Summary Basis of Decision for Orladeyo

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Orladeyo is located below.

Recent Activity for Orladeyo

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

The following table describes post-authorization activity for Orladeyo, a product which contains the medicinal ingredient berotralstat. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

Updated: 2025-06-25

Drug Identification Number (DIN):

DIN 02527693 - 150 mg berotralstat, capsule, oral administration

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 287743

2024-06-13

Issued NOC 2025-05-07

Submission filed as a Level I – Supplement to update the PM with new safety and efficacy information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions and Drug Interactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

SNDS # 269449

2022-11-04

Cancellation Letter Received 2022-12-28

Submission filed as a Level I – Supplement to update the PM. The changes were not in scope of a Labelling Only SNDS but were considered to be a Clinical Only SNDS. The sponsor cancelled the submission administratively.

Drug product (DIN 02527693) market notification

Not applicable

Date of first sale 2022-09-22

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NDS # 252301

2021-04-30

Issued NOC 2022-06-02

NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Orladeyo

Date SBD issued: 2022-10-19

The following information relates to the New Drug Submission for Orladeyo.

Berotralstat (supplied as berotralstat hydrochloride)

Drug Identification Number (DIN):

  • DIN 02527693 ‑ 150 mg berotralstat, capsule, oral administration

BioCryst Pharmaceuticals, Inc.

New Drug Submission Control Number: 252301

 

On June 2, 2022, Health Canada issued a Notice of Compliance to BioCryst Pharmaceuticals, Inc. for the drug product Orladeyo.

The market authorization was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit‑harm-uncertainty profile of Orladeyo is favourable for the routine prevention of attacks of hereditary angioedema in adults and pediatric patients 12 years of age and older.

 

1 What was approved?

 

Orladeyo, a plasma kallikrein inhibitor, was authorized for the routine prevention of attacks of hereditary angioedema (HAE) in adults and pediatric patients 12 years of age and older.

The safety and efficacy of Orladeyo for the treatment of acute HAE attacks have not been established. Orladeyo should not be used for the treatment of acute HAE attacks. Additional doses or doses of Orladeyo higher than the 150 mg once‑daily dose are not recommended due to the potential for QT prolongation.

Based on the data reviewed by Health Canada, the safety and efficacy of Orladeyo in pediatric patients 12 years of age and older and weighing 40 kg and over have been established, and Health Canada has authorized an indication for use in this pediatric patient population. The safety and efficacy of Orladeyo have not been established in pediatric patients younger than 12 years of age.

Evidence from clinical studies and experience suggests that use in the geriatric population (patients 65 years of age and older) is not associated with differences in safety or effectiveness relative to those younger than 65 years of age. Orladeyo has not been studied in patients 75 years of age and older.

Orladeyo (150 mg berotralstat, supplied as berotralstat hydrochloride) is presented as a capsule. In addition to the medicinal ingredient, the capsule contains black iron oxide, colloidal silicon dioxide, crospovidone, gelatin, indigo carmine (FD&C Blue No. 2), magnesium stearate, pharmaceutical grade printing ink, pregelatinized starch, red iron oxide, and titanium dioxide.

The use of Orladeyo is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Orladeyo Product Monograph is available through the Drug Product Database.

For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

 

2 Why was Orladeyo approved?

 

Health Canada considers that the benefit‑harm-uncertainty profile of Orladeyo is favourable for the routine prevention of attacks of hereditary angioedema (HAE) in adults and pediatric patients 12 years of age and older.

The safety and efficacy of Orladeyo for the treatment of acute HAE attacks have not been established. Orladeyo should not be used for the treatment of acute HAE attacks. Additional doses or doses of Orladeyo higher than the 150 mg once‑daily dose are not recommended due to the potential for QT prolongation.

Hereditary angioedema is a rare autosomal dominant disorder characterized by recurrent, unpredictable, complex, and self‑limiting attacks of edema, inflammation and pain of the face, larynx, extremities, genitals, and gastrointestinal tract. Hereditary angioedema attacks may or may not be precipitated by a stimulus such as stress, trauma, infection, or changes in hormonal levels with menses, and typically progress over several hours. However, oropharyngeal swelling (especially laryngeal swelling) can be life‑threatening, as symptoms progress more rapidly in laryngeal attacks due to the anatomy of the upper airway. Attacks in other sites can be painful, disabling, and disfiguring. Abdominal attacks are especially painful, and may lead to unnecessary surgical procedures if HAE is not recognized as the cause of the abdominal attack.

