Tafamidis Meglumine

Newly released details from AstraZeneca and partner Ionis Pharmaceuticals' failed Phase III CARDIO-TTRansform study of eplontersen are raising questions about the role of TTR silencers in transthyretin-mediated amyloid cardiomyopathy (ATTR-CM), with possible implications for Alnylam Pharmaceuticals and its rival silencer Amvuttra (vutrisiran).The results, presented Friday at the European Society of Cardiology (ESC) meeting and published simultaneously in NEJM, confirmed that eplontersen failed to significantly reduce the primary composite endpoint of cardiovascular (CV) death and recurrent CV events compared with placebo (see – Spotlight On: What to watch at ESC 2026 and Spotlight On: Alnylam's whiplash over AstraZeneca's TTRansformative miss).The drug, sold as Wainua in the US and Wainzua in the EU, is already approved to treat the polyneuropathy form of the disease.Market reactionInvestors initially appeared to take Friday's presentation as a negative read-through for Alnylam, whose shares fell nearly 5% in premarket trade following the release of full data from CARDIO-TTRansform, though the company went on to regain much of that loss.The concern appears to be whether TTR-silencing drugs provide any meaningful additional benefit for patients who are already on TTR stabilisers, an issue particularly relevant to Amvuttra. Alnylam's drug was approved last year for ATTR-CM based on the pivotal HELIOS-B study, where there was an apparent benefit among patients taking Pfizer's TTR stabiliser Vyndaqel/Vyndamax (tafamidis).The 1432 patient CARDIO-TTRansform trial enrolled a sicker, more heavily treated group than HELIOS-B, with far more patients receiving TTR stabilisers. About 57% of patients in both treatment arms of CARDIO-TTRansform were already on a stabiliser when they entered the trial, rising to around 81% by its end.Stabiliser status splits outcomesAccording to data presented at ESC, the rate of primary-endpoint events up to week 140 was 29.4% with eplontersen and 32.2% for placebo, for a rate ratio of 0.89 (p=0.28).Results diverged sharply according to baseline stabiliser use: the rate ratio was 0.71 in patients not receiving a stabiliser, compared to 1.14 among those already on one, "a surprising suggestion of harm" for adding eplontersen in tafamidis-treated patients, Jefferies analysts said.That could complicate the case for combining silencers with stabilisers. "Given CARDIO-TTRansform enrolled more than twice as many patients vs HELIOS-B, the negative outcome raises the possibility that the incremental benefit of combining a silencer with a stabiliser is smaller than previously assumed as seen in HELIOS-B, rather than the study having been designed poorly," they said.The analysts also pointed to the relatively late separation of the overall event curves in CARDIO-TTRansform and the lack of widening over time, arguing that simply extending follow-up "wouldn't help" produce a larger treatment effect.Next-gen silencer at risk?The "biggest smoking gun" in CARDIO-TTRansform, they said, is that the data seem to favour uptake of TTR stabilisers over Amvuttra as first-line therapy, and also "points to problems" for Alnylam's next-generation silencer nucresiran, which is being tested in the ongoing Phase III TRITON-CM study (see – Vital Signs: BridgeBio steps up in Alnylam duel).The picture wasn't all negative for eplontersen. The drug lowered TTR levels by 77.2% more than placebo at week 140. Patients treated with eplontersen also showed slower functional decline, with a smaller drop in six‑minute walk distance (−27.5 m vs −47.3 m for placebo) and better quality‑of‑life scores on the Kansas City Cardiomyopathy Questionnaire (KCCQ). Still, while those figures were "good to see," they showed "less benefit than HELIOS-B," Jefferies analysts noted.All-cause mortality was also lower with eplontersen at week 140 (15.5% vs. 18.1%; HR 0.77) and week 160 (17.6% vs. 20.5%; HR 0.78), despite CV mortality itself not being significantly reduced.

