Crovalimab dose justification based on Phase 3 data in paroxysomal nocturnal hemoglobinurea patients

The main question was: Do the pharmacokinetic (PK) and drug exposure-response characterization of the observed Phase 3 data support the proposed weight-based two-tiered crovalimab dosing approach for the treatment of adult and adolescent patients with PNH not currently treated with complement inhibitors?

19.06.2023

Case study: Crovalimab dose justification based on Phase 3 data in paroxysomal nocturnal hemoglobinurea patients

About the case

Therapeutic area: Blood diseases/Rare diseases
Phase III
Impact of Model Informed Drug development: Describing

Conclusion

The analyses showed that crovalimab concentrations above approximately 100 μg/mL resulted in inhibition of terminal complement activity as indicated by low values of terminal complement activity as a pharmacodynamic (PD) efficacy marker (Figure 1). The predicted drug trough concentration at steady state remained above the threshold of 100 µg/mL in >95% of simulated patients (Figure 2).

CH50-as-measured-by-LIA — Figure 1. Graphical analysis of terminal complement activity (50% hemolytic activity [CH50] as measured by liposome immunoassay show good at efficacy at crovalimab exposure above 100 µg/mL.

Main challenges were short timelines and several pre-defined subgroup (covariate) analyses to perform.
Pharmetheus infrastructure, with scripted reports directly connected to the data and analysis results, enabled a fast turnaround of the regulatory submission ready report within only a few weeks after data base lock, assisting the client with dose justification and reporting of PK, PK/PD and exposure-response (efficacy/safety) analyses.
Methodologically, a model-based population PK analysis, with evaluation of potential covariates and graphical exposure-response analysis of terminal complement activity (50% hemolytic activity [CH50] as measured by liposome immunoassay) were performed.

Crovalimab-concentration-e1781262861274 — Figure 2. >95% of a representative study population achieved crovalimab trough exposure ≥ 100 µg/mL

Linked publication

Blood 2022, et al.. 64th ASH Annual Meeting and Exposition. New Orleans, LA; December 10-13, 2022. Poster number 1247.

19/06/23