29 patients randomized to receive SOC only in the HERCULES study and 32 of 49 randomized to receive caplacizumab in the HERCULES study completed the RBANS. The mean total RBANS score was 98.0 (SD = 16.6) in patients randomized to receive SOC alone in the HERCULES study and 96.5 (SD = 17.0) in patients randomized to receive caplacizumab in the HERCULES study.

Table 19: Total RBANS Score in the Post-HERCULES Trial (Efficacy ITO Population)

ITO = intent to observe; RBANS = Repeatable Battery for the Assessment of Neurologic Status; SD = standard deviation; SOC = standard of care.

Source: Post-HERCULES Clinical Study Report (2021).¹⁴

Hospitalization

Duration of hospitalization in the post-HERCULES study recurrence population is summarized in Table 20. Among patients experiencing a first recurrence in the post-HERCULES study who were treated with PE plus immunosuppression only (n = 3), the mean duration of hospitalization was |||| |||| ||| ||| |||||. Among patients experiencing a first recurrence in the post-HERCULES study who were treated with caplacizumab (n = 11), the mean duration of hospitalization was ||| |||| ||| ||| |||||| Only 1 patient treated with PE plus immunosuppression in the post-HERCULES study and 3 patients treated with caplacizumab in the post-HERCULES study required intensive care.

Harms

Only those harms identified in the review protocol are reported subsequently. Refer to Table 21 and Table 22 for detailed harms data in the overall ITO population and the recurrence population, respectively.

Adverse Events

In the overall ITO population, 90.7% of patients treated with caplacizumab in the HERCULES study and 89.7% of patients treated with SOC only in the HERCULES study experienced AEs. Common AEs in both groups of patients included headache (caplacizumab-treated in HERCULES: 21.3%; SOC-treated in HERCULES: 31.0%) and aTTP (caplacizumab-treated in HERCULES: 14.7%; SOC-treated in HERCULES: 27.6%). Decreased ADAMTS13 activity was observed in 17.3% of patients treated with caplacizumab in the HERCULES study but in no patients treated with SOC only in the HERCULES study.

Among patients who received caplacizumab in the post-HERCULES study in the recurrence population (n = 13) and in the repeat caplacizumab use population (n = 9), 92% and 89%, respectively, experienced AEs.

Serious Adverse Events

In the overall ITO population, 37.3% of patients treated with caplacizumab in the HERCULES study and 55.2% of patients treated with SOC only in the HERCULES study experienced SAEs. The most common SAE was aTTP (caplacizumab-treated in HERCULES: 14.7%; SOC-treated in HERCULES: 27.6%).

Among patients who received caplacizumab in the post-HERCULES study in the recurrence population (n = 13) and in the repeat caplacizumab use population (n = 9), 38% and 44%, respectively, experienced SAEs.

Withdrawals Due to Adverse Events

In the overall ITO population, most patients were not treated in the post-HERCULES study and thus withdrawals due to AEs were not applicable.

Among patients who received caplacizumab in the post-HERCULES study in the recurrence population (n = 13) and in the repeat caplacizumab use population (n = 9), 15% and 22%, respectively, experienced AEs leading to study drug interruption, and 8% and 11%, respectively, experienced SAEs.

Mortality

In the overall ITO population, 1 patient (3.4%) treated with SOC only in the HERCULES study died. The death was aTTP-related.

Among patients who received caplacizumab in the post-HERCULES study in the recurrence population (n = 13) and in the repeat caplacizumab use population (n = 9), no patients died.

Notable Harms

In the overall ITO population, 21.3% of patients treated with caplacizumab in the HERCULES study and 31.0% of patients treated with SOC only in the HERCULES study experienced at least 1 bleeding event (based on Standardized MedDRA query “Haemorrhage” excluding the preferred term “aTTP”). Information on hypersensitivity reactions was not provided. |||||||||||| |||| ||||||||| |||||| ||||||||| || ||||||||| |||| |||||||| || ||||| || |||||||| ||||||| |||| |||||||||||| || |||||||| ||| || || |||||||| ||||||| |||| ||| |||| || |||||||||

Among patients who received caplacizumab in the post-HERCULES study in the recurrence population (n = 13) and in the repeat caplacizumab use population (n = 9), 54% and 56%, respectively, experienced at least 1 bleeding event (based on Standardized MedDRA query “Haemorrhage” excluding the preferred term “aTTP”); 23% and 22%, respectively, experienced hypersensitivity reactions; and ||| ||| |||| ||||||||||||| ||| |||||||||||| |||||

Table 21: Summary of Harms in the Post-HERCULES Trial (Overall ITO Population)

ADA = antidrug antibody; ADAMTS13 = a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13; AE = adverse event; aTTP = acquired thrombotic thrombocytopenic purpura; ITO = intent to observe; MedDRA = Medical Dictionary for Regulatory Affairs; NR = not reported; SAE = serious adverse event; TTP = thrombotic thrombocytopenic purpura; WDAE = withdrawal to adverse event.

^aFrequency > 15%.

^bBased on investigator reporting.

^cSAEs occurring in more than 2 patients in either group are reported.

^dBased on Standardized MedDRA query excluding TTP.

^eBased on investigator documentation of event indicating an increased bleeding tendency.

^fBased on specific preferred terms “drug hypersensitivity” and “hypersensitivity.”

Source: Post-HERCULES Clinical Study Report (2021).¹⁴

Table 22: Summary of Harms During First Recurrence Period in the Post-HERCULES Trial (Recurrence and Repeat Caplacizumab Use Populations)

ADA = antidrug antibody; AE = adverse event; aTTP = acquired thrombotic thrombocytopenic purpura; MedDRA = Medical Dictionary for Regulatory Affairs; NR = not reported; SAE = serious adverse event; TTP = thrombotic thrombocytopenic purpura; WDAE = withdrawal to adverse event.

Note: Recurrence period was defined as the period from recurrence to 1 week post caplacizumab discontinuation.

^aFrequency > 15%.

^bAll SAEs are reported.

^cBased on Standardized MedDRA query excluding TTP.

^dBased on Standardized MedDRA queries “Hypersensitivity” (narrow), “Anaphylactic reaction” (narrow), and “Angioedema” (narrow).

Source: Post-HERCULES Clinical Study Report (2021).¹⁴

Critical Appraisal

Internal Validity

As a long-term follow-up study, many of the internal validity issues of the HERCULES study affect the post-HERCULES study as well. Refer to the Clinical Review Report for the initial submission of caplacizumab¹³ for details, the executive summary of which is reproduced as Appendix 2.

The data from the post-HERCULES study should be interpreted within the context of potential for bias inherent to its design. Only patients who completed the HERCULES study (108 of 145, 74.5%) were eligible for the post-HERCULES study, and thus the study provides no information on patients who discontinued the HERCULES study. The most common reasons for discontinuation from the HERCULES study were AEs (11 patients, 7.6%) and withdrawal of consent (10 patients, 6.9%); reasons for discontinuation were broadly similar for both arms of the study. Because of potential for crossover to OL caplacizumab in the HERCULES study, only a small number of participants (n = 29) in the post-HERCULES study overall ITO population were caplacizumab-naive. Higher proportions of caplacizumab-naive patients (n = 6, 20.7%) than patients who received caplacizumab in the HERCULES study (n = 5, 6.7%) discontinued the post-HERCULES study. The clinical experts consulted by CADTH for this review did not expect that any resulting biases would be directional in favour of caplacizumab or limit interpretation of the study findings.

Baseline demographic characteristics were provided for the post-HERCULES study overall ITO population (arranged by prior caplacizumab experience in HERCULES). Although demographic characteristics appeared well balanced between these groups, it should be noted that the protections of randomization against bias and confounding do not apply.

No formal statistical analyses were conducted in the post-HERCULES study and all results were presented in descriptive and exploratory fashion. The study involved no testing of a priori hypotheses, no adjustment for multiple comparisons, no sensitivity analyses, and no subgroup analyses. There were high rates of missing data for some outcomes at later time periods in the study and these were not imputed. Data on aTTP-related events (aTTP-related death, recurrence of aTTP, and major thromboembolic events) were assumed to be complete for patients who did not discontinue the post-HERCULES study.

Because the double blind in the HERCULES study was lifted before the post-HERCULES study, patients and investigators were aware of treatment assignment in the HERCULES as well as in post-HERCULES studies (for patients who experienced aTTP recurrence). The OL nature of the study may have affected evaluation of patient-reported outcomes (HIT-6, SF-36, and RBANS) and safety outcomes. The measurement properties of the patient-reported outcomes used in the post-HERCULES study have not been studied in patients with aTTP and MIDs have not been determined.

External Validity

As a long-term follow-up study, many of the external validity issues of the HERCULES study affect the post-HERCULES study as well. Refer to the Clinical Review Report for the initial submission of caplacizumab¹³ for details, the executive summary of which is reproduced as Appendix 2.

As for the HERCULES study, the clinical experts consulted by CADTH felt that the post-HERCULES study population was generally reflective of adult patients with aTTP in Canada. Mortality rates in the HERCULES and post-HERCULES studies were lower than expected in routine clinical practice and patients may have been observed and followed by health care teams for aTTP recurrence and/or thromboembolic events more vigilantly compared to real-world practice.

In the post-HERCULES study, caplacizumab could be administered following up to 1 PE, but this was not a requirement as it was in the HERCULES study. Approximately half (6 of 13, 46.2%) of patients treated for their first recurrence in the post-HERCULES study with caplacizumab received rituximab, higher than what would be expected in Canadian practice according to the clinical experts consulted by CADTH for this review. The clinical experts consulted by CADTH for this review noted that the proportion of patients with aTTP in Canada who receive upfront rituximab in addition to PE and corticosteroids is not known with certainty but is likely lower than in the post-HERCULES trial. However, the proportion in clinical practice has increased in recent years due to improved access to rituximab.

The clinical experts consulted by CADTH did not feel that the post-HERCULES study population was likely to be significantly enriched for patients more likely to respond to caplacizumab. This could occur, if for example, patients who experienced AEs in the HERCULES study (n = 11, 7.6%) or withdrew consent (n = 10, 6.9%) were less likely to tolerate or respond to caplacizumab. The clinical experts also emphasized that evaluating the efficacy of caplacizumab for treating aTTP recurrences was not the major purpose of the post-HERCULES study.

The clinical experts consulted by CADTH stated that the duration of follow-up in the post-HERCULES study was adequate to assess both early recurrence of aTTP (within the first month of presentation) and later recurrences (which often occur within the 2 years following cessation of PE). The clinical experts felt that the aTTP-related events (aTTP-related death, recurrence of aTTP, and major thromboembolic events) evaluated in the post-HERCULES study would appropriately capture the burden of disease associated with long-term aTTP recurrence. However, the patient-reported outcomes (HIT-6, SF-36, AND RBANS) administered in the study are not used in clinical practice and their clinical relevance was uncertain. Nevertheless, HRQoL and neurocognitive symptoms were identified by patient groups, clinical experts, and clinician groups as important outcomes for patients with aTTP.

