Summary Basis of Decision for Ruzurgi

Clinical Pharmacology

The mechanism by which the medicinal ingredient in Ruzurgi (amifampridine) exerts its therapeutic effect in patients with LEMS has not been fully elucidated. Amifampridine is a broad-spectrum potassium channel blocker. It acts on voltage-gated potassium channels in the presynaptic membrane, which prolongs the depolarizing phase of the action potential, thus lengthening the open time for voltage-gated calcium channels. This leads to the availability of more acetylcholine at the neuromuscular junction and may result in stronger muscle contractions.

The pharmacokinetic parameters of Ruzurgi were evaluated in a Phase I, randomized, double-blind, placebo-controlled, parallel-group study (JPC 3,4-DAP.PK1) involving healthy male and female volunteers. Subjects were randomized to receive either 20 mg Ruzurgi, 30 mg Ruzurgi, or placebo. On Study Day 1, a single dose was administered under fasting conditions. On Study Day 2, the same procedure was repeated under fed conditions (a high-calorie, high-fat meal).

Steady state was generally reached within 1 day of dosing. For both amifampridine and its metabolite, 3-N-acetyl amifampridine (3‑AC), pharmacokinetic parameters appeared to change proportionally to dose. The apparent oral clearance of amifampridine was 149 to 214 L/h and the average elimination half-life (t_1/2) was 3.6 to 4.2 hours. The average t_1/2 for 3‑AC was 4.1 to 4.8 hours. The majority (>65%) of amifampridine was recovered in urine as either the parent compound or 3‑AC. Food did not significantly alter the urine recovery, nor did it have a clinically relevant impact on t_1/2, C_max, or overall exposure. Ruzurgi can be taken without regard to food intake. However, food may mitigate paresthesia and abdominal discomfort.

Amifampridine is primarily metabolized by N-acetyltransferase 2 (NAT2) to the inactive 3‑AC metabolite. Metabolism of amifampridine by N-acetyltransferase 1 (NAT1) can also occur, but at a slower rate. Genetic variants in the NAT2 gene affect the rate and extent of amifampridine metabolism. Subjects with the slow acetylator phenotype had an average peak serum concentration (C_max) just over 2‑fold higher compared to those with the intermediate acetylator phenotype in the fasted state, and between 2‑ to 4‑fold higher compared to those with the fast acetylator phenotype in the fed state.

Controlled clinical drug‑drug interaction studies have not been performed with Ruzurgi; however, drugs that affect NAT2 metabolism may affect the pharmacokinetics of amifampridine.

The effect of amifampridine on QTc interval prolongation was studied in a double-blind, randomized, placebo-and positive-controlled crossover study (JPC 3,4‑DAP.TQT) involving 52 healthy subjects (including 23 subjects with the NAT2 slow acetylator phenotype). Study participants were administered 120 mg amifampridine for 1 day in four equal doses of 30 mg at 4‑hour intervals. Amifampridine was associated with a QTcF (QT interval corrected for heart rate by the Fridericia formula) prolongation from 1 to 24 hours post‑dose. The maximum difference compared to placebo in mean change from baseline QTcF was 6.14 ms (90% confidence interval [CI]: 4.03, 8.25) at 15 hours post‑dose. In the slow acetylator subgroup, the maximum difference from placebo in mean change from baseline QTcF was 8.29 ms (90% CI: 5.10, 11.49) at 13.5 hours post‑dose. No individual subject had an increase in QTcF >30 ms.

Amifampridine treatment was associated with a reduction in heart rate, with a maximum difference from placebo in mean change from baseline heart rate of ‑3.15 beats per minute (bpm) (90% CI: ‑4.81, ‑1.50) at 13 hours post‑dose. In the slow acetylator subgroup, the maximum difference from placebo in mean change from baseline heart rate was ‑5.91 bpm (90% CI: ‑8.35, ‑3.48) at 12.5 hours post‑dose.

Of note, after the first 30 mg dose, the mean C_max of amifampridine was 113 ng/mL (coefficient of variation [CV%] = 24.5) in slow acetylators, 52.4 ng/mL (CV% = 54.4) in intermediate acetylators, and 20.9 ng/mL (CV% = 7.0) in rapid acetylators.

