An official website of the United States government
NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
Indication: For routine prevention of attacks of hereditary angioedema in adults and pediatric patients 12 years of age and older
CADTH recommends that Orladeyo be reimbursed by public drug plans for routine prevention of attacks of hereditary angioedema (HAE) in adults and pediatric patients 12 years of age and older, if certain conditions are met.
Orladeyo should only be reimbursed for adults and adolescents with HAE according to the criteria used by public drug plans for lanadelumab for the prevention of HAE attacks.
In addition to following pre-existing criteria for lanadelumab, Orladeyo should not be used in combination with other medications for long-term prevention of angioedema. Orladeyo should only be reimbursed if its cost is reduced.
HAE is a rare hereditary disorder, with which patients experience recurring episodes of painful and potentially life-threatening swelling of the skin, abdomen, or throat. It is estimated that 1 in 93,000 to 1 in 50,000 people have HAE.
Current treatments reimbursed to prevent HAE attacks require injection, and some are made from blood products. Other treatment options are needed that reduce HAE attacks but are easier to administer.
Treatment with Orladeyo is expected to cost approximately $310,463 per patient annually.
The CADTH Canadian Drug Expert Committee (CDEC) recommends that berotralstat be reimbursed for the routine prevention of attacks of hereditary angioedema (HAE) in adults and pediatric patients 12 years of age and older, only if the conditions listed in Table 1 are met.
Two double-blind randomized controlled trials (APeX-2 [N = 80] and APeX-J [N = 13]) in patients with type 1 or 2 HAE who had experienced at least 2 confirmed HAE attacks in the 56 days before the start of the trials demonstrated that, compared with placebo, 24-week treatment with berotralstat 150 mg daily was associated with statistically significant and clinically meaningful reduction in the frequency of investigator-confirmed HAE attacks. In the pivotal APeX-2 study, the rate of investigator-confirmed HAE attacks per month was 1.31 for the berotralstat 150 mg daily group and 2.35 for the placebo group during the 24-week double-blind treatment period, with a relative rate reduction of 44.2% (95% CI, 23.0% to 59.5%; P < 0.001) versus placebo. The relative rate reduction in investigator-confirmed HAE attacks was consistent in the supportive APeX-J study (49.1%; 95% CI, 20.4% to 67.5%; P = 0.003). Patients who received berotralstat 150 mg daily reported approximately 13 fewer symptom-days over the 24-week treatment period than those in the placebo group of the APeX-2 study. Also, 58% of patients in the berotralstat 150 mg group, compared with 25% in the placebo group, achieved at least a 50% relative reduction in the rate of investigator-confirmed HAE attacks compared to baseline.
Patients seek additional treatment options that offer a convenient mode of delivery (including for those who have damaged veins), are effective in preventing attacks, have fewer side effects, and improve health-related quality of life (HRQoL). The trials demonstrated that, compared to placebo, some patients may see some of these important unmet needs addressed by berotralstat, including preventing HAE attacks.
Using the sponsor-submitted price for berotralstat, and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio (ICER) for berotralstat was $14,559,490 per quality-adjusted life-year (QALY) compared with no long-term prophylaxis (LTP). A price reduction is required for berotralstat to be considered cost-effective at a $50,000 per QALY threshold.
Reimbursement Conditions and Reasons.
HAE is a rare autosomal-dominant disorder that is characterized by recurrent attacks of nonpruritic subcutaneous or submucosal edema, most commonly affecting the skin (cutaneous attacks), gastrointestinal tract (abdominal attacks), and respiratory tract (laryngeal attacks). The reported prevalence of HAE ranges from 1 in 93,000 to 1 in 50,000. 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 level and function (prevalence is uncertain). Therapeutic options available in Canada for LTP treatment include C1-INHs, lanadelumab, oral attenuated androgens (e.g., danazol), and antifibrinolytics (e.g., tranexamic acid). The most commonly used treatments in Canada are C1-INHs, which act by replacing the missing or malfunctioning C1-INH protein, 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 for use in 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. The Health Canada indication is for the routine prevention of attacks of AE in adults and pediatric patients aged 12 years and older. Berotralstat is available as a 150 mg oral capsule and the recommended dose is 150 mg once daily. Health Canada states berotralstat should not be used for the treatment of acute HAE attacks, as the safety and efficacy for this use has not been established.
