Tanvex BioPharma USA, Inc.TX01

BLA 761126 COMPLETE RESPONSE

Tanvex BioPharma USA, Inc.

Attention: Bonnie J. Mills, PhD

Vice-President, Clinical Development & Regulatory Affairs 2030 Main Street, Suite 600

Irvine, CA 92614

Dear Dr. Mills:

Please refer to your biologics license application (BLA), dated and received September 28, 2018, and your amendments, submitted under section 351(k) of the Public Health Service Act for TX01.

We acknowledge receipt of your amendment dated November 20, 2020, which constituted a complete response to our September 24, 2019, action letter.

We also acknowledge receipt of your amendment dated May 3, 2021, which was not reviewed for this action. You may incorporate applicable sections of the amendment by specific reference as part of your response to the deficiencies cited in this letter.

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.

PRODUCT QUALITY Facility Inspections

1. Following an evaluation of the last inspection performed at Tanvex BioPharma, Inc. (FEI: 3013021112) manufacturing facility at 10394 Pacific Center Court, San Diego, CA 92121 for this application, our field investigator observed objectionable conditions at the facility and conveyed that information to the representative of the facility at the close of the inspection. Satisfactory resolution of the remaining objectionable conditions, and verification by the FDA, is required before this application may be approved.

We will continue to monitor the public health situation as well as travel restrictions. We are actively working to define an approach for scheduling outstanding inspections, once safe travel may resume and based on public health need and other factors.

Reference ID: 4798988

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For more information, please see the FDA guidances related to COVID 19. These guidances can be found at htips://www.fda.gov/emergency-preparedness- and-response/coronavirus-disease-2019-covid-19/covid-19-related-quidance- documents-industry-fda-staff-and-other-stakeholders.

2. During a recent inspection of the on

facility, our field investigator observed objectionable conditions at the facility and conveyed that information to the representative of the facility at the close of the inspection. Satisfactory resolution of the observations is required before this BLA may be approved.

Comparative Analytical Assessment

3. The Agency’s evaluation of the January 27, 2020, third party Analytical Similar Assessment Data Review Report identified several issues regarding data omission in the analysis of G-CSF receptor binding by SPR © assay) as indicated in the March 15, 2021 Information Request (IR). Your March 19, 2021 IR response did not adequately address the following issues, impacting the reliability of the data provided to demonstrate that TX01 is highly similar to U.S.- licensed Neupogen:

(b) (4)

In addition, in Complete Response (CR) comment 2b in the CR letter dated September 24, 2019, issues were raised regarding data omission for the competitive binding ELISA assay. In the response to the March 15, 2021 IR, you provided a list of all the runs and samples that were excluded from the analysis. However, inadequate justification was provided for the exclusion of data with binding ratios

®® and replicates that do not appear to be identical. Given the number of runs with binding ratios " there is a concern that the method was not sufficiently qualified for its intended use.

Overall, these issues raise concerns regarding the quality of the data from G-CSF receptor binding analysis by SPR and competitive binding analysis by ELISA

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

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BLA 761126 Page 3

submitted to support the comparative analytical assessment between TX01 and U.S.-licensed Neupogen. Therefore, at this time, there is insufficient information to make a determination that TX01 is highly similar to U.S.-licensed Neupogen notwithstanding minor differences in clinically inactive components. To address these issues, reliable data collected using binding assays that have been demonstrated to be fit for their intended use are needed to support the comparative evaluation of G-CSF receptor binding affinity between TX01 and U.S.-licensed Neupogen. The analysis should include lots of the proposed TX01 commercial material and TX01 lots used in the clinical studies. If TX01 lots from the clinical studies are not available, TX01 material representative of the clinical process may be acceptable with appropriate justification.

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 PLR Requirements for Prescribing Information’ 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. In addition, we encourage you to review the FDA guidance for industry Labeling for Biosimilar Products.

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.3

CARTON AND CONTAINER LABELING

We acknowledge receipt of your proposed container label and carton labeling dated November 20, 2020. We reserve comment on the proposed container label and carton labeling until the application is otherwise adequate.

PROPRIETARY NAME

Please refer to correspondence dated February 12, 2021, which addresses the proposed proprietary name, NYPOZI. This name was found acceptable pending

’ http:/Awww.fda.gov/Drugs/GuidanceComplianceRequlatoryInformation/LawsActsandRules/ucm08415 9.htm

2 http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm09330 Zhtm

3 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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approval of the application in the current review cycle. Please resubmit the proposed proprietary name when you respond to the application deficiencies. SAFETY UPDATE

When you respond to the above deficiencies, include a safety update. The safety update should include data from all nonclinical and clinical studies 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 and their relevance, if any, to whether there may be clinically meaningful differences between the proposed biosimilar product and the U.S.-licensed reference product.

. 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 clinical studies for the proposed indication using the same format as the original BLA submission.

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

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

Present a retabulation of the reasons for premature study discontinuation by incorporating the drop-outs from the newly completed studies. Describe any new trends or patterns identified.

Provide case report forms and narrative summaries for each patient who died during a Clinical study or who did not complete a study because of an adverse event. In addition, provide narrative summaries for serious adverse events.

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 BLA data.

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

Provide a summary of worldwide experience on the safety of this product, including adverse events known to be associated with the use of the product and immunogenicity. Include an updated estimate of use for this 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:

Drug Substance

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

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Drug Substance and Drug Product Manufacturing

Reference Standard

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

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(b) 4)

Microbiology

19. Provide bioburden method qualification with three lots “

20. Provide a low endotoxin recovery study performed with two additional drug product lots.

21.Repeat the rabbit pyrogen test with the highest dose of TX01 drug product used in humans.

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 Biosimilar Biological Product Sponsors or Applicants.

The drug 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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If you have any questions, contact Brittany Garr-Colon, MPH, Regulatory Project Manager, at (301) 796-6153 or via email at Brittany.Garr-Colon@fda.hhs.gov.

Sincerely,

{See appended electronic signature page}

Albert Deisseroth, MD, PhD

Supervisory Associate Director

Division of Nonmalignant Hematology

Office of Cardiology, Hematology, Endocrinology, and Nephrology

Center for Drug Evaluation and Research

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

Reference ID: 4798988

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.

ALBERT B DEISSEROTH 05/20/2021 07:26:23 PM

Reference ID: 4798988