Tegsedi Shows Sustained Benefits, Long-term Safety in FAP Patients

Tegsedi (inotersen) continued to slow disease progression and improve the quality of life in people with familial amyloid polyneuropathy (FAP) after two years of treatment, and also maintained a positive safety profile up to five years, according to an extension study of the NEURO-TTR trial.

While patients who started the therapy earlier experienced greater benefits, those who switched from a placebo to Tegsedi had their FAP stabilized, suggesting that Tegsedi can still be helpful when begun at a later stage. 

The results of the extension study, “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,” were published in the journal European Journal of Neurology.

FAP, also called hereditary transthyretin amyloidosis (hATTR), is characterized by the aggregation of transthyretin (TTR) protein primarily in peripheral nerves and heart.

Tegsedi, developed and marketed by Ionis Pharmaceuticals and its subsidiary Akcea Therapeutics, is designed to suppress production of TTR in the liver, where the protein is mostly produced. 

The benefits of Tegsedi were demonstrated in the NEURO-TTR Phase 2/3 trial (NCT01737398). Results showed that Tegsedi administered under the skin (subcutaneously) over 15 months delayed nerve cell damage and improved quality of life of adults with FAP, compared to placebo. 

The improvements were seen regardless of disease stage, type of underlying mutation, and heart involvement (cardiomyopathy). Kidney disease (glomerulonephritis) and low platelet count (thrombocytopenia) were the most-often reported side effects, both managed with close monitoring. 

Patients who completed NEURO-TTR were offered the opportunity to enroll in a long-term open-label extension (OLE) study (NCT02175004) sponsored by Ionis.

Of the 139 patients who completed NEURO-TTR, 135 (97%) participated in the OLE. Eighty-five continued to receive Tegsedi and 50 switched from placebo to the therapy. 

The OLE study was designed to treat patients once weekly for a period of up to five years, followed by a three-month post-treatment evaluation. 

At the time of this analysis, median treatment time was 591 days, up to 1,429 days (about 3.9 years). The longest combined Tegsedi exposure of any patient, including NEURO-TTR trial plus the OLE, was 1,885 days (5.2 years). Also, 93 (69%) patients were receiving treatment, and 59 (44%) patients had completed two years of treatment.

Comparing the start of NEURO-TTR with that of the OLE study, scores for neurologic disease progression — measured by the modified Neuropathy Impairment Score +7, or mNIS+7 — and quality of life, as assessed by the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy score (Norfolk QOL-DN), were similar in patients who received Tegsedi during the main study.

As expected, scores in patients switching to Tegsedi reflected more severe disease due to disease progression during NEURO-TTR.

Participants who stayed on Tegsedi experienced sustained reductions in blood TTR levels over two years, representing a 77% decrease comparing to the start of the main trial. TTR levels in the placebo-Tegsedi group declined substantially by week 7 and reached stable levels by week 13 of the OLE study for a 78% reduction compared to baseline.

Patients who continued treatment with Tegsedi showed sustained slowing of the disease progressing and improved quality of life, while those who switched from placebo showed improvements or stabilization over time compared to the predicted worsening without treatment.

Notably, patients treated earlier with Tegsedi achieved greater benefit in mNIS+7 (17.06 points) and Norfolk QoL-DN (11.89 points) compared to participants who switched from placebo.

No additional safety concerns were observed in patients exposed to Tegsedi for up to five years. The most common side effects in both treatment groups included nausea, urinary tract infection, vomiting, diarrhea, fatigue, injection-site pain, headache, and thrombocytopenia. 

A total of 25 patients who stayed on Tegsedi, and 23 who switched from placebo, experienced thrombocytopenia. There were no cases of acute kidney damage in the OLE.

“The long‐term safety of inotersen [Tegsedi] is promising, with no additional safety concerns or increased toxicity,” the scientists wrote. 

“As someone who sees firsthand the devastating effects of this disease on patients and their families, the availability of an evidence-based therapy in treating the polyneuropathy symptoms of hATTR amyloidosis over the long term, as shown with these OLE study data, is critical,” Thomas Brannagan, MD, said in a press release. Brannagan is director of the Peripheral Neuropathy Center at Columbia University Medical Center and a principal author of the study.

Brett P. Monia, PhD, CEO at Ionis added: “We are very proud of our role in addressing an area of significant unmet medical need for patients and will continue our efforts to bring TEGSEDI to more patients with the polyneuropathy of hATTR around the world.”