Plozasiran

Today, BioPharma Dive is highlighting some notable clinical trial updates presented at the annual meeting of the European Society of Cardiology. Over the weekend, several large pharmaceutical and biotechnology companies released detailed study data on medicines for an array of different heart conditions.Below are three notable datasets and a look at how theyre being interpreted by investors and analysts.Cytokinetics stock sell-offCytokinetics claimed one of the bigger clinical trial victories in biotech this year when, in June, it disclosed that its drug Myqorzo succeeded in a Phase 3 trial in people with the non-obstructive form of the heart condition hypertrophic cardiomyopathy. That study made Myqorzo the first drug of its kind to prove beneficial against both forms of the condition, and separated it from Bristol Myers Squibbs market leading medicine Camzyos.On Friday, detailed data from that study were published in The New England Journal of Medicine and presented at ESC. Multiple Wall Street analysts claimed those findings reinforced Myqorzos potential despite the disclosure of a possible safety concern that sank Cytokinetics stock price.According to the NEJM paper, patients randomized to receive Myqorzo had an average 11.4-point improvement on a questionnaire assessing heart health after 36 weeks, compared to an 8.4-point change for placebo recipients. Peak oxygen consumption also improved for those treated with Myqorzo and slightly declined for those in the placebo group.Overall, Myqorzos effects were consistent across all study groups analyzed, reiterating Cytokinetics initial results, wrote Leerink Partners analyst Roanna Ruiz. And, importantly, the drugs impact on assessment scores appeared to grow over time, added Stifels James Condulis.The efficacy data are robust, Condulis wrote in his own note.Still, Cytokinetics shares fell more than 7% on Friday, as the paper also revealed 10 patients receiving Myqorzo experienced a specific kind of heart failure, versus three patients on placebo. That disclosure will likely add to an already lingering debate about the safety of Myqorzo and other drugs like it for people with non-obstructive disease, according to Condulis. (About one-third of patients have this form of HCM, which doesnt impede blood flow to the heart but can still put people at risk of poor health outcomes.)Yet Condulis and others argued the overall evidence should still support a new approval for Myqorzo and lead to broader uptake. Mizuho Securities analyst Salim Syed, for example, noted how there were no deaths among Myqorzo-treated patients, compared to three in the placebo arm. And patients with that form of the condition have essentially zero options currently.The stock sell-off is like missing [the] forest for trees, Syed added.Arrowheads edgeArrowhead Pharmaceuticals and Ionis Pharmaceuticals are already dueling for market supremacy in a rare disease that leads to extremely high triglycerides. That battle is soon to extend to a more common condition, with potentially billions of dollars at stake and where some analysts believe Arrowhead might have an advantage.Arrowhead in July said its drug plozasiran met the objectives of two late-stage studies in adults with severe hypertriglyceridemia, or sHTG. Those findings positioned Arrowhead to expand plozasirans use and directly challenge Ionis, which nabbed an approval in sHTG for its drug Tryngolza in June.At ESC, Arrowhead provided fuller details from those two studies and, to multiple analysts, described a drug with comparable efficacy to Tryngolza but potentially better safety. Prakhar Agrawal, of Cantor Fitzgerald, argued that plozasiran appears safer across several metrics, among them side effects leading to study discontinuations and liver enzyme or fat increases the latter of which has been a key focus for investors.The two drugs havent been tested against one another. But among patients who underwent a specialized imaging test in Arrowheads trials, plozasiran recipients had a roughly 1.5% placebo-adjusted increase in liver fat, compared to a 2% or 4% increase for Tryngolza recipients in Ionis studies, Agrawal noted.While specialists Agrawal spoke with suggested the liver fat increases Ionis reported may not be clinically meaningful, his team nonetheless expects it to be a factor in Arrowheads drug becoming the preferred option.Plozasirans results arguably support a best-in-class profile, wrote Condulis, from Stifel, in a separate note.Arrowhead intends to file for approval by the end of the year, setting up a potential launch in 2027. Agrawal expects plozasiran to claim 60% of a market opportunity that could reach $6 billion by 2035.A heart drug autopsyIn July, AstraZeneca and Ionis stunned industry watchers when they revealed eplontersen, a medicine theyve been developing, missed the central objective of a Phase 3 study in transthyretin amyloidosis-mediated cardiomyopathy, a progressive and deadly heart condition. At ESC, study investigators presented a detailed autopsy of those results, and Wall Street analysts began assessing the fallout for others with rival medicines.Alnylam already markets one drug called Amvuttra that, like eplontersen, interferes with the production of a protein implicated in the condition. It also has another, next-generation medication known as nucresiran thats in late-stage testing. Eplontersens failure raised doubts about Amvuttras impact on the disease, and heightened skepticism about nucresirans chances of success.William Blair analyst Myles Minter noted how AstraZeneca and Ionis findings call into question the benefits of combination therapy in TTR cardiomyopathy, where these silencer drugs might be used alongside the protein stabilizers patients typically receive. The results also fuel debate around the positioning of available therapies, which include Amvuttra and two branded stabilizers, Pfizers Vyndamax and BridgeBio Pharmas Attruby, according to Minter.In a separate note, Mizuhos Syed wrote that AstraZeneca and Ionis