CADTH Reimbursement Review

Berotralstat (Orladeyo)

Sponsor: BioCryst Pharmaceuticals Inc.

Therapeutic area: Hereditary angioedema (HAE)

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.

Table 1: Submitted for Review

NOC = Notice of Compliance.

Introduction

Hereditary angioedema (HAE) is a rare autosomal-dominant disorder characterized by recurrent episodes of nonpruritic subcutaneous or submucosal edema, most commonly affecting the skin (cutaneous attacks), gastrointestinal tract (abdominal attacks), and respiratory tract (laryngeal attacks).¹ The reported prevalence of HAE ranges from 1 in 93,000 to 1 in 50,000.^1-3 There are 3 types of HAE: type 1 (85% of patients) is caused by decreased secretion of complement 1 esterase inhibitor (C1-INH); type 2 (15% of patients) is characterized by normal or elevated production of functionally impaired C1-INH; and a third type, known as HAE with normal C1-INH (formerly referred to as type 3 HAE), is characterized by normal C1-INH levels and function (prevalence is uncertain).¹ Therapeutic options available in Canada for long-term prophylactic (LTP) treatment include C1-INHs, lanadelumab, oral attenuated androgens (e.g., danazol), and antifibrinolytics (e.g., tranexamic acid).¹ The most commonly used treatments in Canada are C1-INHs, which replace missing or malfunctioning C1-INH proteins, but all are derived from human plasma and are administered by IV or subcutaneous (SC) injection. Lanadelumab also requires SC administration. Oral danazol and tranexamic acid are not approved to treat HAE and are limited by frequent and potentially serious adverse effects or poor efficacy.

Berotralstat is a plasma kallikrein inhibitor that decreases plasma kallikrein activity and controls excess bradykinin generation in patients with HAE.⁴ The Health Canada indication is for the routine prevention of HAE attacks in adults and pediatric patients aged 12 years and older.⁴ Berotralstat is available as a 150 mg oral capsule and the recommended dose is 150 mg once daily.⁴ Health Canada states that berotralstat should not be used for the treatment of acute HAE attacks, as the safety and efficacy for this use has not been established.

The objective of this report is to perform a systematic review of the beneficial and harmful effects of berotralstat for the routine prevention of recurrent episodes of HAE in adults and pediatric patients aged 12 years and older.

Stakeholder Perspectives

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

Patient Input

One patient group, Hereditary Angioedema Canada (HAEC), submitted patient input for this review. HAEC is dedicated to creating awareness about HAE and related angioedemas, helping speed the diagnosis of patients, improving access to treatments, and enabling patients to become champions of their own quality of life. The input was based on data collected from surveys in 2019 (n = 66) and 2021 (n = 138), qualitative interviews with 11 patients with a mix of either type 1 or type 2 HAE, and comments from 3 patients who had experience with the treatment under investigation in a clinical trial.

Respondents rated on a scale of 1 (not at all) to 5 (significant) the impacts HAE had on their day-to-day activities, with weighted averages ranging from 2.20 for impacts on their ability to conduct household chores to 2.94 for affecting their ability to travel. The majority had to miss time from work due to HAE. Approximately 20% of patients reported that HAE required out-of-pocket expenditures for medical care, or that they were either very dissatisfied or dissatisfied with their current treatments. Among the 3 patients who had experience with berotralstat, 1 patient described the treatment as extremely effective in preventing episodes of HAE and the adverse effects as easy to tolerate. Two patients did not find the treatment effective in the prevention of episodes of HAE.

According to the patient input received, a majority of patients are seeking treatments with an easier mode of delivery, and some prefer a product that is not derived from plasma. Patients continue to seek treatments that better control attacks while offering greater convenience and ease of use. Treatments that eliminate or substantially reduce attacks compared to existing treatments are of critical importance to patients, as each angioedema attack can be severely debilitating, and in many cases life-threatening. Greater control of attacks would also reduce the anxiety and fear many patients experience due to unpredictable attacks and reduce the negative impact on a patient’s ability to work, pursue education, travel, exercise, do household chores, and socialize with family and friends.

Clinician Input

Input From Clinical Expert Consulted by CADTH

According to the clinical expert consulted by CADTH, the treatment burden of the injectable products used for LTP therapy can be substantial, particularly for those who have difficulty with self-administration by IV or SC injection, and considering the frequency of administration of C1-INH. Although androgens are administered orally, they are associated with significant adverse effects, and are contraindicated in certain patient populations. The expert noted that berotralstat could be considered a first-line option for LTP therapy, although it may not be the preferred option for use in women who are pregnant or in patients aged younger than 12 years due to limited clinical data.

The expert indicated that patients could be considered good candidates for treatment with berotralstat if they experience frequent HAE attacks that require acute treatment. The oral route of administration may be preferred for some patients and could be useful for patients who have to travel, for whom an LTP with C1-INH may be impractical. Patients who may not be appropriate candidates for treatment with berotralstat include those who were misdiagnosed as having HAE, but actually have histaminergic chronic urticaria or histaminergic idiopathic angioedema; those with HAE but who only have mild and intermittent symptoms (i.e., patients for whom on-demand therapy is sufficient); those who are currently well controlled and satisfied with their existing LTP therapy; and those who have a significant adverse reaction to berotralstat.

The ability to prescribe berotralstat should be limited to specialists with an expertise in the diagnosis and management of patients with angioedema, including immunologists, allergists, and hematologists. This will help ensure that the correct diagnosis has been made before initiating treatment with berotralstat and that the response to treatment is appropriately monitored. Response to treatment would be assessed based on a reduction in the frequency, severity, and duration of attacks. Patients and clinicians would also be seeking an increase in the ability to perform activities of daily living during attacks if these were previously affected. The expert noted that response to treatment with an LTP such as berotralstat would be initially assessed after 3 months, with subsequent follow-ups occurring every 6 or 12 months. The following were identified as situations in which discontinuing treatment with berotralstat could be appropriate: pregnancy, as adverse effects during pregnancy are unknown and C1-INH is the preferred option; intolerable adverse effects with berotralstat; or an inadequate response or loss of response (e.g., increase in attacks requiring rescue medication).

Clinician Group Input

Ten clinicians representing the Canadian Hereditary Angioedema Network provided input for this review. The input noted a need for a treatment to prevent attacks, improve the acute management of HAE, and provide convenient methods of self-administration. Patients with HAE are at risk of experiencing a life-threatening laryngeal attack, which can have a considerable impact on their health-related quality of life (HRQoL). Furthermore, IV treatments may have the effect of requiring patients to spend much time travelling to treatment and undergoing treatment if they are unable to self-administer. Current off-label oral prophylaxis options for Canadians include androgen therapy such as danazol. Androgens are associated with a range of severe adverse effects, such as headaches, hypertension, weight gain, masculinizing effects for women, hepatocellular carcinoma, dyslipidemia, and cardiac disease. The input suggests the treatment under review may provide a safe and effective oral prophylactic that may be preferred to the current standard of care by some patients, particularly those averse to long-term injections. The input recommends that the treatment be considered for all patients who are candidates for long-term prophylaxis.

Drug Program Input

The drug programs asked several questions regarding the place in therapy of berotralstat, potential for use in combination with other LTP treatments, and use in patients with HAE and normal C1-INH or children less than 12 years of age. The expert stated that the place in therapy of berotralstat would be similar to that of lanadelumab (Takhzyro), and that alignment with lanadelumab initiation, renewal, and discontinuation criteria were reasonable. No specific number of attacks is used as a threshold to initiate LTP therapy in clinical practice, but the criteria used in the clinical trials are often used as a guide. Patients with infrequent but severe HAE attacks may also benefit from LTP therapy. The clinical expert stated that no efficacy or safety data currently support the use of berotralstat in patients with HAE with normal C1-INH levels or in pediatric patients younger than 12. Data are lacking on the efficacy of berotralstat as add-on LTP therapy, although concurrent use with short-term prophylaxis or rescue treatment of acute attacks was allowed during the trials. The expert noted that patients may switch between different LTPs, although establishing response criteria for reimbursement in these patients may be difficult as the baseline (untreated) attack rate may not be known.

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Studies

The systematic review included 2 double-blind randomized controlled trials (RCTs) that evaluated the efficacy and safety of berotralstat versus placebo in patients aged 12 years and older with type 1 or 2 HAE who experienced at least 2 investigator-confirmed HAE attacks during the run-in period. The APeX-2 and APeX-J studies randomized patients to placebo, berotralstat 110 mg daily, or berotralstat 150 mg daily for 24 weeks (part 1), after which all patients in the placebo group were randomized to berotralstat 110 mg or 150 mg daily, and those on the active drug continued with the same dose for part 2 (double-blind, up to week 48 in the APeX-2 study or week 52 in APeX-J). In the subsequent part 3 of the trials, all patients were switched to open-label berotralstat 150 mg daily (up to week 240 in the APeX-2 study or week 104 in APeX-J). During the trials, all patients had access to standard-of-care treatments for acute HAE attacks (e.g., C1-INH or icatibant acetate). The primary outcome in both studies was the rate of investigator-confirmed HAE attacks over 24 weeks (part 1). All patient-reported HAE attacks were confirmed by the investigator if they included symptoms of swelling, which could be visible swelling or symptoms in the oropharyngeal or abdominal regions that are indicative of internal swelling. This review focused on a comparison of berotralstat 150 mg and placebo at 24 weeks that included 80 patients from the APeX-2 study and 13 patients from the APeX-J trial. Data from the berotralstat 110 mg group are not summarized in this report.

The APeX-2 study was conducted in 11 countries, including Canada (3 sites), the US, and Europe. The mean ages of patients enrolled were 40.0 years (standard deviation [SD] = 14.0) and 44.5 years (SD = 14.1) in the berotralstat 150 mg and placebo groups, respectively. Patients were predominantly female (58% and 68%, respectively), and white (95% and 93%, respectively), with mean baseline rates of 3.1 (SD = 1.6) and 2.9 (SD = 1.1) investigator-confirmed HAE attacks per month in the berotralstat 150 mg and placebo groups, respectively.

The APeX-J study was conducted at multiple centres in Japan. The enrolled patients had a mean age of 37.3 years (SD = 9.1) in the berotralstat 150 mg group and 42.3 years (SD = 13.5) in the placebo group. Most patients were female (86% and 83%, respectively) and Asian (86% and 100% in the berotralstat and placebo groups, respectively). At baseline, the mean expert-confirmed attacks per month was 2.0 (SD = 1.1) in the berotralstat 150 mg group and 2.5 (SD = 1.5) in the placebo group.

Efficacy Results

In the APeX-2 study, the rate of investigator-confirmed HAE attacks per month was 1.31 for the berotralstat 150 mg group and 2.35 for the placebo group, during the 24-week double-blind treatment period. The relative rate reduction was 44.2% (95% confidence interval [CI], 23.0% to 59.5%; P < 0.001) for berotralstat 150 mg versus placebo (Table 2). The results of the primary outcome were similar in the APeX-J study, which reported 1.11 and 2.18 expert-confirmed HAE attacks per month in the berotralstat 150 mg and placebo groups, respectively, with a rate reduction of 49.1% (95% CI, 20.4% to 67.5%; P = 0.003).

In the APeX-2 study, 58% of patients in the berotralstat 150 mg group and 25% in the placebo group achieved at least a 50% relative reduction in the rate of investigator-confirmed HAE attacks compared to baseline (odds ratio = 3.91, 95% CI, 1.51 to 10.16; P = 0.005) (Table 2). However, these analyses were not adjusted for multiple testing and should be interpreted with caution because of the potential for inflated type I error rate.

█ ██ █ ███ █ ███ in the berotralstat 150 mg group (██) of the APeX-2 study, and 1 patient in the placebo group (2.6%) had no investigator-confirmed HAE attacks during the 24-week treatment period. ████ █ █ ██ █ ████ the APeX-J study reported ██ █ █ █ █ ██ █ ██████ █ █ during the first 24 weeks of treatment.

The number and proportion of days with HAE symptoms during the first 24 weeks was a secondary outcome in the APeX-2 study. Patients in the berotralstat 150 mg group reported a mean of 19.4 days (SD = 21.5) with HAE symptoms compared with 29.2 days (SD = 24.3) for patients in the placebo group. The least squares (LS) mean difference in the proportion of days with symptoms was −0.078 (95% CI, −0.133 to −0.023), which translates to approximately 13 fewer symptom-days in the berotralstat versus placebo group (out of a total of 169 treatment days). Although the proportion of days with HAE symptoms favoured berotralstat over placebo, these data should be interpreted as indeterminate due to failure of a prior outcome in the statistical analysis hierarchy. In the APeX-J study, no statistically significant difference was detected between groups in the proportion of days with HAE symptoms (LS mean difference = −0.122; 95% CI, −0.280 to 0.036; P = 0.12).

HRQoL was measured using the Angioedema Quality of Life (AE-QoL) questionnaire. While both the berotralstat 150 mg and placebo groups of the APeX-2 study reported improvements in AE-QoL total scores at week 24 relative to baseline, no statistically significant difference was detected between groups in the LS mean difference (−4.9 points; 95% CI, −12.2 to 2.4; P = 0.19). In the APeX-J study, the LS mean difference for the change from baseline in the AE-QoL total score was −19.0 (95% CI, −39.0 to 1.0).

New information supplied by the sponsor as part of its Request for Reconsideration showed that, during part 2 of the APeX-2 study (week 24 to 48), the mean investigator-confirmed attack rates per month in the berotralstat 150 mg group were 1.7 (SD = ███) at 24 weeks (N = ██), and 1.1 (SD = ███) at week 48 (N = ██). The mean number of days with angioedema symptoms during part 2 was ████ days (SD = ████), and the proportion of days with symptoms was █████ (SD = █████) for patients in the berotralstat 150 mg group. Among the patients who switched from placebo to berotralstat 150 mg at week 24 (N = 17), the mean attack rate per month was ███ events (SD = ███) at 24 weeks (i.e., start of active treatment), and 0.6 events (SD = ███; N = 14) at 48 weeks. The proportion of days with angioedema symptoms was █████ █ ████ █ ███ for patients who switched to berotralstat 150 mg. Overall 83% of patients completed part 2 of the study, with 7 patients (13%) stopping therapy due to adverse events or lack of efficacy, and 2 others (4%) stopping for other reasons.

Among the ██ patients who entered part 3 of the APeX-2 study and received open-label berotralstat 150 mg daily, the overall adjusted patient-reported HAE attack rate was ███ events per month (SD = ███) while patients remained on treatment. The mean number of days with angioedema symptoms was ████ days (SD = ████), which corresponds to a proportion of days of ███ █ █ (SD = █████). During part 3, ██ patients (███) stopped treatment for the following reasons: █ █ ████ █ █ █ ███ █ ██ █ █ █ █ █ █ █ █ ██████ █ █████ █ ███████████████ █ ███████████ █ ████████ █ ███ █ ████ █ █████████ █ █ █ █ █ █ █ █ █ ██████ █ █████ █ ██████ █ ███████████ █ █ ██ █ ███████ █ ███████ █ █████████████ █ ███

Harms Results

Adverse events were reported by 85% of patients in the berotralstat 150 mg group and 77% of those in the placebo group during the first 24 weeks of the APeX-2 study. The most frequently reported events in the berotralstat group were nasopharyngitis (23%), nausea (15%), vomiting (15%), and diarrhea (13%). Gastrointestinal adverse events were reported more frequently by patients who received berotralstat 150 mg compared with those who received placebo (50% versus 36%).

No patients in the berotralstat group experienced a serious adverse event during the first 24 weeks of the APeX-2 study, whereas 3 patients in the placebo group experienced 4 serious adverse events (uterine leiomyoma, diverticulum intestinal hemorrhage, pneumonia, and transient ischemic attack). One patient in the berotralstat 150 mg group stopped treatment due to abnormal liver function test results, and 1 patient in the placebo group stopped the study drug due to a depressive episode. No deaths were reported, and no new safety signals were identified in part 2 ██ █ ████ of the APeX-2 trial among patients who received berotralstat 150 mg ██ █ ████ █ █ █ █████

All patients in the APeX-J study experienced 1 or more adverse events in the first 24 weeks. Gastrointestinal adverse events were reported by 43% of patients in the berotralstat 150 mg group compared with 17% of patients in the placebo group. One placebo-treated patient stopped treatment due to urticaria and no patients stopped treatment in the berotralstat 150 mg group. No serious adverse events were reported.

Table 2: Summary of Key Results From Pivotal and Protocol-Selected Studies

CI = confidence interval; HAE = hereditary angioedema.

^aNegative binomial model, with covariate for baseline HAE attack rate (< 2 or ≥ 2 attacks per month) and log of treatment duration as offset for the intention-to-treat population.

^bFor the APeX-2 study the analysis was based on logistic regression model with covariate for baseline HAE attack rate for the intention-to-treat population.

^cP value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

^dFisher’s exact test.

^eSafety population.

Source: Clinical Study Report for APeX-2 and⁶ Clinical Study Report for APeX-J.⁷

Critical Appraisal

Both RCTs were conducted using a similar 3-part study design and comparable statistical methods. Patients were allocated to treatment groups using appropriate methodology, with randomization stratified by a relevant prognostic factor (i.e., baseline HAE attack rate). Due to the small sample size of the trials (40 or 7 patients per treatment group), randomization may not have ensured the groups were balanced for all measured or unmeasured prognostic factors or confounders, and imbalances between treatment groups were observed at baseline for some patient characteristics. In addition, more patients in the placebo group of the APeX-2 study stopped treatment or withdrew before 24 weeks, which may also contribute to imbalances between groups. However, the impact of these differences on the study’s findings is unclear, and sensitivity analyses that explored different missing data assumptions were generally supportive of the primary analyses. There was ███ █ █ █ █ ██ of rescue C1-INHs in the berotralstat group compared with placebo in the APeX-2 study, which may have biased the results in favour of berotralstat, as C1-INH may provide a protective effect in the days after administration.

The primary outcome (investigator-confirmed HAE attack rate over 24 weeks) was considered clinically relevant by the expert consulted by CADTH. Other outcomes of interest to this review (e.g., laryngeal, treated or severe attack rate, and responder analyses) were either exploratory or ad hoc outcomes, and these analyses were not included in the hierarchical statistical analysis. Any analyses with P < 0.05 should be interpreted with caution because of the potential for an inflated type I error rate. Although the AE-QoL has been used in clinical trials of other HAE treatments, the instrument contains domains that are not specific to HAE. Neither study was designed to test for differences in the need for hospitalization or emergency visits, or mortality. As with most clinical trials, the studies were not powered to detect infrequent adverse effects or those with a lag time.

Although the data from part 2 and part 3 of the APeX-2 study suggest that patients who continued on berotralstat 150 mg may maintain a reduction in HAE attacks, these data were limited by potential selection and reporting bias and the lack of a comparator group. Investigators and patients were aware that patients were receiving active treatment, and their expectations of treatment could therefore affect reporting of subjective outcomes, such as symptoms of swelling or adverse effects. Moreover, HAE attacks in part 3 were not adjudicated by the investigator but based instead on patient-reported events. Attack events analyzed in part 3 therefore may not be comparable to the investigator-confirmed events in part 1 and 2. In both parts 2 and 3, the efficacy analyses were reported descriptively based on observed data with no imputation for missing data, and with no sensitivity analyses to assess the robustness of the results. Given the attrition observed, these results may overestimate treatment effects and under-report adverse effects, as patients who were tolerant of therapy and showed adequate response were more likely to continue in the trial. Finally, part 2 and part 3 were uncontrolled, which makes the change in the HAE attack rate difficult to interpret, particularly as HAE attacks are sporadic and can fluctuate through the year due to exposure to seasonal triggers, hormonal changes, or other factors.

With regard to external validity, the findings of the pivotal APeX-2 study were reflective of those enrolled, who were patients with type 1 or 2 HAE with an average of 3 HAE attacks per month, most of whom had experienced a prior laryngeal attack. The trial included patients who were medically appropriate for on-demand treatment as the sole management of HAE, and therefore may have excluded patients with more severe HAE who could not tolerate discontinuation of current LTP therapy. Compared to the Canadian population, the racial diversity in the APeX-2 trial was limited as most patients were white (94%). In addition, patients were predominantly female (63%) and between 18 and 65 years of age. Because only 4 adolescents and 4 patients over 65 years of age were enrolled in the berotralstat 150 mg and placebo groups, the ability to extrapolate to younger and older age groups is limited. The APeX-J study provided additional data from 13 patients from Japan. These patients were generally similar to those in the pivotal study, although patient weight and body mass index (BMI) were lower, as was the mean baseline HAE attack rate. Overall, the clinical expert consulted described the characteristics of the patient population enrolled in the trials as a good representation of the target population and the expert did not identify any issues that could substantially limit the generalizability of the findings.

