Summary Basis of Decision for Fampyra ™

3.3.1 Bioequivalence

Two comparative bioavailability studies were part of the review of the New Drug Submission for Fampyra.

One study was a single-dose, two-way crossover comparative bioavailability study in 18 healthy adult male and female volunteers under fasting conditions comparing the bioavailability of two proposed commercial formulations of Fampyra produced at two production facilities.

The other study was a single-dose, two-way crossover food-effect study in 30 healthy adult male and female volunteers to compare bioavailability under fasted and fed (high-fat, high-calorie meal) conditions.

The two bioavailability studies, as part of the New Drug Submission for Fampyra tablets, met the requirements of the Food and Drugs Act and Regulations insofar as the Safety and Efficacy (clinical, comparative bioavailability) information was concerned. It was recommended, on the basis of the data submitted in support of comparative bioavailability, that this product be granted clearance with respect to safety and efficacy.

3.3.2 Clinical Pharmacology

There were several clinical pharmacology studies, which included safety pharmacology, pharmacokinetics and drug interaction studies. Under the provisions of the Draft Guidance Document: The Use of Foreign Reviews by Health Canada, the Canadian regulatory decision on the clinical pharmacology studies was based on the detailed review reports completed in detail by the EMA and Australia's Therapeutic Goods Administration (TGA). Health Canada's review was based on a critical assessment of both foreign reviews, referring to the data filed in Canada as necessary, the pharmacodynamic studies and the pharmacokinetic studies including the absorption, distribution, metabolism, excretion, and interaction studies, and those conducted in special populations. Health Canada did not identify any new safety concerns related to clinical pharmacology.

The pharmacokinetic program has satisfactorily characterized the key variables for fampridine in MS. However, there are little or no pharmacokinetic data for patients with hepatic or in particular renal impairment; or in children, adolescents, the elderly or in different racial groups.

3.3.3 Clinical Efficacy

Under the provisions of the Draft Guidance Document: The Use of Foreign Reviews by Health Canada, the Canadian regulatory decision on the clinical efficacy of Fampyra was based on a critical assessment of the Canadian data package, with the foreign reviews completed by the EMA and TGA as an added reference. The active ingredient is well known, and has been available for years, via compounding pharmacies, for use in MS and spinal cord injuries. A primary concern with the drug is risk of seizures, and the sustained-release formulation of Fampyra is one of the risk-management steps.

The efficacy of Fampyra in improving walking in patients with MS was evaluated in two adequate and well-controlled Phase III studies (MS-F203 and MS-F204) involving 540 patients. Patients in these two clinical studies had a mean disease duration of 13 years and a median Kurtzke Expanded Disability Status Scale (EDSS) score of 6. Patient inclusion criteria included the ability to walk 25 feet in 8 to 45 seconds. Patient exclusion criteria included a history of seizures or evidence of epileptiform activity on a screening electroencephalogram (EEG), and onset of an MS exacerbation within 60 days.

MS-F203 was a randomized, placebo-controlled, parallel group, 21-week study (one week post screening, two-week, single-blind placebo run-in, 14-week double-blind treatment, and 4-week no treatment follow-up) in 301 patients with MS at 33 centres in the United States and Canada: 229 patients assigned to Fampyra 10 mg twice a day (BID) and 72 patients assigned to placebo. A total of 283 patients (212 Fampyra and 71 placebo) completed all study visits.

MS-F204 was a randomized, placebo-controlled, parallel group, 14-week study (one week post-screening, two weeks of single-blind, placebo run-in, nine weeks of double-blind treatment, and two weeks of no-treatment follow-up) in 239 patients with MS at 39 centres in the United States and Canada: 120 patients assigned to 10 mg BID; and 119 assigned to placebo. A total of 227 patients (113 Fampyra and 114 placebo) completed all study visits.

The primary measure of efficacy in both studies was walking speed (in feet per second) as measured by the Timed 25-foot Walk (T25W), using a responder analysis. A responder was defined as a patient who showed faster walking speed for a least three visits out of a possible four during the double-blind period than the maximum value achieved in the five non-double-blind no treatment visits (four before the double-blind period and one after).

In both studies, a significantly greater proportion of patients taking Fampyra 10 mg BID were "Timed Walk Responders" compared to patients taking placebo, as measured by the T25W [MS-F203: 34.8% versus (vs.) 8.3%; MS-F204: 42.9% vs. 9.3%]. Upon first review, Health Canada concluded that the primary endpoint (measure) was not sufficient to demonstrate clinically meaningful efficacy, as the threshold for being considered a "Timed Walk Responder" was any amount of improvement over baseline for at least 3 of 5 on-treatment measurements of the T25W test. Upon the second review when the findings were recalculated as the frequency distribution of "mean % improvement for each patient", Health Canada was able to conclude that there was a significant treatment effect, as follows: From the pooled recalculated data, 33% of the patients treated with Fampyra showed a clinically meaningful change of 20% improvement, compared to 14% of the patients that were treated with placebo. This was the primary, though not sole factor in concluding that the efficacy demonstrated by Fampyra in these studies was clinically significant.