Indirect Evidence

No indirect evidence was submitted by the sponsor. A focused literature search for network meta-analyses dealing with aTTP was run in MEDLINE All (1946–) on July 5, 2022. No limits were applied to the search. No published indirect evidence was identified from the literature search comparing caplacizumab to comparators of interest for this review.

Other Relevant Evidence

This section includes additional relevant studies included in the sponsor’s submission to CADTH that were considered to address important gaps in the evidence included in the systematic review. Studies that were deemed not to address important gaps in the evidence included in the systematic review, or that were not described in sufficient detail to permit critical appraisal as outlined in Appendix 3, are described in Appendix 4 for reference only. In addition, the sponsor’s submission provided an interview with Canadian clinical experts and an Environmental Scan of Health Technology Assessment (HTA) reviews, which have been summarized in Appendix 4.

Other Clinical Trial Evidence

Three clinical trials were included in the sponsor’s resubmission: HERCULES, TITAN, and a phase II/III, OL, single-arm, multicentre trial of caplacizumab conducted among adult patients with aTTP in Japan (NCT04074187, N = 21).³⁵ Because of the noncomparative design of the phase II/III trial and description only in a conference abstract, the results of this study are described in Appendix 4 for reference only.

HERCULES and TITAN

The phase III HERCULES trial^21-23 and phase II TITAN trial^24-26 were reviewed in the CADTH Clinical Review Report for the initial caplacizumab submission¹³ (refer to Appendix 2 for details) and were considered relevant evidence for this review. For reference, the designs of the HERCULES and TITAN trials are summarized in Figure 7 and a summary of the main results from the TITAN and HERCULES trials is provided in Table 23.

The primary outcome in both studies was time to platelet response. Statistically tested secondary outcomes in the HERCULES study included the composite end point of aTTP-related events (aTTP-related death, recurrence of aTTP, or at least 1 major thromboembolic event), proportion of patients with aTTP recurrence, proportion of patients with refractory aTTP, and time to normalization of all 3 of the organ damage markers LDH, cardiac troponin, and serum creatinine. There were no statistically tested secondary outcomes in the TITAN trial. Both studies documented statistically significant differences in time to platelet count response that were viewed by the clinical experts consulted by CADTH for the previous review as too small to be clinically relevant. In the HERCULES study, the proportion of patients randomized to receive caplacizumab who experienced recurrence during the HERCULES overall study period was statistically significantly lower compared with patients randomized to receive SOC. Differences between study randomization arms in the proportion of patients with refractory aTTP were not statistically significant, precluding further statistical testing. The duration and volume of daily PE was shorter in the caplacizumab arm, which the clinical experts consulted by CADTH felt was encouraging and potentially clinically relevant. In addition, duration of hospitalization and ICU stay was shorter in the caplacizumab arm, but missing data and absence of statistical testing prevented interpretation of these results. Analysis of mortality and time to normalization of organ damage markers numerically favoured caplacizumab but without formal, prespecified statistical testing, these differences could not be interpreted.

Post Hoc Analyses of Clinical Trial Data

Six post hoc analyses were included in the sponsor’s resubmission: a publication of an integrated analysis of the HERCULES and TITAN¹⁶ studies as well as 4 posters and 1 abstract describing subgroup analyses of the HERCULES³⁶ and post-HERCULES³⁷ study data by rituximab use in the HERCULES study, subgroup analyses of the HERCULES study data by baseline disease severity³⁸ and time to platelet count response,³⁹ and a subgroup analysis of patients in the HERCULES study who had suboptimal responses to PE.⁴⁰ As outlined in Appendix 3, because of their post hoc design and incomplete description, the results of the posters/abstracts are described in Appendix 4 for reference only.

Integrated Analysis of the HERCULES and TITAN Study Data

One post hoc analysis of data from the HERCULES and TITAN trials was summarized to provide additional evidence regarding the clinically important outcomes of survival, health care use, organ damage, and refractory aTTP. The study did not address long-term aTTP recurrence beyond the duration of the trials. Peyvandi et al. (2021) conducted an integrated analysis of data from the HERCULES and TITAN trials as suggested by the FDA.¹⁶ The goal was to increase statistical power for assessing treatment differences in efficacy and safety outcomes. The study was funded by the sponsor.

Methods

The integrated analysis included all randomly assigned patients (ITT populations) from the HERCULES and TITAN studies, which were described in detail in the Clinical Review Report for the initial review of caplacizumab (the executive summary of which is reproduced as Appendix 2).

Populations

Baseline demographic and disease characteristics of the integrated ITT population are shown in Table 24. The characteristics of the integrated ITT population reflected the ITT populations of the individual trials. Approximately 3-quarters (74.1%) of patients were white, approximately two-thirds (65.5%) were women, and the average age was 44.6 years. Higher proportions of patients randomized to receive caplacizumab presented with an initial aTTP episode (66.7%) compared with patients randomized to receive placebo (54.5%). Other characteristics were broadly similar in both groups.

Figure 7: Designs of the TITAN (A) and HERCULES (B) Trials

TPE = therapeutic plasma exchange; TTP = thrombotic thrombocytopenic purpura.

Note: Notable differences between the TITAN and HERCULES study designs were the requirement for 1 prior PE session in HERCULES, the possibility to extend treatment beyond the first 30 days after PE in the HERCULES study, and the option to switch to open-label caplacizumab in case of exacerbation or relapse during the HERCULES study.

* Study drug treatment period: covered the period from the date of the first study drug administration until the date of the last study drug administration. The treatment period incorporated a period of variable duration, during which PE was administered and a 30-day post-PE period starting after the date of the last daily PE.

^† Participants were randomized prior to the start of PE treatment. After the approval and implementation of Clinical Study Protocol version 12.0, a participant could be randomized after an initial PE session, in which case the next PE session was designated as the first PE on study.

^‡ Daily PE: required.

^§ PE tapering: optional, per local standard site practice.

Source: Peyvandi et al. (2021).¹⁶ Reprinted from Blood Advances, Vol 5/No 8, Peyvandi F, Cataland S, Scully M, et al., Caplacizumab prevents refractoriness and mortality in acquired thrombotic thrombocytopenic purpura: integrated analysis, Pages 2137-2141, Copyright 2021, with permission from The American Society of Hematology.

Table 23: Summary of Key Results From the HERCULES and TITAN Trials

ADA = antidrug antibody; AE = adverse event; aTTP = acquired thrombotic thrombocytopenic purpura; CI = confidence interval; CMH = Cochran-Mantel-Haenszel; cTnI = cardiac troponin I; DB = double blind; GCS = Glasgow Coma Scale; ICU = intensive care unit; ITT = intention to treat; LDH = lactate dehydrogenase; NR = not reported; NT = not tested; PE = plasma exchange; SAE = serious adverse event; SB = single blind; SD = standard deviation; SE = standard error; ULN = upper limit of normal; WDAE = withdrawal due to adverse event.

Notes: Recurrence was defined as recurrent thrombocytopenia after initial recovery of platelet count requiring reinitiation of daily PE and after discontinuation of caplacizumab. An exacerbation was defined as a recurrence that occurred within 30 days after the last PE. A relapse was defined as a recurrence that occurred more than 30 days after cessation of PE. Refractory was defined as the absence of platelet count doubling after 4 days of treatment and LDH greater than the ULN. Platelet count response was defined as initial platelet count ≥ 150 × 10⁹/L with subsequent stopping of daily PE within 5 days of treatment.

Data on major thromboembolic events during the overall study period and refractory aTTP were not reported in the TITAN Clinical Study Report and are instead inferred from the integrated analysis of Peyvandi et al. (2021).¹⁶

^aHERCULES trial: SE and TITAN trial: SD.

^bFrequencies of major thromboembolic events and refractory aTTP were not presented in the TITAN Clinical Study Report and thus these values are inferred from Peyvandi et al. (2021) by subtracting frequencies from the HERCULES trial from the total for the integrated population.

^cFrom Kaplan-Meier analysis.

^dFrom stratified CMH test adjusted for GCS category at randomization.

^ePatients who had not undergone PE before enrolment (n = 69).

^fPatients who had undergone a PE before enrolment (n = 6).

^gFrom stratified log-rank test adjusted for GCS category at randomization (HERCULES) or PE before enrolment (TITAN).

Sources: HERCULES Clinical Study Report (2018),²¹ TITAN Clinical Study Report (2015),²⁴ and Peyvandi et al. (2021).¹⁶

Table 24: Study Participant Demographics and Baseline Disease Characteristics (ITT Analysis Set)

ADAMTS13 = a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13; ITT = intention to treat; LDH = lactate dehydrogenase; TPE = therapeutic plasma exchange; ULN = upper limit of normal; TTP = thrombotic thrombocytopenic purpura.

Note: This table is reproduced from original source and may not follow CADTH style.

^aAlthough inclusion criteria in HERCULES required platelet counts to be < 100 × 10⁹/L at screening, some participants had higher platelet counts by randomization, most likely owing to the prior PE session.

^bThe smallest value of ADAMTS13 activity at admission or baseline was summarized as ADAMTS13 activity levels could be substantially affected by prior PE in HERCULES (as well as platelet counts and LDH, troponin, and creatinine levels).

Source: Peyvandi et al. (2021).¹⁶ Reprinted from Blood Advances, Vol 5/No 8, Peyvandi F, Cataland S, Scully M, et al., Caplacizumab prevents refractoriness and mortality in acquired thrombotic thrombocytopenic purpura: integrated analysis, Pages 2137-2141, Copyright 2021, with permission from The American Society of Hematology.

Interventions

Patients received either caplacizumab plus PE and immunosuppression or a matching-administration placebo (double blind in the HERCULES study, single blind in the TITAN study) plus PE and immunosuppression. Treatments were administered as described in HERCULES and TITAN studies, which were described in detail in the Clinical Review Report for the initial review of caplacizumab. There were several notable differences in treatment between the TITAN and HERCULES studies, including the requirement for 1 prior PE session in the HERCULES study, the possibility to extend treatment beyond the first 30 days post-PE in the HERCULES study, and the option to switch to OL caplacizumab in case of exacerbation or relapse during the HERCULES study.

Outcomes

Time to platelet count response was assessed during the blinded study periods. Secondary efficacy end points (assessed during blinded study periods unless otherwise specified) included time to normalization of organ damage markers, duration of PE, proportion of participants with aTTP-related death, aTTP recurrence, or major thromboembolic events (assessed both as a composite end point and as individual events), aTTP recurrence (occurring ≤ 30 days after the end of daily PE [exacerbation] or > 30 days after end of daily PE [relapse]) during the blinded treatment period and the overall study period, and refractory aTTP.

Statistical Analysis

For analysis of time to platelet count response, treatment groups were compared using a 2-sided log-rank test stratified by trial based on Kaplan-Meier analysis. HRs and 95% CIs were calculated using a Cox proportional hazards model with time to platelet count response as a dependent variable, treatment group as an independent variable, and study as a random effect. To compare secondary outcomes between treatment groups, a stratified Cochran-Mantel-Haenszel test was used as a stratification factor in the trials. Time to first normalization of organ damage markers was performed as for the primary analysis of time to platelet count response.

