CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 212102Orig1s000 OTHER REVIEW(S) Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research | Office of Surveillance and Epidemiology (OSE) Epidemiology: ARIA Sufficiency Date: June 29, 2020 Reviewer: Silvia Perez-Vilar, PharmD, PhD Division of Epidemiology I Team Leader: Kira Leishear, PhD, MS Division of Epidemiology I Division Director: CAPT Sukhminder K. Sandhu, PhD, MPH, MS Division of Epidemiology I Subject: ARIA Sufficiency Memo for Fenfluramine-associated Valvular Heart Disease and Pulmonary Arterial Hypertension Drug Name(s): FINTEPLA (Fenfluramine hydrochloride, ZX008) Application Type/Number: NDA 212102 Submission Number: 212102/01 Applicant/sponsor: Zogenix, Inc. OSE RCM #: 2020-953 The original ARIA memo was dated June 23, 2020. This version, dated June 29, 2020, was amended to include “Assess a known serious risk” as FDAAA purpose (per Section 505(o)(3)(B)) to make it consistent with the approved labeling. The PMR development template refers to the original memo, dated June 23, 2020. Page 1 of 13 Reference ID: 46331494640015 EXECUTIVE SUMMARY (place “X” in appropriate boxes) Memo type -Initial -Interim -Final X X Source of safety concern -Peri-approval X X -Post-approval Is ARIA sufficient to help characterize the safety concern? Safety outcome Valvular Pulmonary heart arterial disease hypertension (VHD) (PAH) -Yes -No X X If “No”, please identify the area(s) of concern. -Surveillance or Study Population X X -Exposure -Outcome(s) of Interest X X -Covariate(s) of Interest X X -Surveillance Design/Analytic Tools Page 2 of 13 Reference ID: 46331494640015 1. BACKGROUND INFORMATION 1.1. Medical Product Fenfluramine hydrochloride1 (FINTEPLA, Zogenix, Inc.) is an amphetamine analogue that increases the extracellular levels of serotonin (5-HT) in nervous tissue.2 FINTEPLA, an oral solution containing 2.2 mg/mL fenfluramine equivalent to 2.5 mg/mL of the hydrochloride salt, is a new formulation of a previously approved product for the treatment of obesity, which was initially voluntarily withdrawn from the U.S. market in 1997 due to an association with valvular heart disease (VHD), then subsequently removed by the U.S. Food and Drug Administration (FDA) in 2015 (Food and Drug Administration 2015). Risk of pulmonary arterial hypertension (PAH) was the second reason for fenfluramine’s withdrawal from the market (Abenhaim, Moride et al. 1996).3 Fenfluramine is not currently marketed in any country.4 It is a racemic compound of two stereoisomers, (+)-fenfluramine (dexfenfluramine) and (-)-fenfluramine (levofenfluramine), which are N-de-ethylated in the liver to form the main metabolites, (+)- and (-)-norfenfluramine (Rothman and Baumann 2009). The new proposed indication is the treatment of seizures associated with Dravet syndrome (DS) in patients two years of age and older. DS, previously known as severe myoclonic epilepsy of infancy, is a severe developmental and epileptic encephalopathy characterized by the onset of prolonged febrile and afebrile seizures in infancy, and evolving to drug-resistant epilepsy with accompanying cognitive, behavioral, and motor impairment. It occurs in 1 in 15,700 births in the United States (Wu, Sullivan et al. 2015). Most cases are known to be caused by pathogenic variants in the sodium channel gene SCN1A (Steel, Symonds et al. 2017). Mortality during childhood and adolescence in patients with DS is about 15% (5– 20%), primarily due to status epilepticus in the early years and sudden unexpected death in epilepsy patients in adolescence and adulthood (Akiyama, Kobayashi et al. 2010, Cooper, McIntosh et al. 2016). Older children and adults with DS tend to have improved seizure control, but moderate to severe intellectual disability and motor system abnormalities (Connolly 2016). Although FINTEPLA’s mechanism of action is unclear and likely depends on multiple factors, it is theorized that it reduces seizures by increasing extrasynaptic serotonin levels through modulation of serotonin receptors (primarily 5-HT1A receptors); however, there is some evidence that the fenfluramine molecule (and possibly its metabolites) reduce seizures by binding at specific receptors. 5 The proposed dosing regimen is initiation of dosing at 0.2 mg/kg/day and increase to 0.4 mg/kg/day on day 7 and 0.7 mg/kg/day (maximum) on day 14 in patients who are not on concomitant stiripentol. For patients taking concomitant stiripentol, the starting dose is 0.2 mg/kg/day with an increase to 0.4 mg/kg/day. The maximum daily dose for patients not on stiripentol is 26 mg and 17 mg for those on concomitant stiripentol.6 The half-life is 20 hours following oral administration of FINTEPLA in healthy subjects.7 1 N-ethyl- -methyl-3-(trifluoromethyl)phenethylamine hydrochloride. 2 FINTEPLA (fenfluramine hydrochloride). Draft clinical review dated May 26, 2020. Division of Neurology 2. U.S. Food αand Drug Administration 3 Ibid. 4 Ibid. 5 Ibid. 6 Ibid. 7 Proposed FINTEPLA labeling dated June 25, 2020 Page 3 of 13 Reference ID: 46331494640015 Prior to 2018, there were no approved treatments of seizures associated with DS in the United States. In June 2018, FDA approved cannabidiol (EPIDIOLEX, GW Research Ltd) for the treatment of seizures associated with Lennox-Gastaut syndrome or DS in patients two years of age and older.8 In August 2018, FDA approved stiripentol (DIACOMIT, Biocodex SA) for the treatment of seizures associated with DS in patients two years of age and older taking clobazam.9 There are also number of drugs used off-label as part of standard of care, including clobazam, valproic acid, topiramate, and levetiracetam. The ketogenic diet is typically used as an adjunct to pharmacologic treatment(s).10 1.2. Describe the Safety Concern Summary of Historical Evidence for an Association of Fenfluramine and Dexfenfluramine with PAH and VHD at Higher Dosage Strengths When Used for Weight Loss FDA approved PONDIMIN (fenfluramine hydrochloride) tablets 20 mg and PONDEREX (fenfluramine hydrochloride) capsules 20 mg in 1973, PONDIMIN sustained release tablets 60 mg in 1982, and REDUX (dexfenfluramine hydrochloride) capsules 15 mg in 1996, as prescription appetite suppressants for the treatment of obesity (Food and Drug Administration 2015). Both fenfluramine and dexfenfluramine appeared to act by affecting the metabolism of the neurotransmitter serotonin in the brain (Centers for Disease and Prevention 1997). Although FDA did not approve the combination with phentermine, another appetite suppressant approved in 1959, the “fen-phen” combination became very popular; in 1996 the total number of prescriptions for fenfluramine and phentermine in the United States exceeded 18 million (Connolly, Crary et al. 1997). In 1993, French investigators reported a cluster of cases of PAH among patients who had used derivatives of fenfluramine (Brenot, Herve et al. 1993). In a case-control study conducted in Europe and published in 1996, the use of anorexic drugs, mainly derivates of fenfluramine, was associated with an increased risk of PAH (Abenhaim, Moride et al. 1996). In 1997, U.S. cardiac ultrasonographers and clinicians described VHD in 24 women without history of cardiac disease who had been treated with the combination of fenfluramine and phentermine (Connolly, Crary et al. 1997). On the basis of prepublication notification of this finding, FDA issued a Public Health Advisory in which it requested that other cases be reported. Graham et al. described 28 additional U.S. cases, all in women, with a similar history of VHD in association with the use of a combination of fenfluramine and phentermine (Graham and Green 1997). FDA announced the voluntary withdrawal of fenfluramine and dexfenfluramine from the market on September 15, 1997. As of September 30, 1997, FDA had received 144 individual spontaneous reports involving fenfluramine or dexfenfluramine, with or without phentermine, in association with valvulopathy (Centers for Disease and Prevention 1997). A subsequent meta-analysis of potential cases (n=3,769) indicated that fenfluramine-associated valvular regurgitation was less common than initially reported, but still present in one of eight patients treated for more than 90 days (Sachdev, Miller et al. 2002). Other studies provided additional information, but 8 EPIDIOLEX U.S. label dated December 12, 2018. Accessed on May 19, 2020, at https://www.accessdata.fda.gov/drugsatfda docs/label/2018/210365s002lbl.pdf 9 DIACOMIT U.S. label dated August 20, 2018. Accessed on May 19, 2020, at https://www.accessdata.fda.gov/drugsatfda docs/label/2018/206709s000,207223s000lbl.pdf 10 See footnote 2 Page 4 of 13 Reference ID: 46331494640015 the prevalence of VHD among obese patients not exposed to fenfluramine is not well- established because such individuals did not routinely have echocardiography prior to exposure, the relative risks of fenfluramine, alone or in combination with phentermine, as well as the effects of dose and duration of exposure, and the risk factors for fenfluramine-associated VHD are not well defined (Jick, Vasilakis et al. 1998, Khan, Herzog et al. 1998, Weissman, Tighe et al. 1998, Li, Serdula et al. 1999, Shively, Roldan et al. 1999). When given alone, phentermine has not been implicated in the pathogenesis of VHD. The suspected mechanism for fenfluramine-induced cardiac valvulopathy is off-target activation of 5-HT2B receptors located in cardiac valves by norfenfluramine (Rothman and Baumann 2009), whereas the mechanisms