Inotersen (IONIS-TTRRxis an antisense agent currently being evaluated for the treatment of familial amyloid polyneuropathy (FAP). In May 2017, Ionis Pharmaceuticals, the therapy’s developer, announced positive results from an ongoing Phase 3 clinical trial, citing benefits in both disease progression and quality of life in FAP patients treated with inotersen.

How Inotersen works

People with FAP have a mutation or fault in the gene that codes for a protein called transthyretin (TTR). The mutation changes the shape of the TTR protein in a way that causes it to build up in organs and tissues. In FAP, the buildup of TTR in peripheral nerves leads to nerve damage and loss of motor function.

Inotersen belongs to a class of drugs called antisense agents, which are small strands of nucleic acids that can bind to genetic material and “turn off” their expression. In the case of FAP, inotersen can interact with RNA to block the production of both the mutant and normal forms of TTR.

Investigators hope that decreasing the production of TTR can slow or stop the nerve damage caused by TTR deposits.

Inotersen in clinical trials

The Phase 3 NEURO-TTR clinical trial (NCT01737398) is an international, randomized and placebo-controlled study to evaluate the safety and efficacy of inotersen, administered as an under-the-skin injection, for 65 weeks.. Investigators used the Neuropathy Impairment Score +7 (mNIS+7) and Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) to assess changes in nerve function and quality of life, respectively.

Results announced by Ionis in May showed that, compared to FAP patients who were taking a placebo, people treated with inotersen had statistically significant benefits in both disease progression (a lesser progressive loss of nerve function) and quality of life. The benefits extended to patients regardless of disease stage or the type of genetic mutation.

Adverse effects observed in treated patients included low platelet levels and kidney-related issues. The long-term safety and efficacy of inotersen are now being evaluated in an open-label Phase 3 extension (NCT02175004) of the NEURO-TTR trial. Patients who participated in the earlier study are being invited to participate.

Other information

In March 2017, the U.S. Food and Drug Administration (FDA) sent a letter to a clinical trial site (an independent, investigator-sponsored trial, not part of the Ionis-sponsored study) with a warning about platelet monitoring in patients on inotersen between May and June 2016. FDA inspectors had uncovered breaks in protocol with platelet testing. Because inotersen has been associated with low platelet levels, monitoring platelet levels is important to avoid the risk of bleeding (platelets are involved in blood clotting).

Applications to regulatory agencies like the FDA, requesting approval of Inotersen as a familial amyloid polyneuropathy treatment, are now being prepared, Ionis reported in the May announcement.

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