The US Food and Drug Administration (FDA) has approved inotersen (Tegsedi, Akcea Therapeutics, and Ionis Pharmaceuticals) for the treatment of polyneuropathy (PN) in adults with hereditary transthyretin amyloidosis (hATTR).
hATTR-PN is a rare, progressive condition in which a mutation in the transthyretin (TTR) gene can lead to TTR amyloidosis, a severe, progressive deposition of amyloid in organs that results in multiorgan failure. Inotersen is an antisense oligonucleotide inhibitor of both mutant and wild-type TTR protein.
FDA's approval of inotersen
The FDA's approval of inotersen was based on results from the phase 3 NEURO-TTR study, which were presented at the American Neurological Association Annual Meeting in 2017 and were reported.
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.
Treatment with inotersen produced up to a 79% mean decrease from baseline in serum TTR protein in patients regardless of TTR mutation, sex, age, or race.
Patients treated with inotersen showed a mean improvement of nearly 20 points in the primary endpoint of the modified Neuropathy Impairment Score+7 (mNIS+7) compared with patients given a placebo.
A statistically significant benefit was seen as early as month 8. The mNIS+7 score includes measures of factors such as muscle weakness, reflexes, nerve conduction, autonomic function, and sensation.
Patients treated with inotersen also improved concerning 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.
"The rapid and sustained improvements compared to placebo and reversal in measures of disease seen in a substantial proportion of patients coupled with the independence offered through self-injection provide a sense of hope not only to patients but to their caregivers and families as well," Morie Gertz, MD, the Mayo Clinic, Minnesota.
"This approval represents a significant advancement for the patients, families, caregivers and healthcare professionals in the US who need more options for the medical management of this disease," added Isabelle Lousada, founder and CEO of the Amyloidosis Research Consortium.
"I am now more optimistic than ever that we can increase awareness of this rare disease, support faster diagnosis and provide better treatment," said Lousada.
Inotersen is associated with risk for thrombocytopenia and glomerulonephritis. Enhanced monitoring is required to support the early detection and management of these identified risks. The drug is being marketed with a risk evaluation and mitigation strategy. Full prescribing information, including a boxed warning, is available online.