Atogepant is an oral calcitonin gene–related peptide (CGRP) receptor antagonist indicated for preventive treatment of episodic migraine. CGRP is thought to be causally involved in migraine pathophysiology.
Drug approval was based on the ADVANCE phase 3 trial. Patients received once-daily atogepant or placebo. Among 873 participants who were included in the efficacy analysis, 214 received atogepant 10 mg, 223 received atogepant 30 mg, 222 received atogepant 60 mg, and 214 were in the placebo group. Mean number of migraine days per month at baseline ranged from 7.5 to 7.9 in the 4 groups. Changes from baseline over 12 weeks were -3.7 days with 10-mg atogepant, -3.9 days with 30-mg atogepant, -4.2 days with 60-mg atogepant, and -2.5 days with placebo (P<0.001 for all comparisons with placebo). N Engl J Med. 2021 Aug 19; 385:695-706
Vyvgart (efgartigimod alfa)
Efgartigimod alfa is an Fc receptor antagonist indicated for generalized myasthenia gravis (gMG) in adults who are anti-acetylcholine receptor (AChR) antibody positive. Myasthenia gravis is an autoimmune disease in which IgG autoantibodies are formed against the nicotinic AChR or other components of the neuromuscular junction.
Efgartigimod alfa is an antibody fragment that targets the neonatal Fc receptor (FcRn), thereby reducing circulating IgG. FcRn prolongs IgG half-life. Antagonizing FcRn causes IgG catabolism, resulting in reduced overall IgG and pathogenic autoantibody levels, while avoiding widespread immunosuppression.Efgartigimod was effective and well-tolerated in the phase 3, randomized, placebo-controlled ADAPT trial, which enrolled 187 adults with gMG regardless of acetylcholine receptor antibody status. For 26 weeks, 84 patients were randomly assigned to receive efgartigimod 10 mg/kg and 83 to receive matching placebo. Both treatments were administered as 4 weekly IV infusions per cycle. The process was repeated as needed, depending on clinical response no sooner than 8 weeks after initiation of the previous cycle. Treatment with efgartigimod reduced disease burden and improved strength and quality of life in patients with gMG across 4 MG-specific scales. In addition, these benefits were observed early and were reproducible and durable. Lancet Neurol. 2021 Jul;20(7):526-536
Ponesimod is a sphingosine 1-phosphate (S1P) receptor 1 modulator that binds with high affinity to S1P receptor 1 and blocks the capacity of lymphocytes to regress from lymph nodes, reducing the number of lymphocytes in peripheral blood. Ponesimod is indicated for relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.
Approval for ponesimod was based on a head-to-head phase 3 trial (n = 1133). In that trial, ponesimod demonstrated superior efficacy in significantly reducing annual relapse by 30.5% compared to teriflunomide in patients with relapsing MS. Over the study period, 71% of patients treated with ponesimod had no confirmed relapses, as compared to 61% in the teriflunomide group. JAMA Neurol. 2021 May 1;78(5):558-567
Amondys 45 (casimersen)
Casimersen is an antisense oligonucleotide of the phosphorodiamidate morpholino oligomer (PMO) subclass. PMO binds to exon 45 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. Casimersen is indicated for Duchenne muscular dystrophy in patients with a confirmed mutation amenable to exon 45 skipping.
The ESSENCE trial—a placebo-controlled confirmatory trial to support the casimersen approval—is ongoing and expected to conclude in 2024. In the study, patients who received casimersen showed a significantly greater increase in dystrophin protein levels from baseline to Week 48 of treatment, as compared to those who received placebo. Study of SRP-4045 and SRP-4053 in DMD Patients (ESSENCE)
Aducanumab is a monoclonal antibody that targets beta-amyloid and binds to aggregated forms of beta-amyloid. The FDA granted accelerated approval for aducanumab based on the reduction in amyloid-beta plaques observed in patients treated for Alzheimer disease. The prescribing information specifies approval for patients with mild cognitive impairment or a mild dementia stage of disease, which was the population studied in the clinical trials. The prescribing information states that continued approval is contingent upon verification of clinical benefit in confirmatory trial(s).
Accelerated approval was based on 2 phase 3 trials. In a letter released by the FDA, the rationale for approval was explained. One of the clinical trials (EMERGE) was the first to show that high-dose aducanumab reduced amyloid-beta plaques—a hallmark finding in the brains of patients with Alzheimer disease—and slowed cognitive decline. The second trial (ENGAGE) showed no benefit of aducanumab versus placebo, at low or high doses. Debate continues regarding this approval. The materials for the FDA Peripheral and Central Nervous System Drugs Advisory Committee Meeting provide detailed analyses of these phase 3 trials.
Fosdenopterin is indicated to reduce the risk of mortality in patients with molybdenum cofactor deficiency type A (MoCD-A), a rare disease. Fosdenopterin provides an exogenous source of cyclic pyranopterin monophosphate (cPMP). MoCD-A is caused by a mutation in the molybdenum cofactor synthesis 1 gene (MOCS1), which causes a deficiency in molybdenum cofactor production. The exogenous intermediate substrate cPMP provided by the drug is subsequently converted to molybdenum cofactor, which is required for the activation of essential enzymes (eg, sulfite oxidase) to reduce the levels of neurotoxic sulfites. Decreased sulfite oxidase activity is thought to cause the severe and rapidly progressive CNS damage observed in patients with MoCD-A.
Fosdenopterin is the first effective therapy for patients with MoCD. A study in 15 neonates showed restoration of molybdenum cofactor-dependent enzyme activities following fosdenopterin and greatly improved neurodevelopmental outcome when fosdenopterin was started sufficiently early. Lancet. 2015 Nov 14;386(10007):1955-1963
Other neurology approvals
Botox (onabotulinumtoxinA) - Six additional muscle groups approved for upper limb spasticity in adults.
Gocovri (amantadine) - Gained FDA approval as adjunctive treatment to levodopa/carbidopa for Parkinson disease in patients experiencing "off" episodes.
Nurtec ODT (rimegepant) - Indication for migraine expanded to include preventive therapy. Originally approved for acute treatment.
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Cite this: FDA Approvals, Highlights, and Summaries: Neurology - Medscape - Feb 17, 2022.