FDA Drug Approvals: Neurology — Year in Review 2018

Mary L Windle, PharmD


January 15, 2019

Other Neurology Drug Approvals

Onpattro (patisiran)

Patisiran is indicated for adults with hereditary transthyretin-mediated amyloidosis with polyneuropathy (hATTR-PN). The drug contains a double-stranded, small-interfering ribonucleic acid (siRNA) formulated as a lipid complex for delivery to hepatocytes. It specifically binds to a genetically conserved sequence in the 3' untranslated region (3'UTR) of mutant and wild-type TTR mRNA, causing degradation via RNA interference.

Approval was based on the APOLLO clinical trial (n=225). At 18 months, patients taking patisiran showed significantly improved scores for the Neuropathy Impairment Score+7 and Norfolk QOL-DN compared with those taking placebo (P<.001). (N Engl J Med. 2018 Jul 5;379(1):11-21)

Tegsedi (inotersen)

Inotersen was approved by the FDA about 2 months after patisiran was approved for adults with hereditary transthyretin-mediated amyloidosis with polyneuropathy (hATTR-PN). Unlike patisiran, which is administered as an intravenous infusion every 3 weeks, inotersen is a once weekly subcutaneous injection that the patient or caregiver can administer. It is an antisense oligonucleotide that causes degradation of mutant and wild-type TTR mRNA by binding to TTR mRNA, which results in a reduction of serum TTR protein and TTR protein deposits in tissues.

Results from a placebo-controlled trial (n=172) supported approval. Patients were randomly assigned in a 2:1 ratio to receive weekly inotersen or placebo. Efficacy assessments observed in the modified Neuropathy Impairment Score+7 and the Norfolk QOL-DN showed improvement in those receiving inotersen (P<.001). (N Engl J Med. 2018 Jul 5;379(1):22-31)

Galafold (migalastat)

Migalastat is indicated for adults with Fabry disease and an amenable galactosidase-alpha gene (GLA) variant. Migalastat binds to and stabilizes endogenous alpha-galactosidase A (alpha-Gal A), which is made in the patient’s own cells, with the intention of enabling its trafficking from the endoplasmic reticulum to lysosomes (designed to act as a “pharmacological chaperone”). Once delivered to lysosomes, the alpha-Gal A enzyme can degrade the accumulated glycolipid (globotriaosylceramide [GL-3]) and globotriaosylsphingosine (lyso-Gb3).

Efficacy of migalastat is supported by the FACETS and ATTRACT clinical trials. Results from the FACETS trial showed that after 6 months, significantly more patients receiving migalastat experienced improvement in diarrhea compared with placebo (43% vs 11%; P=.02), including the subset with baseline diarrhea (71% vs 20%; P=.02). A decline in kidney peritubular capillary globotriaosylceramide inclusions correlated with diarrhea improvement; patients with a reduction of greater than  0.1 were 5.6 times more likely to have an improvement in diarrhea than those without such a reduction(P = .031). (Orphanet J Rare Dis. 2018 Apr 27;13(1):68)

Results from the ATTRACT trial showed that migalastat and enzyme replacement therapy (ERT) had similar effects on renal function. Left ventricular mass index decreased significantly with migalastat treatment (-6.6 g/m2 [-11.0 to -2.2]); there was no significant change with ERT. Predefined renal, cardiac, or cerebrovascular events occurred in 29% and 44% of patients in the migalastat and ERT groups, respectively. Plasma globotriaosylsphingosine remained low and stable following the switch from ERT to migalastat. (J Med Genet. 2017 Apr;54(4):288-296)

Firdapse (amifampridine phosphate)

Amifampridine is indicated for adults with Lambert-Eaton myasthenic syndrome (LEMS). Amifampridine blocks voltage-dependent potassium channels, thereby prolonging presynaptic cell membrane depolarization, which enhances calcium transport into nerve endings. The increased intracellular calcium concentrations facilitate exocytosis of acetylcholine-containing vesicles, which, in turn, enhances neuromuscular transmission.

Approval was based on two phase 3 placebo-controlled trials. Efficacy was assessed on the basis of scores on the Quantitative Myasthenia Gravis test (a 13-item physician-rated categorical scale assessing muscle weakness) and the Subject Global Impression scale (a 7-point scale on which patients rate their overall impression of the effects of the study treatment on their physical well-being). (Muscle Nerve. 2016 May;53(5):717-725)

A trial evaluating maintenance of strength showed that patients who were randomized to continuous amifampridine did not show greater than 30% deterioration in triple-timed up-and-go (3TUG) times, whereas 72% of those who tapered to placebo had more than 30% deterioration (P<.0001). (Muscle Nerve. 2018 Apr;57(4):561-568)


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