Drug-target-drug complexes (DTDCs) can form in patients with paroxysmal nocturnal hemoglobinuria (PNH) who switch from eculizumab to crovalimab. However, it is possible to reduce the proportion of large DTDCs, ensure adequate complement inhibition, and improve safety by optimizing the dosing regimen of crovalimab, according to a new study published in Clinical Pharmacology & Therapeutics.

COMPOSER (NCT03157635) is a global, open-label, multicenter, phase 1/2 study of crovalimab comprised of 4 sequential parts.

In part 3, the study authors recruited 19 patients with PNH to evaluate 3 subcutaneous crovalimab dosing regimens following an initial intravenous loading dose. The patients received 1000 mg of crovalimab intravenously, after which they were administered subcutaneous doses of 680 mg every 4 weeks, 340 mg every 2 weeks, or 170 mg once a week.

As a result, the crovalimab exposure was transiently reduced and the formation of DTDCs in all 19 patients was confirmed by size-exclusion chromatography and crovalimab-specific enzyme-linked immunosorbent assays. Moreover, 2 patients experienced self-limiting mild to moderate symptoms of type III hypersensitivity.

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Next, a biochemical mathematical model was developed to investigate the kinetics of the formation and dissociation of DTDCs using data from part 3. The researchers expected that “increased crovalimab concentrations could reduce the proportion of large, slow-clearing DTDCs in the blood.”

In part 4, all patients received an initial intravenous loading dose of 1000 mg of crovalimab, followed by subcutaneous doses of 340 mg on days 2, 8, 15, and 22. From day 29 onward, all patients received 680 mg of crovalimab subcutaneously every 4 weeks.

As anticipated, the altered dosing regimen was successful at maintaining target crovalimab concentrations, while mean proportions of large DTDCs decreased by more than 50%. In addition, there were no reports of type III hypersensitivity reactions.

“As more antibody-based therapies are developed, DTDCs may become common phenomena in patients who switch between antibody therapies that bind to different epitopes of the same soluble target. It is important to understand how these complexes affect the [pharmacokinetics], [pharmacodynamics], efficacy, and safety of therapeutic antibodies, so that strategies to minimize their negative impacts can be developed,” Nishimura and colleagues wrote.

As crovalimab and the currently available C5 inhibitors eculizumab and ravulizumab bind to different C5 epitopes, DTDCs may form temporarily in the serum of patients who switch from other available C5 inhibitors to crovalimab. A washout period is not possible due to the risks of thromboembolic events and recurrent intravascular hemolysis.

References

Nishimura JI, Soubret A, Arase N, et al. Mitigating drug-target-drug complexes in patients with paroxysmal nocturnal hemoglobinuria who switch C5 inhibitors. Clin Pharmacol Ther. Published online January 20, 2023. doi:10.1002/cpt.2851

Study to assess safety, efficacy, pharmacokinetics, and pharmacodynamics of crovalimab in healthy volunteers and participants with paroxysmal nocturnal hemoglobinuria (COMPOSER). ClinicalTrials.gov. May 17, 2017. Updated December 7, 2022. Accessed January 25, 2023.