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Akcea and Ionis Announce Publication of Long-Term Clinical Data of TEGSEDI® in Patients with Polyneuropathy Driven by Hereditary Transthyretin Amyloidosis Demonstrating Sustained Improvements and Even Greater Stabilization in Patients Starting Earlie | ||
By: GlobeNewswire - 28 May 2020 | Back to overview list |
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Results from the ongoing, open-label extension (OLE) study of the pivotal NEURO-TTR trial published in the European Journal of Neurology show that patients treated with TEGSEDI® (inotersen) experienced sustained improvements in measures of neuropathic progression at 39 months of therapy, and clinically relevant improvements in measures of quality of life compared to the natural history of the disease No new safety signals were identified TEGSEDI is an at-home subcutaneous injection BOSTON and CARLSBAD, Calif., May 28, 2020 (GLOBE NEWSWIRE) -- Akcea Therapeutics, Inc. (NASDAQ: AKCA), a majority-owned affiliate of Ionis Pharmaceuticals, Inc., and Ionis Pharmaceuticals, Inc. (NASDAQ: IONS), today announced publication of long-term data from the open-label extension (OLE) of the pivotal NEURO-TTR study of TEGSEDI® (inotersen) in patients with hereditary transthyretin (hATTR) amyloidosis with polyneuropathy. The primary objective of the OLE study was to evaluate the safety and tolerability of long-term dosing with TEGSEDI. Secondary objectives of the study included understanding progression based on measures such as the modified Neuropathy Impairment Score +7 (mNIS+7) and the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN). Understanding changes over time in generic health-related quality of life based on the Short Form 36 Health Survey (SF-36) was an exploratory objective. This interim analysis, published in the European Journal of Neurology, show that treatment with TEGSEDI was not associated with additional safety concerns or signs of increased toxicity in study participants treated for up to five years. Treatment with TEGSEDI resulted in continued efficacy in patients after two years. Results also showed that patients who started treatment with TEGSEDI earlier (received TEGSEDI treatment in the NEURO-TTR study) achieved greater long-term disease stabilization compared to those who switched from placebo to TEGSEDI in the OLE study. For the full text of this publication, please visit: https://onlinelibrary.wiley.com/doi/abs/10.1111/ene.14285 "These data further validate the favorable benefit-risk profile seen in hATTR patients treated with TEGSEDI for their polyneuropathy,” said Louis O’Dea, MB, BCh, BAO. FRCP(C), chief medical officer of Akcea Therapeutics. “Patients living with hATTR amyloidosis are faced with progressive and debilitating symptoms. These results demonstrate that the benefits we observed in the original 15-month Phase 3 study, such as improved outcomes relative to placebo for neuropathy progression and quality of life, are extended with long term treatment.” “The burden of hATTR amyloidosis is significant as patients suffer from progressive neuropathic, gastrointestinal and psychosocial symptoms that can affect every aspect of their lives including the ability to work, take care of their families or participate in everyday activities. Without therapeutic intervention, patient quality of life rapidly deteriorates,” said Thomas Brannagan, M.D., director of the Peripheral Neuropathy Center at Columbia University Medical Center and a principal author of the study. “As someone who sees firsthand the devastating effects of this disease on patients and their families, the availability of an evidence-based therapy in treating the polyneuropathy symptoms of hATTR amyloidosis over the long term, as shown with these OLE study data, is critical.” hATTR amyloidosis is an under-recognized, debilitating and progressive disease that is caused by the buildup of TTR proteins that misfold due to inherited mutations. It is characterized by the deposition of amyloid fibrils throughout the body including in nervous tissue and can have a devastating impact on patients’ quality of life. TEGSEDI is a once-weekly, at-home subcutaneous injection that targets the polyneuropathy of hATTR amyloidosis at its source by reducing production of the TTR protein. Results from the pivotal, randomized, double-blind, placebo-controlled NEURO-TTR study demonstrated that hATTR amyloidosis patients treated with TEGSEDI experienced significant benefit compared to patients treated with placebo across both co-primary endpoints: mNIS+7, a measure of neuropathic disease progression and the Norfolk QoL-DN. At the end of the study, participants were given the opportunity to enroll in the OLE study and continue treatment with TEGSEDI or switch from placebo. Of the 139 patients who completed the NEURO-TTR study, 135 participants (97%) continued in the OLE study. Among those who participated in the ongoing OLE study, 85 continued to receive TEGSEDI and 50 switched from placebo to TEGSEDI. No new safety concerns were identified in patients treated with TEGSEDI in the OLE study. There was also no evidence