Patient Disposition

Patient disposition in the integrated safety populations is presented in Table 25. Higher proportions of patients receiving placebo (35.5%) discontinued from the studies prematurely compared with patients receiving caplacizumab (26.4%). Discontinuations due to AEs occurred with similar frequencies in patients receiving caplacizumab (8.5%) and placebo (9.1%).

Table 25: Study Participant Disposition and Discontinuations (Safety Population)

^aThis reason was only relevant for TITAN.

Note: This table is reproduced from original source and may not follow CADTH style.

Source: Peyvandi et al. (2021).¹⁶ Reprinted from Blood Advances, Vol 5/No 8, Peyvandi F, Cataland S, Scully M, et al., Caplacizumab prevents refractoriness and mortality in acquired thrombotic thrombocytopenic purpura: integrated analysis, Pages 2137-2141, Copyright 2021, with permission from The American Society of Hematology.

Exposure to Study Treatments

Exposure to caplacizumab and placebo in the HERCULES and TITAN studies is described in detail in the Clinical Review Report for the initial review of caplacizumab (the executive summary of which is reproduced as Appendix 2). Exposure and adherence were high in both studies.

Efficacy

A summary of efficacy outcomes in the integrated ITT population is shown in Table 26. During blinded study drug treatment, no patients randomized to receive caplacizumab and 4 patients (3.6%) randomized to receive placebo died; during the overall study periods, 1 patient (0.9%) randomized to receive caplacizumab and 5 patients (4.5%) randomized to receive placebo died. The proportion of patients who experienced aTTP-related events (aTTP-related death, major thromboembolic events, or aTTP exacerbation) while receiving blinded study drug treatment was 13.0% in patients randomized to receive caplacizumab versus 47.3% among patients randomized to receive placebo. During the treatment-free follow-up periods, 14 patients (13.0%) randomized to receive caplacizumab and no patients randomized to receive placebo experienced aTTP relapses. During blinded study drug treatment, no patients randomized to receive caplacizumab and 8 patients (7.1%) randomized to receive placebo had refractory aTTP.

Table 26: Integrated Efficacy End Points for the Overall ITT Population

ADAMTS13 = a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13; ITT = intention to treat; MedDRA = Medical Dictionary for Regulatory Activities; n/s = not statistically significant (P ≥ 0.05); nt = not tested; TPE = therapeutic plasma exchange; TTP = thrombotic thrombocytopenic purpura.

Note: This table is reproduced from original source and may not follow CADTH style.

^aBased on Standardized MedDRA (Medical Dictionary for Regulatory Activities) queries (Standardized MedDRA Query) in the TITAN trial (post hoc); confirmed after adjudication in the HERCULES trial.

^bRecurrence was defined as a new drop in platelet count after initial platelet count normalization, necessitating reinitiation of TPE. Exacerbation is a recurrence within 30 days after the end of daily TPE. Relapse is a recurrence occurring more than 30 days after the end of daily TPE.

^cDefined as a lack of sustained platelet count increment or platelet counts < 50 × 10⁹/L throughout the assessment period and persistently increased lactate dehydrogenase (> 1.5 × upper limit of normal) despite 5 TPEs and steroid treatment.

^dIn the TITAN trial, 1 participant in the placebo group died 2 days after study treatment was permanently discontinued by physician decision and therefore counted as a death during the follow-up period, despite dying from severe refractory disease in the acute setting. In the HERCULES trial, 1 participant in the caplacizumab group died in the follow-up period after completing treatment and reaching complete remission. Both participants had a confirmed TTP diagnosis (ADAMTS13 < 10%).

Source: Peyvandi et al. (2021).¹⁶ Reprinted from Blood Advances, Vol 5/No 8, Peyvandi F, Cataland S, Scully M, et al., Caplacizumab prevents refractoriness and mortality in acquired thrombotic thrombocytopenic purpura: integrated analysis, Pages 2137-2141, Copyright 2021, with permission from The American Society of Hematology.

Consistent with the individual studies, treatment with caplacizumab resulted in a numerically faster time to platelet count response (HR = 1.65; 95% CI, 1.24 to 2.20), numerically faster time to normalization of LDH (HR = 1.43; 95% CI, 1.04 to 1.96), numerically faster time to normalization of troponin (HR = 1.32; 95% CI, 0.86 to 2.04), and numerically faster time to normalization of serum creatinine (HR = 1.68; 95% CI, 0.89 to 3.15). Also consistent with the individual studies, median duration of PE was numerically shorter in patients randomized to receive caplacizumab (5.0 days; range, 1 to 35 days) compared with patients randomized to receive placebo (7.5 days; range, 2 to 46 days).

Harms

A summary of safety outcomes in the integrated safety population is shown in Table 27. The safety data were consistent with the results of the individual studies and no new safety signals were identified. Seven patients (6.6%) treated with caplacizumab and 8 patients (7.3%) treated with placebo experienced AEs leading to treatment interruption. Seven patients (6.6%) treated with caplacizumab and 11 patients (10.0%) treated with placebo experienced WDAEs. No patients treated with caplacizumab and 4 patients (3.6%) treated with placebo died. Bleeding excluding aTTP occurred in 58.5% of patients treated with caplacizumab and 42.7% of patients treated with placebo. Serious bleeding excluding aTTP occurred in 11.3% of patients treated with caplacizumab and 1.8% of patients treated with placebo.

Table 27: Summary of TEAEs Occurring in the Blinded Study Periods (Safety Analysis Set)

AE = adverse event; MedDRA = Medical Dictionary for Regulatory Affairs; TEAE = treatment-emergent adverse event; TTP = thrombotic thrombocytopenic purpura.

Notes: This table is reproduced from original source and may not follow CADTH style.

Participants may have had more than 1 adverse event (AE) per preferred term. An individual was counted only once if he or she experienced 1 or more AE.

^aA bleeding AE was defined as a Standardized MedDRA Query bleeding TEAE (excluding TTP events), with an onset date on or after the first dose of study medication.

Source: Peyvandi et al. (2021).¹⁶ Reprinted from Blood Advances, Vol 5/No 8, Peyvandi F, Cataland S, Scully M, et al., Caplacizumab prevents refractoriness and mortality in acquired thrombotic thrombocytopenic purpura: integrated analysis, Pages 2137-2141, Copyright 2021, with permission from The American Society of Hematology.

Critical Appraisal: Internal Validity

Overall, the results of the integrated analysis supported and reinforced the consistent numeric improvements in the clinically important outcomes of survival, refractory aTTP, and duration of PE observed in the clinical development program (phase II TITAN and phase III HERCULES studies). However, the internal validity issues of the individual HERCULES and TITAN trials affect the integrated analysis as well. Refer to the Clinical Review Report for the initial submission of caplacizumab¹³ for details, the executive summary of which is reproduced as Appendix 2. In particular, the clinical experts consulted by CADTH for this review were concerned that the higher proportion of patients receiving placebo with recurrent rather than initial aTTP may have contributed to poorer outcomes, including higher mortality.

In addition, there were several notable differences between the TITAN and HERCULES studies, including the time they were conducted (2010 to 2014 versus 2015 to 2017) and the administration of caplacizumab (requirement for 1 prior PE session in HERCULES and the possibility to extend treatment beyond the first 30 days post-PE in HERCULES). Thus, the clinical experts consulted by CADTH for the present review relayed their uncertainty that the data from the 2 studies could be pooled. No poolability assessments or evaluation of heterogeneity of treatment effects of caplacizumab between the 2 studies were conducted. Statistical analyses of integrated data in the study by Peyvandi et al. (2021) were post hoc, not adjusted for multiple comparisons, and should be interpreted in descriptive and exploratory fashion. The results of post hoc analyses are considered hypothesis-generating only.

Critical Appraisal: External Validity

The external validity issues of the individual HERCULES and TITAN trials affect the integrated analysis as well. Refer to the Clinical Review Report for the initial submission of caplacizumab¹³ for details, the executive summary of which is reproduced as Appendix 2.

Real-World Evidence

Three studies of 2 RWE cohorts in France^17-19 and the UK²⁰ describing the efficacy and safety of caplacizumab were summarized to provide additional evidence regarding the clinically important outcomes of survival, refractory aTTP, and health care utilization. The studies did not address organ damage or long-term aTTP recurrence.

In addition, a RWE study of a German cohort^41-43 that was included in the sponsor’s submission was not considered by the CADTH review team to address an important gap in the evidence due to the lack of a comparison between patients who received caplacizumab and patients who did not receive caplacizumab, as outlined in Appendix 3. Similarly, 4 abstracts describing other RWE cohorts^44-47 were not described in sufficient detail to enable the CADTH review team to rigorously evaluate their conduct and reporting. Finally, 2 additional studies of RWE cohorts^48,49 were identified from the literature search results for the Systematic Review section, but also made no comparison between patients who did and did not receive caplacizumab. For reference only, these data have been described in Appendix 4.

French RWE Cohort

Coppo et al. (2021)¹⁸ prospectively analyzed outcome data for 90 patients with aTTP from France treated from September 2018 to December 2019 with a compassionate frontline triplet regimen consisting of PE, immunosuppression with corticosteroids and rituximab, and caplacizumab. Outcomes were compared with 180 historical control patients treated from June 2015 to September 2018 with standard frontline therapy (PE plus corticosteroids, with rituximab as salvage therapy).

Methods

All data from French patients with a clinical diagnosis of aTTP and treated with PE, immunosuppression with corticosteroids and rituximab, and caplacizumab from September 2018 to December 2019 were analyzed. The French Mortality in TTP Score (French severity score or French score)⁵⁰ was calculated in patients with features of thrombotic microangiopathy and no associated condition (cancer, chemotherapy, pregnancy, transplant, severe disseminated intravascular coagulopathy). Diagnosis of aTTP was considered in patients with features of thrombotic microangiopathy and a French score of 1 or 2. Patients with a French severity score of 0 (platelet count ≥ 30 × 10³/mm³ and serum creatinine ≥ 200 mmol/L) were considered having an alternative diagnosis, mostly hemolytic and uremic syndrome, and were not part of the cohort. A French severity score of 2 (platelet count < 30 × 10³/mm³ and serum creatinine < 200 mmol/L) was highly suggestive of aTTP; patients meeting only 1 of these criteria were considered having probable aTTP, and daily PE with corticosteroids and caplacizumab was immediately started; in this scenario; however, rituximab was started only after aTTP diagnosis was confirmed (ADAMTS13 activity < 10%). The final diagnosis of aTTP was confirmed in patients with ADAMTS13 activity less than 10% and anti-ADAMTS13 antibodies of 15 U/mL or greater. After PE cessation, ADAMTS13 activity was assessed weekly until normalization (activity ≥ 50%).

Severity of aTTP at baseline was assessed using cerebral involvement (including confusion, stupor, coma, or focal deficiency), age, and LDH level. Patients were classified into 2 groups: low-intermediate and high risk of early death, according to age, cerebral involvement, and LDH levels. Cardiac involvement was defined as an increase of troponin and/or electrocardiographic abnormalities. However, troponin assessment was not performed homogeneously through all centres; consequently, troponin was used for initial prognostic evaluation, but detailed prognostic analyses were not performed.

