ACT-1004-1239 / Idorsia - LARVOL DELTA

A patent review of CXCR7 modulators (2019-present). (PubMed, Expert Opin Ther Pat) - "WW-12, which was derived from the chemical modifications of conolidine, became a novel small-molecule pain modulator by activating ACKR3, which in turn boosted endogenous opioid peptides for the classical opioid receptors.ACKR3 antagonist ACT-1004-1239 from Idorsia Pharmaceuticals Ltd. has demonstrated the ability to treat cancer, acute lung injury/ARDS, and autoimmune diseases, including multiple sclerosis. The outcomes of these clinical trials will direct the development and indications of future ACKR3 modulators."

Journal • Review • Acute Lung Injury • Acute Respiratory Distress Syndrome • Cardiovascular • CNS Disorders • Immunology • Multiple Sclerosis • Oncology • Pain • Respiratory Diseases • ACKR3

The effect of itraconazole, a strong CYP3A4 inhibitor, on the pharmacokinetics of the first-in-class ACKR3/CXCR7 antagonist, ACT-1004-1239. (PubMed, Clin Transl Sci) - "The most frequently reported TEAEs were headache and nausea. In conclusion, ACT-1004-1239 is classified as a moderately sensitive CYP3A4 substrate (i.e., increase of AUC ≥2- to <5-fold), and this should be considered in further clinical studies if CYP3A4 inhibitors are concomitantly administered."

Journal • PK/PD data • CNS Disorders • Multiple Sclerosis • Pain • ACKR3

ACKR3 Antagonism Enhances the Repair of Demyelinated Lesions Through Both Immunomodulatory and Remyelinating Effects. (PubMed, Neurochem Res) - "Combining ACT-1004-1239 with siponimod, an approved immunomodulatory treatment for MS, synergistically reduced EAE severity. It confirms the dual mode of action of ACT-1004-1239, exhibiting both immunomodulatory effects by reducing neuroinflammation and promyelinating effects by accelerating myelin repair. The results further strengthen the rationale for evaluating ACT-1004-1239 in clinical trials for patients with demyelinating diseases."

Immunomodulating • Journal • CNS Disorders • Immunology • Inflammation • Multiple Sclerosis • ACKR3 • CXCL11 • CXCL12

Regulation of the Hippo/YAP axis by CXCR7 in the tumorigenesis of gastric cancer. (PubMed, J Exp Clin Cancer Res) - "In general, we identified a novel positive feedback loop between CXCR7 and the Hippo/YAP axis, and blockade of CXCR7 could be a plausible strategy for gastric cancer."

Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • ACKR3

A Study to Investigate the Effect of Itraconazole on the Way the Body Absorbs, Distributes, and Gets Rid of ACT-1004-1239 Given as a Single Dose of 10 mg to Healthy Male Subjects (clinicaltrials.gov) - P1 | N=16 | Completed | Sponsor: Idorsia Pharmaceuticals Ltd. | Not yet recruiting ➔ Completed

Trial completion

The CXCR7 antagonist ACT-1004-1239 increases CXCL12 levels in the CNS and promotes myelination (ECTRIMS 2022) - "These results support the use of MRI imaging and CXCL12 CSF measurement as meaningful biomarkers to investigate the promyelinating MoA of ACT-1004-1239 in patients with MS."

CNS Disorders • Immunology • Inflammation • Multiple Sclerosis • Solid Tumor • ACKR3 • CXCL12

A Study to Investigate the Effect of Itraconazole on the Way the Body Absorbs, Distributes, and Gets Rid of ACT-1004-1239 Given as a Single Dose of 10 mg to Healthy Male Subjects (clinicaltrials.gov) - P1 | N=16 | Not yet recruiting | Sponsor: Idorsia Pharmaceuticals Ltd.

New P1 trial

Absorption, Metabolism, and Excretion of ACT-1004-1239, a First-In-Class CXCR7 Antagonist: In Vitro, Preclinical, and Clinical Data. (PubMed, Front Pharmacol) - P1 | "In conclusion, CYP3A4 contributes to a relevant extent to ACT-1004-1239 disposition and two major circulating metabolites were observed in humans. Clinical Trial Registration: (https://clinicaltrials.gov/ct2/show/NCT03869320) ClinicalTrials.gov Identifier NCT03869320."

Clinical data • Journal • Preclinical • CYP3A4

CXCR7 Antagonism Reduces Acute Lung Injury Pathogenesis. (PubMed, Front Pharmacol) - "Both preventive and therapeutic treatment with ACT-1004-1239 reduced lung vascular permeability and decreased inflammatory cell infiltrates. In conclusion, these results demonstrate a key pathological role of CXCR7 in ALI/ARDS and highlight the clinical potential of ACT-1004-1239 in ALI/ARDS pathogenesis."

Journal • Acute Lung Injury • Acute Respiratory Distress Syndrome • Immune Modulation • Immunology • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases • CXCL11 • CXCL12 • CXCR3

Target engagement of the first-in-class CXCR7 antagonist ACT-1004-1239 following multiple-dose administration in mice and humans. (PubMed, Biomed Pharmacother) - "Overall, multiple oral doses of ACT-1004-1239 showed target engagement with CXCR7 in healthy mice and humans, therefore, assessment of CXCL12 as translational tool for further investigations in patients is warranted. Favorable safety/tolerability and PK profiles allow for further clinical development."