of increased risk for grade 4 thrombocytopenia or acute glomerulonephritis with increased duration of exposure to TEGSEDI. Regular, required platelet and renal monitoring proved to be effective in managing patients’ risk. The most common (>10%) adverse events (AEs) include nausea, urinary tract infection, vomiting, diarrhea, fatigue, peripheral edema, injection site pain and thrombocytopenia. Overall, 19 (14.1%) patients discontinued TEGSEDI due to treatment-emergent adverse events (TEAEs). Nine (6.7%) patients died during the OLE study but none of the deaths were considered related to TEGSEDI. Patients administered TEGSEDI throughout the NEURO-TTR and OLE studies experienced substantial reductions in TTR protein levels (77% reduction on average) compared to their baseline from the NEURO-TTR study. In addition, those treated with TEGSEDI for 39 cumulative months in the NEURO-TTR and OLE studies showed sustained benefit compared to the predicted worsening with placebo. Likewise, those patients who switched from placebo to TEGSEDI demonstrated sustained improvement of neurologic disease progression and quality of life as measured by the mNIS+7, the Norfolk QoL-DN, and the SF-36 Physical Component Summary score (PCS) compared with a continued predicted worsening with placebo. Finally, patients treated earlier with TEGSEDI achieved greater benefit in mNIS+7 (17.06 points) and Norfolk QoL-DN (11.89 points) compared to patients who switched from placebo to TEGSEDI in the OLE study, highlighting the importance of early commencement of TEGSEDI in appropriate patients. “We are very proud of our role in addressing an area of significant unmet medical need for patients and will continue our efforts to bring TEGSEDI to more patients with the polyneuropathy of hATTR around the world,” said Brett P. Monia, Ph.D., chief executive officer at Ionis Pharmaceuticals. “We look forward to reviewing future data from this ongoing OLE study and to the prospect of patients with this debilitating disease having access to a treatment that can deliver long-term clinical benefits.” ABOUT TEGSEDI® (INOTERSEN) The approval is based on data from the NEURO-TTR study that was a Phase 2/3 randomized (2:1), double-blind, placebo-controlled, 15-month, international study in 172 patients with hATTR amyloidosis with symptoms of polyneuropathy. In NEURO-TTR, TEGSEDI demonstrated significant improvement compared to placebo in measures of neuropathy and quality of life as measured by the modified Neuropathy Impairment Score +7 (mNIS+7) and in the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QOL-DN) total score. Patients treated with TEGSEDI experienced similar benefit regardless of subgroups such as age, sex, race, region, Neuropathy Impairment Score (NIS), Val30Met mutation status, and disease stage. The approval is also based on early data from the NEURO-TTR OLE that is an ongoing study for patients who completed the NEURO-TTR study. The OLE study is designed to evaluate the long-term safety and efficacy of TEGSEDI. For TEGSEDI’s full prescribing information, please visit www.TEGSEDI.com. IMPORTANT SAFETY INFORMATION BOXED WARNING: THROMBOCYTOPENIA AND GLOMERULONEPHRITIS Thrombocytopenia
Glomerulonephritis
TEGSEDI REMS Program
CONTRAINDICATIONS TEGSEDI is contraindicated in patients with
WARNINGS AND PRECAUTIONS Thrombocytopenia TEGSEDI causes reductions in platelet count that may result in sudden and unpredictable thrombocytopenia that can be life-threatening. In Study 1, platelet counts below 100 x 109 /L occurred in 25% of TEGSEDI-treated patients compared with 2% of patients on placebo. Platelet counts below 75 x 109 /L occurred in 14% of TEGSEDI-treated patients compared with no patients on placebo. One patient in a clinical trial experienced a fatal intracranial hemorrhage. Do not initiate TEGSEDI in patients with a platelet count below 100 x 109 /L. Follow recommended monitoring and treatment recommendations for platelet count. Symptoms of thrombocytopenia can include unusual or prolonged bleeding (eg, petechiae, easy bruising, hematoma, subconjunctival bleeding, gingival bleeding, epistaxis, hemoptysis, irregular or heavier than normal menstrual bleeding, hematemesis, hematuria, hematochezia, melena), neck stiffness, or atypical severe headache. Patients and caregivers should be instructed to be vigilant for symptoms of thrombocytopenia and seek immediate medical help if they have concerns. Glomerulonephritis and Renal Toxicity TEGSEDI can cause glomerulonephritis that may result in dialysis-dependent renal failure. In Study 1, glomerulonephritis occurred in 3 (3%) TEGSEDI-treated patients compared with no patients on placebo. One patient did not receive immunosuppressive treatment and remained dialysis-dependent. If glomerulonephritis is suspected, pursue prompt diagnosis and initiate immunosuppressive treatment as soon as possible. Follow recommended monitoring and treatment recommendations for renal parameters. TEGSEDI should generally not be initiated in patients with a UPCR of 1000 mg/g or greater. If acute glomerulonephritis is confirmed, TEGSEDI should be permanently