CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 213498Orig1s000 SUMMARY REVIEW Summary Review Summary Review Date March 18, 2021 Paul Lee, MD, PhD, Depu ty Director, Division of Neu rology (DN) 2 From Nick Kozauer, MD, Director, DN2 Eric Bastings, MD, Deputy Director, Office of Neu roscience Subject Cross-Discipline Team Leader Summary Review NDA# 213498 Applicant Janssen Pharmaceuticals, Inc. Date of Submission March 18, 2020 PDUFA Goal Date March 18, 2021 Proprietary Name Ponvory Established or Proper Name Ponesimod Dosage Form(s) 2, 3, 4, 5, 6, 7, 8, 9, 10, and 20 mg tablets Treatment of relapsing forms of multiple sclerosis, Applicant Proposed to include clinically isolated syndrome, relapsing- Indication(s)/Population(s) remitting d isease, and active secondary progressive disease, in adults Initiate Ponvory treatmen t w ith a 14 day titration; Applicant Proposed Dosing start with one 2 mg tablet orally once daily, and Regimen(s) p rogress with the titration schedule to a maintenance dose of 20 mg orally once daily. Recommendation on Approval Regulatory Action Recommended As proposed Indication(s)/Population(s) Recommended Dosing As proposed Regimen(s) (if applicable) 1 Reference ID 4764774 Summary Review 1. Benefit-Risk Assessment Benefit-Risk Assessment Framework Benefit-Risk Integrated Assessment Ponvory (ponesimod) is a sphingosine-1-phosphate (S1P) receptor modulator that binds selectively to S1P1 receptors and is proposed by the applicant as a treatment for relapsing forms of multiple sclerosis (MS). There are three S1P modulators approved for the treatment of relapsing forms of MS. Gilenya (fingolimod) binds to S1P receptors nonspecifically. Mayzent (siponimod) and Zeposia (ozanimod) are selective for the S1P1 and S1P5 receptor subtypes. All three S1P modulators approved to treat relapsing forms of MS reduce the frequency or likelihood of patients with MS experiencing a relapse; fingolimod and siponimod have a significant effect on the prevention of MS-associated disability. Relapsing forms of MS, which include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease (secondary progressive MS with relapses), are phenotypes of the chronic and potentially disabling central nervous system disease of apparent autoimmune etiology termed “multiple sclerosis.” In the relapsing forms of MS, patients experience episodes of focal neurological deficits and disseminated lesions of demyelination within the brain. Symptoms of relapsing forms of MS commonly include recurrent paroxysms of diminished sensory or motor function that can be disabling and usually resolve within one month. Over time, many, but not all, patients with relapsing forms of MS experience some degree of persistent disability that may gradually worsen over years. There are nineteen unique therapies approved for the treatment of relapsing forms of MS, and all share a basic common feature of modifying the immune response. Ponesimod will be the fourth approved therapy in the class of S1P modulator therapies. The other approved S1P modulators (fingolimod, siponimod, and ozanimod) approved for the treatment of relapsing forms of MS have been shown to be effective in significantly reducing the frequency of patients’ relapses. All S1P modulators with established efficacy in reducing relapses bind to the S1P1 receptor, which is the predominant S1P receptor expressed on lymphocytes and cardiac cells; ponesimod would represent the only treatment in this class that does not bind at any other S1P receptor subtypes. The precise mechanism of action by which S1P modulators exert their therapeutic effects in patients with MS is unknown. The applicant presents the results from an adequate and well-controlled clinical trial (Study AC-058B301) as the basis of support for the effectiveness of ponesimod for the treatment of relapsing forms of MS. Study AC-058B301 was a prospective, multicenter, 1133-patient, double- blind, active-controlled, randomized, double-blind, superiority study to evaluate the effectiveness, safety, and tolerability of ponesimod 20 mg daily compared to Aubagio (teriflunomide) 14 mg daily in patients with relapsing forms of MS. The primary efficacy endpoint of Study AC­ 058B301 was the annualized relapse rate (ARR), defined as the number of confirmed relapses that occurred per patient-year. Secondary 2 Reference ID: 4764774 Summary Review endpoints included the change in the Fatigue Severity Impact Scale-Relapsing Multiple Sclerosis (FSIQ-RMS) score assessment, magnetic resonance imaging outcome measure of combined unique active lesions (CUAL) (comprising new or enlarging T2 lesions and number of gadolinium-enhancing T1 lesions), and confirmed disability accumulation at 3 and 6 months. In Study AC-058B301, treatment