Early clinical development of ACT-1004-1239, a first-in-class CXC chemokine receptor 7 (CXCR7) antagonist

The human body is highly dependent on signaling proteins such as chemokines to maintain its physiology. The CXC chemokine receptor 7 (CXCR7) and its interacting chemokines, CXC chemokine ligand (CXCL) 11 and CXCL12, play a crucial role in several processes, for instance homeostasis, and therefore are vital components in human biology. CXCR7 functions as a decoy receptor for its chemokines, and hence modulates their extracellular concentrations. As CXCL11 and CXCL12 bind not only to CXCR7 but also to CXCR3 and CXCR4, respectively, the scavenging activity of CXCR7 can indirectly impact CXCR3- and CXCR4-mediated functions. Apart from physiological conditions, the CXCR3/CXCR4/CXCR7–CXCL11/CXCL12 axis is assumed to have a relevant role in various diseases and is widely discussed in the field of cancer and multiple sclerosis (MS). Under these pathophysiological conditions, there is evidence that these chemokine-receptor interactions can modulate several cell signaling pathways including but not limited to cell proliferation, differentiation, and maturation, and therefore, contribute to disease induction. Changes to the CXCR3/CXCR4/CXCR7–CXCL11/CXCL12 axis by modulators demonstrated an improved disease outcome in several preclinical studies. CXCR7 in particular provided promising data as a druggable target due to its close network to CXCR3 and CXCR4. However, to date, only a few CXCR7 modulators have been used for preclinical investigations, and none have been clinically investigated. Idorsia Pharmaceuticals Ltd developed a potent and selective first-in-class CXCR7 antagonist ACT-1004-1239, which showed favorable efficacy in animal models of MS. ACT-1004-1239 fulfilled all the preclinical prerequisites to enter the clinical development stage. Here, two clinical pharmacology studies including a single- and multiple-ascending dose study with ACT-1004-1239 are reported. In the single-ascending dose study, besides the investigation of safety/tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single-dose ACT-1004-1239, several additional assessments were incorporated into the study design to evaluate food effect, absolute bioavailability, and absorption, distribution, metabolism and excretion (ADME) characteristics. An integrated approach was also applied for the multiple-ascending dose study. In addition to investigation of safety/tolerability, PK, and PD of multiple-dose ACT-1004-1239, the study incorporated the evaluation of the concentration-QTc relationship. The incorporation of various sub-investigations in both studies enabled a thorough characterization of ACT-1004-1239 in healthy adult human subjects. ACT-1004-1239 was safe and well tolerated up to and including a dose of 200 mg after single-and multiple-dose administration. The PK profile was characterized by a fast absorption, high volume of distribution, almost no accumulation, and an elimination that fits with a once-daily dosing regimen. No clinically relevant changes were observed for sex (males vs. females) or food state (fasted vs. fed). The evaluation of ADME revealed that ACT-1004-1239 is extensively metabolized and predominantly eliminated through a pathway that is catalyzed by cytochrome P450 (CYP) 3A4. Consequently, this indicated the need of a follow-up clinical pharmacology study, i.e., drug-drug interaction (DDI) study with a strong CYP3A4 inhibitor. Such a study was conceptualized by taking several factors into consideration (e.g., study design, treatment duration, dose strength) and finally, a suitable DDI study design for ACT-1004-1239 was established. Besides PK, the PD profile of ACT-1004-1239 was also evaluated in both studies using CXCL12 plasma concentration as biomarker. Target engagement of ACT-1004-1239 was demonstrated in both studies, reflected in a dose-dependent increase of the CXCL12 plasma concentration. An increase in CXCL12 concentrations was preclinically associated with efficacy. However, this remains to be investigated in patients.
In conclusion, the two completed clinical pharmacology studies generated convincing data for ACT-1004-1239 in healthy subjects for further clinical investigations in patients.