The outcomes of patients treated with the triplet regimen (PE plus immunosuppression with corticosteroids and rituximab plus caplacizumab) was compared with a historical cohort of patients with aTTP (historical cohort) managed with the standard regimen (daily PE and corticosteroids in association with salvage rituximab in patients experiencing refractoriness or an exacerbation of the disease). Patients from the triplet regimen were compared on a 1:2 ratio with the more recent patients of the historical cohort from the CNR-MAT registry. The choice of a 1:2 ratio with the historical cohort was driven by the rarity of aTTP and the desire to include patients with standardized management. The study was conducted according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) methodology.

Populations

The characteristics of patients treated with the triplet regimen including caplacizumab and historical controls receiving standard therapy are shown in Table 28. Patients receiving the triplet regimen including caplacizumab were treated from September 2018 to December 2019, while the historical controls were treated from June 2015 to September 2018. In both groups, similar proportions of patients had relapsed aTTP (12% to 13%), cerebral involvement (61% to 62%), and cardiac involvement (47% to 56%). Median LDH levels were 5.1 times the upper limit of normal (ULN) in patients receiving the triplet regimen including caplacizumab compared with 3.7 times the ULN in historical controls. All patients receiving the triplet regimen including caplacizumab received frontline rituximab (median time between first infusion and first PE = 2 days), while approximately two-thirds of historical controls received rituximab (68%) as salvage therapy (median time between first infusion and first PE = 7 days).

Table 28: Clinical Features and Concomitant Treatment of Patients on Diagnosis According to the Treatment Regimen

ADAMTS13 = a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13; GFR = glomerular filtration rate; iTTP = immune-mediated thrombotic thrombocytopenic purpura; LDH = lactate dehydrogenase; MDRD = modification of diet in renal disease; N = normal; nt = not tested; TPE = therapeutic plasma exchange; ULN = upper limit of normal; y = year.

Notes: Table reproduced from original source and may not follow CADTH style.

Data are given as median (25th-75th percentile) for quantitative variables and as n (%) for qualitative variables. Severe ADAMTS13 activity was defined as an activity < 10% (normal range for ADAMTS13 activity: 50% to 100%). The positivity threshold for anti-ADAMTS13 immunoglobulin G (IgG) was 15 U/mL, according to the manufacturer’s instructions (Technoclone). Cardiac involvement was defined as an increase of troponin and/or electrocardiographic abnormalities. Patients at high risk of early death of iTTP were defined by a French severity score ≥ 3 (cerebral involvement: yes = 1/no = 0, LDH: > 10 × ULN = 1/ ≤ 10 × ULN = 0, age: > 60 year = 2/ > 40 and ≤ 60 year = 1/ ≤ 40 year = 0).

^aData from 89 patients.

^bData from 166 patients.

Source: Coppo et al. (2021).¹⁸ Reprinted from Blood, Vol 137/No 6, Coppo P, Bubenheim M, Azoulay E, et al., A regimen with caplacizumab, immunosuppression, and plasma exchange prevents unfavorable outcomes in immune-mediated TTP, Pages 733-742, Copyright 2021, with permission from The American Society of Hematology.

Interventions

The triplet regimen including caplacizumab administered is summarized in Figure 8. Daily PE, corticosteroids (prednisone 1.0 mg/kg per day, maximum dose: 100 mg/day), and caplacizumab (10 mg IV loading dose followed by daily 10 mg SC doses) were started as soon as the clinical diagnosis of aTTP was suspected based on the French score. Rituximab (375 mg/m²) was administered IV on days 1, 4, 8, and 15 of PE; rituximab could be started from day 1 if the French score was highly suggestive for the diagnosis of aTTP (French score = 2) or alternatively by day 4 once severe ADAMTS13 deficiency was ascertained (French score = 1). Caplacizumab was continued for 30 days after PE cessation and could be extended until ADAMTS13 improvement (activity of 20% or greater). PE was performed daily until 2 days of a normal platelet count (150 × 10³/mm³) and interrupted with no maintenance. Corticosteroids were administered for 3 weeks.

Outcomes

The primary outcome was a composite of refractoriness and death within 30 days since diagnosis. Key secondary outcomes were refractoriness, death, exacerbations, the time to durable platelet count recovery, the number of PEs, the volume of plasma required to achieve durable platelet count recovery, the length of hospitalization, and caplacizumab-related AEs.

Complete response was defined as full resolution of the neurologic manifestations (or stabilization of neurologic abnormalities in patients considered as having permanent sequelae) and renal failure and recovery of normal platelet count (greater than 150 × 10³/mm³) for at least 2 days. Durable remission was defined as complete response with no further thrombocytopenia, renal failure, or clinical worsening for more than 30 consecutive days from the first day of platelet count recovery; at this step, the episode is considered as ended. Exacerbation was defined as initial treatment response but reappearance of clinical manifestations and/or thrombocytopenia (platelets less than 100 × 10³ for at least 2 days) before durable remission. Relapse was defined as reappearance of clinical features of aTTP (platelet counts less than 100 × 10³/mm³ for at least 2 days, with or without organ involvement; i.e., a new aTTP episode) after durable remission had been achieved. Refractoriness was defined as platelet count less than double the initial count after 4 days of standard intensive treatment, together with persistently elevated LDH levels. The definition of major bleeding and clinically relevant nonmajor bleeding events was adapted from the International Society on Thrombosis and Hemostasis.

Statistical Analysis

Data were presented as descriptive and summary statistics. The sample size was grounded in the hypothesis that the triplet regimen including caplacizumab would result in frequencies of the primary outcome at least 3 times lower than historically observed (10%). It was estimated that at least 65 patients were needed. To assess differences between baseline characteristics and treatment outcomes of the 2 cohorts, the Mann–Whitney-Wilcoxon test was used for ordinal variables, and Freeman-Halton test was used otherwise. Because follow-up time varied between patients, Poisson regression was used for statistical testing of efficacy end points.

Patient Disposition

A summary of patient flow in Coppo et al. (2021)¹⁸ is shown in Figure 9. Among 139 patients with a clinical suspicion of aTTP, 3 died before any treatment and 22 were treated without caplacizumab. Of the 114 patients receiving caplacizumab, 6 subsequently received an alternative diagnosis and 18 received caplacizumab as salvage therapy. Thus, a total of 90 patients received the triplet regimen including caplacizumab as frontline therapy. The median follow-up for these patients was 4.2 months.

Figure 8: The CAPLAVIE Regimen

A13 = ADAMTS13; ADAMTS13 = (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13); iTTP = immune-mediated thrombotic thrombocytopenic purpura; TPE = therapeutic plasma exchange.

Note: ADAMTS13 activity was assessed weekly until normalization or day 56.

Source: Coppo et al. (2021).¹⁸ Reprinted from Blood, Vol 137/No 6, Coppo P, Bubenheim M, Azoulay E, et al., A regimen with caplacizumab, immunosuppression, and plasma exchange prevents unfavorable outcomes in immune-mediated TTP, Pages 733-742, Copyright 2021, with permission from The American Society of Hematology.

Figure 9: Flow Chart of the Study

iTTP = immune-mediated thrombotic thrombocytopenic purpura.

* Mostly because of unawareness of practitioners about the availability of the compound (18 cases) or because patients were considered at risk of bleeding (1 case of recent surgery and 3 cases of active bleeding).

Source: Coppo et al. (2021).¹⁸ Reprinted from Blood, Vol 137/No 6, Coppo P, Bubenheim M, Azoulay E, et al., A regimen with caplacizumab, immunosuppression, and plasma exchange prevents unfavorable outcomes in immune-mediated TTP, Pages 733-742, Copyright 2021, with permission from The American Society of Hematology.

Exposure to Study Treatments

Information on exposure and compliance was not provided.

Efficacy

Efficacy outcomes for the RWE cohort of Coppo et al. (2021)¹⁸ are summarized in Table 29.The percentage of patients receiving the triplet regimen including caplacizumab with the composite primary outcome including death and refractoriness was 2.2% versus 12.2% in historical controls (RR = 6.2; 95% CI, 1.4 to 26.3). One patient (1.1%) treated with the triplet regimen died of pulmonary embolism compared with 12 (6.7%) historical controls. One patient (1.1%) treated with the triplet regimen experienced refractory aTTP compared with 16 (18%) historical controls.

Consistent with data from the HERCULES trial, patients receiving the triplet regimen including caplacizumab experienced fewer exacerbations compared with historical controls (3.4% versus 44% ; RR 16.4, 95% CI 5.2 to 52.1), recovered durable platelet count faster (median time to recovery of 5 days versus 12 days; RR 1.8, 95% CI 1.41 to 2.36), had fewer PE sessions (median 5 versus 10 sessions), required lower overall PE volume until remission (median 24.2 versus 44.2 L), and had shorter duration of hospitalization (median 13 versus 22 days). Patients receiving the triplet regimen including caplacizumab had faster time to ADAMTS13 activity over 20% compared with historical controls (median 28 versus 48 days; RR 4.0, 95% CI 3.03 to 5.26). The frequency of major thromboembolic events was similar in patients receiving the triplet regimen including caplacizumab and in historical controls.

Table 29: Primary and Secondary Outcomes According to the Treatment Regimen

ADAMTS13 = a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13; TPE = therapeutic plasma exchange.

^aIncludes 10 refractory patients who survived (only 1 event per patient was considered).

^bIncludes 6 deaths.

Notes: This table is reproduced from original source and may not follow CADTH style.

Data are given as median (25th-75th percentile) for quantitative variables and as n (%) for qualitative variables. Patients at high risk of early death from aTTP were defined by a French severity score ≥ 3 (cerebral involvement: yes = 1/no = 0, LDH: > 0 × ULN = 1/ ≤ 10 × ULN = 0, age: > 60 year = 2/ > 40 y and ≤ 60 year = 1/ ≤ 40 y = 0).

Source: Coppo et al. (2021).¹⁸ Reprinted from Blood, Vol 137/No 6, Coppo P, Bubenheim M, Azoulay E, et al., A regimen with caplacizumab, immunosuppression, and plasma exchange prevents unfavorable outcomes in immune-mediated TTP, Pages 733-742, Copyright 2021, with permission from The American Society of Hematology.

Harms

Safety outcomes for the RWE cohort of Coppo et al. (2021)¹⁸ are summarized in Table 30. Overall, 46 patients (51%) experienced at least 1 caplacizumab-related AE. Two patients (2%) experienced major bleeding and 11 patients (12%) experienced clinically relevant nonmajor bleeding.

Table 30: Caplacizumab-Related Adverse Events

Note: This table is reproduced from original source and may not follow CADTH style.

Source: Coppo et al. (2021).¹⁸ Reprinted from Blood, Vol 137/No 6, Coppo P, Bubenheim M, Azoulay E, et al., A regimen with caplacizumab, immunosuppression, and plasma exchange prevents unfavorable outcomes in immune-mediated TTP, Pages 733-742, Copyright 2021, with permission from The American Society of Hematology.