Hereditary angioedema can be caused by a quantitative (Type I) or qualitative (Type II) deficiency of the complement 1 esterase inhibitor (C1‑INH). An estimated 75% of cases represent familial angioedema, whereas 25% of cases arise from new mutations in the gene for C1‑INH, SERPING‑1. A C1‑INH insufficiency leads to abnormally upregulated cleavage of high‑molecular-weight kininogen (HMWK) by plasma kallikrein. This produces bradykinin, a potent vasodilator that increases vascular permeability resulting in swelling and pain associated with HAE.

In Canada, the estimated prevalence of HAE is 1 in 10,000 to 1 in 50,000 individuals (675 to 3,374 patients). The frequency of attacks varies in patients not taking a prophylactic medication, ranging from rare occurrences in some patients to attacks occurring every few days in others, with 59% reporting at least one attack per month. The management of HAE involves both the prevention of attacks and treatment of attacks.

Orladeyo has been developed as an oral treatment for the prevention of attacks in HAE. Berotralstat, the medicinal ingredient in Orladeyo, inhibits the proteolytic activity of plasma kallikrein, and controls the excess bradykinin generation that causes the swelling and pain in patients with HAE.

The clinical efficacy of Orladeyo was evaluated in Part 1 of the Phase III Study BCX7353‑302 (Study 302) conducted in 120 patients 12 years of age or older with Type I or II HAE. In Part 1 of the study, patients were randomized 1:1:1 to receive berotralstat 110 mg, berotralstat 150 mg, or a placebo once daily with food over a 24‑week treatment period. Eighty‑one patients received at least one dose of berotralstat, and 40 of these patients received the 150 mg dose. A history of laryngeal angioedema attacks was reported in 74% of patients, and prior use of long‑term prophylaxis was reported in 75% of patients. The median attack rate during the prospective run‑in period (baseline attack rate) was 2.9 attacks per month. Seventy percent of patients enrolled had a baseline attack rate of ≥2 attacks per month.

The primary efficacy endpoint was the rate of investigator‑confirmed HAE attacks during the 24‑week dosing period. In the intent‑to‑treat (ITT) population, the HAE attack rates were reduced by 44.2% (95% confidence interval [CI]: 23.0, 59.5; p<0.001) in the 150 mg group and by 30% (95% CI: 4.6, 48.7; p = 0.024) in the 110 mg group, compared with placebo. At both dose levels, the reduction in HAE attack rate was found to be statistically significant and clinically meaningful.

In the 150 mg treatment group, the median attack rate at baseline was 2.7 attacks per month. At Month 1, the rate decreased to 1.28 attacks per month. The rate remained steady through Month 6, with median attack rates of 1.00 or slightly below 1.00.

The rate of attacks classified as moderate or severe was reduced by 40% in patients receiving 150 mg Orladeyo relative to placebo. The rate of attacks requiring standard‑of-care treatment for acute attacks was reduced by 49.2% (95% CI: 25.5%, 65.4%) in patients treated with 150 mg Orladeyo compared to placebo (rate per 28 days: 1.04 vs. 2.05).

The primary safety evaluation was based on data from Part 1 of Study 302, collected over the 24‑week dosing period. The most common adverse reactions associated with the 150 mg dose were gastrointestinal reactions, which included abdominal pain in any location (23%), vomiting (15%), and diarrhea (15%). These reactions generally occurred early after initiation of treatment with Orladeyo, became less frequent with time, and typically self‑resolved. No patients in the Orladeyo 150 mg dose group discontinued treatment due to a gastrointestinal adverse reaction. There were no serious drug‑related treatment‑emergent adverse events (TEAEs) or serious adverse events in patients treated with Orladeyo.

In the Orladeyo 150 mg treatment group, TEAEs were reported in 85% of patients and 77% of patients in the placebo group. In the Orladeyo 150 mg dose group, 37.5% of TEAEs were determined to be drug‑related. The most common TEAEs in this group (reported in ≥10% of patients) were nausea, vomiting, diarrhea, abdominal pain, nasopharyngitis, back pain, and headache. Gastrointestinal TEAEs were reported in 50% of patients treated with Orladeyo 150 mg, none of which were found to be severe, and in 36% of patients in the placebo group. Concomitant medication was required for 10% of Orladeyo‑treated patients and 7.7% of placebo‑treated patients.

