CADTH Reimbursement Review

Maribavir (Livtencity)

Sponsor: Takeda Canada Inc.

Therapeutic area: Post-transplant cytomegalovirus infection

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

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

Introduction

Cytomegalovirus (CMV) infection may occur in post-transplant patients for a variety of factors — including due to the immunosuppression required for transplantation procedures and when transplant donors’ or recipients’ serostatus is positive depending on the type of transplant (HSCT/SOT). CMV infection may be asymptomatic and only detectable by viral replication; however, when symptoms are present (i.e., in the case of CMV infection manifesting into CMV disease or CMV syndrome) patients may experience fever, low white blood cell counts (leukopenia), muscle weakness, fatigue, shortness of breath, blurry vision or loss of vision and abdominal pain, blood in stools, nausea, vomiting or diarrhea.¹ The possible complications of CMV in transplant patients include transplant failure, liver and digestive disease (i.e., hepatitis or colitis) and infections in different organs (i.e., pneumonia, pancreatitis, meningitis, myocarditis) or the blood (i.e., bacteremia).¹ Although national data for CMV infections in solid organ transplant (SOT) and hematopoietic stem-cell transplant (HSCT) patients in Canada is limited, adult CMV seroprevalence of organ donors in Canada is estimated to be approximately 53%.²

Current approaches for the management of post-transplant CMV infection can be categorized into 3 groups: primary prophylaxis (involves the administration of antiviral drugs to prevent primary infection in patients at increased risk), secondary prophylaxis or maintenance (involves the administration of prophylactic doses of antiviral drugs to prevent CMV infection following primary infection), and pre-emptive therapy involves initiation of antiviral therapy based on serial screening with a sensitive polymerase chain reaction (PCR) assay in attempt to detect early infection mitigating the occurrence of CMV disease.³ Managing post-transplant CMV infection either through prophylaxis or for treatment rely on therapies such as foscarnet, valganciclovir, ganciclovir, letermovir, and cidofovir. However, treatment with these therapies is prone to resistance, toxicity, and hospitalization.

Patients who are refractory or resistant to 1 or more lines of antivirals have limited treatment options that typically require hospitalization for administration. The toxic side effects of some existing therapies also present challenges. For example, foscarnet has considerable nephrotoxicity and can interfere with the ability to deliver other important drugs, such as immune suppressors. Similarly, ganciclovir and/or valganciclovir may result in cytopenia that predisposes patients to graft failure and infection and also interferes with ability to deliver other important drugs. When patients are resistant to ganciclovir, foscarnet may be an option; however, when patients are resistant to both ganciclovir and foscarnet, clinical experts described subsequent therapies as limited.

Maribavir (Livtencity) is an oral tablet with a Health Canada indication for treatment of adults with post-transplant CMV infection or disease who are refractory (with or without genotypic resistance) to 1 or more prior antiviral therapies. The recommended dose is 400 mg (2 tablets of 200 mg) twice daily, resulting in a daily dose of 800 mg. Maribavir received Notice of Compliance (NOC) on September 15, 2022.

The objective of this review is to perform a systematic review of the beneficial and harmful effects of maribavir for the treatment of adults with post-transplant CMV infection or disease who are refractory (with or without genotypic resistance) to 1 or more prior antiviral therapies.

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 expert(s) consulted by CADTH for the purpose of this review.

Patient Input

A total of 9 patient advocacy groups provided input on maribavir for the treatment of adults with post-transplant CMV infection or disease who are refractory and/or resistant to 1 or more prior antiviral therapies. The groups conducted a total of 3 surveys to capture input. The patients were predominantly those with myeloma and/or auto HSCT, noted by clinical experts to be a group for which CMV infection is not a concern, rather than patients who are allogenic-HSCT recipients at risk for CMV infection. Patients reported on the negative impact of staying in the hospital and away from home for weeks to months for treatment. CMV infection also affected patients’ ability to work and perform in school, mental health (i.e., stress and anxiety), ability to care for and spend time with families and friends, sexual life (i.e., intimacy concerns due to spreading CMV to their partners), and finances. Patients value effective medications with fewer side effects (i.e., taste disturbance, nausea, or vomiting, feeling weak or tired, urinary changes), no contraindications and interactions with immunosuppressants, that are simple to administer and covered by the drug plans. Patients also value an improvement to their quality of life, relieving CMV infection, eliminating overnight stays at a hospital, and reducing the severity of side effects (most commonly anxiety, weight loss, pain in the back, joints, or muscles, and diarrhea) caused by currently available treatments.

Clinician Input

Input From Clinical Experts Consulted by CADTH

The clinical experts identified that based on the limitations of existing therapies, the goals of anti-CMV treatment are to control the virus and its symptoms until a patient’s immune system is strong enough to fight the virus rather than eradicating it. As such, the goals of existing treatments are to improve symptoms (if the patient has end-organ disease), reduce mortality, improve graft function and/or reduce graft loss, minimize adverse effects, and improve quality of life.

The clinical experts indicated that challenges with existing treatments include high rates of hospitalizations for treatment administration and toxic side effects. The clinical experts also described concerns around patients becoming resistant to current treatment options, though they likely expect patients using maribavir to develop resistance as well. Clinical experts stressed the importance of treating patients with the least toxic and most effective drug early, citing that some of the outcomes from delayed treatment are irreversible (e.g., if graft loss due to ganciclovir or valganciclovir causing myelosuppression that cannot be reversed).

According to the clinical experts, resistance and refractory definitions are important to identify patients most suitable for treatment with maribavir. Patients most likely to respond to maribavir include those who have intolerances or life-threatening side effects to other drugs, those who can have their immunosuppression reduced and/or those that can have their immune function improve.

In routine clinical practice, the clinical experts indicated that anti-CMV treatment is given until CMV is either negative or low level; however, the definition of low level is unclear and treatment duration must be individualized based on multiple patient characteristics, for example, graft-versus-host disease (GVHD) or toxicity.

Per the clinical experts, complete response to maribavir would be defined as resolution of symptoms of end-organ disease and eradication of CMV viremia.

Clinician Group Input

The input provided by clinician groups generally aligned with the input provided by the clinical experts consulted by CADTH. Cell Therapy Transplant Canada (CTTC) submitted input. Pertaining to the patient population, the clinician group added that patients post-transplant often struggle with a lack of appetite and/or poor oral intake, therefore, the patients with difficulties of eating might be less suitable for maribavir, which is associated with dysgeusia but emphasized that toxicity profile of conventional salvage therapies is much more concerning. Furthermore, the clinician group emphasized that it is particularly challenging to treat CMV infection in patients with GVHD since GVHD therapies are immunosuppressive (i.e., increase the risk of CMV infection), myelosuppressive, and nephrotoxic (i.e., exacerbate the toxicities caused by valganciclovir or foscarnet, respectively).

Drug Program Input

Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a CADTH recommendation for maribavir:

• considerations for initiation of therapy

• considerations for discontinuation of therapy

• considerations for prescribing of therapy

• care provision issues

• system and economic issues.

The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.

Clinical Evidence

Pivotal Studies and Protocol Selected Studies

Description of Studies

One open-label randomized (2:1), double-arm phase III trial (SOLSTICE, N = 352) was included in the CADTH systematic review. The primary objective of the SOLSTICE study was to compare the efficacy and safety of maribavir versus IAT for treatment of refractory CMV infection (with or without resistance) in SOT and HSCT recipients. The trial included adult patients with documented CMV infection that is refractory to the most recent treatment or resistant to it (only if patients also met refractory criteria). Patients received 400 mg oral maribavir twice daily or another IAT (foscarnet, ganciclovir, valganciclovir, or cidofovir) for up to 8 weeks. The primary end point was confirmed CMV viremia clearance at the end of week 8 (regardless of premature treatment discontinuation). The key secondary end point was a composite of confirmed CMV viremia clearance and symptom control at the end of week 8, maintained through week 16 (8 weeks beyond the treatment phase) after receiving exclusively study-assigned treatment. Other secondary end points included recurrence, all-cause mortality, resistance to maribavir or IAT, health care resource utilization, and health-related quality of life (HRQoL). Harms outcomes were also examined. In the SOLSTICE study, both treatment groups were generally balanced but notable differences were observed in characteristics such as age, type of preparative conditioning regimen, presence of CMV RASs, and CMV serostatus for HSCT Donor/Recipient, CMV DNA level, and net immunosuppression use changed before initiation of study treatment.

The mean age of enrolled patients was 53.0 years (SD: 13.22 years). Most patients were White (75.6%) and male (60.5%). Most patients underwent a SOT (59.9%), with the kidney (50.2% of SOT patients), lung (29.4% of SOT patients), and heart (10.9% of SOT patients) being the most transplanted solid organs. Patients who underwent HSCT predominantly underwent allogenic transplant procedures (99.3%). Most patients who underwent SOT and HSCT had functioning graft status (89.1% and 85.1%, respectively). Most patients did not have confirmed acute or chronic GVHD, 91.2% and 96.9%, respectively, and did not use antilymphocyte treatment (57.7%). Majority of patients had some renal impairment (32.1% with mild and 23.3% with moderate), but no hepatic impairment (92.3%).

Efficacy Results

Results for the key efficacy outcomes in the SOLSTICE study are summarized in Table 2.

CMV Viremia Clearance

The primary end point was confirmed CMV viremia clearance at the end of week 8 (regardless of premature treatment discontinuation) as measured by CMV DNA levels. The adjusted difference in proportion of responders between maribavir and IAT was 32.8% (95% CI, 22.80% to 42.74%; P < 0.001), in favour of maribavir.

The key secondary end point was a composite of confirmed CMV viremia clearance and symptom control at the end of week 8, maintained through week 16. The adjusted difference in proportion of responders between maribavir and IAT is 9.5% (95% CI, 2.02% to 16.88%; P = 0.013), in favour of maribavir.

Time to CMV Viremia Clearance

The median observed time to CMV viremia clearance was 17.0 days (minimum: 5.0 days, maximum: 114.0 days) in the maribavir group and 20.0 days (minimum: 6.0 days, maximum: 111.0 days) in the IAT group. The Kaplan–Meier estimate for median days to CMV viremia clearance was 22.0 days (95% CI, 21.0 to 23.0 days) for the maribavir group and 29.0 days (95% CI, 22.0 days to 35.0 days) for the IAT group.

Recurrence

Of patients who responded to treatment, 33 (17.9%) in the maribavir group and 8 (12.3%) in the IAT group had CMV viremia recurrence during the first 8 weeks of the study. Comparative recurrence data cannot be interpreted because clearance is a prerequisite for recurrence.

All-Cause Mortality

The number of patients who died in the maribavir group was 27 (11.5%) and 13 (11.1%) in the IAT group. The median observed event time for those that died was 55.0 days (minimum: 3.0 days, maximum:182.0 days) in the maribavir group and 73.0 days (minimum: 13.0 days, maximum: 186.0 days) in the IAT group. The hazard ratio was 1.14 (95% CI, 0.549 to 2.357). Conclusions for all-cause mortality could not be drawn because the 95% confidence interval around the hazard ratio was wide, including the possibility of both appreciable benefit and harm for maribavir compared with IAT.

Resistance to Maribavir

In the maribavir group, 42 (19.6%) patients had new maribavir treatment-emergent known resistance-associated amino acid substitution (RASs) in pUL97 or pUL27. Of the patients in the maribavir group, 12.9% had new treatment-emergent RASs known to confer resistance to IAT detected in their genotype and 4.9% of patients in the IAT group had new treatment-emergent RASs known to confer resistance to IAT detected in their genotype.

Health Care Resource Utilization

The adjusted difference in rates ratio of hospital admissions between the maribavir and IAT groups during the on-treatment phase was 0.65 (95% CI, 0.45 to 0.94), favouring maribavir. The adjusted difference IRR of length of stay between the maribavir and IAT groups during the on-treatment phase was 0.46 (95% CI, 0.23 to 0.92), favouring maribavir.

HRQoL

Although HRQoL data were collected, it was only reported descriptively. Generally, patients reported an improvement in the HRQoL scores (i.e., EQ-5D utility score, SF-36) over time and across both treatment groups. No definitive conclusions can be made between the treatment groups due to a lack of statistical testing and missing data.

Harms Results

Overall, 228 (97.4%) patients in the maribavir group and 106 (91.4%) patients in the IAT group experienced at least 1 treatment-emergent adverse event (AE). Ninety (38.5%) patients in the maribavir group and 43 (37.1%) in the IAT group experienced at least 1 severe AE (SAE). Thirty-one (13.2%) patients in the maribavir group and 37 (31.9%) in the IAT group permanently discontinued treatment with study drugs due to AEs.

Table 2: Summary of Key Results from SOLSTICE

AE = adverse event; CMV = cytomegalovirus; CI = confidence interval; GVHD = graft-vs.-host disease; IAT = investigator-assigned anti-CMV treatment; LOS = length of stay; MRS = maribavir-resistance set; NE = not estimable; PRS = primary resistance set; RASs = resistance-associated amino acid substitution; SAE = severe adverse event; SD = standard deviation; WDAE = withdrawal due to adverse event.

^aSpecify model, covariates, analysis population and time point for each outcome. Includes maribavir RASs with cross-resistance to IAT.

^bP value has not been adjusted for multiple testing.