discontinued. TEGSEDI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the TEGSEDI REMS Program because of risks of serious bleeding caused by severe thrombocytopenia and because of glomerulonephritis. Stroke and Cervicocephalic Arterial Dissection TEGSEDI may cause stroke and cervicocephalic arterial dissection. In clinical studies, 1 of 161 (0.6%) TEGSEDI-treated patients experienced carotid artery dissection and stroke. Educate patients on the symptoms of stroke and central nervous system arterial dissection. Instruct patients to seek help as soon as possible if symptoms of stroke or arterial dissection occur. Inflammatory and Immune Effects Inflammatory and immune changes are an effect of some antisense oligonucleotide drugs, including TEGSEDI. In clinical studies, serious inflammatory and immune adverse reactions occurred in TEGSEDI treated patients, including immune thrombocytopenia and glomerulonephritis, as well as a single case of antineutrophil cytoplasmic autoantibody (ANCA)–positive systemic vasculitis. Liver Injury In clinical studies, 8% of TEGSEDI-treated patients had an increased alanine aminotransferase (ALT) at least 3 times the upper limit of normal (ULN) compared with 3% of patients on placebo; 3% of TEGSEDI treated patients had an ALT at least 8 times the ULN compared with no patients on placebo. Monitor ALT, aspartate aminotransferase, and total bilirubin at baseline and every 4 months during treatment with TEGSEDI. If a patient develops clinical signs or symptoms suggestive of hepatic dysfunction, promptly measure serum transaminases and total bilirubin and interrupt or discontinue treatment with TEGSEDI, as appropriate. Liver Transplant Rejection In a clinical study, cases of liver transplant rejection were reported 2-4 months after starting TEGSEDI in patients whose liver allografts had previously been clinically stable (for over 10 years) prior to starting TEGSEDI. In these cases, the patients clinically improved and transaminase levels normalized after glucocorticoid administration and cessation of TEGSEDI. In patients with a history of liver transplant, monitor ALT, AST, and total bilirubin monthly. Discontinue TEGSEDI in patients who develop signs of liver transplant rejection. Hypersensitivity Reactions/Antibody Formation TEGSEDI can cause hypersensitivity reactions. In clinical studies, 6 of 161 (4%) TEGSEDI-treated patients stopped treatment because of a hypersensitivity reaction. These reactions generally occurred within 2 hours of administration of TEGSEDI. Antibodies to TEGSEDI were present when the reactions occurred. If a hypersensitivity reaction occurs, discontinue administration of TEGSEDI and initiate appropriate therapy. Do not use in patients who have a history of hypersensitivity reactions to TEGSEDI. Uninterpretable Platelet Counts: Reaction Between Antiplatelet Antibodies and Ethylenediaminetetraacetic acid (EDTA) In Study 1, 23% of TEGSEDI-treated patients had at least 1 uninterpretable platelet count caused by platelet clumping compared with 13% of patients on placebo. If there is suspicion of EDTA-mediated platelet clumping, perform a repeat platelet count using a different anticoagulant (eg, sodium citrate, heparin) in the blood collection tube. Recheck the platelet count as soon as possible if a platelet measurement is uninterpretable. Hold TEGSEDI dosing until an acceptable platelet count is confirmed with an interpretable blood sample. Reduced Serum Vitamin A Levels and Recommended Supplementation TEGSEDI treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance of vitamin A is advised for patients taking TEGSEDI. Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (eg, night blindness). ADVERSE REACTIONS The most common adverse reactions that occurred in at least 20% of TEGSEDI-treated patients and more frequently than in those on placebo were injection site reactions, nausea, headache, fatigue, thrombocytopenia, and fever. Serious adverse reactions were more frequent in TEGSEDI-treated patients (32%) than in patients on placebo (21%). DRUG INTERACTIONS Because of the risk of thrombocytopenia, caution should be used when using antiplatelet drugs (including nonprescription products that affect platelets) or anticoagulants concomitantly with TEGSEDI. Because of the risk of glomerulonephritis and renal toxicity, caution should be used when using nephrotoxic drugs and other drugs that may impair renal function concomitantly with TEGSEDI. Please see full Prescribing Information, including boxed WARNING, at TEGSEDIhcp.com. ABOUT HEREDITARY TRANSTHYRETIN (hATTR) AMYLOIDOSIS ABOUT IONIS PHARMACEUTICALS, INC. ABOUT AKCEA THERAPEUTICS, INC. AKCEA AND IONIS FORWARD-LOOKING STATEMENT In this press release, unless the context requires otherwise, “Ionis”, “Akcea,” “Company,” “Companies” “we,” “our,” and “us” refers to Ionis Pharmaceuticals and/or Akcea Therapeutics. Ionis Pharmaceuticals™ is a trademark of Ionis Pharmaceuticals, Inc. Akcea Therapeutics®, TEGSEDI® and WAYLIVRA® are trademarks of Akcea Therapeutics, Inc. Akcea Investor Contact: Akcea Media Contacts: Bill Berry Ionis Investor Contact: Ionis Media Contact: |
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