A Risk Management Plan (RMP) for Orladeyo was submitted by BioCryst Pharmaceuticals, Inc. to Health Canada. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. Upon review, the RMP was considered to be acceptable.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Orladeyo Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

The sponsor submitted a brand name assessment that included testing for look‑alike sound‑alike attributes. Upon review, the proposed name Orladeyo was accepted.

Orladeyo has an acceptable safety profile based on the non‑clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Orladeyo Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has issued the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

 

3 What steps led to the approval of Orladeyo?

 

Initially, the sponsor filed a request for priority review status under the Priority Review Policy for the review of the New Drug Submission (NDS) for Orladeyo. An assessment was conducted to determine if sufficient evidence was presented demonstrating that the drug provides a significant increase in efficacy and/or significant decrease in risk such that the overall benefit‑risk profile is improved over existing therapies for the treatment of hereditary angioedema (HAE). The efficacy results from the pivotal studies did not provide evidence of an improved overall benefit‑risk profile over existing therapies. The submission did not meet the criteria for obtaining a priority review status and therefore the request was denied. The submission was subsequently filed and reviewed as a regular NDS.

The review of the NDS for Orladeyo was based on a critical assessment of the data package submitted to Health Canada and of the foreign reviews completed by the United States Food and Drug Administration as described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. Several methods for the use of the foreign reviews were applied during Health Canada’s review of the non‑clinical component of the submission. The Canadian regulatory decision on the Orladeyo NDS was made independently.

For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.

 

Submission Milestones: Orladeyo

Submission Milestone Date
Request for priority status filed 2021-03-12
Request for priority status rejected by Director, Bureau of Medical Sciences 2021-04-01
New Drug Submission filed 2021-04-30
Screening  
Screening Deficiency Notice issued 2021-06-17
Response to Screening Deficiency Notice filed 2021-07-08
Screening Acceptance Letter issued 2021-08-09
Review  
Review of Risk Management Plan completed 2022-04-28
Non-clinical evaluation completed 2022-05-18
Labelling review completed 2022-06-01
Quality evaluation completed 2022-06-01
Clinical/medical evaluation completed 2022-06-02
Notice of Compliance issued by Director General, Pharmaceutical Products Directorate 2022-06-02

 

4 What follow-up measures will the company take?

 

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

 

5 What post-authorization activity has taken place for Orladeyo?

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

The PAAT for Orladeyo is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

 

6 What other information is available about drugs?

 

Up-to-date information on drug products can be found at the following links:

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

 

Clinical Pharmacology

Berotralstat, the medicinal ingredient in Orladeyo, inhibits the proteolytic activity of plasma kallikrein, a serine protease that cleaves high‑molecular-weight-kininogen (HMWK) to generate cleaved HMWK (cHMWK) and bradykinin. Bradykinin is a potent vasodilator that increases vascular permeability, resulting in swelling and pain associated with hereditary angioedema (HAE). In patients with HAE, normal regulation of plasma kallikrein activity is not present due to complement 1 esterase inhibitor (C1‑INH) deficiency or dysfunction. This leads to uncontrolled increases in plasma kallikrein activity and results in angioedema attacks. Berotralstat decreases plasma kallikrein activity to control excess bradykinin generation in patients with HAE.

The clinical pharmacology of berotralstat was evaluated in 12 Phase I studies in healthy participants, participants with HAE, and participants with renal and hepatic impairment, and in three Phase II studies and two Phase III studies in participants with HAE. Analyses were also conducted using a population pharmacokinetic model.

The pharmacokinetics of berotralstat is similar in healthy participants and participants with HAE. A prolonged absorption phase was observed, which includes enterohepatic recirculation. Berotralstat exposure, as measured by the maximum plasma concentration (Cmax) and the area under the concentration‑time curve (AUC), increases in a manner greater than dose‑proportional over the range of 30 to 1,000 mg (single dose) and 125 to 500 mg/day (multiple dose). Steady state was reached between Day 6 and Day 12. The exposure of berotralstat at steady state is approximately 6 times that observed after a single dose. No differences were observed in exposure following the administration of berotralstat with a high‑fat meal. However, the median time to the maximum plasma concentration (Tmax) was delayed by 3 hours (from 2 hours [fasted] to 5 hours [fed, range 1 to 8 hours]). Berotralstat should be administered with food to minimize gastrointestinal adverse events.

Plasma protein binding of berotralstat is approximately 99%. Berotralstat is metabolized by the cytochrome P450 (CYP) enzymes CYP2D6 and CYP3A4, with low turnover in vitro. After a single oral radiolabelled 300 mg dose, the blood‑to-plasma ratio was approximately 0.92. Berotralstat accounted for 34% of the total plasma radioactivity. Eight metabolites collectively represented 39% of the total radioactivity, with individual metabolites each accounting for 1.8% to 7.8% of the total radioactivity. It remains unclear whether any metabolites are pharmacologically active. At the 150 mg once‑daily dose, berotralstat is a moderate inhibitor of CYP2D6 and CYP3A4, and a weak inhibitor of CYP2C9. Appropriate monitoring is recommended for concomitant medications with a narrow therapeutic index that are predominantly metabolized by CYP2D6 (e.g., thioridazine, pimozide) or CYP3A4 (e.g., cyclosporine, fentanyl). Berotralstat is not an inhibitor of CYP2C19. At two times the recommended dose, berotralstat is a weak inhibitor of P‑glycoprotein (P‑gp), and is not an inhibitor of breast cancer resistance protein (BCRP). No dose reductions for berotralstat are recommended when administered concomitantly with P‑gp inhibitors.

After a single 150 mg dose, the median half‑life of berotralstat was found to be approximately 93 hours (range: 39 to 152 hours). After a single oral radiolabelled 300 mg dose, 79% was excreted in feces (50% as unchanged berotralstat), and 9% was excreted in urine (3.4% as unchanged berotralstat).

The pharmacokinetics of berotralstat was examined in subjects with mild, moderate, and severe hepatic impairment (Child‑Pugh Class A, B, or C) following a single 150 mg dose. In subjects with mild hepatic impairment, the pharmacokinetics of berotralstat was unchanged relative to subjects with normal hepatic function. In subjects with moderate hepatic impairment, a 77% increase in the Cmax and a 78% increase in the AUC0‑inf were observed. In subjects with severe hepatic impairment, a 27% increase in the Cmax and a 6% decrease in the AUC0‑inf were observed. The percentage of unbound berotralstat was two times higher in subjects with severe hepatic impairment (mean of 2.4%) than in subjects with normal hepatic function (mean of 1.2%). The use of berotralstat should therefore be avoided in patients with moderate or severe hepatic impairment (Child‑Pugh Class B or C), as increased plasma concentrations of berotralstat are associated with a risk of QT prolongation.

The pharmacokinetics of berotralstat was assessed in subjects with severe renal impairment (defined as an estimated glomerular filtration rate [GFR] of <30 mL/min/1.73 m2) following a single 200 mg dose. No clinically relevant differences were observed compared to subjects with normal renal function (defined as an estimated GFR of >90 mL/min/1.73 m2). The Cmax was approximately 39% higher in subjects with severe renal impairment than in subjects with normal renal function, and no difference was observed in the AUC. The use of berotralstat should be avoided in patients with severe renal impairment, as they may be at risk of QT prolongation. No dose adjustment is required for patients with mild or moderate renal impairment. The pharmacokinetics of berotralstat has not been studied in patients with end‑stage renal disease (defined as creatinine clearance <15 mL/min or estimated GFR of <15 mL/min/1.73 m2 or patients requiring hemodialysis).

Overall, the findings from the clinical pharmacology studies support the administration of berotralstat at the recommended dose of 150 mg once daily in adults and adolescents (weighing 40 kg or more) with HAE.

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

Clinical Efficacy

Evidence of the clinical efficacy of Orladeyo was provided through the results from Part 1 of Study 302, a Phase III study conducted in 120 patients 12 years of age or older with Type I or II hereditary angioedema (HAE). The patients enrolled in this study included 114 adults and 6 adolescents (12 years of age or older and weighing at least 40 kg) who experienced at least two investigator‑confirmed attacks within the first 8 weeks of the run‑in period and who had taken at least one dose of the study treatment. Nine patients were 65 years of age or older.

Part 1 of the study included patients randomized 1:1:1 to receive berotralstat 110 mg, berotralstat 150 mg, or a placebo once daily with food over a 24‑week treatment period. Patients were stratified by baseline attack rate (fewer than two attacks per month vs. two or more attacks per month). Patients discontinued the use of other prophylactic HAE medications prior to entering the study, but were allowed to use rescue medications to treat breakthrough HAE attacks. During the 24‑week period, 81 patients received at least one dose of berotralstat, and 40 of these patients received the 150 mg dose. A history of laryngeal angioedema attacks was reported in 74% of patients, and prior use of long‑term prophylaxis was reported in 75% of patients. The median attack rate during the prospective run-in period (baseline attack rate) was 2.9 attacks per month. Seventy percent of patients enrolled had a baseline attack rate of ≥2 attacks per month.

