CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 204684Orig1s000 OFFICE DIRECTOR MEMO Deputy Office Director Decisional Memo Page 2 of 17 NDA 204,684 Miltefosine Capsules 1. Introduction Leishmania organisms are intracellular protozoan parasites that are transmitted to a mammalian host by the bite of the female phlebotomine sandfly. The main clinical syndromes are visceral leishmaniasis (VL), cutaneous leishmaniasis (CL), and mucosal leishmaniasis (ML). VL is the result of systemic infection and is progressive over months or years. Clinical manifestations include fever, hepatomegaly, splenomegaly, and bone marrow involvement with pancytopenia. VL is fatal if untreated. Liposomal amphotericin B (AmBisome®) was FDA approved in 1997 for the treatment of VL. CL usually presents as one or more skin ulcers at the site of the sandfly bite. In most cases, the ulcer spontaneously resolves within several months, leaving a scar. The goals of therapy are to accelerate healing, decrease morbidity and decrease the risk of relapse, local dissemination, or mucosal dissemination. There are no FDA approved drugs for the treatment of CL. Rarely, CL disseminates from the skin to the naso-oropharyngeal mucosa, resulting in ML. ML can also develop some time after CL spontaneous ulcer healing. The risk of ML is thought to be highest with CL caused by the subgenus Viannia. ML is characterized in the medical literature as progressive with destruction of nasal and pharyngeal structures, and death may occur due to complicating aspiration pneumonia. There are no FDA approved drugs for the treatment of ML. Paladin Therapeutics submitted NDA 204, 684 seeking approval of miltefosine for the treatment of VL caused by L. donovani and for the treatment of CL and ML caused by members of the subgenus Viannia. The dosage form is a 50 mg capsule for oral use. The proposed dosing regimen is daily for 28 days with food for patients 12 years of age and weighing ≥ 30 kg. The number of 50 mg capsules per day is determined by bodyweight. For a body weight of 30-44 kg the dose proposed is: two 50 mg capsules daily; 1 capsule taken with breakfast and 1 with dinner. For a body weight of ≥ 45 kg the dose proposed is: three 50 mg capsules daily; one taken with breakfast, lunch, and dinner. The efficacy review for this NDA relies upon the results of the following studies: VL o Study 3154, a randomized, open-label, noninferiority trial conducted in VL patients in India in 1999-2000. o Study Z025, a randomized, open-label trial conducted in Ethiopia in 2003-2005. CL o Study 3168, a randomized, placebo-controlled trial conducted in Colombia and Guatemala in CL patients in 2000-2002. o Study Z020, a randomized, open-label trial conducted in Brazil in 2007-2009 o Study Soto, an open-label study conducted in Bolivia in 2005-2007. ML o Study Z022, a single-arm study conducted at a single site in Bolivia in ML patients in 2004-2006. The applicant submitted patient level data for each of these studies with the exception of Study Z025. The applicant did not conduct these studies. Page 2 of 17 Reference ID: 3472914 Deputy Office Director Decisional Memo Page 3 of 17 NDA 204,684 Miltefosine Capsules The review team has reviewed issues pertinent to their respective disciplines with regard to the safety and efficacy of miltefosine for the indications proposed. For a detailed discussion of NDA 204,684, the reader is referred to individual discipline specific reviews, the Cross- Discipline Team Leader Review, and the Division Director Review. 2. Background The genus Leishmania is divided into two subgenera, Leishmania and Viannia. The Leishmania subgenus includes L. donovani, L. chagasi/infantum, L. tropica, L. major, L. aethiopica, L. mexicana and L. amazonensis. The subgenus Viannia includes L. braziliensis, L. peruviana, L. guyanensis and L. panamensis. Traditionally, Leishmania infections that occur in Asia, Africa, Europe and the Middle East are designated “Old World”, while infections that occur in the Americas are designated “New World”. Miltefosine is an alkyllysophospholipid analogue with in vitro activity against the promastigote and amastigote stages of Leishmania species. In vitro, L. donovani is generally considered the most susceptible, and L. braziliensis and L. major the least susceptible. Variability in susceptibility between species and within species from different geographic areas as well as the limitations of the NDA data with respect to these issues were discussed at the Advisory Committee meeting (see Section 9) and is a review issue impacting labeling (see Section 12). The mechanism of action of miltefosine is likely to involve interaction with lipids (phospholipids and sterols), including membrane lipids, inhibition of cytochrome c oxidase (mitochondrial function), and apoptosis-like cell death. Adverse drug effects are anticipated based on the mechanism of action and were observed in pre-clinical studies (see Section 4). The adverse drug effects observed in clinical trials and post-marketing in other countries