There is no direct evidence comparing berotralstat to other LTP therapies. The comparative evidence was limited to 2 24-week randomized, placebo-controlled trials in which a total of 47 patients received berotralstat 150 mg daily.

Indirect Comparisons

No indirect evidence was available.

Other Relevant Evidence

Data from 1 open-label, long-term study was summarized in this report.

Description of Studies

APeX-S is an uncontrolled, phase II study that was conducted to evaluate the safety and efficacy of berotralstat in adults and pediatric patients aged 12 years and older with type 1 or 2 HAE. In this study, 127 patients were enrolled from either a prior berotralstat trial or recruited from the community, and all received open-label berotralstat 150 mg once daily for up to 48 weeks (interim analysis). At baseline the median age was 44.0 years (range = 12 to 72) and the majority of patients were female (61%), white (87%), and had a family history of HAE (80%).

Efficacy Results

Through to week 48, a total of █ ██ █ █ adjusted HAE attacks were reported among patients who received berotralstat 150 mg daily. The mean attack rate was 1.36 (SD = 1.51) attacks per month and the median attack rate was 0.93 attacks per month (range = 0 to 7.6).

Harms Results

During the 48-week period, 91% of patients in the berotralstat 150 mg group reported 1 or more adverse events, the most common being nasopharyngitis (34%), headache (15%), and diarrhea (14%). Overall, 41% of patients experienced gastrointestinal adverse events. A total of 9% of patients experienced a serious adverse event, with ███ █ ████ █ ███ experiencing an HAE attack requiring hospitalization. No deaths were reported.

Critical Appraisal

This study was limited by the open-label design and lack of randomization or control group. Moreover, there is potential selection and attrition bias. A total of 26% of patients treated with berotralstat 150 mg discontinued the long-term study, mainly due to adverse events or a lack of perceived efficacy. This attrition could have resulted in a population of patients more tolerant of and responsive to berotralstat, which may have biased the estimates in favour of efficacy and safety.

Conclusions

In patients with type 1 or 2 HAE, treatment with berotralstat 150 mg daily reduced the rate of investigator-confirmed HAE attacks, relative to placebo, based on 24-week data from the APeX-2 and APeX-J studies. The impact of berotralstat on HRQoL was uncertain; although improvement in the AE-QoL total score was observed, the difference versus placebo was not statistically significant. Longer-term, uncontrolled studies suggest that a reduction in HAE attacks may be maintained in patients who continued on therapy up to 48 weeks; however, due to the limitations associated with these data, the longer-term safety and efficacy of berotralstat are uncertain. No evidence was available regarding the impact of berotralstat on hospitalization, emergency visits, or mortality. Also, because no direct or indirect evidence comparing berotralstat to other LTP therapies was available, the relative efficacy and safety of berotralstat compared to other LTP treatments are unknown. Gastrointestinal adverse events were reported more frequently among patients who received berotralstat compared with those who received placebo. Due to the limited sample size and duration of the trials, the studies were not designed to detect infrequent adverse effects or those with a lag time.

Introduction

Disease Background

HAE is a rare autosomal-dominant disorder characterized by recurrent episodes of nonpruritic subcutaneous or submucosal edema, most commonly affecting the skin (cutaneous attacks), gastrointestinal tract (abdominal attacks), and respiratory tract (laryngeal attacks).¹ The estimated prevalence of HAE is typically cited as 1 in 50,000,^1,2 while estimates from Europe range from 1 in 93,000 to 1 in 64,000.³ HAE is caused by a deficiency or dysfunction of the C1-INH enzyme, a protease inhibitor that is a key regulator of the complement and contact systems, which leads to the activation of kallikrein and subsequent overproduction of the nanopeptide bradykinin.^1,2 Bradykinin binds to bradykinin type 2 receptors on endothelial cells, causing increased vascular permeability, which may lead to angioedema if present in excessive amounts.^1,2

There are 3 types of HAE: type 1 (85% of patients) is caused by decreased secretion of C1-INH; type 2 (15% of patients) is characterized by normal or elevated production of functionally impaired C1-INH; and a third type, known as HAE with normal C1-INH (formerly referred to as type 3 HAE), characterized by normal C1-INH levels and function (prevalence is uncertain).¹ Mutations in the SERPING1 gene, which codes for C1-INH, are inherited in approximately 75% of patients with HAE, but de novo mutations may appear in 25% of patients.² Although the age of onset in patients with HAE varies, the majority of patients experience their first attack in childhood or adolescence, with 12 years being the median age of onset.²

The diagnosis of type 1 and type 2 HAE is based on a detailed history and physical examination, along with confirmatory laboratory diagnostic tests (Table 3). Clinical practice guidelines from the World Allergy Organization and the European Academy of Allergy and Clinical Immunology recommend that all patients suspected of having type 1 or type 2 HAE should be assessed for blood levels of complement 4 (C4) and C1-INH proteins and C1-INH function.² Other forms of angioedema that should be ruled out include acquired angioedema, angiotensin-converting-enzyme inhibitor–induced angioedema, mast cell–medicated angioedema, and idiopathic angioedema.² The clinical presentation of these other forms of angioedema may be similar to HAE but the pathology and management are different.²

Cutaneous and abdominal attacks are the most frequent type of HAE attacks, reported in more than 90% of patients with HAE.⁸ Cutaneous attacks may involve areas of the face, extremities, and genitals. Facial swelling may involve the lips, tongue, oropharynx, and periorbital tissues, while extremity swelling can progress to affect large areas of the arms or legs. Abdominal attacks involve the gastrointestinal tract and can be extremely painful, accompanied by nausea, vomiting, and diarrhea. Laryngeal attacks are the least frequent type of attack, but 50% of patients may experience 1 or more episodes in their lifetime.⁹ Laryngeal attacks are the primary cause of mortality in patients with HAE due to the risk of asphyxiation.¹⁰

The onset of an HAE attack is often unpredictable and can occur without a clear precipitating factor or trigger.² Known or suspected triggers for HAE attacks include accidental trauma, dental and medical procedures, psychological stress, fatigue, febrile illness, and the menstrual cycle.² Exposure to some drugs, including estrogen-containing contraceptives, hormone replacement therapy, and angiotensin-converting-enzyme inhibitors, may also trigger HAE attacks.² The frequency of attacks in patients who are symptomatic but untreated can range from weekly to less than yearly. Without treatment, each attack can last several days.¹¹

Table 3: Types of Hereditary Angioedema

C1-INH = complement 1 esterase inhibitor; HAE = hereditary angioedema.

Source: Maurer et al. (2018).²

Standards of Therapy

The clinical management of HAE can be categorized as follows:

• LTP treatment: ongoing long-term treatment to reduce the frequency and severity of HAE attacks and improve patient HRQoL)

• short-term prophylactic treatment to reduce the risk of an attack when exposure to a trigger is anticipated (e.g., before dental or medical procedures)

• acute treatment of HAE attacks to reduce the severity and alleviate the symptoms of an attack, minimize the functional impact of an attack, and reduce morbidity and potential mortality.¹

Therapeutic options available in Canada for LTP treatment include plasma-derived C1-INHs, lanadelumab, oral attenuated androgens (e.g., danazol), and antifibrinolytics (e.g., tranexamic acid).¹ The most commonly used treatments in Canada are C1-INHs, which replace missing or malfunctioning C1-INH proteins in patients with HAE. Three C1-INHs products are used in Canada for the treatment of HAE: Cinryze and Haegarda, which are indicated for LTP therapy, and Berinert, which is indicated for the acute treatment of HAE attacks. In addition to its use in the acute management of HAE attacks, Berinert is also routinely administered as an LTP treatment option, although this is beyond the indication approved by Health Canada. All 3 C1-INH products are derived from human plasma and are administered by IV or SC injection. Berinert is approved for IV administration; however, the clinical expert consulted by CADTH indicated that Berinert 1,500 IU is commonly administered by SC injection, in accordance with the dosages recommended in the product monograph for Haegarda (Table 4). Lanadelumab is a plasma kallikrein inhibitor that is approved for use as an LTP. This recombinant monoclonal antibody is administered by SC injection every 2 to 4 weeks.

The Canadian Hereditary Angioedema Guideline Committee recommends the use of C1-INH or lanadelumab as a first-line option for patients who require LTP treatment to manage their condition.¹ These guidelines state that attenuated androgens may be effective for some patients who require LTP treatment but are not recommended as first-line treatments.¹ Androgens or antifibrinolytics may be considered for LTP treatment of patients who have already demonstrated a benefit from these treatments or for those who have problems accessing first-line options, but the Canadian guidelines state that patients should not have to fail androgens or antifibrinolytics before using C1-INHs or lanadelumab as an LTP.¹ The evidence of effectiveness of antifibrinolytics for LTP is limited, and androgens are associated with frequent and potentially serious adverse effects.^1,2

Drug

Berotralstat is a plasma kallikrein inhibitor that decreases plasma kallikrein activity and controls excess bradykinin generation in patients with HAE.⁴ Plasma kallikrein is a protease that cleaves high-molecular-weight kininogen to generate cleaved high-molecular-weight kininogen and bradykinin, a potent vasodilator that increases vascular permeability, resulting in the swelling and pain associated the HAE. In patients with HAE due to C1-inhibitor deficiency or dysfunction, uncontrolled increases in plasma kallikrein activity result in angioedema attacks. Berotralstat is indicated for the routine prevention of episodes of HAE in adults and pediatric patients aged 12 years and older.⁴ It is available as a 150 mg oral capsule and the recommended dosage is 150 mg once daily.⁴ Dosages greater than 150 mg once daily are not recommended due to the potential for QT prolongation.⁴ Health Canada states that the safety and efficacy of berotralstat for the treatment of acute attacks have not been established, and the drug should not be used for acute attacks.⁴

Berotralstat was approved by Health Canada through the standard review process. The sponsor has requested reimbursement according to the indication. This drug has not been reviewed by CADTH previously. Berotralstat is approved for use in Australia, Europe, and the US.¹

Table 4: Key Characteristics of Preventive Treatments for HAE

C1-INH = complement 1 esterase inhibitor; HAE = hereditary angioedema; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; SC = subcutaneous.

^aHealth Canada–approved indication.

Source: Product monographs for Orladeyo,⁴ Takhzyro,¹² Berinert,¹³ Cinryze,¹⁴ and Haegarda¹⁵ and CADTH Technology Review.¹⁶

Stakeholder Perspectives

Patient Group Input

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

One patient group, HAEC, submitted patient input for this review. HAEC is dedicated to creating awareness about HAE and related angioedemas, speeding the diagnosis of patients, improving access to treatments, and helping patients become champions of their own quality of life. The input was based on data collected from surveys in 2019 (n = 66) and 2021 (n = 138), qualitative interviews with 11 patients with a mix of either type 1 or type 2 HAE, and comments from 3 patients who had experience with the treatment under investigation in a clinical trial.

Respondents rated the impacts HAE had on their day-to-day activities on a scale of 1 (not at all) to 5 (significant), with weighted averages ranging from 2.20 for impacts on their ability to conduct household chores to 2.94 for affecting their ability to travel. Some patients reported that HAE required out-of-pocket expenditures for medical care and some patients indicated that they were either very dissatisfied or dissatisfied with their current treatments. Among the 3 patients who had experience with the treatment under review, 1 patient described the treatment as extremely effective in prevention of episodes of HAE and the adverse effects as easy to tolerate. Two patients did not find the treatment effective in the prevention of episodes of HAE.

According to the patient input received, a majority of patients are seeking treatments with an easier mode of delivery, and some prefer a product that is not derived from plasma. Patients continue to seek treatments that better control attacks while offering greater convenience and ease of use. Treatments that eliminate or substantially reduce attacks compared to existing treatments are of critical importance to patients as each edema attack can be severely debilitating, and in many cases life-threatening. Greater control of attacks would also reduce the anxiety and fear many patients experience due to unpredictable attacks and reduce the negative impact on a patient’s ability to work, pursue education, travel, exercise, do household chores, and socialize with family and friends. A copy of the patient input is presented at the end of this report.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise in 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 1 clinical specialist with expertise in the diagnosis and management of HAE.

Description of the Current Treatment Paradigm for the Disease

Current LTP treatments for HAE include C1-INH replacement therapy, which restores C1-INH in the contact activation system pathway, reducing HAE attacks. It also restores C1-INH in the complement system pathway and restores C4 levels, which may be important in fighting infection and destroying autoreactive and malignant cells. C1-INH also acts in the coagulation pathway and normalizes the D-dimer, which is often elevated in HAE without any clinical consequence. Lanadelumab is a fully human monoclonal antibody that binds plasma kallikrein and inhibits its proteolytic activity. In patients with HAE due to C1-INH deficiency or dysfunction (i.e., type 1 or type 2), an uncontrolled increase in plasma kallikrein activity leads to an increase in bradykinin and results in angioedema attacks. Lanadelumab controls bradykinin generation by decreasing plasma kallikrein activity in patients with HAE.

Additional treatment options include anabolic steroids and tranexamic acid. Anabolic steroids (e.g., danazol) increase the production of endogenous C1-INH from the liver, but their use is limited by masculinizing effects and an increased risk of hepatic tumours. Tranexamic acid reduces the symptoms of HAE attacks, but its mechanism of action is unknown, it increases the risk of thrombosis, and it may not be tolerated due to gastrointestinal side effects.

Treatment Goals

An ideal treatment for HAE would:

• prolong life by reducing or eliminating life-threatening HAE attacks (e.g., laryngeal attacks)

• reduce the frequency, severity, and duration of HAE attacks

• be associated with minimal or no adverse effects

• improve HRQoL for those living with HAE and reduce the burden on their caregivers

• help maintain independence, increasing the ability to maintain employment and attend school

• reduce other health care utilization (e.g., emergency room visits and hospital admissions)

• offer more convenient administration than existing options.

Unmet Needs

Many patients living with HAE find it inconvenient or impossible to self-administer C1-INH intravenously twice-weekly (e.g., because it is difficult to find a vein), and some do not like administering 3 times the dose of C1-INH by SC injection twice-weekly (Haegarda). Because C1-INHs currently approved in Canada are derived from human plasma, there is a remote risk of transmitting viral infections, and some patients may not wish to use these products. Lanadelumab, which requires only a single SC injection once every 2 weeks may be more convenient to administer and is not plasma-derived, but still requires injections. As previously noted, the other available LTP treatments are less effective (e.g., tranexamic acid) or have significant side effects (e.g., danazol).

Place in Therapy

Berotralstat, an oral therapy, may offer advantages over existing treatments for ease of administration and has the potential to shift the current treatment paradigm. It could be considered a first-line option for LTP treatment, although it may not be the preferred option for people who are pregnant or younger than 12 years of age, given the limited clinical data for these groups. Patients who experience breakthrough symptoms while using berotralstat could administer C1-INH IV or icatibant SC to manage attacks.

Although not specifically indicated for combination usage in Canada, berotralstat could be added to C1-INH (IV or SC twice-weekly prophylaxis), danazol, or lanadelumab if patients wanted extra assurance that they would not have an attack. However, patients would most likely start this medication and then withdraw their existing LTP therapies completely.

Berotralstat is a plasma kallikrein inhibitor that decreases plasma kallikrein activity and controls excess bradykinin generation in patients with HAE. It does not address the underlying disease process, as it does not replace the deficient or dysfunctional C1-INH protein in patients with type 1 or 2 HAE, respectively.

Patient Population

HAE can be challenging to diagnose, as patients with chronic urticaria may also develop swelling. Accurate diagnosis of type 1 and 2 HAE typically requires testing C1-INH levels, C1-INH function, and C4 levels. It may be challenging in some areas of Canada to access testing for C1-INH levels and function in a timely manner. Diagnosis of HAE with normal C1-INH can require genetic testing that is only available in some specialized centres and out-of-pocket expenditures may be required. Acquired angioedema may pose additional challenges for clinicians, as this condition can have many of the same biochemical abnormalities as type 1 HAE. Although acquired C1-INH deficiency can be differentiated from type 1 HAE by the presence of low C1q levels, this testing is not generally available in Canada.

Patients could be considered good candidates for treatment with berotralstat if they experience frequent HAE attacks that require acute treatment. The oral route of administration would be beneficial for patients who are unable to self-administer C1-INH by IV (e.g., because of arthritis or problems finding veins) or SC injection and do not have a caregiver to assist. Berotralstat may also be useful for patients who must travel, for whom LTP treatment with C1-INH may be impractical. In addition, many patients may prefer the convenience offered by berotralstat over that of existing treatment options.

Based on the available clinical evidence, patients with type 1 or 2 HAE are the most likely to respond to treatment with berotralstat (as other forms of HAE have not been studied). The patients who could benefit most (i.e., those in greatest need of an additional intervention) are those who experience frequent and severe attacks, those who have an inadequate response to LTP with C1-INH or lanadelumab, and those who require larger amounts of C1-INH to control their attacks. This would be true for patients with any form of bradykinin-mediated angioedema, including patients who have HAE with normal levels of C1-INH or acquired angioedema. The clinical expert noted that it would not be necessary to try another LTP treatment before initiating treatment with berotralstat.

The following patients may not be appropriate candidates for treatment with berotralstat:

• those who are misdiagnosed as having HAE but actually have histaminergic chronic urticaria or histaminergic idiopathic angioedema

• those with HAE who have only mild and intermittent symptoms (i.e., for whom on-demand therapy is sufficient)

• those whose HAE is currently well controlled and who are satisfied with their existing LTP therapy

• those who have a significant adverse reaction to berotralstat.

Assessing Response to Treatment

Assessing a response to LTP treatment in clinical practice is similar to the evaluations conducted in clinical trials. Patients and clinicians are seeking a reduction in the frequency, severity, and duration of attacks, which, in turn, can result in a reduced need for rescue medications, emergency department visits, and hospital admissions. There should be an increase in the ability to perform activities of daily living during attacks, if these were previously affected. Assessments can vary across individual patients, as a certain level of symptoms may be acceptable to some patients living with the condition but not to others. Initial response to treatment would typically be assessed at 3 months. Patients would subsequently visit a clinic once every 6 months, and those with very well-controlled HAE would often be seen only once per year.

Discontinuing Treatment

The following were identified as situations in which discontinuing treatment with berotralstat could be appropriate:

• pregnancy — adverse effects during pregnancy are unknown, and C1-INH is the preferred option

• allergic reaction or any significant adverse event to berotralstat

• inadequate response or loss of response (e.g., increase in attacks requiring rescue medication).

Prescribing Conditions

Prescribing authority should be limited to specialists with an expertise in the diagnosis and management of patients with angioedema, including immunologists, allergists, and hematologists. This will help ensure that the correct diagnosis has been made before initiating treatment with berotralstat and that the response to treatment is appropriately monitored.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by a clinician group. A copy of the clinician group input received is available at the end of this report.

Input was received from 1 clinician group, the Canadian Hereditary Angioedema Network, a not-for-profit organization of physicians who treat, or are interested in HAE. Its members contribute to the knowledge of HAE and its treatments by participating in clinical trials, conducting observational research, developing clinical practice guidelines, and assessing health technologies.

Unmet Needs

Patients with HAE require a variety of treatment options to address a range of unmet needs, including improvement in prevention of attacks, improvement in the acute management of HAE, and more convenient methods of administration that do not require injections or carry the risk of transmitting an infectious agent. No oral prophylactic treatments for HAE are currently licensed in Canada. Attenuated androgens have been used off-label, but are associated with severe adverse effects, require regular monitoring, and cannot be used during pregnancy. Tranexamic acid is a popular option for children but has an incomplete evidence base and poor efficacy.

Different treatment options are vital to ensure patients have options when they are faced with drug shortages, which is currently a reality and potentially will continue to be in the future. Ensuring the availability of optional treatments is particularly important when dealing with a potentially life-threatening condition.