To make their recommendation, the committee considered the following information:
One patient group, HAE Canada (HAEC), submitted patient input for this review. HAEC is dedicated to creating awareness about HAE and other related angioedema, to help speed the diagnosis of patients, improve access to treatments, and enable patients to become champions for 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 from 1 (not at all) to 5 (significant impact), with weighted averages ranging from 2.20 for impacts on their ability to conduct household chores to 2.94 for impacting their ability to travel. The majority (62%) had to miss time from work due to HAE. Approximately 20% of patients reported that HAE required them to spend out-of-pocket for medical care; similarly, approximately 20% of patients were either very dissatisfied or dissatisfied with their current treatments. Among the 3 patients who had experience with berotralstat, 1 patient reported that the treatment was extremely effective in preventing attacks of HAE and that the adverse effects were easy to tolerate. Two patients did not find the treatment effective in the prevention of attacks 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 plasma-derived. 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.
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 as a first-line option for LTP therapy, although it may not be the preferred option for use in patients who are pregnant or in patients younger than 12 years of age, 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, where LTP with C1-INH may be impractical. The following patients may not be appropriate candidates for treatment with berotralstat: 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., 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.
Prescribing of 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 LTP such as berotralstat would be initially assessed after 3 months, with subsequent follow-up occurring every 6 or 12 months. The following were identified as situations in which discontinuing treatment with berotralstat could be appropriate: pregnancy, since 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).
Ten clinicians representing the Canadian Hereditary Angioedema Network (CHAEN) provided input for this review. They noted a need for a treatment to prevent attacks, improve the acute management of HAE, and provide convenient methods of self-administration. HAE patients are at risk of experiencing a life-threatening laryngeal attack, which can have a considerable impact on their HRQoL. Furthermore, IV treatments may have the effect of requiring patients to spend extra time travelling to treatment appointments and undergoing treatment if they are unable to self-administer. Current off-label oral prophylaxis options for people living in Canada include androgen therapy, such as danazol. Androgens are associated with a range of severe adverse effects, including headaches, hypertension, weight gain, masculinizing effects for women, hepatocellular carcinoma, dyslipidemia, and cardiac disease. The input suggests that the treatment under review may provide a safe and effective oral prophylactic, which may be preferred to the current standard of care by some patients, particularly those who are averse to long-term injections. The input recommends that the treatment be considered for all patients who are candidates for LTP.
Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a CADTH recommendation for berotralstat:
The clinical expert consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.
Responses to Questions From the Drug Programs.
The systematic review included 2 double-blind 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, 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 week 48 [APeX-2] or week 52 [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 [APeX-2] or week 104 [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 and had to include symptoms of swelling, which could be visible swelling or symptoms in the oropharyngeal or abdominal regions that were indicative of internal swelling. This review focused on the comparison between berotralstat 150 mg and placebo at 24 weeks, which included 80 patients from the APeX-2 study and 13 patients from the APeX-J study. Data from the berotralstat 110 mg group has not been summarized in this report, since this dose has not been approved by Health Canada.
The APeX-2 study was conducted in 11 countries, including Canada (3 sites), the US, and several countries in Europe (Germany, Romania, the UK, France, Spain, Hungary, Macedonia, Czech Republic, and Austria). The mean age of patients enrolled was 40.0 years (standard deviation [SD] = 14.0) in the berotralstat 150 mg group and 44.5 years (SD = 14.1) in the placebo group. Patients were predominantly female (58% and 68%) and white (95% and 93%), with a mean baseline rate 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%) and Asian (86% and 100%) in the berotralstat and placebo groups, respectively. At baseline, the mean number of 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.
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% CI, 23.0% to 59.5%; P < 0.001) for berotralstat 150 mg versus placebo. 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, and 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 [OR] = 3.91; 95% CI, 1.51 to 10.16; P = 0.005). 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. |||||||||||||||||||||||||||||||| in 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 to 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 (out of a total of 169 treatment days) in the berotralstat group versus the placebo group. Although the proportion of days with HAE symptoms favoured berotralstat over placebo, the 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 Questionnaire (AE-QoL). While both the berotralstat 150 mg and placebo groups in 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 the request for reconsideration showed that, during part 2 of the APeX-2 study (week 24 to 48), the mean investigator-confirmed attack rate per month in the berotralstat 150 mg group was 1.7 (SD |||||||||) at 24 weeks (n = 37), and 1.1 (SD |||||||||) at week 48 (n = 31). 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 switched from placebo to berotralstat 150 mg at week 24 (n = 17), the mean attack rate per month was 2.6 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 ||||||||||||||| (SD |||||||||||||||) for patients switched to berotralstat 150 mg. Overall ||||||||| of patients completed part 2 of the study, with ||| patients (|||||||||) stopping therapy due to adverse events or lack of efficacy, and ||| others (||||||||| 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: |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 among patients who received berotralstat 150 mg compared to 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 of 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 tests, 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 to 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.
