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Multi-Discipline Review &(17(5 )25 '58* (9$/8$7,21 $1' 5(6($5&+ APPLICATION NUMBER: 2ULJV 08/7,',6&,3/,1( 5(9,(: 6XPPDU\ 5HYLHZ 2IILFH 'LUHFWRU &URVV 'LVFLSOLQH 7HDP /HDGHU 5HYLHZ &OLQLFDO 5HYLHZ 1RQ&OLQLFDO 5HYLHZ 6WDWLVWLFDO 5HYLHZ &OLQLFDO 3KDUPDFRORJ\ 5HYLHZ Cross Discipline Team Leader Review NDA212327 Cross-Discipline Team Leader Review Date August 15, 2019 From Kathy M. Robie-Suh, M.D., Ph.D. Subject Cross-Discipline Team Leader Review NDA/BLA# NDA212327 Supplement# Applicant Impact Biomedicines, Inc. (subsidiaiy of Celgene Corporation) Date of Submission Letter date, Januaiy 4, 2019 (received Januaiy 3, 2019) PDUFA Goal Date September 3, 2019 Proprietary Name I Inrebic (fedratinib) Established (USAN) names Dosage forms I Strength 100 mg capsules Indication(s) Proposed indication being sought: "Inrebic (fedratinib) is indicated for the treatment of inte1mediate - or high-risk prima1y or secondaiy (post- polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF) (b)(-41 I Recommended: Approval for indication: "Inrebic (fedratinib) is indicated for the treatment of inte1mediate - or high-risk primaiy or secondaiy (post-polycythemia vera or post-essential thrombocvthemia) mvelofibrosis (MF)" Page I of 26 1 Reference ID 4477859 Cross Discipline Team Leader Review NDA 212327 1. Introduction Fedratinib is an oral kinase inhibitor with activity against wild type and mutationally activated Janus Associated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3). Fedratinib is not approved anywhere in the world for any indication. In this application the applicant (sponsor) is seeking approval of fedratinib for the indication “for the treatment of intermediate – or high- risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF) (b) (4) ”. To support this application the sponsor has provided the final reports for one concurrently - controlled clinical trial (Study EFC12153 (JAKARTA)) and one open-label, single arm trial (Study ARD12181 (JAKARTA2)). Fedratinib has been granted orphan designation for the “treatment of secondary and primary myelofibrosis” (5/18/2009) and for the “treatment of polycythemia vera” (3/21/2013). The sponsor requested priority review of the application asserting that most patients are not eligible for allogeneic stem cell transplant (SCT), which is the only curative treatment for patients with MF, and that despite availability of ruxolitinib for the treatment of patients with intermediate or high-risk MF, more than half of patients on ruxolitinib require dose reductions due to myelosuppression which limits continuation of treatment. Priority review was granted for this application. See the Multi-Disciplinary Review and Evaluation (signed 8/15/2019) for detailed review and discussion of the application. 2. Background Myelofibrosis (MF) is a serious and life-threatening, stem-cell derived clonal myeloproliferative neoplasm. It can present either de novo as primary myelofibrosis (PMF) or following previously diagnosed polycythemia vera (PV) and essential thrombocythemia (ET) (post-PV MF and post-ET MF, respectively [i.e., secondary MF]). Clinical manifestations include splenomegaly, anemia, thrombocytopenia, fatigue, constitutional symptoms (night sweats, fever, cachexia), bone marrow reticulin and collagen fibrosis, increased risk of leukemic transformation as well as symptoms associated with bone pain, pruritus, thrombosis and related bleeding in the setting of thrombocytopenia and platelet dysfunction. Symptomatic enlargement of the spleen and liver, the need for red blood cell (RBC) transfusions, cachexia, and the other MF associated symptoms result in greatly compromised quality of life (QoL) in patients with MF. Onset is usually age 50 or older and patients have shortened survival. Primary MF, PV and ET are Philadelphia chromosome (Ph1)-negative myeloproliferative disorders. Almost all primary MF and about half of PV and ET myeloproliferative neoplasms Page 2 of 26 2 Reference ID: 4477859 Cross Discipline Team Leader Review NDA 212327 have a Janus kinase (JAK2) mutation. Abnormal activation of JAK2 is associated with myeloproliferative neoplasms (MPNs), including myelofibrosis and polycythemia vera. Ruxolitinib (JAKAFI), a small molecule inhibitor of JAK1 and JAK2, was approved on 11/16/2011 for the treatment of intermediate or high-risk myelofibrosis, including primary MF, post-polycythemia vera MF (post-PV MF) and post-essential thrombocythemia MF (post- ET MF), based on results of two randomized Phase 3 studies in patients with MF, which demonstrated an increase in proportion of patients showing a >35% reduction in spleen volume (measured by MRI or CT) at Week 24 and also showed improvement in patient symptom score. Fedratinib is an oral kinase inhibitor with activity against wild type and mutationally activated Janus Associated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3). In cell models expressing mutationally active JAK2 or FLT3, fedratinib reduced phosphorylation of STATs, inhibited cell proliferation, and induced apoptotic cell death. Fedratinib product development has been conducted by three manufacturers: The IND for fedratinib was opened in October 2007 by TargeGen with a first-in-human (FIH) Phase 1 dose-escalation study in patients with MF followed by an extension study. TargeGen was acquired by Sanofi in September 2010 and the clinical development program was expanded; however, Sanofi terminated the clinical development program in November 2013 because of safety concerns of Wernicke’s encephalopathy (WE) and heart failure. At the time of the clinical hold/program termination, the FIH dose- escalation study in myelofibrosis subjects had been completed as well as 10 clinical pharmacology studies. Ongoing studies at the time of the clinical hold/program termination were: One clinical pharmacology study (a QT interval [QT] study); the randomized, double-blind, placebo-controlled Phase 3 study (Study EFC12153, JAKARTA); the long-term extension study to the Phase 1 study; the Phase 2 study in MF subjects previously exposed to Ruxolitinib (Study ARD12181, JAKARTA2); a Phase 2 dose-ranging study; a Phase 2 study in Japan in MF subjects; and a Phase 2 study in subjects with PV or ET who were resistant or intolerant to hydroxyurea. Impact Biomedicines, Inc. acquired fedratinib in November 2016. Celgene acquired Impact and the fedratinib compound and the IND was transferred to Celgene in February 2018. The sponsor indicates that Impact is a wholly owned subsidiary of Celgene. For this application the sponsor has provided the final report for one controlled clinical trial, Study EFC12153 (JAKARTA) and a supporting single-arm trial, Study ARD12181 (JAKARTA2) as shown in the sponsor’s table below: Page 3 of 26 3 Reference ID: 4477859 Cross Discipline Team Leader Review NDA 212327 Sponsor’s table from section 2.5 Clinical Overview of the application JAKARTA was a randomized, placebo-controlled, multicenter, Phase 3 study in subjects with intermediate-2 or high-risk PMF, post-PV MF, or post-ET MF with splenomegaly. JAKARTA2 was an open-label, single-arm Phase 2 study in subjects with intermediate-1 with symptoms, intermediate-2, or high-risk PMF, post-PV MF, or post-ET MF who had been previously exposed to ruxolitinib. JAKARTA enrolled patients who were naïve to a JAK inhibitor, while JAKARTA2 enrolled patients who were previously exposed to ruxolitinib. The JAKARTA Study was a randomized (1:1:1), double-blind, parallel-group, multicenter, multinational clinical trial of two fedratinib (SAR302503) dosing regimens in patients with intermediate-2 or high-risk primary MF, post-PV MF or post-ET MF with splenomegaly. Patients were to receive either 400 mg or 500 mg fedratinib or placebo daily for at least 6 consecutive 28-day cycles. Dose could be interrupted and/or decreased for toxicity, notably for Grade 4 thrombocytopenia, Grade >3 hepatic transaminase or total bilirubin elevation, Grade >3 nausea, vomiting diarrhea, constipation, or fatigue unresponsive to therapeutic/supportive measures within 48 hrs, and any Grade >3 nonhematologic/nongastrointestinal toxicity or Grade >2 peripheral neuropathy. Efficacy assessments included spleen volume, spleen size, myelofibrosis-associated symptoms using the modified MFSAF, investigator assessment of response using the modified IWG-MRT criteria, HRQOL and utility using the EQ-5D questionnaire, MPN-associated symptoms using the MPN-SAF, and hospitalizations. The primary objective was to evaluate the efficacy of Page 4 of 26 4 Reference ID: 4477859 Cross Discipline Team Leader Review NDA212327 daily oral doses of 400 mg or 500 mg of fedratinib compared to placebo in the reduction of spleen volume as detennined by magnetic resonance imaging (MRI) (or computed tomography (CT) scan in patients with contraindications for MRI). The primaiy efficacy assessment was spleen response rate (RR) which was defined as the propo1tion of subjects with ~ 35% spleen volume reduction (SVR) at the End of Cycle 6 (EOC6). A conf111nato1y MRI/CT was required 4 weeks later. Assessments were by Independent Review Committee (IRC) review of the MRI/CT images done in a blinded manner. 3. CMC The primaiy Quality Assessment Review of the application with regard to drng substance was conducted by Shai·on Kelly, CDER Office of Biotechnology Products (final signature in Panoram a 5/16/2019) and with regard to the diug product prima1y review was conducted by Xing Wang (final signature in Panoram a 5/7/2019). The primaiy Biophannaceutics Review was
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