Blocking production of transthyretin (TTR) improves the polyneuropathy caused by hereditary TTR amyloidosis (hATTR), two new phase III trials have shown. The two drugs, patisiran and inotersen, also improved quality of life for patients.

hATTR is caused by mutations in the TTR gene, which lead to misfolding and systemic deposition of the TTR protein. Polyneuropathy is a major manifestation of the disease.

“Neuropathic changes result in profound sensorimotor disturbances, with deterioration in activities of daily living and ambulation, diarrhoea, hypotension, impotence and bladder disturbances,” explains David Adams, who led one trial and was involved in the other.

TTR is primarily synthesized in the liver, and both of the trialled therapeutic strategies are designed to stop its production. Patisiran is an RNA interference therapeutic that is specifically targeted to hepatic cells by lipid nanoparticles, and inotersen is an antisense oligonucleotide. Both of the agents target TTR mRNA.

The trial of patisiran included 225 patients with hATTR stages 1 or 2. Patients were randomly assigned to receive intravenous patisiran or a placebo. The drug was administered once every 3 weeks for 18 months.

After 18 months of treatment, mean scores on the modified Neuropathy Impairment Score + 7 (mNIS + 7) were significantly lower among patients who received patisiran than among those who received placebo. Scores decreased from baseline in 56% of patients who received patisiran and in just 4% of patients who received placebo. Furthermore, quality of life (assessed with the Norfolk Quality of Life–Diabetic Neuropathy (QOL–DN) questionnaire) at 18 months was better than baseline among patients who received patisiran. Mild or moderate adverse events were common with patisiran, but the rate of serious adverse events was no higher than with placebo.

“Patisiran reversed the disease and efficacy was observed regardless of the stage of the disease,” says Adams. “Until now, only a few patients have had access to liver transplantation or TTR stabilizers, which slow progression only in stage 1 disease. We think that most patients can benefit from patisiran.”

In the trial of inotersen, led by Teresa Coelho, 172 patients with stage 1 or 2 hATTR were randomly assigned to receive weekly injections of inotersen or a placebo for 15 months. Reductions in mNIS + 7 scores and Norfolk QOL–DN scores were greater with inotersen than with placebo. “The efficacy against both co-primary end points was remarkable,” says Coelho. “Not only did patients do better, but many experienced improvements in their disease.”

Safety was a greater concern with inotersen than with patisiran. One person died from an intracranial haemorrhage associated with thrombocytopenia, an adverse effect seen in 54% of patients who received inotersen. Three patients who received inotersen developed glomerulonephritis.

Nevertheless, the results of both trials suggest that RNA-based therapies could transform treatment of hATTR. “We look forward to the potential approval of inotersen so we can begin getting this important drug to patients,” says Coelho.

The success of these drugs could be just the beginning. “Ionis is developing a drug similar to inotersen that is even more potent and convenient to use, so I am looking forward to participating in clinical trials of ‘next-generation’ antisense drugs,” concludes Coelho.