with ponesimod resulted in a statistically significant (p<0.0003) reduction in ARR compared to treatment with teriflunomide. Compared with teriflunomide, the relative reduction in ARR with ponesimod was 30.5%. There was a statistically significant, but not interpretable as clinically meaningful, relative decrease of approximately 3.5 points compared to teriflunomide treatment in a patient reported fatigue instrument, the FSIQ-RMS score, for patients treated with ponesimod at Week 108 of the trial. Several factors, including inadequate anchoring, missing data, and uncertainty regarding teriflunomide’s treatment effect on fatigue, rendered the FSIQ-RMS finding uninterpretable. The numbers of T1 gadolinium-enhancing and new or enlarging T2 lesions in the ponesimod treatment group were reduced by 56% (p<0.0001) relative to teriflunomide. An analysis of disability progression at 3-months did not show a statistically significant treatment difference between the ponesimod and teriflunomide treatment groups indicating that ponesimod was not superior to an active comparator which has an established treatment effect on disability outcomes. The reliance on a single trial as the basis for an approval is justified because this single Phase 3 trial was a large, multicenter, international trial with a highly-statistically significant finding consistent across trial sites and subgroups on a clinically meaningful endpoint, a reduction in the likelihood of experiencing a disabling relapse. The safety profile of ponesimod is consistent with that of the other approved S1P modulators. As is the case with all S1P modulators, ponesimod reduces heart rate and can cause atrioventricular conduction delays; because of the potential for inducing serious arrhythmias, ponesimod should be titrated to its maintenance dose. However, given the relatively mild reduction in heart rate and the lack of serious adverse events associated with first dose administration that were observed in clinical studies, first dose monitoring in a medical setting is not required for most patients initiating ponesimod treatment. Based on clinical trial findings in patients with MS, patients treated with ponesimod are at risk for infections, macular edema, increased serum liver transaminases, hypertension, cutaneous malignancies, and respiratory effects consistent with a restrictive airway disease. Progressive multifocal leukoencephalopathy, posterior reversible encephalopathy syndrome, and severe exacerbations in disability after discontinuation are assumed risks associated with all S1P modulator therapies and will be included as labeled risks, even though these adverse events were not observed in ponesimod’ s clinical trials likely due to inadequate long-term exposure. The overall benefit-risk profile of ponesimod appears similar to that of the other three S1P modulator therapies approved for the treatment of relapsing forms of MS, and supports approval for the treatment of relapsing forms of MS. The first dose of ponesimod appears to be safe to administer to most patients outside of a monitored medical setting. The safety profile of ponesimod otherwise conforms to the established safety issues identified with the other approved S1P modulators, such as increased risk of lymphopenia, infections, liver transaminase increases, restrictive airway symptoms, hypertension, and cutaneous malignancies. Based on findings suggesting that strong PXR agonists may reduce ponesimod exposure, a post-marketing commitment for a drug-drug interaction study is necessary to clarify whether co-administration of ponesimod with strong PXR agonists reduces circulating serum levels to an extent that may reduce efficacy. Enhanced pharmacovigilance will be requested to evaluate for serious or fatal infections, malignancies, thromboembolic events, and for symptoms consistent with abuse potential. 3 Reference ID: 4764774 Summary Review Benefit-Risk Dimensions Dimension Evidence and Uncertainties Conclusions and Reasons • Relapsing forms of MS, which include clinically isolated Relapsing forms of MS are serious and syndrome, relapsing-remitting disease, and active secondary disabling. progressive disease (SPMS with relapses), are phenotypes of the chronic and potentially disabling central nervous system disease The defining symptom of relapsing fom1s multiple sclerosis, a disease of apparent autoimmune etiology of MS are paroxysms of focal neurological which in its relapsing form is characterized by episodes of deficits termed "relapses", which can be worsening focal neurological deficits and disseminated lesions temporarily disabling, and reduce quality representing demyelination. of life. .......... The usual age of onset of relapsing forms of MS is 20 to 50 years .