SOLSTICE Clinical Study Report⁴

Critical Appraisal

There are limited concerns for internal validity. SOLSTICE was an open-label study. Stratified randomization was conducted using interactive response technology (IRT), suggesting allocation concealment. For the primary end point and multiple secondary end points, a central lab and an End point Adjudication Committee (EAC) was appropriately used to reduce the risk of detection bias. The study population in SOLSTICE study was adequately defined and the clinical experts consulted by CADTH indicated the eligibility criteria were overall appropriate. Both treatment groups were relatively balanced, with some notable differences in characteristics such as age, type of preparative conditioning regimen, presence of CMV RASs, and CMV serostatus for HSCT Donor/Recipient, CMV DNA level, and net immunosuppression use changed before initiation of study treatment. The analysis populations used in the SOLSTICE trial were appropriate for measuring the effect of the assignment to the interventions and all analyses were pre-specified. The comparators used were identified by the clinical experts as appropriate. Statistical testing was performed for the primary and key secondary outcome. However, the open-label design can increase the risk of performance and detection bias, particularly for outcomes that are subjective in measurement and interpretation (e.g., CMV symptom controls, subjective AEs). There were some outcomes in the study for which results may be biased due missing outcome data, notably, HRQoL.

There are some implications of the trial on external validity. One stark difference between how the treatment was administered in SOLSTICE and what would be expected in routine clinical practice was the 8-week fixed duration. As identified by the clinical experts consulted by CADTH for this review, clinicians treat patients until CMV DNA levels are low enough or negative, not for a fixed duration. The clinical experts indicated that the baseline characteristics of patients enrolled in SOLSTICE were generally representative of the post-transplant CMV patient population in Canada, although they noted that the SOLSTICE study patients would represent the most fit patients in this population, which is common in clinical trials. Furthermore, the clinical experts noted that although the comparators (i.e., IAT) used are reflective of routine clinical practice, the distribution of each IAT in SOLSTICE is not reflective of Canadian clinical practice. It may be difficult to design a trial with IAT distributions that reflect the diversity of Canadian clinical practice. As a result, generalizability of results to the Canadian setting is uncertain. Moreover, conclusions on comparative efficacy for each antiviral cannot be drawn.

Indirect Comparisons

No indirect treatment comparisons were appraised for this review.

Other Relevant Evidence

The sponsor provided a series of additional exploratory analyses of individual patient data (IPD) from SOLSTICE. The results of the IPD analyses were used as direct inputs into the base case and scenarios of the cost-effectiveness model. Details are presented in Appendix 5.

Conclusions

One open-label, randomized, double-arm phase III trial (SOLSTICE, N = 352) was included in the CADTH systematic review. The primary objective of the SOLSTICE study was to compare the efficacy and safety of maribavir versus IAT for treatment of refractory CMV infection (with or without resistance) in SOT and HSCT recipients. There is evidence of maribavir being more efficacious when compared to the IAT on achieving CMV viremia clearance and symptom control. However, disease control with maribavir is time-limited, in line with other antivirals. Conclusions for all-cause mortality could not be drawn because the 95% confidence interval around the hazard ratio was wide, including the possibility of both appreciable benefit and harm for maribavir compared with IAT. The proportion of patients experiencing taste disturbance, increased immunosuppressant concentration levels, and infections and infestations was higher with maribavir, but these events were manageable. The lower rates of hematologic and renal toxicities with maribavir fill a gap in the treatment landscape whereby other drugs have known toxicities limiting their use. Fewer patients in the maribavir group discontinued treatment due to AEs. There remains uncertainty on interpreting data for outcomes related to CMV recurrence, antiviral resistance, HRQoL, health care resource utilization, and subgroup analyses given the various methodological limitations.

Introduction

Disease Background

Transplantation is used as a therapy across many conditions, often with curative intent. SOT procedures using donor-provided solid organs such as hearts, kidneys, and lungs involves specialized surgery to treat end-organ dysfunction. HSCT procedures using donor-provided (allogeneic) hematopoietic stem cells involves IV infusion of stem cells to re-establish hematopoietic function and can be a potentially curative therapy for malignancies, severe aplastic anemia, and rare inborn errors of metabolism or primary immunodeficiencies.^5-11

Patients having undergone any type of transplantation are at risk of developing life-threatening infections. Despite good donor-to-recipient matching, HSCT patients typically still require immunosuppressive medications to mitigate GVHD and reduce the risk of transplant rejection.^6,12 The immunosuppression associated with transplantation also commonly allows micro-organisms to cause infection more easily, even those with limited pathogenicity.^6,12 Important viruses to consider in transplant recipients include CMV which is a beta-herpes virus that remains dormant in the human body after primary infection for life. Although benign in patients with adequate immune function (patients remain asymptomatic despite CMV infection), patients with already compromised immune systems, immune suppression in preparation for transplantation, and post-transplant maintenance immunosuppression, are at significantly increased risk of CMV infection, which can manifest into clinical complications, including CMV disease.^13,14

CMV infection may be asymptomatic and characterized by viral replication; however, CMV disease is likely to be symptomatic.¹ CMV disease is characterized by symptoms such as fever, malaise, leukopenia, thrombocytopenia, and elevated liver enzymes.¹ The possible complications of CMV in transplant patients include transplant failure, liver, and digestive disease (i.e., hepatitis or colitis) and infections in different organs (i.e., pneumonia, pancreatitis, meningitis, myocarditis) or the blood (i.e., bacteremia).¹

Generally, risk factors for CMV infection after transplantation include CMV seropositivity of the transplant (i.e., seropositive donor and/or recipient), immune status and degree of immunosuppression, transplant type and organ type, advanced age, HLA-mismatch, acute rejection, and GVHD.¹ However, the most important risk factor post-HSCT is CMV seropositivity of the transplant recipient.^15-18 In post-SOT patients, the clinical experts consulted by CADTH indicated that the most important risk factor is mismatch CMV serostatus between the donor and recipient, precisely Donor+/Recipient-. Due to the impaired cellular immunity as a result of the induction and conditioning regimen, viral reactivation is the dominant mechanism of infection in HSCT patients. Furthermore, patients with a history of CMV disease (e.g., pneumonitis, gastrointestinal disease, and retinitis) 6 months before HSCT, which is reported to be rare by the clinical experts consulted by CADTH, are at a very high risk for infection and death.^17,19

Definitions of common CMV infection and disease terms can be found in Table 3.

Table 3: Definitions of CMV Infection and Disease in Transplant Patients

CMV = cytomegalovirus; dGTP = deoxyguanosine triphosphate; HSCT = hematopoietic stem-cell transplant; NAT = nucleic acid test; PBL = peripheral blood leukocyte; RNA = ribonucleic acid; WBC = white blood cell.

Source: Ljungman et al., 2017²¹

Disease Prevalence and Incidence

The number of patients undergoing transplants in Canada has been rising over the past decades. The Canadian Institute for Health Information reported that the number of SOT procedures in Canada (excluding Quebec) increased from 1,036 in 2011 to 2,594 in 2020, where kidneys, livers, lungs, and hearts were the most transplanted organs (e.g., 1,459 kidneys were transplanted in 2020).²² Similarly, the Canadian Institute for Health Information reported that the number of autologous and allogeneic HSCT procedures in Canada increased steadily from 1,236 in 2010 to 1,605 in 2014.^22,23 Globally, approximately 47% of HSCTs were allogeneic HSCTs.

National data for CMV infections in SOT and HSCT patients are limited. Adult CMV seroprevalence of organ donors in Canada is estimated to be approximately 53%.² Per the sponsor’s submission, a sponsor-led systematic review of European and US studies found that CMV infection may occur in approximately 34% (ranging from 16% to 73%), and CMV disease occurs in approximately 8% (ranging from 3% to 16%), of SOT recipients.²⁴ The Center for International Blood and Marrow Transplant Research reported that among the 9,469 allogeneic HSCTs performed between 2003 and 2010 (including sites in Canada), approximately 62% were performed in CMV-seropositive recipients (i.e., considered at high risk for CMV infection).^{15,18,23,25-27} Per the sponsor-led systematic review, CMV infection occurs in approximately 48% (ranging from 17% to 82%), and CMV disease occurs in about 7% (ranging from 2% to 18%), of HSCT patients.

Despite the limited data on refractory and resistant CMV infections in the Canadian context, the sponsor-submitted systematic review found that between 19% and 21% of SOT and 9% and 47% of HSCT patients experienced refractory CMV infection in Europe and the US.²⁴ The majority of studies (4 studies) identified in the sponsor’s systematic review reported resistant CMV infection in 1% to 8% of SOT recipients, with 1 study from the Netherlands reporting that as many as 37% of SOT recipients had mutations conferring CMV resistance.²⁴ In HSCT patients, 2% to 3% had resistant infection.²⁴ Furthermore, a single-centre analysis of 735 lung transplant patients in Canada reported the incidence of drug-resistant CMV to be 1.98% in Donor+ and/or Recipient+ CMV patients and 4.7% in Donor+/Recipient- patients.²⁸

Standards of Therapy

Current approaches for the management of CMV infection can be categorized into 3 groups: primary prophylaxis (involves the administration of antiviral drugs to prevent primary infection in patients at increased risk), secondary prophylaxis or maintenance (involves the administration of prophylactic doses of antiviral drugs to prevent CMV infection following primary infection) and pre-emptive therapy (involves initiation of antiviral therapy based on serial screening with a sensitive PCR assay in attempt to detect early infection and prevent the occurrence of CMV disease).³ According to the clinical experts consulted by CADTH, existing therapies do not eradicate CMV and therefore, the treatment goals are to improve symptoms (if end-organ CMV disease), reduce mortality, improve graft function and/or reduce graft loss, minimize adverse effects, and improve patients’ quality of life.

The most widely used antivirals for first-line pre-emptive therapy are IV ganciclovir, valganciclovir (oral prodrug of ganciclovir), and foscarnet. For post-HSCT patients, either IV ganciclovir or foscarnet may be used in the first-line setting.²⁹ Generally, monitoring for CMV infection in a pre-emptive therapy setting using PCR should be performed weekly in CMV-seropositive recipients of an HSCT, until at least 100 days post-transplant.⁹ In post-SOT patients, valganciclovir or IV ganciclovir would be used for pre-emptive therapy. Oral valganciclovir is also used as a first-line therapy in non–severe CMV disease.³⁰ Testing is often performed once a week, where 2 consecutive negative samples (1 week apart) would indicate clearance.³¹

In patients at higher risk of CMV infection (e.g., recipients of a transplant from CMV-seropositive donors who received T-cell-depleted allografts, HLA-mismatched allograft, an umbilical cord blood graft or those who are significantly immunosuppressed), PCR monitoring can be performed twice weekly to ensure timely treatment.³²

Before approval of maribavir, no treatments were approved by Health Canada for patients with refractory or resistant CMV. Patients who are refractory to valganciclovir can be treated with high-dose IV ganciclovir and/or foscarnet; however, foscarnet is associated with considerable nephrotoxicity.³² If patients who are non–responsive to valganciclovir demonstrate life-threatening CMV disease, the clinical experts suggest that the typical subsequent treatment would be foscarnet. In the instance that patients who are non–responsive to valganciclovir have non–life-threatening disease, subsequent treatment would be high-dose IV ganciclovir. In either scenario, clinical experts described often considering maribavir if the patient meets the Health Canada criteria for Special Access. Additionally, the experts identified CMV immunoglobulin (Cytogam) as also used in SOT patients as an adjunctive drug. IV immunoglobulin G (IVIgG) is also used for replacement therapy in HSCT patients who have both low IgG, and infection in general (not only CMV, but also other bacterial and fungal infections), and is administered monthly until the IgG recovers.

Given that all currently available antivirals are DNA polymerase inhibitors, resistance to ganciclovir and valganciclovir can occur from mutations in the UL97 subunit protein, while mutations in UL54 can confer multi-drug resistance affecting foscarnet and cidofovir.^33,34 According to the clinical experts consulted by CADTH, treating post-SOT patients with treatment-resistant CMV infection on valganciclovir would consist of reducing immunosuppression if possible. The clinical experts maintain that when reducing immunosuppression is not possible, they may switch to immunosuppressive drugs with better antiviral effect, for example, mammalian target of rapamycin (mTOR) inhibitors. In post-HSCT patients, the clinical experts indicated that it is more difficult to reduce immunosuppression due to patients often having GVHD.

When patients have multi-drug resistance (e.g., ganciclovir and/or valganciclovir and foscarnet), the clinical experts described subsequent therapy options to be limited. If the patient has multi-drug resistance or resistance and life-threatening intolerances to alternative drugs (ganciclovir and foscarnet), maribavir was accessed through Health Canada’s Special Access Program before regulatory approval. However, if maribavir was not available, combination therapy with ganciclovir and foscarnet was used. Cidofovir, another antiviral is typically considered a third-line drug and is associated with both myelotoxicity and nephrotoxicity.³² The clinical experts further noted that cidofovir has ocular toxicity and does not work well in clinical practice. Both foscarnet and cidofovir are available in Canada. Clinical experts also indicated using leflunomide in these scenarios, although to limited success. As per the clinical experts consulted for this review, there are also a growing number of discussions about whether letermovir would be an option although access to this for treatment (i.e., off-label indication) is limited and there is uncertainty about the dosing and benefit due to only case series and case report-level data being available. Viral specific T-cells are in the experimental phase across Canada.

Drug

Maribavir (Livtencity) is an oral tablet with a Health Canada indication for the treatment of adults with post-transplant CMV infection or disease who are refractory (with or without genotypic resistance) to 1 or more prior antiviral therapies. The recommended dose is 400 mg (2 tablets of 200 mg) twice daily, resulting in a daily dose of 800 mg. The sponsor is seeking reimbursement in accordance with the Health Canada indication. Maribavir has not previously been reviewed by CADTH for any indication.

