Long-term efficacy and safety of inotersen for hereditary transthyretin amyloidosis: NEURO-TTR open-label extension 3-year update

Abstract

Background: Hereditary transthyretin amyloidosis (hATTR/ATTRv) results from the deposition of misfolded transthyretin (TTR) throughout the body, including peripheral nerves. Inotersen, an antisense oligonucleotide inhibitor of hepatic TTR production, demonstrated a favorable efficacy and safety profile in patients with the polyneuropathy associated with hATTR in the NEURO-TTR (NCT01737398) study. We report longer-term efficacy and safety data for inotersen, with a median treatment exposure of 3 years.

Methods: Patients who satisfactorily completed NEURO-TTR were enrolled in its open-label extension (OLE) study. Efficacy assessments included the modified Neuropathy Impairment Score + 7 (mNIS + 7), Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) questionnaire total score, and the Short Form 36 (SF-36v2) Health Survey Physical Component Summary score. Safety and tolerability were also assessed. Efficacy is reported for patients living in Europe and North America (this cohort completed the study approximately 9 months before the remaining group of patients outside these regions); safety is reported for the full safety dataset, comprising patients living in Europe, North America, and Latin America/Australasia. This study is registered with ClinicalTrials.gov, identifier NCT02175004.

Results: In the Europe and North America cohort of the NEURO-TTR study, 113/141 patients (80.1%) completed the study, and 109 patients participated in the OLE study. A total of 70 patients continued to receive inotersen (inotersen-inotersen) and 39 switched from placebo to inotersen (placebo-inotersen). The placebo-inotersen group demonstrated sustained improvement in neurological disease progression as measured by mNIS + 7, compared with predicted worsening based on projection of the NEURO-TTR placebo data (estimated natural history). The inotersen-inotersen group demonstrated sustained benefit, as measured by mNIS + 7, Norfolk QoL-DN, and SF-36v2, compared with estimated natural history as well as compared with the placebo-inotersen group. With a maximum exposure of 6.2 years, inotersen was not associated with any additional safety concerns or increased toxicity in the OLE study. Platelet and renal monitoring were effective in reducing the risk of severe adverse events in the OLE study.

Conclusion: Inotersen treatment for > 3 years slowed progression of the polyneuropathy associated with hATTR, and no new safety signals were observed.

Keywords: Clinical trial; Familial amyloid polyneuropathy; Hereditary transthyretin amyloidosis; Inotersen; Peripheral neuropathies; Polyneuropathy.

Fig. 1

OLE median serum transthyretin (TTR) levels relative to NEURO-TTR baseline. The OLE baseline on the graph is noted as occurring 4 weeks after the end of the NEURO-TTR study because the maximum screening period in the OLE study was  generally 4 weeks. OLE open-label extension, SE standard error, TTR transthyretin

Fig. 2

Mean change from NEURO-TTR baseline to OLE week 156 in efficacy measures. Mean (± SE) change from NEURO-TTR baseline in A the Modified Neuropathy Impairment Score + 7 (mNIS + 7); B the Norfolk Quality of Life–Diabetic Neuropathy Questionnaire Total Score (QoL-DN); C the 36-Item Short-Form Health Survey, version 2 (SF-36), Physical Component Summary score (PCS). The vertical dashed line represents OLE baseline (OLE week 0). Sample sizes for each time point and treatment group are indicated under the figure. The OLE baseline values were carried forward from the week 65 visit of the NEURO-TTR study for the SF-36 and from the week 66 visit for mNIS + 7 and QoL-DN measures. The OLE baseline on the graph is noted as occurring 4 weeks after the end of the NEURO-TTR study because the maximum screening period in the OLE study was generally 4 weeks. OLE, open-label extension, SE, standard error

Fig. 3

Responder analyses for the NEURO-TTR Europe and North America cohort. Data are presented for A the Modified Neuropathy Impairment Score + 7 Neurophysiological Tests Composite Score (mNIS + 7), B the Norfolk Quality of Life–Diabetic Neuropathy Questionnaire Total Score (QoL-DN), and C the 36-Item Short-Form Health Survey, version 2 (SF-36), Physical Component Summary score (PCS). A patient was classified as a responder at various time points through week 156 if they showed no clinically meaningful progression based on the applicable threshold and had a recorded measurement at baseline and at the relevant time point. The OLE baseline on the graph is noted as occurring 4 weeks after the end of the NEURO-TTR study because the maximum screening period in the OLE study was generally 4 weeks. A For the inotersen–inotersen group, responders at all visits are based on change < 12.2 points from NEURO-TTR baseline. For the placebo–inotersen group, responders at NEURO-TTR week 35 and week 66 visits and OLE baseline visits are based on change < 12.2 points from NEURO-TTR baseline, while responders at all post-baseline OLE visits are based on change < 12.2 points from OLE baseline. B For the inotersen–inotersen group, responders at all visits are based on change < 8.8 points from NEURO-TTR baseline. For the placebo–inotersen group, responders at NEURO-TTR week 35 and week 66 visits and OLE baseline visits are based on change < 8.8 points from NEURO-TTR baseline, while responders at all post-baseline OLE visits are based on change < 8.8 points from OLE baseline. C For the inotersen–inotersen group, responders at all visits are based on change > –5 points from NEURO-TTR baseline. For the placebo–inotersen group, responders at NEURO-TTR week 35 and week 66 visits and OLE baseline visits are based on change > –5 points from NEURO-TTR baseline, while responders at all post-baseline OLE visits are based on change > –5 points from OLE baseline. OLE, open-label extension, RD, responder definition