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 ensure the groups were balanced for all measured or unmeasured prognostic factors or confounders, and at baseline, imbalances between treatment groups were observed 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 also may 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 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
The primary outcome (investigator-confirmed HAE attack rate over 24 weeks) was considered to be clinically relevant by the expert consulted by CADTH. Other outcomes of interest to this review (e.g., laryngeal attacks, treated or severe attack rate, and the responder analyses) were either exploratory or ad hoc outcomes, and these analyses were not included in the hierarchical statistical analysis. Therefore, any analyses with P values lower than 0.05 should be interpreted with caution because of the potential for inflated type I error rate. Although the AE-QoL questionnaire has been used in clinical trials of other HAE treatments, the instrument contains domains that are not specific to HAE. Neither study were 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 |||||||||||||||||||||||| of the APeX-2 study suggest that patients who continued on berotralstat 150 mg may maintain a reduction in HAE attacks, the 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 thus their expectations of treatment could 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 were based on patient-reported events; thus, attack events analyzed in part 3 may not be comparable to the investigator-confirmed events in part 1 and part 2. In |||||||||||| part 2 ||||||||||||, 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 underreport adverse effects, as patients who are tolerant of therapy and showed adequate response were more likely to continue in the trial. Finally, part 2 |||||||||||||||||||||||| were uncontrolled which makes the change in HAE attack rate difficult to interpret, particularly since HAE attacks are sporadic and may fluctuate throughout the year, owing 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 the enrolled participants, who were 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. The trial included patients who were medically appropriate for on-demand treatment as the sole management of HAE, and thus may have excluded patients with more severe HAE who could not tolerate discontinuation of current LTP therapy. Compared to the overall population in Canada, the 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. Only 4 adolescents and 4 patients older than 65 years of age were enrolled in the berotralstat 150 mg and placebo groups; therefore, there is limited data to extrapolate to the younger and older age groups. The APeX-J study provided additional data from 13 patients in Japan. These patients were generally similar to those in the pivotal study, although the patients’ weight and body mass index (BMI) were lower, as was the mean baseline HAE attack rate. Overall, the clinical expert felt that the characteristics of the patient population enrolled in the trials offered a good representation of the target population, and 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 two 24-week randomized, placebo-controlled trials, in which a total of 47 patients received berotralstat 150 mg daily.
The sponsor conducted a feasibility assessment 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. The authors of the feasibility assessment identified a number of important differences in the study design 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. Based on the information presented in the sponsor’s feasibility assessment, the CADTH reviewer agrees that the heterogeneity between the berotralstat and C1-INH trials is significant, and thus any ITC is unlikely to produce robust estimates of comparative efficacy or safety. However, fewer differences exist between berotralstat and lanadelumab trials, such that an ITC may have been possible.
Data from 1 open-label, long-term study were summarized in this report.
The APeX-S study is an ongoing, uncontrolled, phase II study, which was conducted to evaluate the safety and efficacy of berotralstat in adults and pediatric patients aged 12 years or older with type 1 or 2 hereditary angioedema. In this study, 127 patients were enrolled from either a prior berotralstat trial or were 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 years to 72 years) and the majority of patients were female (61%), white (87%), and had a family history of HAE (80%).
From the beginning of the study through to week 48, there were a total of ||||||||||||||| adjusted HAE attacks 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 (range, 0 to 7.6) attacks per month.
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, 44.9% 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.
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 24% 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 who were more tolerant of and responsive to berotralstat, which could lead to biased estimates of efficacy and safety.
Cost and Cost-Effectiveness.
CADTH identified key limitations with the sponsor’s analysis related to the likely underestimation of market uptake for berotralstat; the underestimation of prevalence of HAE in Canada; uncertainty in the proportion of patients eligible for public coverage to determine the target population; and lack of clarity surrounding discontinuation criteria for berotralstat, which may be a driver of budget impact estimates. A CADTH reanalysis increased the market shares for berotralstat and prevalence of HAE in Canada. Although the sponsor suggested that berotralstat would be associated with a budget impact of $14,164,290 over the 3-year time horizon, based on the CADTH combined exploratory reanalysis, the reimbursement of berotralstat for the treatment of HAE in adults and pediatric patients aged 12 years and older would be associated with a budgetary increase of $24,529,115 in year 1, $31,074,770 in year 2, and $37,288,339 in year 3, for a 3-year total of 92,892,224. CADTH found the budget impact of berotralstat to be sensitive to market shares, prevalence of HAE, and proportion of patients eligible for public coverage.
The sponsor filed a request for reconsideration for the draft recommendation for berotralstat for the routine prevention of attacks of HAE in adults and pediatric patients aged 12 years and older. In their request, the sponsor identified the following issues:
In the meeting to discuss the sponsor’s request for reconsideration, CDEC considered the following information:
All stakeholder feedback received in response to the draft recommendation from patient and clinician groups and the public drug programs is available on the CADTH website.
Dr. James Silvius (Chair), Dr. Sally Bean, Mr. Dan Dunsky, Dr. Alun Edwards, Mr. Bob Gagne, Dr. Ran Goldman, Dr. Allan Grill, Dr. Christine Leong, Dr. Kerry Mansell, Dr. Alicia McCallum, Dr. Srinivas Murthy, Ms. Heather Neville, Dr. Danyaal Raza, Dr. Emily Reynen, and Dr. Peter Zed
Regrets: 2 expert committee members did not attend.
Conflicts of interest: None
Dr. James Silvius (Chair), Dr. Sally Bean, Mr. Dan Dunsky, Dr. Alun Edwards, Mr. Bob Gagne, Dr. Ran Goldman, Dr. Allan Grill, Mr. Morris Joseph, Dr. Christine Leong, Dr. Kerry Mansell, Dr. Alicia McCallum, Dr. Srinivas Murthy, Ms. Heather Neville, Dr. Danyaal Raza, Dr. Emily Reynen, and Dr. Peter Zed
Regrets: 1 expert committee member did not attend.
Conflicts of interest: None
Disclaimer: The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services.
While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date the material was first published by CADTH, CADTH does not make any guarantees to that effect. CADTH does not guarantee and is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document. The views and opinions of third parties published in this document do not necessarily state or reflect those of CADTH.
CADTH is not responsible for any errors, omissions, injury, loss, or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the contents of this document or any of the source materials.
This document may contain links to third-party websites. CADTH does not have control over the content of such sites. Use of third-party sites is governed by the third-party website owners’ own terms and conditions set out for such sites. CADTH does not make any guarantee with respect to any information contained on such third-party sites and CADTH is not responsible for any injury, loss, or damage suffered as a result of using such third-party sites. CADTH has no responsibility for the collection, use, and disclosure of personal information by third-party sites.
Subject to the aforementioned limitations, the views expressed herein are those of CADTH and do not necessarily represent the views of Canada’s federal, provincial, or territorial governments or any third party supplier of information.
This document is prepared and intended for use in the context of the Canadian health care system. The use of this document outside of Canada is done so at the user’s own risk.
This disclaimer and any questions or matters of any nature arising from or relating to the content or use (or misuse) of this document will be governed by and interpreted in accordance with the laws of the Province of Ontario and the laws of Canada applicable therein, and all proceedings shall be subject to the exclusive jurisdiction of the courts of the Province of Ontario, Canada.
The copyright and other intellectual property rights in this document are owned by CADTH and its licensors. These rights are protected by the Canadian Copyright Act and other national and international laws and agreements. Users are permitted to make copies of this document for non-commercial purposes only, provided it is not modified when reproduced and appropriate credit is given to CADTH and its licensors.
Redactions: Confidential information in this document may be redacted at the request of the sponsor in accordance with the CADTH Drug Reimbursement Review Confidentiality Guidelines.
About CADTH: CADTH is an independent, not-for-profit organization responsible for providing Canada’s health care decision-makers with objective evidence to help make informed decisions about the optimal use of drugs, medical devices, diagnostics, and procedures in our health care system.
Funding: CADTH receives funding from Canada’s federal, provincial, and territorial governments, with the exception of Quebec.
Indication: For routine prevention of attacks of hereditary angioedema in adults and pediatric patients 12 years of age and older
Sponsor: BioCryst Pharmaceuticals Inc.
Final recommendation: Reimburse with conditions
Copyright © 2023 - Canadian Agency for Drugs and Technologies in Health. Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial- NoDerivatives 4.0 International licence (CC BY-NC-ND).
Your browsing activity is empty.
Activity recording is turned off.
See more...