Maribavir was approved by the FDA in November 2021 and is under review at the EMA.^35,36 The FDA indication is for the treatment of adults and pediatric patients 12 years of age and older and weighing at least 35 kg with post-transplant CMV infection or disease that is refractory to treatment (with or without genotypic resistance) with ganciclovir, valganciclovir, cidofovir, or foscarnet.³⁷ Maribavir does not appear to be under review at the Australian Therapeutic Goods Administration.³⁸

Maribavir’s mechanism of action is through the inhibition of the UL97 protein kinase and the phosphorylation of its natural substrates. The drug under review exerts its effect by attaching to the UL97 encoded kinase at the adenosine triphosphate binding site, abolishing phosphorylation needed in processes including DNA replication, encapsidation, and the egress of viral capsules from the nuclei of infected cells.^39-42 Key characteristics of maribavir and relevant comparator antiviral therapies are described in Table 4.

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups.

A total of 9 patient advocacy groups provided input on maribavir for the treatment of adults with post-transplant CMV infection or disease who are refractory and/or resistant to 1 or more prior antiviral therapies. Groups included the Kidney Foundation of Canada (KF), the Canadian Liver Foundation (CLF), Leukemia and Lymphoma Society of Canada, Myeloma Canada, Aplastic Anemia and Myelodysplasia Association of Canada, Lymphoma Canada, Myeloproliferative Neoplasm Canadian Research Foundation, Canadian Myeloproliferative Neoplasm Network, Canadian Chronic Myelogenous Leukemia Network, and Chronic Lymphocytic Leukemia Canada. These organizations are involved in advocacy and empowerment activities such as education, funding research, dissemination of information, and increasing awareness of diseases to support patients, their families and caregivers.

The groups designed and administered a total of 3 surveys to capture input. The KF survey, which was a self-administered questionnaire and distributed through KF social media channels, website, and e-newsletter between February and March 2022, had 9 respondents (8 kidney transplant recipients, 1 donor; unspecified number of patients with post-transplant CMV) from across Canada. The CLF survey, an online survey which was promoted on the organization’s website and social media channels from February 22 to March 25, 2022, was completed by 2 health professionals from Ontario and Alberta. The 7 blood cancer organizations co-administered a survey with multiple choice, open-ended and rating questions, which was distributed through social media networks and e-mail between February 1 and March 14, 2022, in English and French. One hundred respondents (97 from Canada, 3 from the UK and Belgium) completed the survey. Out of 100 responders, 93 received a HSCT, and 13 had a post-transplant CMV.

Patients described the impact of CMV and its treatment on their quality of life. One patient with a kidney transplant reported that their CMV got better after 8-week IV antiviral therapy; however, experienced relapse 3 weeks after viremia clearance. Patients reported that they had to stay in hospital away from home for weeks to months for treatment, and CMV infection affected their ability to work and perform in school, their mental health (i.e., stress and anxiety), their ability to care for and spend time with families and friends, their sexual life (i.e., intimacy concerns due to spreading CMV to their partners), and their finances.

Patients described their expectations for new CMV treatments. Patients value effective medications with fewer side effects (i.e., taste disturbance, nausea, or vomiting, feeling weak or tired, urinary changes), no contraindications and interactions with immunosuppressants, that are simple to administer and covered by the drug plans. Patients with blood cancer value an improvement to their quality of life, relieving CMV infection, eliminating overnight stays at a hospital, and reducing the severity of side effects (most commonly anxiety, weight loss, back/joint/muscle pain, and diarrhea) caused by currently available treatments.

The patients were predominantly those with myeloma and/or autologous-HSCT, noted by clinical experts to be a group for which risk of CMV infection is much lower than recipients of allogenic-HSCT. One respondent had reported experience taking maribavir.

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 post-transplant CMV infection and/or disease in adults.

Unmet Needs

Per the clinical experts, given the limitations of existing anti-CMV therapies, treatment goals are to control the virus and its symptoms until a patient’s immune system is strong enough to fight the virus itself, rather than eradicating it. As such, the goals of existing treatments are to improve symptoms (if the patient has end-organ disease), reduce mortality, improve graft function and/or reduce graft loss, minimize adverse effects, and improve quality of life.

Challenges with existing treatments may include high rates of hospitalizations for treatment administration and toxic side effects. The clinical experts described that the current treatment options require hospitalization for IV therapy, which are inconvenient, expensive, and toxic (e.g., mucosal toxicity from foscarnet, renal toxicity from foscarnet and cidofovir, myelosuppression from high-dose ganciclovir). Drug toxicity was described to have subsequent downstream impacts, for example, lower blood counts with ganciclovir requires growth factor which increases risk of infection and potential for graft loss while renal toxicity from foscarnet requires adjusting other drug doses (i.e., calcineurin inhibitors) which are important for immune suppression and prescribing other antibiotics with potentially negative effects on other patient outcomes.

The clinical experts also described concerns around patients becoming resistant to current treatment options, though they likely expect patients using maribavir to develop resistance as well.

Place in Therapy

Clinical experts underscored the importance of treating patients with the least toxic and most effective drug early, citing that some of the outcomes from delayed treatment are irreversible (e.g., if graft loss due to ganciclovir or valganciclovir causes myelosuppression that cannot be reversed in post-HSCT patients and foscarnet causes graft loss in kidney transplant patients). The clinical experts indicated there is uncertainty about whether it would be better to combine therapies, especially if the patient has a high viral load, or to use it as a monotherapy. Per the clinical experts, if maribavir is used as part of combination therapy, it should not be combined with ganciclovir due to antagonistic mechanism of action. Determining which patients are likely to benefit from immediate maribavir and which patients may need combination therapy was identified as a potential area that would require further evidence generation. Per the experts, maribavir could be a combination therapy with foscarnet for patients who may be at risk of failing maribavir alone (e.g., very high viral loads at the time of therapy initiation) but there is no data on how best to do this.

If maribavir is reimbursed and available, the experts suggested it is expected to shift the treatment paradigm for refractory and/or resistant CMV infection, such that foscarnet would be shifted further down the lines of therapy from its current first-line as administering foscarnet requires hospital admission and toxicity management.

The clinical experts indicated that it would be inappropriate to recommend that patients try other treatments before initiating maribavir, noting the exception of an appropriate first-line therapy such as a trial of valganciclovir or ganciclovir. In the context of HSCT, a trial of foscarnet would be considered appropriate if cytopenia is an issue.

Patient Population

According to the clinical experts, resistance and refractory definitions are important to identify patients most suitable for treatment with maribavir. Patients most likely to respond to maribavir include those who have intolerances or life-threatening side effects to other drugs, those who can have their immunosuppression reduced and/or those that can have their immune function improve. The clinical experts indicated that in most cases, patients who are responding to ganciclovir or valganciclovir would not be appropriate recipients for maribavir; however, maribavir may be appropriate for those responding to ganciclovir or valganciclovir if intolerances exist (e.g., cytopenia). The patient populations currently most in need of an intervention are patients with lung transplant and bone marrow transplant.

The clinical experts indicated that patients best suited for maribavir would be identified by either a lack of change in CMV viral load or increase in CMV viral load after at least 2 weeks of appropriately dosed valganciclovir or ganciclovir. The CMV PCR test result at the third week would be needed to determine eligibility. If patients switch too early from the prior anti-CMV therapy to maribavir, then overdiagnosis of refractory and/or resistant infection can occur. Formal resistance testing should ideally be conducted before starting patients on maribavir; however, given the turnaround time for receiving results (i.e.,10 calendar days to 2 weeks), the experts suggested it may not be necessary to have results before initiating treatment.

The clinical experts emphasized that since maribavir has not been studied in some disease sites (e.g., central nervous system or retina) and penetration is unknown, those patients would be better suited to alternative drugs.

Assessing Response to Treatment

In routine clinical practice, the clinical experts indicated that anti-CMV treatment is given until CMV is either negative or low level; however, the definition of low level is unclear and treatment duration must be individualized based on multiple patient characteristics (e.g., GVHD, toxicity). The clinical experts clarified that treatment may be given for as little as 2 weeks but can be months of therapy. Clinically meaningful response to therapy would be resolution of any symptoms or resolution of end-organ disease. Patients would ideally have no evidence of CMV replication and no symptoms of CMV, however, this is not always feasible so if patients have either low level CMV without any evidence of CMV end-organ disease or symptoms, this is satisfactory for clinical experts. The experts added that highly sensitive assays make it challenging to identify the ideal end point for CMV negativity and there is a lack of literature around this.

According to the clinical experts, monitoring weekly CMV DNA level from plasma is the standard of care in Canada and transplant physicians follow-up with patients weekly or twice a month to regularly monitor CMV DNA levels.

Discontinuing Treatment

Per the clinical experts, complete response to maribavir would be defined as resolution of symptoms of end-organ disease and eradication of CMV viremia. Complete response would indicate that maribavir could be discontinued. On the contrary, lack of response to maribavir would generally be defined as rising viral loads despite therapy, resistance documented by genotyping, and progression of end-organ disease or symptoms. Lack of response would indicate that additional or alternative therapy might be necessary.

The experts added that clinicians would adhere to standard guidelines if maribavir was reimbursed and available. Per the Kotton et al. (2018)³⁰ post-SOT guidelines identified by the experts, if highly sensitive assays (lower limit of quantification [LLOQ] < 200 IU/mL) are being used, therapy should be discontinued after 1 result is less than the LLOQ followed by confirmatory testing 1 week after discontinuation. In routine clinical practice, the experts described that the LLOQ of a highly sensitive assay may currently be a grey area. If the assay is not highly sensitive, the guidelines recommend that 2 consecutive undetectable (negative) results are needed to discontinue therapy.³⁰ Per the Ljungman et al. (2019)²⁹ post-HSCT guidelines, the clinicians may aim for 2 weeks of treatment and at least 1 negative CMV test. In both post-SOT and post-HSCT cases, if there is end-organ disease, there should be resolution of signs and symptoms before treatment is discontinued. The clinical experts also added that if CMV levels are good, falling and low, especially if there is toxicity with low blood cell counts or increase serum creatinine then therapy may be stopped before 2 negative tests, but the patient would be watched closely for rebound viremia.

Prescribing Conditions

According to the clinical experts, the appropriate setting for treatment with maribavir would be the community and/or outpatient setting. Specialists in transplant infectious disease or infectious diseases, if available, combined with the patients' primary transplant provider, are required to diagnose, treat, and monitor patients who might receive maribavir. The clinical experts also emphasized that the appropriate setting may depend on the availability of experts in a given province or region, suggesting that, for example, transplant infectious disease may not be available in some provinces so infectious disease or internal medicine may fulfill that role. Though, clinical experts maintained that clinicians with expertise both in the transplant type (SOT or HSCT) and in infections must be involved.

Additional Considerations

Per the clinical experts, clinicians are more concerned with resistance than refractory disease in routine clinical practice. The experts added that in trials, refractory CMV is defined as a 1 log10 rise in CMV viral load after 2 weeks of appropriately dosed antiviral therapy, probable refractory CMV is a CMV viral load that does not decrease in the same time frame, and resistant CMV refers to the viral genotyping that has mutations associated with reduced response to antiviral therapy. As per the experts, in routine practice, viral loads may not be reported in log numbers and stable or rising CMV viral loads on the third week post-transplant despite appropriate therapy are usually taken as an indication of refractory or resistant CMV which would trigger resistance testing. Providers are often concerned with any numerical rise but sometimes these do not fit the log definition and if testing is repeated too frequently or early, viral loads can fluctuate as much of the CMV in plasma is fragmented and does not represent whole genomes.

The clinical experts indicated that developing resistance to therapies is an important consideration. Per the experts, resistance is common in those who experience relapse after maribavir therapy and cross-resistance to ganciclovir is possible.⁴⁷

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by 1 clinician group.

The input provided by the clinician group generally aligned with the input provided by the clinical experts consulted by CADTH. CTTC, a multidisciplinary organization engaged in patient care, research, education in the field of HSCT and cell therapy, submitted input. A total of 6 clinicians and 2 CTTC committees (board of directors and standing committee of program directors) contributed to the input. Pertaining to the patient population, the clinician group also added that patients post-transplant often struggle with a lack of appetite and/or poor oral intake; therefore, the patients with difficulties of eating might be less suitable for maribavir, which is associated with dysgeusia but emphasized that toxicity profile of conventional salvage therapies is much more concerning. Furthermore, the clinician group emphasized that it is particularly challenging to treat CMV infection in patients with GVHD since GVHD therapies are immunosuppressive (i.e., increase the risk of CMV infection), myelosuppressive, and nephrotoxic (i.e., exacerbate the toxicities caused by valganciclovir or foscarnet, respectively). The group suggested that maribavir would be the new standard of care of these patients, if funded and available.

There was no input provided on the use of maribavir for post-SOT patients.

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

CMV = cytomegalovirus; HSCT = hematopoietic stem-cell transplant; PCR = polymerase chain reaction; SOT = solid organ transplant.

Clinical Evidence

The clinical evidence included in the review of maribavir is presented in 3 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. The second section includes indirect evidence selected from the literature that met the selection criteria specified in the review. The third section includes sponsor-submitted long-term extension studies and 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 maribavir 400 mg (2 tablets of 200 mg) twice daily (resulting in a daily dose of 800 mg) for the treatment adults with post-transplant cytomegalovirus (CMV) infection/disease who are refractory and/or resistant to 1 or more prior antiviral therapies.

Methods

Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission 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.

Of note, the systematic review protocol presented below was established before the granting of a NOC from Health Canada.

Table 6: Inclusion Criteria for the Systematic Review

AE = adverse event; CMV = cytomegalovirus; D = donor; GVHD = graft vs. host disease; HLA = human leukocyte antigen; HSCT = hematopoietic stem-cell transplant; R = recipient; RCT = randomized controlled trial; SAE = serious adverse event; SCr = serum creatinine; SOT = solid organ transplant; WDAE = withdrawal due to adverse event.