The primary efficacy endpoint was the rate of investigator‑confirmed HAE attacks during the 24‑week dosing period. In the intent‑to‑treat (ITT) population, the HAE attack rates were reduced by 44.2% (95% confidence interval [CI]: 23.0, 59.5; p<0.001) in the 150 mg group and by 30% (95% CI: 4.6, 48.7; p = 0.024) in the 110 mg group, compared with placebo. At both dose levels, the reduction in HAE attack rate was found to be statistically significant and clinically meaningful.

As estimated by a negative binomial regression analysis, over the dosing period, attack rates per 28 days were 1.65 in patients who received the 110 mg dose, 1.31 for the patients who received the 150 mg dose, and 2.35 for the patients in the placebo group. The attack rate was reduced at both doses in the first month of treatment and was stable over the 24‑week treatment duration. In the 150 mg treatment group, the median attack rate at baseline was 2.7 attacks per month. At Month 1, the rate decreased to 1.28 attacks per month. The rate remained steady through Month 6, with median attack rates of 1.00 per month or slightly below 1.00 per month.

The robustness of the primary analysis outcomes was demonstrated through the results of six sensitivity analyses of treatment with both doses of berotralstat. The results of subgroup analyses showed the benefit of berotralstat across subgroups in reducing the on‑study attack rate when compared with placebo, with the exception of three subgroups in which the sample sizes were too small for interpretation (adolescents, elderly, and other race).

Relative to their baseline attack rates, at least a 50% reduction in the adjusted HAE attack rate was observed in 58% of responders in the Orladeyo 150 mg group and 25% of patients in the placebo group (p = 0.005). In post hoc analyses of patients receiving the 150 mg dose, 50% had reductions of 70% or greater and 23% had reductions of 90% or greater in their HAE attack rates compared to baseline. In the placebo group, 15% had reductions of 70% or greater and 8% had reductions of 90% or greater in their HAE attack rates compared to baseline.

The rate of attacks classified as moderate or severe was reduced by 40% in patients receiving 150 mg Orladeyo relative to patients receiving placebo. The rate of HAE attacks requiring standard-of-care treatment for acute attacks was reduced by 49.2% (95% CI: 25.5%, 65.4%) in patients treated with 150 mg Orladeyo compared to those treated with placebo (rate per 28 days: 1.04 vs. 2.05).

Indication

Health Canada approved the following indication:

  • Orladeyo (berotralstat) is indicated for the routine prevention of attacks of hereditary angioedema (HAE) in adults and pediatric patients 12 years of age and older.

The Product Monograph specifies that pediatric patients must weigh 40 kg or more, which is consistent with the characteristics of the pediatric patients enrolled in the pivotal study. Limitations of use were added to the indication to highlight certain circumstances in which the safety and efficacy of Orladeyo have not been established. Orladeyo should not be used for the treatment of acute HAE attacks. Additional doses or doses of Orladeyo higher than the 150 mg once‑daily dose are not recommended due to the potential for QT prolongation.

For more information, refer to the Orladeyo Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

Clinical Safety

The overall safety of Orladeyo was evaluated in multiple long‑term clinical studies, including 381 patients with HAE. The primary safety evaluation was based on data from the placebo‑controlled blinded Phase III study (Study 302, Part 1; described in the Clinical Efficacy section) over the 24‑week dosing period.

In Part 1 of Study 302, the most common adverse reactions associated with the 150 mg dose were gastrointestinal reactions, which included abdominal pain in any location (23%), vomiting (15%), and diarrhea (15%). These reactions generally occurred early after initiation of treatment with Orladeyo, became less frequent with time, and typically self‑resolved. No patients in the Orladeyo 150 mg dose group discontinued treatment due to a gastrointestinal adverse reaction. There were no serious drug‑related treatment‑emergent adverse events (TEAEs) or serious adverse events in patients treated with Orladeyo.