Place in Therapy

Berotralstat, which is administered orally, may be associated with a lower treatment burden for some patients compared to injectable prophylactics such as lanadelumab or a plasma-derived C1-INH. A safe and effective oral prophylactic may be preferred to the current standard of care by some patients, particularly those who are averse to a long-term injection regimen, have difficulty with injections due to disability or phobias, are on anticoagulants or may bruise easily, or will not use blood products. While most recent guidelines recommend berotralstat as a first-line option, this (and any therapy) should be the subject of shared decision-making between the patient and the HAE specialist.

The issue of combining prophylactic therapies has not been addressed in studies available at this time. All patients should be equipped to treat angioedema attacks, and patients and physicians should agree on an acute treatment plan.

Patient Population

As stated in The International/Canadian Hereditary Angioedema Guideline, all effective treatments for long-term prophylaxis should be offered to patients, and all available treatments should be the subject of shared decision-making between the patient and the HAE specialist. Like any LTP, if 1 treatment is not effective, or if a patient has adverse effects from a therapy or has technical difficulties administering a therapy, the patient should be able to try another. Additionally, some patients will prefer less-frequent dosing of an LTP, such as with lanadelumab, which is self-administered every 2 weeks, over daily oral medication.

There are no specific predictors as to who would preferentially respond to berotralstat. LTP is considered at every follow-up visit for patients with HAE. Those already on LTP would also have a review at each follow-up visit, to determine if a switch in treatment would be beneficial for that patient.

Those least suitable for treatment with berotralstat are patients who are pregnant or lactating and patients younger than 12 years of age.

Diagnosis and treatment of HAE may be a problem in some patients given how rare it is, which is why HAE should be treated and managed by an HAE specialist.

Assessing Response to Treatment

The opinion of the patient on their response to treatment is a key consideration. But more objectively meaningful response is assessed by decreased frequency of HAE attacks, need for rescue treatments, decreased severity of attacks, decrease in emergency room visits, ability to work, increased quality of life, and adverse effects profile.

Response should be assessed at every follow-up visit. Follow-up frequency varies according to the nature and severity of the patient’s disease but can occur every 3, 6, or 12 months.

Discontinuing Treatment

Considerations leading to treatment discontinuation include ineffectiveness (poor control of HAE with increased or continued attack frequency and severity) and adverse effects.

Prescribing Conditions

A large majority of HAE patients will be under the care of an HAE specialist, such as an allergist or immunologist, hematologist, dermatologist, or possibly a pediatrician or internist.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may affect 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

C1-INH = complement 1 esterase inhibitor; CBS = Canadian Blood Services; CDEC = CADTH Canadian Drug Expert Committee; HAE = hereditary angioedema; LTP = long-term prophylactic; pCPA = pan-Canadian Pharmaceutical Alliance; SC = subcutaneous.

Clinical Evidence

The clinical evidence included in the review of berotralstat 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 berotralstat 150 mg oral capsules for the routine prevention of recurrent episodes of HAE in adults and pediatric patients aged 12 years and older.

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.

Table 6: Inclusion Criteria for the Systematic Review

AE = adverse event; HAE = hereditary angioedema; SAE = serious adverse event; WDAE = withdrawal due to adverse event.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.¹

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) via Ovid and Embase (1974–) via Ovid. All Ovid searches were run simultaneously as a multifile search. Duplicates were removed using Ovid deduplication for multifile searches, followed by manual deduplication in EndNote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concept was Orladeyo (berotralstat). Clinical trials registries searched included the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform 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. Appendix 1 provides detailed search strategies.

The initial search was completed on March 14, 2022. Regular alerts updated the search until the meeting of the CADTH Canadian Drug Expert Committee on July 27, 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.² Included in this search were the websites of regulatory agencies (US FDA and European Medicines Agency). Google was used to search for additional internet-based materials. Appendix provides more information on the grey literature search strategy.

In addition, the sponsor 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 2 studies were identified from the literature for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 7. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Description of Studies

Two double-blind, placebo-controlled RCTs met the inclusion criteria for the systematic review (APeX-2, APeX-J) (Table 7).

The objective of the APeX-2 study was to determine the efficacy, safety, and tolerability of prophylactic berotralstat compared with placebo in patients with type 1 or 2 HAE. The study included a run-in phase and 3 treatment phases (Figure 2). The patients enrolled underwent a 14- to 56-day run-in period to determine the baseline rate of HAE attacks, and those with 2 or more qualifying attacks during the run-in were eligible for randomization. A total of 121 patients were randomized 1:1:1 to placebo, berotralstat 110 mg, or berotralstat 150 mg daily for 24 weeks via an interactive web or voice response system (part 1). Randomization was stratified by the investigator-confirmed HAE attack rate during the screening period (≥ 2 attacks or < 2 attacks per 28 days). After 24 weeks, patients in the placebo group were rerandomized 1:1 to double-blind berotralstat 110 mg or 150 mg daily. Patients initially randomized to a berotralstat group continued the same double-blind dose from week 24 to week 48 (part 2). After 48 weeks, all patients continued on open-label berotralstat, and those receiving the 110 mg dose were transitioned to 150 mg daily for week 48 to 96 (part 3). The primary outcome was the rate of investigator-confirmed HAE attacks during the first 24 weeks of treatment. The study was conducted in 11 countries including Canada (3 sites), the US, and Europe.

The objective of the APeX-J study was to evaluate the efficacy and safety of berotralstat 110 mg and 150 mg daily for the suppression of events in patients with type 1 or 2 HAE. The trial used a design similar to that shown in Figure 2 and included a 56-day run-in period and 3 treatment phases: part 1, week 0 to week 24 (double-blind, placebo-controlled); part 2, week 24 to week 52 (double-blind, uncontrolled); and part 3, week 52 to week 104 (open-label, uncontrolled). Patients were eligible for randomization if they reported at least 2 qualifying angioedema events during the run-in phase. The randomization methods, treatment groups, and dosages used in APeX-J were the same as those reported for the APeX-2 study. The primary outcome was the rate of expert-confirmed HAE attacks during the first 24 weeks of treatment for berotralstat versus placebo. A total of 19 patients were randomized from 10 study sites in Japan.

Both trials were ongoing at the time this report was drafted, with limited or no information available for parts 2 or 3. The interim clinical study reports provided data from part 1 of the APeX-2 study (up to April 10, 2019) and the APeX-J study (up to November 15, 2019). This report focuses on the results of the berotralstat 150 mg daily dosage group, as this dosage was consistent with Health Canada recommendations. The results of the berotralstat 110 mg dose are not summarized in this report.

Table 7: Details of Included Studies

ACE = angiotensin-converting enzyme; AE-QoL = Angioedema Quality of Life questionnaire; C1-INH = complement 1 esterase inhibitor; C4 = complement 4; CFB = change from baseline; CrCl = creatinine clearance; CV = cardiovascular; ECG = electrocardiogram; HAE = hereditary angioedema; LLN = lower limit of normal; RCT = randomized controlled trial; SOC = standard of care.

Note: Five additional reports were included (FDA Multidiscipline Review,¹⁹ European Public Assessment Report for Orladeyo,²⁰ Zuraw et al. [2021],¹⁷ Wedner et al. [2021],⁵ Ohsawa et al. [2021]¹⁸) in the original systematic review. One additional unpublished report was supplied by the sponsor as part of the Request for Reconsideration, and this report is summarized in Appendix 5.²¹

^aDefined as having a C1-INH functional level below 50% and a C4 level below the LLN reference range, as assessed during the screening period. In the absence of a low C4 value drawn during the intercritical period (i.e., patient was not having an HAE attack), 1 of the following was acceptable to confirm the diagnosis of HAE: SERPING1 gene mutation known or likely to be associated with type 1 or type 2 HAE assessed during the screening period; confirmed family history of C1-INH deficiency; or C4 redrawn and retested during an attack in the screening period with the results below the LLN reference range. For patients with a C1-INH function of 50% or greater but less than the assay LLN (74%), a SERPING1 gene mutation known or likely to be associated with type 1 or type 2 HAE, as assessed during the screening period or a repeat C1-INH functional level below 50%, was considered acceptable for enrolment.

^bDuring the run-in period, HAE attacks had to meet all the following criteria: the attacks were unique, which was defined as an attack that did not begin within 48 hours of the end of a previous attack; the attacks must have either been treated, required medical attention, or been documented to cause functional impairment based on patient entry in an electronic diary, with functional impairment defined as the patient being unable to perform daily activities without restriction (i.e., patients recorded that they were at least slightly restricted in their daily activities during their HAE attack); the attacks included symptoms of swelling, and symptoms of swelling, in addition to visible swelling, and may also have included symptoms in the oropharyngeal or abdominal regions that were indicative of internal swelling; and the attacks were confirmed by the investigator in the APeX-2 study or the independent expert in the APeX-J study to be HAE attacks. Patients were contacted within 2 business days of the attack to discuss the attack and any queries on the data entered in the electronic diary, as applicable.

^cDosage for berotralstat during part 1 and part 2 of the study. During part 3 of the study, all patients received open-label berotralstat. Those receiving berotralstat 110 mg daily were switched to 150 mg daily.

^dNot a Health Canada–recommended dosage.

^eAt 24 weeks, patients in the placebo group were randomized to receive either double-blind berotralstat 110 mg or 150 mg daily. During part 3 all patients were switched to berotralstat 150 mg daily.

Source: Clinical Study Report for APeX-2⁶ and Clinical Study Report for APeX-J.⁷

Figure 2: Study Schematic for APeX-2

BCX7353 = berotralstat; QD = once daily.

Note: In the APeX-2 study, the run-in phase ranged from 14 to 56 days. Once a patient had recorded 2 attacks that met the criteria, they could be randomized on or after day 28. Patients who experienced 3 or more attacks could be randomized on or after day 14. In the APeX-J study, the run-in phase was 56 days for all patients and patients had to report at least 2 eligible attacks to qualify for randomization.

Source: Clinical Study Report for APeX-2.⁶

Populations

Inclusion and Exclusion Criteria

Both studies enrolled patients aged 12 years and older with a confirmed diagnosis of type 1 or 2 HAE, who experienced at least 2 qualifying HAE attacks during the run-in phase. In addition, the patients had to have access to standard-of-care treatments for acute attacks and be medically appropriate for on-demand treatment as the sole medical management of their HAE (Table 7).

Patients were excluded if they had been diagnosed with another form of recurrent angioedema, had suspected C1-INH resistance, or had a preplanned procedure for which short-term prophylaxis was required. Patients were required to stop prophylactic use of C1-INH, androgens, or tranexamic acid, 14 or 28 days before screening.

Baseline Characteristics

The mean ages of patients enrolled in the APeX-2 study were 40.0 years (SD = 14.0) and 44.5 years (SD = 14.1) in the berotralstat 150 mg and placebo groups, respectively (Table 8). Two patients per group (5%) were adolescents 12 to 17 years of age. Patients were predominantly female (58% and 68%), and white (95% and 93%), and most had a family history of HAE (█ █ ██ █ ████ in the berotralstat and placebo groups, respectively). Most patients had at least 2 attacks per month at baseline (75% and 68%) and the mean baseline rates were 3.1 (SD = 1.6) and 2.9 (SD = 1.1) investigator-confirmed HAE attacks per month in the berotralstat 150 mg and placebo groups, respectively. Approximately 75% of patients enrolled had received prior prophylactic treatments for HAE, with a similar frequency between treatment groups (Table 9).

In the APeX-J study, the mean ages of patients enrolled were 37.3 years (SD = 9.1) in the berotralstat 150 mg group and 42.3 years (SD = 13.5) in the placebo group (Table 8). █ █ ███ █ ██ █ ███ █ ████ █ █████ █ █████ █ ███. Most patients were female (86% and 83%) and Asian (86% and 100%) in the berotralstat and placebo groups, respectively. The mean baseline attack rates were 2.0 (SD = 1.1) and 2.5 (SD = 1.5) per month for the berotralstat and placebo groups, respectively. In the berotralstat group, 86% had received prior prophylactic treatment for HAE, compared with 67% of patients in the placebo group (Table 9).

There were imbalances between groups within the trials in the mean age, proportion of females, weight, prior laryngeal attack, and prior emergency visit in past year (Table 8). Differences were also noted between the studies in the mean weight, race, baseline attack rate, family history of HAE, emergency visit for HAE in the past year, and type of prior prophylactic therapy for HAE.

Interventions

In both the APeX-2 and APeX-J studies, eligible patients were randomized to receive double-blind placebo, berotralstat 110 mg, or berotralstat 150 mg daily for the first 24 weeks (part 1). The study drug was supplied as identical-looking capsules containing either placebo, berotralstat 55 mg, or berotralstat 75 mg. Patients were instructed to take 2 capsules daily with food.

During part 2 of the trials, patients in the berotralstat groups continued on the same dose of study drug, and those in the placebo group were rerandomized to berotralstat 110 mg or berotralstat 150 mg daily for 24 weeks in APeX-2 study, or for 28 weeks in the APeX-J study. Patients were informed they were receiving the active drug during part 2 but were not aware of the dose of berotralstat. During part 3 of the studies, patients received open-label berotralstat, with those who previously received the 110 mg dose switched to 150 mg daily.

Table 8: Summary of Baseline Characteristics

BMI = body mass index; C4 = complement 4; C1-INH = complement 1 esterase inhibitor; HAE = hereditary angioedema; LLN = lower limit of normal; SD = standard deviation.

^aThe baseline attack rate in the APeX-2 study was based on the investigator-confirmed events between screening and the first dose of the study drug. The median number of days was 36.5 (range = 15 to 72 days) in the berotralstat 150 mg group and 36 days (range = 20 to 66 days) in the placebo group.

Source: Clinical Study Report for APeX-2⁶ and Clinical Study Report for APeX-J.⁷

Table 9: Summary of Prior Long-Term Prophylactic Treatments for Hereditary Angioedema

C1-INH = complement 1 esterase inhibitor; HAE = hereditary angioedema; NR = not reported.

^aOther medications included desogestrel (APeX-2) and goreisan (APeX-J).

^bIncludes androgens (unspecified), oxandrolone, methyl-testosterone, danazol, and stanozolol.

^cIncludes plasma-derived C1-INH (Cinryze, Berinert, Haegarda), recombinant C1-INH (Ruconest) and fresh frozen plasma.

Source: Clinical Study Report for APeX-2⁶ and Clinical Study Report for APeX-J.⁷

All patients were required to have access to acute treatments for angioedema events and to administer these treatments for an attack following the medical management plan advised by their physician. Use of C1-INH for short-term prophylaxis of unplanned procedures was allowed.

Patients were prohibited from using androgens or tranexamic acid for prophylaxis within 28 days before screening and during the trial. C1-INH used for prophylaxis of HAE was prohibited within 14 days before screening and during the study. Use of an angiotensin-converting-enzyme inhibitor within 7 days, or initiation of estrogen-containing contraceptives within 56 days before screening was not permitted as these drugs may exacerbate HAE. Other prohibited treatments included concurrent use of drugs metabolized by cytochrome P450 enzyme (CYP) 2D6, CYP2C9, CYP2C19, or CYP3A4 that have a narrow therapeutic index or are known to prolong the QT interval, as well as drugs with a narrow therapeutic index that are transported by the P-glycoprotein efflux pump.

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is provided in Table 10. These end points are further summarized in the following section. A detailed discussion and critical appraisal of the outcome measures are provided in Appendix 4.

Table 10: Summary of Outcomes of Interest Identified in the CADTH Review Protocol

AE-QoL = Angioedema Quality of Life questionnaire; EQ-5D-5L = 5-Level EQ-5D questionnaire; EQ VAS = EQ visual analogue scale; HAE = hereditary angioedema, NR = not reported.

^aThe proportion of responders defined as a 70% or greater or a 90% or greater reduction in HAE attack rate were ad hoc analyses in the APeX-2 study.

Source: Clinical Study Report for APeX-2⁶ and Clinical Study Report for APeX-J.⁷

The primary outcome of part 1 in both studies was the investigator-confirmed attack rate from day 1 to 24 weeks. Patients were required to document the presence or absence of symptoms of an HAE attack daily using an electronic diary. If an attack was reported, details regarding the location, severity, symptoms, and duration of attack were required to be recorded, along with the timing of any treatments administered and whether additional medical care was sought for the attack. Administration of the study drug was also recorded daily using the diary. All patients were required to complete the diary symptom data during the run-in period to determine the baseline rate of HAE attacks, and then daily throughout the treatment period until the study was completed or the patient discontinued the trial. Adherence was monitored electronically and if at any time the diary completion was less than 90%, then additional training was provided or patients were reminded via phone. Patients who stopped the study drug continued to record HAE attacks until their last study visit. Investigators could view electronic diary entries in real time and contacted patients within 2 business days of the end of an attack to review the attack details and gather additional data if needed to confirm the event as an HAE attack. Attacks reported verbally to the investigator, but not recorded using the diary, were also counted. In APeX-2, only investigator-confirmed events were included in the primary outcome analysis. In the APeX-J study, all HAE events were adjudicated by an independent expert selected by the sponsor.

During the run-in phase, HAE attacks had to meet all 4 criteria to qualify as an event, but during the treatment period only criteria 3 and 4 were required. The criteria were:

• The attacks were unique, which was defined as an attack that did not begin within 48 hours of the end of a previous attack.

• The attacks must have either been treated, required medical attention, or been documented to cause functional impairment based on patient entry in the electronic diary. Functional impairment was defined as the patient being unable to perform daily activities without restriction (i.e., patients recorded that they were at least slightly restricted in their daily activities during their HAE attack).

• The attacks included symptoms of swelling. In addition to visible swelling, these may also have included symptoms in the oropharyngeal or abdominal regions that were indicative of internal swelling.

• The attacks were confirmed by the investigator to be HAE attacks in the APeX-2 study, or by the independent expert in the APeX-J study.

The baseline attack rate was calculated as the number of attacks that met the criteria from the screening visit to the first dose date multiplied by 28 and divided by the date of the first study drug dose minus the screening date plus 1. After randomization, the investigator-confirmed attack rate was based on the entire dosing period, from day 1 (first dose in part 1) to the first dose of the study drug in part 2 of the study (primary outcome) or the effective treatment period (once drug concentration reached a steady state), which was day 8 to the administration of the first dose in part 2 (secondary outcome). For any patients who stopped treatment early, an attack that began within 24 hours of stopping therapy was included in the calculation of the attack rate; otherwise, any attacks that occurred after treatment was stopped were not included.

For the responder analyses, the on-treatment investigator-confirmed attack rate had to meet the same criteria as attacks in the run-in period and were reported as adjusted investigator-confirmed events. Two additional criteria were applied: the attacks had to be unique (> 48 hours between attacks), and the attacks had to be treated, require medical attention, or cause functional impairment. In the APeX-2 study the preplanned responder analysis was defined as a 50% or greater relative reduction in the attack rate versus baseline. Post hoc analyses based on 70% or greater and 90% or greater thresholds were also conducted. In the APeX-J study, all 3 analyses (≥ 50%, ≥ 70%, and ≥ 90%) were preplanned. According to the clinical expert consulted for this review, a 20% improvement in the attack rate is considered a mild effect, 50% is considered moderate, and 70% is considered a marked effect.

The number and proportion of days with HAE symptoms were calculated from day 1 to week 24. In both studies, an ad hoc analysis was conducted for laryngeal attacks (defined as visible swelling in the mouth, tongue, or lips, lump in throat [tightness], difficulty swallowing, change in voice, or difficulty breathing), and investigator-confirmed events that were rated as moderate to severe by the patient. Ad hoc data were reported in the APeX-2 study for attack-free months, based on the number of patients with no investigator-confirmed attacks in each 28-day period. For this outcome, patients who discontinued the study drug in a given month were not considered attack-free in that month.

The AE-QoL score was a secondary outcome in both studies. The AE-QoL is a patient-reported angioedema-specific HRQoL measure that consists of 17 questions in 4 domains (functioning, fatigue or mood, fears or shame, and food).²² Each item has 5 responses from 1 (never) to 5 (very often) that is scored from 0 to 4 over a 4-week recall period. A total score and individual domain scores are generated and converted to a linear scale of 1 to 100, with higher scores representing higher impairment. The evidence to support the validity, reliability, and responsiveness of the AE-QoL in patients with recurrent angioedema is summarized in Appendix 4. A minimal important difference (MID) of 6 points has been reported for patients with angioedema in the literature.²³

Other HRQoL measures were reported as exploratory outcomes. The 5-Level EQ-5D (EQ-5D-5L) questionnaire includes 2 parts: a descriptive system and a visual analogue scale (EQ VAS). The descriptive system has 5 dimensions (mobility, self-care, usual activities, pain or discomfort, and anxiety or depression), each of which has 5 levels (no problems, slight problems, moderate problems, severe problems, and extreme problems). In both berotralstat studies, the descriptive system was converted to an index score using the US value set.²⁴ The EQ VAS records the patient’s self-rated health on a vertical scale, with anchors labelled “the worst health you can imagine” and “the best health you can imagine” (scored from 0 to 100, respectively). The EQ-5D-5L has not been validated in patients with HAE.

