FDA Drug Approvals — 2019 Midyear Review

Mary L Windle, PharmD


August 09, 2019

Neurologic Agents

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 (1105 patients) or placebo (546 patients) 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 multiple sclerosis 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.[13]

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.[14]

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).[15,16]

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 were randomized to receive 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).[17]

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).[18]

Other notable neurology approvals

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.

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

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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