Type of information: Granting of a Market Authorisation in the EU
Product name: Tegsedi™
Therapeutic area: Rare diseases - Genetic diseases
- antisense drug/antisense oligonucleotide. Inotersen is an antisense oligonucleotide designed to reduce the production of transthyretin to treat patients with TTR amyloidosis (ATTR), a severe, rare and fatal disease. In patients with ATTR, both the mutant and wild-type (wt) TTR 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.
Company: Akcea Therapeutics (USA - CA) Ionis Pharmaceuticals (USA - CA)
- polyneuropathy in adult patients with hereditary transthyretin amyloidosis (hATTR)
- • On July 6, 2018, Tegsedi™ (inotersen) has received marketing authorization approval from the European Commission (EC) for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin amyloidosis (hATTR). The abnormal formation and aggregation of transthyretin results in TTR amyloid deposits throughout the body and is the underlying cause of hATTR amyloidosis.
- The approval is based on results from the Phase 3 NEURO-TTR study in patients with hATTR amyloidosis with symptoms of polyneuropathy. Results from that study demonstrated that patients treated with Tegsedi™ experienced significant benefit compared to patients treated with placebo across both co-primary endpoints: the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) and modified Neuropathy Impairment Score +7 (mNIS+7), a measure of neuropathic disease progression.
Tegsedi™ is associated with risk of thrombocytopenia and glomerulonephritis. Enhanced monitoring is required to support early detection and management of these identified risks. The efficacy of this treatment in patients with stage 3 polyneuropathy has not yet been demonstrated.
- In April, Akcea licensed the worldwide rights to commercialize Tegsedi™ from Ionis. Based on the EC authorization of Tegsedi™ , Ionis will receive a $40 million milestone payment from Akcea payable in shares of Akcea common stock. Commercial profits and losses from Tegsedi™ will be split 60% to Ionis and 40% to Akcea. Tegsedi was designated as an orphan medicine in 2014.
- • On January 8, 2018, Ionis Pharmaceuticals announced that its New Drug Application (NDA) for inotersen has been accepted for Priority Review by the FDA. The FDA has set a Prescription Drug User Fee Act (PDUFA) date of July 6, 2018.
- The FDA previously granted inotersen Orphan Drug Designation and Fast Track Status. A Marketing Authorization Application (MAA) has been submitted to the European Medicines Agency, which has granted Accelerated Assessment and Orphan Drug Designation to inotersen for the treatment of patients with ATTR.
- Inotersen completed a Phase 3 study, NEURO-TTR, in patients with polyneuropathy due to hereditary TTR amyloidosis (hATTR) in May 2017. 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.
Submission of marketing authorization application USA :
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
UE authorization: 2018-07-06
Favourable opinion UE:
Favourable opinion USA:
Orphan status USA:
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE: