CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 761169Orig1s000 RISK ASSESSMENT and RISK MITIGATION REVIEW(S) Division of Risk Management (DRM) Office of Medication Error Prevention and Risk Management (OMEPRM) Office of Surveillance and Epidemiology (OSE) Center for Drug Evaluation and Research (CDER) Application Type BLA Application Number 761169 PDUFA Goal Date October 25, 2020 OSE RCM # 2020-264 Reviewer Name(s) Elizabeth Everhart, MSN, RN, ACNP Team Leader Naomi Boston, PharmD Acting Deputy Division Doris Auth, PharmD Director Review Completion Date August 10, 2020; date entered into DARRTS, August 20, 2020 Subject Evaluation of Need for a REMS Established Name atoltivimab – odesivimab – maftivimab (REGN-EB3) Trade Name Inmazeb Name of Applicant Regeneron Pharmaceuticals, Inc. Therapeutic Class Human IgG monoclonal antibody Formulation Solution for infusion Dosing Regimen 50 mg of each mAb/kg (3mL/kg) IV (b) (4) × 1 1 Reference ID: 4659652 Table of Contents EXECUTIVE SUMMARY ............................................................................................................................................................3 1 Introduction........................................................................................................................................................................3 2 Background .........................................................................................................................................................................3 2.1 Product Information..............................................................................................................................................3 2.2 Regulatory History .................................................................................................................................................4 3 Therapeutic Context and Treatment Options ......................................................................................................4 3.1 Description of the Medical Condition.............................................................................................................4 3.2 Description of Current Treatment Options .................................................................................................4 4 Benefit Assessment..........................................................................................................................................................5 5 Risk Assessment & Safe-Use Conditions.................................................................................................................6 (b) (4) 5.1 Hypersensitivity Including Infusion-Related ..................................6 5.2 Avoiding Concurrent Administration with Live Vaccines………………………………………………...7 6 Expected Postmarket Use .............................................................................................................................................7 6.1 [Healthcare Setting]...............................................................................................................................................7 7 Risk Management Activities Proposed by the Applicant.................................................................................7 8 Discussion of Need for a REMS...................................................................................................................................8 9 Conclusion & Recommendations...............................................................................................................................8 10 Appendices .....................................................................................................................................................................8 10.1 References..................................................................................................................................................................8 2 Reference ID: 4659652 EXECUTIVE SUMMARY This review evaluates whether a risk evaluation and mitigation strategy (REMS) for the new molecular entity REGN3470-3471-3479 (atoltivimab, odesivimab, and maftivimab), also known as REGN-EB3, is necessary to ensure the benefits outweigh its risks. Regeneron Pharmaceuticals, Inc. submitted a Biologics Licensing Application BLA 761169 for REGN3470-3471-3479 with the proposed indication of treatment of adult and pediatric patients of infection caused by Zaire ebolavirus (EBOV). If approved, REGN-EB3 will be indicated as follows: for the treatment of infection caused by Zaire ebolavirus in adult and pediatric patients, including neonates born to a mother who is RT-PCR positive for Zaire ebolavirus infection. The serious risks associated with REGN-EB3 include hypersensitivity, including infusion- related (b) (4) as well as a recommendation to avoid concurrent administration with live vaccines. Neither of these risks will require a Boxed Warning in the product label. REGN-EB3 will likely be prescribed by healthcare practitioners who have experience in the use of medications to treat EBOV, including monoclonal antibodies and other drugs currently used in clinical trials and/or expanded access protocols. The applicant did not submit a proposed REMS or risk management plan with this application. The Division of Risk Management (DRM) has determined that a REMS is not needed to ensure the benefits of REGN3470-3471-3479 outweigh its risks. EBOV is a serious, life-threatening disease with a high case fatality rate and no approved therapy. While there has been some success in terms of prevention of EBOV with the approval of the Ervebo vaccine, there is still an unmet need for treatment of patients already infected. REGN-EB3 has an acceptable safety profile and was shown to have greater efficacy than the comparator product in the clinical trial with a decrease in mortality over comparator of 17% overall. This decrease in mortality is meaningful and clinically significant in a patient population with a life-threatening disease with currently no approved treatment. 1 Introduction This review evaluates whether a risk evaluation and mitigation strategy (REMS) for the new molecular entity (NME) a REGN3470-3471-3479, referred to as REGN-EB3, is necessary to ensure the benefits outweigh its risks. Regeneron Pharmaceuticals, Inc. submitted a Biologic Licensing Application (BLA) 761169 for REGN-EB3 proposed for adult and pediatric patients for the treatment of infection caused by Zaire ebolavirus (EBOV). If approved, REGN-EB3 will be indicated as follows: for the treatment of infection caused by Zaire ebolavirus in adult and pediatric patients, including neonates born to a mother who is RT-PCR positive for Zaire ebolavirus infection. This application is under review in the Division of Antivirals (DAV). The applicant did not submit a proposed REMS or risk management plan with this application. a Section 505-1 (a) of the FD&C Act: FDAAA factor (F): Whether the drug is a new molecular entity. 3 Reference ID: 4659652 2 Background 2.1 PRODUCT INFORMATION REGN-EB3 is a combination of 3 human immunoglobulin G (IgG) monoclonal antibodies (mAbs) directed against different, non-overlapping epitopes on EBOV glycoprotein (GP). Each mAb, REGN3470 (atoltivimab), REGN3471 (odesivimab), and REGN3479 (maftivimab), is a human mAb (IgG1 isotype). It is supplied as a solution for infusion, proposed to be administered at a dose of 50 mg of each mAb/kg (3mL/kg) IV (b) (4) × 1.b REGN3470-3471-3479 is not currently approved in any jurisdiction. 2.2 REGULATORY HISTORY The following is a summary of the regulatory history for BLA 761169 relevant to this review: 09/03/2019: Breakthrough designation granted 10/15/2019: Applicant informed at pre-NDA meeting that a REMS for REGN-EB3 was likely not needed 02/25/2020: BLA 761169 final submission for adult and pediatric patients for the treatment of infection caused by Zaire ebolavirus received 06/08/2020: A Post Mid-cycle meeting was held between the Agency and the Applicant via teleconference. The Agency informed the Applicant that based on the currently available data, there were no safety issues that require a REMS for REGN-EB3 3 Therapeutic Context and Treatment Options 3.1 DESCRIPTION OF THE MEDICAL CONDITION Ebolavirus is a member of the Filoviridae family and is a single-stranded RNA virus, which includes genus Ebolavirus, as well as Marburgvirus and Cuevavirus; Ebolavirus and Marburgvirus are among the most virulent human pathogensc, the Cuevavirus is only seen in bats. Ebolavirus consists of five subtypes: Zaire, Sudan, Tai Forest, Bundibugyo, and Reston1. The focus of this review will be the Zaire species of Ebolavirus. Zaire ebolavirus (EBOV) has caused many of the large outbreaks in Central Africa since it was first identified in 1976 and the outbreaks are at this time limited to Africa. It was the responsible agent in a 2014-2016 outbreak in West Africa and is also the causative agent in the current epidemic in the Democratic Republic of the Congo (DRC), ongoing since 2018. EBOV has a very high fatality rate of greater than 50% to close to 90% d. Most cases of Ebolavirus occur in Africa, with cases occurring as part b Section 505-1 (a) of the FD&C Act: FDAAA factor (D): The expected or actual duration of treatment with the drug. c Section 505-1 (a) of the FD&C Act: FDAAA factor (B): The seriousness of the disease or condition that is to be treated with the drug. d Section 505-1 (a) of the FD&C Act: FDAAA factor (A): The estimated size of the population likely to use the