Abstract
Objective: Assess the effectiveness of patisiran, an RNAi therapeutic approved for patients with hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy, in those with a V122I or T60A variant.
Background: hATTR amyloidosis is a rapidly progressive disease caused by transthyretin gene variants. V122I and T60A variants are associated with cardiomyopathy, yet evidence of a mixed cardiac and neurologic phenotype is emerging.
Design/Methods: In this multicenter, observational, Phase 4 study of US patients with V122I/T60A variants and polyneuropathy (NCT04201418), the primary endpoint is the proportion of patients with improved/stable polyneuropathy disability (PND) score vs baseline after 12 months of patisiran treatment. Neuropathy- and cardiomyopathy-related quality of life (QOL; Norfolk QOL-Diabetic Neuropathy [QOL-DN], Kansas City Cardiomyopathy Questionnaire [KCCQ]), autonomic symptoms (Composite Autonomic Symptom Score-31 [COMPASS-31]), and severity of cardiac dysfunction (New York Heart Association [NYHA] class) were assessed. PND score change from baseline to 12 months is reported for patients completing the study.
Results: 58 patients were included: V122I, n=45; T60A, n=13. At baseline, evaluable patients had impaired QOL (mean [range] QOL-DN, 28.4 [−2 to 78]) and dysautonomia (mean [range] COMPASS-31, 22.4 [0–46]). Patients experienced a wide range of ambulatory dysfunction, with 25 (43.1%) with a PND score of II/IIIA/IIIB. 52 (89.7%) patients had heart failure. At 12 months, out of 45 patients completing the study, 42 (93.3%) demonstrated stabilization or improvement in PND score from baseline. Patients improved in Norfolk QOL-DN (mean change [SE], −7.9 [4.9]), mBMI (+201.8 [139.0]), and COMPASS-31 (−11.0 [4.5]) from baseline. Patisiran treatment in this population demonstrated an acceptable safety profile, consistent with existing data.
Conclusions: Almost 90% of the patients in this study with V122I/T60A variants demonstrated a mixed phenotype, with 10.3% having peripheral neuropathy without heart failure. Regardless of genotype/phenotype, patients demonstrated improved/stabilized PND score and improvement in QOL and autonomic function after 12 months of patisiran.
Disclosure: Raymond L. Comenzo has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Raymond L. Comenzo has received intellectual property interests from a discovery or technology relating to health care. Raymond L. Comenzo has received intellectual property interests from a discovery or technology relating to health care. Dr. Shu has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alnylam. Dr. Shu has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Shu has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Akcea. Dr. Shu has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alnylam. Dr. Shu has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for NIH. Dr. Shu has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Alnylam. Dr. Shu has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for The CM Group. Dr. Shu has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for T&Associates. The institution of Dr. Shu has received research support from Biogen. The institution of Dr. Shu has received research support from Alnylam. Dr. Malhotra has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pfizer Inc.. Dr. Malhotra has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Pfizer Inc. . Dr. Malhotra has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Alnylam Therapeutics. Dr. Hussain has nothing to disclose. Dr. Zolty has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alnylam. Dr. Zolty has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alnylam. Dr. Zolty has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Alnylam. Dr. Desai has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Desai has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alnylam. Dr. Desai has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Akcea. Dr. Desai has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Desai has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Takeda. Dr. Desai has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Argenx. Dr. Desai has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Acceleron. Dr. Desai has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Alexion. Dr. Desai has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for CSL Behring. Dr. Desai has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Argenx. Dr. Fernandez MD has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Zoll. The institution of Dr. Fernandez MD has received research support from Pfizer. Dr. Yureneva has received personal compensation for serving as an employee of Alnylam. Dr. Yureneva has stock in Alnylam. Ms. Chou has received personal compensation for serving as an employee of Alnylam Pharmaceuticals, Inc.. Dr. Capocelli has received personal compensation for serving as an employee of Alnylam Pharmaceuticals. Dr. Capocelli has stock in Alnylam Pharmaceuticals.
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