Regulatory Decision Summary for Orladeyo

The purpose of this submission was to obtain marketing authorization for Orladeyo (berotralstat) for routine prevention of recurrent attacks of hereditary angioedema (HAE) in adult and adolescent patients 12 years of age or older.

Hereditary angioedema (HAE) is a rare, debilitating, autosomal dominant disorder characterized clinically by recurrent, unpredictable, complex, and self-limiting attacks of edema, inflammation and pain of the face, larynx, extremities, genitals, and gastrointestinal tract that can be fatal in some patients. HAE can be caused by a quantitative (Type I) or qualitative (Type II) deficiency of the complement 1 esterase inhibitor (C1-INH). Insufficiency of C1-INH results in abnormally upregulated cleavage of high-molecular-weight kininogen by plasma kallikrein, releasing bradykinin, which mediates angioedema. Orladeyo (berotralstat) is an inhibitor of plasma kallikrein that was developed as an oral treatment for the prevention of attacks in HAE.

The primary data to support the efficacy and safety of Orladeyo for the prevention of recurrent attacks of HAE was provided by the pivotal Phase 3 study performed in the target population (including adults and adolescents ≥ 12 years of age and weighing ≥ 40 kg). The BCX7353-302 study (Study 302) was a three-part, randomized, double-blind, multicentre, three-arm study of berotralstat versus placebo in patients with Type I or Type II HAE. Part 1 was the basis for the evaluation of the current indication. Patients were randomized 1:1:1 to receive oral berotralstat 110 mg, berotralstat 150 mg, or placebo once daily and were stratified based on HAE attack rate during the screening period (≥ 2 vs. < 2 attacks per month). Patients were permitted to continue to use acute attack medication during the study. The sponsor proposed an indication for the 150 mg dose only; therefore, results for the 110 mg dose were not presented in this summary.

The primary efficacy endpoint was the rate of investigator-confirmed HAE attacks during the 24-week treatment period. Three secondary endpoints included: i) the change from baseline in the Angioedema Quality of Life questionnaire total score at Week 24, ii) the number and proportion of days with angioedema symptoms through 24 weeks, and iii) the rate of investigator-confirmed HAE attacks during dosing in the effective treatment period (beginning at Day 8 through to the end of 24 weeks; when berotralstat was expected to have reached steady-state plasma concentrations).

Study 302 randomized 121 participants. Baseline demographic characteristics were generally similar across treatment groups and representative of the HAE population. Overall, 66% of subjects were female, and the mean age was 41.6 years, including six adolescents and nine elderly subjects aged 65 to 74 years. The mean baseline attack rate was three attacks per month. In the year prior to screening, laryngeal attacks occurred in 30% of subjects; 31% reported a mean of 4.2 visits to the emergency room due to HAE; and 7% reported a mean of 3.6 hospitalizations due to HAE.

The primary efficacy endpoint was met, with the 150 mg dose reducing HAE attacks by 44% (p < 0.001) compared with placebo. The negative binomial analysis estimated attack rates per 28 days were 1.31 for berotralstat 150 mg subjects and 2.35 for placebo subjects over the 24-week period. The attack rate reductions occurred over the first month of treatment and were sustained for the remaining five months of Part 1. The robustness of the primary analysis was supported by sensitivity analyses. The study was not designed or powered to assess subgroups, but all subgroups experienced a reduction in attack rate from berotralstat treatment compared with placebo, with the exception of three subgroups that were too small to interpret (adolescents [n = 6], elderly [n = 9], and other race [n = 8]).

There was a larger attack rate reduction in males than females; however, an ad hoc multiple regression analysis found that sex was not a significant predictor of the on-study attack rate. Further, it demonstrated that the baseline attack rate was a significant predictor of the on-study attack rate, and females in the berotralstat 150 mg treatment group had a higher mean baseline attack rate (standard deviation) of 3.4 ± 1.6 attacks/month relative to the total group (3.0 ± 1.4 attacks/month). The mean baseline attack rate in males in the berotralstat 150 mg group was lower (2.7 ± 1.4 attacks/month).

The first secondary endpoint of the change from baseline in the Angioedema Quality of Life questionnaire total score did not meet statistical significance, as all treatment groups experienced a minimally clinically important difference (a reduction in the score of ≥ 6 points) improvement in the total score. The least squares mean improvements from baseline were -14.6 and -9.7 for the 150 mg and placebo groups, respectively. The domain that assessed functioning reported a nominally significant improvement in ability to function for subjects who received the 150 mg dose. This result halted the hierarchical testing of the other secondary endpoints; however, the remaining endpoints supported the berotralstat 150 mg dose. The second secondary endpoint, the number of days with angioedema symptoms, was nominally statistically significant through 24 weeks: 19.4 and 29.2 days for the 150 mg and placebo groups, respectively (nominal p = 0.006). The third secondary endpoint, the HAE attack rate in the effective treatment period, demonstrated results similar to the primary efficacy endpoint, with reductions in attack rates relative to placebo of 47% for the berotralstat 150 mg group (nominal p < 0.001). Exploratory endpoints including responder analysis, use of HAE standard of care acute attack medications, freedom from attacks, attack characteristics, and health outcome endpoints also favoured treatment with the 150 mg dose.

Administration of berotralstat 150 mg once daily was safe and well-tolerated in Study 302. During Part 1, 85% of subjects using 150 mg and 77% of subjects using placebo experienced a treatment-emergent adverse event, most of which belonged to the system organ class of gastrointestinal disorders. The most frequently reported events were nausea, vomiting, diarrhea, abdominal pain, nasopharyngitis, back pain, and headache. The majority were mild to moderate in severity. No subject experienced a treatment-emergent serious adverse event that was considered to be related to berotralstat. One subject permanently discontinued berotralstat due to a treatment-emergent adverse event (3%; liver function test abnormal) as required per protocol. No berotralstat-treated subjects had a clinically significant abnormal electrocardiogram finding.

In summary, the investigator-confirmed attack rate reduction was considered substantial evidence to support the clinical benefit of Orladeyo in adult and adolescent patients with HAE aged 12 years and older and weighing at least 40 kg. Additional support was provided by secondary and exploratory endpoints, as well as other Phase 2 and Phase 3 non-pivotal data. Clinical risks were adequately labelled in the Product Monograph and were considered acceptable and manageable in the intended population.

An updated Risk Management Plan for Orladeyo was submitted and reviewed by the Marketed Health Products Directorate. Upon review, the Risk Management Plan was considered to be acceptable. The Risk Management Plan was designed to describe known and potential safety issues, to present the monitoring scheme, and when needed, to describe measures that would be put in place to minimize risks associated with the product.

Based on the benefit-harm-uncertainty profile of the product, it was recommended that Orladeyo be authorized for use in the prevention of acute HAE attacks in patients with Types I and II HAE. As the first oral preventative therapy for HAE, this targeted a significant unmet medical need in reducing the burden of intravenous and subcutaneous prophylactic regimens.

For further details about Orladeyo, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.