Optimized study designs to characterize the clinical pharmacology of a novel complement factor 5a receptor 1 (C5aR1) antagonist

Anliker-Ort, Marion. Optimized study designs to characterize the clinical pharmacology of a novel complement factor 5a receptor 1 (C5aR1) antagonist. 2023, Doctoral Thesis, University of Basel, Faculty of Medicine.

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The complement system is an evolutionary preserved central hub of the immune system. It is activated by pathogenic stimuli and amplified through an elaborate protein cascade to orchestrate downstream effects in inflammation, infection, cell regeneration, coagulation, and priming of the adaptive immune system. Given the multitude of physiological functions, complement deficiencies cause or contribute to a range of rare inflammatory human diseases. The field of complement-targeting therapeutics only emerged a few years ago and is rapidly evolving. A plethora of potential therapeutic agents was discovered, covering a variety of molecular, physicochemical, and pharmacological properties. Nonetheless, many of these rare diseases remain without treatment targeting the specific pathophysiology as of now and novel treatments could improve existing therapeutic options.
The aim of this PhD thesis was to design, set up, supervise, analyze, and report the first-in-human and early Phase 1 clinical studies of ACT-1014-6470, a novel, orally available complement factor 5a receptor 1 (C5aR1) antagonist and potential treatment for rare inflammatory diseases. In order to investigate as many clinical pharmacology characteristics of the compound as early as possible, I developed and applied integrative and optimized study designs, including add-on study parts and assessments, which I scrutinized in pharmacometric analyses.
In the first-in-human, double-blind, placebo-controlled, randomized study, we investigated the safety, tolerability, and pharmacokinetics (PK) of ACT-1014-6470 in 6 single-ascending dose levels. In one cohort, I included a nested two-period subpart to evaluate the effect of food on the PK of the compound for early optimization of its posology. Thereafter, we assessed the multiple-dose safety, tolerability, PK, and pharmacodynamics (PD) of ACT-1014-6470 in a new double-blind, placebo-controlled, randomized study with 3 ascending dose levels, in which the compound was administered twice daily for 4.5 days. At all dose levels, I implemented the sampling and measurement of a novel PD biomarker, enabling the determination of target engagement of the compound, which I further investigated with pharmacometric approaches. The recording of Holter electrocardiograms in both studies allowed me to characterize the cardiodynamics of ACT-1014-6470, also employing pharmacometrics. Furthermore, we optimized the determination of the inhibition potential of ACT-1014-6470 on cytochrome P450 isozymes (CYP) by studying CYP2C19 and CYP3A4 simultaneously in an open-label, fixed-sequence drug-drug interaction (DDI) cocktail study.
ACT-1014-6470 was well tolerated in all studies and at all assessed dose levels. After single- and multiple-dose administration, ACT-1014-6470 was absorbed with a time to reach maximum plasma concentrations of 2–3 h and exposure to the compound increased approximately dose-proportionally. A terminal half-life of 30–46 and 115–146 h was determined after single and multiple doses, respectively. Under fed compared to fasted conditions, ACT-1014-6470 exposure was approximately 2-fold higher. Release of matrix metalloproteinase 9 upon ex vivo C5aR1 stimulation, the PD biomarker, remained suppressed in all multiple-ascending dose levels, confirming target engagement of ACT-1014-6470. The cardiodynamics of ACT-1014-6470 could be described by a sigmoidal maximum effect concentration-QT model including an effect compartment and the circadian rhythm. Therewith, ACT-1014-6470 dose levels with a predicted effect on the QT interval below the regulatory threshold were identified. In the DDI study, ACT-1014-6470 weakly inhibited CYP2C19 and CYP3A4, indicated by a 1.9- and 1.5-fold increased exposure to the respective sensitive substrates omeprazole and midazolam, respectively.
Overall, I designed, set up, managed, and analyzed three Phase 1 clinical studies including integrative study parts for an optimized clinical development. Their results allowed me to determine the safety, tolerability, and PK profile of a novel, potent, selective, orally available C5aR1 antagonist in healthy subjects. Through implementation of the add-on study parts and assessments, I could characterize the clinical cardiodynamics, DDI potential, and target engagement of the compound early in development. Altogether, these data will inform the future of ACT-1014-6470 and serve as the foundation to pave the way to a novel treatment for patients suffering from rare and life-long inflammatory diseases.
Advisors:van den Anker, Johannes
Committee Members:Pfister, Marc and Kaufmann, Priska and Hammann, Felix
Faculties and Departments:03 Faculty of Medicine > Bereich Kinder- und Jugendheilkunde (Klinik) > Kinder- und Jugendheilkunde (UKBB) > Pädiatrische Pharmakologie (van den Anker)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Kinder- und Jugendheilkunde (Klinik) > Kinder- und Jugendheilkunde (UKBB) > Pädiatrische Pharmakologie (van den Anker)
UniBasel Contributors:Hammann, Felix
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:15119
Thesis status:Complete
Number of Pages:175
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss151198
edoc DOI:
Last Modified:19 Oct 2023 04:30
Deposited On:18 Oct 2023 10:12

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