Tegsedi’s Therapeutic Benefits Sustained Over 3 Years in Study
Patient quality of life improved in NEURO-TTR trial and its extension
Treatment with Tegsedi (inotersen) for more than three years continued to slow disease progression and improve the quality of life in people with familial amyloid polyneuropathy (FAP), according to new data from the extension study of the NEURO-TTR trial.
Patients who started treatment earlier experienced greater benefits, but benefits were still seen in patients who started treatment after a 15-month delay.
The study, “Long-term efficacy and safety of inotersen for hereditary transthyretin amyloidosis: NEURO-TTR open-label extension 3-year update,” was published in the Journal of Neurology.
FAP, a form of hereditary transthyretin amyloidosis, is caused by inheritable mutations in the TTR gene. These mutations lead to the buildup of a misfolded version of a protein called transthyretin (TTR) that accumulates primarily in peripheral nerves — those found outside the brain and spinal cord — interfering with their function.
Tegsedi, developed and marketed by Ionis Pharmaceuticals and its subsidiary Akcea Therapeutics, is designed to suppress the production of TTR in the liver, where the protein is mostly produced.
In the Ionis-sponsored Phase 3 NEURO-TTR (NCT01737398) trial, Tegsedi’s effectiveness and safety were compared with those of a placebo when administered under the skin (subcutaneously) for more than 15 months.
Results showed Tegsedi delayed nerve cell damage and significantly improved the quality of life in adults with FAP compared with a placebo. Improvements were independent of disease stage, type of underlying mutation, and heart involvement.
Patients who completed NEURO-TTR were allowed to enter in its long-term open-label extension (OLE) study (NCT02175004).
Greater benefits seen in patients treated with Tegsedi from the start of trial
From the 139 patients who completed NEURO-TTR, 135 (97%) participated in the OLE, including 109 patients in Europe and North America. From these, 70 (51 men, median age of 65 years) continued to receive Tegsedi (Tegsedi-Tegsedi group) and 39 (28 men, median age of 66 years) switched from placebo to the therapy (placebo-Tegsedi group).
At the start of the study, the proportion of patients with lower polyneuropathy disability scores was higher among those in the Tegsedi-Tegsedi group compared with those in the placebo-Tegsedi group (65.7% vs 53.8%).
Patients in the Tegsedi-Tegsedi group received the treatment for a median of 1,063 days (nearly three years; range 1–1,814 days) and those in the placebo-Tegsedi group for 938 days (about 2.5 years; range 106–1,728 days). The longest combined Tegsedi exposure of any patient, including the period in the NEURO-TTR trial plus OLE, was 2,270 days (6.2 years).
Improvements in neurological dysfunction were assessed with the modified Neuropathy Impairment Score +7 (mNIS+7), a measure of neuropathic disease progression, with higher scores indicating poorer neurological function. Changes in quality of life were evaluated with the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy score (Norfolk QoL-DN), in which higher scores are associated with a worse quality of life. The 36-Item Short-Form Health Survey version 2 Physical Component Summary score was also used to assess health-related quality of life, with lower scores indicating worse outcomes.
According to all three measures, patients who were on Tegsedi from the start of the study continued to experience sustained benefits compared with those in the placebo-Tegsedi group and with an estimation of the disease’s natural course.
Patients who switched to Tegsedi in the OLE also had lessening of disease progression when compared with the predicted worsening from the estimated natural history of the NEURO-TTR placebo group.
By week 156 of the OLE, patients in the Tegsedi-Tegsedi group achieved greater benefits in mean mNIS+7 (mean change of 19.2 vs. 40.6 points) and Norfolk QoL-DN (mean change of 9.8 vs. 17.3 points) scores compared with those who switched from placebo to Tegsedi.
Safety analyses were conducted with data from all patients, including those from Latin America, Australia, and New Zealand. Tegsedi’s use was not linked to any new safety concerns or increased toxicity in the OLE study.
In agreement with prior findings, the most common adverse events reported included reductions in platelet counts (thrombocytopenia), diarrhea, nausea, and urinary tract infection. Monitoring of platelets and kidney function were effective in reducing the risk of severe adverse events.
A total of 30 patients discontinued treatment due to a treatment-emergent adverse event: 23 in the Tegsedi-Tegsedi group and seven in the placebo-Tegsedi group. Sixteen patients died during the study, but none of the deaths were considered to be related to the therapy.
“Extended treatment with inotersen for over 3 years slowed progression of the polyneuropathy associated with [FAP] and maintained [quality of life] in patients, with greater benefit observed in patients who initiated inotersen earlier versus patients with delayed treatment initiation,” the researchers wrote. “These long-term results further highlight the importance of early initiation of treatment.”
Of note, the researchers have financial links to pharmaceutical companies, including Ionis Pharmaceuticals and Akcea Therapeutics.