In the Orladeyo 150 mg treatment group, TEAEs were reported in 85% of patients and 77% of patients in the placebo group. In the Orladeyo 150 mg dose group, 37.5% of TEAEs were determined to be drug‑related. The most common TEAEs in this group (reported in ≥10% of patients) were nausea, vomiting, diarrhea, abdominal pain, nasopharyngitis, back pain, and headache. Gastrointestinal TEAEs were reported in 50% of patients treated with Orladeyo 150 mg, none of which were found to be severe, and in 36% of patients in the placebo group. Concomitant medication was required for 10% of Orladeyo‑treated patients and 7.7% of placebo‑treated patients.

No deaths occurred during the study.

One patient permanently discontinued study treatment due to liver function test abnormalities, in accordance with the study protocol. None of the patients treated with Orladeyo experienced an adverse event that led to temporary interruption of the study drug.

Baseline measurements of the QT interval corrected using Fridericia’s formula (QTcF) ranged from >30 to ≤60 ms. The incidence of change from baseline was 5.2% in patients treated with Orladeyo, compared with 2.7% in the placebo group. None of the abnormal electrocardiogram findings were found to be clinically meaningful.

Health Canada has determined that appropriate risk management measures are in place to address the safety concerns identified for Orladeyo and to support its safe and effective use. Overall, the benefit‑harm-uncertainty profile of Orladeyo is favourable for the approved indication. 

For more information, refer to the Orladeyo Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

7.2 Non-Clinical Basis for Decision

 

As described above, during the review of the non-clinical component of the New Drug Submission for Orladeyo, Health Canada used the foreign review completed by the United States Food and Drug Administration by applying several methods described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

The non‑clinical studies submitted in support of Orladeyo (berotralstat) included pharmacology, pharmacokinetics, and toxicology studies. In pharmacology studies, berotralstat displayed a high selectivity for kallikrein over other serine proteases and inhibited kallikrein activity across species. Results from safety pharmacology studies suggest that adverse effects on the central nervous system and respiratory system are of low concern.

Berotralstat was shown to have the potential for drug‑drug interactions due to the inhibition and induction of cytochrome P450 (CYP) enzymes, the inhibition of transporters, and to being a substrate of drug transporters. These potential drug‑drug interactions are managed with appropriate monitoring and dose adjustments of these medications.

Repeat‑dose toxicity studies were conducted in rats and cynomolgus monkeys, for durations of 6 months and 9 months, respectively. In rats, berotralstat was well tolerated at doses up to and including 20 mg/kg, which corresponds to 3.8‑fold the exposure in human adults at the recommended dose as measured by the area under the concentration‑time curve (AUC). As the highest dose tested, 20 mg/kg was the no‑observed-adverse‑effect level (NOAEL). Signs of minimal liver toxicity were observed. In cynomolgus monkeys, berotralstat was well tolerated at 30 mg/kg, which corresponds to 1.5‑fold the exposure in human adults at the recommended dose as measured by the AUC. The NOAEL was determined to be 30 mg/kg, as signs of liver and kidney toxicity were observed at higher doses. In both rats and monkeys, evidence of phospholipidosis was found in the small intestine, lungs, spleen, and lymphoid tissue.

The carcinogenicity of berotralstat was assessed in a 2‑year study in Wistar rats and a 26‑week study in Tg.rasH2 transgenic mice. The highest doses administered were 20 mg/kg/day in rats and 50 mg/kg/day in mice, which resulted in exposures approximately 5 and 10 times the exposure from the maximum recommended human daily dose, respectively. No evidence of tumourigenicity was observed in either species.

No genotoxic effects were identified for berotralstat in the in vitro bacterial reverse mutation assay (Ames test), the in vitro chromosomal aberration assay in human peripheral blood lymphocytes, and in the in vivo rat micronucleus assay.

The reproductive and developmental toxicity studies included teratology studies in rats and rabbits, a fertility and early embryonic development study in rats, and a prenatal and postnatal development study in rats. No effects were observed in these studies with respect to reproductive toxicity.

The results of the non‑clinical studies as well as the potential risks to humans have been included in the Orladeyo Product Monograph. Considering the intended use of Orladeyo, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Orladeyo Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

7.3 Quality Basis for Decision

 

The chemistry and manufacturing information submitted for Orladeyo has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 48 months is acceptable when the drug product is stored at 20 ºC to 25 ºC.

Proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation [ICH] limits and/or qualified from toxicological studies).

All sites involved in production are compliant with good manufacturing practices.

None of the non‑medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations.

The biologic raw materials used during manufacturing originate from sources with no or minimal risk of contamination with transmissible spongiform encephalopathy agents or other human pathogens.

 

Date modified: