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.

"*" indicates required fields The European Society of Cardiology (ESC) Congress 2026 took place in Munich from August 28 to 31, with new clinical trial results presented across cardiovascular disease. From major phase 3 successes and failures to earlier-stage programs, we selected some of the readouts that stood out to us. Cytokinetics’ aficamten has become the first cardiac myosin inhibitor to succeed in a phase 3 trial in non-obstructive hypertrophic cardiomyopathy (HCM), potentially opening a new treatment option for a form of the disease with no targeted therapy. The company plans to file for an expanded U.S. approval in the fourth quarter of 2026. HCM causes the heart muscle to thicken and can make it harder for the heart to fill and pump blood. Myosin inhibitors such as aficamten reduce excessive contraction of the heart muscle and have already proven effective in obstructive HCM, where thickened muscle also restricts blood leaving the heart. Whether the approach could work without that obstruction was less clear. Bristol Myers Squibb’s mavacamten raised further doubts last year when it failed the phase 3 ODYSSEY-HCM trial in non-obstructive HCM. The drug improved exercise capacity and patient-reported health scores numerically, but it didn’t reach its primary endpoint. ACACIA-HCM has now produced a different outcome. Among 517 patients, aficamten improved the Kansas City Cardiomyopathy Questionnaire (KCCQ) score by 11.4 points after 36 weeks, compared with 8.4 points for placebo. Peak oxygen uptake, a measure of exercise capacity, increased by 0.64 mL/kg/min with aficamten and was essentially unchanged with placebo. The differences aren’t dramatically larger than those seen with mavacamten, but it still is the first phase 3 evidence that inhibiting cardiac myosin can benefit patients with non-obstructive HCM. Additional analyses presented at ESC also found improvements in measures of how well the heart relaxes and fills. The benefit also came with a reduction in cardiac function in some patients. Left ventricular ejection fraction fell below 50% in 10.5% of patients receiving aficamten versus 0.8% on placebo, although these reductions were reversible. Aficamten is not the only sarcomere-targeting approach moving forward in HCM. Edgewise Therapeutics presented 12-week phase 2 data for EDG-7500, a cardiac sarcomere modulator designed to improve contraction and relaxation while preserving systolic function. The small, open-label study reported improvements in biomarkers and symptoms. Arrowhead Pharmaceuticals’ plozasiran delivered one of the clearest RNAi successes at ESC 2026. In two phase 3 trials, the drug reduced triglycerides in people with severe hypertriglyceridemia and cut the rate of acute pancreatitis. Plozasiran targets APOC3, a protein made in the liver that slows the breakdown and clearance of triglyceride-rich particles from the blood. By silencing the APOC3 gene, the drug removes that brake on triglyceride clearance. It is already approved as Redemplo for familial chylomicronemia syndrome, a rare form of severe hypertriglyceridemia, but Arrowhead is now trying to expand it to the broader severe hypertriglyceridemia population. In the SHASTA-3 and SHASTA-4 trials, 757 patients received plozasiran or placebo once every three months. After a year, median triglyceride levels had fallen by 79% and 81% in the two studies. More than 90% of treated patients brought their triglycerides below 500 mg/dL, the threshold used to define severe hypertriglyceridemia. Plozasiran reduced the rate of acute pancreatitis events by 78% compared with placebo, corresponding to a 4.1% risk reduction over one year. In patients with a previous history of pancreatitis, who are at particularly high risk of another attack, the reduction reached 91%. Safety was broadly similar between groups, although worsening glycemic control was reported more often with plozasiran, in 14.3% of treated patients versus 8.7% on placebo. Arrowhead plans to file for U.S. approval in severe hypertriglyceridemia before the end of 2026. At the same time, the field is already pushing toward even less frequent dosing. Ionis presented phase 1 data for ION775, another APOC3-targeting siRNA, showing that a single dose reduced triglycerides by as much as 68.4% at six months, with the effect of the higher doses still visible at 12 months. The study included only 40 participants, but Ionis is now testing the drug in phase 2, aiming to treat every six months or less. CRISPR Therapeutics aims to go beyond plozasiran and ION775 by editing the relevant gene once and making the effect permanent. CTX310 is an in vivo CRISPR-Cas9 therapy targeting ANGPTL3, a protein produced by the liver that regulates triglycerides and cholesterol. People carrying naturally occurring loss-of-function variants in ANGPTL3 tend to have lower triglyceride and LDL cholesterol levels, and those variants have also been associated with a lower risk of coronary artery disease. Regeneron’s antibody evinacumab, which blocks ANGPTL3, is already approved for homozygous familial hypercholesterolemia. CTX310 tries to reproduce that protective genetic state directly. It uses lipid nanoparticles to deliver CRISPR-Cas9 components to liver cells, where they disable ANGPTL3. The phase 1a study is still very small. Fifteen people with difficult-to-control high cholesterol, high triglycerides, or both received a single intravenous dose of CTX310 on top of their existing lipid-lowering treatment. Earlier results had already shown strong reductions in ANGPTL3 and blood lipids. At ESC, the focus was on durability, and the effects were still present after one year. At the highest dose, circulating ANGPTL3 was reduced