Regulatory Decision Summary for Opfolda

The purpose of this New Drug Submission (NDS), filed by Amicus Therapeutics Canada Inc., was to obtain market authorization for Opfolda, pursuant to section C.08.004 of the Food and Drugs Regulations.

This submission was filed for Opfolda (miglustat capsules), 65 mg, orally administered, for the indication:

Opfolda (miglustat capsules) is an enzyme stabilizer indicated for use in combination with the enzyme replacement therapy cipaglucosidase alfa for long-term treatment in adult patients with late-onset Pompe disease (acid α-glucosidase [GAA] deficiency).

Upon review of the submitted data package, Health Canada authorized Opfolda for the following indication:

Opfolda (miglustat capsules) is an enzyme stabilizer indicated in combination with Pombiliti (cipaglucosidase alfa) for the treatment of adult patients with late-onset Pompe disease (acid α-glucosidase [GAA] deficiency) weighing ≥40 kg. Opfolda must be used in combination with cipaglucosidase alfa. Consult the Product Monograph of cipaglucosidase alfa for detailed information.

This submission was filed concurrently with a separate New Drug Submission to the Biologics and Radiopharmaceutical Drugs Directorate (BRDD) for Pombiliti (cipaglucosidase alfa) under control number 284815. Opfolda and Pombiliti were evaluated as a combination therapy in clinical studies involving patients with Pompe disease.

The sponsor consented to information sharing between Health Canada and health technology assessment organizations as part of an aligned review pathway.

Opfolda (miglustat 65 mg capsules) is a small-molecule enzyme stabilizer intended for co-administration with Pombiliti (cipaglucosidase alfa). Miglustat binds to cipaglucosidase alfa to enhance its stability, preventing enzymatic degradation in circulation and improving bioavailability for uptake by muscle cells in patients with Pompe disease. Opfolda and Pombiliti were evaluated as a combination therapy in clinical studies involving patients with Pompe disease. Pombiliti (cipaglucosidase alfa) was reviewed by the Biologics and Radiopharmaceutical Drugs Directorate (BRDD).

Although this New Drug Submission (NDS) was for Opfolda, the proposed combination therapy included a novel component, as cipaglucosidase alfa had not been previously approved for this indication. The submission represents new conditions of use and targets a new patient population for miglustat, which is not a new active substance in Canada. Miglustat is the active ingredient in Zavesca (miglustat 100 mg capsules), first authorized in Canada on May 26, 2004, for the treatment of Type 1 Gaucher disease and Niemann-Pick type C disease in patients for whom enzyme replacement therapy is not an option.

The clinical benefit of Opfolda in combination with Pombiliti in adult patients with late-onset Pompe disease (LOPD) is supported by results from the pivotal PROPEL (ATB-200-03) study, a Phase 3, double-blind, active-controlled trial. Patients were randomized in a 2:1 ratio to receive cipaglucosidase alfa with miglustat or alglucosidase alfa with placebo every two weeks for 52 weeks. A total of 122 adult patients weighing at least 40 kg were included in the efficacy population, of whom 78% were enzyme replacement therapy experienced and 22% were enzyme replacement therapy naïve.

Efficacy endpoints included changes from baseline to Week 52 in motor function, measured by six-minute walk distance (6MWD) as the primary endpoint, and pulmonary function, measured by sitting percentage predicted forced vital capacity (FVC) as the first key secondary endpoint. The treatment group showed a mean improvement in six-minute walk distance of 20.5 meters compared to 7.7 meters in the control group. For forced vital capacity, the treatment group demonstrated an absolute change of -1.5%, compared to -3.5% in the control group. Although not statistically significant, these findings suggest clinically meaningful trends in favor of the combination therapy. While statistical significance was not achieved, this outcome is not unexpected for rare disease trials with limited sample sizes.

Thresholds for clinical relevance in Pompe disease are not well established; however, published criteria suggest that an increase of six percent or more in six-minute walk distance indicates improvement, while a change between minus six percent and less than plus six percent indicates stabilization. For forced vital capacity, an increase of three percent or more indicates improvement, while a change between minus three percent and less than plus three percent indicates stabilization. Applying these thresholds to PROPEL, increases in six-minute walk distance ranging from three to eleven percent and improvements in forced vital capacity ranging from two to six percent for the treatment group were considered clinically meaningful. Both primary and secondary efficacy endpoints met the criteria for disease stabilization, and the primary endpoint approached the improvement threshold.

Safety data for Opfolda in combination with Pombiliti were primarily derived from the pivotal PROPEL study involving 123 adult subjects with late-onset Pompe disease. Additional data from two open-label studies were included, resulting in a total safety population of 151 patients. In the pivotal study, the mean duration of exposure was 11.9 months for both treatment and control groups. In the combined pool of studies, the mean duration of exposure was 28.0 months.

The most frequently reported adverse events occurring in more than five percent of subjects treated with cipaglucosidase alfa and miglustat included headache, diarrhea, fatigue, nausea, abdominal pain, pyrexia, and chills. Important potential risks associated with cipaglucosidase alfa included hypersensitivity reactions such as anaphylaxis, infusion-associated reactions, and cardiorespiratory failure. These risks are consistent with the known safety profile of existing enzyme replacement therapies. Adverse events potentially related specifically to miglustat included abdominal discomfort, tremor, constipation, jittery feeling, decreased platelet counts, and mild elevations in serum creatinine levels. No cases of paresthesia or peripheral neuropathy were reported. No fatal events were attributed to treatment with the cipaglucosidase alfa and miglustat combination.

Data on the effects of cipaglucosidase alfa or miglustat during pregnancy were limited. Nonclinical studies indicated a potential risk of cardiac birth defects in fetuses exposed to the combination therapy. Additional safety concerns included uncertainties regarding risks to infants during lactation, use in patients with renal impairment, and potential for electrocardiogram changes and cardiac arrhythmias associated with miglustat, as a thorough QT study has not been conducted. These risks were addressed through labelling updates and routine pharmacovigilance measures.

A Risk Management Plan for Opfolda was submitted and deemed acceptable by Health Canada. The plan outlines identified and potential safety concerns, monitoring strategies, and risk minimization measures. The final Product Monograph and labelling were also considered acceptable.

Based on the results of the pivotal PROPEL study, the overall benefit-risk-uncertainty profile for Opfolda (miglustat), when co-administered with Pombiliti (cipaglucosidase alfa), was considered favourable for the approved indication under the recommended conditions of use outlined in the Product Monograph. A Notice of Compliance was issued.

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