A single subcutaneous dose of Kylo-11, a very long-acting small interfering RNA targeting lipoprotein(a), cut median serum lipoprotein(a) by up to -97% at 48 weeks in healthy adults with elevated concentrations, with reductions of -53% at 9 mg and -96% in participants above 200 nmol/L given 225 mg. In the 70 dosed participants, adverse events occurred in 53%, mostly grade 1-2 and deemed unrelated; there were no serious or drug-related events. The findings support durable lipoprotein(a) lowering from one dose.
Eli Lilly has won FDA approval for Mounjaro to reduce the risk of heart attack or stroke in at-risk adults with type 2 diabetes. The decision adds a cardiovascular risk reduction use to the drug as Lilly competes with Novo Nordisk in diabetes and obesity. Lilly secured the approval on Friday.
Cytokinetics said on Friday that aficamten met both primary endpoints, symptom improvement and exercise capacity, in the pivotal ACACIA trial in non-obstructive hypertrophic cardiomyopathy (nHCM). The company plans to submit a marketing application to the FDA by the end of the year; if approved, it could become the first dedicated treatment for nHCM, though some experts consider the benefit limited.
Why it matters: Aficamten met both primary endpoints in an nHCM pivotal trial and could be the first approved drug for the indication, though some experts see limited benefit.
ICD implantation did not reduce the composite of sudden cardiac death or hemodynamically significant ventricular arrhythmia in patients with LVEF of 36% to 50% and CMR-defined myocardial scar. In the randomized trial of 353 patients followed for a median of 6.3 years, the composite occurred in 7.8% with an ICD vs 9.2% with an implantable loop recorder (HR 0.76; 95% CI, 0.37-1.58), though sudden cardiac death alone was lower with ICDs (1.7% vs 5.8%; HR 0.26). A scar-based selection strategy beyond the LVEF 35% cutoff did not change the primary outcome overall.
Aficamten, a cardiac myosin inhibitor, improved both exercise capacity and symptoms in symptomatic nonobstructive HCM, a condition with no previously proven medical therapy. In the phase 3 ACACIA-HCM trial, 258 patients received aficamten and 259 received placebo; at 36 weeks, peak oxygen uptake differed by a least-squares mean of 0.67 ml per kilogram per minute (P = 0.003) and KCCQ-CSS by 3.0 points (P = 0.02) in favor of aficamten. Reversible ejection fraction reductions below 50% occurred in 10.5% of aficamten patients versus 0.8% on placebo.
Stopping antibiotics early based on clinical response was safe and effective in left-sided infective endocarditis caused by S. aureus, E. faecalis, or streptococcus species. In the POET II trial of 508 stabilized adults, response-tailored therapy gave a median 183 days alive without antibiotics within 6 months versus 169 days with standard 4-to-6-week therapy, and was noninferior for the safety composite (8.2% vs. 10.7%). Relapse of bacteremia or endocarditis was more frequent with tailored therapy (5.1% vs. 1.6%).
Gut microbes convert dietary inorganic nitrate and non-heme iron into dinitrosyl iron complexes (DNICs) that spread systemically and improve host metabolism. DNICs were detected by electron paramagnetic resonance in tissues of conventional but not germ-free mice, and nitrate plus iron citrate supplementation or synthetic DNICs ameliorated cardiometabolic dysfunction in Western diet-fed mice while reducing steatosis in HepG2 cells and human hepatocyte spheroids. The bioactivity resides in the Fe(NO)2 entity, acting through soluble guanylyl cyclase activation, leucine uptake inhibition, and mTORC1 normalization.
A single-cell analysis across six organs and tissues in angiotensin II-treated mice, Dahl salt-sensitive rats, and spontaneously hypertensive rats mapped gene programs tied to blood pressure and renal injury, including conserved vascular smooth muscle cell and renal tubular programs. Integration with human genomic data linked cell types to hypertension traits and prioritized a noncoding variant, rs28451064, whose genome-edited validation showed an in vivo effect on blood pressure and allele-specific regulation of local genes. The work delivers a multimodel, cross-organ cellular resource for hypertension research.
Once-weekly subcutaneous zenagamtide, a unimolecular GLP-1, amylin and calcitonin receptor agonist, lowered HbA1c in adults with type 2 diabetes on metformin with or without an SGLT2 inhibitor in a 36-week phase 2 dose-finding trial. Across doses of 0·4 to 40 mg, HbA1c fell from a baseline mean of 7·8% by up to -1·7%, with a treatment difference versus placebo of -1·56% at the highest dose (p<0·0001). Adverse events were mostly mild to moderate gastrointestinal effects; 21 of 261 exposed participants had serious adverse events and no deaths occurred.