by an average of 79%, while triglycerides fell by 48% and LDL cholesterol by 53%. The largest reductions seen in individual patients reached 89%, 78%, and 84%, respectively. CRISPR Therapeutics reported no treatment-related serious adverse events. The study was designed primarily to assess safety, and the small number of participants means much longer follow-up will be needed to understand the risks of permanently switching off ANGPTL3. CRISPR Therapeutics has now moved CTX310 into phase 1b, focusing on severe hypertriglyceridemia and refractory hypercholesterolemia. The program is still early-stage, but CTX310 could eventually treat some lipid disorders with a single genetic intervention. Medera presented 12-month data at ESC for SRD-002, a one-time gene therapy aiming to improve how the heart relaxes in patients with heart failure with preserved ejection fraction (HFpEF). The first-in-human study included only ten patients, but the physiological effects persisted and, in some cases, increased a year after treatment. HFpEF is characterized in part by the heart becoming less able to relax and fill normally even though its pumping capacity remains preserved. SRD-002 targets SERCA2a, a calcium pump inside heart muscle cells that helps remove calcium after each contraction so the muscle can relax. SERCA2a activity is impaired in heart failure, and Medera uses an AAV1 vector to deliver an additional copy of the gene directly to the heart through a single infusion. In the phase 1/2a trial, five patients received a lower dose and five a higher dose. At 12 months, eight of the ten patients met a prespecified threshold for normalization of cardiac filling pressure, while average pulmonary capillary wedge pressure during peak exercise fell by around 30%. This pressure rises when the heart struggles to fill properly and is one of the physiological abnormalities in HFpEF. The reductions were generally greater at 12 months than at six months and at the higher dose. The average KCCQ score also increased by 17.8 points, while five of six patients who entered the trial with NYHA class 3 symptoms improved to class 2. SRD-002 is not the first attempt to treat heart failure by restoring SERCA2a. The same target and AAV1 vector approach were previously tested in patients with heart failure with reduced ejection fraction (HFrEF), where the heart’s pumping capacity is impaired. Early studies produced encouraging signals, but the subsequent randomized 250-patient CUPID 2 trial failed as the gene therapy did not reduce recurrent heart failure events compared with placebo. However, Medera is testing the approach in a different form of heart failure. The trial is still far too small to establish that restoring SERCA2a changes the clinical course of HFpEF. With ten patients, no placebo group, and endpoints centered on physiology and symptoms, the improvements could look very different in a randomized trial. Medera plans to move SRD-002 into a randomized phase 2b study, which should provide a much more meaningful test. AstraZeneca and Ionis had already disclosed in July that eplontersen had failed the phase 3 CARDIO-TTRansform trial in transthyretin amyloid cardiomyopathy (ATTR-CM). At ESC, the full results showed why the miss is particularly interesting: the drug successfully suppressed its intended target, but that did not translate into a significant reduction in cardiovascular events or deaths. ATTR-CM develops when misfolded transthyretin (TTR) accumulates in the heart and gradually impairs its function. TTR stabilizers such as tafamidis are designed to stop the protein from misfolding, while gene-silencing drugs reduce production of TTR in the liver. Eplontersen is a gene-silencing antisense oligonucleotide already approved for hereditary ATTR polyneuropathy. CARDIO-TTRansform enrolled over 1,400 patients and compared eplontersen with placebo for up to 140 weeks. The primary endpoint combined cardiovascular deaths with recurrent cardiovascular events such as heart failure episodes. There were 381 events in the eplontersen group and 392 with placebo, and cardiovascular deaths were also almost identical, at 74 with eplontersen and 70 with placebo. The drug, however, hit its target and produced a sustained reduction in circulating TTR. Patients also deteriorated less rapidly on some measures of physical function and quality of life. After 140 weeks, six-minute walking distance had fallen by 27.5 meters with eplontersen compared with 47.3 meters on placebo, while the decline in KCCQ health-status scores was also smaller. In the trial, 57% of patients were already taking a TTR stabilizer when they entered the study, mostly tafamidis, and another 24% started one during the trial. Among patients who were not receiving a stabilizer at baseline, eplontersen was associated with a 29% lower rate of the primary endpoint. Among those already taking one, there was no evidence of benefit. Safety was not an issue, as serious adverse events occurred in 57.8% of patients receiving eplontersen and 59.4% receiving placebo, with fewer treatment discontinuations due to adverse events in the eplontersen group. Milvexian was testing an attractive idea in anticoagulation: blocking factor XIa to prevent dangerous clots without causing the same bleeding problems as conventional anticoagulants. The phase 3 results presented at ESC 2026 showed that Milvexian did not increase the most serious forms of bleeding, and also failed to reduce cardiovascular events. The idea of targeting factor XIa comes from its role in thrombosis, as factor XI appears to be less important for normal hemostasis, suggesting that inhibiting it could separate antithrombotic efficacy from bleeding risk. The phase 3 trial enrolled about 14,000 patients within seven days of an acute coronary syndrome event. All received standard antiplatelet therapy and were randomized to milvexian or placebo. Bristol Myers Squibb and Johnson & Johnson had already stopped the trial for futility in November 2025, but the full ESC data gave more insight into how the trial missed the mark. After a median follow-up of 12.2 months, cardiovascular death, myocardial infarction, or ischemic stroke occurred in 5.4% of patients taking milvexian and 5.1% receiving placebo. LIBREXIA-ACS tested the drug on top of antiplatelet therapy after acute coronary syndrome, where patients already receive intensive antithrombotic treatment. Two other large phase 3 trials remain in progress: LIBREXIA-STROKE, testing milvexian for secondary prevention after ischemic stroke or high-risk transient ischemic attack, and LIBREXIA-AF, comparing it with apixaban in atrial fibrillation. Pacibekitug only joined Novartis’ pipeline recently. The pharma acquired the anti-IL-6 antibody through its $1.4 billion takeover of Tourmaline Bio in 2025, betting that reducing persistent inflammation could address cardiovascular risk. The drug targets interleukin-6 (IL-6), a protein involved in the inflammatory response. Elevated inflammation, measured through high-sensitivity C-reactive protein (hs-CRP), is associated with increased cardiovascular risk, and IL-6 sits upstream of CRP production. Pacibekitug blocks IL-6 itself and potentially maintains that suppression with injections only once every three months. At ESC 2026, the phase 2 TRANQUILITY trial provided longer-term evidence that the approach can do what it is designed to do. The study enrolled just under 150 people with stage 3 or 4 chronic kidney disease and elevated hs-CRP, and compared three pacibekitug dosing regimens with placebo over six months. Inflammation fell rapidly and remained suppressed throughout the study. Average hs-CRP levels over six months decreased by 76% with 25 mg of pacibekitug every three months and by 85% with 50 mg every three months, compared with a 7% increase on placebo. Monthly dosing produced an 89% reduction. What TRANQUILITY cannot show is whether those biomarker improvements translate into fewer heart attacks, strokes or cardiovascular deaths. And that question caused the failure of another IL-6 antibody. In July, Novo Nordisk reported that ziltivekimab failed the phase 3 ZEUS trial, despite successfully suppressing IL-6 activity and hs-CRP. Among more than 6,300 patients with cardiovascular disease, chronic kidney disease, and inflammation, ziltivekimab had essentially no effect on major cardiovascular events compared with placebo. The ESC results provide evidence that pacibekitug can deliver durable IL-6 inhibition, but after ZEUS, lowering inflammatory biomarkers alone is not enough to validate the approach. The bigger test will be whether Novartis can turn those biomarker changes into an actual cardiovascular benefit in a phase 3 trial. AstraZeneca is revisiting a heart failure mechanism that has already been tested and dropped once. AZD5462 activates RXFP1, the receptor for relaxin, a hormone that helps the cardiovascular system adapt during pregnancy. Relaxin signaling can widen blood vessels, reduce the resistance against which the heart has to pump, increase renal blood flow, and potentially promote favorable cardiac remodeling. Novartis previously developed serelaxin, a recombinant form of human relaxin-2, for acute heart failure. Early data were encouraging, but the drug later failed to reduce cardiovascular death or worsening heart failure in phase 3. AZD5462 approaches the same biology, but instead of administering the relaxin protein intravenously during an acute episode, AstraZeneca has developed a small molecule that can activate RXFP1 orally. The phase 2b LUMINARA trial presented at ESC 2026 tested whether that translated into measurable effects on heart function. The study enrolled 375 patients already receiving standard heart failure therapy and split them into two groups according to how well their hearts were pumping. In patients with more severely reduced ejection fraction, the 20 mg dose reduced end-systolic volume index, the amount of blood left in the ventricle after it contracts, by 5.4 mL/m² more than placebo. This suggests that the heart is emptying more effectively. The result narrowly missed conventional statistical significance, and the higher doses did not produce a stronger effect. The signal was clearer in patients with mildly reduced ejection fraction. Across all three doses, AZD5462 significantly reduced systemic vascular resistance, essentially lowering the resistance the heart has to pump against. The drug was also generally well tolerated, with some mild blood-pressure lowering but no increase in clinically significant hypotension versus placebo. Those results are not enough to show that AZD5462 improves symptoms, reduces hospitalizations, or helps patients live longer, but the oral RXFP1 agonist did engage the relaxin pathway and produced the hemodynamic changes AstraZeneca was aiming for. Longer trials will be needed to determine whether the physiological effects translate into clinical benefit. Several of the programs presented at ESC 2026 will now move into their next tests. Aficamten and plozasiran have phase 3 evidence behind them, while CTX310, SRD-002 and pacibekitug remain much earlier in development. The results from eplontersen and milvexian also show why those later trials matter. Both entered phase 3 with strong biological rationales and ultimately failed their primary endpoints. For the earlier programs presented at ESC, larger trials will determine whether the signals seen so far translate into clinical benefit. Partnering 2030: The Biotech Perspective 2023