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213026Orig1s000 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 213026Orig1s000 OTHER REVIEW(S) IMMUNOGENICITY ASSESSMENT Application Type NDA Application Number 213026 Submit Date 01/10/2020 Received Date 01/10/2020 Division/Office CDER/OND/ON/DNI Review Completion Date 01/10/2021 Product Name Casimersen Proposed Proprie tary AMONDYS 45 Name Error! Bookmark not defined. Pharmacologic Class PMO exon Skipping Applicant Sarepta Therapeutics, Inc. (b) (4) Applicant Proposed Duchenne muscular dystrophy (DMD) in Indication(s) patients who have a confirmed mutation of the DMD gene that is amenable to exon 45 skipping. Immunogenicity Assessors Primary Assessor(s) Seth Thacker PhD Secondary Assessor (s) Daniela Verthelyi PhD MD Assessor Recommendation: The sponsor has submitted data for anti-dystrophin antibodies in the casimersen trials. These data were generated using assays that were developed for assessing anti-dystrophin antibodies in patients treated with eteplirsen and golodirsen and have already been deemed fit for use. The sponsor submitted anti-dystrophin ADA data for Study 4045-101, which had 12 patients enrolled No positive samples were found. The FPR for these assays in Study 4045-101 were 1.3%(IgG), 7.9% (IgE), and 39% (IgM) as calculated by the assessor. The sponsors has not submitted an assay for the detection of Casimersen-specific ADAs or provided a plan on how they assess the risk associated with the generation of novel epitopes in the dystrophin formed by exon 45 skipping. PMRs will be issued to the sponsor to develop and validate the assays and to assess the patients in study 4045-101 and 4045-301 for Abs to the product and to the peptide generated through the exon skipping strategy. Suggested language for the PMRs 1) Anti-dystrophin response: 1 Reference ID: 47519774753420 (b) (4) Evaluate patient immune responses to dystrophin in patients from Study 4045-301 (b) (4) Test samples collected using fully validated anti-dystrophin assays that detect IgM, IgG and IgE antibodies. Provide antibody titers for samples that are positive for antibodies to dystrophin. Assess the impact of immune responses on product pharmacokinetics and clinical efficacy and safety. 2) Anti-casimersen response: a. Develop and validate assays to measure antibodies to Casimersen. The assays should measure IgM, IgG and IgE antibody isotypes. (b) (4) b. Evaluate the samples from patients in Study 4045-101 and Study 4045-301 (b) (4) for antibodies to casimersen. Test samples that are positive for antibodies to casimersen for titer and neutralizing activity using fully validated assays. Until these assays have been fully validated and reviewed by FDA, sufficient samples should be banked and stored under appropriate conditions to allow for retesting as needed. Determine the impact of immune responses on product pharmacokinetics and clinical efficacy and safety. 3) Immunogenicity of novel epitopes induced by exon skipping: Evaluate the immunogenicity of casimersen-induced truncated dystrophin protein. Assess the immunogenicity risk of any novel epitopes that will be present in the casimersen-induced truncated dystrophin protein. This can be done using clinical data, in silico or in vitro assays. If there are novel epitopes that could increase the immunogenicity risk, evaluate the immunogenicity of casimersen- induced truncated dystrophin protein in the corresponding patients treated with casimersen in Study (b) (4) 4045-301 2. Review Document Reviewed Link to Document Submission Date 5.3.5.3 Study SR-19-008, Study SR-19-008 08/19/2020 SR-19-010, and SR-18- SR-19-010 074 SR-18-074 5.3.3.2 Study 4045-101 \\CDSESUB1\evsprod\nda213026\0001\m5\53-clin-stud- 1/10/2020 rep\533-rep-human-pk-stud\5332-patient-pk-init-tol-stud- rep\4045-101\4045-101-immuno-rep.pdf 5.3.3.2 Study 4045-101 \\CDSESUB1\evsprod\nda213026\0001\m5\53-clin-stud- 1/10/2020 rep\533-rep-human-pk-stud\5332-patient-pk-init-tol-stud- rep\4045-101\4045-immuno-tables-list.pdf Immunogenicity Risk Assessment: This immunogenicity risk associated with this product is low. The DP targets an endogenous protein to induce exon skipping and allow a truncated protein to be produced. The exon skipping can create novel epitopes which 2 Reference ID: 47519774753420 could induced an immune response to the newly generated protein. Any immune response that is generated to dystopian would have the potential to induce further muscle damage and reverse any benefit the patient would have received, but there is scientific evidence this occurs naturally in these patatients. The rare disease nature of DMD also means there is a small population of patients making the studies small and the assessment