This first-in-human, randomised, double-blind, placebo-controlled phase 1 trial assessed the safety profile of Kylo-11, a long-duration small interfering RNA targeting lipoprotein(a), following a single subcutaneous dose. The primary endpoint was the incidence of investigator-assessed adverse events within 24 weeks. All participants who received any investigational product were included in the safety analysis set.
Among 70 dosed participants (57 Kylo-11, 13 placebo? — see source: 14 placebo assigned, 70 received a dose), 37 (53%) experienced adverse events up to 24 weeks. The majority were grade 1–2 and judged by investigators to be unrelated to the study drug. Notably, there were no injection-site reactions reported, no adverse events attributed to the investigational drug, no serious adverse events, and no deaths during the observation period reported in the source.
Three grade 3 or higher events were documented and adjudicated as unrelated to Kylo-11: two events in the 225 mg Kylo-11 cohort (transient hypertriglyceridaemia and elevated creatine phosphokinase at day 168) and one event in the placebo group (transient hypertriglyceridaemia at day 84).
The trial was conducted at a single hospital-based site in China in adults aged 18–55 years with elevated lipoprotein(a) concentrations who were otherwise healthy. Participants were randomly assigned in an 8:2 ratio to receive a single subcutaneous dose of Kylo-11 or placebo across seven dosing cohorts. Kylo-11 recipients could enter conditional extension follow-up up to day 337; placebo recipients were followed up to day 169.
Randomisation schedules were generated by an unmasked statistician who did not participate in study conduct or blinded analyses, and treatment assignment was managed via an interactive web response system. Participants, investigators, and study personnel were masked to cohort assignment.
Participants with baseline lipoprotein(a) concentrations of 75–200 nmol/L were enrolled into cohorts 1–6, receiving single doses of 9, 30, 75, 225, 450, and 600 mg of Kylo-11, respectively. A seventh cohort enrolled participants with baseline lipoprotein(a) concentrations >200 nmol/L and administered a 225 mg dose.
Between May 30 and Dec 30, 2024, 71 participants were randomly assigned across Kylo-11 (n=57) and placebo (n=14); 70 participants received investigational product. The median participant age was 27.5 years (IQR 22.0–32.0), 65% were male, and the median follow-up duration was 337 days (IQR 334–337).
Prespecified pharmacodynamic secondary endpoints included median percent and absolute reductions in serum lipoprotein(a) over time, with a final follow-up timepoint at 48 weeks. The pharmacodynamic analysis set comprised all randomly assigned participants who received Kylo-11 and had at least one post-dose pharmacodynamic datapoint. Missing data were not imputed, per the protocol reported in the source.
Kylo-11 produced dose-dependent reductions in serum lipoprotein(a) that were durable at 48 weeks. Median percent and absolute reductions at the 48-week timepoint for Kylo-11 cohorts were reported as follows:
In cohort 7, which included participants with baseline lipoprotein(a) >200 nmol/L who received 225 mg, the median reduction at 48 weeks was –96% (IQR –98 to –91) with an absolute median decrease of –208 nmol/L (IQR –222 to –198). These results indicate both substantial relative and absolute reductions in participants with very high baseline lipoprotein(a).
Adverse events up to 24 weeks affected roughly half of dosed participants and were predominantly mild to moderate. The trial report emphasises the absence of injection-site reactions and the absence of drug-related and serious adverse events. The three grade ≥3 events described above were adjudicated as unrelated to Kylo-11.
The trial authors interpret the data to indicate that a single subcutaneous dose of Kylo-11 was well tolerated in this healthy adult population with elevated lipoprotein(a) and that doses of 225 mg or higher produced durable reductions in serum lipoprotein(a) for up to 48 weeks. The magnitude of reduction increased with dose, and participants with very high baseline lipoprotein(a) (>200 nmol/L) achieved large absolute decreases.
The source provides phase 1 safety and pharmacodynamic findings only. Details on longer-term clinical outcomes, larger or diverse populations, or comparisons with other Lp(a)-lowering agents were not reported in this phase 1 report and would require subsequent trials.
The trial was funded by Kylonova Biopharma. Several authors are employees of Hygieia Pharmaceuticals or inventors on submitted patents; some authors reported roles in other Lp(a) trials or industry relationships. Other authors declared no competing interests. Specific conflict of interest details are reported in the source.