Summary Basis of Decision for Onstryv

Clinical Pharmacology

The mechanism through which safinamide (the medicinal ingredient in Onstryv) exerts its therapeutic effect in Parkinson's disease is not known. Safinamide is a highly selective and reversible inhibitor of monoamine oxidase B (MAO-B). By blocking catabolism of dopamine, inhibition of MAO-B is thought to increase extracellular levels of dopamine in the striatum and subsequently increase dopaminergic activity.

Pharmacodynamics

Safinamide inhibits MAO-B activity with more than 1000-fold selectivity over MAO-A. Complete inhibition (>90%) of MAO-B was observed in clinical studies with doses >20 mg. The relative selectivity of safinamide for inhibiting MAO-B activity decreases at doses above the maximum recommended daily dose of 100 mg.

Hepatic impairment

Mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment were shown to increase safinamide exposure (AUC) following a single oral dose of safinamide 50 mg, safinamide exposure (AUC) was increased by 30% and 80%, respectively. The maximum recommended dose for patients with moderate hepatic impairment is 50 mg/day. Safinamide is contraindicated in patients with severe hepatic impairment since the effects of severe hepatic impairment were not studied.

Renal impairment

Neither moderate (estimated glomerular filtration rate [eGFR] of 30 to 59 mL/min inclusive) nor severe (eGFR of <30 mL/min, no dialysis required) renal impairment altered the pharmacokinetics of safinamide. Exposure to pharmacologically inactive safinamide metabolites NW-1153, NW-1689 and NW-1689 acyl glucuronide was increased in patients with moderate and severe renal impairment compared to subjects with normal renal function, with NW-1689 acyl glucuronide showing the most pronounced increase in exposure (approximately 4 to 4.5-fold increase in AUC). The clinical significance of the increase in metabolite exposure with moderate or severe renal impairment is not known.

Pharmacokinetics

Safinamide (the medicinal ingredient in Onstryv) is rapidly absorbed following single and multiple oral dosing, with time to maximum plasma concentration (T_max) ranging between 1.8 and 2.8 hours under fasting conditions. A slight delay in T_max was observed in the fed state relative to the fasted condition, but safinamide's area under the plasma drug concentration time curvefrom time zero to infinity (AUC_0-∞) and the maximum plasma concentration (C_max) were not affected. Safinamide is almost completely absorbed (95% bioavailability) after oral administration, shows extensive extravascular distribution and is approximately 90% bound to plasma proteins. In humans, safinamide is almost completely metabolised, with approximately 5% eliminated as unchanged drug, mainly in urine. Metabolism of safinamide is mediated predominantly by non-microsomal enzymes (uncharacterized cytosolic amidases, monoamine oxidase type A [MAO-A]) and cytochrome P450 enzymes (CYP3A4, CYP2C19, CYP2J2) have a minor role in the overall biotransformation of safinamide. Steady state concentrations are reached in approximately 1 week. The elimination half-life of safinamide is 20 to 26 hours.

Drug interactions

Safinamide has shown limited potential for pharmacokinetic drug-drug interactions. Safinamide does not significantly induce or inhibit CYP iso-enzymes at clinically relevant systemic concentrations. In vitro studies showed that safinamide transiently inhibits intestinal breast cancer resistance protein (BCRP) and based on clinical drug interaction studies with BCRP substrates (diclofenac and rosuvastatin), the potential for increases in BCRP substrate plasma concentrations during concomitant administration with safinamide cannot be excluded.

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

Clinical Efficacy

The efficacy of Onstryv, as an add-on therapy to a stable dose of levodopa alone or levodopa in combination with other Parkinson's Disease medications, was established in two pivotal, Phase III, multinational, randomized, double-blind, placebo-controlled clinical trials conducted over 26 weeks (Study 1 and Study 2).

Studies 1 and 2 were conducted in patients with mid - to late-stage Parkinson's disease who experienced at least 1.5 hours of daily 'OFF time', despite treatment with an optimal dose of levodopa or levodopa derivatives, used alone or in combination with other anti-Parkinson medications (i.e., dopamine agonists, catechol-O-methyl transferase (COMT) inhibitors, anticholinergics, and/or amantadine; use of other monoamine oxidase inhibitors was prohibited).

