Summary: In 66 participants with homozygous familial hypercholesterolaemia, lerodalcibep did not establish noninferiority to evolocumab for LDL cholesterol reduction at 24 weeks. The treatment difference was 5.4 percentage points (95% CI -0.2 to 11.1), crossing the prespecified 6-percentage-point noninferiority boundary.
PICO Summary
| Element | Detail |
|---|---|
| Population | 66 participants aged at least 10 years with genetically confirmed homozygous familial hypercholesterolaemia at 12 lipid clinics across six countries. Mean age 28.7 years; 20 participants were paediatric. Mean baseline LDL cholesterol 10.59 mmol/L. |
| Intervention | Lerodalcibep 300 mg by monthly subcutaneous injection for 24 weeks. Participants crossed to the alternate treatment after an eight-week washout. |
| Comparator | Evolocumab 420 mg monthly by subcutaneous administration for 24 weeks in the alternate crossover period. Treatments were open-label, but efficacy measurements were masked to participants, staff and sponsor. |
| Outcomes | Primary intention-to-treat LDL cholesterol change at week 24 was -4.9% with lerodalcibep and -10.3% with evolocumab. Difference 5.4 percentage points (95% CI -0.2 to 11.1): noninferiority was not demonstrated at the 6-point margin. Average reductions across monthly visits were -9.1% and -10.8%, respectively, a different analysis from the primary endpoint. No treatment-related serious adverse events were reported. Injection-site reactions occurred in 1/65 (2%) receiving lerodalcibep and 15/62 (24%) receiving evolocumab. Individual LDL responses varied substantially. |
| Study Design | Phase 3, randomised, open-label crossover noninferiority trial; two 24-week treatment periods separated by eight weeks. NCT04034485. Funded by LIB Therapeutics, with employees, shareholders and the founder among authors. This trial did not measure cardiovascular event benefit. |
Expert Commentary
I interpret LIBerate-HoFH primarily as a failed noninferiority comparison, not as evidence that the two treatments are interchangeable. The confidence interval extends beyond the prespecified margin, which is the relevant statistical test. Similar average responses at other visits cannot rescue that primary result. Can I use this with my patients? The study is informative for specialist appraisal of PCSK9-directed treatment in homozygous familial hypercholesterolaemia, particularly because responses were highly variable. It does not justify switching a responding patient on the assumption of equivalent LDL lowering. The same individual often responded similarly to both agents, but that observation is not a substitute for the failed population-level comparison. I would also avoid translating these modest short-term lipid changes into a claim of fewer cardiovascular events. The crossover design offers useful within-person comparisons, although the small rare-disease population limits precision and subgroup conclusions. Fewer injection-site reactions with lerodalcibep are relevant, but tolerability and efficacy answer different questions. Sponsor involvement and the open-label administration should remain explicit when discussing convenience or acceptability. The next priority is to understand response heterogeneity and to establish robust comparative effectiveness in clinically defined groups, rather than describing a statistically inconclusive noninferiority result as a successful demonstration of equivalence.
References
Raal FJ, Mehta V, Kayikcioglu M, et al. Lerodalcibep and evolocumab for the treatment of homozygous familial hypercholesterolaemia with PCSK9 inhibition (LIBerate-HoFH): a phase 3, randomised, open-label, crossover, non-inferiority trial. Lancet Diabetes Endocrinol. 2025;13(3):178-187. doi:10.1016/S2213-8587(24)00313-9. PMID: 39870096.
