Inotersen Slows Progression of hATTR Amyloidosis

May 6, 2020
Marco Meglio
Marco Meglio

Marco Meglio, Associate Editor for NeurologyLive, has been with the team since October 2019. Follow him on Twitter @marcomeglio1 or email him at

Early treatment with Ionis Pharmaceuticals’s inotersen resulted in greater long-term disease stabilization than delayed initiation.

Thomas H. Brannagan III, MD

Results from the open-label extension (NCT02175004) of the phase 3 NEURO-TTR trial suggests treatment with inotersen (Tegsedi; Ionis Pharmaceuticals) slowed disease progression and reduced the deterioration of quality of life in patients with hereditary transthyretin (hATTR) polyneuropathy.1

Of the 135 patients who enrolled in the open-label extension, 85 continued to receive inotersen (inotersen—inotersen group) and 50 switched from placebo to inotersen (placebo–inotersen group). The mean change from the extension baseline to Week 104 for both the inotersen–inotersen and placebo–inotersen groups on modified Neuropathy Impairment Score +7 (mNIS+7) neurophysiologic tests composite score was 11.18 points (standard error [SE], 3.347) and 5.08 points (SE, 4.159), respectively.

Among the 139 patients who completed the NEURO-TTR study, 135 (95%) enrolled into the open-label extension. The open-label extension, conducted by Thomas H. Brannagan III, MD, director, Peripheral Neuropathy Center, Columbia University Medical Center, and colleagues, examined the long-term efficacy and safety of inotersen in patients with hATTR polyneuropathy.

“Throughout the open-label extension, the placebo—inotersen group exhibited greater neurologic worsening from NEURO-TTR baseline than the inotersen–inotersen group, and earlier initiation of inotersen resulted in better outcomes in measures of neuropathy progression, neuropathy-related QOL, and health-related QOL,” Brannagan and colleagues concluded. “However, initiation of inotersen in patients previously given placebo resulted in disease stabilization, suggesting that intervention later in disease can still elicit a significant drug response.”

After 92, 118, and 170 weeks of cumulative treatment during NEURO-TTR and the open-label extension study, mNIS+7 improved for 37%, 30%, and 24% of the inotersen—inotersen patients. Of the placebo–inotersen patients, 28%, 47%, and 47% improved from open-label extension baseline to Weeks 26, 52, and 104. The mean change from NEURO-TTR baseline for the mNIS+7 was 40.9 points lower in the inotersen–inotersen group and 23.8 points lower in the placebo–inotersen group.

The Norfolk Quality of Life—Diabetic Neuropathy (Norfolk QOL–DN) questionnaire total score improvements relative to NEURO-TTR baseline at 92, 118, and 170 weeks were found in 51%, 44%, and 46% of inotersen–inotersen patients compared with a 46%, 53%, and 42% change of patients in the placebo–inotersen group at 26, 52, and 104 weeks, respectively.

For the inotersen—inotersen and placebo–inotersen groups, respectively, Short Form 36 Health Survey (SF-36) Physical Component Summary score (PCS) mean change from open-label extension to Week 104 was 0.08 (SE, 1.397) and –1.15 (SE, 1.367). SF-36 PCS scores were 8.4 points higher in the inotersen–inotersen group and 3.2 points higher in the placebo–inotersen group relative to the placebo–slope extrapolation.

Nausea, urinary tract infection, vomiting, diarrhea, fatigue, chills, and fall were among some of the most common adverse events (AEs) observed in the study. Treatment-emergent AEs (TEAEs) leading to dose pause, dose reduction, or study drug discontinuation occurred in 48.9% (n = 66) of patients and included thrombocytopenia in 17.8% (n = 24). Platelet count decreased in 3.0% (n = 4) of patients, and renal and urinary disorders in 3.7% (n = 5).

Overall 6.7% (n = 9) patients died in the open-label extension, and of the 3 deaths which occurred on treatment, and none were considered related to treatment.

In October 2018, the FDA approved inotersen for the treatment of polyneuropathy of hATTR in adults. Marketed as Tegsedi, the treatment became the first and only RNA-targeting therapeutic that effectively reduces the production of TTR protein. The NEURO-TTR study was the basis of the approval, demonstrating the therapy’s significant benefit across both Norfolk QOL—DN and mNIS+7 end points, compared with placebo.2


1. Brannagan TH, Wang AK, Coelho T, et al. Early data on long-term efficacy and safety of inotersen in patients with hereditary transthyretin amyloidosis: a 2-year update from the open-label extension of the NEURO-TTR trial. Eur J Neurol. Published online April 28, 2020. doi: 10.1111/ene.14285

2. Akcea and Ionis receive FDA approval of TEGSEDI (inotersen) for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults [news release]. Carlsbad, CA: Akcea Therapeutics; Published October 5, 2018. Accessed May 5, 2020.

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