In both studies, the primary efficacy endpoint was the mean change from baseline to endpoint (Week 24) in total daily 'ON time' without troublesome dyskinesia, based on diaries completed by patients for at least three days before each scheduled assessment. The 'ON time' was defined as time when Parkinson's disease medication was providing benefit with regard to mobility, slowness and stiffness. The 'ON time' without troublesome dyskinesia was defined as 'ON time' without dyskinesia plus 'ON time' with non-troublesome dyskinesia. In both studies the use of rescue medication was permitted, when considered absolutely necessary for the management of worsening PD symptoms.

Study 1

Study 1 compared the efficacy and safety of two fixed doses of Onstryv (50 mg and 100 mg) and placebo as add-on therapy to a stable dose of levodopa alone or levodopa in combination with other Parkinson's disease medications in Parkinson patients with motor fluctuations.

A total of 669 patients were enrolled in the study and began by entering a stabilization phase in which their optimal dose of levodopa was determined and maintained for 4 weeks. In addition, the time to 'end-of dose wearing off' following the patient's morning dose of levodopa, and the total time in the 'OFF phase' during the day (>1.5 hr) was determined, based on daily diary recordings by the patients.

Following the 4-week stabilization phase, patients then had a baseline visit and were randomized (1:1:1) to receive add-on treatment with either Onstryv 50 mg/day (total number of patients [n] = 223), Onstryv 100 mg/day (n = 224) or a placebo (n = 222). Baseline assessments were performed and the patients received their first dose of study medication in the clinic. Patients were dispensed medication and returned for scheduled visits at Weeks 2, 4, 8, 12, 18, and 24 for efficacy and safety assessments. Patients who needed an increase in their anti-Parkinsonian treatments prior to Week 24 (i.e., needed rescue medication) were requested to undergo all Week 24 assessments prior to the intervention and to return for all scheduled assessments up to Week 24. Efficacy data collected after the intervention were excluded from the primary endpoint analysis. Patients who completed 24 weeks of treatment with study medication (Onstryv or placebo) and were eligible, could continue to receive the same treatment (Onstryv or placebo) in a double blind extension study. Patients who were not eligible to continue treatment had their dose tapered over a one-week period before discontinuation (Week 25); a safety follow-up assessment was performed 4 weeks later (Week 29).

Study 2

Study 2 evaluated the efficacy and safety of a dose range of Onstryv (50 mg and 100 mg) compared to placebo as add-on therapy to a stable dose of levodopa in patients with a diagnosis of idiopathic Parkinson's disease with motor fluctuations. The study allowed the inclusion of patients taking the standard therapy of multiple concomitant anti-Parkinsonian medications (not MAO-B inhibitors).

A total of 549 patients were enrolled in the study and began by entering a 4-week levodopa stabilization phase. Following the 4-week stabilization phase, patients then had a baseline visit and were randomized (1:1) to receive either a placebo or Onstryv 50-100 mg/day as add-on treatment to levodopa. All patients initiated treatment with 50 mg/day of study medication and depending on tolerability the dose was to be increased to the target dose of 100 mg/day on Day 14 for the remainder of the study. Patients were dispensed medication and returned for scheduled visits at Weeks 2, 4, 8, 12, 18, and 24 for efficacy and safety assessments. All patients or their caregivers were called on Days 7 and 21 to assess tolerability of the study medication. Patients who needed an increase in their anti-Parkinsonian treatments prior to Week 24 (i.e. rescue medication) were requested to undergo all Week 24 assessments prior to the intervention and to return for all scheduled assessments up to Week 24. Efficacy data collected after the intervention were excluded from the primary endpoint analysis. At the end of the 24-week period, patients that completed the study could continue treatment in an open-label extension study. Those patients who elected not to continue treatment had their dose tapered over a one-week period before discontinuation (Week 25); a safety follow-up assessment was performed 4 weeks later (Week 29).