are described in Section 8 and are addressed in labeling (see Section 12). Miltefosine is registered in Germany as a topical drug to treat cutaneous cancers. As an oral dosage form, it is registered in Germany, several countries in South America and the Indian subcontinent for the treatment of VL and CL. Miltefosine was included in the WHO essential medicines list as an anti-leishmaniasis medicine in March 20111. The FDA granted miltefosine orphan designation in October 2006 and Fast Track Designation in May 2010. The NDA was submitted on April 19, 2013 and granted a priority review with an original goal date of December 19, 2013. During the initial CMC review, validation data for the high-performance thin layer chromatography (HPTLC) method used to analyze some of the impurities was found to be inadequate. The applicant’s response to this deficiency was considered a major amendment, and the user fee goal date was extended 3 months to March 19, 2014. The applicant has requested a tropical disease priority review voucher as authorized by Section 524 of the Food, Drug, and Cosmetic Act, which lists leishmaniasis as a tropical disease for the purposes of the legislation. 1Available at: http://whqlibdoc.who.int/hq/2011/a95053_eng.pdf Page 3 of 17 Reference ID: 3472914 Deputy Office Director Decisional Memo Page 4 of 17 NDA 204,684 Miltefosine Capsules 3. CMC I concur with the conclusions reached by the CMC reviewers regarding the acceptability of the manufacturing of the drug product and drug substance. There are no outstanding CMC issues precluding approval, but PMCs are recommended to develop a method for release and stability testing appropriate for life-cycle management. Miltefosine is a new chemical entity (NCE). The specifications for miltefosine drug substance include tests for description, identity, water, impurities, (b) (4) heavy metals, and residual solvents. Inadequate validation data to support the HPTLC method used to analyze some of the impurities was identified as a deficiency early in the course of review. Upon review of an amendment submitted by the applicant, the CMC reviewers concluded that adequate validation data for the HPTLC method had been provided and that the method may be used as an interim method. The reviewers recommended that an HPLC method rather than an HPTLC method was more appropriate for life-cycle management. They recommended a PMC for the applicant to develop an appropriate method (such as HPLC) for release and stability testing (assay and impurities) of the drug product and the drug substance to facilitate life-cycle management of miltefosine capsules. They recommended an additional PMC in conjunction with the development and implementation of the HPLC methodology to perform (b) (4) testing in accordance with the 2003 FDA draft guidance for stratified testing. I concur with their recommendations. The applicant provided 12 month stability data under long term conditions and 6 month stability data under accelerated conditions for close to commercial scale batches of the drug substance. The data support an expiration dating period of 24 months for the drug product, when stored at 20-25 oC (68-77 oF); excursions permitted to 15-30 oC (59-86 oF). The proposed dissolution method and the revised dissolution acceptance criteria were deemed acceptable. The product quality microbiology reviewer has found the NDA acceptable. The Office of Compliance has made an “Acceptable” overall recommendation for all the drug manufacturing facilities. 4. Nonclinical Pharmacology/Toxicology I concur with the conclusions reached by the pharmacology/toxicology reviewer that there are no outstanding pharm/tox issues that preclude approval. Embryotoxicity and teratogenicity were observed in animal studies which impact the overall risk benefit of the drug in pregnant women. The effect on male fertility warrants further clinical evaluation. Miltefosine is embryotoxic and teratogenic in animals at doses lower than the therapeutic human dose. Embryo-fetal toxicity, including death and teratogenicity, was observed in animals administered prior to mating, during early pregnancy, and during organogenesis at doses lower than the maximum recommended human dose (MRHD). Miltefosine caused fetal resorption Page 4 of 17 Reference ID: 3472914 Deputy Office Director Decisional Memo Page 5 of 17 NDA 204,684 Miltefosine Capsules during the period of organogenesis and fetal deaths in rats and rabbits and was a potent teratogen in rats. Female fertility was affected in both rats and dogs. In a rat study, estrus cycle arrest in the metestrus or diestrus phases occurred at 1.0 times the MRHD based on BSA comparison. In a 52 week dog study, increased numbers of atretic follicles in the ovaries, and cycle arrest in the uterus, vagina, and mammary gland with morphology consistent with anestrus or diestrus was observed at doses below the MRHD based on BSA comparison. There were effects on male fertility noted in rats; these effects were attenuated or absent in dogs at similar plasma exposures.