The literature search was performed by an information specialist using a peer-reviewed search strategy. 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.⁴⁸

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 multi-file search. Duplicates were removed using Ovid deduplication for multi-file searches, followed by manual deduplication in Endnote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Patient Headings), and keywords. The main search concept was maribavir. 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 April 29, 2022. Regular alerts updated the search until the meeting of the CADTH Canadian Drug Expert Committee (CDEC) on August 24, 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.⁴⁹ Included in this search were the websites of regulatory agencies (US FDA and EMA). 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

A total of 1 study was identified from the literature for inclusion in the systematic review (Figure 1). The included study is summarized in Table 7. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Table 7: Details of Included Study

CNS = central nervous system; CMV = cytomegalovirus; GI = gastrointestinal; HIV = HIV; HSCT = hematopoietic stem-cell transplant; IAT = investigator-assigned treatment; LLOQ = lower limit of quantitation; qPCR = quantitative polymerase chain reaction; SOT = solid organ transplant; ULN = upper limit of normal; Wk = week.

Source: SOLSTICE Clinical Study Report.⁴

Description of Studies

One trial met the inclusion criteria for this review.^4,50 Study-specific details are listed in Table 7, and schematics of the trial design are included in Figure 2.

SOLSTICE (N = 352) was a randomized, multicenter, parallel assignment (2:1), open-label, active-controlled phase III trial comparing 8 weeks of treatment with either maribavir or investigator-assigned choice of comparator antiviral therapies (ganciclovir, valganciclovir, foscarnet, or cidofovir) in adult HSCT and SOT patients with CMV infections that are refractory (with or without resistance) to 1 or a combination of the antivirals.⁴ Patients were enrolled from 135 sites in 12 countries across North America, Europe, and Asia Pacific. The primary objective of the study was to compare the efficacy of maribavir to IAT in CMV viremia clearance at the end of study, week 8. Patients received 400 mg of oral maribavir (N = 235) twice daily (800 mg/day) or investigator-assigned treatment (N = 117) for at least 8 weeks, and up to 29 weeks. For drug administration as outpatients, a study diary for tracking adherence to study treatment dosing was dispensed for home use. A proportion of patients randomized to the IAT were entered into the maribavir rescue arm upon discretion of the investigator, after a minimum of 3 weeks of IAT. Patients visited the study site up to 19 times for up to 22-week period. The SOLSTICE study consisted of 3 phases: a screening phase of up to 2 weeks; an 8-week study treatment phase; and a 12-week follow-up phase. The screening phase consisted of collecting informed consent, checking the inclusion and exclusion criteria, and other clinical assessments. The screening phase was followed by stratification of patients based on 2 factors: transplant type (SOT or HSCT) and the most recent screening of whole blood or plasma CMV DNA viral load (categorized as per the 3 categories in Table 8). Following stratification, patients were randomized in a 2:1 allocation ratio using IRT. In the 12-week follow-up phase, study-specific evaluations, including CMV tests and safety assessments, occurred weekly for the first 4 weeks, then every 2 weeks for the final 8 weeks. Patients who entered the maribavir rescue arm participated in the study for up to 29 weeks. Patients in the IAT group who had an ineffective response to IAT could be evaluated to receive rescue treatment with maribavir for 8 weeks. The eligibility of patients who had to discontinue IAT for lack of antiviral activity and/or intolerance was assessed at week 3 up to week 7 for entry into the rescue arm of treatment with maribavir 400 mg twice daily for up to 8 weeks. No washout phase was reported, however, the minimum washout period before the first dose of study treatment for letermovir was changed from 14 days to 3 days to facilitate enrollment.

Figure 2: SOLSTICE Study Design

BID = twice daily; BL = baseline; CMV = cytomegalovirus; R = rescue; Rand = randomized; Wk = week.

Source: SOLSTICE Clinical Study Report.⁴

Table 8: Stratification of Patients by CMV DNA Viral Load Category

CMV = cytomegalovirus.

Source: SOLSTICE Clinical Study Report.⁴

Populations

Inclusion and Exclusion Criteria

Patients (≥ 12 years) were eligible for the SOLSTICE study if they underwent a SOT or HSCT and were diagnosed with CMV infection that was refractory to the most recently administered of the 4 anti-CMV treatment drugs. Specifically, refractory was defined as documented failure to achieve a greater than 1 log 10 decrease in CMV DNA level in whole blood or plasma after a 14-day or longer treatment period with IV ganciclovir, oral valganciclovir, IV foscarnet, or IV cidofovir. Eligible patients were also required to have an absolute neutrophil count (ANC) of at least 1,000/mm³ (1.0 × 10⁹/L), platelet count of at least 2,5000/mm³ (25 × 10⁹/L), hemoglobin of at least 8 g/dL, estimated glomerular filtration rate (eGFR) greater than 30 mL/min/1.73 m², and a life expectancy of ≥ 8 weeks. Patients were excluded if they had vomiting, diarrhea, or other severe GI illness within 24 hours before the first dose of study treatment. Patients were also excluded if they had a current CMV infection that was considered refractory or resistant due to inadequate adherence to prior anti-CMV treatment and had tissue-invasive CMV disease with central nervous system involvement (including the retina). Patients with known positive results for HIV and undergoing treatment for acute or chronic hepatitis C were also considered ineligible. Additional detail regarding inclusion and exclusion criteria in the SOLSTICE study are provided in Table 7.

Baseline Characteristics

Baseline characteristics of all patients enrolled in the SOLSTICE study are presented in Table 9 and Table 10.

The mean age of enrolled patients was 53.0 years (SD: 13.22 years). Most patients were White (75.6%) and male (60.5%). Most patients underwent a SOT (59.9%), with the kidney (50.2% of SOT patients), lung (29.4% of SOT patients), and heart (10.9% of SOT patients) being the most transplanted solid organs. Patients who underwent HSCT predominantly underwent allogeneic transplant procedures (99.3%). Most patients who underwent SOT and HSCT had functioning graft status (89.1% in SOT patients versus 85.1% in HSCT patients). Most patients did not have confirmed acute or chronic GVHD (91.2% in acute GVHD versus 96.9% in chronic GVHD), and did not use antilymphocyte treatment (57.7%). Most patients had some renal impairment (32.1% with mild, 23.3% with moderate, and 3.1% with severe), but no hepatic impairment (92.3%).

For most patients, the current CMV infection is the first episode post-transplant (68.2%), there was no prior use of CMV prophylaxis (58.8%), and the current CMV infection was asymptomatic (86.4%). The CMV serostatus for patients who underwent SOT was mostly Donor +/Recipient- (83.4%), while for patients who underwent HSCT it was mostly either Donor +/Recipient + or Donor -/Recipient + (41.8% and 46.1%, respectively). The CMV DNA levels of most patients as assessed by central laboratory was low (67.6%). Most of the patients had a presence of CMV RASs known to confer resistance to ganciclovir, foscarnet, and/or cidofovir (54.3%), but did not have RASs known to confer resistance to maribavir (88.6%). The Karnofsky Scale Performance Status scores for most patients was 80 or above (60.2%).

Overall, both the maribavir and IAT treatment groups were relatively balanced in terms of baseline demographic and clinical characteristics. Some notable differences between the groups were observed in following characteristics: age, type of preparative conditioning regimen, presence of CMV RASs, and CMV serostatus for HSCT Donor/Recipient, CMV DNA level, and net immunosuppression use changed before initiation of study treatment. The differences were as follows: patients aged 65+ years (maribavir: 23.0% versus IAT: 13.7%), CMV serostatus for HSCT Donor+/Recipient+ (maribavir: 45.2% versus IAT: 35.4%), HSCT Donor-/Recipient+ (maribavir: 41.9% versus IAT: 54.2%).

There was a difference between the groups in CMV DNA level low category (maribavir: 65.1% versus IAT: 72.6%) and intermediate category (maribavir: 28.9% versus IAT: 21.4%). Net immunosuppression use changed before initiation of study-assigned treatment was also imbalanced (maribavir: 23.0% versus IAT: 30.8%).

Table 9: Summary of Baseline Characteristics (Randomized Set, N = 352)

CMV = cytomegalovirus; GVHD = graft vs.-host disease; HSCT = hematopoietic stem-cell transplant; IU = international units; IAT = investigator-assigned treatment; NA = not applicable; SD = standard deviation; SOT = solid organ transplant.

^aOther category includes Native Hawaiian or other Pacific Islander, American Indian or Alaska Native, and multiple races. The number of patients in each of those categories was 0.

^bPercentages are based on the number of patients within the category.

Source: SOLSTICE Clinical Study Report.⁴

Table 10: Summary of Baseline Resistance Profile (Modified Randomized Set)

CMV = cytomegalovirus; IAT = investigator-assigned treatment; RASs = resistance-associated amino acid substitutions.

Source: SOLSTICE Clinical Study Report.⁴

Interventions

Randomized patients received either maribavir (N = 235) or IAT (N = 117). The IATs were chosen and prescribed by the investigator and were either administered at the hospital or other facilities used to administer IV products or were prescribed by the investigator and typically purchased by the patients at a commercial or hospital pharmacy.

Maribavir was administered every 12 hours. When it was not feasible to dose every 12 hours, the doses were separated by a minimum of 8 hours. If the timing of the first dose of maribavir on day 0 did not allow for a minimum of 8 hours between doses, only 1 dose of maribavir was administered on day 0. The strength of tablets was 200 mg, and patients were required to take 2 tablets of 200 mg maribavir every 12 hours (200 mg × 2 tablets in the morning and 200 mg times 2 tablets in the evening totalling to 800 mg/day). Maribavir was administered without regard to food and could have been crushed and/or dispersed in water via orogastric or nasogastric tube for a short period of time during the study treatment phase to avoid interruption or discontinuation of treatment. Interruption of therapy for a maximum of 7 consecutive days, or up to 2 study treatment interruptions for a total of up to 7 days was permitted at the investigator’s discretion if the end of the maribavir administration period remained fixed at a maximum of 8 weeks after the date of the start of treatment. Dose adjustments and dose interruptions were to be recorded on the electronic case report form (eCRF).

IAT drug type and the dose was at the direction of the investigator. Dual therapy with 2 IATs was permitted. Dose adjustment for safety or efficacy were allowed but had to be documented in the eCRF. During treatment with IAT, the investigator could interrupt therapy without permanent study treatment discontinuation as long as the interruption was for a maximum of 7 consecutive days, or up to 2 study treatment interruptions for a total of up to 7 days and the end of the IAT administration period remained fixed at a maximum of 8 weeks after the date of the start of treatment. After randomization, switching between valganciclovir and ganciclovir was permitted, but changing IAT to another anti-CMV drug or adding another anti-CMV drug during the treatment period was not permitted.

Concomitant Medications

Patients were permitted to use concomitant medications to complement the use of the anti-CMV drugs in the study (e.g., immunosuppressant drug or hemopoietic growth factors as needed for neutropenia) and prevent or treat viral infections (i.e., acyclovir, valacyclovir, or famciclovir). Antifungal and antibacterial drugs were also permitted. Maribavir was administered cautiously with drugs that are substrates of CYP2C19 and P-glycoprotein (P-gp), as inhibition of these enzymes by maribavir could increase concentrations of the substrates, particularly for tacrolimus and other narrow therapeutic index immunosuppressants.

Irrespective of the study group, patients were not permitted concomitant use of any unapproved drug or device, any investigational anti-CMV drug (e.g., receipt of CMV vaccine), and infusion of T-cells specific for CMV or regulatory T-cells for the control of transplant tolerance. In the maribavir group, patients were not permitted concomitant use of CYP3A inducers (e.g., avasimibe, carbamazepine, phenytoin, rifampin, rifabutin, St. John’s wort), herbal medications known to have potential toxicities or drug interactions (e.g., Ginkgo biloba or Piper methysticum) and select systemic anti-CMV therapies (i.e., ganciclovir, valganciclovir, foscarnet, cidofovir, leflunomide, artesunate, and letermovir) unless administration was unintentional for no longer than 1 day. In the IAT group, patients were not permitted concomitant use of leflunomide, artesunate, or letermovir while they were receiving IAT (except unintentional administration for no longer than 1 day).

Patients in the IAT group were eligible to transition into the maribavir rescue arm if after a minimum of 3 weeks of therapy with IAT (week 3) if they met protocol-defined criteria for lack of improvement or worsening of CMV infection. Criteria included increased whole blood or plasma CMV viremia levels of at least 1 log10 from baseline, tissue-invasive CMV disease that did not improve or worsened, and/or patient who did not achieve CMV viremia clearance (requiring continued anti-CMV treatment), and intolerance to the IAT.

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 11. These end points are further summarized below. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 4.

Table 11: Summary of Outcomes of Interest Identified in the CADTH Review Protocol

AE = adverse event; CMV = cytomegalovirus; GVHD = graft vs. host disease; IAT = investigator-assigned treatment; LLOQ = lower limit of quantification; RAS = resistance-associated amino acid substitution; SAE = serious adverse event; SF-36v2 = Short Form Health Survey 36 item Version 2; WDAE = withdrawal due to adverse event.

Source: SOLSTICE Clinical Study Report.⁴

Efficacy Assessments

Disease response assessments were made according to CMV DNA concentrations using PCR assay (COBAS AmpliPrep/COBAS TaqMan CMV Test) at a central virology laboratory. The first DNA sample was taken during the screening phase and then subsequent samples were taken weekly during the treatment phase. To note, blood samples were taken at all study visits (processed to obtain plasma) for all CMV DNA tests (quantitation, genotyping) and were tested in a central specialty laboratory; however, during the screening period local specialty laboratory results for CMV DNA quantitation could have been used only for eligibility assessment. Time points for evaluation of viral load for the primary end point were weeks 7 and 8. The permissible assessment windows were as follows: Week 0.5 (day 4) ± 1 day; week 1 (day 7) plus 2 days; weeks 2 to 4 ± 2 days; and weeks 5 to 8 ± 3 days.