Adverse events were any untoward medical occurrence, which may or may not be related to the study drug. HAE attacks and their symptoms were not defined as adverse events unless they met the criteria for a serious adverse event. The criteria for serious adverse events included death; events that were life-threatening, required hospitalization or prolongation of hospitalization; those resulting in a persistent or significant disability or incapacity; a congenital anomaly or birth defect; or an event that may have required medical or surgical intervention to prevent 1 of the other outcomes listed.

The primary outcomes for parts 2 and 3 of the trials were safety-related, and the secondary efficacy outcomes were the frequency of angioedema events, HRQoL, and durability of treatment response.

Statistical Analysis

The rate of confirmed HAE events was analyzed using a negative binomial regression model that included the treatment, the stratification variable (< 2 or ≥ 2 confirmed attacks per month at baseline), and the log of treatment duration as the offset. The primary analysis was based on the intention-to-treat (ITT) population for patients who were on treatment and did not include any data after treatment discontinuation. A negative binomial model was selected for the primary analysis because the Poisson model showed evidence of overdispersion (i.e., the variance in the data was greater than the mean). Similar methods were used to analyze secondary or exploratory attack-rate outcomes in both trials (Table 11). The change from baseline in the HRQoL measures was analyzed using a mixed model of repeated measures that included the baseline attack rate, baseline score, visit, and visit by treatment interaction terms as covariates. The proportion of days with HAE symptoms through 24 weeks was analyzed using an analysis of covariance model, and the responder analysis used a logistic regression model, both of which included the baseline attack rate as a covariate.

There was no imputation for missing data for any outcomes reported in either study. For the primary outcome in the APeX-2 study, 3 sensitivity analyses were to explore the impact of missing data. One analysis included event data reported after the patient stopped treatment, and a second analysis included post–treatment-cessation data (where available) plus multiple imputation methods to impute data for patients who stopped treatment but did not continue to report attacks. The APeX-2 study also conducted a tipping-point analysis, which estimated the magnitude of effect required among patients with missing data in the active treatment group to change the result to nonstatistically significant. Other sensitivity analyses were conducted using the per-protocol population and only patients who completed the study. Similar sensitivity analyses were conducted in the APeX-J study (Table 11).

In both the APeX-2 and the APeX-J studies, the type I error rate was controlled for the primary and 3 secondary outcomes, and for the 2 dosage groups versus placebo using hierarchical testing and the Hochberg procedure. Both the 110 mg and 150 mg berotralstat groups were tested for the primary outcome at an alpha level of 0.05, and if both showed a P value of less than 0.05, then testing continued for both groups at the alpha 0.05 level. If the highest P value was greater than 0.05 and the lowest was less than 0.025, then testing for the statistically significant dosage group continued at the 0.025 level. If the primary outcome null hypothesis was not rejected for both dosage groups, then testing stopped. The order of testing in the APeX-2 study was the rate of confirmed HAE attacks during the entire 24-week treatment period (primary), the change from baseline in AE-QoL, the proportion of symptom-days, and the rate of HAE attacks in the effective treatment period (day 8 to 24 weeks). For the APeX-J study, the order of testing was the rate of confirmed attacks during the entire 24-week treatment period (primary), the proportion of symptom-days, the rate of HAE attacks (day 8 to 24 weeks), and the change from baseline in AE-QoL. There was no control of the type I error rate for the exploratory or other outcomes tested. Both trials were ongoing at the time this report was written. The analysis of the efficacy outcomes for part 1 (an interim analysis) was conducted once the last patient had completed part 1.

In the APeX-J study, the primary analysis was based on the ITT population, but a pooled analysis was also planned that combined patients from the APeX-J study with those from the APeX-2 study. The same hierarchical and Hochberg procedure was applied to the testing of outcomes for the combined analysis; however, this testing was conducted independently of the primary ITT analysis (which failed to reject the null hypothesis on the second outcome tested for the berotralstat 150 mg group).

Of the subgroups of interest to this review, the APeX-2 study conducted preplanned analyses based on the baseline attack rate (≥ 2 versus < 2 per month) and age group (< 18 years, 18 to 65 years, > 65 years). An ad hoc analysis was conducted based on subgroups with or without prior use of androgens. The same 3 subgroups of interest were preplanned for analyses in the APeX-J study, but due to the small sample size, the analyses were not conducted. Instead, subgroup data were reported for the combined APeX-2 and APeX-J population.

With 40 patients per group, the APeX-2 study had a 94% power to detect a 50% attack-rate reduction (treatment difference of 0.5 attacks per week) between berotralstat and placebo (2-sided test, significance level of 0.05). The power calculations assumed a normalized placebo attack rate of 1 with a common SD of 0.55, and a 20% dropout rate. Data from the phase II Study 203 (APeX-1) were used to support these assumptions.

Study APeX-J had limited statistical power and did not meet its target enrolment of 8 patients per group. Assuming a weekly angioedema event rate of 0.9 for placebo and a common SD of 0.5, with 8 patients per group, the study had a 61% power to detect an event-rate reduction of 67% or greater (i.e., a treatment difference of 0.6 events per week) for each dose of berotralstat versus placebo. Due to the sample size limitations, a supplemental statistical analysis was conducted that combined the patients enrolled in the APeX-J trial with those in APeX-2. A combined sample size of 48 patients per group would have better than a 99% power to detect an event rate reduction of 67% or greater between each dose of berotralstat and placebo (2-sided alpha 0.05).

Table 11: Statistical Analysis of Efficacy End points

AE-QoL = Angioedema Quality of Life questionnaire; ANCOVA = analysis of covariance; EQ-5D-5L = 5-Level EQ-5D questionnaire; EQ VAS = EQ visual analogue scale; HAE = hereditary angioedema; MMRM = mixed model for repeated measures; NR = not reported.

^aIncluded data recorded after the study drug was stopped until patient started a new prophylactic treatment.

^bAd hoc analysis.

^cThe combined analyses that pooled data from the APeX-2 and APeX-J studies also included a covariate for the statistical models.

Source: Clinical Study Report for APeX-2⁶ and Clinical Study Report for APeX-J.⁷

Analysis Populations

In both studies the ITT population included all randomized patients, regardless of whether the study drug was administered. The safety population included all patients who received at least 1 dose of the study drug according to the drug received at first dose.

Results

Patient Disposition

In part 1 of the APeX-2 study, 160 patients were screened for entry, of whom 121 (76%) were randomized. The most common reasons for excluding patients were: █ █ █ █ ████ █ ████████ █ █████████ █ ██████████ █ █ █ ███ █ ████ █ ██ █ █ █ █ █ █ █ ███ █ ███ █ █████ █ ██ █ ███ █ █████ █ ██████████ █ █████████████ █ █ █ █████ █ ██ █ ███ █ ██ █ █ █ █ █ █ █ █ █████ █ ████ In the berotralstat 150 mg group, ██ █ █ █ ███ patients (██) randomized discontinued the study early (withdrawal of consent) compared with █████ patients (███) in the placebo group (due to withdrawal of consent, increased frequency of attacks, or other reasons). Three patients (8%) in the berotralstat 150 mg group stopped the study drug early compared with 5 patients (13%) in the placebo group. One patient treated with placebo never received any study drug (Table 12).

In the berotralstat 150 mg group, 37 patients (93%) completed part 1 of APeX-2 and entered part 2. Six patients discontinued early (16%).⁵ Reasons for discontinuation were adverse events for 2 patients, lack of efficacy for 3 patients, and other reasons for 1 patient. Among patients initially randomized to placebo, 34 patients (85%) completed part 1 and 17 patients were randomized to berotralstat 150 mg daily. Two of these patients (18%) discontinued early due to lack of efficacy and 1 patient withdrew consent.⁵

In the APeX-J study, 25 patients were screened for entry, 19 of whom (76%) were randomized to 1 of 3 treatment groups. None of the patients in the berotralstat 150 mg and placebo groups withdrew from part 1 of the study, and only 1 patient in the placebo group (17%) stopped treatment early due to an adverse event (Table 12).

Table 12: Patient Disposition (Part 1)

^aIn the APeX-2 study, of the 39 patients who failed screening, 36 did not meet inclusion criteria (most common: 15 patients did not meet HAE diagnostic criteria, 7 patients did not record 2 or more HAE attacks during run-in), and 3 patients withdrew consent.

^bIn the APeX-J study 6 patients failed screening including 3 patients who did not record 2 or more HAE attacks during run-in, 2 patients who did not meet other inclusion criteria, and 1 patient who withdrew consent.

^cIncludes 41 patients who were randomized to the berotralstat 110 mg dose group.

^dIncludes 6 patients who were randomized to the berotralstat 110 mg dose group.

^eOne patient did not receive treatment.

Source: Clinical Study Report for APeX-2⁶ and Clinical Study Report for APeX-J.⁷

Exposure to Study Treatments

The median treatment duration was 168 days in the berotralstat 150 mg and placebo groups in both the APeX-2 and APeX-J studies (Table 13). All patients had access to treatments to manage acute HAE attacks, and the most commonly reported options were C1-INH or icatibant acetate. The proportions of acute events that were treated were generally similar in the berotralstat 150 and placebo groups of the APeX-2 study (87% and 88%) and the APeX-J study (███ and ███, respectively), although there were differences between groups in the specific medications administered (Table 13). More attacks were treated with a C1-INH in in the berotralstat group than in the placebo group in the APeX 2 study (55% versus 36%, respectively), but the ██ █ ██ █ ███ █ █ █ ██ in the APeX-J study (███ versus ███).

Table 13: Extent of Exposure (Part 1 Safety Population)

C1-INH = complement 1 esterase inhibitor; HAE = hereditary angioedema; NR = not reported; SD = standard deviation.

^aIncludes plasma-derived C1-INH (Cinryze, Berinert, Haegarda).

^bIncludes Cinryze, Berinert, Haegarda, recombinant C1-INH (Ruconest) and fresh frozen plasma.

Source: Clinical Study Report for APeX-2⁶ and Clinical Study Report for APeX-J.⁷

Efficacy

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

Hereditary Angioedema Attacks

In the APeX-2 study, the mean number of attacks per month at baseline was 3.1 (SD = 1.6) in the berotralstat 150 mg group and 2.9 (SD = 1.1) in the placebo group (The attack criteria used to determine the baseline rate were different than the criteria used during the on-treatment period.) During part 1, there were 402 and 601 HAE attacks reported by patients in the berotralstat 150 mg and placebo groups, of which 357 (89%) and 508 (85%) were confirmed by the investigator in the berotralstat 150 mg and placebo groups, respectively. During treatment, the rate of confirmed attacks per month was 1.31 for the berotralstat 150 mg group and 2.35 for the placebo group, with a relative rate reduction of 44.2% (95% CI, 23.0% to 59.5%; P < 0.001) (Table 14). The mean investigator-confirmed attack rate by month is shown in Appendix 3, Figure 3 and Table 26.

The results of the sensitivity analyses for the rate of investigator-confirmed HAE attacks were generally supportive of the results of the primary analysis, although the magnitude of the treatment effects was reduced for the analysis that included imputed or observed HAE attack data after the patient stopped the study drug (rate reduction = 35%; 95% CI, 9.2% to 52.9%; P = 0.011) for berotralstat 150 mg versus placebo). The tipping-point analysis showed that a doubling of the attack rate in the berotralstat 150 mg group would be required for the missing data to alter the results of the analysis.

The relative rate reduction in investigator-confirmed HAE attacks during the effective treatment period (day 8 to start of part 2) for the berotralstat 150 mg group versus placebo was 46.5% (95% CI, 25.6% to 61.5%). No conclusions can be drawn with regard to the statistical significance of this difference, as testing was stopped due to failure of a prior outcome in the testing hierarchy.

During the 24-week treatment period, █ █ ██████ in the berotralstat 150 mg group ██ █ █ and ██ █ █ █ ██ in the placebo group █ █ ██ █ █ experienced no investigator-confirmed HAE attacks, with ███ █ ████ █ █ detected between groups in the APeX-2 study █ █ █ ████.

For investigator-confirmed attacks that received acute treatment, the APeX-2 study reported an attack rate of 1.04 events per month in the berotralstat 150 mg group, compared with 2.05 events per month in the placebo group (Table 14). The rate reduction was 49.2% (95% CI, 25.5 to 65.4; P < 0.001). These data should be interpreted with caution because there was no control of the type I error rate.

Ad hoc, exploratory analyses reported a rate reduction of 62.6% (95% CI, 9.6% to 84.6%; ████████) for laryngeal HAE attacks, and a rate reduction of 39.5% (95% CI, ████ to █████; ███████) for investigator-confirmed moderate-to-severe HAE attacks (Table 14). These data should be interpreted with caution as they were not controlled for the type I error rate.

During part 2 of the APeX-2 study, the mean investigator-confirmed attack rate per month in the berotralstat 150 mg group was 1.7 (standard error [SE] = 0.32) at 24 weeks (N = 37), 1.3 (SE = 0.26) at week 28, and 1.1 (SE = 0.25) at week 48. The number of patients contributing data to the week 28 and week 48 results was not reported (31 of 37 patients [84%] completed part 2).⁵ Among the patients switched from placebo to berotralstat 150 mg (n = 17), the mean attack rate per month was 2.6 events (SE = 0.61) at 24 weeks, 1.3 events (SE = 0.41) at 28 weeks and 0.6 events (SE = 0.23) at 48 weeks (number of patient not reported; 14 of 17 patients [82%] completed part 2).⁵ Additional unpublished data supplied by the sponsor for part 2 and part 3 of the APeX-2 study are summarized in Appendix 5.

In the APeX-J study, a total of ██ angioedema events were reported by patients in the berotralstat 150 mg group compared with █ ██ events among patients who received placebo during the first 24 weeks of the study. Overall, ███ of events were confirmed by the expert (██ events in the berotralstat group and ██ in the placebo group). █ ██ █ ████ █ ██ █ ███████ █ ████ █ ██ █ █ █ █ █ ████ █ ████ █ ███ █ ██. During part 1, the rate of expert-confirmed HAE events was 1.11 attacks per month and 2.18 per month in the berotralstat 150 mg and placebo groups, respectively (Table 14). The relative rate reduction was 49.1% (95% CI, 20.4% to 67.5%; P = 0.003) for ber otralstat 150 mg versus placebo. ██ █ ████████ █ █ █ █ █████ █ ██████ █ █████ █ █ █ ███████ █ █████████ █ ███████ █ ██████, as did the expert-confirmed event rate for the effective treatment period (day 8 to start of part 2) (rate reduction = 47.6%; 95% CI, 17.7% to 66.6%; P value not reported as statistical testing was stopped due to failure of a prior outcome). Exploratory analysis of the treated attack rate and ad hoc analyses on the rate of laryngeal, or moderate-to-severe HAE attacks are shown in Table 14.

█ █ █ ████████ █ ████████████ █ ███ █ ████ █ █████ █ ██ █ █ ██████ █ ███████ █ ██ █ █████ █ █████ █ █ █ █ █ █ ███ █ ██ █ █ █ ███ █ █████ █ ████████ █ ███████ █ █ █. This analysis reported a confirmed HAE attack rate of █ █ ██ events per months in the berotralstat 150 mg group (N = ██) and █ █ ██ events per month in the placebo group (N = ██), with a relative rate reduction of █ █ ███ (95% CI, ██ █ ██ to █ ████; P < █ █ ███) which should be interpreted as supportive evidence only.

Subgroup analyses for the APeX-2 study and the combined results for APeX-2 and APeX-J studies are reported in Appendix 3, Table 27. The direction of treatment effects was generally consistent across subgroups based on baseline attack rate, and prior androgen use. The subgroup of adolescents was too small to draw any meaningful inferences from the data.

Table 14: Investigator-Confirmed HAE Attack Rate (Part 1 Intention-to-Treat Population)

CI = confidence interval; HAE = hereditary angioedema; NR = not reported.

^aNegative binomial model, with covariate for baseline HAE attack rate and log of treatment duration as offset for the intention-to-treat population.

^bP value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

^cSeverity rating according to the patient electronic diary.

Source: Clinical Study Report for APeX-2⁶ and Clinical Study Report for APeX-J.⁷

During part 1 of the APeX-2 study, patients in the berotralstat 150 mg group reported a mean of 19.4 (SD = 21.5) days with HAE symptoms compared with 29.2 days (SD = 24.3) for patients in the placebo group (Table 15). The LS mean difference in the proportion of days with symptoms was −0.078 (95% CI, −0.133 to −0.023), which translates to approximately 13 fewer symptom-days in the berotralstat versus placebo group (out of a total of 169 treatment days). No conclusions can be drawn with regard to statistical significance of this difference, as testing was stopped due to failure of a prior outcome in the statistical testing hierarchy.

In the APeX-J study, no difference between groups was detected in the proportion of days with HAE symptoms (LS mean difference −0.122; 95% CI, −0.280 to 0.036; P = 0.12) (Table 15).

In the APeX-2 study, █████ █ ██████ of patients in the berotralstat 150 mg versus placebo groups, respectively, reported 1 or more attack-free months during the 24-week treatment period (Appendix 3, Table 28). Attack-free months were not reported in the APeX-J study.

Table 15: Days With Angioedema Symptoms (Part 1 Intention-to-Treat Population)

CI = confidence interval; LS = least squares; NR = not reported; SD = standard deviation; SE = standard error.

^aAnalysis of covariance model with baseline attack rate as covariate for the intention-to-treat population.

^bOne patient from the placebo group who did not receive any study drug was missing from the analysis because this patient had no on-treatment days.

^cStatistical testing stopped due to failure of prior outcome in the statistical testing hierarchy.

Source: Clinical Study Report for APeX-2⁶ and Clinical Study Report for APeX-J.⁷

The responder analyses were exploratory end points in both studies. As these analyses have not been controlled for type I error rate, they should be interpreted with caution because of the potential for inflated type I error rate.

More patients in the berotralstat 150 mg group than the placebo group achieved at least a 50% relative reduction in the rate of investigator-confirmed HAE attacks compared to baseline (58% versus 25%; odds ratio = 3.91; 95% CI, 1.51 to 10.16; P = 0.005). The differences favoured berotralstat versus placebo for the proportion of patients with at least a 70% relative reduction, but not for the proportion with at least a 90% relative reduction (both analyses were conducted an ad hoc) (Table 16).

Similar trends were observed for the APeX-J study (Table 16).

Table 16: Responder Analysis (Part 1 Intention-to-Treat Population)

CI = confidence interval; HAE = hereditary angioedema; NE = not estimable.

^aFor the APeX-2 study, the analysis was based on logistic regression model with covariate for baseline HAE attack rate for the intention-to-treat population.

^bP value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

^cFisher’s exact test.

^dAd hoc analysis in the APeX-2 study.

Source: Clinical Study Report for APeX-2⁶ and Clinical Study Report for APeX-J.⁷

Health-Related Quality of Life

HRQoL was measured using the AE-QoL (secondary outcome) and EQ-5D-5L (exploratory outcome) instruments. While both the berotralstat 150 mg and placebo groups of the APeX-2 study reported improvements in the AE-QoL total scores at week 24, no statistically significant difference was detected between groups in the LS mean difference (−4.9 points; 95% CI, −12.2 to 2.4; P = 0.19) (Table 17). In the APeX-J study, the LS mean difference for the change from baseline in the AE-QoL total score was −19.0 (95% CI, −39.0 to 1.0).

In the APeX-2 study, no differences were detected between the berotralstat 150 mg and placebo groups for the change from baseline to week 24 in the EQ-5D-5L index score (█████ █ ███ █ ████ █ ███ █ █ █ █ ████ █ ██████████ █ ██████ █ █ █ ██ or the EQ VAS (█ █ ██ █ ████ █ █ ██ █ ████ █ █ ██ █ ████ █ ██ █ ██ █ █████). In the APeX-J study the LS mean difference for the change from baseline in the EQ VAS was █ █ █ █ █ █ █ █ ██ █ ███ █ ██████ █ █████; not controlled for type I error rate) and the EQ-5D-5L index score was ███ █ ████ █ █████ █ ████ █ █ ████ █ █ █ ███ for the berotralstat 150 mg group versus placebo groups.