data increases [the] gap between stabilizers and silencers and effectively boosted the case for Attruby. In the placebo group in the failed eplontersen trial, a majority of the patients were on Vyndamax and the level of protein stabilization observed was well short of what was seen in testing of Attruby. Syed argued that the results show why a practitioner would choose Attruby over Vyndamax which will lose market exclusivity in 2031 and suggests investors may be modeling Attruby too conservatively once generics are available, he wrote.Analysts at Oppenheimer, meanwhile, rallied to Alnylams defense, noting that new analyses the company presented Sunday suggest Amvuttra may be more potent than eplontersen and that nucresiran might perform even better in Phase 3 testing. The reason, Oppenheimers Kostas Biliouris contended, is modality differences between Alnylam and Ionis drugs. Both medicines use different approaches RNA interference for Alnylams drugs and antisense oligonucleotide therapy for Ionis to achieve their intended effects. '

Readying to submit a supplemental FDA application for Redemplo (plozasiran) — and cashing in a newly-purchased priority review voucher to speed up the review — Arrowhead Pharmaceuticals has shared detailed 12-month data for the APOC3-targeting RNA therapy as it attempts to add severe hypertriglyceridaemia (sHTG) to its label. The biotech presented updated results from the Phase III SHASTA-3 and SHASTA-4 trials at the European Society of Cardiology (ESC) congress on Sunday, about a month after it first reported that Redemplo met both studies' primary endpoints by significantly lowering triglycerides and reducing acute pancreatitis.In July, Arrowhead said patients taking Redemplo in SHASTA-3 and SHASTA-4 saw median triglyceride reductions of 79% and 81%, respectively. The siRNA also led to statistically significant reductions in acute pancreatitis event rate and total incidence rate. Across the two Phase III trials, about 750 adults with sHTG were randomised to receive a 25-mg subcutaneous injection of Redemplo every three months or placebo, for four total doses.At the time, investors were optimistic that Redemplo may be able to challenge the RNA first-comer in sHTG, Ionis' Tryngolza (olezarsen), which is dosed as a monthly injection (see – Vital Signs: Arrowhead's SHASTA readout hits Ionis in the CORE).For Arrowhead to take on Ionis, Oppenheimer analysts wrote in a note ahead of ESC that they would be looking to the 12-month results to "provide a longer-term assessment of triglyceride control, dosing durability, pancreatitis events and safety…Particular focus should be placed on the proportion of patients reaching clinically relevant triglyceride thresholds" (see – Spotlight On: What to watch at ESC 2026).Physicians were also eager for more details on Redemplo's safety profile as a potential point of differentiation from Tryngolza. "Now that efficacy looks the same, both in terms of triglyceride reduction and pancreatitis prevention, I think what is really going to distinguish these drugs is safety," Michael Shapiro, professor of cardiology and molecular medicine at Wake Forest University, previously told FirstWord. "You see some blood sugar issues with Tryngolza, but the real bothersome thing is hepatic steatosis" (see – KOL Views Q&A: Leading cardiologist sees an HTG favourite in battle of Ionis' speed vs Arrowhead's safety).Tackling triglyceridesFor a fuller picture of Redemplo's triglyceride-lowering potential, Arrowhead reported how successfully the siRNA helped patients reach key thresholds after 12 months of treatment. In SHASTA-3 and SHASTA-4, 91% and 93% of Redemplo-treated patients, respectively, achieved triglyceride levels below 500 mg/dL compared with 51% and 50% for placebo (p<0.0001). The proportion of patients taking Redemplo whose triglyceride levels fell below 150 mg/dL were 52% and 55% in the two studies, respectively, versus 7.9% and 2.0% of patients in the placebo group (p<0.0001).Additionally, patients across both trials with high-risk disease — those whose baseline triglyceride levels exceeded 880 mg/dL — saw median reductions of 85% after taking Redemplo for 12 months.Acute pancreatitis risk reductionArrowhead also provided a few more data points regarding Redemplo's impact on acute pancreatitis; the company previously reported that the siRNA reduced the rate of all acute pancreatitis events by 78% compared with placebo.Updated findings show that among patients with triglycerides above the 500 mg/dL threshold with or without a prior history of acute pancreatitis, Redemplo reduced the acute pancreatitis event rate by 91% versus placebo, for a 34% absolute risk reduction (p=0.002).In addition, the biotech reported that Plozasiran significantly reduced the risk of a first acute pancreatitis event (p=0.016).Liver safety, but glycaemic dysfunctionThe drugmaker shared specific safety findings from SHASTA-3 and SHASTA-4, which showed an 8.3% serious treatment-emergent adverse event (TEAE) rate in patients taking Redemplo, compared with a 10% rate for placebo. Importantly, Arrowhead said there was no statistically significant treatment-emergent increase in hepatic fat fraction in the experimental treatment group; Tryngolza has been linked to an elevation in liver fat and enzymes. However, the most common TEAE was worsening glycaemic control, reported in 14.3% of patients, a side effect also seen with Tryngolza treatment. Arrowhead emphasised that "despite the imbalance in reported glycaemic control-related TEAEs, mean HbA1c showed minimal to modest absolute change from baseline with no worsening of mean HbA1c over time."Other TEAEs in Redemplo-treated patients were diarrhoea (5.6%) and injection-site reactions (3.2%). Arrowhead reported three fatal events in the Redemplo arm — two cardiovascular deaths and one due to chronic myelomonocytic leukaemia — though all were determined to be unrelated to the siRNA therapy and were instead attributed to pre-existing cardiovascular or haematologic disease.