Amvuttra (vutrisiran) / Alnylam, Sanofi - LARVOL DELTA

Vutrisiran: a new therapeutic option for cardiac transthyretin amyloidosis (PubMed, G Ital Cardiol (Rome)) - No abstract available

Journal • Amyloidosis • Cardiac Amyloidosis

Alnylam Announces U.S. Food and Drug Administration Acceptance of Supplemental New Drug Application for Vutrisiran for the Treatment of ATTR Amyloidosis with Cardiomyopathy (Businesswire) - "Alnylam Pharmaceuticals, Inc...announced that the U.S. Food and Drug Administration (FDA) has accepted for review the Company’s supplemental New Drug Application (sNDA) for vutrisiran, an investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis with cardiomyopathy (ATTR-CM). Based on the Company’s use of a Priority Review Voucher, the FDA has set an action date goal of March 23, 2025, under the Prescription Drug User Fee Act (PDUFA). The FDA has informed the Company that it is not planning to hold an advisory committee meeting at this time to review the application."

FDA filing • PDUFA • Cardiomyopathy • Cardiovascular

Outpatient Worsening Heart Failure in Patients with Transthyretin Amyloidosis with Cardiomyopathy in the HELIOS-B Trial. (PubMed, J Am Coll Cardiol) - "Outpatient worsening HF was frequent in patients with ATTR-CM in HELIOS-B, and was associated with increased mortality, and reduced by vutrisiran."

Journal • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure

Impact of vutrisiran on outpatient worsening heart failure in patients with transthyretin amyloidosis with cardiomyopathy in the HELIOS-B trial (AHA 2024) - P3 | "Outpatient worsening HF was frequent in patients with ATTR-CM and was associated with an increased risk of mortality and recurrent CV events. Vutrisiran reduced the risk of outpatient worsening HF vs placebo."

Clinical • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure

Assessing the Impact of a First-to-Market Product on the Orphan Designation Status for Subsequent Products Across the EU4 (ISPOR-EU 2024) - "The final sample included Uplizna, Zilbrysq, Lytgobi, Amvuttra. Orphan drug designation status can facilitate market access in countries like Germany and France. However, manufacturers of second- and third-to-market products must consider factors such as the significant benefit and time of approval to successfully maintain its orphan designation status. Direct comparative data, indirect comparisons, and protocol assistance can aid in demonstrating benefit."

Rare Diseases

A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy (clinicaltrials.gov) - P3 | N=800 | Enrolling by invitation | Sponsor: Alnylam Pharmaceuticals

New P3 trial • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular

Alnylam Pharmaceuticals Reports Third Quarter 2024 Financial Results and Highlights Recent Period Activity (Businesswire) - "Continued growth momentum in total TTR, achieving global net product revenues for ONPATTRO and AMVUTTRA for the third quarter of $50 million and $259 million, respectively, which combined represent 34% TTR annual growth compared to Q3 2023...Alnylam will present additional findings from the ongoing Phase 1 study of ALN-TTRsc04 in patients with ATTR amyloidosis at the American Heart Association Scientific Sessions 2024. The Company plans to share its Phase 3 development plan for ALN-TTRsc04 in the first quarter of 2025. Alnylam intends to initiate a Phase 2 study of mivelsiran in patients with Alzheimer’s disease at or around year-end."

Commercial • New P2 trial • New P3 trial • P1 data • Alzheimer's Disease • Amyloidosis • CNS Disorders • Metabolic Disorders

ATTRv Neuropathy (ICNMD 2024) - "Transthyretin protein stabilisers diflunisal, tafamidis and acoramidis, can delay the progression of the disease, if treated early in the course. Additionally, TTR gene silencing medications, patisiran and inotersen, and second-generation silencers vutrisiran and eplontersen, have resulted in up to 80% reduction in TTR production leading to stabilisation or improvement of peripheral neuropathy and cardiac dysfunction, as well as improvement in quality of life and functional outcomes...Furthermore, current management strategies do not modify occular or CNS TTR production, and as such late occurrence of the disease in these compartments is becoming more prevalent. As such, novel treatment strategies or optimised CNS and ocular penetrance of existing treatments are required to treat these emerging manifestations."

Amyloidosis • Cardiac Amyloidosis • Musculoskeletal Pain • Pain

Alnylam Submits Regulatory Application to the European Medicines Agency for Vutrisiran for the Treatment of ATTR Amyloidosis with Cardiomyopathy (Businesswire) - "Alnylam Pharmaceuticals, Inc...today announced the submission of a Type II Variation to the European Medicines Agency (EMA) for vutrisiran, an investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis with cardiomyopathy (ATTR-CM)...The regulatory application is based on positive results from the pivotal HELIOS-B Phase 3, randomized, double-blind, placebo-controlled multicenter global study which met all 10 of its primary and secondary endpoints across both the overall and monotherapy populations, each with statistical significance."