Table 17: Change From Baseline in AE-QoL Total Score (Part 1 Intention-to-Treat Population)

AE-QoL = Angioedema Quality of Life questionnaire; CI = confidence interval; LS = least squares; NR = not reported; SD = standard deviation; SE = standard error.

Note: AE-QoL scores range from 0 to 100, with a negative change in score indicating an improvement in health-related quality of life.

^aMixed model for repeated measures analysis with baseline attack rate, baseline AE-QoL value, visit, and visit by treatment interaction as covariates based on the intention-to-treat population (includes patients who stopped the study drug but remained in the study).

^bStatistical testing stopped due to failure of prior outcome in the statistical testing hierarchy.

Source: Clinical Study Report for APeX-2⁶ and Clinical Study Report for APeX-J.⁷

Mortality

No deaths were reported in the first 48 weeks of the APeX-2 study or the first 24 weeks of the APeX-J study.

Hospitalization or Emergency Visits

Professional care was sought for █ █ █████ █ █████ investigator-confirmed HAE attacks reported by patients in the berotralstat 150 mg group during the first 24 weeks of the APeX-2 study. Of these attacks, █ █ ██████ █ ██ █ █ █ █ █ ███ █ █ █████ █ █ █ █ █ ██visit and █ █ ██ █ ████ █ █ █ ███████ █ ██████. In the placebo group, patients sought care for ████ █ ████ █ ███ attacks, including ██ █ ██████ █ █████ █ ███ █ ███ and █ ███ █ █████ █ ██. ██████ █ ████ █ █ █ ████████ █ ██ █ █ █ █ █ █ █ ██ █ ██████████ █ █ █████████████████ █ █████ █ ██████ █ ███ █ ██.

In the APeX-J study, professional care was sought for ████ █ ██ █ █████ expert-confirmed attacks in patients who received berotralstat 150 mg, and in ██ █ ████ █ █████ █ █████ reported among those who received placebo. Of these events, █ █ █ █ █ █ ██ in the berotralstat group and █ █ ████ █ ██ in the placebo group required an emergency visit. █████ █ ███████ █ ██ █ █ ██ █ ███ █ ██████████ █ █████.

Harms

Only those harms identified in the review protocol are reported. Table 18 provides detailed harms data for part 1 of the trials (first 24 weeks).

Adverse Events

Adverse events were reported by 85% of patients in the berotralstat 150 mg group and 77% of those in the placebo group during the first 24 weeks of the APeX-2 study. The most frequently reported events in the berotralstat group was █ ███ █ ███ █ ███ █ █ █ █ █ ███, nausea (15%), vomiting (15%) and diarrhea (15%). The most common events in the placebo group were ██ █ ███████ █ █ ███ █ ████ and nausea (18%) (Table 18). One patient in the berotralstat 150 mg group reported a grade 3 or 4 adverse event of back pain. Four patients in the placebo group reported grade 3 or 4 adverse events of diverticular hemorrhage, uterine leiomyoma, pneumonia, increased gamma-glutamyl transferase, and transient ischemic attack.

All patients in the APeX-J study reported 1 of more adverse events during part 1, with nasopharyngitis reported most frequently in the berotralstat 150 mg and placebo groups (Table 18). One grade 3 or 4 adverse event was reported in the APeX-J study in a patient treated with placebo who reported decreased platelet count.

Serious Adverse Events

No patients in the berotralstat group of the APeX-2 study experienced a serious adverse event during the 24-week study period. Three patients in the placebo group experienced 4 serious adverse events of uterine leiomyoma, diverticulum intestinal hemorrhage, pneumonia, and transient ischemic attack.

No serious adverse events were reported in the first 24 weeks of the APeX-J study.

Withdrawal Due to Adverse Events

In the APeX-2 study, 1 patient in the berotralstat 150 mg group stopped treatment due to abnormal liver function test results, and 1 patient in the placebo group stopped the study drug due to a depressive episode. One placebo-treated patient in the APeX-J study stopped treatment due to urticaria.

Mortality

No deaths were reported during the first 48 weeks of the APeX-2 study or the first 24 weeks of the APeX-J study.

Notable Harms

Gastrointestinal adverse events were reported more frequently among patients who received berotralstat 150 mg compared with placebo in the APeX-2 study (50% versus 36%, respectively), and in the APeX-J study (43% versus 17%, respectively). No patients stopped treatment due to gastrointestinal adverse events in the first 24 weeks of either study. The product monograph states that gastrointestinal adverse effects generally occur early after therapy begins, become less frequent over time, and typically self-resolve.⁴

Table 18: Summary of Harms (Part 1 Safety Population)

GI = gastrointestinal; NR = not reported.

^aFrequency higher than 10% in any treatment group in the APeX-2 study.

Source: Clinical Study Report for ApeX-2 study⁶ and Clinical Study Report for ApeX-J study.⁷

ApeX-2 Study – Part 2 (Week 24 to Week 48)

Wedner et al. (2021)⁵ provided a summary of adverse events for patients who received berotralstat for up to 48 weeks (N = 40) in the APeX-2 study. Most patients (95%) reported at least 1 adverse event, including 1 serious adverse event in a patient who was hospitalized for a routine screening procedure. The most common adverse events were upper respiratory tract infection (53%), abdominal pain (30%), nausea (20%), and diarrhea (18%). In part 2 of the study, 2 patients who received the 150 mg dose (8%) stopped treatment due to adverse events; 1 due to gastrointestinal events (anal incontinence), and 1 due to palpitations and tachycardia. Among patients who switched from placebo to berotralstat 150 mg (N = 17), no new serious adverse events were reported and no patients stopped treatment due to adverse events.⁵ No new safety signals were detected based on data up to 48 weeks treatment.⁵

Critical Appraisal

Internal Validity

APeX-2 and APeX-J Part 1

Both RCTs were conducted using a similar 3-part study design and comparable statistical methods. Patients were allocated to treatment groups using appropriate methodology (i.e., interactive web or voice response technology), with randomization stratified by a relevant prognostic factor (i.e., investigator-confirmed HAE attack rate during the screening period [≥ 2 attacks or < 2 attacks per 28 days]). Due to the small sample size of the trials, randomization may not have ensured the groups were balanced for all measured or unmeasured prognostic factors or confounders, and imbalances between treatment groups were observed for some of the baseline patient characteristics. Differences were noted in the mean age and weight, proportion of females, history of laryngeal attacks, and HAE-related emergency visits in past year. However, the clinical expert consulted for this review noted that these baseline differences were unlikely to bias the results. Four patients in the placebo group (10%) withdrew from the APeX-2 study during the first 24 weeks, compared with 2 patients in the berotralstat group (5%). In addition, efficacy outcomes were analyzed using the on-treatment time only, which meant that 1 patient in the placebo group who did not receive any study drug did not contribute any data to the analyses. There were more patients who stopped treatment early in the placebo group than in the berotralstat 150 mg group (13% versus 8%, respectively). It is possible the differences in losses or exclusions could contribute to imbalances between groups, although the potential impact on the study’s results is unclear.

Both studies were double-blind during part 1, with the active study drug and placebo supplied as identical-looking capsules. Gastrointestinal adverse effects were reported more frequently among patients who received berotralstat compared with placebo, but it is unclear if this contributed to unblinding, given that these adverse effects are similar to gastrointestinal symptoms associated with HAE attacks.

The primary efficacy outcome was based on the rate of investigator-confirmed HAE attacks, which was considered to be appropriate and clinically relevant by the clinical expert consulted and by regulators.^19,20 All patient-reported events were reviewed by the investigator to ensure they met the predefined criteria for an attack. Given the subjective nature of the events, patients may over-report the frequency of attacks. Moreover, the clinical expert noted that patients may have difficulty distinguishing gastrointestinal adverse effects associated with berotralstat from gastrointestinal symptoms of an HAE attack. The FDA stated that investigator confirmation of attacks may help ensure that only swelling attacks, and not prodromal symptoms or pre-emptive rescue medication use, were counted as events.¹⁹ According to the clinical expert consulted for this review, a 20% improvement in the attack rate is generally considered a mild effect, 50% is considered moderate, and 70% is considered a marked effect.

The sample size of the pivotal APeX-2 trial was small, but due to the rarity of HAE, it was considered acceptable by regulators.^19,20 Both studies reported power calculations, and despite the low power of the APeX-J study, it did detect a statistically significant difference between the berotralstat 150 mg and placebo group for the primary outcome. Due to the anticipated small sample size in the APeX-J study (which was conducted in Japan only), the study protocol described a pooled analysis that combined the patients from APeX-J and APeX-2. However, because the study’s protocol specified the primary analysis would be based on patients enrolled in APeX-J only, the pooled analysis was considered supplementary data by CADTH.

The rate of HAE attacks was analyzed using a negative binomial model, which, according to the APeX-2 statistical analysis plan, was selected as the primary analysis because overdispersion was detected with the Poisson model. Analyses were based on the on-treatment time, with no imputation for missing data. Three sensitivity analyses were conducted in APeX-2 to explore the impact of missing data. The sensitivity analyses included data for attacks reported after stopping therapy with or without imputation for patients with no outcome data reported after stopping study drug, and a tipping-point analysis that estimated the response level at which the missing data in the berotralstat groups would change the results. The results of the sensitivity analyses were supportive of the primary analysis in general, but the magnitude of the effect for berotralstat 150 mg was not as strong in the analysis that used observed data post–treatment discontinuation and also imputed missing data post–treatment discontinuation. Subgroup analyses by baseline attack rate of prior androgen use were generally consistent with the overall treatment population. Too few adolescents were enrolled to allow for meaningful interpretation of this subgroup.

There were differences between groups in the type of acute treatments administered for HAE attacks. In the APeX-2 study, a greater proportion of attacks were treated with any C1-INH in the berotralstat group compared with the placebo group (55% versus 36%, respectively), and fewer attacks were treated with icatibant acetate (38% versus 59%, respectively). The clinical expert noted that the C1-INHs have a longer duration of action (3 days) compared with icatibant acetate (which may be administered every 6 hours). In addition to alleviating symptoms of the acute attack, C1-INHs may provide a protective effect for patients and reduce the risk of subsequent attacks for days after administration. The █ █ ███ █ ███ of C1-INH in the berotralstat group may therefore potentially favour active treatment versus placebo in the APeX-2 study. Possible bias favouring placebo was noted for the APeX-J study, as fewer patients in the active group were treated with C1-INHs.

Both trials used hierarchical testing and the Hochberg procedure to control the type I error rate for the primary outcome and 3 secondary outcomes as well as the 2 berotralstat dosage groups. Other outcomes that were of interest to this review (e.g., the responder analysis) were not controlled for multiplicity of testing. Moreover, the rate of laryngeal, moderate or severe attacks, and the 70% or greater and 90% or greater responder threshold analyses (in the APeX-2 study) were conducted post hoc. Both trials used a relatively short run-in period to determine the baseline rate of attacks (14 to 56 days in the APeX-2 study; 56 days in APeX-J). Given the unpredictable nature of HAE attacks, this limited observation time could add uncertainty to the baseline rate. Variability in the baseline attack rate would not affect the interpretation of the primary outcome (which was based on on-treatment attack rate), but it could affect the interpretation of the responder analyses (which was based on the change from the baseline rate).

Neither study was designed to test for differences in the need for hospitalization or emergency visits. HRQoL was measured using the AE-QoL as a secondary outcome, and the EQ-5D-5L as an exploratory outcome. The AE-QoL has evidence to support the validity, reliability, and responsiveness in patients with recurrent angioedema, which included patients with histamine- or bradykinin-mediated angioedema. However, the FDA did not consider the AE-QoL a well-defined or reliable assessment of HAE-related quality of life for the purpose of labelling, noting that the nutrition and mood domains of the AE-QoL are not specific to HAE, the clinically meaningful within-person change has not been established, and the 4-week recall period was long.¹⁹

As both trials included a placebo control group, there is no direct evidence comparing berotralstat to other LTP therapies. As with most clinical trials, the studies were not powered to detect infrequent adverse effects or those with a lag time.

APeX-2 Parts 2 and 3

Several limitations were identified for parts 2 and 3 of the APeX-2 study. First, the investigators and patients were aware that patients were receiving active treatment, and their expectations of treatment could affect reporting of subjective outcomes such as symptoms or adverse effects. In addition, there was potential selection bias, as patients who respond to berotralstat and are able to tolerate treatment are more likely to continue therapy compared to patients with less favourable outcomes. The efficacy analyses were based on observed data with no imputation for missing data, and with no sensitivity analyses to assess the robustness of the results. Given the attrition observed, the reported results may overestimate the treatment effects and under-report adverse effects. Finally, part 2 and 3 were uncontrolled, which makes the change in HAE attack rate difficult to interpret, particularly because HAE attacks are sporadic and may fluctuate through the year due to exposure to seasonal triggers, hormonal changes, or other factors.

A full-text report of part 3 of the APeX-2 study was not available at the time of the initial systematic review, and the sponsor-submitted posters and data tables did not allow CADTH to fully appraise the potential for bias.^25-28 As part of the Request for Reconsideration, the final Clinical Study Report that contained data from part 2 and part 3 of APeX-2 study was supplied by the sponsor, and additional appraisal points are included in Appendix 5.

External Validity

The findings of the pivotal APeX-2 study were reflective of those enrolled: patients with type 1 or 2 HAE who had on average 3 HAE attacks per month, most of whom had experienced a prior laryngeal attack. Although the proportion of patients with type 1 versus type 2 HAE were not reported in either study, most patients (88% to 100%) had their diagnosis confirmed by low C4 levels plus a functional level of C1-INH of less than 50%, which is consistent with clinical practice. Approximately a third of patients had a baseline attack rate of less than 2 attacks per month, which the clinical expert stated may be lower than the typical frequency at which an LTP is initiated in clinical practice. Although the expert acknowledged that patients with infrequent but more severe attacks may also be considered for an LTP. The trial included patients who were medically appropriate for on-demand treatment as the sole management of HAE, and therefore may have excluded patients with more severe HAE who could not tolerate discontinuation of current LTP therapy.

Compared to the Canadian population, racial diversity in the APeX-2 trial was limited as most patients were white (94%). In addition, patients were predominantly female (63%) and aged between 18 and 65 years. Because only 4 adolescents and 4 patients over 65 were enrolled in the berotralstat 150 mg and placebo groups in the APeX-2 study, there are limited data to extrapolate to younger and older age groups. In total, 10 of the randomized patients (8%) were from Canada. The study reported that 24% of patients screened were excluded from the study, with most patients eliminated because they did not meet the diagnostic or baseline attack-rate criteria for the trial. The APeX-J study provided additional data from 13 patients from Japan. These patients were generally similar to those in the pivotal study, although patient weight and BMI were lower, as was their mean baseline HAE attack rate. Overall, the clinical expert consulted for this review considered the characteristics of the patient population enrolled in the trials to be a good representation of the target population and the expert did not identify any issues with the use of concurrent treatments or conduct of the trials that could substantially affect the generalizability of the findings.

The duration of the controlled portion of the trials was limited to 24 weeks, which may be considered short, given that LTP treatment is potentially life-long therapy. Due to the limitations of the longer-term data, the efficacy and safety of berotralstat beyond 24 weeks are uncertain.

Indirect Evidence

Objectives and Methods for the Summary of Indirect Evidence

As no direct comparative data for the use of berotralstat for the routine prevention of recurrent episodes of HAE were identified in the systematic review, a search for indirect evidence was conducted.

A focused literature search for indirect treatment comparisons (ITCs) dealing with Orladeyo (berotralstat) and HAE was run in MEDLINE All (1946–) on March 14, 2022. No limits were applied. The search results for ITCs that met the patient, intervention, comparator, and outcome criteria in the review protocol (Table 6) were screened by 1 researcher. Although no ITC was submitted by the sponsor, an indirect comparison feasibility assessment included in the sponsor’s submission was reviewed.²⁸

No relevant ITCs were found in the literature search. CADTH’s review of the sponsor’s feasibility assessment is provided in the following section.

Appraisal of the Feasibility Assessment

The sponsor conducted a feasibility assessment²⁸ to determine if the clinical trials for treatments used for routine prevention of HAE attacks were sufficiently similar to permit valid comparison in an ITC. Five studies were evaluated: APeX-2¹⁷ and APeX-J¹⁸ (berotralstat), HELP−03²⁹ (lanadelumab), COMPACT³⁰ (C1-INH SC), and CHANGE³¹ (C1-INH IV).

The authors of the feasibility assessment identified a number of important differences in the study designs and patient characteristics of the trials and concluded that it was not possible to generate robust estimates of the comparative treatment effects due to between-study heterogeneity. The sponsor cited reviews by other health technology assessment agencies that support their conclusions; however, none of these reports included both lanadelumab and berotralstat. Three reports^32-34 compared lanadelumab to C1-INH, and 1 compared berotralstat to C1-INH.³⁵ Similarly, a recent National Institute for Health and Care Excellence review did not consider lanadelumab a relevant comparator, based on the treatment patterns of HAE in the UK at the time of the review.³⁶ The Scottish Medicines Consortium stated that lanadelumab, C1-INH, androgens, and tranexamic acid were all considered relevant comparators to berotralstat, but in its review, comparative data were not provided and the sponsor’s economic model was based on a no-treatment comparator.³⁷

Based on the information presented in the sponsor’s feasibility assessment,²⁸ the clinical expert consulted for this review agreed that the heterogeneity between the berotralstat and C1-INH trials is significant and that any ITC is unlikely to produce robust estimates of comparative efficacy or safety. However, because fewer differences exist between berotralstat and lanadelumab trials, such an ITC may have been possible. The APeX and HELP−03 RCTs were both parallel, double-blind design trials, with a run-in period to establish the baseline attack rate and a treatment duration of 24 and 26 weeks. There were some differences in the enrolment criteria related to the baseline attack rate, with the lanadelumab trial enrolling patients with 1 or more attacks per 4 weeks, whereas the berotralstat studies enrolled those with 2 or more events during the run-in period (14 to 56 days). However, the mean baseline attack rate was generally similar for the berotralstat (2.9 to 3.1 attacks per month) and lanadelumab trials (3.5 to 4.0 attacks per month), as was the on-treatment attack rate in the placebo groups (APeX: 2.35 and 2.18 attacks per 4 weeks; HELP−03: 1.97 attacks per 4 weeks). The mean age, BMI, sex, and racial distribution were comparable between trials. The treatments used for acute attacks were similar, and both studies prohibited the concurrent use of other prophylactic treatments for HAE. There was a difference in the reporting of events, with the berotralstat studies requiring patients to record attack-related data every 24 hours, compared with 72 hours in the lanadelumab study, but in both studies, all attack events had to be confirmed by the investigator or clinical expert. The sample size of the trials was limited (19 and 80 patients in the APeX studies, and 125 patients for HELP−03), which may contribute to uncertainty in an ITC, and may limit the ability to use methods such as a matching adjusted indirect comparison.

Lanadelumab was listed as a comparator of interest in the protocol to CADTH’s systematic review. While an ITC that included all relevant treatments for the prevention of HAE attacks was likely not feasible, a focused ITC comparing berotralstat to lanadelumab may have been possible and would have been of interest to CADTH.

Other Relevant Evidence

This section includes submitted long-term extension studies and additional relevant studies included in the sponsor’s submission to CADTH that were considered to address important gaps in the evidence included in the systematic review.

The open-label study, APeX-S, provides longer-term safety and efficacy data that supplement the evidence from the RCTs in the systematic review.

Long-Term Studies

APeX-S is an ongoing phase II study conducted to evaluate the safety and efficacy of berotralstat in adults and pediatric patients aged 12 years and older with type 1 or 2 HAE.

Methods

Approximately █ █ ████ █ ███ who participated in a previous study of berotralstat or who were expected to benefit from treatment were to be manually allocated to receive an oral dose of berotralstat (110 mg or 150 mg) once daily. Results for the berotralstat 110 mg group are not described in this report given that it is not a Health Canada–recommended dose. A total of 127 patients were enrolled into the 150 mg group and results were presented through to week 48 in the interim report.

