Kylo-11 Shows Durable Lp(a) Reduction at 48 Weeks, With Ashish Sarraju, MD

A single dose of Kylo-11, a non-canonical, long-duration small interfering RNA (siRNA) targeting lipoprotein(a) [Lp(a)], was well tolerated and produced durable reductions in serum Lp(a) concentrations through 48 weeks, according to results from a first-in-human phase 1 trial presented at the European Society of Cardiology (ESC) Congress 2026 in Munich, Germany.¹

Ashish Sarraju, MD, of Cleveland Clinic, discussed the findings with HCPLive, describing the study as evaluating both safety and long-term durability from a single injection of Kylo-11, an siRNA designed to reduce hepatic apolipoprotein(a) expression and, in turn, serum Lp(a) levels.

Kylo-11 Phase 1 Trial Design and Lp(a)-Lowering Results

This randomized, double-blind, placebo-controlled phase 1 trial was conducted at a single site in China in adults aged 18 to 55 years with elevated Lp(a) who were otherwise healthy. Participants were randomly assigned in an 8:2 ratio to a single subcutaneous dose of Kylo-11 or placebo across 7 dosing cohorts. Cohorts 1 through 6 enrolled participants with baseline Lp(a) of 75 to 200 nmol/L across doses of 9, 30, 75, 225, 450, and 600 mg, while cohort 7 enrolled participants with baseline Lp(a) above 200 nmol/L at the 225 mg dose.¹

Between May and December 2024, investigators randomized 71 participants (n = 57 Kylo-11, n = 14 placebo), with 70 receiving a dose.¹ The median age was 27.5 years, and 65% of participants were male.¹ Among the 70 dosed participants, 53% had an adverse event through 24 weeks, most grade 1 to 2 and deemed unrelated to the study drug; there were no injection-site reactions, no serious adverse events, no drug-related adverse events, and no deaths.¹

At the final follow-up timepoint of 48 weeks, median Lp(a) reductions among Kylo-11 recipients ranged from -53% in the 9 mg cohort to -97% in the 600 mg cohort. In cohort 7, participants with baseline Lp(a) > 200 nmol/L had a median reduction of -96% (IQR, -98 to -91), an absolute reduction of 208 nmol/L. The trial's authors concluded a single dose of Kylo-11 was well tolerated and, at doses of 225 mg or higher, durably reduced Lp(a) through 48 weeks.¹

Clinical Meaningfulness, Mechanism, and Outcome Trial Design

Asked how close these reductions come to biologically meaningful normalization, Sarraju pointed to Mendelian randomization data as a starting estimate, but said outcome trials will ultimately answer the question: "From observational Mendelian randomization data, we estimate that somewhere between 50 to 100 mg per deciliter reduction in lipoprotein(a) levels may equate to a similar risk reduction as 1 mmol per liter of LDL cholesterol reduction," he said. "But really I think it's the placebo-controlled cardiovascular outcome trials that are going to answer the key question of whether pharmacologically lowering the Lp(a) reduces cardiovascular events... pharmacologic lowering may not be the exact same thing as being born with genetic variants that lower Lp(a). Now, we hope it's the same, and that model's been proven in other cases like PCSK9 inhibition. But... we need to prove it here with Lp(a) too, with the cardiovascular outcome trials."

On the mechanism behind Kylo-11's durability, Sarraju said the working hypothesis centers on its structure: 4 GalNAc moieties conjugated to the siRNA, more than seen with other Lp(a)-targeted siRNAs studied to date. He said this non-canonical design may increase hepatocyte uptake and intracellular concentration while conferring greater resistance to degradation by exonucleases, though he characterized this as a working hypothesis rather than a confirmed mechanism.

Sarraju noted current Lp(a)-lowering outcome trials generally enroll at-risk populations already well treated with first- or second-line lipid-lowering therapy to control LDL cholesterol, then assess whether Lp(a) lowering reduces residual event risk on top of background therapy. He noted a broader competitive landscape testing this hypothesis, including antisense oligonucleotides, other siRNAs, and small-molecule Lp(a) assembly inhibitors such as muvalaplin.

Dosing Frequency, Adherence, and Safety Signals to Watch

Regarding the clinical significance of annual or less frequent dosing, Sarraju drew a lesson from LDL cholesterol management. "With LDL cholesterol, statin adherence rate, no matter how much we try, seems to cap out at around 50%. And the uptake of PCSK9 inhibitors was very slow in the beginning," Sarraju said. "If we rely on a single agent to get us LDL cholesterol control or a single route of administration, oral or injectable, we'd probably fail. Patients want different things. Patients have different abilities to adhere to these medications... I think the key is [to] have as many options as possible, so you can match the correct therapy with the correct patient and the correct physician."

Sarraju noted early phase 1 data suggest once-yearly dosing may be feasible with Kylo-11 at higher doses, which he said could prove more practical for many patients than a daily pill or monthly injections.

He additionally pointed to 2 areas of focus as these therapies move from healthy volunteers into patients with atherosclerotic cardiovascular disease and other comorbidities:. "One of the first questions we want to ask is are there injection site reactions, because we see that even across the PCSK9 injectables. In this phase 1 study, there were no injection site reactions observed whatsoever, which was reassuring, but we'll have to replicate that across a broader cohort," Sarraju said. "We want to watch liver effects, because these are hepatocyte-targeting agents. And again, we did not see any evidence of a dose-dependent increase in ALT or increase in bilirubin... but we're going to want to keep an eye on that as well."

Editors’ note: Sarraju reports relevant disclosures with New Amsterdam Pharma, Kardigan, vTv Therapeutics, CRISPR Therapeutics, Ionis, Novartis, and Regeneron.

References

1. Sarraju A, et al. Safety and lipoprotein(a)-lowering effects of Kylo-11, a non-canonical, long-duration small interfering RNA targeting lipoprotein(a): a first-in-human, randomised, double-blind, placebo-controlled, phase 1 trial. Presented at: ESC Congress 2026; August 29, 2026; Munich, Germany.

2. Sarraju A, Du X, Zhou L, et al. Safety and lipoprotein(a)-lowering effects of Kylo-11, a non-canonical, long-duration small interfering RNA targeting lipoprotein(a): a first-in-human, randomised, double-blind, placebo-controlled, phase 1 trial. Lancet. Published online August 28, 2026. doi:10.1016/S0140-6736(26)01484-4