Risdiplam is an mRNA-splicing modifier of survival of motor neuron 2 (SMN2) designed to treat mutations in band 5q that lead to SMN protein deficiency. It is indicated for treatment of spinal muscular atrophy (SMA), including types 1, 2, and 3, in adults and children aged 2 months and older.
FIREFISH was an open-label, 2-part pivotal clinical trial in infants aged 2-7 months with type 1 SMA. Results showed 7 (41%) of 17 infants achieved the ability to sit without support for at least 5 seconds and 19 (90%) of 21 were alive without permanent ventilation at 12 months. After a minimum of 23 months of treatment and reaching age 28 months or older, 17 (81%) of 21 were alive without permanent ventilation. ( Neurology. April 14, 2020;94(15 suppl))
The SUNFISH study was a 2-part, double-blind, placebo-controlled pivotal clinical trial in children and young adults (aged 2-25 years) with type 2 or 3 SMA. A clinically meaningful and statistically significant improvement in motor function among children and adults was observed as measured by a change from baseline in the Motor Function Measure 32 (MFM-32) total score. Improved upper limb motor function compared with baseline, as measured by the Revised Upper Limb Module (RULM), a secondary independent motor function endpoint of the study, also showed statistically significant improvement. (Evrysdi prescribing information)
Viltolarsen is indicated for Duchenne muscular dystrophy (DMD) in adults and children with a confirmed DMD gene mutation that is amenable to exon 53 skipping. It is an antisense oligonucleotide of the phosphorodiamidate morpholino oligomer (PMO) subclass. Viltolarsen binds to exon 53 of dystrophin pre-mRNA, resulting in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 53 skipping. Exon skipping is intended to allow for production of an internally truncated dystrophin protein. The underlying cause of DMD is a mutation or error in the gene for dystrophin, an essential protein involved in muscle fiber function.
Results were from the phase 2, two-period study in patients aged 4 to less than 10 years conducted in North America (N=16) and a multicenter, open-label study in boys aged 5 to less than 18 years conducted in Japan (N=16). In the North American study, of those patients who received the recommended dose of 80 mg/kg/wk (N=8), 100% of patients showed an increase in dystrophin levels after treatment. (Viltepso prescribing information)
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. April 9, 2020;381(15):1430-1442)
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 2 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) compared with placebo (P=.001). The trials also showed a higher percentage of patients achieved a 75% reduction in MMDs compared with placebo. ( Cephalalgia. March 2020;40(3):241-254; Neurology. March 31, 2020;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 and 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 placebo (P <.001). ( N Engl J Med. July 11, 2019;381(2):142-149) A corroborating study (n=1811) showed similar results. ( Lancet. August 31, 2019;394(10200):737-745)
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 (MS) 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 2 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 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). ( Lancet Neurol. November 2019;18(11):1009-1020)
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. November 2019;18(11):1021-1033)
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 that included approximately 1000 patients. A significant reduction of daily OFF time and dyskinesia with opicapone 50 mg was observed compared with placebo (P <.0001). ( Eur J Neurol. July 2019;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 neuropathological 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 notable neurology approvals
Epidiolex (cannabidiol) - Indicated for seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex in patients aged 1 year and older
Kesimpta (ofatumumab SC) - New subcutaneous dosage form indicated for relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease
Xeomin (incobotulinumtoxinA) - Indication for spasticity expanded to include upper limb spasticity (except cerebral palsy) in children aged 2-17 years
Vimpat (lacosamide) - New indication for adjunctive therapy of primary generalized tonic-clonic seizures in patients aged 4 years and older
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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Cite this: FDA Approvals, Highlights, and Summaries: Neurology - Medscape - Feb 24, 2021.