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc . (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced that it will present new clinical and real-world data across its transthyretin-mediated amyloidosis (ATTR) and hypertension programs at the European Society of Cardiology (ESC) Congress 2026, taking place August 28-31, 2026, in Munich, Germany. These presentations add to the existing and growing body of evidence demonstrating strength in RNAi-powered transthyretin (TTR) silencing with AMVUTTRA ® (vutrisiran) and underscore the potential of zilebesiran as an innovative treatment approach for hypertension, the leading preventable risk factor for cardiovascular disease (CVD) worldwide. “We're excited to share new data at this year's ESC Congress that reinforce our leadership in transthyretin-mediated amyloidosis and advance our hypertension program," said Yvonne Greenstreet, M.D., Chief Executive Officer of Alnylam. "HELIOS-B remains the foundation of our approach to ATTR-CM, and the multiple presentations we're sharing this week reflect the continued depth of that program alongside the progress we're making in hypertension." The data being presented at ESC further characterize treatment outcomes with AMVUTTRA across ATTR manifestations, patient populations and treatment settings. Highlights include a Late-Breaking Science presentation of pre-specified analyses from the HELIOS-B Phase 3 study of vutrisiran evaluating treatment outcomes in patients on background stabilizer therapy. Additional HELIOS-B analyses examine healthy aging and functional capacity, safety and treatment outcomes by sex. Amylo'ExTTRa, a large real-world analysis from the French National Health Data System, further characterizes the multisystem burden of ATTR-CM beyond cardiac manifestations. The Company will also present new data from its hypertension program, including a subgroup analysis of the KARDIA-3 Phase 2 study evaluating zilebesiran in combination with a diuretic in patients with uncontrolled hypertension. Zilebesiran is an investigational RNAi therapeutic with the potential to provide continuous control of blood pressure with biannual dosing and is being evaluated in the Phase 3 cardiovascular (CV) outcomes trial, ZENITH. The ESC abstracts are available here . Alnylam may share additional data and information during the Congress through its Investors website and/or its Capella site. ESC Congress Presentation Details ATTR Abstracts Amylo'ExTTRa: Exploring Extra-Cardiac Manifestations in Patients with ATTR-CM Using a French National Health Data System Abstract Session: Aetiology, Comorbidities, and Outcomes in Heart Failure Time: Friday, August 28, 2026, 1:27 – 1:39 pm (CEST), 7:27 – 7:39 am (EDT) Presenting Author: Thibaud Damy, France Room: Science Box 3 – Research Gateway Hall A1 Vutrisiran is Associated with Preservation of Intrinsic Capacity and Healthy Ageing in Patients with Transthyretin Amyloidosis with Cardiomyopathy: Post Hoc Analysis of HELIOS-B Abstract Session: Approaching Heart Failure Therapy From all Angles Time: Sunday, August 30, 2026, 8:15 – 8:25 am (CEST), 2:15 – 2:25 am (EDT) Presenting Author: Olivier Lairez, France Room: Science Box 3 – Research Gateway Hall A1 Fewer Adverse Events Reported in ATTR-CM Patients Treated with Vutrisiran Versus Placebo: Post Hoc Safety Analysis from HELIOS-B Moderated Poster : Heart Failure Redefined: Hypertrophic Cardiomyopathy and Transthyretin Amyloid Cardiomyopathy Precision Treatments Time: Sunday, August 30, 2026, 9:15 – 9:21 am (CEST), 3:15 – 3:21 am (EDT) Presenting Author: Stéphanie Schwarting, Germany Room: Station 5 – Research Gateway Hall A1 Effect of Vutrisiran According to Baseline Tafamidis Use in Transthyretin Amyloidosis with Cardiomyopathy Late-Breaking Clinical Science: Cardiac Amyloidosis Time: Sunday, August 30, 2026, 2:15 – 2:30 pm (CEST), 8:15 – 8:30 am (EDT) Presenting Author: Yasuhiro Hamatani, U.S. Room: Ashgabat (Hall A3) Cardiac Presentation and Treatment Response by Sex in Patients with Transthyretin Amyloidosis: Pooled Analysis of Vutrisiran and Patisiran Phase 3 Studies Abstract Session: Improving Care in Cardiac Amyloidosis Time: Monday, August 31, 2026, 10:00 – 10:10 am (CEST), 4:00 – 4:10 am (EDT) Presenting Author: Amira Zaroui, France Room: Science Box 3 – Research Gateway Hall A1 Hypertension Abstract Zilebesiran in Combination with a Diuretic in Patients with Uncontrolled Hypertension: A Subgroup Analysis from the Phase 2 KARDIA-3 Trial Abstract Session : Treatment of Hypertension Time: Sunday, August 30, 2026, 8:15 – 8:25 am (CEST), 2:15 – 2:25 am (EDT) Presenting Author: Neha Pagidipati, U.S. Room: Science Box 4 – Research Gateway Hall A1 AMVUTTRA ® (vutrisiran) INDICATIONS AND IMPORTANT SAFETY INFORMATION Indications In the EU, AMVUTTRA ® (vutrisiran) is indicated for the treatment of: hereditary transthyretin amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy (hATTR-PN). wild-type or hereditary transthyretin amyloidosis in adult patients with cardiomyopathy (ATTR-CM). Availability across the EU is subject to local reimbursement timelines. Important Safety Information Reduced Serum Vitamin A Levels and Recommended Supplementation Vutrisiran treatment can lower serum vitamin A levels, therefore supplementation of approximately, but not exceeding, 2500 IU to 3000 IU vitamin A per day is advised for patients. Adverse Reactions Commonly reported adverse reactions with vutrisiran were injection site reactions and increase in blood alkaline phosphatase and alanine transaminase. For additional information about vutrisiran, please see the full Summary of Product Characteristics . About AMVUTTRA ® (vutrisiran) AMVUTTRA ® (vutrisiran) demonstrates strength in RNAi-powered transthyretin (TTR) silencing, delivering rapid knockdown of TTR at the source of disease to address the underlying cause of transthyretin amyloidosis (ATTR). In the HELIOS-B Phase 3 study, AMVUTTRA reduced the risk of all-cause mortality and recurrent CV events compared to placebo in the overall and monotherapy populations by 28.2% and 32.8%, respectively, through 36 months. It is the only TTR silencer approved for both the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) and cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in countries