Critical Appraisal: Internal Validity

Comparisons between patients receiving the triplet regimen including caplacizumab and historical controls receiving SOC were limited by risk of bias in selection of participants and potential for confounding. Approximately 16% of patients who were eligible for the triplet regimen were not treated with caplacizumab due to lack of awareness of the drug, and approximately 16% of patients treated with the triplet regimen received caplacizumab as salvage therapy and were excluded from the analysis. As an observational cohort study, comparisons could be biased due to both measured and unmeasured confounders, neither of which were accounted for. In particular, the 2 cohorts analyzed had nonoverlapping time frames, and changes in treatment practice could potentially influence the results. In addition, all patients receiving the triplet regimen including caplacizumab received frontline rituximab, while only approximately two-thirds of historical controls received rituximab as salvage therapy only. Thus, differences in outcomes between the 2 groups of patients are difficult to attribute specifically to caplacizumab and may be partially explained by differences in rituximab use.

The rationale for statistical hypothesis testing was not provided and it was unclear whether statistical tests were prespecified or conducted post hoc for some outcomes. Statistical tests were not adjusted for multiple comparisons and should be interpreted in descriptive and exploratory fashion.

Critical Appraisal: External Validity

According to the clinical experts consulted by CADTH for this review, upfront use of rituximab and upfront-only treatment with caplacizumab (i.e., no salvage therapy) is not consistent with the current or expected use of either drug in Canadian clinical practice.

French RWE Cohort: Reanalysis

||||| ||| |||||| ||||||||||| ||||||||| || ||||||| |||||||||| || ||| |||| |||| ||| ||| |||||| || ||||| || ||| ||||||||| ||| ||||| ||||||||||| || ||| ||||||| |||||||| ||||| ||| ||||||||| || ||| |||||||||| |||||||| || ||| ||||||| |||||||| ||||||| ||||||| ||||||| |||| ||| |||||| ||||| ||| |||| ||||||||||| || | |||||||||| ||||| ||||| || ||||||| |||||||| ||| ||||||||| |||| || || |||| || || |||||||||| |||||| || |||||||||||| ||||||||| ||||||||||| ||| ||| ||||||| |||||||||| || ||||| ||| |||||| ||||||||||| || ||||||||| || |||| |||||| |||| ||||| || ||||||| |||| |||| ||||||||| ||| ||| |||||||| |||||||| || ||||| || ||| |||||||||||||||||||||| |||| ||||||||| ||||||||||||||| ||| |||||||| || ||| ||||||| |||||||| ||| |||||||| ||| ||||||| ||||||| ||||||||| |||||||||||| ||||||||| || ||||| || ||| |||||||| |||| ||||||||| |||| || |||||||| |||| |||||| ||| ||| |||||||| ||||||||| |||||||| || |||| ||| |||| ||||||||||||||||| |||| |||||||||||||||| |||| || ||||||| ||||||||| || ||||||| |||||||| ||||||| ||||||| |||| ||| |||||| |||| |||||||||||||||||||||||| ||||||||||||||| || ||| ||| |||||| || |||||||| || ||| ||||||| ||||||||||| ||| ||||| ||

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Table 31: Redacted

Note: Table redacted as per sponsor’s request.

|||||||| | | ||||||||||| |||| | |||||||| |||||||||| |||||||||||||||| |||||||| ||| | |||| |||| |||||| ||| | |||||||||| |||||||||| ||||| ||| | ||||||||||||| |||||| ||| | ||||||| |||||||||||||| |||| | |||||||||||| || |||| || ||||| |||||||| || | ||| ||||||||| || | |||||| ||||||||| || | |||||||| |||||||||| ||| | ||||| ||||| || |||||||||||||||| ||||||||||| ||| ||||||| || || |||||||| || |||||||| |||||| |||||||||||||||||||| |||||||||||||||||||||| |||||||| |||||| |||| ||||||||| ||| || || || |||||||| ||||||||| ||| ||||||| ||||||| ||| ||| || ||| |||||||| || ||| |||||||||| ||||||||||||||| ||||| ||| |||||| ||||||||||||||||||||||||||||||| ||||||||||||| |||||||||||| |||||||| ||||||| ||||||||| |||||||||||| || |||||||| ||||||| |||||||||| || || |||| |||||||||||||||||| |||| || ||||||||| || ||||| || ||| |||||||| ||||||| ||||||||||| || |||||||||| |||||||| || ||| ||||||| ||||||||||| ||||||| |||||||| ||||||||| || ||||||| ||||||| |||||||| |||| ||| |||||||| |||||||| ||||||||||||||||||||| ||||||| |||||||| ||| ||||| |||||| || |||| ||||||||| ||||||||| || ||||| ||||||||| |||||||| |||||||| ||||| || |||||||||| |||||||| | ||||||||| |||||||| || ||||| |||||| || |||| ||| |||||||||| |||||||| ||||| |||||| || |||| || |||||||||| |||||||||||| || ||||| |||||||||| || || ||||| ||| |||||||||||||| |||||| |||| |||| ||||||||| |||||||||| || |||||||| |||||||||||||| |||| |||| ||||||||| |||||||||| || |||||||| |||||||| || ||| || |||||||| |||||| || ||||| || |||||||| ||||| |||||||||| ||||| || |||||| ||||| |||||||||| ||| |||||| || |||||||| ||||||||||||||||| || ||||||||| |||||||||| ||||||||||||| |||||||| ||| |||||||||||||| |||| || ||| ||| || ||||| || ||| |||||| ||| |||| |||||| |||| ||||||||||||||||||| |||||||||| |||||||||| ||||| ||| |||||||||| ||| |||||||| || |||| ||||||| ||||| || |||| ||| |||||||| |||||| |||||||||||| ||| ||||||| |||||||||||||| ||| |||||| ||| |||||||||| |||||||||| ||||| ||||| ||||||||| |||| |||||||||| || |||| ||||||| ||| ||||| || |||||||| ||||||| ||||||||| || |||| |||| ||| ||||||| ||||||||| |||||||||||| ||||||||| |||| ||||||||| ||||||||||||||||| |||||||| || ||| ||||||| |||||||| ||||||||||| || ||||| |||||| || |||| ||||||||| ||||||||||| | |||||| |||||||| ||| ||||||| ||| ||| |||||||||| || ||||| || || |||| ||| ||||||| || |||||||| ||||||||||| ||| |||||||| |||||||| ||| ||| |||||||||| || ||||| |||||| || |||| ||||||||| |||||||||| ||| ||| ||||||||||| |||||||| ||| ||| |||||| || ||||| |||||||| |||| |||||||| ||||||||||||| |||||| |||||| |||||||||| |||||||| | |||||||||||| ||||| ||| ||||||||||| || ||||||||| ||| |||||||||| ||||| || | ||||||||| || || |||||||| ||||| ||| |||| || |||||||||| || |||||||||| |||||| || ||||| || |||||||| ||| |||||||||| || ||| ||||||||| ||| ||||||| |||||||| ||| |||||||| |||| ||| |||||||||| |||||||| ||| |||||||||| || ||| ||||||||| |||| || ||||||||| ||| |||||||||| |||||| ||| |||| ||||||| ||||||||| || ||| |||||||||| ||||| |||| ||| ||| || ||||||||| || ||||||| ||||||||||| ||||||||| ||||| |||| || |||||| | ||||||||| |||||||| |||||||||| ||||| ||||||| |||||||||||| ||| |||| ||||||| |||||||| ||||||||| |||||||||

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Figure 10: Patient Selection — Redacted

Note: Figure redacted based on the sponsor request.

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Table 32: Redacted

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Figure 11: Redacted

Note: Figure redacted based on the sponsor request.

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Critical Appraisal: Internal Validity

The internal validity issues described for the original analysis by Coppo et al. (2021)¹⁸ apply to the updated reanalysis as well, including potential for bias and impact of unmeasured confounders. While the clinical experts consulted by CADTH for the present review felt that the variables used for calculation of propensity scores appropriately captured disease severity and mortality risk, they did not account for the major treatment differences between the 2 groups (frontline rituximab in all patients receiving the triplet regimen, and salvage rituximab in approximately two-thirds of historical controls). In addition, the 2 cohorts analyzed had nonoverlapping time frames, and changes in treatment practice could potentially influence the results. An additional source of bias in the updated reanalysis was that some patients ||||| || |||||||||||||||||||| |||||||| ||| ||||| || |||||||||| ||||||||| had missing data for propensity scores and were thus excluded from the multivariate analysis. The impact of this bias was unclear.

Statistical tests were not adjusted for multiple comparisons and should be interpreted in descriptive and exploratory fashion. There was substantial variation evident in the 95% CIs for the odds ratio from logistic regression, and associated P values, depending on the analytical technique used. Use of propensity scores as covariates in adjusted multivariate models can result in biased estimation of HRs,⁵¹ although sensitivity analyses using alternative methodological approaches were performed.

Critical Appraisal: External Validity

The external validity issues described for the original analysis by Coppo et al. (2021)¹⁸ apply to the updated reanalysis as well.

UK RWE Cohort

Dutt et al. (2021)²⁰ conducted a retrospective analysis of data from 85 patients with aTTP (including 4 children) who received caplacizumab in 22 UK hospitals from May 2018 and January 2020. Outcomes for these patients were compared with data from the HERCULES study and to a group of historical control patients consisting of 39 consecutive cases from the UK TTP registry who received standard treatment (PE plus immunosuppression with corticosteroids and rituximab) from 2014 to 2018.

Methods

An invitation to participate in RWE data collection for patients receiving caplacizumab was sent to all UK TTP registry collaborators. Data were retrospectively collected from consecutive eligible patients’ medical records from UK hospitals between May of 2018 and January of 2020. Inclusion criteria were patients of any age, who had received at least 1 dose of caplacizumab through the patient drug access scheme, following a confirmed diagnosis of acute aTTP. There were no exclusion criteria. Characteristics and outcomes for patients receiving caplacizumab compared with outcome data from the HERCULES study and a historical control group consisting of 39 consecutive cases from the UK TTP registry from 2014 to 2018.

Anonymized data were submitted by participating centres on specific patient characteristics and outcome data. Relevant outcome parameters were identified ahead of data collection, comparable with the HERCULES study end points. These included patient demographics, ADAMTS13 serology, serological markers of organ injury, platelet count recovery, PE, aTTP recurrences, bleeding and thromboembolic complications, and mortality.

Populations

The baseline characteristics of patients treated with caplacizumab in the RWE cohort of Dutt et al. (2021) are shown in Table 33. Approximately two-thirds (66%) of patients were women, approximately two-thirds (67%) were white, and the average age was 46 years. The median cardiac troponin level was 98 ng/mL, the median serum creatinine level was 90 µmol/L, and approximately two-thirds (66%) of patients had neurologic symptoms at presentation. Approximately one-quarter of patients (26%) required intubation during hospitalization for aTTP.

Table 33: Characteristics at Presentation of Patients Receiving Caplacizumab

ADAMTS13 = a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13; d = day; IQR = interquartile range; IU = international units; NHS = National Health Service; y = year.

Note: This table is reproduced from original source and may not follow CADTH style.

^aEthnicity was determined by the hematologist submitting the data for each center. Data on race were missing for 2 patients.

^bMedian cardiac troponin on admission is based on n = 81 patients for whom data were available. Data are based on troponin T, the more commonly used cardiac enzyme in the NHS Trusts submitting the data.

