Clarus Therapeutics, Inc.testosterone undecanoate (TU) (oral)

NDA 206089 COMPLETE RESPONSE

Clarus Therapeutics, Inc. Attention: Robert E. Dudley, Ph.D. President and CEO

555 Skokie Blvd., Suite 340 Northbrook, IL 60062

Dear Dr. Dudley:

Please refer to your New Drug Application (NDA) dated and received, January 3, 2014, and your amendments, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for testosterone undecanoate (TU) (oral).

We acknowledge receipt of your amendment dated June 22, 2017, which constituted a complete response to our November 3, 2014, action letter.

We acknowledge receipt of your major amendments dated September 20 and 25, 2017, which extended the goal date by three months.

We also acknowledge receipt of your amendment dated February 27, 2018, which was not reviewed for this action. You may incorporate applicable sections of this 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.

Deficiencies:

1. Jatenzo causes clinically meaningful increases in blood pressure. For example, on ambulatory blood pressure monitoring (ABPM) there was a daytime average systolic blood pressure (SBP) increase of 5.0 mmHg and a larger increase among subjects with hypertension. In comparison, the daytime average SBP change from baseline in the concurrent comparator group (Topical Axiron) was -0.1 mmHg. Further, in the Jatenzo group, 7.2% of subjects in the Safety Population started antihypertensive medications after baseline or required an antihypertensive dose increase, compared to 1.8% of subjects in the Topical Axiron group. These BP changes, with a chronically administered drug such as Jatenzo, will increase the risk of major cardiovascular adverse events, including myocardial infarction, stroke and

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cardiovascular death, and would not necessarily be detected in routine clinical practice nor prompt initiation or intensification of antihypertensive therapy. These risks outweigh the benefits of Jatenzo among many men who are already at increased risk of cardiovascular disease.

Information Needed to Resolve Deficiency #1

In your resubmission, propose detailed strategies in labeling (including proposals for a Boxed Warning, Indication, Contraindication, and Warnings and Precautions) and strategies beyond labeling, such as a Risk Evaluation and Mitigation Strategy (REMS) with elements to assure safe use, together with an ssment of how your proposal will mitigate the risks and ensure a favorable benefit/risk profile. We will determine whether your proposed strategies can ensure that the benefits outweigh the risks after a complete review of your resubmission.

2. You propose to monitor patients treated with Jatenzo using total testosterone (T) concentrations from plasma in sodium fluoride (NaF)/ethylenediaminetetraacetic acid (EDTA) tubes instead of serum in plain tubes. You state that the NaF/EDTA tubes prevent TU to T ex vivo conversion, and you report higher T concentrations from serum in plain tubes compared to T concentrations from plasma in NaF/EDTA. tubes in Jatenzo-treated subjects. However, serum and NaF/EDTA samples were held at different temperatures after collection and each sample type was analyzed using different LC-MS/MS methods. You have not assessed the extent to which these factors contributed to the observed differences between sample types. In addition, based on the limited data submitted, the extent to which NaF/EDTA tubes prevents TU to T ex vivo conversion is unknown. Further investigation of the rate and extent of TU to T ex vivo conversion during the time course of plasma sample preparation is warranted to determine whether T concentration measurements from plasma in NaF/EDTA tubes in your Phase 3 trial are accurate and reproducible.

Information Needed to Resolve Deficiency #2

Conduct a study that doses subjects with your product and compares the total T concentrations measured from serum in plain tubes and from plasma in NaF/EDTA tubes at different time points (e.g., 0, 15, 30, 60, 90, and 120-minutes post-sample collection) using various temperature conditions (e.g., at room temperature and on ice) to definitively determine the rate and extent of TU to T ex vivo conversion during the expected time course of plasma sample preparation. Prespecify in the protocol the maximum amount of T concentration overestimation from TU to T ex vivo conversion that would be acceptable for the matrix you propose for clinical use and to support the reliability of the efficacy data from your Phase 3 trial. You may also wish to consider evaluating plasma collected in tubes without NaF. Enroll enough subjects (e.g., 12 subjects), administer your drug product at the maximum recommended to-be-marketed dose, and achieve the same TU concentration as expected at steady state during clinical

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use. Assessment of the zero timepoint (i.e., centrifuged immediately upon blood collection) for plasma in tubes with and without NaF is critical for this assessment.

In addition, conduct a study comparing total T concentrations measured from serum (in plain tubes) and plasma (in NaF/EDTA tubes and non NaF-containing plasma tubes) collected in the same subjects without administering TU and then split, prepare, and analyze these samples in the same bioanalytical laboratory. Include the correlation analysis between the total T concentrations obtained from serum and plasma from the same subjects in your study report.

We strongly recommend that you submit these protocols for review and await our comments before initiating the studies.

In your NDA resubmission, include the bioanalytical method validation and study (performance) reports for all matrices (e.g., serum, plasma, plasma in the presence of NaF).

