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Risk Assessment and Risk Mitigation Review(S) CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 213498Orig1s000 RISK ASSESSMENT and RISK MITIGATION REVIEW(S) Division of Risk Management (DRISK) Office of Medication Error Prevention and Risk Management (OMEPRM) Office of Surveillance and Epidemiology (OSE) Center for Drug Evaluation and Research (CDER) Application Type NOA Application Number 213498 POU FA Goal Date March 18, 2021 OSE RCM # 2020-534 Reviewer Name(s) Carlisha Gentles, PharmD, BCPS Team Leader Jacqueline Sheppard, PharmD Deputy Director Doris Auth, PharmD Review Completion Date March 2, 2021 Subject Eva luation of Need for a REMS Established Name Ponesimod Trade Name Ponvory Name of Applicant Janssen Pharmaceuticals Inc Therapeutic Class Sphingosine 1-phosphate (SlP) receptor modulator Formulation(s) Film-coated tablets: 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg Dosing Regimen Treatment init iation with a 14-day titration (see table), followed by a maintenance regimen of 20 mg orally once daily Treatment init iation titration: Titration Day Daily Dose Day 1 a nd 2 2mg Day 3 a nd 4 3mg Day 5 a nd 6 4mg Day7 Smg Dav8 6mg Day9 7mg Day10 8mg Day ll 9mg Day 12, 13, and 14 10mg 1 Reference ID 4755518 Table of Contents EXECUTIVE SUMMARY ......................................................................................................................................................... 3 1 Introduction ..................................................................................................................................................................... 3 2 Background ...................................................................................................................................................................... 3 2.1 Product Information ........................................................................................................................................... 3 2.2 Regulatory History ............................................................................................................................................... 5 3 Therapeutic Context and Treatment Options .................................................................................................... 5 3.1 Description of the Medical Condition .......................................................................................................... 5 3.2 Description of Current Treatment Options ............................................................................................... 5 4 Benefit Assessment ....................................................................................................................................................... 6 5 Risk Assessment & Safe-Use Conditions .............................................................................................................. 7 5.1 Adverse Events of Special interest ................................................................................................................ 8 5.1.1 Lymphopenia and Infection ................................................................................................................... 8 5.1.2 Bradyarrhythmia ........................................................................................................................................ 8 5.1.3 Liver injury .................................................................................................................................................... 9 5.1.4 Respiratory Effects ..................................................................................................................................... 9 6 Expected Postmarket Use ........................................................................................................................................... 9 7 Risk Management Activities Proposed by the Applicant ............................................................................... 9 8 Discussion of Need for a REMS ............................................................................................................................... 10 9 Conclusion & Recommendations ........................................................................................................................... 10 10 Appendices ................................................................................................................................................................ 10 10.1 References ............................................................................................................................................................. 10 10.2 Treatment Options for Multiple Sclerosis13............................................................................................. 11 2 Reference ID: 4755518 EXECUTIVE SUMMARY This review evaluates whether a risk evaluation and mitigation strategy (REMS) for the new molecular entity Ponvory (ponesimod) is necessary to ensure the benefits outweigh its risks. Janssen Pharmaceuticals Inc submitted a New Drug Application NDA 213498 on March 18, 2020 for ponesimod with the proposed indication for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. The clinical reviewer concluded that ponesimod was effective in treating patients with relapsing forms of multiple sclerosis. There were no treatment related deaths in the clinical trials; however similar to other products in this class of drugs, ponesimod carries the following risks: lymphopenia and infections, bradyarrhythmias, liver injury and respiratory effects. The applicant did not submit a proposed REMS or risk management plan with this application but proposed a medication guide as part of the labeling to align with the other sphingosine-1-phosphate (S1P) receptor modulators. The safety profile of ponesimod is consistent with other approved sphingosine-1-phosphate (S1P) receptor modulators and does not carry additional risks. The Division of Risk Management (DRM) and the Division of Neurology 2 (DN2) agree that a REMS is not necessary to ensure the benefits of ponesimod outweigh its risks for the proposed indication for treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. 1 Introduction This review by the Division of Risk Management (DRM) evaluates whether a risk evaluation and mitigation strategy (REMS) for the new molecular entity (NME) Ponvory (ponesimod) is necessary to ensure the benefits outweigh its risks. Janssen Pharmaceuticals Inc (Janssen) submitted a New Drug Application (NDA) 213498 on March 18, 2020 for ponesimod with the proposed indication for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. This application is under review in the Division of Neurology 2. The applicant did not submit a proposed REMS but proposed a medication guide as part of labeling. 2 Background 2.1 PRODUCT INFORMATION Ponvory (ponesimod), a new molecular entity (NME)a, is a sphingosine-1-phosphate (S1P) receptor modulator proposed for the treatment of relapsing forms of multiple sclerosis (RMS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. The a Section 505-1 (a) of the FD&C Act: FDAAA factor (F): Whether the drug is a new molecular entity. 3 Reference ID: 4755518 exact mechanism of action for therapeutic effects in MS is unknown. Ponesimod binds with high affinity to the SlPl receptor on lymphocytes and blocks the ability of lymphocytes to egress from lymph nodes. This results in reduced lymphocytes circulating in peripheral blood. Ponesimod is proposed to be available as fi lm coated tablets ava il able in 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, and 20 mg strengths. The proposed dosage regimen includes an initial 14-day titration to the maintenance dose of 20 mg orally daily. The proposed t itration is summarized in Table 1. It is proposed to be supplied as a starter pack fo r the initial tit ration and maintenance dose bottles. Ponesimod may be administered in both the outpatient and inpatient settings for chronic therapy fo r MS.b Ponesimod is not currently approved in any jurisdiction. Table 1. Ponesimod Initial Treatment Titration Schedule1 Titration Day Dally Dose Day 1 and 2 2 mg Day 3 and 4 3 mg Day 5 and 6 4 mg Day 7 Smg Day8 6mg Day9 7mg Day 10 8mg Day 11 9mg Day 12, 13, and 14 10mg Source: Adapted from proposed DRAFT prescribing information for ponesimod, NOA 213498 There are three other SlP receptor modulators approved for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. These are Gil enya (fingo li mod), a non-selective SlP receptor modulator; Mayzent (siponimod), which is selective for SlPl and SlPS; and Zeposia (ozanimod), also selective for SlPl and SlPS. Known safety issues with this drug class include infections and lymphopenias, bradyarrhythmias, liver injury, and respiratory risks. The serious risks are similar to those associated with ponesimod and are communicated via labeli ng for the approved agents in this class. Fingoli mod was originally approved with a Communication Plan (CP) REMS
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