The findings, “Neuropathy Symptom and Change: Inotersen Treatment of Hereditary Transthyretin Amyloidosis,” were published in the journal Muscle & Nerve,
FAP — also called hereditary transthyretin amyloidosis (hATTR) — is caused by the abnormal buildup of the transthyretin (TTR) protein. Tegsedi, developed by Ionis Pharmaceuticals, is an antisense oligonucleotide, a type of RNA molecule designed to lower TRR production by cells. The therapy is administered once per week by subcutaneous (under-the-skin) injection.
Tegsedi was approved to treat stage 1 or 2 polyneuropathy in adults with FAP in Europe, the U.S., and other locations. Its regulatory approval was based on the results of NEURO-TTR (NCT01737398), a Phase 2/3 trial of Tegsedi’s safety and effectiveness that ran for 15 months. In the study, which included 173 adults with FAP, the treatment significantly improved quality of life and eased neuropathic disease progression relative to a placebo.
In NEURO-TTR, the Neuropathy Symptoms and Change (NSC) score was used as an exploratory goal. NSC is a 38-item questionnaire that assesses neuropathy symptoms in three broad categories: muscle weakness, issues with sensation, and autonomic symptoms, which refers to problems with involuntary bodily processes, such as heart rate and sweating. NSC scores range from 0 to 114 for men and 108 for women (two items on sexual dysfunction are only applicable to men), with higher scores indicating worse symptoms.
The analysis included data on 165 patients (70.3% men, mean age 59.5 years). Tegsedi was given to 106 study participants and a placebo to 59. The two groups were similar in terms of age, sex, disease stage, as well as NSC scores prior to treatment. Mean disease duration was 42.1 months (about three and a half years).
Results showed that treatment with Tegsedi led to significantly lesser symptom worsening relative to placebo at both week 35 (eight months) and week 66 (15 months).
Significant differences favoring Tegsedi were seen across all subdomains of the NSC except for reduced sensation, which was similar in both groups. A subsequent analysis of NSC subdomain scores revealed less disease progression with the therapy, except in weakness of head and chest.
A greater percentage of patients given Tegsedi also reported eased or unchanged symptoms at week 66 than was found in the placebo group.
“In our analysis of the total NSC score, treatment with inotersen [Tegsedi] resulted in stabilized symptom severity compared with placebo in all subdomains except for sensory loss,” the researchers wrote. “It is noteworthy that positive sensory symptoms (prickling and pain) showed an effect in favor of inotersen, whereas negative sensory symptoms (loss of feeling) did not. One may surmise that the positive symptoms were more troubling and noticeable” to these people.
“These results suggest that inotersen may prevent worsening of autonomic symptoms and that the NSC may be an effective measure of autonomic symptom severity in hATTR,” the scientists concluded, adding they saw NSC as a “valuable” trial measure because of its emphasis on a patient’s experience of disease.
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