FDA Briefing Document NDA 206089 Testosterone Undecanoate (proposed trade name Jatenzo) For replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone. Bone, Reproductive, and Urologic Drugs Advisory Committee (BRUDAC) Meeting January 9, 2018 Division of Bone, Reproductive, and Urologic Products Office of New Drugs Division of Clinical Pharmacology 3 Office of Clinical Pharmacology Center for Drug Evaluation and Research 1 DISCLAIMER STATEMENT The attached package contains background information prepared by the Food and Drug Administration (FDA) for the panel members of the advisory committee. The FDA background package often contains assessments and/or conclusions and recommendations written by individual FDA reviewers. Such conclusions and recommendations do not necessarily represent the final position of the individual reviewers, nor do they necessarily represent the final position of the Review Division or Office. We have brought a new drug application (NDA 206089) for testosterone undecanoate oral capsules (proposed trade name, JATENZO), intended for replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone sponsored by Clarus Therapeutics, Inc, to this Advisory Committee in order to gain the Committee’s insights and opinions. The background package may not include all issues relevant to the final regulatory recommendation and instead is intended to focus on issues identified by the Agency for discussion by the advisory committee. The FDA will not issue a final determination on the issues at hand until input from the advisory committee process has been considered and all reviews have been finalized. The final determination may be affected by issues not discussed at the advisory committee meeting. 2 Table of Contents INTRODUCTORY MEMORANDUM ....................................................................................... 4 INTRODUCTION AND BACKGROUND .............................................................................. 12 OVERALL EFFICACY ............................................................................................................. 15 SUMMARY OF ISSUES FOR ADVISORY COMMITTEE CONSIDERATION .............. 16 INDIVIDUAL ISSUE OVERVIEW .......................................................................................... 16 Cardiovascular .......................................................................................................................... 16 Hematocrit................................................................................................................................. 28 Testosterone Metabolites (DHT and Estradiol) ........................................................................ 30 Cmax Outliers .............................................................................................................................. 33 Adrenal Findings in Animals and in Humans ........................................................................... 35 Clinical Pharmacologic Issues .................................................................................................. 39 APPENDIX .................................................................................................................................. 55 9.4.2 CLAR-15012 (3-month pivotal Phase 3 trial) .............................................................. 55 OBJECTIVES: ............................................................................................................................ 55 STUDY DESIGN AND CONDUCT: ......................................................................................... 56 Subject Disposition ............................................................................................................... 66 Demographics ....................................................................................................................... 68 Safety Findings ..................................................................................................................... 82 3 Introductory Memorandum To: The Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC) From: Hylton V. Joffe, M.D., M.M.Sc. Director Division of Bone, Reproductive, and Urologic Products (DBRUP) Subject: New Drug Application (NDA) 206089 Testosterone undecanoate (proposed tradename Jatenzo) Overview of topics to be discussed at the January 9, 2018, advisory committee meeting ______________________________________________________________________________ Introduction: The FDA is convening this advisory committee meeting to discuss the New Drug Application (NDA) submitted by Clarus Therapeutics for oral testosterone undecanoate (TU) capsules (proposed tradename Jatenzo). The Applicant is seeking an indication that is identical to the indication for the class of FDA-approved testosterone therapies – replacement therapy in adult men for conditions associated with a deficiency or absence of endogenous testosterone. Marketed testosterone products include topical formulations that are applied to the skin, a buccal system that is applied to the gums, an intranasal gel, formulations administered by intramuscular injection and subcutaneously implanted pellets. Methyltestosterone is the only other orally administered testosterone therapy but is not used much because of hepatotoxicity. Therefore, if the Clarus product is approved, it will likely dramatically change the landscape of testosterone therapies, because the oral route of administration will be considerably easier to use than the more cumbersome routes of administration available with the commonly used marketed products. Testosterone itself has low bioavailability because of extensive first-pass metabolism in the liver. The Applicant esterified testosterone with undecanoate to help render Jatenzo lipophilic so it could be absorbed through the intestinal lymphatic system, bypassing the first-pass hepatic effect, and making Jatenzo orally bioavailable. Once absorbed, Jatenzo is converted to testosterone by circulating esterases in the blood. This introductory memorandum will provide a brief overview of the key issues that FDA will present to the advisory committee panel. More detailed information is included in the accompanying document prepared by the FDA review team. 4 Background: This is the second advisory committee meeting for Jatenzo. At the last advisory committee meeting, held in September 2014,1 four members voted for approval and 17 members voted against approval. The FDA agreed that the benefit/risk profile was not acceptable and did not approve the product. Key issues specified in FDA’s letter denying approval included: • In the single-dose food effect study, the amount of fat content in meals influenced the absorption of TU, testosterone and dihydrotestosterone (DHT) concentrations. Based on these data, FDA stated that taking the product with food will not lead to consistent concentrations unless the fat content for every breakfast and every dinner is similar from day to day, which is not practical in the real world nor would we expect patients to always know the fat content of their meals. • The primary efficacy endpoint in the Phase 3 trial that tested the regimen proposed for marketing was narrowly met,2 but failed in sensitivity analyses when we attempted to account for missing data. In contrast, mean serum concentrations of DHT, a metabolite of testosterone and potent androgen, were above the upper limit of the reference range. This did not appear consistent with the goal of testosterone replacement therapy, which is to restore concentrations of testosterone and its major metabolites to normal. • None of the key secondary endpoints that assessed unacceptably high maximal exposures to testosterone met the prespecified success targets. • There were increases in blood pressure in the first Phase 3 trial, with a larger blood pressure increase with Jatenzo relative to the Androgel 1% comparator. Blood pressure was also increased in the second Phase 3 trial, but to a smaller degree than in the first trial. • In a toxicity study, dogs developed moderate to marked atrophy of the adrenal cortex with a possible reduction in serum cortisol, raising the possibility of adrenal insufficiency. The Applicant chose to address these concerns with a new randomized Phase 3 trial that included an Axiron comparator arm and a new food effect study. The new Phase 3 trial included the following design features to address our previously identified efficacy and safety concerns: • A revised starting dose and titration regimen for Jatenzo. Titration decisions were based on a pharmacokinetic parameter known as Cavg, which is a time-averaged testosterone concentration based on pharmacokinetic sampling over 24 hours. This approach is not feasible in clinical 1 https://wayback.archive-it.org/7993/20170404145836/https://www.fda.gov/AdvisoryCommittees/Calendar/ucm406131.htm 2 To meet the primary efficacy endpoint, at least 75% of subjects were to achieve testosterone Cavg in the normal range, and the lower bound of the corresponding 95% confidence interval was to be at least 65%. In the Applicant’s prespecified analysis, 75.0% of subjects had Cavg for testosterone in the normal range, and the lower bound of the corresponding 95% confidence interval was 66.1%. 5 practice so the Applicant is proposing a single testosterone concentration drawn several hours after the morning dose for clinical use. • Ambulatory blood pressure