A study published in the Journal of General Physiology proposes an agonism-while-blocking mechanism to explain facilitation, the phenomenon in which certain hERG blockers increase hERG current under specific conditions.
Why it matters: Uses rate theory and atomistic models to break facilitation into testable steps, giving a mechanistic baseline for arrhythmia risk of hERG blockers.
Sodium bicarbonate did not improve sustained return of spontaneous circulation in adults with in-hospital cardiac arrest. In this double-blind trial at 21 Danish hospitals, 372 patients given up to 100 mmol of sodium bicarbonate and 407 given placebo achieved sustained ROSC at similar rates (39% vs 37%; risk ratio 1.05, P = .62), with no significant differences in 30-day survival or favorable neurologic outcome. The findings do not support routine administration of sodium bicarbonate during in-hospital cardiac arrest, and alkalosis and hypernatremia were more common with it.
Sinobioway Seiton announced positive topline results from WS016CT301, the Phase III trial of its self-developed Class 1 polymer-based drug WS016 dry powder for suspension, in adult hyperkalemia in China. In Part A, both the primary endpoint and key secondary endpoints met the prespecified statistical criteria.
Why it matters: Phase III data for a domestic polymer potassium-lowering drug, with 24-hour reduction and over 60% of subjects restored to normal potassium, comparable to approved peers.
FDA approved orforglipron just 50 days after its NDA submission, making it the first new molecular entity cleared under the FDA's National Priority Voucher program and the fastest NME approval since 2002. In a late-stage trial, patients taking one highest-dose tablet daily lost an average of 27.3 pounds, or 12.4% of body weight, over 72 weeks. It is not the first oral GLP-1 weight-loss drug, as Novo Nordisk's oral Wegovy (semaglutide) was approved in December 2015.
TMEM141, a mitochondrial inner membrane protein, acts as a negative regulator of complex I assembly. When cells switch from glucose to galactose, TMEM141 levels drop markedly, and its loss increases respiration and complex I assembly; TMEM141 works by interacting with the assembly factor TIMMDC1, limiting its association with complex I subunits. Its deficiency raises oxidative damage and mtDNA release, activating cGAS-STING, and in Drosophila dTMEM141 is required for glial cell integrity in the eye.
SGLT2 inhibitors reduce mortality in heart failure by directly activating pantothenate kinase 1 (PANK1), the rate-limiting enzyme in coenzyme A synthesis, rather than through their known glucose transport target. Stable isotope infusions showed the drugs stimulate CoA synthesis and fuel use in human cardiac tissue, and binding at physiological concentrations was mapped by in silico modeling and confirmed by mutagenesis. PANK activation proved necessary and sufficient to increase contractility of human cardiomyocytes, identifying a plausible mechanism for the clinical benefit.
Roche, through its Genentech unit, is paying Hanmi Pharmaceutical $190 million up front for rights to HM17321, a Ucn2 analog for obesity that has begun a Phase I trial in healthy volunteers and patients with obesity. Milestones could raise the deal's value to $2.3 billion, and Hanmi is eligible for royalties outside South Korea, where it retains the program's rights. The asset would complement at least four other clinical programs in Roche's obesity pipeline.
Coronary collateral arteries form mainly from capillary endothelial cells rather than from arterial endothelial cells migrating away from preexisting arteries, whose contribution is modest, dual genetic lineage tracing shows. The capillary-to-collateral conversion is functionally crucial for cardiac repair. Transient Vegfa expression via modified mRNA promoted collateral formation, acting through YY1/SETD1A-mediated H3K4 trimethylation of HES1 transcription to drive arterialization.
Why it matters: It overturns the accepted arterial-origin model of de novo collateral formation and identifies a VEGF-driven arterialization mechanism.
Genentech has licensed HM17321, Hanmi Pharmaceutical's non-incretin drug designed to reduce fat while preserving or increasing lean body mass, under an exclusive agreement. Hanmi receives $190 million upfront, with total deal value up to $2.3 billion through development, regulatory and commercial milestones, plus tiered royalties after launch. Hanmi keeps all rights in South Korea, while Genentech handles development, manufacturing and commercialization elsewhere; next steps are further development of the molecule.
Roche has struck a deal with Hanmi Pharm, paying $190 million upfront in a transaction worth up to $2.5 billion, to license the company's clinical-stage obesity drug targeting urocortin-2. According to the source, this mechanism is a less-explored direction and represents Roche's bet on unknown territory in the field.
