Nancy A. Melville

October 20, 2017

SAN DIEGO — The investigational drug inotersen (Ionis Pharmaceuticals) shows high efficacy in the treatment of the hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) in a phase 3, double-blind, placebo-controlled trial.

"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 here at the ANA 2017: 142nd  Annual Meeting of the American Neurological Association.

There are no treatments approved by the US Food and Drug Administration  for hATTR-PN, 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 TTR protein.

In the pivotal, placebo-controlled trial, 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.

"A higher score means worse neuropathy, so the patients on placebo worsened by 20 points compared to the patients who received inotersen," Dr Wang told Medscape Medical News. "All patients were walking before they entered the study."

She added in a press statement that "A 20-point benefit in mNIS+7 is unprecedented and could mean the difference between the ability to walk and being confined to a wheelchair for patients suffering from this debilitating and fatal disease."

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.

In addition to the endpoint of the mNIS+7 score, patients also improved in the other primary endpoint of the Norfolk Quality of Life Diabetic-Neuropathy score, with a mean change from baseline of –11.68 compared with placebo.

Those scores varied with stage 1 (P = .01) and stage 2 (P = .008) disease compared with placebo, as well as according to previous use of stabilizers (P = .05) and being treatment naive (P = .003).
More than 80% of patients completed the study and more than 95% (n = 135) enrolled in the open-label extension study, looking at treatment for up to 5 years.

In terms of safety, three serious adverse events were reported involving thrombocytopenia, all inotersen-treated, including two patients who fully recovered and one patient who died of intracranial hemorrhage and low platelet counts. An additional patient treated with inotersen discontinued use because of nonserious thrombocytopenia.

Renal events occurred in two inotersen-treated patients because of treatment-emergent renal serious adverse events and in two because of pre-existing renal disease, as well as in one placebo-treated patient.

The authors noted that all five serious adverse events occurred before full implementation of enhanced monitoring.

"Changes in platelet counts and renal function were seen, but with close monitoring could be picked up earlier before there were significant changes," Dr Wang said. "Kidney function can also be affected in hATTR, so that may also play a role."

Inotersen is in competition with a drug with a similar mechanism of action, patisiran (Alnylam), also in development for hATTR, and details on that drug's phase 3 trial are expected to be reported next month.

In commenting on the inotersen findings, Conrad C. Weihl, MD, PhD, associate professor of neurology at Washington University School of Medicine, St Louis, Missouri, said interest is high in the prospect of the new treatment approach.

"The excitement relates to this being the very first use of antisense mediated therapy in a dominantly inherited proteinopathy," he told Medscape Medical News.

"This same type of therapy is being proposed for Huntington's disease and SOD1 in ALS [amyotrophic lateral sclerosis], so this study, while being effective, is more exciting as it relates to proof of concept for the much larger group of neurodegenerative disorders that are associated with amyloidosis."

He agreed that the adverse events are a concern, but other results on the drug are anticipated to provide a fuller picture of its risks and benefits.  

"The renal side effects are worrisome but monitorable," Dr Weihl said.

"It will be interesting to see if the other systemic problems with TTR amyloidosis, specifically cardiac and hepatic, are corrected as well, as this study was powered for neuropathy."

The study was sponsored by Ionis Pharmaceuticals Inc. Dr Wang and Dr Weihl have disclosed no relevant financial relationships.

ANA 2017: 142nd Annual Meeting of the American Neurological Association. Abstract S318WIP. Presented October 16, 2017.

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