FDA Approvals, Highlights, and Summaries: Neurology

February 27, 2020

Nourianz (istradefylline)

Istradefylline, a selective adenosine A2A antagonist, is indicated as adjunctive treatment to levodopa/carbidopa in adults with Parkinson disease experiencing OFF episodes. Approval was based on several randomized, placebo-controlled trials (n=1143) in patients stabilized on levodopa/carbidopa with or without other medications for their Parkinson disease. Results showed statistically significant decreases in OFF time in the istradefylline treatment groups compared with placebo.

Mov Disord. 2018 July;28(8):1338-1141

Clin Neuropharmacol. 2015 Mar-Apr;38(2):41-6

Mov Disord. 2010 Jul 30;25(10):1437-43

Reyvow (lasmiditan)

Lasmiditan is the first of a new serotonin agonist drug class that binds to 5-HT1F. Serotonin 5-HT1F agonists (ie, ditans) do not elicit a vasoconstrictive effect. It is indicated for treatment of acute migraine with or without aura. Approval was based on 2 phase 3 studies, SAMURAI and SPARTAN, and an open-label GLADIATOR trial, totaling nearly 4000 patients. Collectively, the trials found the percentage of patients who were free of migraine pain at 2 hours postdose ranged from 28.2 to 38.8% compared with a placebo range of 15.3 to 21.3% (P<.001 to .003).

Neurology 2018 Dec 11;91(24):e2222-32232;

Brain. 2019 Jul 1;142(7):1894-1904;

Cephalalgia. 2019 Oct;39(11):1343-1357

Xcopri (cenobamate)

Cenobamate is indicated for adults with partial-onset seizures as either monotherapy or adjunctive therapy. The precise mechanism is unknown, but it has been shown to reduce repetitive neuronal firing by inhibiting voltage-gated sodium currents. It is also a positive allosteric modulator of the GABA-A ion channel.

The clinical trial program included over 1900 patients. Adjunctive treatment with cenobamate was found to significantly decrease seizure frequency in 2 well-controlled studies; however, cases of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome were reported in early clinical development among the first patients exposed to the drug. In December 2018, results from a large phase 3 safety study showed that among the 1037 patients exposed to cenobamate, no cases of DRESS syndrome were identified; reducing the starting dose and slowing the titration rate appeared to reduce the risk.

Results from a multicenter, double-blind, randomized, placebo-controlled study (Study 013) at 107 epilepsy and neurology centers in 16 countries were reported. The dose-response study included a 6-week titration phase followed by a 6-week maintenance phase. A statistically significant 56% reduction in median seizure frequency was seen with cenobamate 200 mg/day (n=113) compared with a 22% reduction with placebo (n=108). In Study 017, which included a 6-week titration phase followed by a 12-week maintenance phase, patients randomized to cenobamate 100 mg/day (n=108), 200 mg/day (n=109), or 400 mg/day (n=111) had statistically significant 36%, 55%, and 55% reductions in median seizure frequency, respectively, compared with a 24% reduction with placebo (n=106).

Lancet Neurol. 2020 Jan;19(1):38-48

Vyondys 53 (golodirsen)

Golodirsen is an antisense oligonucleotide indicated for Duchenne muscular dystrophy in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping.

Approval was based on an increase in dystrophin production in skeletal muscle observed in patients who were treated. Mean dystrophin levels increased from 0.1% (standard deviation [SD], 0.07) of normal at baseline to 1.02% (SD, 1.03) of normal by week 48, with a mean change in dystrophin of 0.92% (SD, 1.01) of normal levels (P<.001); the median change from baseline was 0.88%.

Vyondys 53 prescribing information

Ubrelvy (ubrogepant)

Ubrogepant is the first drug in the class of calcitonin gene–related peptide (CGRP) antagonists approved for treatment of acute migraine. Ubrogepant is administered orally. Previously approved CGRP antagonists are indicated for migraine prophylaxis.

Approval was based on 2 randomized, double-blind, placebo-controlled trials (ACHIEVE I and ACHIEVE II). In total, 1439 adults with a history of migraine, with and without aura, received ubrogepant to treat an ongoing migraine headache. The percentage of participants who had freedom from pain at 2 hours in the ACHIEVE I study was 11.8% in the placebo group, 19.2% in the 50-mg ubrogepant group (P=.002, adjusted for multiplicity, for the comparison with placebo), and 21.2% in the 100-mg ubrogepant group (P<.001).

N Engl J Med. 2019 Dec 5;381(23):2230-2241

The ACHIEVE II trial had similar results of 14.3% in the placebo group and 21.8% in the 50-mg ubrogepant group (P = .01).

JAMA. 2019 Nov 19;322(19):1887-1898

Mayzent (siponimod)

Siponimod, an oral sphingosine 1-phophate (S1P) receptor modulator, is indicated for adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive MS (SPMS). It binds with high affinity to S1P receptors 1 and 5, thereby blocking lymphocyte egress from lymph nodes, which reduces the number of lymphocytes in peripheral blood.

