Regulatory Decision Summary for Onstryv

Because the motor symptoms of Parkinsons disease (PD) are largely related to degeneration of the dopaminergic nigrostriatal system and depletion of dopamine, the mainstay of treatment for the motor symptoms of PD is drugs that increase dopamine levels in the brain, with levodopa being the most effective treatment for motor symptoms. Motor fluctuations are characterized by ON time, when antiparkinson medication provides benefit with regard to mobility, slowness, stiffness, and OFF time, when antiparkinson medication is not working well. Once motor fluctuations develop it often becomes necessary for a patients treatment regimen to include levodopa and a combination of other antiparkinson medications such as dopamine agonists, monoamine oxidase Type B (MAO-B) inhibitors, a catechol-O-methyltransferase inhibitor and/or amantadine.

Onstryv (safinamide) is a new chemical entity that acts as a selective and reversible inhibitor of MAO-B. The efficacy of safinamide 50 mg/day and 100 mg/day for the treatment of signs and symptoms of idiopathic Parkinsons disease (PD) was demonstrated in two Phase 3, randomized, double-blind, placebo controlled clinical trials in which safinamide was used as an adjunctive therapy to a treatment regimen that included levodopa, in patients experiencing OFF episodes while on a stable dose of levodopa. In the clinical trials, patients were treated for 24 weeks with either placebo, 50 mg/day safinamide or 100 mg/day safinamide. The primary efficacy endpoint was the mean increase from baseline at endpoint (24 weeks) in total daily ON time, which was defined as ON time without dyskinesia plus ON time with non-troublesome dyskinesia, as reported over an 18-hour period in daily patient diaries. In both studies there was a statistically significant greater mean increase in total daily ON time in the patients that received safinamide (50 mg/day or 100 mg/day) as adjunct to levodopa alone or levodopa in combination with other antiparkinson medications compared to those that received placebo as adjunct. ON time was increased by approximately 0.5 hour in one study and 0.9 hour in the other study. In both studies the mean reduction in total daily OFF time from baseline to endpoint and mean improvement in the motor examination subscale (Part 3) score of the Unified Parkinsons Disease Rating Scale (UPDRS) from baseline to endpoint were also greater in patients that received safinamide compared to those that received placebo.

Overall, the safety profile of safinamide is consistent with that of the MAO inhibitor drug class and with that of other dopaminergic antiparkinson medications. The known risks associated with these drugs are mitigated for safinamide by incorporating in the Onstryv Product Monograph (PM) approved class contraindications and class warnings for MAO inhibitors as well as antiparkinson medication class warnings. The most common treatment emergent adverse event (AE) in patients that received safinamide as adjunct to levodopa was dyskinesia, which was reported twice as frequently in the safinamide groups (18%-21%) compared to the placebo group (9%). Dyskinesia was also the most frequently reported AE leading to discontinuation of treatment (1.4% of patients in the safinamide groups vs 0.4% in the placebo group).

Several types of AEs of special interest which are known to occur with dopaminergic antiparkinson medications (e.g., dyskinesia, melanoma, hallucinations, hypotension, impulse control disorders, sudden onset of sleep, neuroleptic malignant syndrome), AEs that are associated with the MAO inhibitor class of drugs (e.g., hypertensive crisis, serotonin syndrome), or AEs that may be consistent with nonclinical toxicology findings (e.g., hepatic, retinal toxicity, phototoxicity) were evaluated in the safinamide clinical trials. Adverse events of special interest that were reported only with safinamide or more frequently with safinamide than placebo included: hypertensive crisis (1 patient), serotonin syndrome (1 patient on concomitant fluoxetine during long-term treatment), neuroleptic malignant syndrome (1 patient during long-term treatment), potential impulse control AEs (1 or 2 patients with hypersexuality, libido increased, hypomania, obsessive thoughts, restlessness, abnormal thinking). Sudden onset of sleep and sleep attacks were not reported in the studies with the target population but were reported in the 24-week Phase 3 studies involving patients without motor fluctuations that were treated with safinamide or placebo as adjunct to a single dopamine agonist.

Due to the key nonclinical finding of safinamide-induced retinal degeneration in pigmented and non-pigmented rats, comprehensive ophthalmological monitoring was conducted in several Phase 3 clinical trials. The most common treatment emergent ocular-related AEs were cataract, vision blurred, dry eyes, and conjunctivitis, with no consistent trend of a higher frequency of these AEs in patients treated with safinamide. Treatment emergent AEs affecting the retina occurred in few patients overall, but safinamide treatment may have been associated with a slightly increased incidence of some of these AEs (e.g., retinal function abnormal, retinal degeneration, retinal vein occlusion, macular degeneration). A consistent observation from the ocular coherence tomography (OCT) that was done in two 24-week studies was a very small mean decrease in the retinal nerve fiber layer (RNFL) thickness in the safinamide group (100mg/day). Changes reported in the placebo groups in these studies were difficult to interpret but, the consistent small mean reductions observed in the patients treated with 100 mg/day safinamide suggests that a relationship to safinamide treatment cannot be entirely excluded at this time. To address the uncertainty of the clinical relevance of these ocular findings, the PM includes a contraindication and warning indicating that safinamide should not be used in patients with an ophthalmologic history or current condition and that patients should be monitored periodically for vision changes, with special attention to the retina. Ophthalmologic safety and retinal degeneration will remain a subject of special interest for post-market reports of AEs and the sponsor has commitments to use targeted questionnaires for collecting information from spontaneous cases.

Due to the QTc interval shortening effect observed in the thorough QTc study, a warning recommending caution for use in patients with congenital short QT syndrome has also been incorporated into the PM.

Because moderate hepatic impairment resulted in an 80% increase in safinamide exposure, the maximum recommended dose for patients with moderate hepatic impairment is 50 mg/day. Most of the risks associated with safinamide are related to its pharmacological actions as a MAO inhibitor and increases in dopaminergic tone, which are risks that are associated with other approved antiparkinson medications and which are mitigated through labelling in the PM. Based on the available safety data, at this time, the main uncertainty for safinamide is the extent to which there may be clinically significant adverse effects on the retina and this uncertainty has been addressed in the PM with a contraindication, warning and inclusion of the nonclinical findings. The efficacy of safinamide did not show a relationship to dose and the safety profile did not consistently show a dose effect.

For more information on Health Canadas decision, please view the Summary Basis of Decision.