Clinical • Journal • Preclinical • Acute Lung Injury • CNS Disorders • Multiple Sclerosis • Respiratory Diseases • CXCL11 • CXCL12

"#AANAM: ACT1004-1239 effect on CXCR7 in #MS" (@KantorNeurology)

CNS Disorders

[VIRTUAL] A FirstinClass CXCR7 Antagonist Increases Plasma Concentrations of the Target Engagement Biomarker CXCL12 in a MultiPurpose FirstinHuman Study (ACTRIMS Forum 2021) - "The first in class CXCR7 antagonist ACT-1004-1239 demonstrated properties in favor of further clinical development in inflammatory demyelinating diseases such as MS."

Biomarker • P1 data • CNS Disorders • Immune Modulation • Inflammation • Multiple Sclerosis • Solid Tumor • CXCL12

[VIRTUAL] CXCR7 antagonism with ACT10041239 reduces neuroinflammation and accelerates remyelination in murine demyelinating models (ACTRIMS Forum 2021) - P1 | "These results confirm the dual mode of action of ACT-1004-1239 in a therapeutic setting in murine models of MS, providing both an immunomodulatory effect by reducing neuroinflammation and promyelination by accelerating myelin repair."

Preclinical • CNS Disorders • Immune Modulation • Immunology • Inflammation • Multiple Sclerosis • Solid Tumor • CXCL12

[VIRTUAL] ACT10041239, a firstinclass CXCR7 antagonist with both immunomodulatory and promyelinating effects, for the treatment of inflammatory demyelinating diseases (ACTRIMS Forum 2021) - P1 | "The CXCR7 antagonist ACT-1004-1239 both reduced neuroinflammation and enhanced myelin repair in preclinical models of demyelinating neuropathy. Taken together, these studies substantiate the rationale to explore the therapeutic potential of ACT-1004-1239 in a clinical setting."

CNS Disorders • Immune Modulation • Immunology • Inflammation • Multiple Sclerosis • Pain • Solid Tumor • CXCL12 • Plasma NfL

ACT-1004-1239, a first-in-class CXCR7 antagonist with both immunomodulatory and promyelinating effects for the treatment of inflammatory demyelinating diseases. (PubMed, FASEB J) - "In vitro, ACT-1004-1239 promoted the maturation of OPCs into myelinating oligodendrocytes. These results provide evidence that ACT-1004-1239 both reduces neuroinflammation and enhances myelin repair substantiating the rationale to explore its therapeutic potential in a clinical setting."

Journal • CNS Disorders • Immune Modulation • Immunology • Inflammation • Multiple Sclerosis • Solid Tumor • CXCL12 • Plasma NfL

Study in Healthy Subjects to Examine the Safety and Tolerability of ACT-1004-1239 Given as Multiple, Gradually Increasing Doses and to Examine the Effects of ACT-1004-1239 on the Body and the Way the Body Takes up, Distributes, and Gets Rid of ACT-1004-1239 (clinicaltrials.gov) - P1; N=50; Completed; Sponsor: Idorsia Pharmaceuticals Ltd.; Recruiting ➔ Completed

Clinical • Trial completion

A multi-purpose first-in-human study with the novel CXCR7 antagonistACT-1004-1239 using CXCL12 plasma concentrations as target engagement biomarker. (PubMed, Clin Pharmacol Ther) - "The absolute bioavailability was 53.0 % based on radioactivity data after oral vs. intravenous C-radiolabeled microtracer administration of ACT-1004-1239. Overall, these comprehensive data support further clinical development of ACT-1004-1239."

Biomarker • Clinical • Journal • P1 data • Immunology • Oncology • CXCL1 • CXCL12

Discovery of the Potent, Selective, Orally Available CXCR7 Antagonist ACT-1004-1239. (PubMed, J Med Chem) - "Biological characterization of ACT-1004-1239 demonstrated that it is a potent, insurmountable antagonist. Oral administration of ACT-1004-1239 in mice up to 100 mg/kg led to a dose-dependent increase of plasma CXCL12 concentration."

Journal • CNS Disorders • Immunology • Oncology • CXCL1 • CXCL12

Study in Healthy Subjects to Examine the Safety and Tolerability of ACT-1004-1239 Given as Multiple, Gradually Increasing Doses and to Examine the Effects of ACT-1004-1239 on the Body and the Way the Body Takes up, Distributes, and Gets Rid of ACT-1004-1239 (clinicaltrials.gov) - P1; N=50; Recruiting; Sponsor: Idorsia Pharmaceuticals Ltd.; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open

Study in Healthy Subjects to Examine the Safety and Tolerability of ACT-1004-1239 Given as Multiple, Gradually Increasing Doses and to Examine the Effects of ACT-1004-1239 on the Body and the Way the Body Takes up, Distributes, and Gets Rid of ACT-1004-1239 (clinicaltrials.gov) - P1; N=50; Not yet recruiting; Sponsor: Idorsia Pharmaceuticals Ltd.

Clinical • New P1 trial