Akcea Therapeutics, Inc., an affiliate of Ionis Pharmaceuticals, Inc., and Ionis Pharmaceuticals, Inc., have announced that TegsediTM (inotersen) has received marketing authorisation approval from the European Commission (EC) for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin amyloidosis (hATTR). This follows the positive opinion recommending approval provided by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA).1
“With the EC’s decision, inotersen is now the world’s first and only RNA-targeted therapeutic approved for patients with hATTR amyloidosis. With subcutaneous delivery, inotersen puts treatment in the patients’ hands while bringing the significant benefits shown in the NEURO-TTR study in both measures of neuropathy and quality of life for people living with this serious and fatal disease. This is an important day for the hATTR amyloidosis community as we believe inotersen enables people and their families impacted by this disease to move forward with their lives,” said Paula Soteropoulos, chief executive officer at Akcea Therapeutics. “Today is a milestone for Akcea with our first drug approval. It is an achievement we share with the courageous hATTR patient community in Europe and around the globe. We are ready to launch inotersen along with our patient and physician support services across Europe.”
The abnormal formation and aggregation of transthyretin (TTR) protein results in TTR amyloid deposits throughout the body and is the underlying cause of hATTR amyloidosis. Inotersen is designed to block production of the TTR protein. In the NEURO-TTR study, treatment with inotersen produced substantial reductions in the levels of the TTR protein regardless of mutation type or stage of disease.2
“hATTR amyloidosis is an inherited, progressive and fatal disease for which treatment options are limited. The approval of inotersen brings us into a new era of treatment with an efficacious and disease modifying medicine that potentially allows patients to achieve a greater degree of independence,” said Teresa Coelho, M.D., neurologist and neurophysiologist at Santo António Hospital, Porto, Portugal. “Inotersen has demonstrated rapid and sustained benefits in improving the course of this disease and preserving quality of life.”
The European Commission’s approval of inotersen was based on results from the Phase 3 NEURO-TTR study in patients with hATTR amyloidosis, with symptoms of polyneuropathy.2 Results from that study demonstrated that patients treated with inotersen 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.2
Inotersen is associated with risk of thrombocytopenia and glomerulonephritis. Enhanced monitoring is required to support early detection and management of these identified safety risks.2
“Today, we are thrilled to see our successful research and development efforts result in the approval of an important new medicine for patients with hATTR amyloidosis. Using our antisense technology platform, we set out to design a therapy to block the production of the underlying cause of this disease, the TTR protein,” said Brett P. Monia, Ph.D., chief operating officer at Ionis Pharmaceuticals. “Approval of inotersen further establishes Ionis as a multi-product company. We are confident that the experienced team at Akcea will deliver on the promise of inotersen. We are grateful to all of the physicians and patients who participated in the inotersen clinical program and who made this landmark approval possible.”
For important safety information for inotersen, including method of administration, special warnings, drug interactions and adverse drug reactions, please see the European Summary of Product Characteristics (SmPC), available from the EMA website at www.ema.europa.eu.
Inotersen is also under regulatory review in the United States and Canada. Inotersen’s U.S. Prescription Drug User Fee Act, or PDUFA, date is October 6, 2018.
Inotersen is an antisense oligonucleotide (ASO) inhibitor of human transthyretin (TTR) production. Inotersen is approved in the E.U. for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin amyloidosis (hATTR) and is currently under regulatory review in the U.S. and Canada.
The approval is based on data from the NEURO-TTR study which was a Phase 3 randomised (2:1), double-blind, placebo-controlled, international study in 172 patients with hATTR amyloidosis with symptoms of polyneuropathy. The 15-month study measured the effects of inotersen on neurological function and on quality-of-life by measuring the change from baseline in the modified Neuropathy Impairment Score +7 (mNIS+7) and in the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QOL-DN) total score. Inoterson provided significant benefit on both of these co-primary endpoints in the NEURO-TTR study, including improvement in disease relative to baseline measurements in both co-primary endpoints for a substantial portion of patients.
Inotersen is associated with risk of thrombocytopenia and glomerulonephritis. Enhanced monitoring is required to support early detection and management of these identified risks. The most frequently observed adverse reactions during treatment with inotersen were events associated with injection site reactions. The other most commonly reported adverse reactions (over 10%) seen with inotersen were nausea, anaemia, headache, pyrexia, peripheral oedema, chills, vomiting, thrombocytopenia and platelet count decreased.
The approval is also based on data from the NEURO-TTR Open Label Extension (OLE) which is an ongoing study for patients who completed the NEURO-TTR study, designed to evaluate the long-term efficacy and safety of inotersen. For more information on inotersen, please visit www.TEGSEDI.eu.
ABOUT HEREDITARY TRANSTHYRETIN (hATTR) AMYLOIDOSIS
hATTR amyloidosis is a progressive, systemic and fatal inherited disease caused by the abnormal formation of the TTR protein and aggregation of TTR amyloid deposits in various tissues and organs throughout the body, including in peripheral nerves, heart, intestinal tract, eyes, kidneys, central nervous system, thyroid and bone marrow.3,4 The progressive accumulation of TTR amyloid deposits in these tissues and organs leads to sensory, motor and autonomic dysfunction often having debilitating effects on multiple aspects of a patient’s life.4 Patients with hATTR amyloidosis often present with a mixed phenotype and experience overlapping symptoms of polyneuropathy and cardiomyopathy.4
Ultimately, hATTR amyloidosis results in death within three to fifteen years of symptom onset. Therapeutic options for the treatment of patients with hATTR amyloidosis are limited and there are currently no disease-modifying drugs approved for the disease. There are an estimated 50,000 patients with hATTR amyloidosis worldwide.4
1 European Medicines Agency. Tegsedi. Available here. Last accessed July 2018.
2 Benson, MD et al. (2018) Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis. NEJM. 379:22-31.
3 Damy T, et al. (2015) Cardiac Findings and Events Observed in an Open-Label Clinical Trial of Tafamidis in Patients with non-Val30Met and non-Val122Ile Hereditary Transthyretin Amyloidosis. J Cardiovasc Transl Res. 8(2):117-127.
4 Hawkins PN, et al. (2015) Evolving landscape in the management of transthyretin amyloidosis. Ann Med. 47(8):625-638.