Relyvrio (sodium phenylbutyrate/taurursodiol)
Sodium phenylbutyrate/taurursodiol is indicated for treatment of amyotrophic lateral sclerosis (ALS) in adults. The precise mechanism is unknown. Sodium phenylbutyrate is a histone deacetylase inhibitor shown to upregulate heat-shock proteins and act as a small molecular chaperone, thereby ameliorating toxicity from endoplasmic reticulum stress. Taurursodiol recovers mitochondrial bioenergetics deficits through several mechanisms, including by preventing translocation of the Bax protein into the mitochondrial membrane, thus reducing mitochondrial permeability and increasing the cell’s apoptotic threshold. The precise mechanism of action in patients with ALS is unknown.
Approval was based on the CENTAUR trial. The phase 2 CENTAUR trial (n = 89 treatment; n = 48 placebo) showed patients treated with sodium phenylbutyrate/taurursodiol had slower progression of disease compared to those randomized to placebo. Also, the ALS functional rating scale revised (ALSFRS-R) score showed the highest score preservation in fine motor skill subscales. N Engl J Med. 202 Sep 3:383(10):919-930
The open-label extension (OLE) of the CENTAUR trial included 56 participants from the treatment group (ie, early start group) and 34 from the placebo group. In the early start group subjects, the risk of any key event was 47% lower (p = 0.003), and the risk of death or tracheostomy or permanent assisted ventilation was 49% lower (p = 0.007). Also, first hospitalization was 44% lower in this group (p = 0.03). J Neurol Neruosurg Psychiatry. 2022 May 16;93(8):871-875
The CENTAUR OLE showed the median survival in the early start group was 25 months compared to 18.5 months for the group starting treatment during the extension. Muscle Nerve. 2021 Jan;63(1):31-39
Ublituximab is a CD20-directed monoclonal antibody indicated for relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.
Approval was supported by results from the ULTIMATE I (n = 549) and ULTIMATE II (n = 545) trials. Compared with teriflunomide, ublituximab resulted in lower annualized relapse rates and fewer brain lesions on MRI than teriflunomide over a period of 96 weeks but did not result in a significantly lower risk of worsening of disability. In the ULTIMATE I trial, the annualized relapse rate was 0.08 with ublituximab and 0.19 with teriflunomide (p < 0.001); in the ULTIMATE II trial, the annualized relapse rates were 0.09 and 0.18, respectively (p = 0.002). N Engl J Med. 2022 Aug 25;387(8):704-714
Skysona (elivaldogene autotemcel)
Elivaldogene autotemcel is a one-time gene therapy designed to add functional copies of the ABCD1 gene into a patient’s own hematopoietic stem cells, resulting in the production of the adrenoleukodystrophy protein (ALDP). It is indicated to slow the progression of neurologic dysfunction in boys aged 4 to 17 years with early, active cerebral adrenoleukodystrophy (CALD), a rare, X-linked, peroxisomal disorder that affects production of ALDP.
Accelerated approval from the FDA was supported by interim results from the phase 2/3 STARBEAM study, which concluded that elivaldogene autotemcel may be an effective alternative to allogeneic stem-cell transplantation in boys with early stage CALD. N Engl J Med. 2017 Oct 26;377(17):1630-1638
Ganaxolone is a GABAA receptor–positive modulator. It binds specifically to GABAA receptors to enhance their inhibitory effects. It is indicated for seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in patients aged 2 years and older. CDD, a rare developmental epileptic encephalopathy, is largely a disease of pediatric and young adult patients.
Approval was based on the phase 3 MARIGOLD trial. Patients treated with ganaxolone (n = 49) showed a median 30.7% reduction in 28-day major motor seizure frequency, compared to a 6.9% reduction for those receiving placebo (n = 51) (p=0.0036). In the open-label extension study, patients treated with ganaxolone for at least 12 months (n = 48) experienced a median 49.6% reduction in major motor seizure frequency. Prescribing Information
Other neurology approvals
DaTscan (ioflupane I 123) – New indication as an adjunct to other diagnostic evaluations for striatal dopamine transporter visualization using single photon emission computed tomography (SPECT) brain imaging in adult patients with suspected Lewy body dementia
Adlarity (donepezil transdermal) – New transdermal patch indicated for treatment of mild, moderate, and severe Alzheimer dementia; originally approved as tablet and oral disintegrating tablet
Hyftor (sirolimus topical) – New dosage form indicated for treatment of facial angiofibroma associated with tuberous sclerosis in patients aged 6 years and older
Fintepla (fenfluramine) – New indication for seizures associated with Lennox-Gastaut syndrome (previously approved for seizures associated with Dravet syndrome) in patients aged 2 years and older
Ultomiris (ravulizumab) – C5 complement inhibitor, new indication for generalized myasthenia gravis
Radicava ORS (edaravone) – New oral suspension dosage form for adults with ALS
Firdapse (amifampridine) – Indication for Lambert-Eaton myasthenic syndrome expanded to include children aged 6 to 17 years
Dextromethorphan/bupropion is a new fixed-dose combination product indicated for treatment of adults with major depressive disorder (MDD). Dextromethorphan is an antagonist of the N-methyl-D-aspartate (NMDA) receptor. The tablet is formulated to increase the bioavailability and half-life of dextromethorphan by utilizing the bupropion component to increase plasma dextromethorphan concentrations by inhibiting its metabolism.
In the phase 3 GEMINI (glutamatergic and monoaminergic modulation in depression) study, there were significant improvements in depressive symptoms compared to placebo starting 1 week after treatment initiation. J Clin Psychiatry 2022 May 30;83(4)
Daridorexant is a dual orexin receptor antagonist. The orexin neuropeptide signaling system plays a role in wakefulness. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R is thought to suppress wake drive. Daridorexant is indicated for adults with insomnia characterized by difficulties with sleep onset and/or sleep maintenance.
Approval was based on two phase 3 multicenter, randomized, double-blind, placebo-controlled trials. Participants were randomized 1:1:1 to receive daridorexant 50 mg, daridorexant 25 mg, or placebo (study 1; n = 930), or daridorexant 25 mg, daridorexant 10 mg, or placebo (study 2; n = 307) every evening for 3 months. The primary endpoints were change from baseline in wake time after sleep onset (WASO) and latency to persistent sleep (LPS), measured by polysomnography, at months 1 and 3. In study 1, the daridorexant 25-mg and 50-mg doses showed a statistically significant improvement in all endpoints, compared to placebo, at both month 1 and month 3 (p<0.0001). In study 2, the daridorexant 25-mg dose showed statistically significant improvement in WASO at month 1 (p=0.0001) and month 3 (p=0.0028) compared to placebo. Lancet Neurol. 2022 Feb;21(2):125-139
Other psychiatry approvals
Vraylar (cariprazine) – New indication for adjunctive therapy for major depressive disorder
Xelstrym (dextroamphetamine transdermal) – New transdermal patch indicated for treatment of attention deficit hyperactivity disorder (ADHD) in adults and children aged 6 years and older
Nalmefene – Opioid antagonist reintroduced to the US market for management of known or suspected opioid overdose
Qelbree (viloxazine) – Indication for ADHD expanded to include adults
Igalmi (dexmedetomidine) – New buccal dosage form and indication for acute treatment of agitation associated with schizophrenia or bipolar I or II disorder
Zulresso (brexanolone) – Indication for postpartum depression expanded to include adolescents aged 15 years and older
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Cite this: Mary L. Windle. FDA Approvals, Highlights, and Summaries: Neurology and Psychiatry - Medscape - Mar 02, 2023.