EMA filing • Amyloidosis • Cardiomyopathy • CNS Disorders

Alnylam Canada Signs Letter of Intent from pan-Canadian Pharmaceutical Alliance for the Public Reimbursement of AMVUTTRA For The Treatment Of Hereditary Transthyretin-Mediated (hATTR) Amyloidosis In Adults (Canada Newswire) - "Alnylam Canada ULC is pleased to announce that it has signed a Letter of Intent (LOI) with the pan-Canadian Pharmaceutical Alliance (pCPA) for the public reimbursement of AMVUTTRA (vutrisiran injection)...for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis). This comes following a positive recommendation from the Canadian Drug Agency (CDA) and the Institut national d'excellence en santé et services sociaux (INESSS)...The positive recommendations for reimbursement were supported by the results of the HELIOS-A Phase 3 study..."

Reimbursement • Amyloidosis • CNS Disorders

Use of technetium-99m-pyrophosphate single-photon emission computed tomography/computed tomography in monitoring therapeutic changes of RNA interference therapeutics in patients with hereditary transthyretin amyloid cardiomyopathy. (PubMed, J Formos Med Assoc) - "Our results demonstrated a significant decrease in volumetric H/L ratio in hereditary ATTR-CA patients receiving RNA interference therapeutics."

Journal • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular

Alnylam Submits Supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration for Vutrisiran for the Treatment of Transthyretin Amyloidosis with Cardiomyopathy (Businesswire) - "Alnylam Pharmaceuticals, Inc...announced the submission of its supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for vutrisiran, an investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis with cardiomyopathy (ATTR-CM)....The application to the FDA was based on positive results from HELIOS-B..."

FDA filing • Amyloidosis • Cardiomyopathy • Cardiovascular

Exploratory Biomarker Analyses From HELIOS-B, A Phase 3 Study Of Vutrisiran In Patients With Transthyretin Amyloidosis With Cardiomyopathy (HFSA 2024) - P3 | "HELIOS-B completed enrollment (655 pts; 654 dosed) in August 2021 across 26 countries. Median (range) age, 77 (45-85) years; ≥75 years old, 61%; male, 92.5%; on tafamidis at BL, 40%; mean (SD) BMI, 27 (3.7) kg/m2. The treatment effect of vutrisiran on clinical manifestations of cardiac TTR amyloid involvement will be presented across select exploratory measures."

Biomarker • Clinical • Late-breaking abstract • P3 data • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • Pain

Effects of Vutrisiran on Echocardiographic Cardiac Structure and Function: The HELIOS-B Trial (HFSA 2024) - "Changes in echocardiographic parameters from BL to month 30 were evaluated using mixed models for repeated measures with the BL value, treatment group, visit, treatment-by-visit interaction, BL tafamidis use, treatment-by-BL tafamidis use interaction, type of ATTR amyloidosis, and age group included as fixed effect terms. Among the 654 participants with available echocardiographic data at BL (median age 77 years, 93% male, 88% wild-type TTR), mean LVEF was 56 ± 13%, absolute global longitudinal strain (GLS) 14 ± 3%, and mean LV wall thickness 1.8 ± 0.3 cm. Over 30 months, vutrisiran significantly attenuated decline in LVEF (least squares mean difference: 2.03%; 95% CI: 0.34, 3.73), absolute GLS (1.23%; 95% CI: 0.73, 1.73), and LV stroke volume (4.05 mL; 95% CI: 1.72, 6.38) compared with placebo. Vutrisiran also significantly decreased the ratio of early mitral inflow velocity to lateral early diastolic mitral annular velocity (E/e′) (-1.82; 95% CI: -2.67,..."

Late-breaking abstract • Amyloidosis • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure

Contextualizing the results of HELIOS-B in the broader landscape of clinical trials for the treatment of transthyretin cardiac amyloidosis. (PubMed, Heart Fail Rev) - "Discontinuation rates and adverse events were similar between treatment and control arms, suggesting that vutrisiran is well tolerated. In this review, these promising results are explored and compared with other treatment trials in ATTR-CM."

Journal • Review • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular

Exploratory Analyses From HELIOS-B, A Phase 3 Study Of Vutrisiran In Patients With Transthyretin Amyloidosis With Cardiomyopathy (HFSA 2024) - P3 | "At baseline, patients were either not on tafamidis or were receiving tafamidis per the approved indication and dose for their country. Vutrisiran has the potential to improve the CM associated with ATTR. The exploratory endpoint results will help further define the impact of vutrisiran across a range of cardiac measures in patients with ATTR-CM."

