FDA Drug Approvals, Neurology — 2020 Midyear Review

August 14, 2020

Koselugo (selumetinib)

Selumetinib is an inhibitor of mitogen-activated protein kinases 1 and 2 (MEK1/2). MEK 1/2 proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway. Inhibition of ERK phosphorylation is thought to reduce neurofibroma numbers, volume, and proliferation. Selumetinib is indicated for neurofibromatosis type 1 (NF1) in pediatric patients aged 2 years or older who have symptomatic, inoperable plexiform neurofibroma.

FDA approval was based on results from the phase 2 SPRINT Stratum 1 trial, in which 50 patients with NF1 received selumetinib as twice-daily oral monotherapy. Of this group, 33 (66%) patients had a partial response of at least a 20% reduction in tumor volume.

( N Engl J Med 2020 Apr 9;381(15):1430-1442)

Vyepti (eptinezumab)

Eptinezumab is a humanized IgG1 monoclonal antibody specific for binding to the calcitonin gene-related peptide (CGRP) ligand. CGRP is thought to be causally involved in migraine pathophysiology. It is administered as a 30-minute intravenous infusion every 3 months for prevention of migraine . Approval was based on two phase 3 trials, PROMISE-1 (n=665) and PROMISE-2 (n=1072). The percentage of responders with at least 50% reduction of monthly migraine days (MMDs) from baseline was higher with eptinezumab (100 mg or 300 mg IV every 3 months) than with placebo (P=.001). The trials also showed a higher percentage of patients achieved a 75% reduction in MMDs compared with patients who received placebo.

(Cephalalgia 2020 Mar;40(3):241-254

Neurology 2020 Mar 31;94(3)e1365-1377)

Nurtec ODT (rimegepant)

Rimegepant is a calcitonin gene-related peptide (CGRP) antagonist. The oral disintegrating tablet is indicated for treatment of acute migraine with or without aura.  Rimegepant approval was supported by a phase 3 trial (n=1186) of patients with moderate-to-severe migraine, with a frequency of 2-8 attacks per month. The percentage of patients who were pain-free 2 hours after receiving rimegepant was 19.6% compared with 12% in the placebo group (P <.001). The percentage of patients who were free from their most bothersome symptom 2 hours after rimegepant was 37.6% compared with 25.2% for the placebo group (P <.001). A corroborating study (n=1811) showed similar results.

( N Engl J Med 2019 Jul 11;381(2):142-149

Lancet 2019 Aug 31;394(10200):737-745)

Zeposia (ozanimod)

Ozanimod is a sphingosine 1-phosphate (S1P) receptor modulator. It binds with high affinity selectively to S1P subtypes 1 (S1P1) and 5 (S1P5) and, thereby, blocks lymphocyte egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which ozanimod exerts therapeutic effects in multiple sclerosis is unknown, but it may involve reduction of lymphocyte migration into the CNS. Ozanimod is indicated for relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

Approval of ozanimod by the FDA was based on two phase 3 clinical trials (SUNBEAM, RADIANCE). The SUNBEAM trial (n=1346) was conducted at 152 academic medical centers and clinical practices in 20 countries. Patients were randomly assigned to ozanimod 1 mg (n=447), ozanimod 0.5 mg (n=451), or interferon-beta1a (n=448). The primary endpoint was the annualized relapse rate (ARR). Patients treated for at least 12 months had a significantly lower relapse rate compared with those who received interferon-beta1a. Adjusted ARRs were 0.35 for interferon-beta1a, 0.18 for ozanimod 1 mg (P <.0001), and 0.24 for ozanimod 0.5 mg (P=.0013). The RADIANCE trial (n=1320) analyzed ozanimod data at 24 months of duration. Ozanimod was associated with significantly lower rates of clinical relapses compared with interferon-beta1a. Adjusted ARRs were 0.17 with ozanimod 1 mg, 0.22 with ozanimod 0.5 mg, and 0.28 with interferon-beta1a, with rate ratios versus interferon-beta1a of 0.62 (P <.0001) for ozanimod 1 mg and 0.79 (P=.0167) for ozanimod 0.5 mg

(Lancet Neurol 2019 Nov;18(11):1009-1020

Lancet Neurol 2019 Nov;18(11):1021-1033)

Ongentys (opicapone)

Opicapone is a once-daily, peripherally acting catechol-o-methyl transferase (COMT) inhibitor. COMT inhibitors decrease the conversion rate of levodopa to 3-O-methyldopa, and thereby prolong the levodopa half-life to reduce Parkinson disease motor fluctuations. Opicapone is indicated as an adjunct to levodopa/carbidopa to reduce “OFF” episodes in patients with Parkinson disease.

Approval was based on the BIPARK-1 and BIPARK-2 phase 3 clinical studies, which included approximately 1000 patients. A significant reduction of daily OFF time and dyskinesia with opicapone 50 mg was observed when compared with placebo (P <.0001).

(Eur J Neurol 2019 Jul;26(7):953-960 )

Tauvid (flortaucipir F18)

Flortaucipir F18 binds to aggregated tau protein. In brains of patients with Alzheimer disease, tau aggregates combine to form neurofibrillary tangles (NFTs), 1 of 2 components required for neuropathologic diagnosis of Alzheimer disease. It is indicated for use with positron-emission tomography (PET) imaging of the brain to estimate the density and distribution of aggregated tau NFTs in adults with cognitive impairment who are being evaluated for Alzheimer disease.

The safety and effectiveness were demonstrated in 2 clinical studies. In each study, 5 evaluators, blinded to clinical information, interpreted the flortaucipir F18 PET scan results as positive or negative. The first study included 156 terminally ill patients who agreed to undergo flortaucipir F18 PET imaging and to donate their brains after death. Of these patients, 64 died within 9 months of undergoing brain scanning. The evaluators' readings of these scans were compared with postmortem readings from independent pathologists blinded to scan results.

Evaluators reading the flortaucipir F18 PET scans had a "high probability" of correctly evaluating patients with tau pathology and had an "average-to-high probability" of correctly evaluating patients without tau pathology. Reader sensitivity ranged from 92% (95% confidence interval [CI], 80-97%) to 100% (95% CI, 91-100%). Specificity ranged from 52% (95% CI, 34-70%) to 92% (95% CI, 75-98%).

(Tauvid prescribing information)

Other neurology approvals

Fintepla (fenfluramine) - Reintroduced to US market with new indication for seizures associated with Dravet syndrome in patients aged 2 years or older.

Bafiertam (monomethyl fumarate) - Indicated for relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

Xywav (oxybate mixed salts) - New mixed-salt oxybate for narcolepsy with 92% lower sodium content.

Qutenza (capsaicin transdermal) - New prescription-strength product for neuropathic pain associated with postherpetic neuralgia.


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