The main secondary endpoint for both studies was the 12-item multiple sclerosis walking scale (MSWS-12), which is a well-established validated patient-reported outcome measure specifically developed to assess walking ability in MS patients. Satisfactory consistency in this outcome was shown between the two studies for the MSWS-12, and in fact, similarly consistent results between studies were seen for almost all of the secondary endpoints. As well, the calculated correlation between T25W and MSWS-12 was consistent between the studies, as was the small amount of error seen with predicting of values for one study based on the other.

In summary, the totality of findings support statistical and clinical validation of T25W, as well as a clinically meaningful treatment effect with Fampyra in the two pivotal Phase III studies.

Beneficial response to Fampyra was found to be independent of MS disease course (relapsing or progressive, including primary progressive), independent of concomitant treatment with the major immunomodulatory drugs approved for this condition, and similar in magnitude across the full range of baseline ambulatory deficits examined, including patients with EDSS from 2.5 to 7. No differences in efficacy based on degree of impairment, age, gender, or body mass index were detected. There were too few non-Caucasians in the patient population to evaluate the effect of race.

Maintenance of benefit was established from long-term studies, but the benefit was lost after discontinuation. Based on the hypothesized mechanism of action, treatment benefit will likely be lost at some point with progressive deterioration of the nerves.

3.3.4 Clinical Safety

Under the provisions of the Draft Guidance Document: The Use of Foreign Reviews by Health Canada, the Canadian regulatory decision on the clinical safety of Fampyra was based on a critical assessment of the Canadian data package, with the foreign reviews completed by the EMA and TGA as an added reference.

In the clinical studies evaluating the effect of Fampyra in MS patients, 1,075 patients were treated with Fampyra for at least 12 weeks, 819 patients for 6 months, 628 patients for at least one year, and 526 patients for at least two years. The majority of the adverse events (AEs) reflected the mechanism of action, i.e. stimulation of the nervous system. These nervous system disorders included seizure; insomnia; anxiety; balance disorder; dizziness; paraesthesia; tremor; headache; and asthenia.

In the placebo-controlled studies [number (n) = 400 on Fampyra; n = 238 on placebo], the most common AE seen in patients treated with Fampyra 10 mg BID was urinary tract infection (UTI). This AE was reported in approximately 12% of the patients treated with Fampyra compared to 8% of the patients treated with placebo. The reporting of UTI may be due to the effect of fampridine on the sensory and/or motor innervation of the bladder. Reported UTIs were usually moderate in severity and transient.

Fampridine has a narrow therapeutic index, with the risk of seizures being dose-related. In the placebo-controlled studies, the incidence of seizure was not higher in the patients treated with Fampyra 10 mg BID than in the placebo-treated patients (0.19% vs. 0.4%, respectively). The primary safety concern is the risk of seizure when fampridine plasma concentrations exceed those of the recommended dose. Renal impairment and certain concomitant medications are among the factors that can result in increased fampridine plasma levels, along with any dose higher than recommended. Cautionary statements and warnings are stated in the Product Monograph, both in the Contraindications section and the Warnings and Precautions section.

The lowest effective dose has not been established, but the sponsor's commitment to study doses lower than 10 mg BID is considered acceptable in light of the agreed-upon conditions of use.

No deaths were reported in the controlled clinical studies. The reported causes of death in the 8 cases in open-label extension studies (oxycodone overdose; aortic dissection; suicide; unknown/found dead in bed; intracerebral haemorrhage; and fall) did not raise any safety signals.

Analysis of the serious adverse events (SAEs) showed that very few individual SAEs occurred in more than one person at the therapeutic dose: syncope; pneumonia; and UTI were each reported as serious in two patients on 10 mg BID, compared to 0, 0 and 1 patient, respectively, on placebo. The percentages of patients with SAEs were 5.5% and 2.1% for the patients that were treated with Fampyra (10 mg BID) and placebo, respectively. In patients that were treated with Fampyra, the SAEs included chest pain; coronary artery disease; colitis; catheter-related complications; cholelithiases; bacterial pylenephritis; cellulites; influenza; ascetic necrosis bone; spondyltic myelopathy; anxiety; and deep vein thrombosis. In patients treated with placebo, the SAEs included: myocardial infarction; reflux gastritis; chest discomfort; cellulites; and complex partial seizures.