Regeneron Pharmaceuticals, Inc.REGN5458 (linvoseltamab)

BLA 761400 COMPLETE RESPONSE

Regeneron Pharmaceuticals, Inc. Attention: Smita Abbi, PhD Director, Regulatory Affairs

777 Old Saw Mill River Road Tarrytown, NY 10591-6707

Dear Dr. Abbi:

Please refer to your biologics license application (BLA) dated and received December 22, 2023, and your amendments, submitted under section 351(a) of the Public Health Service Act for REGN5458 (linvoseltamab).

We have completed our review of this application, as amended, and have determined that we cannot approve this application in its present form. We have described our reasons for this action below and, where possible, our recommendations to address these issues.

FACILITY INSPECTIONS

1. During a recent inspection of O@ (FEI: ©) listed in this application, FDA conveyed deficiencies to the

representative of the facility. The facility should provide satisfactory responses to these deficiencies to the FDA office indicated on the FDA 483 prior to your complete response to your application. Your complete response should include the date(s) of the facility's response to the FDA Form 483. The assessment of application approvability and the resolution of inspection deficiencies would be evaluated upon receipt of the complete response and may include re-inspection of the facility. Please work with the facility in resolving the related deficiencies.

PRESCRIBING INFORMATION

Submit draft labeling that is responsive to the electronic communication from the FDA dated May 22, 2024. We reserve further comment on the proposed labeling until the application is otherwise adequate.

Prior to resubmitting the labeling, use the SRPI checklist to correct any formatting errors to ensure conformance with the format items in regulations and guidances. In addition,

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submit updated content of labeling [21 CFR 601.14(b)] in structured product labeling (SPL) format as described at FDA.gov.'

To facilitate review of your submission, provide a highlighted or marked-up copy that shows all changes, as well as a clean Word version. The marked-up copy should include annotations that support any proposed changes.

Your proposed Prescribing Information (Pl) must conform to the content and format regulations found at 21 CFR 201.56(a) and (d) and 201.57. As you develop your proposed PI, we encourage you to review the labeling review resources on the Prescription Drug Labeling Resources? and Pregnancy and Lactation Labeling Final Rule? websites, which include:

e The Final Rule (Physician Labeling Rule) on the content and format of the PI for human drug and biological products

e The Final Rule (Pregnancy and Lactation Labeling Rule) on the content and format of information in the PI on pregnancy, lactation, and females and males of reproductive potential

e Regulations and related guidance documents

e Asample tool illustrating the format for Highlights and Contents, and

e The Selected Requirements for Prescribing Information (SRPI) - a checklist of important format items from labeling regulations and guidances.

e FDA's established pharmacologic class (EPC) text phrases for inclusion in the Highlights Indications and Usage heading.

e Additional resources for the Pl, patient labeling, and carton/container labeling.

CARTON AND CONTAINER LABELING

Submit draft carton and container labeling based on our proposed revisions dated June 3, 2024.

1 http://www. fda.gov/Forlndustry/DataStandards/StructuredProductLabeling/default.htm

2 https://www.fda.gov/drugs/laws-acts-and-rules/prescription-drug-labeling-resources

3 httos://www.fda.gov/drugs/labeling-information-drug-products/pregnancy-and-lactation-labeling-drugs- final-rule

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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BLA 761400 Page 3

PROPRIETARY NAME

Please refer to correspondence dated, March 21, 2024, which addresses the proposed proprietary name, Lynozyfic. This name was found conditionally acceptable pending approval of the application in the current review cycle. Please resubmit the proposed proprietary name when you respond to the application deficiencies that have been identified in this letter.

RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS

We acknowledge the submission of your proposed REMS on December 22, 2023, which contains a communication plan, elements to assure safe use, an implementation system and a timetable for submission of assessments of the REMS. We will continue discussion of your proposed REMS after your complete response to this action letter has been submitted.

SAFETY UPDATE

When you respond to the above deficiencies, include a safety update as described at 21 CFR 601.2. The safety update should include data from all nonclinical and clinical

studies/trials of the product under consideration regardless of indication, dosage form, or dose level.

(1) Describe in detail any significant changes or findings in the safety profile.

(2) When assembling the sections describing discontinuations due to adverse events, serious adverse events, and common adverse events, incorporate new safety data as follows:

e Present new safety data from the studies/clinical trials for the proposed indication using the same format as in the original submission.

e Present tabulations of the new safety data combined with the original application data.

e Include tables that compare frequencies of adverse events in the original application with the retabulated frequencies described in the bullet above.

e For indications other than the proposed indication, provide separate tables for the frequencies of adverse events occurring in clinical trials.

(3) Present a retabulation of the reasons for premature trial discontinuation by incorporating the drop-outs from the newly completed trials. Describe any new trends or patterns identified.

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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(4) Provide case report forms and narrative summaries for each subject who died during a clinical trial or who did not complete a trial because of an adverse event. In addition, provide narrative summaries for serious adverse events.

(5) Describe any information that suggests a substantial change in the incidence of common, but less serious, adverse events between the new data and the original application data.

(6) Provide updated exposure information for the clinical studies/trials (e.g., number of subjects, person time).

(7) Provide a summary of worldwide experience on the safety of this product. Include an updated estimate of use for product marketed in other countries.

(8) Provide English translations of current approved foreign labeling not previously submitted.

ADDITIONAL COMMENTS We have the following comments/recommendations that are not approvability issues:

Product Quality

1. You assess size-based product-related impurities using a size exclusion ultra performance liquid chromatography (SE-UPLC) method.

To ensure the suitability of the SE-UPLC method to characterize the purity of linvoseltamab ow ® drug product, you should optimize the SE-UPLC method with adequate resolving power to separate the intact linvoseltamab from known product-related impurities (aggregates and fragments).

Product Quality Microbiolo:

2. m4)

Provide data in your resubmission | specific to each linvoseltamab presentation ]

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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OTHER

Within one year after the date of this letter, you are required to resubmit or take other actions available under 21 CFR 601.3(b)). If you do not take one of these actions, we may consider your lack of response a request to withdraw the application under

21 CFR 601.3(c). You may also request an extension of time in which to resubmit the application.

A resubmission must fully address all the deficiencies listed in this letter and should be clearly marked with "RESUBMISSION' in large font, bolded type at the beginning of the cover letter of the submission. The cover letter should clearly state that you consider this resubmission a complete response to the deficiencies outlined in this letter. A partial response to this letter will not be processed as a resubmission and will not start a new review cycle.

You may request a meeting or teleconference with us to discuss what steps you need to take before the application may be approved. If you wish to have such a meeting, submit your meeting request as described in the draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products.

The product may not be legally marketed until you have been notified in writing that this application is approved.

If you have any questions, contact Laura Wall, Senior Regulatory Project Manager, at

301-796-2237, or email Laura.Wall@fda.hhs.gov. Sincerely, {See appended electronic signature page}

Marc Theoret, MD

Supervisory Associate Director (Acting) Office of Oncologic Diseases

Office of New Drugs

Center for Drug Evaluation and Research

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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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.

MARC R THEORET 08/20/2024 02:54:08 PM

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