Efficacy results related to HAE attacks (i.e., frequency, severity, and disease activity over time) were evaluated as a secondary end point. Safety assessments consisted of all adverse events including treatment-emergent adverse events, serious adverse events, as well as adverse events of special interest.

Populations

In APeX-S, the inclusion and exclusion criteria were generally aligned with those in the pivotal trials,^6,7 with a distinction being that APeX-S patients did not have to meet a minimum number of HAE attacks to qualify for inclusion. A total of 227 of 254 screened patients were allocated to either the berotralstat 110 mg (n = 100) or 150 mg (n = 127) groups at 49 sites in 22 countries in North America, Europe, Asia, and Africa. Baseline demographics were generally consistent with those in the APeX-2⁶ pivotal trial. In the 150 mg group the median age was 44.0 years (range = 12 to 72) and the majority of patients were female (60.6%), white (86.6%), and had a fmily history of HAE (79.5%). No baseline attack rate data were provided for the following reasons: baseline measures for some patients were not collected due to rollover from a previous berotr alstat study (██ █ █████ █ ███████ █ █ █ ██ █ █ █ █ █ █ █ █ ██ █ ███ █ ████ █ ████████ █ ███ █ ████), some patients were on prophylactic HAE medications at study entry ( █ █ █ █ █ of patients in the 150 mg group at screening), and some patients had recently discontinued androgens used as HAE prophylaxis (██ █ ██ of patients discontinued < 2 weeks before berotralstat initiation). Patients enrolled from a previous berotralstat study had to have demonstrated a minimum HAE attack rate for entry into those prior studies. Of the ██ patients who had not previously participated in a berotralstat study, █ ██ █ ██ █ ██ had their HAE diagnosis confirmed by a C4 level below the lower limit of normal plus a C1-INH function of less than 50%.

Table 19: Summary of Baseline Characteristics for APeX-S Study (Safety Population)

C1-INH = complement 1 esterase inhibitor; HAE = hereditary angioedema.

^aThe summary of any androgens includes androgens (unspecified), oxandrolone, methyl-testosterone, danazol (Danocrine), and stanozolol.

^bThe summary of any C1-INH would include plasma-derived C1-INH replacement (Cinryze, Berinert, Haegarda), recombinant C1-INH replacement (Ruconest), and fresh frozen plasma.

^cComplement C1-INH is the WHO coded term for plasma-derived C1-INH (Cinryze, Berinert, Haegarda).

Source: Clinical Study Report for APeX-S.³⁸

Outcomes

The relevant efficacy end points for this study included HAE attack and laryngeal attack frequency, attack severity, number of attacks requiring acute treatment, number and proportion of days with angioedema symptoms, and number of patients who were HAE attack-free. Relevant patient-reported outcomes during long-term administration of berotralstat were evaluated using the AE-QoL. All patient-reported HAE attacks were recorded in a paper diary. These patient-reported HAE attacks were reviewed and confirmed or rejected programmatically according to a set of predefined rules before inclusion to be considered an “adjusted attack.” The prespecified rules for an adjusted attack were: 1 or more symptoms of swelling; no alternative explanation for the attack (i.e., allergic reaction); attack began more than 24 hours from the end of the prior attack (any attack that began within 24 hours from the end of a prior attack was combined with the prior attack); and the attack lasted for longer than 24 hours if untreated. Relevant safety outcomes included treatment-emergent adverse events, serious adverse events, and adverse events of special interest.

Statistical Analysis

All efficacy and safety analyses were descriptive in nature and were conducted using the safety population, which included all patients who received 1 or more doses of the study drug. There was no imputation for missing data.

Patient Disposition

Patient disposition of the APeX-S study is summarized in Table 20. A total of 254 patients were screened and 127 patients were allocated to the berotralstat 150 mg group. A total of 26.0% of patients in this group discontinued the study drug by week 48, mainly due to adverse events (10.2%) or perceived lack of efficacy (8.7%), with 94 patients still in the study as of the data cut-off. All 127 allocated patients were included in the safety population.

Table 20: Patient Disposition in APeX-S Study Through Week 48

Source: Clinical Study Report for ApeX-S.³⁸

Exposure to Study Treatments

In the APeX-S study, through to week 48, the total number of patient-years of exposure was 106.6 for the berotralstat 150 mg group, with a median of 342.0 days (range = 11 to 540). In terms of concomitant medications, most patients (81.9%) had received C1-INH in the period between the first dose through 30 days after the last dose of berotralstat; 63.8% of patients took a plasma-derived C1-INH (i.e., Cinryze, Berinert, and Haegarda). Other concomitant HAE medications included icatibant acetate (Firazyr) (45.8%), icatibant (16.3%), and fresh frozen plasma (16.3%).

Table 21: Extent of Exposure in APeX-S Study Through Week 48 (Safety Population)

C1 = complement 1; C1-INH = complement 1 esterase inhibitor; HAE = hereditary angioedema; SD = standard deviation.

^aThe duration of exposure was calculated as last dose date − first dose date + 1.

^bPatient-years of exposure was calculated for each patient as (last dose date − first dose date + 1)/365.25 and then summed across all patients in a given dose group.

^cThe summary of any C1-INH includes plasma-derived C1-INH replacement (Cinryze, Berinert, Haegarda), recombinant C1-INH replacement (Ruconest), and fresh frozen plasma.

^dComplement C1-INH is the WHO coded term for plasma-derived C1-INH (Cinryze, Berinert, Haegarda).

Source: Clinical Study Report for APeX-S.³⁸

Efficacy

Adjusted Hereditary Angioedema Attacks

Through to week 48, in the 150 mg dose group, there were a total of █████ adjusted HAE attacks. A total of █████ of patients had 1 or more attacks, and █████ of attacks were treated with any medication. The mean attack rate was 1.36 (SD = 1.51) attacks per month and the median attack rate was 0.93 (range = 0 to 7.6) attacks per month.

Adjusted Laryngeal Hereditary Angioedema Attacks

Through to week 48, in the 150 mg dose group, there were a total of ███ adjusted laryngeal HAE attacks. A total of █ █ █ █ █ of patients had 1 or more attacks, and █████ of attacks were treated with any medication.

Adjusted Hereditary Angioedema Attacks Among Subgroups

The trial was not designed to investigate the effectiveness of the treatment by subgroups; all of which had small sample sizes. Among subgroups in the 150 mg group, the median adjusted attack rates per month were ███ █ ██ █ ████ among patients 12 to 17 years of age (n = 5); ██ █ █ █ ██ █ ███ among patients aged 65 years or older (n = 3); and ████ █ ████ among patients aged 18 to 64 years (n = 119).

Patient-Assessed Severity of Adjusted Attacks

Of the █ █ ███ adjusted attacks assessed by patients, (█████) were assessed as moderate in severity, followed by mild (█████), severe (█████), and negligible (████).

Adjusted Attacks Requiring Acute Treatment

Of the █████ adjusted attacks that occurred during the study in the 150 mg dose group, 82% were treated with a standard-of-care acute attack medication, the most common being Berinert (44.6%) and icatibant acetate (Firazyr) (37.6%).

Number and Proportion of Days with Reported Angioedema Symptoms

Through to week 48, the median number of days and proportion of days with reported angioedema symptoms among all patients in the 150 mg dose group was ██ █ █ █ ███ █ ██ and 0.07 (range = 0 to 0.7), respectively.

Number of Patients Who Were Adjusted Hereditary Angioedema Attack–Free

A patient who completed dosing in the period of interest and reported no attacks during this same period was considered attack-free. A total of ██ █ ████ patients (█████) in the 150 mg dose group remained attack-free through to week 24 and █ █ █ █ ██ patients (█ █ ██) remained attack-free from baseline through to week 48.

Health-Related Quality of Life

The AE-QoL total score ranges from 0 points (best) to 100 points (worst). The mean AE-QoL total score among patients in the 150 mg group was 37.8 (SD = 17.9) at baseline (n = 118); with a mean change from baseline of −14.7 (SD = 17.8) points through to week 48 (n = 73).

Table 22: Efficacy Outcomes in APeX-S Study Through Week 48 (Safety Population)

AE-QoL = Angioedema Quality of Life questionnaire; C1-INH = complement 1 esterase inhibitor; HAE = hereditary angioedema; SD = standard deviation.

^aThe attack rate was based on reported attacks up to the time of data cut-off with no distinction between diaries remaining with patients until their next visit (up to 12 weeks of data lag) and diaries with no attacks. Attack rates reported at later study time points may therefore underestimate the number of attacks. The 150 mg dose group has 3 of 673 months of diary data remaining with the patient for months 1 to 6, and it is estimated that approximately 6% of diaries are remaining with patients for months 7 to 12.

^bThese adjusted attacks were determined programmatically and needed to have: 1 or more symptoms of swelling; no alternative explanation for the attack (i.e., allergic reaction); begun more than 24 hours from the end of the prior attack (any attack that began within 24 hours from the end of a prior attack was combined with the prior attack); had a duration of longer than 24 hours if untreated.

^cLaryngeal attacks were attacks that involve visible swelling in the mouth, tongue, and/or lips or any of the following internal swelling symptoms: lump in throat (tightness), difficulty swallowing, change in voice, or difficulty breathing. Laryngeal attack symptoms were a subset of peripheral attack symptoms.

^dMedications were as recorded in the patient diary for each attack. The percentages provided were based on the number of adjusted attacks.

^eThe summary of any C1-INH includes plasma-derived C1-INH replacement (Cinryze, Berinert, Haegarda), recombinant C1-INH replacement (Ruconest), and fresh frozen plasma.

^fA patient who completed dosing in the period of interest and reported no attacks during this same period was considered attack-free. Patients who reported no attacks and discontinued before the end of the planned treatment period or who experienced attacks in the period were not considered attack-free. Denominators were the numbers of patients who completed dosing or discontinued in the period of interest.

Source: Clinical Study Report for APeX-S.³⁸

Harms

A summary of treatment-emergent adverse events at the interim analysis is presented in Table 23. During the 48-week period, 90.6% of patients in the berotralstat 150 mg group reported 1 or more adverse events, the most common being nasopharyngitis (33.9%), headache (15.0%), and diarrhea (14.2%). A total of 9.4% of patients experienced 1 or more serious adverse events, with █ █ █ █ ███████ █ ███ experiencing an HAE attack requiring hospitalization. Adverse events of special interest included a group of gastrointestinal abdominal events consisting of gastrointestinal signs and symptoms or motility and defecation conditions, which occurred in █████ of patients. No deaths were reported in the berotralstat 150 mg group.

Table 23: Summary of TEAEs in APeX-S Study Through Week 48 (Safety Population)

AESI = adverse event of special interest; HAE = hereditary angioedema; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

^aObserved in 5% or more of patients.

^bSAEs affecting 2 or more patients.

^cA gastrointestinal abdominal TEAE was any TEAE with a preferred term within the Medial Dictionary for Regulatory Activities 19.1 hierarchy under the high-level group terms of 1) gastrointestinal signs and symptoms or 2) gastrointestinal motility and defecation conditions.

Source: Clinical Study Report for APeX-S.³⁸

Critical Appraisal

Internal Validity

This phase II study is an ongoing, open-label, long-term study that evaluated the safety and efficacy of berotralstat for up to 48 weeks of treatment. As there was no active comparator and all outcomes were descriptive in nature, it is difficult to make any inferences regarding the results. The baseline attack rates were not calculated and it was therefore not possible to determine changes in attack rates over time from baseline. An additional limitation is the open-label nature of treatment, which can bias the reporting of subjective end points (i.e., harms). The interpretation of efficacy outcomes is limited by the large amount of missing data due to attrition. A total of 26% of patients in the berotralstat 150 mg group discontinued the study, mainly due to adverse events or a lack of perceived efficacy. This attrition could have resulted in a population of patients who were more tolerant of berotralstat, as those not responding to treatment or experiencing adverse events may be less likely to continue participating in the APeX-S study. Including patients more tolerant of berotralstat can also lead to biased estimates of efficacy and adverse events, potentially overestimating efficacy and underestimating the frequency of the adverse events being reported. The use of concomitant HAE drugs among patients throughout the APeX-S study may have increased the risk of observing additional side effects not attributable to berotralstat alone. HRQoL data are difficult to interpret as available scores continued to diminish over time, with 57.5% of patients reporting an AE-QoL total score at week 48.

External Validity

The APeX-S trial used inclusion and exclusion criteria similar to those of the pivotal trials^6,7 and enrolled predominantly middle-aged white females. The expert consulted for this review considered the patients enrolled in the pivotal trials to be representative of patients with type 1 or 2 HAE in Canada. Nevertheless, the high dropout rate of 26% in the APeX-S study may have led to patients who are less representative of the recruited population, decreasing the generalizability of the results of the study.

Discussion

Summary of Available Evidence

The systematic review included 2 double-blind RCTs that evaluated the efficacy and safety of berotralstat versus placebo in patients with HAE type 1 or 2. The APeX-2 and APeX-J studies randomized patients to placebo, berotralstat 110 mg, or berotralstat 150 mg daily for 24 weeks (part 1), after which all placebo patients were randomized to berotralstat 110 mg or 150 mg daily, and those on active drug continued with the same dose for part 2 (double-blind, up to 52 weeks). In the subsequent part 3 of the trials, all patients were switched to open-label berotralstat 150 mg daily (up to 104 weeks). The primary outcome in both studies was the rate of investigator-confirmed HAE attacks over the first 24 weeks (part 1). This review focused on a comparison between berotralstat 150 mg and placebo, which included 80 patients from the APeX-2 study and 13 patients from the APeX-J trial.

One open-label, long-term study was also summarized in this report. The APeX-S trial provided supplemental safety and efficacy data for patients who received berotralstat 150 mg daily for up to 48 weeks (N = 127). No indirect evidence comparing berotralstat to other prophylactic treatments for HAE were submitted by the sponsor and none were found in the literature.

Interpretation of Results

Efficacy

During the first 24 weeks of the APeX-2 study, treatment with berotralstat 150 mg daily reduced the rate of investigator-confirmed attacks by 44% relative to placebo. Patients experienced, on average, 1.3 attacks per month when receiving berotralstat as LTP therapy, compared with 2.4 attacks per month for those receiving placebo. Only █ █ █████ █ █ in the berotralstat group reported no confirmed HAE attacks, and overall, patients reported 13 fewer symptom-days while on berotralstat versus placebo. Other exploratory or ad hoc analyses of the treated, laryngeal, and moderate or severe attack rates were generally supportive of the results of the primary outcome. However, as these outcomes were either not defined a priori or were not controlled for type I errors, any results with a P value of less than 0.05 should be interpreted with caution due to the potentially inflated type I error rate. Similarly, the exploratory and ad hoc responder analyses were not controlled for the type I error rate. These analyses suggest that more patients in the berotralstat group achieved at least a 50% or a 70% reduction (but not a 90% reduction) in the rate of HAE attacks compared with the placebo group. According to the clinical expert consulted, the treatment effects observed were considered modest improvements, given that a 20% reduction in attacks is generally considered a mild effect, and a 50% reduction is considered a moderate effect. Both the European Medicines Agency and FDA evaluations of berotralstat stated that the clinical relevance of the effect size for the primary end point was modest.^19,20

The subgroup analyses based on baseline attack rate, and prior androgen use were generally consistent with the overall results, but due to the small sample size of the groups and the lack of statistical analysis, the subgroup data should be interpreted with caution. Because only 2 adolescents received berotralstat 150 mg, the efficacy and safety data for this population were limited.

Additional supportive data from the APeX-J study showed a 49% reduction in the expert-confirmed HAE attack rate with berotralstat 150 mg versus placebo over 24 weeks of therapy.

While the patient group input indicated that reducing the frequency of attacks was important, improving HRQoL was also a concern. Neither study detected a difference between groups in HRQoL, measured using the AE-QoL or EQ-5D, and the impact of berotralstat on HRQoL is therefore uncertain.

The key limitations of the studies were the small sample size and the short duration of the comparative treatment period (24 weeks). Due to the limited sample size (80 patients in the APeX-2 trial and 13 patients in APeX-J), randomization may not ensure the groups were balanced for all measured or unmeasured prognostic factors or confounders. At baseline, there were imbalances between groups in the mean age, proportion of females, weight, proportion with 2 or more attacks per month, prior laryngeal attacks, and prior emergency visits in the past year, but it is unclear what impact these differences may have had on the findings. In addition, more patients discontinued from the placebo group than from the berotralstat group, which may also lead to bias. However, the results of sensitivity analyses that assessed the impact of missing data were generally supportive of the primary analysis. The clinical expert noted the ██ █ ██████ of C1-INH versus other rescue therapies may have biased the results in favour of the berotralstat group in APeX-2, due to the long duration of action and potential protective effect of C1-INH. The extent to which this may have affected the HAE attack rate results is unclear.

With regard to the duration of the trials, the comparative treatment period was only 24 weeks. Longer-term noncomparative data were available, but had limitations. Wedner et al. (2021)⁵ reported 48-week data of the APeX-2 study, and the sponsor submitted posters and data-output tables that supplied select 96-week results as part of the initial submission to CADTH.^25-28 (In the Request for Reconsideration, new data for parts 2 and 3 of APeX-2 were supplied by the sponsor and these data are summarized in Appendix 5.) Additional 48-week data were available from the uncontrolled, open-label, long-term study (APeX-S). The 48-week results suggest a reduction in HAE attacks may be maintained in patients who continued on therapy. Of the 40 patients initially randomized to berotralstat 150 mg in the APeX-2 study, 31 (78%) completed 48 weeks. █ ███ █ ████ █ ███ █ ████ stopped treatment due to adverse events or lack of efficacy and ██ █ ███ █ █ █ █ ██ stopped for other reasons. As patients who responded to therapy and showed adequate tolerance were more likely to continue treatment, the efficacy results likely overestimated the effects of berotralstat. In addition to the potential selection bias, the lack of a control group limits the ability to draw causal inferences from the findings. Moreover, patients’ awareness that they were receiving active therapy may have biased reporting of subjective outcomes (such as HAE attack symptoms or adverse events) based on patients’ expectations of treatment. The durability of treatment effects of berotralstat beyond 24 weeks therefore remains uncertain.

With regard to external validity, the clinical expert consulted for this review described the characteristics of the patient population enrolled in the trials as representative of the target population and the expert did not identify any issues that could substantially affect the generalizability of the findings. The trials are representative of patients with type 1 and 2 HAE who were suitable for management using on-demand HAE therapy only, and on average, had a baseline rate of 3 HAE attacks per month.

Because limited information were reported in the RCTs on the impact of berotralstat on hospitalization or emergency visits, the impact of treatment on health care resource use or mortality are unknown. There were no head-to-head studies, and the sponsor did not conduct an ITC, and the comparative efficacy and safety of berotralstat relative to other LTP therapies are also unknown.

Harms

Most patients reported 1 or more adverse events during the RCTs, with gastrointestinal adverse events reported more frequently among patients who received berotralstat 150 mg versus placebo. However, no patients stopped treatment due to gastrointestinal adverse events during the first 24 weeks of the studies. The expert noted that the symptoms of an abdominal HAE attack may be difficult to distinguish from gastrointestinal-related adverse events. According to the product monograph, gastrointestinal adverse effects generally occur early, become less frequent over time and usually self-resolve.⁴

Withdrawals due to adverse effects in the first 48 weeks of the APeX-2 study were similar to those in the open-label, long-term study (APeX-S). In the berotralstat 150 mg group, 3 patients (8%) in the APeX-2 study and 13 patients (10%) in the APeX-S study stopped treatment due to adverse effects. Comparative safety data were limited to 24 weeks; however, no new safety signals were identified among patients who received berotralstat 150 mg for up to 48 weeks in part 2 of the APeX-2 trial (N = 37) or in the APeX-S study (N = 127). While serious adverse events were rare, their frequency should be interpreted cautiously considering the small sample size and relatively limited follow-up time. As with most clinical trials, the studies were not powered to detect infrequent adverse effects or those with a lag time.