The clinical relevance of these cardiac‑related findings is apparent in the analysis of more than 600 patients treated with amifampridine through various compassionate use programs (see Clinical Safety). Appropriate warnings and precautions are in place in the Ruzurgi Product Monograph to address the identified safety concerns.

Overall, the clinical pharmacological data support the use of Ruzurgi for the recommended indication.

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

Clinical Efficacy

The clinical efficacy of Ruzurgi (amifampridine) in adults (≥18 years of age) with Lambert-Eaton myasthenic syndrome (LEMS) was evaluated primarily in a small pivotal, randomized, double-blind, placebo-controlled, enriched, withdrawal study known as DAPPER. Two-thirds of the patients were female, 90% were Caucasian and the mean age was 56 years (range: 23 to 83 years). All eligible patients were required to have had a clinical diagnosis of LEMS and to have been stable on amifampridine for at least 90 days prior to study entry (Phase I). During Phase II of the study, a total of 32 patients were randomized to either continue their usual dose of amifampridine (continuous Ruzurgi arm; number of patients [n] = 14) or to be tapered off of amifampridine over 3 days to placebo, with up to an additional 16 hours with no active drug (taper-to-placebo arm; n = 18).

The primary efficacy endpoint was the categorization of the degree of change (e.g., >30% deterioration) in the Triple Timed Up and Go (3TUG) test upon withdrawal of Ruzurgi, compared with the time-matched average of the 3TUG at baseline. The 3TUG is a measure of the time it takes a person to rise from a chair, walk three meters, and return to the chair for three consecutive laps without pause. Higher 3TUG scores represent greater impairment. The key secondary endpoint was the change in the self-assessment of LEMS-related weakness (W‑SAS) score at the end of Phase II. Patients were to take the W‑SAS three times daily.

Results show that 72% of the patients in the taper-to-placebo arm had a >30% deterioration in the final 3TUG test following withdrawal of Ruzurgi, compared to 0% of those in the continuous Ruzurgi arm. Two patients in the taper-to-placebo arm experienced a >200% deterioration and 1 patient experienced a >100% to 200% deterioration. These results were supported by the W‑SAS secondary endpoint. Although there was a clear clinically and statistically significant separation between Ruzurgi and placebo arms, the following three caveats should be acknowledged. Firstly, this was a small study with very few patients randomized to the two groups. Secondly, this study was designed as an enriched withdrawal study with no amifampridine-naïve patients, which meant that, in order to be eligible to participate in Phase II, patients had to display adequate response to amifampridine during Phase I. Thirdly, Phase II of this study was quite short (approximately 5 days). Thus, there are no robust efficacy data in a controlled setting beyond a few days of treatment.

A pediatric (<18 years of age) indication was also sought for Ruzurgi. Due to the extreme rareness of LEMS in the pediatric population, there are no controlled clinical trials of amifampridine in this age group. Isolated reports of effectiveness in children receiving amifampridine through various compassionate use programs are available. A total of 7 pediatric patients with LEMS (age range: 9.6 to <18 years) have received amifampridine (total duration: 23.6 patient‑years). Improvement in function was reported, and etiology, clinical presentation, pathophysiology, and progression appeared to be similar to that of adult patients with LEMS. Further, the pathway for metabolism and clearance of amifampridine appears to reach maturity by 4 to 5 years of age and is the same for both the pediatric and adult populations. The efficacy of Ruzurgi in patients 6 to 17 years of age was further supported by population pharmacokinetic and modelling/simulation studies where exposure and dosing in the pediatric population was predicted utilizing weight allometric scaling based on adult exposure and efficacy data.

Considering the totality of evidence and the fact that patients with LEMS are usually under close supervision of a specialist, Health Canada has approved the use of Ruzurgi in patients 6 years of age and older.

Indication

Dosing recommendations and appropriate warnings and precautions are in place in the Ruzurgi Product Monograph to address the identified safety concerns.To ensure safe and effective use of Ruzurgi in the symptomatic treatment of Lambert-Eaton myasthenic syndrome, Health Canada included caveat statements in the indication related to the diagnosis of this disease and the initiation of treatment with Ruzurgi.

