Regulatory Decision Summary for Firdapse

The purpose of this Supplement to a New Drug Submission for Firdapse (amifampridine), filed by KYE Pharmaceuticals Inc., was to:

• Support the addition of a pediatric indication for patients 6 years and older to the Firdapse label, including dosing instructions specific for an oral suspension preparation for patients requiring doses in increments of less than 5 milligrams (mg), or who have difficulty swallowing or require administration via feeding tubes.

• Request an increase to the maximum daily dose of Firdapse from 80 mg to 100 mg for adults (regardless of weight), and for pediatric patients with Lambert-Eaton Myasthenic Syndrome (LEMS) weighing 45 kilograms (kg) or more; and from 40 mg to 50 mg for pediatric LEMS patients weighing less than 45 kg.

• Add content to the Hepatic Impairment and Carcinogenicity sections of the Product Monograph.

The sponsor submitted two studies to support the addition of a pediatric indication for Firdapse (amifampridine). Study CMS-001 enrolled 12 pediatric patients diagnosed with congenital myasthenic syndrome (CMS). The expanded access program study, EAP-001, included 24 pediatric patients, consisting of 22 with CMS (11 male and 11 female) and 2 with Lambert-Eaton Myasthenic Syndrome (LEMS) (2 female). These studies described the safety results in pediatric patients. No efficacy studies were submitted. Therefore, the pediatric claim was supported by extrapolation of efficacy data from adult patients, pharmacokinetic (PK) modeling studies to predict pediatric dosing, and safety data from a small group of pediatric patients with LEMS and non-LEMS conditions.

The combined adverse events reported in studies CMS-001 and EAP-001 were consistent with those previously observed in the adult population. Most of these events are already described in the Product Monograph for Firdapse. The exceptions, which are potentially new adverse events observed in the pediatric population, included: eyelid ptosis, retching, fatigue, gait disturbance, ear infection, sinusitis, dehydration, myopathy, hypotonia, and dysphonia. These additional adverse events were added in the Firdapse Product Monograph under the section Clinical Trial Adverse Reactions – Pediatrics.

To support the increase in total daily dose from 80 milligrams (mg) to 100 mg, the sponsor submitted two clinical studies (JPC 3,4-DAPPER and JPC 3,4-DAP DUKE) conducted with Ruzurgi, a different amifampridine product. Comparative bioavailability data obtained from Study FRB-001 demonstrated that the maximum observed concentration (C_max) and extent of exposure (area under the concentration–time curve [AUC_T]) of amifampridine were equivalent between Firdapse (amifampridine phosphate) tablets, 10 mg, and Ruzurgi (amifampridine) tablets, 10 mg, following single-dose administration under fasting and fed (high-fat, high-calorie) conditions.

In addition, 36 patient narratives from the post-market pharmacovigilance database described adverse events associated with a total daily dose above 80 mg of Firdpase. Seven patients in Study EAP-001 received total daily doses greater than 80 mg.

In study  JPC 3,4-DAPPER, 50% of patients receiving doses of 80 to less than 100 mg/day and 20% of patients receiving 100 mg/day or more reached the primary endpoint. No patients receiving doses of 80 to less than 100 mg/day and 20% of patients treated with 100 mg/day or more reached the secondary endpoint. As this was the only efficacy data submitted, it is determined that there was insufficient evidence to support an increase in total daily dose from 80 mg to 100 mg. However, based on the positive results of the bioequivalence study and discussions with the sponsor, the following statement, also present in the Ruzurgi Product Monograph, was agreed upon: “Some patients may benefit from a total daily dose of 100 mg, administered in divided doses.”

Overall, the safety profile of the increased daily dose was similar to that of the 80 mg dose. However, some new adverse events were observed. The sponsor was asked to add a paragraph in the Adverse Reactions section of the Product Monograph to reflect this. New reported adverse events included weight decreases, fatigue, asthenia, and dyspnea.

An updated Risk Management Plan (RMP) for Firdapse was reviewed by Health Canada and deemed acceptable. Risks have been communicated in the approved Product Monograph and will continue to be monitored post-market as outlined in the RMP, through both routine and non-routine pharmacovigilance activities.

The chemistry and manufacturing information submitted for Firdapse demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

Comparative bioavailability data (FRB-001) confirmed that the C_max and AUC_T of amifampridine were equivalent between Firdapse and Ruzurgi 10 mg, tablets, under both fasting and fed (high-fat, high-calorie) conditions.

This submission also included additional safety data from a completed carcinogenicity study and a hepatic impairment study.

In the original submission, only one carcinogenicity study was provided. A follow-up transgenic mouse carcinogenicity study was completed and provided in the current submission. No carcinogenic effects were observed following dietary administration of amifampridine to CByB6F1/TgrasH2 hemizygous mice for at least 26 weeks at doses up to 30 mg/kg/day. The corresponding mean C_max and AUC values were 22.5 nanograms per milliliter (ng/mL) and 260 ng·h/mL for males, and 21.5 ng/mL and 293 ng·h/mL for females. The exposures achieved were similar to, or exceeded those expected at the maximum recommended human dose of 80 mg/day of Firdapse.

Firdapse is extensively metabolized, and hepatic impairment may slow its metabolism, resulting in higher plasma drug levels. No hepatic impairment study was included in the original submission. As a post-market commitment, the sponsor provided a study evaluating the PK of Firdapse in otherwise healthy subjects with varying degrees of hepatic impairment. A 10 mg dose of amifampridine administered to participants with mild hepatic impairment resulted in a 22% higher C_max and a 33% higher  AUC_inf compared to participants with normal hepatic function. Dosing recommendations in the Product Monograph were updated to advise starting at the lowest recommended initial dose taken orally in divided doses.

The final labelling and Product Monograph were considered acceptable.

Overall, the benefit-harm-uncertainty profile was favorable for Firdapse tablets, 10 mg amifampridine (equivalent to 18.98 mg amifampridine phosphate) for the authorized indication when used under the conditions outlined in the approved Product Monograph. Therefore, a Notice of Compliance was recommended.

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