Clarus Therapeutics, Inc.testosterone undecanoate (oral)

NDA 206089

Food and Drug Administration Silver Spring MD 20993

COMPLETE RESPONSE

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

555 Skokie Blvd., Suite 340 orthbrook, IL 60062

Dear Dr. Dudley:

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ease refer to your New Drug Application (NDA) dated and received January 3, 2014, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for testosterone undecanoate (oral).

We acknowledge receipt of your amendments dated February 4, 13, 24 and 28, March 28, April 21 and 23, May 1 and 2, June 3, July 18 and 24, August 1, 4, 6, 12, and 19, September 15, 24 and 26(2), and October 1, 2014.

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.

Your amendment dated August 6, 2014, contained bioanalytical study reports for all clinical trials as well as bioanalytical method validation data that were missing at the time of NDA submission. We did not review these bioanalytical data in their entirety as they were submitted late in the review cycle. The complete analytical validation section of your NDA will need to undergo further review in a future resubmission in the context of new trials that are conducted to support your NDA.

Deficiencies

You have not shown that your product can reliably and safely replace testosterone in hypogonadal men. You are proposing that your product be dosed once in the morning and once in the evening with meals. We agree that your product cannot realistically be dosed in the fasted state, particularly because this is not practical for the evening dose. However, based on the food effect study, there are considerable increases in testosterone undecanoate (TU), testosterone, and dihydrotestosterone (DHT) as the fat content in the meal increases. Therefore, taking your product with food will not lead to consistent serum TU, testosterone and DHT concentrations unless the fat content for every breakfast and every dinner is similar from day to day. It is not reasonable to expect patients to be able to maintain such consistency every day while taking this chronic medication nor is it reasonable to expect that patients will always be able to know the fat

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content of their meals. With variations in the fat content from day-to-day, a given dose of your product may sometimes be too high (if the fat content of the accompanying meal is high) and sometimes too low (if the fat content of the accompanying meal is low). This could lead to erratic and variable exposures to TU and its metabolites from one day to the next. The data from the pivotal phase 3 trial are not able to address this concern. In your trial, subjects chose foods from a preset menu on the three pharmacokinetic sampling days (Days 30, 72 and 114). For all the other days, subjects had no food restrictions. Therefore, data used for deciding on titration as well as data collected for the primary and key secondary efficacy endpoints were all obtained on days when the subjects chose food from the preset menu. It is unlikely that the fat content in the meals on these three days is comparable to that of all the unrestricted meals that the subjects could eat on the other 111 days of the trial. Therefore, you have not shown that your product, as proposed, would lead to reliable and appropriate testosterone and DHT concentrations from one day to the next, raising both efficacy and safety concerns.

We have also identified the following additional concerns with your single, open-label, non- randomized, four-month pivotal phase 3 trial, CLAR-12011:

1.

Your completer analysis in the 116 subjects who had sufficient data to calculate a 24- hour average serum total testosterone concentration (T-C,yg) on Day 114, showed that exactly 75% of subjects had a T-C.yg within the normal range, a success rate that just barely achieves the pre-defined target threshold. However, when other analytical approaches are used that account for the approximately 19% of subjects who did not have sufficient data to calculate T-C,yg on Day 114 , the primary efficacy results do not reach the target threshold for success.

None of the key secondary efficacy endpoints for testosterone Cmax outliers met the prespecified success targets for the three Cmax outlier categories.

The starting dose of 200 mg twice daily was too high, resulting in the need to down- titrate a majority of the subjects. Also, the titration regimen requires that serum testosterone concentrations be lower than 250 ng/dL before the dose is increased, preventing some subjects from achieving adequate testosterone replacement. Nearly one- fourth of subjects had a T-Cavg <300 ng/dL at the primary efficacy endpoint subsequent to all titration.

The mean average serum DHT concentration was above the upper limit of normal, and the mean DHT-to-testosterone concentration ratio was twice the upper limit of normal. These data are inconsistent with the goal of testosterone replacement therapy, which is to replace testosterone and its critical metabolites, DHT and estradiol, to within the normal range.

We have also identified the following additional safety concerns, based on the data contained in your NDA:

1.

DHT is a potent androgen. Supraphysiological DHT concentrations and DHT-to- testosterone concentration ratios observed with your product pose an increased risk of serious androgen-related adverse effects.

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2. Very high serum TU and dihydrotestosterone undecanoate (DHTU) concentrations were observed with your product and the clinical ramifications of this finding are unknown. While TU and DHTU appear to have weak affinities for the androgen receptor, at massive exposures they may have effects. In addition, TU and DHTU are further metabolized to DHT and to other steroid molecules that may have pharmacologic effects. The role that TU or its metabolites may have played, if any, in the hypocortisolemia and adrenocortical atrophy observed in dogs in the 13-week toxicity study is unknown.

3. Significantly decreased sex hormone binding globulin (SHBG) was observed with your product and the clinical ramifications of this finding are unknown.

4. Clinically meaningful increases in systolic and diastolic blood pressure were observed with your product in Study CLAR-09007, with a larger blood pressure increase compared to Androgel 1%. The extent to which these blood pressure differences are explained by differences in exposure to testosterone, TU or other TU metabolites is unclear. Blood pressure was also meaningfully increased in Study CLAR-12011, albeit to a lesser degree than in Study CLAR-09007.