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

Clinical Safety

The effects of Ruzurgi on QTc interval prolongation was assessed in a double-blind, randomized, placebo-and positive-controlled crossover study (JPC 3,4‑DAP.TQT) involving healthy adult subjects (see Clinical Pharmacology). In this study, adverse reactions that occurred during Ruzurgi treatment and with incidence of at least 2% greater than with placebo treatment were dysesthesia, abdominal pain, dyspepsia, dizziness, nausea, back pain, muscle spasms, hypoesthesia, diarrhea, chest discomfort, pain in extremity, dysgeusia, paresthesia, hiccups, hot flush, and hypotension.

Amifampridine has been provided to more than 600 patients on a compassionate use basis over the last 27 years in Canada and the United States. The main source of data to support the long-term safety of Ruzurgi in adult patients with LEMS is the retrospective pharmacovigilance review of 162 patients with LEMS (54% female) who were treated with Ruzurgi through compassionate use programs. Among patients with available exposure data (n = 158), the median duration of treatment was 1.7 years (mean: 4.85 years; range: 1 day to 27.6 years) for a total of 766.4 person-years. The mean age at the time of treatment initiation was 58.7 years (range: 21 to 84 years). The median and mean of the maximum total daily dose was 75.0 mg/day and 68.3 mg/day, respectively.

In general, the most frequent adverse reactions observed were similar to those observed in the QT study involving healthy subjects. Additionally, the following adverse reactions were reported in ≥5% of long-term patients: falls, pneumonia, dyspnea, arthralgia, asthenia, depression, dysphagia, headache, insomnia, blurred vision, anemia, anxiety, constipation, feeling cold, gastroesophageal reflux disease, and pain. Of note, these reactions were captured retrospectively from compassionate use programs, and therefore, it is not possible to reliably estimate their frequency or establish a causal relationship to Ruzurgi.

A key safety issue associated with the use of amifampridine is the occurrence of seizures. Across the more than 600 patients who have received amifampridine, seizures were reported in 26 patients. Five of these patients experienced seizures during long-term use, three of whom were taking amifampridine 60 to 80 mg/day and did not have a prior history of seizures. Although seizures have been reported at various doses of amifampridine, data suggest that they are dose-dependent. Ruzurgi is contraindicated in patients with a history of seizures and should be used with caution in combination with drugs that are known to lower the seizure threshold.

Cardiac-related events have also been reported during amifampridine treatment. Across more than 600 patients treated with amifampridine in various compassionate use programs, 57 experienced one or more cardiac-related event, including QT interval prolongation. According to a database consisting of 234 patients who are part of long-term compassionate use programs, 25 patients experienced cardiac-related adverse events such as atrial fibrillation, cardiac arrest, tachycardia, and palpitations. Drugs that prolong the QTc increase the risk of torsade de pointes, a polymorphic ventricular tachyarrhythmia. Caution should be observed if Ruzurgi is administered to patients who have risk factors for torsade de pointes. Hypokalemia, hypocalcemia, and hypomagnesemia should be corrected prior to initiation or continuation of Ruzurgi.

The safety of Ruzurgi was evaluated in 7 pediatric (<18 years of age) patients with LEMS who were treated with amifampridine through compassionate use programs for. Adverse reactions reported in these patients were similar to those seen in adult patients with LEMS and included one patient with palpitations.

Patients classified as slow acetylators, based on genotyping for variants of the NAT2 gene, were more likely to experience adverse reactions during Ruzurgi treatment than intermediate or rapid acetylators. Ruzurgi should be initiated at the lowest recommended starting dose in patients who are known NAT2 slow acetylators and monitored for adverse reactions.

Amifampridine is metabolized by the liver and its inactive metabolite (3‑AC) is largely eliminated through the kidneys. There are no controlled data on the effects of amifampridine in patients with renal or hepatic impairment. Therefore, the Ruzurgi Product Monograph contains specific dosing recommendations for patients with renal or hepatic impairment, based on limited available information.

Considering the totality of evidence and that patients with LEMS are usually under the close supervision of a specialist, Health Canada has approved the use of Ruzurgi in patients 6 years of age and older.

Dosing recommendations and appropriate warnings and precautions are in place in the Ruzurgi Product Monograph to address the identified safety concerns.

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