Inotersen is an antisense drug designed to reduce the production of transthyretin, or TTR protein, to treat hereditary ATTR amyloidosis (hATTR), a severe, rare and fatal genetic disease. In patients with hATTR, both the mutant and wild type (wt) TTR protein builds up as fibrils in tissues, such as the peripheral nerves, heart, gastrointestinal system, eyes, kidneys, central nervous system, thyroid and bone marrow. The presence of TTR fibrils interferes with the normal functions of these tissues. As the TTR protein fibrils enlarge, more tissue damage occurs and the disease worsens, resulting in poor quality of life and eventually death.
Inotersen is currently under regulatory review for marketing authorization in the U.S., EU and Canada. The U.S. Food and Drug Administration has granted Orphan Drug Designation and Fast Track Status to inotersen for the treatment of patients with polyneuropathy due to hereditary ATTR amyloidosis (hATTR). The European Medicines Agency has granted Orphan Drug Designation to inotersen for the treatment of patients with ATTR.
Inotersen was discovered and previously developed by Ionis Pharmaceuticals, before being in-licensed by Akcea in March 2018.
In November 2017, Ionis presented new data from the Phase 3 NEURO-TTR study of inotersen in patients with polyneuropathy due to hereditary ATTR amyloidosis (hATTR) at the first annual European ATTR Amyloidosis meeting for patients and doctors. Results from the study demonstrated benefit compared to placebo across both primary endpoints of the study: the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) and the modified Neuropathy Impairment Score +7 (mNIS+7) at both eight and 15 months of treatment. In addition, consistent and significant benefit was observed in both the Norfolk-QoL-DN and mNIS+7, independent of disease stage, types of mutation, previous treatment with TTR protein stabilizers or presence of cardiomyopathy at the beginning of the study. Inotersen-treated patients benefited significantly in the quality of life primary endpoint with 50% of patients experiencing improved scores compared to baseline and a mean difference in magnitude of 11.68 points, compared to placebo-treated patients, at 15 months of treatment (mean change from baseline of 0.99 vs. 12.67, p<0.001). In addition, clinically meaningful benefit compared to placebo was observed in the SF-36 physical component score, a measure of general health quality of life. Inotersen-treated patients also benefited significantly in the co-primary endpoint of disease control, mNIS+7, with 47% of patients experiencing improved or stable scores compared to baseline and a mean difference in magnitude of 19.73 -points, compared to placebo-treated patients, at 15 months of treatment, (p < 0.001).
Two key safety issues were identified during the study: thrombocytopenia and safety signals related to renal function. Enhanced monitoring was implemented during the study to support early detection and management of these issues. Serious platelet and renal events were infrequent and easily managed with routine monitoring, which has proven effective since implementation. Other serious adverse events were observed in 24.1% of inotersen-treated patients and 21.7% of placebo-treated patients. No cumulative toxicities have been identified with long-term exposure.
Adverse events occurring in >=10% of patients and twice as frequently in inotersen-treated patients compared with placebo-treated patients, included thrombocytopenia/platelet count decreases, nausea, pyrexia, chills, vomiting, and anemia. Injection site reactions accounted for less than 1% of all injections and were mild or moderate in severity. There were no discontinuations due to injection site reactions. The overall mortality rate in the NEURO-TTR study was 2.9% and was lower than overall mortality rates reported in other studies in hATTR patients. There were a total of five deaths in the study, five (4.7%) in the inotersen arm and zero in the placebo arm. Four deaths in the inotersen arm were associated with disease progression and considered unrelated to treatment. As previously reported, there was one fatal intracranial hemorrhage in conjunction with serious thrombocytopenia. No serious thrombocytopenia was observed following implementation of more frequent monitoring.
In July 2016, Ionis reported positive data from an ongoing Phase 2 open-label, investigator-initiated study in patients with cardiomyopathy due to ATTR, and from the ongoing open-label extension (OLE) study of inotersen in patients with polyneuropathy due to hATTR who completed the Phase 3 NEURO-TTR study. The Phase 2 study being conducted by Dr. Benson of Indiana University in patients with hATTR with cardiomyopathy and wild-type TTR amyloidosis (ATTRwt) with baseline intraventricular septum (IVS) thickness >=1.3cm showed evidence of cardiac disease stabilization in patients with TTR amyloid cardiomyopathy treated with inotersen for 12 months. The first eight patients treated with inotersen had a mean decrease of 4 percent in left ventricular mass from baseline as measured by MRI at 12 months. This compares favorably to Dr. Benson’s published natural history study in similar patients with an IVS >=1.3cm at study entry who had a mean increase of 14 percent in left ventricular mass as measured by MRI at 12 months. Improvements in multiple additional endpoints, including imaging, functional and biomarker endpoints also support disease stabilization.
An analysis conducted on patients with 12 different mutations who reached up to 12 months of treatment in the NEURO-TTR OLE study showed approximately equal reduction of both wild-type and mutant TTR levels as measured by liquid chromatography-mass spectrometry (LC-MS). Ionis also reported positive data from an analysis conducted in June 2016 on the subset of patients who have reached three months or more of treatment in the OLE study (n=74).
Inotersen is under regulatory review for marketing authorization in the U.S., EU and Canada. An open-label extension study, or OLE, is ongoing for patients who have completed the NEURO-TTR study, in which all patients are treated with inotersen. More than 95 percent of patients who have completed the NEURO-TTR study elected to participate in the OLE.
Expanded Access/Compassionate Use
An expanded access program (EAP) is available for eligible patients with hATTR. For more information, please visit this link.