5. Clinically meaningful increases in hematocrit were observed with your product in Study CLAR-09007, with a larger increase compared to Androgel 1%. Almost 10% of subjects treated with your product in Study CLAR-09007 had at least one hematocrit value >54%, a clinically meaningful level. The extent to which the hematocrit differences between your product and Androgel 1% are explained by differences in exposure to testosterone, TU or other TU metabolites is unclear. An increase in hematocrit was also observed with your product in Study CLAR-12011.

6. A small number of cardiovascular adverse events were reported with your product in the Phase 3 studies, including events of acute myocardial infarction and stroke. The role played by your product in these events is currently unknown. However, several possible biomarkers of cardiovascular risk, including blood pressure (described above), HDL- cholesterol and high-sensitivity C-reactive protein (hs-CRP) were adversely affected by your product. The extent of worsening of HDL-cholesterol and hs-CRP was greater for your product compared to Androgel 1% in Study CLAR-09007. The extent to which these differences are explained by differences in exposure to testosterone, TU or other TU metabolites is unclear.

Information Needed to Resolve the Deficiencies

You will need to conduct new clinical investigations to show that your product consistently leads to reliable and appropriate exposures to testosterone and DHT in the face of day-to-day variability in meal content that is expected to occur in men who will use the product, if approved. One possible approach may be to first conduct a timed food effect study to assess whether taking your product before or after food (e.g., 1 hour before food, or 1 or 2 hours after food) could minimize the food effect and lead to more predictable testosterone and DHT concentrations. If this is successful, the next step could be to conduct a new phase 3 trial with subjects using the appropriate timing of product administration in relation to food, as determined from the timed food effect study. This new phase 3 trial would need to consider the optimal starting dose and titration thresholds to ensure that the tested dosing and titration regimen results in exposures to

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testosterone and DHT, and DHT-to-testosterone ratios that are within the normal range for eugonadal males. If this new titration algorithm is again expected to lead to considerable reductions in SHBG, you will need to address whether bioavailable testosterone concentrations are within the normal range for eugonadal males. In addition, this new trial would need to be adequately designed to avoid other deficiencies involving the completed phase 3 trial that were described above, such as the large extent of missing data for the primary efficacy endpoint. You will also need to provide convincing evidence that the effects of your product on important cardiovascular risk factors, such as blood pressure, hematocrit, and HDL cholesterol, do not pose an unacceptable risk to the indicated patient population.

In summary, additional investigations of efficacy and safety and the effect of food, will be necessary, including possible changes to the dose and titration algorithm. One possible approach is described above. Based upon the extent and complexity of the deficiencies, you are encouraged to meet with the Division to discuss a path forward towards resolving all the deficiencies.

In addition, you will need to address the following concerns related to the very high TU and DHTU concentrations:

e Whether your product has effects on the human hypothalamic-pituitary-adrenal axis. In the nonclinical repeat-dose toxicity study, dogs developed moderate to marked atrophy of the adrenal cortex with an accompanying reduction in serum cortisol. These findings raise the possibility that your product or its metabolite(s) may have glucocorticoid activity, leading to secondary adrenal insufficiency.

e Whether the findings from the in vitro androgen receptor binding study (which compared the affinity of TU, DHTU, testosterone and DHT for the rat androgen receptor) are generalizable to the human androgen receptor.

e Whether the very high concentrations of TU and DHTU compete with testosterone and DHT at the androgen receptor and whether any of the metabolites of TU and DHTU have pharmacologic effects.

LABELING

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 website including regulations and related guidance documents and the Selected Requirements for Prescribing Information (SRPI) — a checklist of 42 important format items from labeling regulations and guidances.

If you revise labeling, use the SRPI checklist to ensure that the package insert conforms with format items in regulations and guidances. Your response must include updated content of labeling [21 CFR 314.50(1)(1)(i)] in structured product labeling (SPL) format as described at http://www. fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.

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PROPRIETARY NAME

The review of your proposed proprietary name has been terminated due to the deficiencies with the application as described in this letter. 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:

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

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

e Include tables that compare frequencies of adverse events in the original NDA 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 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, ut less serious, adverse events between the new data and the original NDA 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.

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ADDITIONAL COMMENTS We have the following recommendation that is not an approvability issue:

e Conduct an in vivo interaction study with alcohol to determine whether co-administration with alcohol could alter the bioavailability of your product and exposure to its metabolites. Based on physicochemical properties, it is possible that alcohol will solubilize your product, leading to increased absorption via the portal vein, a high first pass effect, and reduced TU bioavailability. However, it is also possible that alcohol could instead enhance absorption via the lymphatics, leading to increased bioavailability of TU. Given these uncertainties, it would be useful to study the potential for interaction with alcohol.

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. A partial response to this letter will not be processed as a resubmission and will not start a new review cycle.

Under 21 CFR 314.102(d), you may request a meeting or telephone conference 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 FDA Guidance for Industry, “Formal Meetings Between the FDA and Sponsors or Applicants,” May 2009 at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U

CM153222.pdf.

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

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 11/03/2014

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