Regeneron Pharmaceuticals, Inc.odronextamab

BLA 761303/Original 2 COMPLETE RESPONSE

Regeneron Pharmaceuticals, Inc. Attention: Hsiao-Chi Lo, PhD Director, Regulatory Affairs

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

Dear Dr. Lo:

Please refer to your biologics license application (BLA) oe

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for (odronextamab).

We have administratively designated your application as follows:

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The subject of this Complete Response letter is for BLA 761303/Original 2.

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.

CLINICAL

(1) The Agency has determined that a confirmatory trial is required to be underway for odronextamab for large B-cell lymphoma (LBCL) prior to approval.’ However, a confirmatory trial in LBCL with odronextamab is not considered to be underway. oe , you had enrolled |) patients in the dose-finding portion of OLYMPIA-3, and a patients have been enrolled in the confirmatory portion of the trial. Additionally, the current conduct of OLYMPIA-3 and projected

1 Federal Food, Drug, and Cosmetic Act (FD&C Act) sections 506(c)(2)(A)(i) and (D)

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completion date do not provide sufficient assurance of timely completion of the rial.

To support resubmission of the BLA, you must address this deficiency. After enrollment and analysis of Part 1 (dose-finding) is completed, we recommend hat you request a meeting with the Agency to discuss trial benchmarks (e.g., enrollment goals, site activation, proportion of primary endpoint events accrued, rial completion date) to allow measurement of the progress of the trial. You should demonstrate in your submission that your milestones are appropriate and hat, prior to approval, you will demonstrate sufficient progress in the conduct of he confirmatory portion of the confirmatory trial to provide sufficient assurance of imely completion of the trial.

PRESCRIBING INFORMATION

We reserve comment on the proposed labeling until the application is otherwise adequate. We encourage you to review the labeling review resources on the Prescription Drug Labeling Resources? and Pregnancy and Lactation Labeling Final Rule? websites, including regulations and related guidance documents and the Selected Requirements for Prescribing Information (SRPI) - a checklist of important format items from labeling regulations and guidances.

If you revise labeling, use the SRPI checklist to ensure that the Prescribing Information conforms with format items in regulations and guidances. Your response must include updated content of labeling [21 CFR 601.14(b)] in structured product labeling (SPL) format as described at FDA.gov.4

CARTON AND CONTAINER LABELING

We reserve comment on the proposed labeling until the application is otherwise adequate.

MEDICATION GUIDE

We reserve comment on the proposed Medication Guide until the application is otherwise adequate.

PROPRIETARY NAME

Please refer to correspondence dated, , which addresses the proposed proprietary name, —_. This name was found conditionally acceptable pending approval of the application in the current review cycle. Please resubmit the

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

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

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

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

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BLA 761303/Original 2 Page 3

proposed proprietary name when you respond to all of the application deficiencies that have been identified in this letter.

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.

(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.

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

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(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

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.

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

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ou ae ee,

Sincerely,

{See appended electronic signature page}

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

Reference ID: 5352255

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.

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03/22/2024 05:50:10 PM

Reference ID: 5352255