Efficacy Results from Study 1 and Study 2

The primary efficacy endpoint for both Study 1 and Study 2 was the mean change (increase) from baseline to Week 24 in mean daily 'ON time' ('ON time' without dyskinesia plus 'ON time' with non-troublesome dyskinesia) as recorded in the patient diaries.

Results from both pivotal studies showed a statistically significant greater increase in total daily 'ON time' in patients that were treated with Onstryv as an add-on to levodopa alone or in combination with other anti-Parkinson medications compared to those that received placebo alone or in combination with other anti-Parkinson medications. In Study 1, total daily 'ON time' over the 18-hour diary recording period increased in patients treated with Onstryv 50 mg/day or 100 mg/day by 0.51 hour (p = 0.0223) and 0.55 hour (p = 0.0130), respectively, relative to the increase observed in the placebo group. In Study 2, total daily 'ON time' was increased by 0.93 hour (p<0.001) in the Onstryv group compared to the placebo group. In both studies approximately 4% to 9% of patients received rescue medication and, per the statistical analysis plan, the data collected for these patients following rescue medication intake were not included in the primary efficacy analysis. For both studies multiple pre-specified sensitivity analyses, which included analyses with all data regardless of rescue medication use and analyses using last observation carried forward (LOCF) to impute missing data, confirmed the results of the primary analysis of each study.

Study 1 and Study 2 also had several secondary endpoints. Secondary endpoints which were considered key for the assessment of efficacy included the mean change (decrease) from baseline to endpoint (Week 24) in total daily 'OFF time' reported in patient diaries and mean change from baseline to endpoint (Week 24) in the Unified Parkinson's Disease Rating Scale (UPDRS) Motor Examination subscale (UPDRS Part 3). In both studies the magnitude of the reduction in total daily 'OFF time' with Onstryv relative to placebo was similar to the increase in total daily 'ON time' and statistically significant. There was also a statistically significant greater reduction in the UPDRS Part 3 score from Baseline to endpoint with both doses of Onstryv. All of these efficacy endpoints are standard endpoints that have been used in clinical trials supporting marketing authorization of other anti-Parkinson medications indicated for the treatment of symptoms of Parkinson's disease.

Indication

The New Drug Submission for Onstryv was filed by the sponsor with the following indication:

• Onstryv (safinamide tablets) is indicated for the treatment of adult patients with idiopathic Parkinson's disease as add-on therapy to a stable dose of levodopa (L-dopa) alone or in combination with other Parkinson's disease medicinal products in mid-to late-stage fluctuating patients.

To ensure safe and effective use of the product, Health Canada approved the following indication:

• Onstryv (Safinamide tablets) is indicated as an add-on therapy to a regimen that includes levodopa for the treatment of the signs and symptoms of idiopathic Parkinson's disease in patients experiencing "off" episodes while on a stable dose of levodopa.


• Onstryv has not been shown to be effective as monotherapy for the treatment of Parkinson's disease.

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

Clinical Safety

The safety review was based primarily on the analyses of pooled 24-week safety data derived from Study 1 and Study 2 previously described in the Clinical Efficacy section. Additional safety data were derived from 1) Study 018 (double-blind extension following Study 1), which provided safety data for up to an additional 18 months of Onstryv exposure; 2) an Ocular Safety Report, which included analyses of ocular-related adverse events and ophthalmological examinations that were conducted in clinical trials including early-stage and later-stage patients; and, 3) the results of a thorough QT study (Study 28559).

The review of safety data included a review of several adverse events that were pre-specified as adverse events of special interest. These include adverse events that are known to occur with dopaminergic anti-Parkinson medications (e.g., dyskinesias, melanoma, hallucinations, hypotension), adverse events that are associated with monoamine oxidase (MAO) inhibitor class of drugs (e.g., hypertensive crisis, serotonin syndrome), or adverse events that may be consistent with non-clinical toxicology findings (e.g., hepatic, retinal toxicity, phototoxicity). Sudden onset of sleep, impulse control disorders, and neuroleptic malignant syndrome were not pre-specified by the sponsor as adverse events of special interest but these were also reviewed because they are considered adverse events of special interest for dopaminergic anti-Parkinson medications.

