Mitigating Drug-Target-Drug Complexes in Patients With Paroxysmal Nocturnal Hemoglobinuria Who Switch C5 Inhibitors

Area of Science:

• Pharmacology
• Immunology
• Clinical Trials

Background:

• Drug-target-drug complexes (DTDCs) emerge when switching C5 inhibitors like eculizumab to crovalimab.
• These complexes can affect drug exposure and potentially lead to hypersensitivity reactions.

Purpose of the Study:

• To investigate DTDC formation in patients switching from eculizumab to crovalimab.
• To evaluate the safety and efficacy of an optimized crovalimab dosing regimen to mitigate DTDCs.

Main Methods:

• Phase I/II COMPOSER study (Part 3) assessed initial crovalimab dosing in PNH patients switching from eculizumab.
• Mathematical modeling simulated DTDC kinetics and dosing effects.
• Part 4 evaluated a simulation-guided optimized crovalimab regimen.

Main Results:

• DTDCs were detected in all 19 patients in Part 3, with transiently reduced crovalimab exposure.
• Two patients experienced mild-to-moderate hypersensitivity reactions.
• The optimized regimen in Part 4 significantly decreased large DTDCs (>50% by Day 22) and maintained target concentrations.
• No hypersensitivity reactions occurred in Part 4.

Conclusions:

• Model-based optimization of crovalimab dosing effectively reduced DTDC formation.
• Optimized dosing ensured adequate complement inhibition and improved safety profile.
• This strategy offers a promising approach for patients switching to novel antibody therapies targeting soluble epitopes.