globally. AMVUTTRA is administered once quarterly via subcutaneous injection. About Transthyretin Amyloidosis (ATTR) Transthyretin amyloidosis (ATTR) is an underdiagnosed, rapidly progressive, debilitating, and fatal disease caused by pathogenic transthyretin (TTR) proteins, which accumulate as amyloid deposits in various parts of the body, including the nerves, heart, and gastrointestinal tract. Patients may present with polyneuropathy, cardiomyopathy, or both manifestations of disease. There are two different forms of ATTR – hereditary ATTR (hATTR), which is caused by a TTR gene variant, and wild-type ATTR (wtATTR), which occurs without a TTR gene variant. It is estimated that more than 500,000 people worldwide live with ATTR, with ~80% remaining undiagnosed. About Zilebesiran Zilebesiran is an investigational, subcutaneously administered RNAi therapeutic in development for cardiovascular (CV) risk reduction in hypertensive patients at high risk or with established CVD. Zilebesiran targets angiotensinogen (AGT), the most upstream precursor in the renin-angiotensin-aldosterone system (RAAS), which plays a role in blood pressure (BP) regulation and impacts CV and renal health. Clinical trial results have shown the potential for zilebesiran to provide continuous control of BP with biannual dosing in a broad population of patients with hypertension. Zilebesiran is being evaluated in a Phase 3 CV outcomes trial, ZENITH, which will assess its ability to reduce the risk of CV death, nonfatal myocardial infarction, nonfatal stroke, or heart failure events in patients with hypertension and established or at high risk of CVD, despite the use of at least two or more antihypertensives. The safety and efficacy of zilebesiran have not been established or evaluated by the FDA, EMA, or any other health authority. Zilebesiran is being co-developed and co-commercialized by Alnylam and Roche. About Cardiovascular Disease and Hypertension Cardiovascular disease (CVD) is a global health crisis and a leading cause of death worldwide, responsible for approximately 20 million deaths annually. Hypertension is the primary cause of and number one modifiable risk factor for CVD. An estimated one in three adults worldwide have hypertension, and despite wide availability of antihypertensives, up to 80% of all patients, and up to one-third of treated patients, do not reach and maintain blood pressure (BP) targets. Even when BP appears well-managed, continuous control of BP may remain suboptimal, leading to variability in BP during the 24-hour period and in the long-term, putting patients at greater risk of cardiovascular events and end organ damage. About RNAi RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines known as RNAi therapeutics is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam’s RNAi therapeutic platform, function upstream of today’s medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing or disease pathway proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases. About Alnylam Pharmaceuticals Alnylam (Nasdaq: ALNY) is a leading global biopharmaceutical company and the pioneer of the RNA interference (RNAi) revolution. The Company is focused on developing transformative therapies with the potential to prevent, halt, or reverse disease. For more than two decades, Alnylam has advanced the Nobel-Prize-winning science of RNAi, delivering critical breakthroughs and six approved medicines. Alnylam has medicines available in more than 70 countries and a rapidly expanding and robust pipeline, in addition to consistently being recognized as an exceptional workplace and socially responsible organization. The Company is executing on its Alnylam 2030 strategy to accelerate innovation and scale impact to transform human health. Alnylam routinely posts information that may be important to investors in the “Investors” section of its website at . Investors and potential investors are encouraged to consult the Alnylam website regularly. Alnylam Forward-Looking Statements This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. All statements other than historical statements of fact regarding Alnylam’s expectations, beliefs, goals, plans or prospects including, without limitation, statements regarding the potential for zilebesiran to provide continuous control of blood pressure with biannual dosing and to be an innovative treatment approach for hypertension; and Alnylam’s ability to execute on its Alnylam 2030 strategy to accelerate innovation and scale impact to transform human health, should be considered forward-looking statements. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation, risks and uncertainties relating to: Alnylam’s ability to successfully execute on its “ Alnylam 2030 ” strategy; Alnylam’s ability to successfully launch, market and sell Alnylam’s approved products globally; Alnylam’s ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for Alnylam’s product candidates; actions or advice of regulatory agencies and Alnylam’s ability to obtain and maintain regulatory approval for its product candidates, as well as favorable pricing and reimbursement; delays, interruptions or failures in the manufacture and supply of Alnylam’s marketed products or its product candidates; obtaining, maintaining and protecting intellectual property; Alnylam’s ability to manage its growth and operating expenses through disciplined investment in operations; Alnylam’s ability to maintain strategic business collaborations; Alnylam’s dependence on third parties for the development and commercialization of certain products; the outcome of litigation and government investigations; the risk of future litigation and government investigations; and unexpected expenditures; as well as those risks and uncertainties more fully discussed in the “Risk Factors” filed with Alnylam’s 2025 Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC), as may be updated from time to time in Alnylam’s subsequent Quarterly Reports on Form 10-Q, and in other filings that Alnylam makes with the SEC. In addition, any forward-looking statements represent Alnylam’s views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements. Contacts Alnylam Pharmaceuticals, Inc. Sarah D’Souza (Media) Media@alnylam.com Josh Brodsky (Investors) Investors@alnylam.com