Secondary evaluation of efficacy assessed the status of tissue-invasive disease and CMV syndrome in addition to CMV viremia clearance using results that were adjudicated by an independent EAC.

End Point Definitions

The primary end point was response confirmed by plasma CMV DNA clearance at the end of study week 8. This end point was defined as proportion of patients with plasma CMV DNA concentration of less than LLOQ (i.e., < 137 IU/mL) per central laboratory result in 2 consecutive post-baseline samples, separated by at least 5 days. Patients who initiated alternative (non–study) anti-CMV therapy or rescue treatment before week 8 were considered non–responders.

The key secondary end point was response defined as proportion of patients with confirmed CMV viremia clearance and symptom control at the end of study week 8, followed by maintenance of this treatment effect for an additional 8 weeks off treatment (i.e., follow-up week 16). Symptom control was defined as resolution or improvement of tissue-invasive CMV disease or CMV syndrome for patients who were symptomatic at baseline. For patients who were asymptomatic at baseline, symptom control was defined as no new symptoms of tissue-invasive CMV disease or CMV syndrome. Patients who initiated alternative (non–study) anti-CMV therapy before week 16 were counted as non–responders. Both the primary and secondary end points were assessed regardless of whether patients completed the 8 weeks of study-assigned treatment.

Three additional secondary end points, similar to the primary and key secondary end points, also captured response. The secondary end points were 1) achievement of the confirmed CMV viremia clearance after 8 weeks of receiving study-assigned treatment, 2) achievement of the confirmed CMV viremia clearance and CMV infection symptom control after 8 weeks of receiving study-assigned treatment, and 3) maintenance of the CMV viremia clearance and CMV infection symptom control achieved at the end of study week 8 through weeks 12 to 20. Achievement of the confirmed CMV viremia clearance after 8 weeks of receiving study-assigned treatment was defined the same as the primary end point except patients were required to complete 8 weeks of study treatment. Achievement of the confirmed CMV viremia clearance and CMV infection symptom control after 8 weeks of receiving study-assigned treatment was defined as proportion of patients who qualified for achievement of confirmed CMV viremia clearance after 8 weeks of study treatment and had resolution or improvement of tissue-invasive disease or CMV syndrome at week 8 and at the time point of interest or did not develop new symptoms at week 8 or time points of interest. Maintenance of the CMV viremia clearance and CMV infection symptom control achieved at the end of study week 8 through weeks 12 to 20 was defined the same as the key secondary end point, but maintenance was evaluated at week 12 and week 20 instead of week 16.

Recurrence of CMV viremia, recurrence of CMV viremia during and off study-assigned treatment, all-cause mortality and resistance to study drugs were additional secondary end points. Recurrence of CMV viremia was defined as proportion of patients with plasma CMV DNA concentrations of at least LLOQ, when assessed by central specialty laboratory, in 2 consecutive plasma samples separated by at least 5 days after achieving confirmed viremia clearance. All-cause mortality was defined by time to all-cause mortality. Resistance profile was defined as the proportion of patients with RASs, RASs to IAT were assessed on the UL97 (ganciclovir/valganciclovir) and UL54 (ganciclovir/valganciclovir, foscarnet, and cidofovir) genes, while RASs to maribavir were assessed on the UL97 and UL27 genes.

The exploratory end points included CMV viral load over time, time to first CMV viremia clearance, time from first CMV viremia clearance to viremia recurrence, |||||||||||||||||||||||, and |||||||||||||||||||||||. The CMV viral load over time was defined as change from baseline in log10 plasma CMV DNA viral load, reported for week 8 and week 16. The time to first CMV viremia clearance was defined as time (days) to first CMV viremia clearance (i.e., time to first of 2 consecutive CMV DNA values < LLOQ). Time from first CMV viremia clearance to viremia recurrence was assessed as presence of CMV DNA after the patient achieved confirmed CMV viremia clearance at any point in the study. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. The EQ-5D is a generic HRQoL instrument that can be applied to a wide range of health conditions and treatments to capture the net effect of treatment benefits and harms.⁵¹ The EQ-5D consists of 5 dimensions of health (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) rated on a scale of 5 levels, ranging from 1 (“no problems”) to 5 (“extreme problems” or “unable to perform”). The EQ-5D index score is generated by applying a multi-attribute utility function to the descriptive system.⁵² The EQ-5D also has a visual analogue scale (VAS), by which overall health is self-rated on a scale ranging from 0 (“the worst health you can imagine”) to 100 (“the best health you can imagine”).⁵¹ |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. The SF-36v2 is a 36-item, generic, self-reported health assessment questionnaire with 8 domains: physical functioning, role limitations due to physical health problems, bodily pain, general health, vitality, social functioning, role limitations due to emotional health problems, and mental health.⁵³ For each of the 8 categories, a subscale score can be calculated. The SF-36v2 also provides 2 component summaries: the Physical Component Summary (PCS) and the Mental Component Summary (MCS), derived from aggregating the 8 domains according to a scoring algorithm.⁵³

The incidence and severity of AEs were part of the safety evaluation in the study. AEs were Medical Dictionary for Regulatory Activities (MedDRA) Version 23 to show the incidence of all AEs by system organ class, preferred term, relationship to treatment, severity and seriousness.

Statistical Analysis

Data for the primary, key secondary, and other secondary end points for response (i.e., CMV viremia clearance and maintenance of response) were analyzed using statistical testing. For time-to-event data, some end points were summarized descriptively (i.e., Kaplan–Meier plots only) while others were analyzed statistically (i.e., hazard ratios, P values). Data for recurrence of CMV viremia, HRQoL and resistance to study treatment were summarized descriptively. For continuous variables, the number of non–missing observations, mean, SD, minimum and maximum values, median and interquartile range were presented. For categorical variables, the number of non–missing observations, number of missing and non–missing observations, and frequencies were reported. If not defined otherwise, the percentage denominator was the number of patients with non–missing information. In case of subgroups, the relative frequencies were calculated based on the patients in the respective category.

Sample Size Determination and Power Calculation

According to the SOLSTICE Statistical Analysis Plan, 90% power in hypothesis testing at an alpha level of 0.05 with a 2-sided test for the primary outcome required 315 patients with post-transplant CMV infection in the ratio of 2:1 (210 patients in the maribavir arm and 105 patients in the control arm).

To determine the sample size, the investigators assumed that at least 60% of maribavir-treated patients would have achieved undetectable plasma CMV DNA at Week 7 and Week 8 based on evidence from the sponsor’s previous phase II studies.^40,41

The investigators considered 40% as an approximately reasonable estimate of the proportion of patients with confirmed undetectable plasma CMV DNA at Week 7 and Week 8 in a control arm. A treatment difference of 20% between the maribavir and control arms was considered a clinically meaningful difference. Applying a 2-arm continuity corrected Chi-square test of equal proportions and considering 10% dropouts, the investigators planned to enroll and randomize 351 patients (234 patients in maribavir arm and 117 patients in the control arm).

Primary and Key Secondary End Points

Confirmed plasma CMV DNA clearance at the end of study week 8 was defined as the proportion of patients with plasma CMV DNA concentration < LLOQ (i.e., < 137 IU/mL) per central laboratory result in 2 consecutive post-baseline samples, separated by at least 5 days. The difference in proportion of responders between treatment groups was obtained using Cochran-Mantel-Haenszel (CMH) weighted average across all strata, and tested using CMH method, with transplant type and baseline plasma CMV DNA concentration as 2 stratification factors. The 95% confidence limits of the weighted average of difference across strata were provided using the normal approximation. If the minimum expected number of patients in a response category in a treatment group, was less than 5, the groups were collapsed into 1 stratum level. Homogeneity across strata was tested using the Breslow-Day test. If the test was significant at alpha = 0.05 level, stratum-specific difference in proportion was also reported and the adjusted difference and 95% CI in proportion of responders between treatment groups was obtained and tested using minimum risk weight method of Mehrotra and Railkar (2000)⁵⁴ instead of the CMH method. In efficacy analyses, the primary method to handle missing data due to early dropouts was to treat it as a non–responder. Time points for evaluation of viral load for the primary end point were weeks 7 and 8, but data from adjacent weeks may have been used to impute missing data. When adjacent data was not available as per the pre-specified imputation requirements, patients were counted as non–responders.⁵⁵

For the key secondary end point, the difference in proportion of responders between treatment groups was obtained and tested using the same method as described for the primary end point.

Subgroup Analyses

The primary end point was reported for the following subgroups identified in the CADTH systematic review: CMV DNA viral load at baseline (low, intermediate, or high), prior antilymphocyte use (yes versus no), type of transplant (i.e., SOT versus HSCT, organ transplanted), and presence of CMV mutation resistant to ganciclovir, foscarnet, and/or cidofovir per central laboratory results (yes versus no). Not all subgroups identified in the protocol were analyzed in SOLSTICE.

Subgroup analysis was only conducted for the key secondary end point using the same subgroups as those for the primary end point: CMV DNA viral load at baseline (low, intermediate, or high), prior antilymphocyte use (yes versus no), type of transplant (i.e., SOT versus HSCT, organ transplanted), and presence of CMV mutation resistant to ganciclovir, foscarnet, and/or cidofovir per central laboratory results (yes versus no). Not all subgroups identified in the protocol were analyzed in SOLSTICE. Subgroup analyses were not conducted for any other end points.

Sensitivity Analyses

Sensitivity analyses were conducted based on CMV DNA concentration values, using the randomized set. The following sensitivity analyses for the primary end point were conducted:

• considering patients with viremia clearance at premature discontinuation as responders

• analyzing primary end point of response using multivariable logistic regression model with a pre-specified list of characteristics

• repeating analyses by excluding patients who discontinue early from the analysis set

• including clearance at any time during the first 8 weeks as response

• including IAT patients who initiated alternative treatment before week 8 as responders if they met the criteria for clearance at week 8

• limiting the sample to patients who completed 8 weeks of assigned therapy

• excluding patients who discontinued treatment early

• using stratification factors assigned at randomization.

Prior use of CMV prophylaxis and CMV serostatus were not included in the multivariable logistic regression model, with the investigators citing the biologic meaning and moderate to strong correlation with transplant type, which was 1 of the fixed variables. If at least 5% of patients had missing CMV DNA data to confirm response at week 8 due to the COVID-19 pandemic, missing CMV DNA levels were imputed using a multiple imputation method.

The sensitivity analyses conducted for the key secondary end point were similar to those conducted for the primary end point.

Multiplicity Testing

The hypothesis testing of the primary and key secondary end point was adjusted for multiple comparisons using a fixed-sequence testing procedure to control the family-wise type 1 error rate at 5% level. If the proportion of response for the primary efficacy end point was higher in the maribavir group and the test of adjusted difference in proportion of responders between treatment groups was statistically significant, and the proportion of response for the key secondary efficacy end point was higher in the maribavir group and the test was significant at the 0.05 level, it was concluded that the treatment effect was more durable for maribavir as compared to the IAT group. No adjustments were made for multiple comparisons for any of the other end points.

Other Secondary and Exploratory End Points

For other secondary end points for response, statistical analyses were conducted following the same method as described for the primary end point, at alpha = 0.05 (2-sided) without adjustment for multiple comparisons.

Recurrence of CMV viremia were summarized descriptively.

For all-cause mortality, mortality status for all patients was summarized descriptively. Additionally, Kaplan–Meier estimates of the minimum, median, maximum were reported. This end point was compared between the 2 groups using the log-rank test. The treatment difference (hazard ratio, and its 95% CI) between maribavir and IAT treatment groups was estimated using the stratified Cox’s regression model with transplant type and baseline plasma CMV DNA level as 2 stratification factors.

Data for resistance to study drugs were summarized descriptively.

|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

All other time-to-event end points (i.e., time to viremia clearance and recurrence events and |||||||||||||||||||||||) were summarized either using Kaplan–Meier method or descriptive statistics (minimum, median, and maximum).

An AE summary table was used to present the number of events, number of patients and the percentage of patients having treatment-emergent AEs, SAEs, and treatment-emergent AEs that led to study discontinuation.

Censoring

||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. For all-cause mortality, patients who were alive at last contact were censored in the analysis.

Analysis Populations

The enrolled set consisted of all patients who had signed informed consent and some study procedures had begun (e.g., dispensed study-assigned treatment, current drug had been withdrawn).

The randomized set was used as the primary population for the analyses of most efficacy end points. The randomized set consisted of patients in the enrolled set who have been randomized to the study. Patients were analyzed in the group to which they were randomized. For all primary and secondary end points other than those assessing recurrence, efficacy evaluations during the treatment phase and follow-up phase included data before patients received alternative anti-CMV treatment or maribavir rescue therapy.

The modified randomized set was used for the analyses of some efficacy end points. This set consisted of all patients in the enrolled set who had been randomized to the study and had taken any dose of study-assigned treatment. Patients were analyzed in the treatment group to which they had been randomized.

The safety set was used to conduct safety analyses. The safety set included all patients who took any dose of the assigned treatment. Patients were analyzed according to the treatment that they received.-Safety data were reported separately for patients in the rescue arm.

The per protocol set consisted of all patients in the randomized set who did not have relevant major protocol deviations that could have affected the primary efficacy assessment. Prior to database lock, the sponsor reviewed the protocol deviations collected throughout the study and determined which of those were relevant major protocol deviations.

The maribavir-resistance set includes patients with pre-existing known (confirmed) maribavir-resistance mutations in UL97 and/or UL27 genes. The non–maribavir-resistance set includes all patients excluded from the maribavir-resistance set (i.e., those patients with evaluable genotyping data but without pre-existing confirmed maribavir-resistance mutations in UL97 and/or UL27 genes). The primary resistance (PRS) set included patients with pre-existing confirmed ganciclovir/valganciclovir, foscarnet, or cidofovir resistance mutations in UL97 and/or UL54 genes. The non–primary resistance set included all patients who were excluded from the PRS (i.e., those patient with evaluable genotyping data but without pre-existing known confirmed ganciclovir/valganciclovir, foscarnet, or cidofovir resistance mutations in UL97 and/or UL54 genes).

