Regulatory Decision Summary for Pombiliti

The purpose of this submission was to seek market authorization pursuant to section C.08.004 of the Food and Drugs Regulations, for Pombiliti (cipaglucosidase alfa), in combination with Opfolda (miglustat), for the long-term treatment of adult patients with late-onset Pompe disease (acid α-glucosidase [GAA] deficiency).

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

The efficacy of Pombiliti in combination with Opfolda in adult patients with late-onset Pompe disease (LOPD) is based on the results of one pivotal clinical trial. This was a randomized, double-blind, active-controlled trial, conducted in adult subjects with LOPD and weighing ≥ 40 kg. Subjects received study treatment (Pombiliti/Opfolda) or control (alglucosidase alfa/placebo) every two weeks for 52 weeks.

Efficacy endpoints included assessment of motor function (6-minute walk distance [6MWD]; primary endpoint) and pulmonary function (sitting % predicted forced vital capacity [FVC]; first key secondary endpoint) as change from baseline to Week 52. The efficacy population included a total of 122 subjects of which 78% had received prior enzyme replacement therapy (ERT) with alglucosidase alfa (ERT-experienced) and 22% had never received ERT (ERT-naïve). Efficacy results were clinically meaningful but not statistically significant. The results represented improvements compared to the control therapy. Both the primary efficacy endpoint and the first key secondary efficacy endpoint met the numerical “disease stabilization” criteria; the primary efficacy endpoint also almost met the “disease improvement” criterion. Additionally, primary and key secondary efficacy results showed a favorable trend over the first 52 weeks of treatment. The lack of statistical significance is not unexpected in small clinical trials conducted for rare diseases. This is the first clinical trial in LOPD where a majority of the adult patients were ERT-experienced.

The safety profile for Pombiliti was derived primarily from one Phase 3 (pivotal) study (ATB200-03) in adult subjects with LOPD (n = 123). The safety database overall included two Pools, Pool 1 comprised subjects from the pivotal study; Pool 2 comprised subjects from the pivotal study as well as two open-label extension studies (n = 151). Interpretation of safety data from the open-label extension studies was limited by a lack of a comparator arm and therefore difficult to make definitive conclusions regarding long-term safety. In Pool 1, the mean exposure was 11.9 [1.5] months for each group; in Pool 2, the mean duration of exposure was 28.0 [14.3] months. The most frequently (> 5%) reported adverse events across all studies in cipaglucosidase alfa/miglustat treated subjects were: headache, diarrhea, fatigue, nausea, abdominal pain, pyrexia, and chills. Important potential risks of Pombiliti included hypersensitivity/anaphylaxis, infusion-associated reactions (IARs), and cardiorespiratory failure. These risks are consistent with already established safety profiles of existing ERTs. The risks are mitigated in the product labelling including information in the Serious Warnings and Precautions box. No fatal events attributed to Pombiliti/miglustat treatment were reported. Uncertainties (i.e., missing information) related to the safety profile of Pombiliti included use in the elderly, use in pregnant and breastfeeding patients, and long-term safety and tolerability.

The identified risks were included in the recommended Product Monograph and will continue to be monitored post-market as outlined in the Risk Management Plan, with routine and non-routine pharmacovigilance activities.

Based on the results of the pivotal trial, the benefit-risk profile was favourable for Pombiliti for the approved indication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance (NOC) was recommended.

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

The Risk Management Plan (RMP) for Pombiliti (cipaglucosidase alfa) was submitted to Health Canada as part of the New Drug Submission (NDS; Control number 284815). The RMP is designed to describe known and potential safety issues, to present the monitoring plan and when needed, to describe measures that will be put in place to minimize risks associated with the product. Upon review, the RMP is considered to be acceptable and identified appropriate monitoring (pharmacovigilance) activities and risk minimization measures for Pombiliti. This includes providing information in the product monograph and identifying populations and areas where more data are needed. Results related to the safety and effectiveness of Pombiliti from ongoing and planned studies will be submitted in Periodic Safety Update Reports (PSURs) as they become available.

The chemistry and manufacturing information submitted for Pombiliti has demonstrated that the drug substance and drug product have been well characterized and can be consistently manufactured to meet the approved specifications.

The Package labels, Package Insert and Pombiliti information submitted for Pombiliti met all applicable regulations and guidance.

Overall, the benefit-harm-uncertainty profile was favourable for Pombiliti for the approved indication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance (NOC) was recommended.

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