Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis

Abstract

Background: Hereditary transthyretin amyloidosis is caused by pathogenic single-nucleotide variants in the gene encoding transthyretin ( TTR) that induce transthyretin misfolding and systemic deposition of amyloid. Progressive amyloid accumulation leads to multiorgan dysfunction and death. Inotersen, a 2'- O-methoxyethyl-modified antisense oligonucleotide, inhibits hepatic production of transthyretin.

Methods: We conducted an international, randomized, double-blind, placebo-controlled, 15-month, phase 3 trial of inotersen in adults with stage 1 (patient is ambulatory) or stage 2 (patient is ambulatory with assistance) hereditary transthyretin amyloidosis with polyneuropathy. Patients were randomly assigned, in a 2:1 ratio, to receive weekly subcutaneous injections of inotersen (300 mg) or placebo. The primary end points were the change in the modified Neuropathy Impairment Score+7 (mNIS+7; range, -22.3 to 346.3, with higher scores indicating poorer function; minimal clinically meaningful change, 2 points) and the change in the score on the patient-reported Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating poorer quality of life). A decrease in scores indicated improvement.

Results: A total of 172 patients (112 in the inotersen group and 60 in the placebo group) received at least one dose of a trial regimen, and 139 (81%) completed the intervention period. Both primary efficacy assessments favored inotersen: the difference in the least-squares mean change from baseline to week 66 between the two groups (inotersen minus placebo) was -19.7 points (95% confidence interval [CI], -26.4 to -13.0; P<0.001) for the mNIS+7 and -11.7 points (95% CI, -18.3 to -5.1; P<0.001) for the Norfolk QOL-DN score. These improvements were independent of disease stage, mutation type, or the presence of cardiomyopathy. There were five deaths in the inotersen group and none in the placebo group. The most frequent serious adverse events in the inotersen group were glomerulonephritis (in 3 patients [3%]) and thrombocytopenia (in 3 patients [3%]), with one death associated with one of the cases of grade 4 thrombocytopenia. Thereafter, all patients received enhanced monitoring.

Conclusions: Inotersen improved the course of neurologic disease and quality of life in patients with hereditary transthyretin amyloidosis. Thrombocytopenia and glomerulonephritis were managed with enhanced monitoring. (Funded by Ionis Pharmaceuticals; NEURO-TTR ClinicalTrials.gov number, NCT01737398 .).

Figure 1.. Randomization and Follow-up.

One patient in the inotersen group underwent randomization in error and did not begin the trial regimen. Adverse events leading to discontinuation of inotersen were thrombocytopenia (in 2 patients), abdominal distention, intestinal perforation, nausea, vomiting, pyrexia, hypersensitivity, decreased platelet count, cachexia (in 2 patients), arthralgia, myalgia, chorea, dementia, embolic stroke, intracranial hemorrhage, myelopathy, myoclonus, acute kidney injury, glomerulonephritis, tubulointerstitial nephritis, pruritus, reticular erythematous mucinosis, and deep-vein thrombosis; 6 of 16 patients (38%) discontinued inotersen because of multiple events. Adverse events leading to discontinuation of placebo were pain, increased weight, and arthralgia. Of the 2 patients in the inotersen group who discontinued the trial regimen because they were withdrawn by the sponsor, 1 patient whose data were unblinded for safety monitoring was allowed to enroll in the open-label extension study. NIS denotes Neuropathy Impairment Score.

Figure 2.. Change from Baseline in Primary End Points.

Brackets indicate the difference in the least-squares mean change from baseline between the inotersen group and the placebo group. Composite scores on the modified Neuropathy Impairment Score+7 (mNIS+7) scale range from −22.3 to 346.3 (the higher the score, the poorer the function), and total scores on the Norfolk Quality of Life–Diabetic Neuropathy (QOL-DN) questionnaire range from −4 to 136 (the higher the score, the poorer the quality of life). A decrease in score indicated an improvement on each scale. A 2-point change in the NIS+7 has been defined as the minimal clinically meaningful change detectable.^, Changes in the patient-reported Norfolk QOL-DN score have been shown to be proportional to changes in the Neuropathy Impairment Score (range, 0 to 244, with a higher score indicating poorer function). I bars indicate standard errors.