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Single Dose of Kylo-11 siRNA Reduces Lipoprotein(a) by Up to 97% at 48 Weeks
A single subcutaneous injection of Kylo-11, a novel long-duration small interfering RNA, produced median reductions in serum lipoprotein(a) ranging from 53% at the lowest dose (9 mg) to 97% at the highest dose (600 mg), sustained through 48 weeks, with no serious or drug-related adverse events recorded. The dose-dependent and durable pharmacodynamic signal across seven cohorts supports continued clinical investigation of this compound as a potential long-acting intervention for elevated lipoprotein(a).
What Was Studied
This phase 1 trial was designed to evaluate the safety profile and lipoprotein(a)-lowering pharmacodynamics of Kylo-11, a non-canonical, very long-acting small interfering RNA that silences the gene encoding lipoprotein(a). The primary endpoint was the incidence of investigator-assessed adverse events within 24 weeks, with lipoprotein(a) reduction over time assessed as a prespecified pharmacodynamic secondary endpoint.
How It Was Studied
This was a randomised, double-blind, placebo-controlled, phase 1 trial conducted at a single hospital-based site in China. Adults aged 18 to 55 years with elevated lipoprotein(a) concentrations who were otherwise healthy were enrolled across seven dosing cohorts and assigned in an 8:2 ratio to receive either a single subcutaneous dose of Kylo-11 or placebo. Of 71 participants randomised, 70 received a dose; 57 received Kylo-11 at doses spanning 9, 30, 75, 225, 450, and 600 mg, with a dedicated cohort for participants with lipoprotein(a) above 200 nmol/L receiving 225 mg. Kylo-11 recipients could be followed for up to day 337 under conditional extension, while placebo recipients were followed only to day 169; pharmacodynamic assessments extended to 48 weeks.
What Was Observed
- Favourable safety profile across all doses: No serious adverse events, no injection-site reactions, no drug-related adverse events, and no deaths were recorded. Overall, 37 of 70 participants (53%) experienced any adverse event through 24 weeks, the large majority of which were grade 1 or 2 and judged unrelated to the study drug. Two grade 3 or higher events in the 225 mg cohort (transient hypertriglyceridaemia and elevated creatine phosphokinase, both at day 168) were also adjudicated as unrelated to Kylo-11.
- Substantial lipoprotein(a) lowering at higher doses: At the 600 mg dose, median lipoprotein(a) fell by 97% (IQR −98 to −97) from baseline, corresponding to an absolute reduction of 129 nmol/L (IQR −153 to −99) at the 48-week follow-up point. Even at the lowest dose tested (9 mg), the median reduction reached 53% (IQR −71 to −41) and −71 nmol/L (IQR −79 to −60).
- Deep reductions in participants with very high baseline lipoprotein(a): In cohort 7, which enrolled participants with baseline lipoprotein(a) exceeding 200 nmol/L treated with a single 225 mg dose, the median percent reduction was 96% (IQR −98 to −91) and the absolute reduction was 208 nmol/L (IQR −222 to −198) at 48 weeks, indicating effectiveness even at substantially elevated baseline concentrations.
Why This Matters
Elevated lipoprotein(a) is identified in this study as a recognised contributor to atherosclerotic cardiovascular disease, and existing pharmacological options for lowering it have been limited. The demonstration that a single injection of Kylo-11 can suppress lipoprotein(a) by up to 97% for as long as 48 weeks introduces a potential very long-acting therapeutic strategy that, if confirmed in larger trials, could meaningfully change how this cardiovascular risk factor is managed.
How to Read This Result
Although the pharmacodynamic signal is striking, these findings come from a small, single-site, phase 1 study conducted exclusively in healthy younger adults in China, and the trial was not statistically powered to establish efficacy, so the estimates of effect size and safety should be interpreted with appropriate caution pending replication in larger, more diverse populations that include patients with established cardiovascular disease.
Limitations
The study was conducted at a single site in China, restricting generalisability across ethnicities and healthcare settings. Individual cohort sizes were small, limiting the precision of both safety and pharmacodynamic estimates. Placebo recipients were followed only to day 169, precluding long-term safety comparisons. As a phase 1 trial, it was not powered to detect efficacy differences. The enrolled population was young (18–55 years) and otherwise healthy, which does not reflect the older patients with comorbid cardiovascular disease for whom lipoprotein(a) lowering would be most clinically relevant. Missing data were not imputed, introducing potential bias in pharmacodynamic summaries.