Type of information: Granting of a Market Authorisation in the US
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 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.
- This product was previously known as ISIS-TTRRx and IONIS-TTRRx.
- In April 2018, Akcea licensed the worldwide rights to commercialize Tegsedi® from Ionis. Based on the U.S. approval of Tegsedi®, Ionis will receive a $50 million milestone payment that may be made in Akcea common stock or cash. Commercial profits and losses from Tegsedi® will be split 60 percent to Ionis and 40 percent to Akcea.
Company: Akcea Therapeutics (USA - CA) Ionis Pharmaceuticals (USA - CA)
- polyneuropathy in adult patients with hereditary transthyretin amyloidosis (hATTR)
- • On October 5, 2018, the FDA approved Tegsedi® (inotersen), an antisense oligonucleotide (ASO) that inhibits the production of the transthyretin protein for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR) in adults. This is the second FDA approved drug for hATTR. Onpattro® (patisiran), was the first treatment approved for this indication on August 10, 2018.
- Tegsedi® is a weekly self-administered injection. It is contraindicated in patients with a history of acute glomerulonephritis (inflammation of filters in the kidney called glomeruli) caused by Tegsedi® , patients with a history of a hypersensitivity reaction to Tegsedi®, and patients with a platelet count less than 100 x 109/L. Tegsedi®’s label contains a Boxed Warning about thrombocytopenia which may be life threatening, and glomerulonephritis which may require immunosuppressive treatment and may result in dialysis-dependent renal failure. Laboratory monitoring for both conditions is required before, during, and after treatment discontinuation. Because of the risks of serious bleeding due to severe thrombocytopenia and glomerulonephritis, Tegsedi is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS) called the Tegsedi® REMS Program.
- Tegsedi®’s label also contains warnings about stroke and cervical artery dissection, inflammatory and immune effects (including serious neurologic adverse reactions), liver effects, hypersensitivity reactions, a potential interaction that can lead to uninterpretable platelet counts, and reduced serum vitamin A levels (this particular risk pertains to ocular toxicity). The most common adverse reactions observed in the clinical efficacy trial with Tegsedi® were injection site reactions, nausea, headache, fatigue, thrombocytopenia, and fever.
The FDA’s approval of Tegsedi® was based on results from the Phase 3 NEURO-TTR study in patients with hATTR amyloidosis with symptoms of polyneuropathy. In hATTR amyloidosis, transthyretin (TTR) protein misfolds and accumulates as amyloid deposits throughout the body. Tegsedi® targets the disease at its source by reducing the production of TTR protein. In the NEURO-TTR study, treatment with Tegsedi® produced up to a 79% mean decrease from baseline in serum TTR protein in patients regardless of TTR mutation, sex, age, or race.
- To assist hATTR amyloidosis patients in gaining access to Tegsedi®, Akcea has created Akcea Connect™, a patient support program made up of dedicated, regionally-based nurse case managers who have a wide range of medical knowledge and experience. This program offers free, private and personalized support to patients and their caregivers and families across the United States. Akcea Connect is now accepting patient enrollment and authorization forms.
- Akcea Therapeutics is also working together with Accredo® specialty pharmacy, a subsidiary of Express Scripts, to distribute Tegsedi® subcutaneous injection for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults.
- On October 4, 2018, Akcea Therapeutics and Ionis Pharmaceuticals announced that Tegsedi®(inotersen injection) is now approved in Canada for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin amyloidosis (hATTR). Following a priority review by Health Canada, Tegsedi®, an RNA-targeted therapeutic, is the first treatment approved for Canadians living with hATTR amyloidosis, a disease caused by the abnormal formation of the transthyretin (TTR protein), resulting in TTR amyloid deposits in various tissues and organs throughout the body. The progressive accumulation of these deposits leads to sensory, motor and autonomic dysfunction, affecting multiple aspects of a patient's life.
- • 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.
• On February 6, 2014, the Committee for Orphan Medicinal Products (COMP) has adopted a positive opinion recommending ISIS-TTRRx for designation as an orphan medicinal product for the treatment of ATTR-Amyloidosis to the European Commission (EC). The opinion will be subject to review by the EC, which ultimately grants the decision on orphan drug designation.
Submission of marketing authorization application USA :
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2018-10-05
UE authorization: 2018-07-06
Favourable opinion UE:
Favourable opinion USA:
Orphan status USA: 2012-07-24
Orphan status UE: 2014-03-26
Pediatric exclusivit _USA:
Pediatric exclusivity UE:
- • On October 4, 2018, the Institute for Clinical and Economic Review (ICER) released a Final Evidence Report and Report-at-a-Glance on inotersen (Akcea Therapeutics) and patisiran (Onpattro™, Alnylam Pharmaceuticals) for the treatment of hereditary transthyretin amyloidosis (hATTR).
- ICER's report was reviewed at a September 2018 public meeting of the Midwest Comparative Effectiveness Public Advisory Council (Midwest CEPAC), one of ICER's three independent evidence appraisal committees. During the meeting, the Council found that both inotersen and patisiran provide a substantial net health benefit when compared to best supportive care alone, but evidence is insufficient to distinguish between the two treatments. However, current pricing far exceeds commonly cited thresholds for cost effectiveness.
- The Council unanimously recognized that the novel mechanism of action was an important other benefit for treating individuals with such a high lifetime burden of illness. A majority also recognized that the new treatments may reduce family and caregiver burden and may improve a patient's ability to return to work. These Council members emphasized that the burden that a hereditary disease places on families cannot be understated, and that these new treatments may also have a positive psychological effect on multiple generations of a family.
- The Council voted unanimously that, despite the net health benefit, both inotersen and patisiran represent a low long-term value for money. The votes were influenced heavily by the $450,000 annual list price of patisiran, and the assumption that inotersen would be priced similarly.
- Following the voting session, a policy roundtable of experts - including patient advocates, physicians, and payers - convened to discuss the implications of the evidence for policy and practice. Key recommendations stemming from the roundtable discussion include:
- Given that newly approved treatments for hATTR have new mechanisms of action, lack long-term safety and efficacy data, and are very expensive, it is reasonable for insurers and other payers to develop prior authorization criteria to ensure prudent use of these treatments.
- Manufacturers should bring the price for innovative treatments for hATTR down to a level that aligns fairly with the added benefits for patients.
- Patient organizations that have a leading role in funding, organizing, and promoting innovative research on new treatments should demand commitments from manufacturers for reasonable value-based pricing of the products patients helped bring to the market.
- Future research should address the durability of improvements in neurological function, longer-term safety, and cardiac outcomes provided by treatments for hATTR.