Regulatory Decision Summary for Ruzurgi

Lambert-Eaton Myasthenic Syndrome (LEMS) is a very rare disorder of the pre-synaptic origin with an annual incidence of about 0.5 per million. It can be an autoimmune disorder or, in the majority of patients, it can develop due to an underlying cancer. The most common type of cancer associated with the development of LEMS is small cell lung carcinoma. LEMS usually begins around 60 years of age with some patients being diagnosed between 40 and 60 years. The number of LEMS patients in the United States is estimated to be between 400 and 700. There are no reliable estimates on the number of LEMS patients in Canada. It occurs extremely rarely in children with only a handful of reported cases across the globe. Patients with LEMS suffer from weakness of proximal muscles, such as hip girdle, and can have profound mobility difficulties including rising from bed or a chair, walking, and climbing stairs.

In patients whose LEMS is associated with an underlying malignancy, both chemotherapy (to treat the underlying cancer) and a variety of immunosuppressive therapies (to treat the autoimmune disorder) may be used. A number of treatments that are currently being employed include immunosuppressive agents such as prednisone, acetylcholinesterase inhibitors (for example [e.g.], pyridostigmine), potassium channel blockers such as guanidine, with serious side effects of renal failure and fatal bone marrow toxicity, and plasmapheresis to remove autoantibodies responsible for the autoimmune component of the disease.

Amifampridine is a potassium channel blocker. It prolongs the depolarizing phase of the action potential in the pre-synaptic nerve, thereby increasing acetylcholine release at the neuromuscular junction and enhancing muscle contraction. This drug has been administered to approximately 600 LEMS patients since 1993 through various compassionate use programs.

The primary support for the adult indication was provided by a randomized, controlled, withdrawal study called DAPPER. The trial duration was approximately one week. All 32 patients were receiving amifampridine for at least 90 days prior to study entry. Patients were randomized to either remain on amifampridine or taper to placebo over three days. Using the primary efficacy end-point, Triple Time-Up and Go test (patients attempt to rise from a chair, walk 3 meters and return to the chair, repeating this circuit 3 times), significant deterioration in function was observed upon withdrawal of amifampridine. Function was restored in patients after their amifampridine regimen was reinstituted. Key secondary end-points supported the results of the primary end-point as well. Long-term safety of amifampridine treatment in LEMS patients is established by a database of 162 patients who have received the drug, in some cases, for several years, through compassionate use programs. Adverse events reported during long-term use included paresthesia/hypoesthesia, abdominal pain, infection, fall, dyspepsia, nausea, pneumonia, and arrhythmia. Some of the events that led to treatment discontinuation included seizures, tremor, pneumonia, fall, and bradycardia.

A key safety issue associated with the use of amifampridine is the occurrence of seizures, which was reported by 4% of the patients in the Expanded Access (compassionate use) Program. Amifampridine treatment is contraindicated for use in patients with history of seizures.

Cardiac-related events have been reported during amifampridine treatment. Across over 600 patients treated with the drug in various programs, 57 experienced one or more cardiac-related events, including QT prolongation. In the database of 234 patients in the long-term compassionate use programs, 25 experienced cardiac-related adverse events (AEs), such as atrial fibrillation, cardiac arrest, tachycardia, and palpitations.

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

Lambert-Eaton myasthenic syndrome occurs extremely rarely in children. There are only 24 reported pediatric patients with a true diagnosis of LEMS worldwide. Therefore, obtaining safety and efficacy data for this population is challenging. This submission contained no controlled safety, efficacy or pharmacokinetic/exposure data for pediatric patients with LEMS. To support the indication in children 6 years of age and older, the clinical efficacy and safety of Ruzurgi were evaluated in 7 pediatric (<18 years of age) patients with LEMS who were treated with Ruzurgi through various compassionate use programs. Improvement in function was reported and etiology, clinical presentation, pathophysiology, and progression appeared to be similar to that seen in adult patients with LEMS. Although improvement in function was reported, 6 of the 7 patients also experienced various adverse events similar to those seen in adults, including one case of palpitations. No serious events were reported. Further, the pathway for the 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 population. The efficacy of Ruzurgi in patients aged 6 to 17 years 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.

This New Drug Submission (NDS) did not contain carcinogenicity (anticipated study completion date: 2023-2024) or juvenile toxicity studies (anticipated completion date: 2021-2022). Due to the very rare nature of LEMS, the fact that amifampridine has been administered to at least 600 patients over the past 27 years, the results of these studies were not considered critical for the time being. The sponsor has committed to providing completed study reports to Health Canada when available. While not essential for market authorization, publicly available safety information for the phosphate salt of amifampridine is included in the Product Monograph to ensure that it contains known information that may be relevant to the optimal, safe, and effective use of Ruzurgi.

Considering the very rare nature of this disease and based on the safety and efficacy data currently available to Health Canada, the Benefit-Harm-Uncertainty of Ruzurgi (amifampridine) therapy in LEMS patients, 6 years and older, is considered favourable.