The sponsor indicated that berotralstat will be available in Canada through a dedicated patient support program that will “connect the patient with both a nurse and a pharmacist qualified to review the patient’s medication history and to educate patients on how to best manage adverse effects and provide adherence strategies.”³⁹

Conclusions

In patients with type 1 or 2 HAE, treatment with berotralstat 150 mg daily reduced the rate of investigator-confirmed HAE attacks, relative to placebo, based on 24-week data from the APeX-2 and APeX-J studies. The impact of berotralstat on HRQoL was uncertain; although improvement in the AE-QoL total score was observed, the difference versus placebo was not statistically significant. Longer-term, uncontrolled studies suggest that a reduction in HAE attacks may be maintained in patients who continued on therapy up to 48 weeks; however, due to the limitations associated with these data, the longer-term safety and efficacy of berotralstat are uncertain. No evidence was available regarding the impact of berotralstat on hospitalization, emergency visits, or mortality. Also, because no direct or indirect evidence comparing berotralstat to other LTP therapies was available, the relative efficacy and safety of berotralstat compared to other LTP treatments are unknown. Gastrointestinal adverse events were reported more frequently among patients who received berotralstat compared with those who received placebo. Due to the limited sample size and duration of the trials, the studies were not designed to detect infrequent adverse effects or those with a lag time.

References

1.Betschel S, Badiou J, Binkley K, et al. The International/Canadian Hereditary Angioedema Guideline. Allergy Asthma Clin Immunol. 2019;15(1):72. PubMed

2.Maurer M, Magerl M, Ansotegui I, et al. The international WAO/EAACI guideline for the management of hereditary angioedema-the 2017 revision and update. Allergy. 2018;73(8):1575-1596. PubMed

3.Aygören-Pürsün E, Magerl M, Maetzel A, Maurer M. Epidemiology of Bradykinin-mediated angioedema: a systematic investigation of epidemiological studies. Orphanet J Rare Dis. 2018;13(1):73-73. PubMed

4.Orladeyo (berotralstat): 150 mg oral capsules [product monograph]. Oakville (ON): Innomar Strategies; 2022 Jun 2.

5.Wedner HJ, Aygoren-Pursun E, Bernstein J, et al. Randomized trial of the efficacy and safety of berotralstat (BCX7353) as an oral prophylactic therapy for hereditary angioedema: results of APeX-2 through 48 weeks (part 2). J Allergy Clin Immunol Pract. 2021;9(6):2305-2314.e2304. PubMed

6.Interim Clinical Study Report: BCX7353-302. Part 1. A phase 3, randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy and safety of two dose levels of BCX7353 as an oral treatment for the prevention of attacks in subjects with hereditary angioedema [internal sponsor's report]. Durham (NC): BioCryst Pharmaceuticals, Inc; 2019 Oct 31.

7.Interim Clinical Study Report: BCX7353-301. Part 1. A phase 3, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of two dose levels of BCX7353 as an oral treatment for the supression of events in subjects with hereditary angioedema [internal sponsor's report]. Durham (NC): BioCryst Pharmaceuticals, Inc; 2019 Dec 26.

8.Bork K, Meng G, Staubach P, Hardt J. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med. 2006;119(3):267-274. PubMed

9.Lumry WR. Overview of epidemiology, pathophysiology, and disease progression in hereditary angioedema. Am J Manag Care. 2013;19(7 Suppl):s103-110. PubMed

10.Bork K, Hardt J, Witzke G. Fatal laryngeal attacks and mortality in hereditary angioedema due to C1-INH deficiency. J Allergy Clin Immunol. 2012;130(3):692-697. PubMed

11.Busse PJ, Christiansen SC, Riedl MA, et al. US HAEA Medical Advisory Board 2020 guidelines for the management of hereditary angioedema. J Allergy Clin Immunol Pract. 2021;9(1):132-150.e133. PubMed

12.Takhzyro (lanadelumab injection): prefilled syringes and vials; 300 mg/2 mL solution for subcutaneous injection [product monograph]. Toronto (ON): Takeda Canada Inc; 2021 Mar 22: https://pdf.hres.ca/dpd_pm/00060484.PDF. Accessed 2022 Apr 20.

13.Berinert 500 / Berinert 1500 (C1 esterase inhibitor, human): powder and diluent for solution for injection; for intravenous administration; 500 IU/vial, reconstituted with 10 mL of diluent; 1500 IU/vial, reconstituted with 3 mL of diluent [product monograph]. Ottawa (ON): CSL Behring Canada, Inc; 2020 Feb 14: https://pdf.hres.ca/dpd_pm/00055050.PDF. Accessed 2022 Apr 20.

14.Cinryze (C1 esterase inhibitor (human)): 500 IU powder for solution/vial reconstituted with 5 mL of diluent for intravenous injection [product monograph]. Toronto (ON): Takeda Canada Inc; 2021 Feb 22: https://pdf.hres.ca/dpd_pm/00060070.PDF. Accessed 2022 Apr 20.

15.Haegarda (C1 esteraase inhibitor subcutanous (human)): powder and iluent for solution for injection for subcutaneous administration; 2000 IU/vial, reconstituted with 4 mL of diluent, 3000 IU/vial, reconstituted with 5.6 mL of diluent [product monograph]. Ottawa (ON): CSL Behring Canada, Inc; 2022 Apr 13: https://pdf.hres.ca/dpd_pm/00065454.PDF. Accessed 2022 Apr 20.

16.Drug therapies for the long-term prophylaxis of hereditary angioedema attacks. (CADTH technology review no. 25). Ottawa (ON): CADTH; 2019: https://www.cadth.ca/sites/default/files/hta-he/ob0007-hae-prophylaxis-redacted.pdf. Accessed 2022 Apr 29.

17.Zuraw B, Lumry WR, Johnston DT, et al. Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: a randomized, double-blind, placebo-controlled phase 3 trial. J Allergy Clin Immunol. 2021;148(1):164-172.e169. PubMed

18.Ohsawa I, Honda D, Suzuki Y, et al. Oral berotralstat for the prophylaxis of hereditary angioedema attacks in patients in Japan: a phase 3 randomized trial. Allergy. 2021;76(6):1789-1799. PubMed

19.Center for Drug Evaluation Research. Multi-discipline review(s). Orladayo (berotralstat) 150 mg oral capsules. Company: BioCryst Pharmaceuticals, Inc. Application No.: 214094. Approval date: 12/3/2020 (FDA approval package). Silver Spring (MD): U.S. Food and Drug Administration (FDA); 2020 Dec 3: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/214094Orig1s000TOC.cfm Accessed 2022 Mar 11.

20.Committee for Medicinal Products for Human Use. Assessment report: Orladeyo (berotralstat). (European public assessment report). Amsterdam (NL): European Medicines Agency; 2021 Feb 25: https://www.ema.europa.eu/en/documents/assessment-report/orladeyo-epar-public-assessment-report_en.pdf. Accessed 2022 Apr 4.

21.Clinical Study Report: BCX7353-302 [APeX-2]. A phase 3, randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy and safety of two dose levels of BCX7353 as an oral treatment for the prevention of attacks in subjects with hereditary angioedema [internal sponsor's report]. Durham (NC): BioCryst Pharmaceuticals, Inc; 2022 Sep 29.

22.Weller K, Groffik A, Magerl M, et al. Development and construct validation of the angioedema quality of life questionnaire. Allergy. 2012;67(10):1289-1298. PubMed

23.Weller K, Magerl M, Peveling-Oberhag A, Martus P, Staubach P, Maurer M. The Angioedema Quality of Life Questionnaire (AE-QoL) - assessment of sensitivity to change and minimal clinically important difference. Allergy. 2016;71(8):1203-1209. PubMed

24.van Hout B, Janssen MF, Feng YS, et al. Interim scoring for the EQ-5D-5L: mapping the EQ-5D-5L to EQ-5D-3L value sets. Value Health. 2012;15(5):708-715. PubMed

25.Aygoren-Pursun E, McNeil D, Collis PJ, Desai B, Tomita DK, Johnston DT. Oral berotralstat treatment for 96 weeks consistently reduces hereditary angioedema (HAE) attack rates regardless of baseline attack rate [poster] [internal sponsor's report]. In: Drug Reimbursement Review sponsor submission: Orladeyo (berotralstat), 150 mg capsule. Durham (NC): BioCyst Pharmaceuticals Inc; 2022 Feb 22.

26.Gower RG, Banerji A, Collis PJ, Desai B, Tomita DK, Lumry WR. Sustained improvement observed in patient-reported quality of life (QoL) with 96 weeks of oral berotralstat treatment [poster] [internal sponsor's report]. In: Drug Reimbursement Review sponsor submission: Orladeyo (berotralstat), 150 mg capsule. Durham (NC): BioCyst Pharmaceuticals Inc; 2022 Feb 22.

27.Wedner HJ, Tachdjian R, Craig T, et al. Sustained reductions in hereditary angioedema (HAE) attack rates observed over 96 weeks of oral berotralstat treatment regardless of initial response [poster] [internal sponsor's report]. In: Drug Reimbursement Review sponsor submission: Orladeyo (berotralstat), 150 mg capsule. Durham (NC): BioCyst Pharmaceuticals Inc; 2022 Feb 22.

28.Drug Reimbursement Review sponsor submission: Orladeyo (berotralstat), 150 mg capsule [internal sponsor's package]. Durham (NC): BioCyst Pharmaceuticals Inc; 2022 Feb 22.

29.Banerji A, Riedl MA, Bernstein JA, et al. Effect of lanadelumab compared with placebo on prevention of hereditary angioedema attacks: a randomized clinical trial. JAMA. 2018;320(20):2108-2121. PubMed

30.Craig T, Zuraw B, Longhurst H, et al. Long-term outcomes with subcutaneous C1-inhibitor replacement therapy for prevention of hereditary angioedema attacks. J Allergy Clin Immunol Pract. 2019;7(6):1793-1802.e1792.

31.Zuraw BL, Busse PJ, White M, et al. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med. 2010;363(6):513-522. PubMed

32.Prophylaxis for hereditary angioedema with lanadelumab and C1 inhibitors: effectiveness and value. (Final evidence report). Boston (MA): Institute for Clinical and Economic Review; 2018 Feb 15: https://icer.org/wp-content/uploads/2020/10/ICER_HAE_Final_Evidence_Report_111518-1.pdf. Accessed 2022 Apr 12.

33.Drug Reimbursement Review clinical report: lanadelumab (Takhzyro) for routine prevention of attacks of hereditary angioedema in adolescents and adults. Ottawa (ON): CADTH; 2020 Jan: https://www.cadth.ca/sites/default/files/cdr/clinical/sr0618-takhzyro-clinical-review-report.pdf. Accessed 2022 Apr 12.

34.Reevaluation of Takhzyro (lanadelumab injection) ereditary angioedema. Montreal (QC): INESSS; 2020: https://www.inesss.qc.ca/fileadmin/doc/INESSS/Produits_sanguins/Aout_2020/INESSS_Takhzyro_english_summary.pdf. Accessed 2022 Apr 12.

35.Berotralstat (hereditary angioedema) – Benefit assessment according to §35a Social Code Book V1. Koln (DE): Institute for Quality and Efficiency in Health Care; 2021 Sep 13: https://www.iqwig.de/download/a21-80_berotralstat_extract-of-dossier-assessment_v1−0.pdf. Accessed 2022 Apr 12.

36.Berotralstat for preventing recurrent attacks of hereditary angioedema. (Technology appraisal guidance TA738). London (GB): National Institute for Health and Care Excellence; 2021 Oct 20: https://www.nice.org.uk/guidance/ta738/resources/berotralstat-for-preventing-recurrent-attacks-of-hereditary-angioedema-pdf-82611261223621. Accessed 2022 Apr 12.

37.Berotralstat 150 mg hard capsules (Orladeyo). (SMC2405). Glasgow (GB): Scottish Medicines Consortium; 2022 Mar 7: https://www.scottishmedicines.org.uk/media/6734/berotralstat-orladeyo-final-feb-2022-amended-220222-for-website.pdf. Accessed 2022 Apr 12.

38.Interim Clinical Study Report: BCX7353-204. An open-label study to evaluate the long-term safety of daily oral BCX7353 in subjects with type 1 and 2 hereditary angioedema (Interim clinical study report) [internal sponsor's report]. Durkam (NC): BioCryst Pharmaceuticals, Inc; 2019 Oct 30.

39.BioCyst Pharmaceuticals Inc comments to Orladeyo (berotralstat) clinical report [internal additional sponsor's information]. Durham (NC): BioCyst Pharmaceuticals Inc; 2022 Jun 2.

40.Aygoren-Pursun E, Bygum A, Grivcheva-Panovska V, et al. Oral plasma kallikrein inhibitor for prophylaxis in hereditary angioedema. N Engl J Med. 2018;379(4):352-362. PubMed

41.Farkas H, Stobiecki M, Peter J, et al. Long-term safety and effectiveness of berotralstat for hereditary angioedema: the open-label APeX-S study. Clin Transl Allergy. 2021;11(4):e12035. PubMed

42.van Reenen M, Janssen B. EQ-5D-5L User Guide. Basic information on how to use the EQ-5D-5L instrument. Rotterdam (NL): EuroQol Research Foundation; 2015.

43.Reeve BB, Wyrwich KW, Wu AW, et al. ISOQOL recommends minimum standards for patient-reported outcome measures used in patient-centered outcomes and comparative effectiveness research. Qual Life Res. 2013;22(8):1889-1905. PubMed

44.McClure N, Sayah F, Xie F, Luo N, Johnson J. Instrument-defined estimates of the minimally important difference for EQ-5D-5L index scores. Value Health. 2017;20(4):644-650. PubMed

Appendix 1: Literature Search Strategy

Note that this appendix has not been copy-edited.

Clinical Literature Search

Overview

Interface: Ovid

Databases:

• MEDLINE All (1946-present)

• Embase (1974-present)

• Note: Subject headings and search fields have been customized for each database. Duplicates between databases were removed in Ovid.

Date of search: March 14, 2022

Alerts: Weekly search updates until project completion

Search filters applied: No filters were applied to limit the retrieval by study type.

Limits:

• Publication date limit: none

• Language limit: none

• Conference abstracts: excluded

Table 24: Syntax Guide

Multi-Database Strategy

1. (Orladeyo* or berotralstat* or bcx-7353 or bcx7353 or who 10907 or 88SH1NBL2B or XZA0KB1BDQ).ti,ab,kf,ot,hw,nm,rn.

2. 1 use medall

3. *berotralstat/ or (Orladeyo* or berotralstat* or bcx-7353 or bcx7353 or who 10907 or 88SH1NBL2B).ti,ab,kf,dq.

4. 3 use oemezd

5. 4 not (conference review or conference abstract).pt.

6. 2 or 5

7. remove duplicates from 6

Clinical Trials Registries

ClinicalTrials.gov

Produced by the US National Library of Medicine. Targeted search used to capture registered clinical trials.

Search – Orladeyo (berotralstat); hereditary angioedema

WHO ICTRP

International Clinical Trials Registry Platform, produced by the World Health Organization. Targeted search used to capture registered clinical trials.

Search – Orladeyo (berotralstat); hereditary angioedema

Health Canada’s Clinical Trials Database

Produced by Health Canada. Targeted search used to capture registered clinical trials.

Search – Orladeyo (berotralstat); hereditary angioedema

EU Clinical Trials Register

European Union Clinical Trials Register, produced by the European Union. Targeted search used to capture registered clinical trials.

Search – Orladeyo (berotralstat); hereditary angioedema

Grey Literature

Search dates: March 10 to 14, 2022

Keywords: Orladeyo (berotralstat); hereditary angioedema

Limits: Publication years: none

Updated: Search updated prior to the completion of stakeholder feedback period

Relevant websites from the following sections of the CADTH grey literature checklist Grey Matters: A Practical Tool for Searching Health-Related Grey Literature were searched:

• Health Technology Assessment Agencies

• Health Economics

• Clinical Practice Guidelines

• Drug and Device Regulatory Approvals

• Advisories and Warnings

• Drug Class Reviews

• Clinical Trials Registries

• Databases (free)

• Internet Search

• Open Access Journals.

Appendix 2: Excluded Studies

Note that this appendix has not been copy-edited.

Table 25: Excluded Studies

Appendix 3: Detailed Outcome Data

Note that this appendix has not been copy-edited.

Figure 3: Plot of Mean Investigator-Confirmed HAE Attack Rate by Month — APeX-2 (Part 1 ITT Population)

BCX7353 = berotralstat; HAE = hereditary angioedema; ITT = intention-to-treat; SD = standard deviation.

Source: Clinical Study Report for APeX-2.⁶

Table 26: Investigator-Confirmed Attacks by Month— APeX-2 Study (Part 1 ITT Population)

ITT = intention-to-treat; SD = standard deviation

Source: Clinical Study Report for APeX-2.⁶

Table 27: Subgroup Analyses for Investigator-Confirmed HAE Attacks (Part 1 ITT Population)

CI = confidence interval; HAE = hereditary angioedema; ITT = intention-to-treat.

^aNegative binomial model, with covariate for baseline HAE attack rate and log of treatment duration as offset for ITT population.

^bP value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

^cModel fit was questionable.

^dPost hoc subgroup analysis in the APeX-2 study.

Source: Clinical Study Report for APeX-2⁶ and Clinical Study Report for APeX-J.⁷

Table 28: Ad Hoc Analysis of Attack-Free Months— APeX-2 Study (Part 1 Completer Population)

NR = not reported; SD = standard deviation.

^aPatients were considered attack-free for a given month if they did not experience any investigator-confirmed attacks in that 28 day period. Patients who discontinued study drug in a given month were not considered attack-free in that month. The analysis excluded any patient who withdrew from the study before 24 weeks.

Source: Clinical Study Report for APeX-2.⁶

Appendix 4: Description and Appraisal of Outcome Measures

Note that this appendix has not been copy-edited.

Aim

To describe the following outcome measures and their measurement properties (validity, reliability, responsiveness to change, and MID):

• Angioedema Quality of Life questionnaire (AE-QoL)

• 5-Level EQ-5D questionnaire (EQ-5D-5L)

Findings

A focused literature search was conducted to identify the psychometric properties and the MID of each of the stated outcome measures. The findings on reliability, validity, responsiveness, and the MID of each outcome measure are summarized in Table 29.

Table 29: Summary of Outcome Measures and Their Measurement Properties

AE-QoL = Angioedema Quality of Life questionnaire; DLQI = Dermatology Life Quality Index; EQ-5D-5L = 5-Level EQ-5D questionnaire; HRQoL = health-related quality of life; MID = minimal important difference; MCS = Mental Component Summary; PCS = Physical Component Summary; QoL = quality of life; SF-12 = Short Form (12) Health Survey; VAS = visual analogue scale.

Angioedema Quality of Life Questionnaire

The AE-QoL questionnaire is an angioedema-specific, patient-reported, HRQoL measure.²² It was developed and validated as the first instrument to measure HRQoL impairment in patients with any type of recurrent angioedema. It is a short, self-administered questionnaire that consists of 17 questions with 5 possible answers each (1 = never to 5 = very often). A recall period of 4 weeks was chosen, based on the heterogeneity in frequency of attacks in recurrent angioedema patients. Each item answered by the respondent is scored between 0 and 4 points, depending on the answer chosen (i.e., never = 0 points, very often = 4 points). The questions address 4 domains, functioning (impairment of work, physical activity and spare time activities); fatigue/mood (difficulties falling asleep, waking up during the night, feeling tired during the day, difficulties concentrating, feeling downhearted); fears/shame (feeling burdened from swellings, fear and embarrassment of new swellings, ashamed to visit public places, fear of long-term negative drug effects); food (limitations in eating and in the selection of foods and beverages).²² A total score, and individual domain scores can be generated, based on the sum of all completed items divided by the maximum sum of all possible items. The raw scores are converted onto a linear scale ranging from 0 to 100, with higher scores representing higher HRQoL impairment.

Validity

The development and content validity of the AE-QoL instrument consisted of data acquisition, item generation and item reduction phases, and final instrument validation in a sample of 120 adult patients with recurring angioedema (n = 10, item generation; n = 110, instrument validation).²² The validation population included 73 (66.4%) females, adults aged 18 years and older, and 3 diagnosis categories: 1) type 1 or 2 HAE, 2) chronic spontaneous urticaria (patients with wheals and angioedema), or 3) other (recurrent angioedema without C1-INH deficiency and without wheals or recurrent angioedema with no clear allocation to either category).