^cADAMTS13 inhibitor value on admission is based on n = 78 patients for whom data were available. The NHS Trusts included in this study used different assays for ADAMTS13 inhibitor; therefore, the normal values for each laboratory were used to determine whether the ADAMTS13 inhibitor was present/absent.

Source: Dutt et al. (2021).²⁰ Reprinted from Blood, Vol 137/No 13, Dutt T, Shaw RJ, Stubbs M, et al., Real-world experience with caplacizumab in the management of acute TTP, Pages 1731-1740, Copyright 2021, with permission from The American Society of Hematology.

Interventions

Patients in the caplacizumab cohort of Dutt et al. (2021)²⁰ received caplacizumab in addition to standard treatment, while historical controls received standard treatment alone. The standard treatment was as per UK national guidance and included PE plus corticosteroids and rituximab as a component of acute management. In the caplacizumab cohort, 84 patients (99%) received rituximab while in the historical control group 34 patients (87%) received rituximab.

Of note, caplacizumab was administered within 2 days of initiation of PE in approximately half of patients, while in 13% of patients, caplacizumab was initiated 1 week or more from beginning PE. The duration of caplacizumab treatment continuation post-PE ranged from 0 to 92 days (median, 28 days), with 55% of patients (47 of 85) discontinuing caplacizumab ahead of the 30-day period due to increased platelets and/or ADAMTS13 activity. The proportion of patients who continued caplacizumab for more than 30 days post-PE plus a 28-day extension as per the product monograph was not stated.

Outcomes

Time to platelet count normalization was defined in line with the HERCULES study as the time from the first IV administration of caplacizumab to the normalization of platelet count (platelet count of 150 × 10⁹/L or greater with discontinuation of PE within 5 days thereafter). Recurrence of aTTP was defined as a new decrease in platelet count after initial normalization, requiring PE therapy to be reinitiated. A recurrence within 30 days after completion of PE was defined as an “exacerbation,” and a recurrence occurring more than 30 days after completion of PE was defined as a “relapse.” Refractory aTTP was defined as progression of clinical symptoms or persistent thrombocytopenia despite PE.

Statistical Analysis

Statistical analyses included descriptive and summary statistics. In addition, between-group comparisons were performed using a Mann-Whitney U test for continuous data and Fisher exact test for binary variables. The Kaplan-Meier estimator was used to calculate median times to events.

Patient Disposition

Between May 2018 and January 2020, 115 patients (110 adult and 5 pediatric) from 25 UK hospitals received caplacizumab through the free drug patient access scheme. Data were provided from 22 hospitals for 85 of 115 patients. Participation in data submission was voluntary, and no data were received for the remaining 30 patients.

No information was provided on the selection of the historical control group of 39 consecutive cases from the UK TTP registry from 2014 to 2018. The criteria for entry of these patients (approximately 10 patients per year) in the registry were not stated.

The median follow-up time for the caplacizumab cohort was 2.6 months (interquartile range [IQR], 1.9 to 5.5 months).

Exposure to Study Treatments

The median duration of caplacizumab treatment was 32 days (IQR, 22 to 47 days).

Efficacy

Treatment outcomes in the caplacizumab cohort of Dutt et al. (2021)²⁰ are summarized in Table 34. Consistent with the results of the HERCULES trial, median time to platelet count normalization in the caplacizumab cohort was 3 days, median duration of PE was 7 days, and median duration of hospitalization was 12 days. Slightly more than half of patients had normalization of neurological symptoms (61%) and creatinine levels (56%) posttreatment. Five patients (6%) experienced aTTP recurrence (2 exacerbations and 3 relapses). Five patients in the caplacizumab cohort (6%) died.

Table 34: Summary of Outcomes for Patients Receiving Caplacizumab for iTTP

d = day; IQR = interquartile range; iTTP = immune-mediated thrombotic thrombocytopenic purpura; PEX = plasma exchange; TTP = thrombotic thrombocytopenic purpura.

Notes: This table is reproduced from original source and may not follow CADTH style.

Unless otherwise noted, data are n (%).

^aTime to normalization of platelet count was defined in line with the HERCULES study as the time from the first IV administration of caplacizumab to normalization of platelet count (i.e., ≥ 150 × 10⁹/L with discontinuation of PEX within 5 days thereafter). Time to normalization of platelet count is based on 81 of 85 patients; the remaining 4 patients did not achieve normalization of their platelet count by 30 days post-PEX discontinuation (1 case because of concomitant diagnosis of immune thrombocytopenia with a history of chronic low-grade thrombocytopenia, 1 case who achieved a normal platelet count by day 43, and 2 patients with multiple organ failure leading to death).

^bBased on n = 81 patients, excluding 4 who died prior to discharge from the hospital.

^cBased on available data for 54 of 55 patients who presented with neurological symptoms. The most common neurological symptoms on discharge were depressed mood and anxiety.

^dBased on available data for 32 of 35 patients who presented with acute kidney injury.

^eRecurrence of TTP was defined as a new decrease in platelet count after initial normalization of the platelet count, requiring PEX therapy to be reinitiated. A recurrence within 30 days after completion of PEX therapy was defined as an exacerbation, and a recurrence occurring > 30 days after completion of PEX therapy was defined as a relapse.

^fThe cause of death was determined by the hematology clinician submitting the data; in all cases the cause was believed to be secondary to severe and/or refractory TTP.

Source: Dutt et al. (2021).²⁰ Reprinted from Blood, Vol 137/No 13, Dutt T, Shaw RJ, Stubbs M, et al., Real-world experience with caplacizumab in the management of acute TTP, Pages 1731-1740, Copyright 2021, with permission from The American Society of Hematology

A comparison of baseline characteristics and treatment outcomes between the caplacizumab cohort of Dutt et al.²⁰ and historical controls is shown in Table 35. Compared with historical controls, higher proportions of the caplacizumab cohort had elevated cardiac troponin (79% versus 64%) and elevated creatinine (41% versus 26%).

Consistent with the HERCULES study, median duration of PE (median 7 days versus 9 days) and time from PE initiation to platelet count normalization (median 4 days versus 6 days) were shorter in the caplacizumab cohort compared with historical controls. Duration of hospitalization was similar in the caplacizumab cohort (median = 12 days) and the historical control cohort (median = 14 days). aTTP recurrence and refractoriness were not compared between the 2 groups. In the caplacizumab cohort, 5 patients (6%) died but there were no deaths among historical control patients.

Table 35: Comparison of Presentation Characteristics and Outcomes in Caplacizumab Cohort Versus a Precaplacizumab Historical Control

ADAMTS13 = a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13; d = days; IQR = interquartile range; IU = international units; PEX = plasma exchange; TTP = thrombotic thrombocytopenic purpura; VTE = venous thromboembolism; y = years.

Notes: This table is reproduced from original source and may not follow CADTH style.

Unless otherwise noted, data are n (%).

^aStandard treatment cohort is from 39 consecutive cases from unpublished TTP Registry data from 2014 to 2018.

^bP values were calculated using the Student t-test/Χ² test for parametric data and the Mann–Whitney U test for nonparametric data.

^cBased on 81 of 85 patients. Four of 85 patients did not achieve a normal platelet count (by 30 days, post-PEX discontinuation); 1 case due to a concomitant diagnosis of immune thrombocytopenia with a history of chronic low-grade thrombocytopenia, 1 case whose platelets returned to normal levels by day 43, and 2 cases with multiple organ failure leading to death.

Source: Dutt et al. (2021).²⁰ Reprinted from Blood, Vol 137/No 13, Dutt T, Shaw RJ, Stubbs M, et al., Real-world experience with caplacizumab in the management of acute TTP, Pages 1731-1740, Copyright 2021, with permission from The American Society of Hematology.

The relationships between ADAMTS13, aTTP recurrence, and mortality in the caplacizumab cohort are shown in Figure 12. In 4 patients who died, caplacizumab was introduced more than 48 hours after PE initiation (range, 3 to 21 days), and in 3 patients who died, caplacizumab was introduced more than 1 week after PE initiation (range, 8 to 21 days). All deaths were believed by the treating hematologist to be secondary to severe and/or refractory TTP.

Figure 12: Drug Initiation, Mortality, and Disease Recurrence in Relation to ADAMTS13 Activity

ADAMTS13 = a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13; PEX = plasma exchange.

Note: (A) Time taken from initiation of PEX therapy to the first dose of caplacizumab (days). < 1 day refers to the first administration of caplacizumab < 24 hours following initiation of PEX. (B) Mortality according to caplacizumab initiation (≤ 48 hours vs > 48 hours). Eighty percent of those who died had caplacizumab initiated > 48 hours after the first PEX. (C) Recurrence status according to ADAMTS13 activity at completion of PEX. (i) Individual patient data with regard to exacerbation status. ADAMTS13 activity after the end of PEX was available for 76 patients. Of these, 37 (48.7%) had ADAMTS13 activity < 10.0% (range, < 1.0 to 5.2); 3 patients experienced exacerbations. The other 39 patients (51.3%) had ADAMTS13 ≥ 10.0% (range, 10.2 to 107.2), without any exacerbations. (ii) Individual patient data with regard to relapse status. No patient with ADAMTS13 activity ≥ 10.0% relapsed, whereas 3 of the 37 patients with ADAMTS13 activity < 10.0% did. Recurrences are termed exacerbations if they occur within 30 days of last PEX and are classified as relapses if they occur > 30 days after last PEX.

Source: Dutt et al. (2021).²⁰ Reprinted from Blood, Vol 137/No 13, Dutt T, Shaw RJ, Stubbs M, et al., Real-world experience with caplacizumab in the management of acute TTP, Pages 1731-1740, Copyright 2021, with permission from The American Society of Hematology.

Harms

Safety outcomes in the caplacizumab cohort of Dutt et al. (2021)²⁰ are summarized in Table 36. Twenty-six patients (30.6%) experienced at least 1 AE, while the numbers of patients who experienced SAEs, AEs leading to treatment interruption, or WDAEs were not reported. Five patients (5.9%) died. Fifteen patients (17.6%) had bleeding AEs, including 17 episodes of which 5 were episodes of major bleeding. Eleven patients (12.9%) had non-bleeding AEs, including 5 patients (5.9%) who experienced venous thromboembolism.

Table 36: Summary of Adverse Events for Patients Receiving Caplacizumab

LFT = liver function test; NA = not applicable.

Note: This table is reproduced from original source and may not follow CADTH style.

^aSome patients were reported to have > 1 adverse event. There were 17 bleeding episodes in 15 patients and 14 nonbleeding episodes in 11 patients.

^bMajor bleeding was defined as per the International Society on Thrombosis Haemostasis bleeding scale guideline. Major bleeding in nonsurgical patients includes fatal bleeding and/or symptomatic bleeding in a critical area or organ (e.g., intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, or pericardial, or intramuscular with compartment syndrome) and/or bleeding causing a decrease in hemoglobin levels ≥ 2 g/dL or leading to transfusion of ≥ 2 units of whole blood or red cells.

^cThis case was associated with a significant reduction in hemoglobin leading to drug interruption.

^dOne case of severe upper gastrointestinal bleeding with subsequent decrease in hemoglobin on background of Barrett’s esophagus, gastroscopy showing small ulcer and esophagitis. One case of minor upper gastrointestinal bleeding.

