CHMP Recommends Approval for Inotersen in hATTR

Susan Jeffrey


June 07, 2018

The European Medicines Agency (EMA)'s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion, recommending market authorization for inotersen (Tegsedi, IONIS USA) for the treatment of stage 1 or stage 2 polyneuropathy (PN) in adults with hereditary transthyretin amyloidosis (hATTR).

The drug, which will be available as a 284-mg solution for injection, was designated an orphan medicinal product in March 2014 and was reviewed under the EMA's accelerated assessment program, notes an EMA statement on the decision dated May 31.  

hATTR-PN is a rare and progressive condition in which a mutation in the transthyretin (TTR) gene can lead to TTR amyloidosis, a severe and progressive deposition of amyloid in organs that results in multiorgan failure. Life expectancy is approximately 5 to 15 years after symptom onset.

Inotersen is an antisense oligonucleotide inhibitor of both mutant and wild-type TTR protein, the EMA release notes. "Inotersen selectively binds to the TTR messenger RNA (mRNA) and causes its degradation," the statement said. "This prevents the synthesis of TTR protein in the liver, resulting in significant reductions in the levels of TTR in the circulation and so reducing amyloid deposition."

Results of a phase 3, double-blind, placebo-controlled trial of inotersen were presented at the 142nd American Neurological Association Annual Meeting in 2017 and reported by Medscape Medical News at that time.

For the study, 172 patients with stage 1 or 2 hATTR-PN were randomly assigned to receive weekly self-administered subcutaneous injections of inotersen (300 mg; n = 112) or placebo (n = 60) for 15 months.

"We found clinically and highly statistically significant benefit in [study endpoints] in favor of inotersen treatment, with significance over placebo achieved as early as 8 months," said first author Annabel K. Wang, MD, an associate professor of neurology and director of the Neuromuscular Diagnostic Laboratory at the University of California Irvine, in presenting the findings.

Patients treated with inotersen for 15 months showed a mean improvement of nearly 20 points in the primary endpoint of the modified Neuropathy Impairment Score+7 (mNIS+7) compared with placebo, with a statistically significant benefit seen as early as month 8. The mNIS+7 score includes such measures as muscle weakness, reflexes, nerve conduction, autonomic function, and sensation.

The most important side effects of inotersen are injection site reactions, thrombocytopenia, and glomerulonephritis, the EMA statement notes. 

"It is proposed that Tegsedi be prescribed by physicians experienced in the treatment of hereditary transthyretin amyloidosis," the release concludes. "Detailed recommendations for the use of this product will be described in the summary of product characteristics (SmPC), which will be published in the European public assessment report (EPAR) and made available in all official European Union languages after the marketing authorisation has been granted by the European Commission."


Another treatment being investigated for hATTR-PN is patisiran (Alnylam Pharmaceuticals). Results of the phase 3 APOLLO trial were presented at the American Academy of Neurology 2018 Annual Meeting and reported by Medscape Medical News.

Patisiran is an investigational lipid nanoparticle formulated RNA1, given by intravenous infusion, targeting hepatic production of mutant and wild-type TTR. It is under priority review as a breakthrough therapy by the US Food and Drug Administration (FDA), a company release said, and is under accelerated assessment by the EMA. The FDA has set a Prescription Drug User Fee Act date of August 11, 2018, the company noted.

The APOLLO trial was a randomized, double-blind, placebo-controlled study looking at the efficacy and safety of patisiran in patients with hATTR-PN. A total of 225 patients from 44 sites in 19 countries were randomly assigned in a 2:1 ratio to patisiran or placebo. Patisiran was given at a dose of 0.3 mg/kg once every 3 weeks for 18 months.

"Patisiran treatment resulted in significant improvement in polyneuropathy from baseline relative to placebo," said lead author David D. Adams, MD, PhD, Department of Neurology at Bicêtre Hospital, Greater Paris University Hospitals, France.

There were also significant improvements in quality of life, reduction in disease symptoms and disability, and improvement especially in ambulation with treatment vs placebo, he noted

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