Protocol Amendments and Deviations

A summary of key protocol amendments implemented in the SOLSTICE study is presented in Table 12. In the original protocol the assessment of invasive bacterial and fungal infection was not part of the safety end point; however, it was added before patient enrollment began.

Table 12: Summary of Key Protocol Amendments in SOLSTICE

DMC = Data Monitoring Committee.

Source: SOLSTICE Clinical Study Report.⁴

Almost all patients (96.9%) had at least 1 protocol deviation or good clinical practice deviation during the study, with similar proportions in both groups (maribavir: 96.6% versus IAT: 97.4%). At least 1 major deviation was reported for 229 (65.1%) patients, with the distribution of major deviations being similar between treatment groups (maribavir: 66.0% versus IAT: 63.2%, respectively). |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

Results

Patient Disposition

Patient disposition in the SOLSTICE study is summarized in Table 13. In total, 415 patients were screened, of which 63 (15.2%) were screen failures. The most frequently reported reasons for screen failure were failure to demonstrate confirmed minimum CMV viral load ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| and failure to demonstrate that current CMV infection was refractory to the most recent CMV treatment ||||||||||||||||||||||||||||||||||||||||||||||. A total of 352 patients were randomized, 235 to the maribavir group and 117 to the IAT group. One randomized patient from each group was not dosed, leaving a total of 350 patients for the modified randomized and safety sets. Overall, 183 (77.9%) and 37 (31.6%) of patients in the maribavir and IAT groups, respectively, completed the 8-week study-assigned treatment. In total, 51 (21.7%) and 79 (67.5%) patients in the maribavir and IAT groups, respectively, discontinued from the study before the 8-week study treatment period; the primary reasons were due to AEs (maribavir: 6.4% versus IAT: 30.8%), lack of efficacy (maribavir: 8.9% versus IAT: 13.7%), and other reasons for discontinuation (maribavir: 1.7% versus IAT: 13.7%). Death led to treatment discontinuation for 3.0% for maribavir-treated patients and 0.9% of IAT-treated patients. Additional details on the reasons for study treatment discontinuation are presented in Table 13.

Table 13: Patient Disposition (Enrolled Set)

IAT = investigator-assigned treatment; NA = not applicable; PP = per protocol.

Source: SOLSTICE Clinical Study Report.⁴

Exposure to Study Treatments

Exposure to study treatment in SOLSTICE is summarized in Table 14. The 350 patients received at least 1 dose of a study drug; 234 patients in the maribavir group and 116 patients in the IAT group. For patients dosed with maribavir, the mean duration of exposure (i.e., days between the date of first exposure to the date of last exposure) was 52.5 days (SD: 11.81 days). The mean number of days in which at least 1 dose of study-assigned treatment was taken or administered was 48.6 days (SD: 13.82 days). For patients dosed with IAT, the mean duration of exposure was 36.0 days (SD: 18.06 days). The mean number of days in which at least 1 dose of study-assigned treatment was taken or administered was 31.2 days (SD: 16.91 days).

Concomitant medications in SOLSTICE were defined as any medication with a start date before the date of the first dose of study-assigned treatment and continuing after the first dose of study-assigned treatment or with a start date on or after the study-assigned treatment initiation and before the end of the on-treatment period. The most frequently reported concomitant medications (≥ 20%) were immunosuppressants (maribavir: 92.3% versus IAT: 94.0%), |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| corticosteroids for systemic use (maribavir: 75.6% versus IAT: 72.4%), |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

Table 14: Investigational Product Exposure (Safety Set)

IAT = investigator-assigned anti-CMV treatment; N = number of subjects; SD = standard deviation.

^aExposure duration is the number of days between the date of the first exposure and the date of last exposure of the drug administered.

^bTwo patients in the IAT group (valganciclovir) and 4 patients in the maribavir group did not have any eDiary data collected for administration of oral study-assigned treatment. These patients are not included in this table.

Source: SOLSTICE Clinical Study Report.⁴

Dose Interruptions and Reductions

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

Table 15: Change in Investigational Product Exposure (Safety Set)

AE = adverse events; IAT = investigator-assigned treatment; n = number of subjects experiencing the event at least once; m = number of events.

^aChange from the previous entry for the medication was collected.

^bPercentages are based on those who had reported a change from the previous entry for the medication. Some patients could have multiple changes throughout the treatment.

Source: SOLSTICE Clinical Study Report.⁴

Adherence

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

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported below. Refer to Appendix 3 for detailed efficacy data.

Clinically Significant CMV Infection

Confirmed CMV Viremia Clearance Response at Week 8 (Primary End Point)

Confirmed CMV viremia clearance results from the SOLISTICE study at week 8 are summarized in Table 16. For overall response, the adjusted difference in proportion of responders between maribavir and IAT was 32.8% (95% CI, 22.80% to 42.74%; P < 0.001), in favour of maribavir. Sensitivity analyses were mainly consistent with the main analysis with the notable exception of 1 analysis, where only patients on-treatment for 8 weeks were included, that failed to reach statistical significance.

In the maribavir group, of the 104 non–responders in the maribavir group, more than half (60, 57.7% patients) were confirmed non–responders for the primary end point.

These patients had CMV DNA measurements through week 8 but did not meet the response criteria at week 8. For 26 of 104 (25.0%) non–responders in the maribavir group, the reason for not achieving the primary end point was due to initiation of alternative (non–study) anti-CMV therapy before week 8. Seventeen (16.3%) maribavir-treated non–responders did not have CMV DNA measurement to evaluate response at week 8, predominantly due to early discontinuation (16 of the 17 patients with missing CMV DNA at week 8). In the IAT group, approximately 1-fifth of the non–responders (18 of 89, 20.2% patients) were confirmed non–responders. The common reasons for failure to achieve the primary end point in the IAT group were evenly distributed across initiation of alternative anti-CMV therapy before week 8 (24 of 89, 27.0% patients), missing CMV measurement (24 of 89, 27.0% patients), and meeting the criteria to switch to maribavir rescue therapy (22 of 89, 24.7% patients).

Results of the subgroup analyses for the primary end point (confirmed CMV viremia clearance response at week 8) are reported in Table 17.

Table 16: Summary of Confirmed CMV Viremia Clearance Response at Week 8 Results (Randomized Set)

CI = confidence interval; IAT = investigator-assigned treatment.

^aUnadjusted difference in proportion (Maribavir to IAT) and the corresponding 95% CI is computed by the normal approximation method.

^bCMH weighted average approach is used for the adjusted difference in proportion (Maribavir – IAT), the corresponding 95% CI, and the P value after adjusting for the transplant type and baseline plasma CMV DNA concentration if homogeneity is met. The minimum risk weight method is used if the homogeneity is not met. Only those with both stratification factors are included in the computation.

^cBreslow-Day test was used for testing the homogeneity across strata. The stratum-specific difference in proportion was reported only if the P value for homogeneity across strata was significant.

Source: SOLSTICE Clinical Study Report.⁴

Table 17: Subgroup Analyses of Confirmed CMV Viremia Clearance Response at Week 8 (Randomized Set)

CI = confidence interval; CMV = cytomegalovirus; HSCT = hematopoietic stem-cell transplant; IAT = investigator-assigned treatment NA = not applicable; SOT = solid organ transplant.

^aCMH weighted average approach was used for the adjusted difference in proportion (maribavir – IAT) and the corresponding 95% confidence interval adjusting for the transplant type and baseline plasma CMV DNA concentration that remained applicable. Kidney transplant included subjects with a most recent SOT type of kidney or kidney and other organ(s).

^bP value has not been adjusted for multiple testing.

Source: SOLSTICE Clinical Study Report.⁴

Confirmed CMV Viremia Clearance and CMV Infection Symptom Control at Week 8 Followed by Maintenance Through Week 16 (Key Secondary End Point)

A summary of the confirmed CMV viremia clearance response and CMV symptom control from the SOLISTICE study at week 8 and maintained through week 16 is summarized in Table 18. For overall response, the adjusted difference in proportion of responders between maribavir and IAT is 9.5% (95% CI, 2.02% to 16.88%; P = 0.013), in favour of maribavir. Sensitivity analyses of the key secondary end point were consistent with the main analysis.

Maintenance of CMV Viremia Clearance and CMV Infection Symptom Control Achieved at the End of Week 8 Through Weeks 12 to 20 (Secondary End Point)

A summary of the confirmed CMV viremia clearance response and CMV symptom control from the SOLISTICE study at week 8 and maintained through week 12 to week 20 is summarized in Table 19. For overall response, the adjusted differences in proportion of responders between maribavir and IAT at weeks 12 to 20 was 13.5% (95% CI, 5.84% to 21.17%) and 9.8% (95% CI, 2.58% to 17.06%), respectively, in favour of maribavir.

Confirmed CMV Viremia Clearance Response at Study Week 8, 12, 16 and 20 After Receiving 8 Weeks of Study Treatment (Secondary End Point)

A summary of the confirmed CMV viremia clearance response from the SOLISTICE study at weeks 8, 12, 16, and 20, after receiving 8 weeks of treatment, is presented in Table 20. At week 8, the adjusted difference in proportion of responders was 36.8% (95% CI, 27.26 to 46.40). At week 12, the adjusted difference in proportion of responders was 17.8% (95% CI, 10.89 to 24.77) in favour of maribavir. At week 16, the adjusted difference in proportion of responders was 13.9% (95% CI, 7.21 to 20.56) in favour of maribavir. At week 20, the adjusted difference in proportion of responders was 14.2% (95% CI, 7.70 to 20.75) in favour of maribavir.

Table 18: Summary of Confirmed CMV Viremia Clearance and CMV Infection Symptom Control at Week 8 Followed by Maintenance Through Week 16 (Randomized Set)

CI = confidence interval; IAT = investigator-assigned treatment.

^aUnadjusted difference in proportion (maribavir to IAT) and the corresponding 95% CI were computed by the normal approximation method.

^bCMH weighted average approach was used for the adjusted difference in proportion (maribavir to IAT), the corresponding 95% CI, and the P value after adjusting for the transplant type and baseline plasma CMV DNA concentration if homogeneity was met. The minimum risk weight method was used if the homogeneity was not met. Only those with both stratification factors were included in the computation.

^cBreslow-Day test was used for testing the homogeneity across strata. The stratum-specific difference in proportion was reported only if the P value for homogeneity across strata was significant.

Source: SOLSTICE Clinical Study Report.⁴

Table 19: Summary of Confirmed CMV Viremia Clearance and CMV Infection Symptom Control Response at Study Week 8, Maintenance Through Week 12 and Week 20 (Randomized Set)

CI = confidence interval; IAT = investigator-assigned anti-CMV treatment.

^aUnadjusted difference in proportion (maribavir to IAT) and the corresponding 95% CI were computed by the normal approximation method.

^bCMH weighted average approach was used for the adjusted difference in proportion (maribavir to IAT), the corresponding 95% CI, and the P value after adjusting for the transplant type and baseline plasma CMV DNA concentration if homogeneity was met. The minimum risk weight method was used if the homogeneity was not met. Only those with both stratification factors were included in the computation. Breslow-Day test was used for testing the homogeneity across strata. The stratum-specific difference in proportion was reported only if the p value for homogeneity across strata was significant.

^cP value has not been adjusted for multiple comparisons.

Source: SOLSTICE Clinical Study Report⁴

Table 20: Summary of Confirmed CMV Viremia Clearance Response at Study Week 8, 12, 16 and 20 After Receiving 8 Weeks of Study Treatment (Randomized Set)

CI = confidence interval; CMV = cytomegalovirus.

^aUnadjusted difference in proportion (maribavir to IAT) and the corresponding 95% CI were computed by the normal approximation method.

^bCMH weighted average approach was used for the adjusted difference in proportion (maribavir to IAT), the corresponding 95% CI, and the P value after adjusting for the transplant type and baseline plasma CMV DNA concentration if homogeneity was met.

^cThe minimum risk weight method was used if the homogeneity was not met. Only those with both stratification factors were included in the computation.

^dP value has not been adjusted for multiple comparisons.

Source: SOLSTICE Clinical Study Report.⁴

Time to CMV Viremia Clearance

The median observed event time for patients who had CMV viremia clearance was 17.0 days (minimum: 5.0 days, maximum: 114.0 days) in the maribavir group and 20.0 days (minimum: 6.0, maximum: 111.0) in the IAT group. The Kaplan–Meier plot of CMV viremia clearance is depicted in Figure 3. The Kaplan–Meier estimate for median days to CMV viremia clearance was 22.0 days (95% CI, 21.0 to 23.0 days) for the maribavir group and 29.0 days (95% CI, 22.0 days to 35.0 days) for the IAT group. The sensitivity analysis was consistent with the main analysis.

New CMV Events

Post-Baseline New Onset of Symptomatic CMV Infection

Results for the new onset of symptomatic CMV infection post-baseline are summarized in Table 22. There were 14 (6.0%) patients in the maribavir group and 7 (6.0%) patients in the IAT group who had a confirmed new onset of CMV disease post-baseline by the EAC.

Figure 3: Cumulative Probability of Achieving First CMV Viremia Clearance at Any Time During the Study (Randomized Set)

Confidential figure redacted at the request of the sponsor.

Table 21: Time to First CMV Viremia Clearance at Any Time on Study (Randomized Set)

CI = confidence interval; CMV = cytomegalovirus; IAT = investigator-assigned treatment.

^aTwo-sided P value comparing treatment groups is from the log-rank test by Kaplan–Meier method. P value was not adjusted for multiple comparisons.