A total of 721 patients were treated with the recommended doses of Onstryv (50 - 100 mg/day) and 497 patients were treated with a placebo in Study 1 and Study 2. Mean and median duration of treatment in the two studies was 22.83 to 23.47 weeks and 24.29 to 24.43 weeks, respectively. In Study 1, most patients were maintained on their assigned dose of Onstryv (50 or 100 mg/day) at all visits from baseline through Week 24 and in Study 2 the mean daily dose was approximately 50 mg/day in the first 2 weeks and >96 mg/day for the remainder of the study. In Study 018, a total of 189, 180 and 175 patients continued treatment with 50 mg/day Onstryv, 100 mg/day Onstryv, and placebo, respectively, for up to an additional 78 weeks (18 months). The mean combined duration of exposure for the 369 patients treated with Onstryv in Studies 1 and 018 was approximately 22 months.

The safety of Onstryv was found to be consistent with what is known for the MAO inhibitor drug class. The most common treatment emergent adverse events in patients that received Onstryv as an add-on therapy to levodopa was dyskinesia. In the 24-week studies treatment emergent dyskinesia adverse events were reported twice as frequently in the Onstryv groups (18% to 21%) compared to the placebo group (9%) and were the most frequently reported adverse events leading to discontinuation of treatment (1.4% of patients in the Onstryv groups versus 0.4% in the placebo group). Most of the other common treatment emergent adverse events were reported in <7% of patients and for most of these adverse events there were no or small differences in the reported frequencies in the Onstryv and placebo groups.

Most of the adverse events of special interest that were reported in the clinical trials that included patients with later stage Parkinson's disease, were reported at low frequencies. Adverse events of special interest that were reported only with Onstryv, or more frequently with Onstryv 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 adverse events (1 or 2 patients with hypersexuality, libido increased, hypomania, obsessive thoughts, restlessness, abnormal thinking), certain retinal adverse events.

Cataract, blurred vision, dry eyes, and conjunctivitis were the most frequently reported ocular adverse events of special interest in Onstryv and placebo groups, with small differences between treatment groups that were not consistent across studies. Some retinal adverse events that were reported only with Onstryv (1 or 2 patients) in the 24-Week studies were also reported during long-term treatment only with Onstryv (few patients) in Study 018 (e.g., retinal degeneration, retinal pigment epitheliopathy, chorioretinal disorder, retinopathy hypertensive).

The assessment of daytime sleepiness using the Epworth Sleepiness Scale did not suggest a meaningful effect of Onstryv on daytime sleepiness in the patients included in Study 1, Study 2, and Study 018. There were no reported adverse events of sleep attack or sudden onset of sleep and somnolence was reported at similar frequencies across treatment groups (approximately 4% to 6%). Sudden onset of sleep and sleep attack adverse events were reported for a small number of patients treated with Onstryv in other clinical studies that included patients with early stage Parkinson's disease.

The analyses of blood pressure and pulse data from Study 1 and Study 2 suggested the potential for clinically significant increases and decreases in blood pressure or pulse in a small proportion of patients during treatment with Onstryv at the recommended doses. The frequencies of treatment emergent adverse events of hypertension, hypotension and orthostatic hypotension were low in all treatment groups, but hypertension and hypotension were each reported more frequently with 50 mg/day than with placebo (7% Onstryv versus 3% placebo for hypertension/increased blood pressure; 2% Onstryv versus 1% placebo for hypotension) and orthostatic hypotension was reported more frequently with both Onstryv doses (2% for each) compared to placebo (1%).

The analyses of electrocardiogram (ECG) data from Study 1 and Study 2 showed small decreases in mean QTc values from Baseline to endpoint in the Onstryv groups. Mean QTcF values decreased by -4.2 and -1.8 msec in the 50 mg/day and 100 mg/day Onstryv groups, respectively, compared to a slight mean increase of 0.6 msec in the placebo group. The main finding from the dedicated thorough QT study (Study 28559) was a QTc interval shortening effect with Onstryv.