Validation of the AE-QoL consisted of construct and convergent validity assessments.²² Construct validity was assessed using a known groups approach; patients received a self-administered questionnaire which included sociodemographic questions, as well as self-rating of angioedema-specific questions based on a 5-point scale for disease activity (response options: “none,””1–2,” “3–4,” “more than 4 attacks,” and “attacks almost every day”) and quality of life impairment (response options: “none,” “mild,” “moderate,” “severe,” and “very severe”). A linear correlation was demonstrated between increasing AE-QoL total scores and increasing levels of self-rated angioedema activity (P < 0.001) and quality of life impairment (P < 0.001).²² Of note, no correlation coefficients were provided in the study results. Convergent validity was assessed by testing the strength of correlation of the AE-QoL with other instruments that measured similar constructs, the Dermatology Life Quality Index (DLQI) and the generic Short Form (36) Health Survey (SF-36). A strong correlation (Pearson coefficient r > 0.50) was observed between the AE-QoL and DLQI total scores, supporting convergent validity of AE-QoL in recurrent angioedema. The individual domain scores were poorly correlated with the DLQI scores (r = 0.44 for functioning, 0.38 for fatigue/mood, 0.40 for fears/shame, and 0.31 for food). The correlation of the AE-QoL total score and the SF-36 Mental Component Summary (MCS) score was strong (r = −0.68), while the correlation with the SF-36 Physical Component Summary (PCS) was found to be weak (r = −0.24).²² With respect to the individual domains, only the functioning domain correlated with the PCS score (r = −0.47), while the fatigue/mood, and fears/shame correlated strongly with the MCS score (r = −0.59 and −0.525, respectively).

Reliability

Reliability of the AE-QoL instrument was demonstrated through internal consistency and test-retest assessments.²² The AE-QoL was found to have excellent internal consistency for the whole instrument (Cronbach alpha 0.89) as well as across each domain (Cronbach alpha between 0.83 to 0.90). To assess test-retest reliability, a subsample of 46 patients (including 15 patients with HAE) were asked to complete the AE-QoL twice in 3-week intervals. The AE-QoL was shown to have acceptable test-retest reliability (Pearson’s coefficient for the total score was 0.83, and ranging from 0.68 to 0.90 for individual domains) based on the generally-accepted threshold for patient-reported outcome measures.^22,43 The domain with the lowest reproducibility was the fatigue/mood domain.

Responsiveness to Change

A subsequent study by Weller and colleagues sought to assess both responsiveness to change and the MID for the AE-QoL instrument.²³ Responsiveness of the AE-QoL measure to change was assessed in a sample of 278 patients with recurrent angioedema by correlating changes in its scores over time with changes in the applied anchors. The chosen anchors were self-rated angioedema specific disease activity and quality of life impairment as described in the initial validation study, as well as the Short Form (12) Health Survey.^22,23 AE-QoL total score changes over time correlated moderately with changes in the self-rated angioedema activity (Spearman’s rho r = 0.39) and strongly with changes in the self-rated angioedema-specific quality of life impairment (r = 0.5). Furthermore, a strong correlation was observed with changes in the AE-QoL functioning domain (r = 0.59), and moderate correlations were observed in the other 3 domains, indicating that the functioning domain is the most sensitive to change. AE-QoL total score changes correlated weakly with changes in the Short Form (12) Health Survey PCS (r = −0.26) and MCS (r = −0.29), and correlations were consistently weak across each AE-QoL domain.

Minimal Important Difference

The MID of the AE-QoL was evaluated by anchor-based and distributional criterion approaches.²³ For the anchor-based approach, the magnitude (mean ± SD) of the total AE-QoL score changes during improved (n = 26), unchanged (n = 60), or worsening (n = 18) self-rated angioedema-related quality of life impairment were –12.5 ± 16.5 (median: –12.5), –0.3 ± 12.6 (median: 0), and 6.3 ± 12.4 (median: 6.5) points, respectively. A change was defined as a 1-step change (e.g., from moderate to severe, or moderate to mild). In a second approach, a receiver operating characteristic curve analysis of the self-rated quality of life impairment ratings identified the best cut-off point for clinically meaningful changes in the AE-QoL total score to be -5.5 points for quality of life improvement and 5.5 points for quality of life worsening, based on a desired balance of sensitivity and specificity.²³ The distributional criterion approach (one-half of the SD of the baseline AE-QoL total score values), estimated a MID of 10.5 points. Given that the anchor-based approach is a more direct and patient-centred method over the distributional criterion approach, the results of the anchor-based approach were favoured by the authors, and a MID of 6 points was chosen as a meaningful change in quality of life to the patient.²³ This MID of 6 points was used in the pivotal trials.^6,7

5-Levels EQ-5D Questionnaire

The EQ-5D-5L questionnaire is a generic, preference-based, HRQoL measure consisting of descriptive questions and the EQ VAS.⁴² The descriptive questions comprise of 5 dimensions, mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is divided into 5 levels (1, 2, 3, 4, 5) representing “no problems,” “slight problems,” “moderate problems,” “severe problems,” and “extreme problems,” respectively. Respondents are asked to choose one level that reflects their own health state for each of the 5 dimensions. The 5 questions are scored and together contribute to the EQ-5D index (utility) score between 0 and 1, where 0 represents death, and 1 represents perfect health. Different utility functions are available that reflect the preferences of specific populations (e.g., US, UK). The second part of the tool records the patient’s self-rated health on a 20 cm scale with end points 0 and 100, with respective anchors of “the worst health you can imagine” and “the best health you can imagine,” respectively.

The EQ-5D-5L measure has not been validated in patients with recurrent angioedema or type 1 or type 2 HAE specifically. Therefore, its validity, reliability, and responsiveness to change has not been evaluated in the patients with HAE. No estimate of the MID for the EQ-5D-5L index score was found in patients with HAE but in the general Canadian population a summarized mean of 0.056 ± a SD of 0.011 (interquartile range = 0.049 to 0.063) has been reported.⁴⁴ Overall, the EQ-5D-5L is not considered to be a validated outcome in the study population.

Appendix 5: Long-term Extension Data Used to Inform the Request for Reconsideration

Note that this appendix has not been copy-edited.

Long-Term Extension Studies

The following summary was prepared based on new information on the longer-term extension phases (part 2 and 3) of the APeX-2 study using data from the September 29, 2022 CSR submitted by the sponsor as part of the Request for Reconsideration.²¹ Only data for the Health Canada approved berotralstat dose of 150 mg daily has been summarized.

Methods

The primary objective of part 2 and 3 of the APeX-2 study was to evaluate the long-term safety and tolerability of berotralstat in patients with HAE type 1 or 2. The secondary objectives were to assess the HAE attack rate and impact on HRQoL. The extension phases of APeX-2 trial did not have a control group and all patients received either berotralstat 110 mg or 150 mg daily. In part 2 (week 24 to 48), patients and investigators were blinded to the berotralstat dose, but in part 3 (week 48 up to week 240), all patients received unblinded berotralstat 150 mg daily. The flow of patients through APeX-2 phases is shown in Figure 4. A total of 54 patients in part 2 and 81 patients in part 3 received berotralstat 150 mg daily. The CSR states that due to attrition of patients between week 144 and 240, the focus of the final CSR was on data through to week 144.

Figure 4: APeX-2 Study Schematic

BCS7353 = berotralstat; QD = once daily.

Source: Clinical Study Report for APeX-2 Parts 2 and 3.²¹

Populations

The APeX-2 study enrolled patients ≥ 12 years of age with a confirmed diagnosis of HAE type 1 or 2, who experienced at least 2 qualifying HAE attacks during the run-in phase. In addition, the patients had to have access to standard-of-care treatments for acute attacks and be medically appropriate for on-demand treatment as the sole medical management of their HAE.

The mean age of patients who received berotralstat 150 mg in part 2 █████ of APeX-2 ranged from 40.7 years (SD = 14.2) to 45.7 years (14.8), 60% to 77% were women and 24% to 41% were men, and most patients were white (88% to 95%) (Table 30).

Table 30: Patient Demographics for Extension Phase of APeX-2

BMI = body mass index; SD = standard deviation.

Source: Clinical Study Report for APeX-2 parts 2 and 3.²¹

Interventions

Patients initially randomized to berotralstat 150 mg daily in part 1 (week 0 to 24), continued to receive double-blind berotralstat 150 mg in part 2 (week 24 to 48). At week 24, patients initially randomized to placebo were rerandomized to receive double-blind berotralstat 150 mg or 110 mg daily during part 2. All patients who entered part 3 (week 48 to 144) received open-label berotralstat 150 mg daily.

Outcomes

Efficacy outcomes that were of interest to this review included the rate of HAE attacks, proportion of days with angioedema symptoms, and durability of AE-QoL and EQ-5D-5L scores.

Patients reported HAE attacks using an electronic diary, and in part 2, all attacks were confirmed by the investigator. During part 3, no investigator confirmation was required, but all patient-reported attacks underwent a computer-based review were confirmed or rejected based on the following criteria:

• Attack must include at least 1 symptom of swelling

• Patient response the diary question, “In retrospect, could there be an alternative explanation for your symptoms other than an HAE attack (i.e., allergic reaction, viral cold etc)?” must have been “no”

• Attack must have been unique (attack began >24 hours from end of the prior attack) otherwise the attack was combined with and treated as a continuation of the preceding attack

• If untreated, attack must have a duration of > 24 hours.

In part 3, the adjusted patient-reported attack rate were reported as events per 28 days, and for the entire dosing period of part 3. The investigator-confirmed attack rate was reported by month (every 28 days) for part 1 and 2, and over the entire dosing period for part 1 and 2. The entire dosing period began on day 1 of part 1 for those randomized to berotralstat, and the day 1 for part 2 on those switched from placebo to berotralstat at week 24 (labelled as the adjusted day 1). For patients who stopped treatment early, any events that started within 24 hours of the last dose of berotralstat were included in the attack rate calculations. The follow-up period ended 24 hours after the last dose of study drug for patients who stopped treatment.

The number and proportion of days with angioedema symptoms were calculated based on diary data for patients who received at least 1 dose of berotralstat in either part 2 or part 3. HRQoL was assessed using the AE-QoL questionnaire and the EQ-5D-5L instrument.

Data were collected on the number and proportion of patients who reported treatment-emergent adverse events, serious adverse events or who stopped treatment due to adverse events.

Statistical Analysis

There was no statistical testing for part 2 or 3. All results were reported descriptively with no imputation for missing data.

Patient Disposition

Of the 40 patients randomized to berotralstat 150 mg daily, 37 patients (93%) continued in part 2. Six patients (16%) discontinued during part 2 due to lack of efficacy (8%), adverse events (5%) or other reasons (3%). Another 5 patients (14%) stopped treatment at the 48 week visit, including 2 patients (5%) due to lack of efficacy. Among patients randomized to placebo at the start of the study, 34 patients (87%) completed part 1 and 17 were rerandomized to receive berotralstat 150 mg daily. Three of these patients (18%) discontinued during part 2 due to lack of efficacy (12%) or withdrawal of consent (6%) (Table 30).

Overall, █ █ █ █ ██████ █ █ █ ██████ █ ██ █ ██ and received at least 1 dose of berotralstat 150 mg during this period. This group consisted of █ █ ███████ █ ██████████████ █ ███ █ ██ █ ███ randomized in APeX-2, including 26 patients initially ██ █ ███ █ ██████ █ ████ █ ████████ █ █ █ ███████ █ ████ █ █████ █ ██ █ ████ randomized to berotralstat 150 mg, then berotralstat 150 mg, and █ █ ████ █ ██████████████████████████████████ █ ██ █ ██ █ █████ in part 1 and 2. During █ █ ██ █ ███ █ █ █ ████, █████ █ ████ █ █ █ ████████ █ ███ █ ████ █ █ ███ █ ███ █ ███ █ █ █ █ ███ █ █ █ █ █ ██ █ ████ █ ██████ █ ██████.

Table 31: Patient Disposition for Part 2 of APeX-2

^aPercentage calculated based on the patients who continued in part 2.

█ ███████████████████████████████████ █ ███████████████████████████████████████████████ █ █ █ █ █ █ █ █ █ ██ █ ████ █ ███████ █ ██████

Source: Clinical Study Report for APeX-2 parts 2 and 3²¹

Exposure to Study Treatments

The mean duration of exposure for the 40 patients initially randomized to berotralstat 150 mg was ████ days (SD = ████), including 21 patients who were exposed for greater than ████ days (████ weeks). The total patient-years of exposure was ████ for this group.

The mean duration of exposure was 639 days (SD = 341) for patients in the placebo then berotralstat 150 mg group for a total of ████ person-years of exposure.

Efficacy

During part 2 of the APeX-2 study, a total ████ investigator-confirmed HAE attacks were reported in berotralstat 150 mg group and ████ events in the placebo then berotralstat 150 mg group, of which ████ and ████ were treated with acute therapies. Among patients who continued on berotralstat 150 mg in part 2, the mean baseline rate of investigator-confirmed attacks was 3.2 (SD = 1.6) events per month (N = 37). In this group at 6 months, the mean attack rate was 1.7 (SD = 1.9) with a mean change of −1.5 (SD = 1.8) events per month, and at 12 months the mean attack rate was 1.1 (SD = 1.4) with a mean change in rate of −1.9 (SD = 1.5, N = 32) (Table 32). Among patients who switched from placebo to berotralstat 150 mg (N = 17), the mean baseline attack rate was 2.8 (SD = 1.4), and at 6 months it was 0.6 (SD = 0.9), with a mean change from baseline of −1.9 (SD = 1.4, N = 14).

The mean overall attack rate was ████ events per month (SD = 1.6) during part 1 and 2 for patients randomized to receive berotralstat 150 mg and who remained on treatment. During part 2, the overall attack rate was ████ events per month (SD = ████) among patients switched from placebo to berotralstat 150 mg.

mean number of days with angioedema symptoms was ████ days (SD = ████) and ████ days (SD = ████), and the proportion of days with symptoms was ████ (SD = ████) and ████ (SD = ████) in the berotralstat 150 mg, and the placebo then berotralstat 150 mg groups, respectively.

For patients who continued berotralstat 150 mg in part 2, the mean AE-QoL total scores were as follows: baseline 44.1 (SD = 16.8, N = 37); week 48, 27.1 (SD = 21.2, N = ████); and change from baseline −15.2 (SD = 14.1). Among patients switched from placebo to berotralstat 150 mg, the baseline mean AE-QoL score was 35.1 (SD = 15.1, N = ████); week 48 was 25.0 (SD = 19.7, N = ████) and change from baseline was −10.0 (SD = 20.9). The AE-QoL and EQ-5D data for part 2 are shown in Table 32.

Table 32: Efficacy Outcomes for Part 2 of APeX-2

AE-QoL = Angioedema Quality of Life; NA = not applicable; SD = standard deviation; VAS = visual analogue scale.

^aAE-QoL score range from 0 (best) to 100 (worst).

^bEQ-5D VAS scores range from 0 (worst health state you can imagine) to 100 (the best health state you can imagine). The index score falls between −1 and 1, where 1 is full health.

Source: Clinical Study Report for APeX-2 Part 2 and 3.²¹

During part 3 of APeX-2, the overall adjusted patient-reported HAE attack rate was ████ █ ███ █ ████ █ ████ █ ███ █ ██ █ █ while patients remained on treatment. The mean attack rate over time for the █ ███ █ ██ █ ███████ █ ███ █ ███ is shown in Table 33. ██ █ ████ █ ███ █ ███ █ ████ █ ██ █ ████ █ ██ █ █████ █ ██████████████ █ ██████ █ ████ █ ██ █ ███ █ ██████ █ █ █ █ █ █ █ ████████████ █ ████████████████ █ █ █ ███████ █ ███

The mean baseline AE-QoL score was █ █ ██ █ ███████ █ █████████ █ █████████ █ ██████ █ █ █ ██ █ ███ who entered part 3, and █ █ ████ █ █████ █ █████ █ ██ █ ████ █ ████ █ █ ████ █ ███ █ █████ █ █ █ ████ █ ████ █ ██ █ █ █ █ █ █ █ ██ █ ███ █ ███ █ ████ █ ██████ █ █ █ ██ █ ████████ █ ████████ █ ██████ █ ██████ █ ██ █ ██ █ █ ██ █ ██████ █ █ █ ██ █ █████ █ ██████ █ ██████ █ █ ███████ █ █████ █ ██ █ ███.

Table 33: Adjusted Patient-Reported HAE Attack Rate per Month for Part 3 of APeX-2

HAE = hereditary angioedema; SD = standard deviation.

^aMonthly attack rate was defined as the total number of adjusted patient-reported HAE attacks experienced during the treatment period adjusted for the length of a month (defined as 28 days) and the number of days the patient was on treatment during that month. The end of month 6 was defined as the start of part 2 treatment or the end of part 1 treatment if the patient did not continue to part 2. Month 7 was defined as beginning on the day after the end of month 6 and continuing through day 196. Remaining months (8 and up) were defined as 28 day intervals. For patients who switched from placebo to berotralstat, visits were adjusted according to the date of the first dose of active treatment.

^bEnd of part 1 for patients initially randomized to berotralstat 110 mg or 150 mg daily. For patients who were switched from placebo to berotralstat, this represents the first 6 months of active therapy during part 2.

Source: Clinical Study Report for APeX-2 Part 2 and 3.²¹

Harms

During part 2, 72% of patients who received berotralstat 150 mg experienced at least one adverse event, including 2 patients who reported a serious adverse event (uterine leiomyoma, patient kept for observation after a radioactive iodine test). Gastrointestinal abdominal-related adverse events were reported by ████ patients (████). Four patients (7%) stopped treatment due to adverse events; 2 of which stopped due to gastrointestinal-related events. In part 2, the most common adverse events reported among all treated patients were nasopharyngitis (18%), nausea (8%), upper respiratory tract infection (8%), abdominal pain (6%), and dyspepsia (5%) (Table 34).

During █ █ ███ █ ██, ██ █ █████ experienced at least 1 adverse event, of which the most frequently reported adverse events were ██ █ █ █ ███ █ ████ █ █████ █ █ ████ █ █ █ █████ █ ██ █ █████ █ ██ █ █████████ █ ████ █ ████ █ ████ █ █ █ ██ █ █████ █ █ █ ███ █ █████████████████ █ █ █ ██ █ ████████████████████████████ █ ██ █ █ █ █ ██ █ █ █ █ █ █ █████ █ █████ █ █ █ █ █ █ ███ █ ████████ █ ██████ █ ████ █ ████ █ █ ███ █ █ ██ █ ███ █ ████ █ ███████ █ ███ █ ██ █ ██████ █ ███ █ █████████ █ ██████ █ ██ █ ███.

No deaths occurred during part 2 or 3 of the APeX-2 study.

Table 34: Summary of Harms in Part 2 and 3 of APeX-2

SAE = serious adverse event.

Source: Clinical Study Report for APeX-2 Part 2 and 3.²¹

Critical Appraisal

Internal Validity

Several limitations were identified for part 2 and 3 of the APeX-2 study. First of all, the investigators and patients were aware that patients were receiving active treatment, and thus their expectations of treatment could affect reporting of subjective outcomes such as symptoms or adverse effects. In addition, there was potential selection bias, as patients who respond to berotralstat and are able to tolerate treatment are more likely to continue therapy than patients with less favourable outcomes. By the end of week 48, 8 of 40 patients (20%) initially randomized to berotralstat 150 mg had stopped treatment, and █ █ ██████ █ ████████ █ ██████. No information was available on the completeness of patient diary data during part 2 or 3, thus the extent of missing diary data is unknown. There was no statistical testing for part 2 and 3. The efficacy analyses were reported descriptively based on observed data with no imputation for missing data, and with no sensitivity analyses to assess the robustness of the results. Given the attrition observed, the results reported may overestimate the treatment effects, and under-report adverse effects.

The HAE attack rate data in part 3 were based on patient-reported events and were not confirmed by an investigator as in part 1 and 2, thus these events may not be comparable.

In addition, part 2 and 3 were uncontrolled which makes the change in HAE attack rate difficult to interpret, particularly since HAE attacks are sporadic and may fluctuate through the year owing to exposure to seasonal triggers, hormonal changes or other factors.

External Validity

Part 2 and 3 of the APeX-2 study share the same potential limitations to external validity as the controlled part of the study. Due to the potential selection bias, the results likely reflect a subset of patients who are able to tolerate berotralstat and have perceived a benefit with treatment and may not truly reflect the longer effects in an unselected HAE population.

Pharmacoeconomic Review

Executive Summary

The executive summary comprises 2 tables (Table 1 and Table 2) and a conclusion.

Table 1: Submitted for Review