If these studies confirm that proper dose adjustment of your product will require T concentrations from plasma samples collected in NaF/EDTA tubes, ensure that accurate and reliable T tests intended for use with NaF/EDTA plasma specimens are available by the time of approval. This may involve a companion diagnostic if you intend to propose the clinical use of a specific T assay to monitor patients taking your drug. Ensure you have adequately addressed these issues with FDA prior to NDA resubmission.

If you are unable to confirm that T concentration measurements from plasma in NaF/EDTA tubes in your Phase 3 trial are accurate and reproducible, you will need a new Phase 3 trial to establish efficacy. The results could also potentially impact the choice of dose(s) that are studied in the new trial, which may prompt the need for additional safety data as well.

In addition, due to the similarities in the chemical structure of T and TU and because of the high concentration of TU relative to T in patient specimens, it is possible that commonly used T immunoassays would significantly cross-react with TU causing an overestimation of T concentration values regardless of sample type. If commercially available assays can be used for measuring T in patients treated with your product, provide data demonstrating the rate of TU cross-reactivity with commonly used immunoassays.

3. The submitted nonclinical studies are unacceptable to support approval of your NDA through the 505(b)(1) pathway. Specifically, your TU doses were inadequate to characterize and provide a meaningful and valid evaluation of the chronic effects of your product on male fertility and carcinogenicity. In the fertility study, the tested doses did not produce the anticipated effects on spermatogenesis and/or fertility, which may reflect insufficient exposure to T and/or TU. You did not submit toxicokinetic data to evaluate drug exposure. With regards to your 6-month carcinogenicity study in male Tg-rasH2 mice, the rationale provided in your

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November 30, 2017, letter does not satisfactorily address the nonclinical deficiency communicated in our letter dated October 4, 2017. Specifically, per International Conference on Harmonization (ICH) guidance $1C(R2) Dose Selection For Carcinogenicity Studies (2008), the maximally tolerated dose (MTD), maximum feasible dose or limit dose was not identified in your 28-day dose range finding study or in your 6-month carcinogenicity study. The use of 25 males/group due to “gender specific effects” is not a valid evaluation in your 6-month carcinogenicity study, as the study remains insufficiently powered for one sex.

Information Needed to Resolve Deficiency #3

Provide justification for dose selection for the fertility study combined with the in vivo micronucleus test, and conduct a new, adequately designed carcinogenicity study. Submit the carcinogenicity study protocol for review by the Division and the Executive Carcinogenicity Assessment Committee per the guidance “Guidance for Industry Carcinogenicity Study Protocol Submissions” found at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid ances/UCM078924. pdf.

Alternatively, you may classify your NDA as a 505(b)(2) application without submitting additional nonclinical studies if you provide appropriate nonclinical published literature references to address the nonclinical deficiencies above. If you proceed with a 505(b)(2) NDA, the results from your completed fertility and carcinogenicity studies will not be included in the product labeling.

ADDITIONAL COMMENTS We have the following comments/recommendations that are not approvability issues: 1. You have provided insufficient data to definitively exclude a risk of adrenal insufficiency with chronic dosing. Further assessment of adrenal function over a longer duration is

warranted.

2. Your product is administered orally as TU and achieves high systemic TU concentrations. Address the drug-drug interaction potential of TU as the perpetrator.

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 (SRPD — 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

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labeling [21 CFR 314.50(1)(1)(i)] in structured product labeling (SPL) format as described at http://www.fda.gov/ForIndustry/DataS tandards/StructuredProductLabeling/default.htm

CARTON AND CONTAINER LABELING

Submit draft carton and container labeling that includes your proposed revisions dated February 21, 2018, and also add the following:

e “Capsule” refers to the dosage form and is not part of the established name. Change the drug product name on both the immediate container and the carton from | to “Jatenzo (testosterone undecanoate) Capsules, 158

mg, 198 mg, or 237 mg”. PROPRIETARY NAME

Please refer to correspondence dated, September 5, 2017, which addresses the proposed proprietary name, Jatenzo. This name was found acceptable pending 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 as described at

21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical and clinical studies/trials of the drug 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:

¢ 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.

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4. Provide case report forms and narrative summaries for each patient 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 drug. Include an updated estimate of use for drug marketed in other countries.

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

OTHER

Within one year after the date of this letter, you are required to resubmit or take other actions available under 21 CFR 314.110. 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 314.65. 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 FDA Guidance for Industry, “Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products,” March 2015 at http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm 43743 | pdf.

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

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If you have any questions, contact Jeannie Roule, Regulatory Health Project Manager, at (301) 796-3993.

Sincerely,

{See appended electronic signature page}

Hylton V. Joffe, M.D., M.M.Sc.

Director

Division of Bone, Reproductive and Urologic Products

Office of Drug Evaluation III Center for Drug Evaluation and Research

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This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature.

HYLTON V JOFFE 03/22/2018

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