FDA Briefing Document Endocrinologic and Metabolic Drugs Advisory Committee Meeting May 10, 2018 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 NDA 210645, Waylivra (volanesorsen) injection for the treatment of familial chylomicronemia syndrome to this Advisory Committee in order to gain the Committee’s insights and opinions, and 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. 1 of 194 Table of Contents Page Division Director Memorandum 3 Draft Points for Discussion 5 Clinical Summary 7 Statistical Summary 128 Clinical Pharmacology Summary 159 Hematology Consult 173 Division of Risk Management Summary 183 Nonclinical Summary 191 2 of 194 MEMORANDUM DATE: April 13, 2018 FROM: James P. Smith, MD, MS Deputy Director, Division of Metabolism and Endocrinology Products (DMEP) Office of Drug Evaluation II / Office of New Drugs Center for Drug Evaluation & Research TO: Members and Consultants, Endocrinologic & Metabolic Drugs Advisory Committee (EMDAC) SUBJECT: EMDAC meeting for volanesorsen (Waylivra) Thank you for agreeing to participate in the May 10, 2018, advisory committee meeting. This meeting is being held to discuss the safety and efficacy of volanesorsen as an adjunct to diet for the treatment of patients with familial chylomicronemia syndrome (FCS), which is the subject of a new drug application (NDA) submitted by Akcea Therapeutics, Inc. Volanesorsen is a modified phosphorothioate antisense oligonucleotide (ASO) that targets apolipoprotein C-III mRNA, leading to its degradation and subsequent reduction in the synthesis of this protein. ApoC-III has a significant role in regulating plasma triglyceride (TG) levels by inhibiting both lipoprotein lipase (LPL)-mediated hydrolysis of TG-rich lipoproteins as well as hepatic lipase activity. Elevated apoC-III reduces the clearance of TG- rich lipoproteins from plasma, resulting in hypertriglyceridemia; therefore, reduction of apoC-III would be expected to lower plasma TG by facilitating clearance. As you will read in this briefing document, the review team is in agreement that volanesorsen markedly lowers fasting TG in patients with FCS, a rare syndrome that currently lacks approved pharmacotherapy. Changes in fasting TG have been used to support approval of drugs intended to treat more common forms of severe hypertriglyceridemia (generally defined as TG ≥500 mg/dL) for several decades, on the assumption that lowering TG will reduce the risk of pancreatitis among patients with this degree of TG elevation. When efficacy is established via an effect on a surrogate endpoint, however, true clinical benefit typically remains unknown; therefore, the benefit/risk assessment must balance an unmeasured clinical benefit against the known and potential risks of the drug. At the time of the volanesorsen end-of-phase 2 meeting, the Division recognized that limited data collected during early-phase trials did not provide adequate reassurance regarding the safety/tolerability of volanesorsen. Thus, the applicant was strongly encouraged to consider assessing outcomes that are meaningful to patients with FCS (e.g., abdominal symptoms), since demonstrating an effect of volanesorsen on how a patient with FCS feels or functions would strengthen the application by better informing clinical benefit. The applicant incorporated a patient-reported outcome instrument to assess abdominal pain on a 0-10 numeric rating scale, added health status questionnaires routinely used in clinical trials (SF-36 and EQ-5D), and adjudicated events of pancreatitis. Refer to the statistical and clinical reviews for further discussion of these endpoints and analyses, since we are interested in how these data impact your thinking with respect to the magnitude of the potential clinical benefit(s) of volanesorsen. Despite the magnitude of the effect observed on TG, the volanesorsen review team remains uncertain whether the benefits of volanesorsen outweighs its risks, considering safety concerns with this product. Although the reviews U.S. Food & Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20903 www.fda.gov 3 of 194 highlight several safety/tolerability issues, the primary focus for both the applicant and the reviewers has been the risk of thrombocytopenia and resulting potential for serious bleeding. As you will read in the FDA hematology consultant’s memo, drug-induced thrombocytopenia is a well-known adverse event associated with exposure to ASOs in preclinical animal studies and clinical trials, although the underlying pathophysiology remains unexplained. Most patients exhibit a gradual decline in platelet count that is typically mild; e.g., in the pivotal FCS trial (CS6), a ~30% decline in platelet count, on average, was observed within the first 6 months among patients treated with volanesorsen. More concerning, however, is the observation that some patients can exhibit a rapid and unpredictable reduction in platelets to extremely low levels. In CS6, no patients assigned to placebo had a platelet count fall below 100,000/uL compared with 18 (55%) of 33 patients assigned to volanesorsen. Three (9%) of 33 patients had a platelet count <50,000/uL, including 2 patients with a nadir <25,000/uL. Across the development program, 9 volanesorsen- treated patients have had platelet counts <50,000/uL; four of these events, including 2 patients with platelet nadirs of 15,000/uL and 17,000/uL, occurred despite enhanced platelet monitoring, which was as frequent as every 1-2 weeks, and dosage adjustments. Switching to biweekly dosing and/or dose interruptions have not always led to a sufficiently timely recovery of platelet count; some patients have required treatment with prednisone, hospitalization, and/or administration of IVIG. To date, serious bleeding events have not been observed in this relatively limited safety database, but the reviewers highlight a higher risk of non-serious bleeding-related adverse events with volanesorsen (e.g., epistaxis, petechiae). Some of these events occurred at platelet levels where spontaneous bleeding would be unexpected, suggesting the possibility of an abnormality of platelet function as well as an effect on platelet count. After the NDA review was well-underway, the applicant unexpectedly submitted an amendment that proposed a new dosing and platelet monitoring strategy for labeling that had not been implemented in any of the clinical trials. The applicant now proposes that dosing recommendations vary by body weight (above or below 70kg) and recommends platelet monitoring to occur at least every other week (more frequently if platelets fall below 100,000/uL). Reviewers from the Office of Clinical Pharmacology have taken the lead in reviewing the rationale and support for this newly proposed dosing strategy; please see their memo for details. Regarding platelet monitoring, the review team (including the hematology consultant) questions the feasibility and effectiveness of a monitoring scheme of this intensity for a lifelong therapy. At present, we have no evidence that the risk of severe thrombocytopenia diminishes with time; the onset of platelets falling to <50,000/uL has ranged from 51 to 300 days in this program. Furthermore, Dr. Roberts notes in her clinical review that the most recent case of a patient with a platelet nadir of 17,000/uL occurred despite weekly platelet assessments. Although not the only safety issue (see Dr. Roberts’s review), the potential risk of serious bleeding due to severe thrombocytopenia associated with volanesorsen has led the review team to propose that if volanesorsen were to be approved, a risk evaluation and mitigation strategy (REMS) would be required to ensure that the benefits of volanesorsen outweigh its risks. Please see the memo from the Division of Risk Management in this briefing document for a discussion regarding FDA’s proposed goals and components for a REMS for volanesorsen. It is important to note, however, that FDA has not yet concluded that the benefits of volanesorsen for its proposed use would exceed its risks even with a REMS in place; therefore, your discussion and input regarding this application will be extremely valuable. We sincerely thank you for your service and commitment to consider this application. We look forward to your discussion and advice regarding the potential approval of volanesorsen. U.S. Food & Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20903 www.fda.gov 4 of 194 Draft Points for Discussion 1. A reduction in fasting triglycerides (TG) has been accepted by FDA as an endpoint that can establish efficacy for several classes of drugs intended to treat patients with severe hypertriglyceridemia (TG >500 mg/dL),