Source: SOLSTICE Clinical Study Report.⁴

Table 22: Summary of Post-Baseline New Onset of Symptomatic CMV Infection (Randomized Set)

CMV = cytomegalovirus; EAC = End point Adjudication Committee; IAT = investigator-assigned treatment.

^aOne patient in the IAT group had new onset of symptomatic CMV infection at both week 12 and week 16.

Source: SOLSTICE Clinical Study Report.⁴

Recurrence of CMV Viremia

Results for the recurrence of CMV viremia are summarized in Table 23, Table 24, and Table 25. There were 33 (17.9%) patients in the maribavir group and 8 (12.3%) patients in the IAT group who had CMV viremia recurrence during the first 8 weeks. During the follow-up weeks (i.e., week 9 through the end of study), there were 71 (38.6%) patients in the maribavir group and 14 (21.5%) patients in the IAT group who had CMV viremia recurrence.

Table 23: Summary of Recurrence of CMV Viremia During the First 8 weeks, the Follow-up Period, and Any Time on Study (Randomized Set)

CMV = cytomegalovirus; IAT = investigator-assigned anti-CMV treatment.

^aPercentages are based on the number of patients in the Randomized Set who had CMV viremia clearance at any time on study.

^bDuring first 8 weeks regardless of whether the study-assigned treatment was discontinued before the end of the stipulated 8 weeks of therapy.

Source: SOLSTICE Clinical Study Report.⁴

Table 24: Summary of Recurrence of CMV Viremia While On and Off Study-Assigned Treatment (Randomized Set)

CMV = cytomegalovirus; IAT = investigator-assigned anti-CMV treatment.

^aPercentages are based on the number of patients in the Randomized Set who had CMV viremia clearance at any time on study, including rescue visits.

Source: SOLSTICE Clinical Study Report.⁴

Table 25: Summary of Recurrence of CMV Viremia During the First 8 weeks, the Follow-up Period and Any Time on Study Restricted to Those Received 8-week Study-Assigned Treatment (Randomized Set)

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Source: SOLSTICE Clinical Study Report.⁴

Time to CMV Viremia Recurrence

Results for the time from first CMV viremia clearance to CMV viremia recurrence are summarized in Table 26. The median observed time from first CMV viremia clearance to CMV viremia recurrence was 42.0 days (minimum: 14.0 days; maximum: 123.0 days) in the maribavir group and 45.5 days (minimum: 16.0; maximum: 89.0) in the IAT group. The Kaplan–Meier plot of time to CMV viremia recurrence in patients who achieved viremia clearance is depicted in Figure 4. The Kaplan–Meier estimate for median days from first CMV viremia clearance to CMV viremia recurrence was 71.0 days (95% CI, 57.0 to 92.0 days) for the maribavir group and NE (95% CI, 58.0 to NE) for the IAT group.

Results for the time from CMV viremia clearance at week 8 to CMV viremia recurrence requiring alternative treatment are summarized in Table 27. The median observed event time for those who had first CMV viremia clearance at study week 8 to CMV Viremia recurrence requiring alternative treatment was 20.5 days (minimum: 13.0 days; maximum: 80.0 days) in the maribavir group and 22.0 days (minimum: 14.0 days; maximum: 36.0 days) in the IAT group. The Kaplan–Meier plot of first CMV viremia clearance at week 8 to CMV viremia recurrence requiring alternative treatment is depicted in Figure 5. The Kaplan–Meier estimate for median days from first CMV viremia clearance at study week 8 to CMV viremia recurrence requiring alternative treatment was NE (95% CI, NE to NE) for the maribavir group and NE (95% CI, 30.0 to NE) for the IAT group.

Figure 4: Cumulative Probability of CMV Viremia Recurrence in Patients Who Achieved Viremia Clearance

Confidential figure redacted at the request of the sponsor.

CMV = cytomegalovirus; IAT = investigator-assigned treatment.

Confidential figure redacted at the request of the sponsor.

Source: SOLSTICE Clinical Study Report.⁴

Figure 5: Cumulative Probability of First CMV Viremia Clearance at Study Week 8 to CMV Viremia Recurrence Requiring Alternative Treatment (Randomized Set)

Confidential figure redacted at the request of the sponsor.

Source: SOLSTICE Clinical Study Report.⁴

Table 26: Time from First CMV Viremia Clearance to CMV Viremia Recurrence (Randomized Set)

CMV = cytomegalovirus; CI = confidence interval; IAT = investigator-assigned treatment; NE = not estimable.

^aTwo-sided P value comparing treatment groups is from the log-rank test by Kaplan–Meier method. P value was not adjusted for multiple comparisons.

Source: SOLSTICE Clinical Study Report.⁴

Table 27: Time from CMV Viremia Clearance at Week 8 to CMV Viremia Recurrence Requiring Alternative Treatment (Randomized Set)

CI = confidence interval; CMV = cytomegalovirus; IAT = investigator-assigned treatment; NE = not estimable.

^aTwo-sided P value comparing treatment groups is from the log-rank test by Kaplan–Meier method. P value was not adjusted for multiple comparisons.

Source: SOLSTICE Clinical Study Report.⁴

All-Cause Mortality

Results for the all-cause mortality are summarized in Table 28. The number of patients who died in the maribavir group was 27 (11.5%) and 13 (11.1%) in the IAT group.

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Figure 6: Cumulative Probability of All-Cause Mortality (Randomized Set)

Confidential figure redacted at the request of the sponsor.

Table 28: Time to All-Cause Mortality (Randomized Set)

CI = confidence interval; IAT = investigator-assigned treatment.

^aTwo-sided P value comparing treatment groups is from the log-rank test by Kaplan–Meier method. P value was not adjusted for multiple comparisons.

^bStratified Cox regression model using transplant type and baseline plasma CMV DNA level as stratification factors.

Source: SOLSTICE Clinical Study Report.⁴

Health Care Resource Utilization

Results from the health care resource utilization data are summarized in Table 29.

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Antiviral Resistance

Results from the treatment-emergent known RASs is summarized in Table 30. In the maribavir group, 42 (19.6%) patients had new maribavir treatment-emergent known RASs in pUL97 or pUL27. For RASs known to confer resistance to IAT (i.e., pUL97 and pUL54), 12.9% of patients in the maribavir group and 4.9% of patients in the IAT group had new treatment-emergent RASs.

HRQoL

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Table 29: Summary of Health Care Resource Utilization

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Table 30: Summary of Treatment-Emergent Known Resistance-Associated Amino Acid Substitutions (Modified Randomized Set)

CMV = cytomegalovirus; IAT = investigator-assigned anti-CMV treatment; MRS = maribavir-resistance set; PRS = primary resistance set; RAS = resistance-associated amino acid substitution.

^aIncludes maribavir RASs with cross-resistance to IAT.

Source: SOLSTICE Clinical Study Report.⁴

Table 31: Summary of SF-36v2 (Randomized Set)

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Note: Some redacted rows have been deleted.

Source: SOLSTICE Clinical Study Report.⁴

Table 32: Summary of EQ-5D (Randomized Set)

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Note: Some redacted rows have been deleted.

Harms

Only those harms identified in the review protocol are reported below. Refer to Table 33 for detailed harms data for the safety analysis set.

Adverse Events

Overall, 228 (97.4%) patients in the maribavir group and 106 (91.4%) patients in the IAT group experienced ≥ 1 treatment-emergent adverse event. The most common AEs were dysgeusia (maribavir: 37.2% versus IAT: 3.4%), nausea (maribavir: 21.4% versus IAT: 21.6%), and diarrhea (maribavir: n = 44, IAT: n = 31).

Serious Adverse Events

Overall, 90 (38.5%) patients in the maribavir group and 43 (37.1%) in the IAT group experienced at least 1 SAE (i.e., treatment-emergent). The most common SAEs were infections and infestations (maribavir: 22.6% versus IAT: 14.7%).

Withdrawal Due to Adverse Events

Overall, 31 (13.2%) patients in the maribavir group and 37 (31.9%) in the IAT group permanently discontinued treatment with study drugs due to treatment-emergent AEs. In the maribavir group, infections and infestations led to the discontinuation of 17 (7.3%) patients. In the IAT group, blood and lymphatic system disorders and renal and urinary disorders led to the discontinuation of 13 (11.2%) and 11 (9.5%) of patients, respectively.

Mortality

In SOLSTICE, a total of 27 (11.5%) patients in the maribavir group and 13 (11.2%) patients in the IAT group died.

Notable Harms

Overall, 55 (23.5%) patients in the maribavir group and 22 (19.0%) patients in the IAT group enrolled in SOLSTICE experienced invasive fungal or bacterial or viral infections. The most common types of infections were pneumonia (maribavir: 3.4% versus IAT: 1.7% patients), BK virus infection (maribavir: 2.1% versus IAT: 3.4% patients) and enterococcal infection and herpes zoster (maribavir: 2.1% versus IAT: 0.0% patients). Increase in immunosuppressant drug concentration levels was experienced by 21 (9.0%) patients in the maribavir group and 1 (0.9%) patient in the IAT group. Taste disturbance was experienced by 87 (37.2%) patient in the maribavir group and 4 (3.4%) patients in the IAT group.

Table 33: Summary of Harms (Safety Set)

AE = adverse event; CMV = cytomegalovirus; GVHD = graft vs. host disease; SAE = serious adverse event.

^aFrequency of greater than 5% in at least one arm.

Source: SOLSTICE Clinical Study Report⁴

Graft Outcomes

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Table 34: Summary of Graft Outcomes (Randomized Set)

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Note: Some redacted rows have been deleted.

Critical Appraisal

Internal Validity

SOLSTICE was an open-label trial, whereby the open-label design can increase the risk for of performance and detection bias, particularly for outcomes that are subjective in measurement and interpretation (e.g., symptoms, HRQoL, subjective AEs). However, the clinical experts noted that the need to individualize IAT, and the route of administration and side effects unique to maribavir would make blinding unfeasible. Given that the primary end point and multiple secondary end points were objective measures relying on a central lab and an EAC, the risk of detection bias is probably low. The end point used to assess response, CMV viremia clearance at the end of 8-week treatment phase, was a validated surrogate end point.^58,59

Patients in SOLSTICE were assigned numbers according to the sequence of presentation for study participation and following stratification (for transplant type and CMV DNA viral load category), patients were randomized to either group using IRT, likely adequate allocation concealment. Both the treatment groups were relatively balanced, with some notable differences in characteristics such as age, type of preparative conditioning regimen, presence of CMV RASs, and CMV serostatus for HSCT Donor/Recipient, CMV DNA level, and net immunosuppression use changed before initiation of study treatment. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. It is uncertain whether the baseline differences between the IAT and maribavir groups are attributable to chance; however, the risk of bias due to the randomization process is probably low.

The analysis populations used in the SOLSTICE trial were appropriate for measuring the effect of assignment to the interventions. The randomized set was used for most analyses. For the primary and key secondary analysis in SOLSTICE, patients who received non–study treatment or were included in the rescue arm before week 8 were counted as non–responders. Safety outcomes were assessed in all patients that were treated with a study drug, which excluded 2 patients from the randomized set (patients in the rescue arm were reported separately). The sample size of 352 patients was adequate to estimate the primary end point of treatment response to detect a statistically significant difference at 90% power. All analyses were pre-specified. Only the primary and key secondary outcomes were adjusted for multiple comparisons, so there is uncertainty in the conclusions for other outcomes.

The comparators used in SOLSTICE were identified by the clinical experts as appropriate. Statistical testing was performed for the primary and key secondary outcomes and results were adjusted for transplant type and baseline plasma CMV DNA concentration levels if homogeneity across strata were not met.

Most of the subgroup analyses for response (primary end point) were pre-specified. Although statistical testing was conducted, the sample sizes for the subgroup analyses were small and the CIs reflected imprecision, and there was no control for type I error due to multiple testing. As a result, no conclusions can be drawn by the CADTH review team based on the subgroup analyses.

Multiple protocol amendments were implemented while the SOLSTICE study was being conducted, which included a minor change to the study eligibility criteria (i.e., ability to swallow pills). It was noted by the clinical experts consulted by CADTH that analyzing those who discontinued early in the primary efficacy analysis as responders seemed appropriate.

A high rate of protocol deviations occurred in SOLSTICE, similar in both groups, which creates some uncertainty in the data. Key protocol deviations were related to investigator patient medical care (i.e., laboratory reports or safety information not reviewed or followed up in a timely manner by the investigator), investigator safety reporting (regulatory or sponsor), visit scheduling, investigator safety reporting eCRF, and study treatment compliance. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| (per the sponsor, if ≥ 5% of patients had missing CMV DNA data to confirm response at week 8 due to the COVID-19 pandemic, missing CMV DNA levels were to be imputed using a multiple imputation method). Although deviations in study drug and treatment could confound results, given that the rate of protocol deviations was similar between the 2 study groups, this is not likely to be of concern.

External Validity

The SOLSTICE trial was an international, multicenter study that included sites in Europe, US, and Canada. One stark difference between how the treatment was administered in SOLSTICE and what would be expected in routine clinical practice was the 8-week fixed duration. As identified by the clinical experts, clinicians treat patients until CMV DNA levels are low enough or negative, not for a fixed duration. Although the comparators used in the trial are reflective of clinical practice, the distribution of selected IAT treatments was noted as inconsistent with Canadian clinical practice. It may be difficult to design a trial with IAT distributions that reflect the diversity of Canadian clinical practice. Given these limitations of the trial, generalizability of results to the Canadian setting is uncertain. Furthermore, because of pooling of effects in the IAT group, no conclusions can be made about maribavir versus any particular antiviral.