^eOne case of secondary hemorrhage of cerebral infarct and 1 case of intracranial hemorrhage following initial ischemic insult. There were no cases of primary intracerebral hemorrhage while on caplacizumab.

^fPostmechanical fall resulting in fractured femoral neck.

^gThrombotic episodes included left brachial and right internal jugular thrombosis (n = 1) and pulmonary embolism (n = 4). These 5 episodes occurred in 4 patients. Two of these episodes occurred outside of the time during which the patient was being administered caplacizumab.

^hCaplacizumab was interrupted because of concerns managing bleeding risk on concurrent therapeutic anticoagulation in all cases.

ⁱOne case had concurrent thrombosis.

^jNot listed on drug summary of product characteristics as a side effect.

Source: Dutt et al. (2021).²⁰ Reprinted from Blood, Vol 137/No 13, Dutt T, Shaw RJ, Stubbs M, et al., Real-world experience with caplacizumab in the management of acute TTP, Pages 1731-1740, Copyright 2021, with permission from The American Society of Hematology.

Critical Appraisal: Internal Validity

Comparisons between patients receiving the triplet regimen including caplacizumab and historical controls receiving SOC were limited by risk of bias in selection of participants. Data for 26% of eligible patients treated with caplacizumab were not submitted for analysis and no data were available for these patients which prevents the evaluation of selection bias for this analysis. Furthermore, data for 115 patients from 2018 and 2019 were in the registry compared with data for 39 consecutive cases for the 4-year period from 2014 to 2018; the lower sample for the comparator group collected over a longer time period suggests that the historical controls represented a small subgroup of the overall population of patients with aTTP treated during this period. Comparisons between the caplacizumab cohort of Dutt et al. (2021)²⁰ and the HERCULES trial data were direct without adjustment, and the baseline characteristics and treatments administered differed substantially; thus, the risk of bias due to measured and unmeasured confounders is high for this comparison. There were baseline differences between the caplacizumab and historical control cohorts in cardiac involvement and serum creatinine level, which could have affected the outcomes including mortality. In addition, the 2 cohorts analyzed had nonoverlapping time frames, and changes in treatment practice could potentially influence the results.

The rationale for statistical hypothesis testing was not provided and it was unclear whether statistical tests were prespecified or conducted post hoc for some outcomes. Statistical tests were not adjusted for multiple comparisons and should be interpreted in descriptive and exploratory fashion.

Critical Appraisal: External Validity

In more than half of patients (55%), caplacizumab was discontinued before 30 days post PE, which is not consistent with the product monograph. The clinical experts consulted by CADTH felt that early discontinuation of treatment could have contributed to worse outcomes in the caplacizumab cohort. In addition, the clinical experts noted that the baseline characteristics of the patients in the caplacizumab cohort reflected severe disease (e.g., cardiac and neurological involvement), which was also supported by intubation of approximately one-quarter of patients; the clinical experts felt it was possible that some patients in the cohort may have been candidates for upfront therapy with caplacizumab but instead received it 2 days or longer after PE initiation. According to the clinical experts consulted by CADTH for this review, upfront use of rituximab is not consistent with the current or expected use of either drug in Canadian clinical practice.

Discussion

Summary of Available Evidence

One phase III, prospective, long-term follow-up study (post-HERCULES, N = 104)^14,15 of patients who completed the HERCULES study (N = 145, n = 108 completed) contributed evidence to the systematic review section of this report. The objectives of post-HERCULES were to evaluate long-term safety and efficacy of caplacizumab, to evaluate the safety and efficacy of repeated use of caplacizumab in participants who experienced a recurrence of aTTP, and to characterize the long-term clinical impact of aTTP. Following the final 4-week follow-up visit in the HERCULES study, adult patients with aTTP were invited to enrol in the post-HERCULES study within 1 month and were then followed for a period of 3 years through twice-yearly visits. During the 3-year follow-up period, patients could receive OL caplacizumab in combination with PE and immunosuppression. Outcomes related to aTTP recurrence were assessed both as a composite outcome (aTTP-related events) and the individual components of this outcome (aTTP-related death, recurrence of aTTP, and major thromboembolic events).

Additionally, the phase III HERCULES^21-23 and phase II TITAN^24-26 trials, which were evaluated in the Clinical Review Report for the initial submission of caplacizumab, were also considered relevant for this review. Refer to the Clinical Review Report for the initial submission of caplacizumab¹³ for details, the executive summary of which is reproduced as Appendix 2.

One post hoc analysis, an integrated analysis of data from the HERCULES and TITAN trials, provided an additional evaluation of the previously assessed evidence regarding the clinically important outcomes of survival, health care use, organ damage, and refractory aTTP. Peyvandi et al. (2021)¹⁶ conducted an integrated analysis of data from the HERCULES and TITAN trials as suggested by the FDA. The goal was to increase statistical power for assessing treatment differences in efficacy and safety outcomes.

Finally, data for 2 RWE cohorts from France^17-19 and the UK²⁰ were summarized to provide additional evidence regarding the clinically important outcomes of survival, aTTP recurrence, refractory aTTP, and health care utilization and to provide additional evidence regarding the impacts of caplacizumab beyond the duration of clinical trials. The French RWE cohort of Coppo et al. (2021)¹⁸ prospectively analyzed outcome data for 90 patients with aTTP from France treated with a compassionate frontline triplet regimen consisting of PE, immunosuppression with corticosteroids and rituximab, and caplacizumab and compared them with 180 historical control patients treated with standard frontline therapy (PE plus corticosteroids, with rituximab as salvage therapy). ||||| ||| |||||| ||||||||||| ||||||||| || ||||||| |||||||||| || ||| |||| |||| |||| ||| ||||||| || ||||||| ||| |||||||||| ||||||| |||||||| |||||| ||| |||||||| |||||| ||| || ||||||||||| | |||||||||| ||||| ||| ||||||| |||||||| || || |||||||||| |||||| || |||||||||||| ||||||||| The UK RWE cohort of Dutt et al. (2021)²⁰ conducted a retrospective analysis of data from 85 patients with aTTP (including 4 children) who received caplacizumab in 22 UK hospitals from May 2018 to January 2020 and compared them with data from the HERCULES study and to a group of historical control patients consisting of 39 consecutive cases from the UK TTP registry who received standard treatment (PE plus immunosuppression with corticosteroids and rituximab).

Interpretation of Results

Efficacy

The final CDEC recommendation for the initial submission of caplacizumab¹² identified the following areas as having insufficient evidence regarding the efficacy and safety of caplacizumab: insufficient evidence of clinically important outcomes, lack of long-term clinical outcome data, lack of an identifiable subpopulation most likely to benefit from treatment, generalizability to Canadian clinical practice, and absence of HRQoL data. Interpretation of efficacy results in the following is organized for each of these points separately.

Insufficient Evidence of Clinically Important Outcomes

In its final recommendation for the initial submission of caplacizumab, CDEC noted that the HERCULES study was not designed to assess the effects of caplacizumab on the clinically important outcomes of survival, reduction in organ damage, health care use, or long-term recurrence of aTTP. Given caplacizumab’s mechanism of action, CDEC could not determine the clinical magnitude of the correlation between time to normalization of platelet count with the aforementioned clinical outcomes. While observational studies have documented correlations between longer times to platelet count response (using various thresholds) and poor outcomes such as mortality^52,53 at the time this report was prepared, there remained uncertainty that small differences in time to platelet normalization impacted risk of major thromboembolic events, organ damage, or mortality.

Of the clinically important outcomes identified by CDEC, the post-HERCULES study^14,15 was designed to assess long-term aTTP recurrence, and it did not directly address any of the other outcomes. More specifically, since the efficacy ITO population excluded patients who were randomized to receive SOC in the HERCULES study who switched to OL caplacizumab, the study assessed long-term aTTP recurrence among patients who received upfront caplacizumab; importantly, the study was not designed to inform the efficacy of caplacizumab in patients receiving the drug as salvage therapy for aTTP recurrence or refractory aTTP (refer to Interpretation of Harms section), which was suggested by the clinical experts consulted by CADTH for this review as a potential place in therapy for the drug. According to the clinical experts consulted by CADTH for the present resubmission, aTTP recurrence tends to occur within the first month of treatment as well as up to 2 years later. The clinical experts relayed that 1 of the challenges of using caplacizumab is that it directly increases platelets through its mechanism, potentially masking an indicator of aTTP disease activity, which would make it difficult to determine when it is time to taper PE. Thus, the clinical experts relayed that a valid concern regarding the HERCULES study was that with a relatively short 4-week follow-up period, additional recurrences in patients treated with caplacizumab occurring in the subsequent weeks and months might be missed. According to the clinical experts, the post-HERCULES study provided additional supportive evidence to address this concern: during its 3-year follow-up period among patients who completed the HERCULES study and had not experienced aTTP recurrence in the HERCULES study or before the beginning of post-HERCULES (efficacy ITO population), a descriptive comparison showed that the frequency of aTTP recurrence was numerically lower in patients randomized to receive caplacizumab in the HERCULES study (8.2%) compared to those randomized to receive SOC alone and who did not receive caplacizumab during the HERCULES trial (37.9%). Though interpretation of these results was limited by the descriptive nature of the comparison and potential for bias due to limitations in the study design, this evidence is not supportive of the concern that treatment with caplacizumab may result in increased relapses after 30 days post PE discontinuation and beyond the HERCULES trial duration. The clinical experts consulted by CADTH for the present resubmission stated that the mechanisms through which caplacizumab could potentially influence long-term aTTP relapse were unknown.

The post hoc integrated analysis of the HERCULES and TITAN study data by Peyvandi et al.¹⁶ provided an additional lens with which to view the results of the HERCULES and TITAN trials, including the clinically important outcomes of survival, health care use, organ damage, and refractory aTTP. This analysis provided no additional information on long-term aTTP recurrence. Consistent with both of the individual trials, the integrated analysis indicated that among patients randomized to receive caplacizumab compared to those randomized to receive placebo, mortality was numerically lower (blinded treatment periods: 0% versus 3.6%, respectively; overall study periods: 0.9% versus 4.5%, respectively), duration of PE was numerically shorter (median 5.0 days versus 7.5 days, respectively), the frequency of aTTP relapse was numerically higher (13.0% versus 0%, respectively), the frequency of aTTP-related events (TTP-related death, major thromboembolic events, or aTTP exacerbation) was numerically lower (13.0% versus 47.3%, respectively), and the frequency of refractory aTTP was numerically lower (0% versus 7.1%, respectively). In addition, caplacizumab was associated with numerically faster normalization of LDH, troponin, and serum creatinine. However, because of the lack of evaluation or justification for naive pooling of the data from 2 distinct trials as well as lack of formal statistical testing of prespecified hypotheses with adjustment for multiple comparisons, the results of the integrated analysis were unable to extend the conclusions regarding these outcomes drawn from the individual trials.