Clinical • Late-breaking abstract • P3 data • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • Pain

Alnylam Highlights New Data From HELIOS-B Study of Vutrisiran for the Treatment of Transthyretin Amyloidosis With Cardiomyopathy at Heart Failure Society of America Annual Scientific Meeting 2024 (Businesswire) - P3 | N=655 | HELIOS-B (NCT04153149) | Sponsor: Alnylam Pharmaceuticals | "New echocardiographic data demonstrated that treatment with vutrisiran slowed disease progression in a contemporary population of patients with ATTR-CM across multiple domains of cardiac structure and diastolic and systolic function at Month 30 as compared to placebo. The magnitude of the treatment effects with vutrisiran compared to placebo were similar or greater in the monotherapy population...At Month 30, the relative reduction in the fold change in NT-proBNP in patients treated with vutrisiran compared to placebo was 32% in the overall population and 43% in the monotherapy population...In the subgroup of patients receiving tafamidis at baseline, a relative reduction in the fold change of 18% was observed in NT-proBNP and 10% in troponin I...at Month 30."

P3 data • Amyloidosis • Cardiomyopathy

Benefit of vutrisiran in transthyretin amyloidosis with cardiomyopathy. (PubMed, Nat Rev Cardiol) - No abstract available

Journal • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular

Assessing the effectiveness and safety of Patisiran and Vutrisiran in ATTRv amyloidosis with polyneuropathy: a systematic review. (PubMed, Front Neurol) - "Indirect treatment comparison studies indicated Vutrisiran's superiority over Tafamidis in treating ATTRv amyloidosis. However, potential biases, conflicts of interest in the studies, and limited follow-up periods in some trials necessitate cautious interpretation. Future research should address these limitations and provide more robust evidence for the long-term efficacy and safety of Patisiran and Vutrisiran in ATTRv treatment."

Journal • Review • Amyloidosis • Cardiomyopathy • Cardiovascular • CNS Disorders • Pain

NEJM at ESC - Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy. (PubMed, N Engl J Med) - No abstract available

Journal • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular

What can we learn from the Baseline Characteristics? The population reflects the reality of ATTR diagnoses in the modern era – median age 77 years, 92% male, 89% wild-type. Most interesting is that by chance it appears sicker patients got randomized to vutrisrian rather than placebo, at least according to NT-BNP and troponin. Median NT-BNP in the overall population was 2021 (vutrisiran) vs….

How about ‘combination’ therapy, comparing vutrisiran + tafamidis to placebo + tafamidis? Keeping in mind that the trial was not powered for this comparison, it’s not surprising that the results don’t hit statistical significance… but directionally they look quite promising (HR 0.785 for primary endpoint, HR 0.588 for mortality).

Advances in the Diagnosis and Management of Cardiac Amyloidosis: A Literature Review. (PubMed, Cardiol Res) - "We detail the effectiveness of emerging treatments, notably gene silencing therapies like patisiran and vutrisiran, which offer transformative potential by targeting the production of amyloidogenic proteins. Additionally, the stabilization therapy acoramidis shows promise in modifying disease progression and improving clinical outcomes. This review underscores the critical need for updated clinical guidelines and further research to expand access to groundbreaking therapies and enhance disease management. Advocating for continued research and policy support, we emphasize the importance of advancing diagnostic precision and treatment effectiveness, which are vital for improving patient outcomes and addressing this debilitating disease globally."

Journal • Review • Alzheimer's Disease • Amyloidosis • Atrial Fibrillation • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular • CNS Disorders • Congestive Heart Failure • Dementia • Heart Failure

Alnylam Presents Detailed Results from the Positive HELIOS-B Phase 3 Study of Vutrisiran in Patients with ATTR Amyloidosis with Cardiomyopathy at the European Society of Cardiology Congress (Businesswire) - P3 | N=655 | HELIOS-B (NCT04153149) | Sponsor: Alnylam Pharmaceuticals | "In the study, treatment with vutrisiran substantially reduced the risk of death and cardiovascular events relative to placebo (see table below for further details). In the overall population, vutrisiran reduced the risk of all-cause mortality and recurrent cardiovascular events by 28%, with similar reductions in both the mortality and cardiovascular events components of the endpoint. Mortality in this population was significantly reduced by 31% during the double-blind period and by 36% up to 42 months. In the monotherapy population, vutrisiran significantly reduced the risk of all-cause mortality and recurrent cardiovascular events by 33% and significantly reduced the risk of mortality by 35% up to 42 months."

P3 data • Amyloidosis • Cardiomyopathy • Cardiovascular • CNS Disorders

Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy. (PubMed, N Engl J Med) - P3 | "Among patients with ATTR-CM, treatment with vutrisiran led to a lower risk of death from any cause and cardiovascular events than placebo and preserved functional capacity and quality of life. (Funded by Alnylam Pharmaceuticals; HELIOS-B ClinicalTrials.gov number, NCT04153149.)."

Journal • Amyloidosis • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular