Regulatory Decision Summary for Vyalev

This New Drug Submission (NDS) was filed to obtain market authorization for Vyalev (foslevodopa/foscarbidopa) for the treatment of motor fluctuations in patients with advanced Parkinson’s disease. After review, Vyalev was recommended for the treatment of motor fluctuations in patients with advanced levodopa-responsive Parkinson’s disease who do not have satisfactory control of severe, debilitating motor fluctuations and hyper-/dyskinesia despite optimized treatment with available combinations of Parkinson’s medicinal products.

To support the New Drug Submission (NDS), the sponsor submitted one pivotal study and three supportive open-label (OL) studies to demonstrate safety and efficacy in patients with advanced Parkinson’s disease (aPD). The design of the pivotal study was considered adequate and used well-known and validated endpoints, as well as appropriate statistical analyses.

The efficacy was mainly supported by a Phase 3, randomized, double-blind, double-dummy, active-controlled, multicenter clinical trial. The main objective was to demonstrate superiority of Vyalev over oral levodopa (LD) therapy for the treatment of motor fluctuations in subjects with aPD following 12 weeks of treatment. The study included 141 subjects with 74 randomized to continuous subcutaneous infusion of Vyalev plus oral placebo capsules and 67 randomized to continuous subcutaneous administration of placebo solution plus oral LD therapy. The Vyalev group demonstrated a statistically significant and clinically meaningful improvement in ON time without troublesome dyskinesia (primary efficacy endpoint) compared with the oral LD therapy (+1.75 hours [h] least squares [LS] mean of difference). Similarly, the Vyalev group demonstrated a statistically significant and clinically meaningful reduction in the OFF time (the first key secondary endpoint) compared with the oral LD therapy (-1.79h LS mean of difference). Additionally, subjects treated with Vyalev also had reduced morning akinesia (third key secondary endpoint) compared with oral therapy, as 79% of the subjects reported morning akinesia at baseline compared to 17% at Week 12. However, this third key secondary endpoint could not be considered statistically significant due to failing of the second key secondary endpoint (motor components of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale [MDS-UPDRS]) and the hierarchical statistical testing procedure to control for type I error.

The efficacy was also supported by an ongoing Phase 3, open-label (OL), single-arm study which, as of the filing date, included 244 subjects with aPD. The primary endpoints were all safety-related and the secondary endpoints included several efficacy evaluations. Statistically significant differences from baseline mean value and clinically meaningful improvements were observed in ON (+3.58h) and OFF (-3.39h) times at Week 52. In addition, there were two 96-week, OL, extension studies that aimed at assessing the long-term safety and tolerability of Vyalev. In both studies, stable ON and OFF times were observed. Despite the limited data collected as of the filing date in the extension studies, the data showed sustained efficacy of Vyalev in improving the motor fluctuations in patients with aPD.

The safety profiles of LD and carbidopa (CD) have been extensively described over more than 50 years of use for the treatment of motor symptoms associated with PD. Vyalev prodrugs are rapidly converted to LD and CD and therefore, most of their known safety risks apply to Vyalev and were observed in the clinical trials. The major differences with Vyalev lie in the subcutaneous route of administration as well as with the higher daily dose of LD due to the 24h administration.

A limited number of patients were exposed to Vyalev over the clinical development, and it was of concern that the data included in the submission (146 subjects exposed to Vyalev for 6 months) did not meet the International Council for Harmonisation (ICH) E1 (300-600 subjects for 6 months). Rates of adverse events (AEs) were similar between the pooled OL trials (87%) and the pivotal trial (85.1% ABBV-951 group) but slightly lower in the oral group of the pivotal trial (67.2%). Serious AEs were reported more frequently in the OL trials, but this was attributed to the longer duration of the OL trials (52 and 96-week trials compared to 12-week trial). Infusion site reactions and infections were the most reported adverse reactions in the four clinical trials. Infusion site reactions were reported in 68% of all subjects included in an OL trial as well as in 62.2% of the subjects exposed to Vyalev and 7.5% of the subjects exposed to oral therapy (plus placebo subcutaneous infusion) in the pivotal trial. Similarly, infection rates were high and reported in 32.3% of subjects included in the pooled analysis of the three OL trials as well as in 28.4% and 3% of the subjects exposed to Vyalev or to oral therapy in the pivotal trial. Despite most of the reactions being qualified as mild or moderate, in three cases the infection led to sepsis or metabolic encephalopathy which required hospitalization. The cause of these infusion site reactions and infections was likely multifactorial but not limited to the insertion technique since the patients included in the oral therapy group, that also used the pump for placebo solution infusion, had significantly fewer infusion site reactions and infections. Although the risk of hallucinations and psychosis are well-known risks associated with LD and dopamine agonists, the rates of hallucinations were high in subjects exposed to Vyalev in all Phase 3 studies. In the pooled analysis of the OL trials, 20.7% of the subjects reported hallucinations/psychosis while in the pivotal trial, those rates were of 14.9% in the ABBV-951 group and 3% in the oral group. Polyneuropathy, another important safety risk associated with continuous LD therapy, was reported in 8.2% of the subjects overall in the four Phase 3 clinical trials. Polyneuropathy AEs were generally consistent with neuropathy peripheral, decreased vibratory sense, neuralgia, sensory disturbance, and sensory loss.

Despite not being essential for market authorization, given the rapid conversion of fosLD and fosCD into LD and CD, safety information included in LD drug products was included in the Vyalev Product Monograph (PM) to ensure that it contains known information that may be relevant to the optimal, safe, and effective use of Vyalev. This included a strengthened indication, the addition of several contraindications (narrow-angle glaucoma, uncompensated diseases, melanoma, etc.), a serious warnings and precautions box (sudden onset of sleep,) and several warnings (presence of hydrazine, polyneuropathy, hallucinations, etc.). Considering the potential for life-threatening complications associated with infusion site reactions and infections, safety information detailing the risk and mitigation strategies was added to the serious warnings and precautions box. In addition, a Patient Guide further describing the risks of infusion site reactions and infections and how to mitigate the risks was requested from the sponsor and will be implemented upon finalizing the PM.

The benefit-harm-uncertainty profile for Vyalev was considered acceptable for the treatment of motor fluctuations in patients with advanced LD-responsive PD when used under the conditions described in the approved PM.

For further details about Vyalev, please refer to the PM, approved by Health Canada and available through the Drug Product Database.