Two additional post hoc analyses were described in a poster and a conference abstract. Coppo et al. (2020)³⁹ conducted a post hoc subgroup analysis of the HERCULES study data by time to platelet count response and reported that caplacizumab was associated with numerically faster time to durable response, numerically longer time to complete remission and numerically longer recurrence-free survival. Scully et al. (2020)⁴⁰ described outcomes among 8 patients randomized to receive SOC in the HERCULES study who had suboptimal responses to PE; suboptimal response to PE occurred in no patients in the caplacizumab arm. However, these studies did not address an important gap in the evidence for the initial review of caplacizumab due to their limitations (hypothesis-generating only, unclear relevance of surrogate outcomes, described in limited detail in poster or abstract form) and thus data are described for reference only in Appendix 4.

Two RWE cohorts provided additional supportive evidence on survival, health care use, and refractory aTTP. These included a French RWE cohort of 90 patients receiving frontline caplacizumab therapy, PE, corticosteroids, and rituximab versus 180 or 216 historical controls, by Coppo et al. (2021)¹⁸ and CEMKA and Sanofi (2021),^17,19 respectively; and a UK RWE cohort of 85 patients receiving caplacizumab, PE, corticosteroids and rituximab versus 39 historical controls by Dutt et al. (2021).²⁰ These studies did not address organ damage or long-term recurrence of aTTP. In the French RWE cohort, mortality was numerically lower in patients who received caplacizumab compared with historical controls (1.1% versus 6.7%, Coppo et al. [2021]¹⁸ | |||| || ||||| CEMKA and Sanofi [2021]^17,19), while in the UK RWE cohort,²⁰ mortality was numerically higher in patients who received caplacizumab compared with historical controls (6% versus 0%). In both RWE cohorts, duration and volume of PE and duration of hospitalization were numerically shorter for patients receiving caplacizumab, although the magnitudes of the differences were smaller for the UK RWE cohort.²⁰ In the French RWE cohort, 1.1% of patients receiving caplacizumab experienced refractory aTTP compared with 10%^17,19 to 18%¹⁸ of historical controls; refractory aTTP was not compared between patients treated with caplacizumab and SOC in the UK RWE cohort. Except for the reanalysis of Sanofi and CEMKA (2021),^17,19 all comparisons were naive and did not take into account baseline differences between populations. None of the analyses accounted for measured and unmeasured confounders including nonoverlapping treatment time frames and differences in treatment, primarily use of rituximab, which was higher in the RWE cohorts. Due to limitations of this evidence related to risk of potential for bias and confounding and lack of formal statistical testing, no conclusions could be drawn that go beyond the HERCULES, post-HERCULES, and TITAN trial data.

Data for an additional German RWE cohort were published by Volker et al. (2020);^41-43 however, because there was no comparison of outcomes between patients treated with caplacizumab and SOC, the study did not address an important gap in the evidence for the initial review of caplacizumab. Similarly, 3 additional RWE studies described as conference abstracts were either noncomparative (Maanaoui et al.⁴⁵) and/or were not described in sufficient detail to enable rigorous evaluation of their conduct and reporting (Vataire et al. [2022]⁴⁶ and Volker et al. [2021]⁴⁷). Data for these studies are described for reference only in Appendix 4

Lack of Long-Term Clinical Outcome Data

In its final recommendation for the initial submission of caplacizumab, CDEC noted that the HERCULES and TITAN studies provided data on the effects of caplacizumab versus placebo for up to 2 aTTP episodes only. As such, CDEC could not determine caplacizumab’s benefit, if any, beyond the duration of the trials.

As explained previously, the 3-year follow-up period of the post-HERCULES study^14,15 provided additional relevant evidence beyond the duration of the HERCULES trial on long-term aTTP recurrence; the results were not supportive of the concern that treatment with caplacizumab may result in increased relapses after 30 days post PE discontinuation and beyond the HERCULES trial duration. The study was not designed to provide information on the effects of caplacizumab versus placebo for more than 2 aTTP episodes, as patients who had experienced aTTP recurrence in the HERCULES study or before the beginning of the post-HERCULES study were excluded from the post-HERCULES study efficacy ITO population. Only 6 patients in the efficacy ITO population in the post-HERCULES study experienced 2 or more recurrences during the study. The post-HERCULES study was not designed to provide conclusive long-term data on other outcomes of interest to CDEC (e.g., survival, health care utilization, organ damage, refractory aTTP, or prevention of further aTTP relapses beyond the second episode).

The 2 RWE cohorts described in this report were potentially able to provide additional supportive evidence on long-term recurrence of aTTP beyond the duration of the HERCULES trial. Median follow-up in the French^17-19 and UK²⁰ RWE cohorts was 4.2 months and 2.6 months, respectively. However, in the French RWE cohort only exacerbation (not long-term relapse) was compared between patients treated with caplacizumab and SOC, and the UK RWE cohort did not compare recurrence rates between patients treated with caplacizumab and SOC. Due to these reasons as well as the limitations noted previously, no conclusions regarding long-term outcomes could be drawn from the RWE that go beyond the HERCULES, post-HERCULES, and TITAN trial data.

Data for an additional German RWE cohort were published by Volker et al. (2020)^41-43 were considered not to address an important gap in the evidence for the reasons noted previously. Similarly, 1 additional RWE study described as a conference abstract (Jimenez et al. [2020]⁴⁴) was not described in sufficient detail to enable rigorous evaluation of its conduct and reporting. Data for these studies are described for reference only in Appendix 4.

Lack of an Identifiable Subpopulation Most Likely to Benefit

In its final recommendation for the initial submission of caplacizumab, CDEC noted that variability in the natural history of aTTP and the limitations in the design and analysis of the HERCULES study prevented CDEC from identifying a subpopulation of patients with aTTP most likely to benefit from treatment with caplacizumab. Post hoc analyses of data from the HERCULES study stratified by disease severity³⁸ and time to platelet count response³⁹ revealed no signals that the impacts of caplacizumab on the occurrence of aTTP-related events in patients varied by subgroup within the HERCULES study (refer to Appendix 4). This result was consistent with the hypothesis, which remains to be tested, that the impact of caplacizumab on the occurrence of aTTP-related events in patients is similar regardless of baseline disease severity or time to platelet count response.

In addition, in the French RWE cohort of Coppo et al. (2021)¹⁸ patients were stratified by baseline French severity score (≤ 2 versus ≥ 3) and the results of the primary analysis were similar in both subgroups. The CADTH review team noted that results from post hoc analyses are considered exploratory and hypotheses generating only. Due to the lack of formal inferential statistical testing, the ability to interpret results of such analyses is significantly limited.

Generalizability to Canadian Clinical Practice

In its final recommendation for the initial submission of caplacizumab, CDEC noted that the percentage of patients who received rituximab in the HERCULES study (40%) was higher than what is expected in Canada and that it is thus unclear if the observed effects of caplacizumab in the trial would be observed in Canadian practice. Post hoc analyses of data from the HERCULES³⁶ and post-HERCULES³⁷ studies stratified by rituximab use (Appendix 4) revealed no signals that the impacts of caplacizumab on occurrence of aTTP-related events in patients varied by subgroup, both within the HERCULES study, and for patients who participated in the post-HERCULES study, for up to 3 years thereafter. The clinical experts consulted by CADTH for this review noted that the proportion of patients living in Canada with aTTP who receive upfront rituximab therapy in addition to PE and corticosteroids is not known with certainty but is likely lower than in the post-HERCULES trial. However, the proportion in clinical practice has increased in recent years due to improved access to rituximab.

The CADTH review team noted that results from post hoc analyses are considered exploratory and hypotheses generating only. Due to the lack of formal inferential statistical testing, the ability to interpret results of such analyses is significantly limited.

Absence of HRQoL Data

In the rationale for its final recommendation on the initial submission of caplacizumab, CDEC made no comments on HRQoL data in the rationale or discussion sections; however, the absence of HRQoL data was noted in the “Summary of evidence considered by CDEC” section of the final recommendation.¹² HRQoL data were collected using 2 instruments (HIT-6 and SF-36) in the post-HERCULES study.^14,15 However, due to variable rates of missing data, lack of formal statistical testing, potential for bias in patient-reported outcomes in an OL study, and uncertainty in the measurement properties of these instruments in patients for aTTP, changes in HRQoL over time and between the arms of the post-HERCULES study efficacy ITO population could not be interpreted.

Harms

Analysis of safety data from the post-HERCULES study,^14,15 a post hoc integrated analysis of the HERCULES and TITAN study data,¹⁶ and data from RWE cohorts^17-20 suggested that the harms profile of caplacizumab is consistent with that observed in the HERCULES and TITAN trials. The post-HERCULES study provided long-term safety data for up to 3 years in 104 patients who participated in the HERCULES trial. No new safety signals were identified. Bleeding AEs were the most common manifestations of caplacizumab treatment. Although 5 patients (5.9%) in the RWE cohort of Dutt et al.²⁰ experienced venous thromboembolism, the clinical experts consulted by CADTH for this review relayed that this was due to the severe disease and poor outcomes of this cohort.

In the post-HERCULES study, harms were evaluated in the overall ITO population (N = 104) while efficacy outcomes were evaluated in the efficacy ITO population (n = 78). All patients who were part of the overall ITO population but excluded from the efficacy ITO population (n = 26) had prior caplacizumab experience in the HERCULES study; the majority (20 of 26; 77%) were randomized to receive double-blind placebo therapy in the HERCULES study and then switched to OL caplacizumab. Comparing the data in Table 14 (in the efficacy ITO population, 4 of 49 patients randomized to receive caplacizumab in the HERCULES study experienced aTTP recurrence in post-HERCULES) and Table 21 (in the overall ITO population, 11 of 75 patients treated with caplacizumab in the HERCULES study experienced aTTP recurrence in the post-HERCULES study) indicated that 7 of 26 patients (27%) who were part of the overall ITO population but excluded from the efficacy ITO population experienced aTTP recurrence during the post-HERCULES study.

Conclusions

Evidence from the HERCULES study suggested that administration of caplacizumab resulted in a statistically significant decrease in the frequency of aTTP recurrence during the HERCULES study period. In the long term follow-up study of the HERCULES study (the post-HERCULES study), there were no signs that treatment with caplacizumab during the HERCULES study resulted in increased frequency of aTTP relapse post PE discontinuation beyond the follow-up period of the HERCULES trial. A post hoc integrated analysis of data from the HERCULES and TITAN trials provided an additional evaluation of survival, health care use, organ damage, and refractory aTTP; however, due to naive pooling of the data and lack of formal statistical testing of prespecified hypotheses, including adjustment for multiple comparisons, its results supported but were unable to extend the conclusions regarding these outcomes drawn from the individual trials. Two RWE cohorts from France and the UK provided additional supportive evidence regarding the frequency of aTTP-related events, including mortality in patients receiving caplacizumab; however, due to potential for biased patient selection in observational studies, intergroup differences in measured and/or unmeasured confounders including treatments received that could not be accounted for, and absence of formal statistical testing, no conclusions could be drawn that go beyond the HERCULES, post-HERCULES, and TITAN trial data. The combined data from the HERCULES and post-HERCULES studies suggested that caplacizumab may decrease overall aTTP recurrence during treatment and immediately following treatment cessation (HERCULES) without producing an increased frequency of long-term aTTP relapse in the subsequent months and years (post-HERCULES).

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