Treatment with the investigative therapy Tegsedi (inotersen) provides early and significant improvements in neuropathy symptoms and quality of life in patients with familial amyloid polyneuropathy (FAP), according to results from a pivotal Phase 2/3 clinical trial.
These results, announced by Ionis Pharmaceuticals, the treatment’s developer, and its affiliate, Akcea Therapeutics, were published in the study, “Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis,” in The New England Journal of Medicine.
The randomized, placebo-controlled NEURO-TTR Phase 2/3 trial (NCT01737398) assessed Tegsedi’s effectiveness and safety in 172 adults with FAP over 15 months.
Tegsedi is an antisense medication designed to inhibit the production of transthyretin (TTR) in the liver.
FAP, also called hereditary transthyretin amyloidosis, is characterized by the aggregation of TTR into amyloid deposits. The liver is the primary source of TTR. A liver transplant has been the standard approach to treat FAP patients, but the accumulation of TTR amyloid after the procedure limits its effectiveness.
Participants in the trial were randomly assigned to receive either a 300 mg dose of Tegsedi administered beneath the skin three times or a placebo on alternate days in the first week and then once a week for 64 weeks.
Improvements in neurological dysfunction were assessed with the modified Neuropathy Impairment Score +7 (mNIS+7), a measure of neuropathic disease progression, while changes in patients’ perceptions on quality of life were evaluated with the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN). These were the study’s primary objectives.
The benefits were observed at both eight and 15 months of treatment.
“In conclusion, weekly subcutaneous (under the skin) injections of inotersen (Tegsedi) provided benefit to patients with [FAP], as measured by both clinical assessments and quality-of-life instruments,” the researchers wrote in the study.
“I am encouraged with the benefit in neuropathy symptoms and quality of life observed in patients treated with Tegsedi in this Phase 3 study,” Morie Gertz, MD, chair of the department of internal medicine at the Mayo Clinic, said in a press release.
Additionally, Tegsedi eased symptoms in patients, compared with initial values at the beginning of the study. The benefits were associated with marked decreases in the level of TTR, with almost 90% of patients achieving over 50% TTR reduction, and nearly 50% achieving over 75% TTR reduction at 15 months.
Treatment with Tegsedi also provided meaningful benefits in the SF-36 physical component score, an assessment of general health quality of life.
“Based on these study results and the feedback we have received from physicians and patients, we believe Tegsedi has the potential to provide people living with hATTR amyloidosis a greater degree of control over their disease and their lives together with the convenience of a once weekly, self-administered subcutaneous (under-the-skin) injection,” said Sarah Boyce, Akcea’s president.
Brett P. Monia, PhD, chief operating officer and senior vice president of antisense drug discovery and translational medicine at Ionis, said that the results suggest a favorable benefit-risk profile for treatment with Tegsedi. He also noted that the improvements in neuropathy and quality of life were “independent of TTR mutation type, disease stage or presence of cardiomyopathy,” which is associated with a worse prognosis in FAP.
“Remarkably, half of the Tegsedi-treated patients in this study experienced improvement in their quality of life over the course of their treatment and nearly 40% improved in a measure of neurological disease progression,” he said.
Adverse events were observed in at least 10% of patients and twice as frequently in Tegsedi-treated patients, compared with those receiving placebo. They included reductions in platelet counts (thrombocytopenia) nausea, pyrexia (fever), chills, anemia, and vomiting. More frequent monitoring prevented the subsequent occurrence of serious thrombocytopenia.
Five patients treated with Tegsedi died during the study, four of whom were associated with disease worsening and not considered related to the therapy.
The scientists are now conducting the NEURO-TTR OLE study in patients who completed the NEURO-TTR trial to analyze Tegsedi’s long-term effectiveness and safety profile.
The medication has been recently approved by the European Commission to treat stage 1 or 2 FAP, which refer to no requirement (stage 1) or requirement (stage 2) of assistance with ambulation.
The U.S Food and Drug Administration has granted Tegsedi orphan drug status and priority review status.
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