Potential safety issues for Onstryv for which the sponsor implemented special monitoring in the Phase III clinical trials included: ocular toxicity due to the retinal toxicity that occurred primarily in pigmented and non-pigmented rats treated with safinamide (the medicinal ingredient in Onstryv); and hypertensive crisis due to the known potential for extreme elevations in blood pressure when tyramine-rich foods are consumed during treatment with MAO inhibitors.

The potential for Onstryv-induced ocular toxicity during clinical use was evaluated through analyses of ocular adverse event data and a comprehensive battery of ophthalmological examinations (i.e., visual acuity, visual fields, color vision, fundus examination) in early and later stage Parkinson's disease patients. Ocular coherence tomography (OCT) to examine changes in the thickness of the retinal nerve fiber layer (RNFL) and macular volume was also done in one study each of early and later stage Parkinson's disease patients (24-week studies). The clinical ocular findings in early and later stage patients suggested that treatment emergent adverse events affecting the retina occurred in few patients overall, but that Onstryv treatment may have been associated with a slightly increased incidence of some of these adverse events (e.g., retinal function abnormal, retinal degeneration, retinal vein occlusion, macular degeneration).

Consuming tyramine-rich foods during treatment with MAO inhibitors can lead to hypertensive crisis. In addition to standard blood pressure monitoring (supine, standing, orthostatic), ambulatory blood pressure monitoring was conducted to evaluate blood pressure (BP) changes in the setting of no dietary restrictions with regard to tyramine in a small subset of patients in Study 2 (n = 28 on Onstryv, n = 23 on placebo) and in a study in early stage PD patients. Ambulatory blood pressure monitoring (ABPM) parameters included systolic BP (SBP), diastolic BP (DBP), heart rate (HR), and mean arterial pressure (MAP). These were measured every 30 minutes starting at 30 minutes prior to ingestion of the main meal of the day and continuing for up to approximately 4 hours after this meal, for 5 consecutive days prior to randomization, and twice during the study for 5 consecutive days each time. The results from one of the studies showed small increases in blood pressure and both studies showed a greater incidence of HR drop in the Onstryv group that may not exclude a post-prandial effect of Onstryv on blood pressure and heart rate, potentially related to an interaction with tyramine-containing foods. A randomized, double-blind, placebo and active comparator controlled clinical trial with healthy subjects (Study 28558), in which Onstryv 100 mg/day and 350 mg/day was administered orally for 16 days with daily tyramine challenges with escalating doses of tyramine beginning on Day 7 (after Onstryv steady state), showed there was a slight Onstryv-induced increase (1.4- and 1.8-fold, respectively) in the tyramine pressor effect relative to placebo. The effect with Onstryv was less than that observed with another MAO-B inhibitor (2.1-fold) or with the control drug phenelzine (6.6-fold).

To reflect the known safety concerns for anti-Parkinson medications and the available safety data for Onstryv, the Onstryv Product Monograph was revised to include: approved class contraindications for MAO inhibitors related to concomitant use of drugs that could result in hypertensive crisis, serotonin syndrome, or episodes of psychosis; MAO inhibitor class warnings for hypertension, hypertensive crisis, interaction with foods containing high amounts of tyramine, serotonin syndrome; anti-Parkinson medication class warnings for neuroleptic malignant syndrome, hallucinations/psychotic behavior, impulse control disorders, melanoma, and sudden onset of sleep (serious warnings and precautions box). A contraindication and warning indicating that Onstryv should not be used in patients with an ophthalmologic history or current condition such as albinism, history of retinal/macular degeneration, family history of hereditary retinal disease, retinitis pigmentosa, any active retinopathy such as diabetic retinopathy, or uveitis were added to the Onstryv PM based on the non-clinical findings of retinal toxicity and some clinical findings suggesting potential retinal effects. 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 Onstryv Product Monograph.

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