After pelacarsen setback, debate over Lp(a) causality and the next pipeline
Lp(a), an LDL-like lipoprotein, is supported by epidemiologic and genetic evidence as a causal risk factor for atherosclerotic cardiovascular disease, but this has not been confirmed by outcome trials. In September 2025 Novartis announced that pelacarsen significantly lowered Lp(a) levels yet did not translate into reduced cardiovascular risk in the overall population; full results are due at the November AHA meeting. Open questions include subgroup benefit signals, event types, and dropout rates, while more potent siRNAs and oral small molecules are in late-stage trials, with readouts starting as early as 2028; guidelines keep one-time adult Lp(a) testing for risk assessment only, with no changes planned.
Background: Lp(a) is an LDL-like lipoprotein; epidemiological and genetic evidence support it as a "causal" risk factor for atherosclerotic cardiovascular disease (one expert said "LDL is bad, Lp(a) is worse"), but this has not been definitively confirmed by intervention trials.; Core event: In September 2025, Novartis announced that pelacarsen (which lowers Lp(a)), despite significantly reducing Lp(a) levels, "did not translate into a reduction in cardiovascular risk in the overall population"; full results will be presented at the AHA meeting in November.; Open questions: Watch for benefit signals in specific subgroups, specific event types, and dropout rates (dropouts due to adverse events may weaken the power of the intention-to-treat analysis); a per-protocol analysis may provide proof of concept for "whether lowering Lp(a) is protective."; Pipeline: More potent siRNA agents (stronger Lp(a) reduction than pelacarsen, with fewer side effects) and oral small molecules are both in Phase 3; some trials enroll high-Lp(a) populations who have "not yet had events," with readouts beginning as early as 2028.; Guidelines: The expert panel emphasized that the current "one-time Lp(a) measurement in adults" is for risk assessment rather than guiding treatment; Lp(a) is largely genetically determined and requires no repeat testing, and there are currently no plans to change guidelines.
- Background: Lp(a) is an LDL-like lipoprotein; epidemiological and genetic evidence support it as a "causal" risk factor for atherosclerotic cardiovascular disease (one expert said "LDL is bad, Lp(a) is worse"), but this has not been definitively confirmed by intervention trials.
- Core event: In September 2025, Novartis announced that pelacarsen (which lowers Lp(a)), despite significantly reducing Lp(a) levels, "did not translate into a reduction in cardiovascular risk in the overall population"; full results will be presented at the AHA meeting in November.
- Open questions: Watch for benefit signals in specific subgroups, specific event types, and dropout rates (dropouts due to adverse events may weaken the power of the intention-to-treat analysis); a per-protocol analysis may provide proof of concept for "whether lowering Lp(a) is protective."
- Pipeline: More potent siRNA agents (stronger Lp(a) reduction than pelacarsen, with fewer side effects) and oral small molecules are both in Phase 3; some trials enroll high-Lp(a) populations who have "not yet had events," with readouts beginning as early as 2028.
- Guidelines: The expert panel emphasized that the current "one-time Lp(a) measurement in adults" is for risk assessment rather than guiding treatment; Lp(a) is largely genetically determined and requires no repeat testing, and there are currently no plans to change guidelines.
Source: YouTube