Approval of siponimod was based on results of the phase 3 EXPAND trial, which randomly assigned 1651 patients with SPMS and an Expanded Disability Status Scale score of 3-6.5 to siponimod 2 mg once daily (n=1105) or placebo (n=546) for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression events. At baseline, the mean time since first MS symptoms was 16.8 years and the mean time since conversion to SPMS was 3.8 years; 64% of patients had not relapsed in the previous 2 years, and 56% needed walking assistance.

The primary endpoint was time to 3-month confirmed disability progression. This occurred in 26% of the siponimod group and in 32% of those receiving placebo (hazard ratio, 0.79; 95% confidence interval, 0.65-0.95; relative risk reduction, 21%; P=.013). Siponimod also meaningfully delayed the risk of 6-month confirmed disability progression (26% vs placebo, P=.0058) and demonstrated favorable outcomes in other relevant measures of MS disease activity and progression.

Lancet. 2018 Mar 31;391(10127):1263-1273

Zolgensma (onasemnogene abeparvovec)

Onasemnogene abeparvovec is a recombinant AAV9-based gene therapy designed to deliver a copy of the gene encoding the human survival motor neuron (SMN) protein. It is indicated for gene replacement therapy in children aged 2 years or younger with spinal muscular atrophy (SMA) type 1 (also called Werdnig-Hoffman disease) who have biallelic mutation in the survival motor neuron 1 (SNM1) gene.

Approval was based on the ongoing phase 3 STR1VE trial and the completed phase 1 START trial. Fifteen patients with SMA type 1 received a single dose of intravenous adeno-associated virus serotype 9 carrying SMN-complementary DNA encoding the missing SMN protein. As of the data cutoff, all 15 patients were alive and event-free at age 20 months, as compared with a rate of survival of 8% in a historical cohort. In the high-dose cohort, a rapid increase from baseline in the score on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale followed gene delivery, with an increase of 9.8 points at 1 month and 15.4 points at 3 months, as compared with a decline in this score in a historical cohort. Of the 12 patients who had received the high dose, 11 sat unassisted, 9 rolled over, 11 fed orally and could speak, and 2 walked independently. Elevated serum aminotransferase levels occurred in 4 patients and were attenuated by prednisolone.

N Engl J Med. 2017 Nov 2;377(18):1713-1722

Interim data analysis from the ongoing phase 3 STR1VE trial described 21 (95%) of 22 patients were alive and event-free. The median age was 9.5 months, with 6 (86%) of 7 patients aged 0.5 months or older surviving event-free. Interim results also showed ongoing improvement of motor milestones (eg, holding head erect, rolling over, sitting without support).

Pediatr Pulmonol. 2019 Feb;54(2):179-185

STR1VE interim data analysis

Sunosi (solriamfetol)

Solriamfetol is a dopamine/norepinephrine reuptake inhibitor indicated to improve wakefulness in adults with excessive daytime sleepiness caused by narcolepsy or obstructive sleep apnea (OSA).

In a phase 3 randomized clinical trial, 239 patients with narcolepsy received solriamfetol 75 mg, 150 mg, or 300 mg (2 times the maximum recommended daily dose), or placebo, once daily. Compared with the placebo group, patients randomized to 150 mg showed statistically significant improvements on the maintenance of wakefulness test (MWT) and on the Epworth Sleepiness Scale (ESS) at week 12. These effects were apparent at week 1 and consistent with the results at week 12. At week 12, a higher percentage of patients treated with solriamfetol 150 mg (78.2%) reported patient global impression of change (PGIc) scale improvement relative to placebo (39.7%; P<.0001).

Ann Neurol. 2019 Mar;85(3):359-370

Approval for excessive daytime sleepiness in adults with OSA was based on the TONES 3 randomized controlled trial. A total of 476 patients with OSA were randomized to receive solriamfetol 37.5 mg, 75 mg, or 150 mg, or placebo, once daily. Coprimary endpoints (MWT and ESS) were met at all solriamfetol doses (P<.05), with dose-dependent effects observed at week 1 maintained over the 12-week study duration. All doses except 37.5 mg resulted in higher percentages of participants reporting improvement on PGIc (key secondary endpoint; P<.05).

Am J Respir Crit Care Med. 2018 Dec 6

Additional 2019 Neurology approvals

Myobloc (rimabotulinumtoxinB) was approved for chronic sialorrhea.

Vumerity (diroximel fumarate) is indicated for relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

Mavenclad (cladribine) was approved for treatment of relapsing forms of multiple sclerosis, including relapsing-remitting disease and active secondary progressive disease.

Nayzilam (midazolam intranasal) is indicated for acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy.

Emgality (galcanezumab) was approved for treatment of episodic cluster headache.

Inbrija (levodopa inhaled) in a new dosage form was approved for intermittent treatment of OFF episodes in patients with Parkinson disease who are treated with carbidopa/levodopa.


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