of the immunogenicity risk challenging. Review: The sponsor has submitted three assays in their NDA package for the assessment of anti-dystrophin IgA, IgG, and IgE. These assays have been submitted previously under the NDA 211970 (golodirsen) and they were deemed fit for use. The sponsor also submitted data from Study 4045-101 in which the samples collected from the twelve patients in the study were tested using the anti-dystophin assays. The sponsor reported no positive samples in their study, but due to the small number of patients tested it is difficult to assess if the cut point established in the validation assay is appropriate for this patient population. The sponsor does have a larger study ongoing (4045-301) which will provide more information regarding the potential immunogenicity risk of the product. There is no expectation that the cut points should be different between eteplirsen and golodirsen treated patients and the established cut point should be appropriate for this population as well, but the cut point will need to be confirmed in the study population. The sponsor has not provided any information regarding their plans to address the potential immunogenicity risk of the novel epitopes that could be formed following exon 45 skipping induced by their drug product. The sponsor has not provided any information regarding their plans to address the potential development of anti-Casimersen antibody development, but in the clinical protocol they have detailed the days they will collect serum for immunogenicity testing. Background: Dystrophin: Dystrophin is localized to the inner part of the sarcolemma of muscle fibers where it is associated with other proteins as part of the dystrophin-associated protein complex. Dystrophin is a large protein with three distinct domains. It’s C and N terminal domains play an important role in the interaction with other proteins in the dystrophin associated complex with the middle stalk region is made up of many spectrin repeats. Dystrophin plays an important role in stabilizing the muscle fibre against the mechanical forces of muscle contraction by providing a shock-absorbing connection between the cytoskeleton and the extracellular matrix and is also believed to have a role in signaling. The absence of dystrophin is thought to render muscle cells susceptible to stretch-induced damage and necrosis. Duchenne and Becker’s muscular dystrophy is a fatal X-linked neuromuscular disorder caused by mutations in the DMD gene that disrupt the open reading frame and prevent the full translation of its protein product, dystrophin. Patients develop muscle weakness in the early years of life and lose the ability to walk by their early teens; unless appropriate respiratory and cardiac treatment is initiated, affected individuals typically die before reaching their twenties. The majority of DMD gene mutations are deletions ( 65%) although duplications ( 10%), small mutations ( 22%) and deep intronic mutations ( 2–3%) are also documented. Restoration of the open reading frame and dystrophin production can be achieved by exon skipping∼ using antisense oligonucleotides∼ targeted to splicing elements.∼ This truncated form will contain∼ a shorten stalk region but will still contain the C and N terminal domains. This approach aims to transform the Duchenne muscular dystrophy phenotype to that of the milder disorder, Becker muscular dystrophy, typically caused by in-frame dystrophin deletions that allow the production of an internally deleted but partially functional dystrophin. There is ongoing debate regarding the 3 Reference ID: 47519774753420 functional properties of the different internally deleted dystrophins produced by exon skipping for different mutations; more insight would be valuable to improve and better predict the outcome of exon skipping clinical trials. 4 Reference ID: 47519774753420 Signature Page 1 of 1 -------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. -------------------------------------------------------------------------------------------- /s/ ------------------------------------------------------------ SETH THACKER 02/24/2021 11:18:57 AM DANIELA I VERTHELYI 02/24/2021 11:20:21 AM Reference ID: 47519774753420 FOOD AND DRUG ADMINISTRATION Center for Drug Evaluation and Research Office of Prescription Drug Promotion ****Pre-decisional Agency Information**** Memorandum Date: February 5, 2021 To: Teresa Buracchio, M.D. Division of Neurology 1 (DN1) Mic hael Matthews, MS, RAC, Regulatory Project Manager, (DN1) Tracy Peters, PharmD, Associate Director for Labeling, (DN1) From: Sapna Shah, PharmD, Regulatory Review Officer Office of Prescription Drug Promotion (OPDP)
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