The clinical experts consulted by CADTH reported that standard of care for assessing treatment response would be PCR testing every week. In the SOLSTICE study, after 8 weeks the treatment response was assessed by PCR testing weekly until week 12, then every 2 weeks through to week 20. The experts highlighted that turnaround time from testing to results for resistance may be longer than what is required for immediate care (irreversible outcomes such as death can occur in patients), often necessitating a treatment switch before the results are available and using the results for decision to continue with the new therapy.

The clinical experts indicated that the baseline characteristics of patients enrolled in SOLSTICE were generally representative of the post-transplant CMV patient population in Canada, although they noted that the SOLSTICE study patients would represent the healthiest patients in this population, which is common in clinical trials. Particularly, the post-transplant patients were assessed for performance using the Karnofsky scores, and clinical experts highlighted those patients in routine clinical practice would not be performing as well (i.e., scores would rarely be 100). Furthermore, the clinical experts noted that healthier patients with lower baseline viral load are less likely to develop resistance.

Overall, the clinical experts thought that the eligibility criteria used in the SOLSTICE study were appropriate and allowed enrollment of patients with post-transplant CMV infection that were generally representative of the Canadian patient population. The experts also noted that excluding CMV central nervous system and CMV retinitis, which is uncommon in patients with HSCT, is appropriate as maribavir may not penetrate the brain and/or eyes. A small proportion of patients screened (15.2%) were screen failures. The most frequently reported reasons for screen failure were failure to demonstrate confirmed minimum CMV viral load and failure to demonstrate that current CMV infection was refractory to the most recent CMV treatment, which are appropriate reasons given the study objectives and drug indication. Discontinuation rates of 79 (67.5%) patients in the IAT arm and 51 (21.7%) patients in the maribavir arm were as expected by the clinical experts. It was noted that most early discontinuations were due to lack of efficacy or clinical reasons (i.e., adverse events or toxicities), which was expected by the clinical experts because for AEs such as myelosuppression or renal toxicity, clinicians strive to get patients off drugs with known toxicities to avoid irreversible outcomes such as transplant failure or death.

In SOLSTICE, health care resource utilization (i.e., hospitalization rates and length of stay) was lower in the maribavir population. However, the clinical experts noted that these findings may not be generalizable given the variation in available health care resources across provinces and territories.

The primary outcome of response confirmed by CMV clearance and the key secondary outcome that also includes CMV symptom control is relevant to clinical practice and clinically meaningful to patients, as noted by the clinical experts and patient groups. Better HRQoL and fewer side effects compared to current therapies were also important considerations for patients.

Indirect Evidence

Objectives and Methods for the Summary of Indirect Evidence

A focused literature search for ITCs dealing with cytomegalovirus infections was run in MEDLINE All (1946-) on April 29, 2022. No limits were applied to the search.

No reports were found.

Other Relevant Evidence

This section includes additional relevant data included in the sponsor’s submission to CADTH that were considered to address important gaps in the evidence included in the systematic review.

IPD Analyses of SOLSTICE

The sponsor-provided IPD analysis conducted on data from SOLSTICE as additional explorations to the analyses already reported in the CSR. Description and results of the IPD analyses can be found in Appendix 5.

The sponsor’s rationale for undertaking the IPD analysis was that in some cases evidence from SOLSTICE was not reported in a format that could be readily incorporated into the maribavir global cost-effectiveness model (CEM) version 2. The results of the IPD analyses were used as direct inputs into the base case and scenarios of the CEM. These analyses were mostly exploratory and descriptive. Analyses with statistical testing were not pre-defined in a statistical analysis plan and were performed in a post-hoc manner. Therefore, definitive conclusion regarding efficacy and safety of maribavir cannot be drawn based on this evidence. As the sponsor has noted, the IPD analyses are exploratory and intended to be used as input for the CEM.

Discussion

Summary of Available Evidence

One open-label, randomized, double-arm phase III trial (SOLSTICE, N = 352) was included in the CADTH systematic review. The primary objective of the SOLSTICE study was to compare the efficacy and safety of maribavir versus IAT for treatment of refractory CMV infection (with or without resistance) in SOT and HSCT recipients. The trial included adult patients with documented CMV infection that is refractory to the most recent treatment or resistant (only if patients also met refractory criteria). Patients received 400 mg oral maribavir twice daily for up to 8 weeks. The primary end point was confirmed CMV viremia clearance at the end of week 8 (regardless of premature treatment discontinuation). The key secondary end point was a composite of confirmed CMV viremia clearance and symptom control at the end of week 8, maintained through week 16 (8 weeks beyond the treatment phase) after receiving exclusively study-assigned treatment. Other secondary end points included recurrence, all-cause mortality, health care resource utilization, and HRQoL. Harms outcomes were also examined. In the SOLSTICE study, both treatment groups were mostly balanced across characteristics, but there were notable differences across characteristics across age, type of preparative conditioning regimen, presence of CMV RASs, and CMV serostatus for HSCT Donor/Recipient, CMV DNA level, and net immunosuppression use changed before initiation of study treatment.

Interpretation of Results

Efficacy

Patients with post-transplant CMV infection that is refractory or resistant to first-line treatments have limited treatment options and poor outcomes. Current therapies have known toxicities and often require IV administration, resistance being a concern in SOT patients, whereby Donor+/Recipient- and lung transplant patients are more likely to develop resistance. Both the clinical experts and patient groups indicated that there is significant unmet need in this patient population, especially in older patients with immunosenescence and renal issues and patients with CMV infection that is resistant to therapies such as ganciclovir and/or valganciclovir and foscarnet.

The SOLSTICE trial investigated maribavir compared with IAT in adult patients with refractory CMV infection with or without resistance. The primary end point of the study was met since the adjusted difference in proportion of responders at week 8 between maribavir and IAT was 32.8% (95% CI, 22.80 to 42.74; P < 0.001), in favour of maribavir. More than 3/4 (78%) of patients completed the assigned 8-week treatment course of maribavir, as opposed to about 1/3 (32%) for IAT. This may be a function of lower efficacy and higher toxicity of the latter treatment, as illustrated by the higher early discontinuation rate and discontinuation due to AEs. The study included multiple sensitivity analyses of the primary and key secondary end points to address the potential for bias due higher rates of discontinuation in the IAT group.

The key secondary end point in SOLSTICE was supportive of the primary end point, as the adjusted proportion of responders at week 8 and maintenance at week 16 was 9.5% (95 CI, 2.02 to 16.88, P = 0.013). The results for other secondary outcomes related to confirmed CMV clearance and CMV symptom control maintenance at different time points was generally supportive of the findings for the primary end point; however, these outcomes were not adjusted for multiplicity and definitive conclusions cannot be drawn.

Comparative recurrence data were difficult to interpret because clearance is prerequisite for recurrence. Recurrence of CMV viremia during the first 8 weeks of the study occurred for 17.9% of maribavir-treated patients and 12.3% of IAT-treated patients. Recurrence occurred more frequently in the maribavir group than in the IAT group during the follow-up after week 8 (maribavir: 38.6% versus IAT: 21.5%). The sponsor indicated that there were a disproportionately higher proportion of patients with virologic clearance in the maribavir arm compared with IAT (maribavir: 78.3% versus IAT: 55.6%), which may have contributed to the higher recurrence rate for maribavir-treated patients compared with IAT in the follow-up period. Though recurrence was more frequent in the maribavir group, recurrence requiring treatment was lower in the maribavir group (maribavir: 26.0% versus IAT: 35.7%). The clinical experts consulted by CADTH indicated that recurrence is expected in this population because of the concomitant use of immunosuppression in some patients and is largely a function of underlying patient factors. Of note, the time to viremia recurrence appears to be similar or shorter for maribavir, which may mean that maribavir does not offer a longer disease-free interval in responders (Table 26 and Table 27). While response was higher with maribavir, it was not maintained and decreased steadily at later time points for both treatments (Table 21). Kinetics of viremia clearance (Figure 3 and Table 22) seem to slightly favour maribavir, but the absence of formal statistical testing precludes drawing definitive conclusions.

Resistance is a concern in this patient population, including developing resistance to maribavir, which would render the drug less efficacious, as noted by the clinical experts. In the maribavir group, 19.6% of patients who received maribavir had new treatment-emergent RASs known to confer resistance to maribavir detected in their genotype. Similarly, 12.9% of patients in the maribavir group had new treatment-emergent RASs known to confer resistance to IAT detected in their genotype and 4.9% of patients in the IAT group had new treatment-emergent RASs known to confer resistance to IAT detected in their genotype.

The findings for all-cause mortality between the treatment groups in the analysis based on all patients and in the analysis censoring patients at the start of alternative anti-CMV treatment or maribavir rescue therapy was inconclusive due to imprecision indicated by the wide confidence intervals. As noted by the clinical experts consulted by CADTH, these patient population has several patient-specific factors that may impact mortality.

Health care resource utilization between the treatment groups demonstrated a slight difference, favouring slightly lower hospitalization rate and length of stay for patients in the maribavir group (during the on-treatment study period). However, as values were not adjusted for multiple comparisons, limited conclusions can be drawn. Furthermore, the clinical experts noted that findings may not be generalizable given the variation in available health care resources across provinces and territories.

HRQoL was identified as an important outcome to patients. Reported HRQoL data seemed to indicate that EQ-5D and SF-36 scores generally improved during the study period, across both treatment groups. Although data were reported, differences between treatment groups were not tested statistically and there are concerns for missing data. Given the lack of literature assessing the EQ-5D or SF-36 for MID, validity, reliability, or responsiveness in patients with post-transplant CMV infection, no definitive conclusions can be drawn by the CADTH review team.

Multiple subgroup analyses that aligned with subgroups of interest in the CADTH review protocol were conducted in the SOLSTICE study. Most of the subgroups were pre-specified in the SOLSTICE study protocol. Results were broadly numerically consistent across various subgroups of interest. However, due to the small sample sizes, wide CIs, and absence of control for type I error, no definitive conclusions can be drawn by the CADTH review team.

Harms

SOLSTICE data related to harms indicated that maribavir is generally a safe option for patients, though there are some concerns with TEAEs such as dysgeusia, bacterial and fungal infections, and increased immunosuppressant drug concentrations.

Although a greater proportion of maribavir-treated patients had at least 1 TEAEs (maribavir: 97.4% versus IAT: 91.4%), the higher AEs in the maribavir group appeared to be driven by dysgeusia (maribavir: 37.2% versus IAT: 3.4%), which only led to discontinuation in 2 (0.9%) patients. Although maribavir may eliminate hospital visits needed for drug administration, which is an unmet need of patients, the side effect of dysgeusia – albeit manageable – still may be a concern for patients.

The rate of infections and infestations was also higher in patients treated with maribavir (maribavir: 22.6% versus IAT: 14.7%). ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

In SOLSTICE, 9.0% of patients in the maribavir group had TEAEs of increased immunosuppressant drug levels compared to 0.9% of patients in the IAT group, which was expected by the clinical experts given this had been explored in prior studies and is listed in the product monograph as a concern. The experts indicated this may be managed by reducing doses of concomitant immunosuppressant drugs.

Known hematologic and renal toxicities of existing drugs indicate a gap in the treatment landscape for post-transplant patients with CMV infection. Maribavir had a lower incidence of overall treatment-emergent SAEs associated with blood and lymphatic system (maribavir: 7.3% versus IAT: 18.1%) and renal and urinary treatment-emergent SAEs (maribavir: 3.8% versus 5.2%). There were no patients in the maribavir group who discontinued treatment for treatment-emergent hematologic disorders or renal and urinary disorders (SAEs).

Conclusions

One open-label, randomized, double-arm phase III trial (SOLSTICE, N = 352) was included in the CADTH systematic review. The primary objective of the SOLSTICE study was to compare the efficacy and safety of maribavir versus IAT for treatment of refractory CMV infection (with or without resistance) in SOT and HSCT recipients. There is evidence of maribavir being more efficacious when compared to the IAT on achieving CMV viremia clearance and symptom control. However, disease control with maribavir is time-limited, in line with other antivirals. Conclusions for all-cause mortality could not be drawn because the 95% confidence interval around the hazard ratio was wide, including the possibility of both appreciable benefit and harm for maribavir compared with IAT. The proportion of patients experiencing taste disturbance, increased immunosuppressant concentration levels, and infections and infestations was higher with maribavir, but these events were manageable. The lower rates of hematologic and renal toxicities with maribavir fill a gap in the treatment landscape whereby other drugs have known toxicities limiting their use. Fewer patients in the maribavir group discontinued treatment due to AEs. There remains uncertainty on interpreting data for outcomes related to CMV recurrence, antiviral resistance, HRQoL, health care resource utilization, and subgroup analyses given the various methodological limitations.

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Appendix 1: Literature Search Strategy

Note that this appendix has not been copy-edited.

Systematic Review Search

Date of final search (as run): April 29, 2022

Limits: conference abstracts excluded

Filters suggested: None

Filters used: None

Databases: MEDLINE, Embase

MEDLINE

(maribavir* or livtencity* or benzimidavir* or benzimidazole riboside* or 1263w or 1263w94 or 1263 w 94 or bw1263 or bw1263w94 or gr 257406 or gr257406 or gw 1263 or gw1263 or GW 257406X or GW257406X or PTB4X93HE1).ti,ab,kf,ot,hw,rn,nm.

Embase

*Benzimidavir/ (maribavir* or livtencity* or benzimidavir* or benzimidazole riboside* or 1263w or 1263w94 or 1263 w 94 or bw1263 or bw1263w94 or gr 257406 or gr257406 or gw 1263 or gw1263 or GW 257406X or GW257406X).ti,ab,kf,dq.

Record search here, final “as run”:

• Database(s): Embase 1974 to 2022 April 28, Ovid MEDLINE(R) ALL 1946 to April 28, 2022

Table 35: Systematic Review Search on Embase and MEDLINE Databases