vicriviroc (MK-7690) / Merck (MSD) - LARVOL DELTA

Scaling a non-human primate physiologically-based pharmacokinetic model of extended-release MK-2048 and combination MK-2048/vicriviroc (MK-2048A) intravaginal rings into humans using phase 1 MTN-027 and MTN-028 studies (HIVR4P 2024) - "This work showcases the adaptation of a mechanistic NHP PBPK model for humans to predict vaginal fluid and plasma concentrations after IVR administration, leveraging data from the Phase 1 studies MTN-027 and MTN-028. The model's ability to predict most drug concentrations within a 90% prediction interval highlights its utility in guiding IVR design and dosing optimization for PrEP. Future work includes continued refinement of the PBPK model and extending the model to evaluate other vaginal formulations for PrEP interventions."

P1 data • PK/PD data

Safety and Efficacy of Vicriviroc (MK-7690) in Combination With Pembrolizumab in Patients With Advanced or Metastatic Microsatellite Stable Colorectal Cancer. (PubMed, Clin Colorectal Cancer) - P2 | "The combination of vicriviroc at doses of 150 or 250 mg plus pembrolizumab 200 mg showed limited antitumor activity in patients with advanced or metastatic MSS/pMMR CRC. Toxicity with the combination was manageable."

Combination therapy • Journal • Metastases • CNS Disorders • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Pneumonia • Solid Tumor

The Role and Therapeutic Targeting of CCR5 in Breast Cancer. (PubMed, Cells) - "Inhibitors of CCR5 (CCR5i), either small molecules (maraviroc, vicriviroc) or humanized monoclonal antibodies (leronlimab) have shown anti-tumor and anti-metastatic properties in preclinical studies. In early clinical studies, reviewed herein, CCR5i have shown promising results and evidence for effects on both the tumor and the anti-tumor immune response. Current clinical studies have therefore included combination therapy approaches with checkpoint inhibitors."

Journal • Review • Breast Cancer • Human Immunodeficiency Virus • Infectious Disease • Oncology • Solid Tumor • Triple Negative Breast Cancer • CCR5

Structural dynamics of chemokine receptors. (PubMed, Vitam Horm) - "Maraviroc and Vicriviroc, two clinically used HIV entry inhibitors, are antagonists of the CCR5 receptor. Accordingly, it is important to understand the structural dynamics of these receptors to develop more effective therapeutics. In this chapter, we describe the latest advances in studies of these two key chemokine receptors with respect to their structures, dynamics and function."

Journal • Human Immunodeficiency Virus • Infectious Disease • Oncology • CXCR4

Evolution of Multiple Domains of the HIV-1 Envelope Glycoprotein during Coreceptor Switch with CCR5 Antagonist Therapy. (PubMed, Microbiol Spectr) - "The current study examined coreceptor shift of HIV-1 from CCR5-tropic strains to CXCR4-tropic or dual-tropic strains among five subjects in a clinical trial of the CCR5 antagonist vicriviroc...The work highlights the importance of mutants present at frequencies of 1% or less in development of drug resistance. This study highlights a critical role of specific amino acid substitutions outside V3 that contribute to coreceptor shift as well as important roles of the V1/V2, V4, C3, and C4 domain residues."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4 • CXCR4

Safety and Efficacy of Vicriviroc (MK-7690) in Combination With Pembrolizumab (MK-3475) in Participants With Advanced/Metastatic Microsatellite Stable (MSS) Colorectal Cancer (CRC) (MK-7690-046) (clinicaltrials.gov) - P2; N=42; Completed; Sponsor: Merck Sharp & Dohme Corp.; Active, not recruiting ➔ Completed

Trial completion • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Activity and structural analysis of GRL-117C: a novel small molecule CCR5 inhibitor active against R5-tropic HIV-1s. (PubMed, Sci Rep) - "These derivatives retained activity against vicriviroc-resistant HIV-1s, but did not show activity against maraviroc (MVC)-resistant HIV-1. On the other hand, one derivative, GRL-10018C, less potent against HIV-1, but more potent in inhibiting CC-chemokine binding, occupied the upper region of the binding cavity with its bis-THF moiety, presumably causing greater steric hindrance with CC-chemokines. Recent studies have shown additional unique features of certain CCR5 inhibitors such as immunomodulating properties and HIV-1 latency reversal properties, and thus, continuous efforts in developing new CCR5 inhibitors with unique binding profiles is necessary."

Journal • Human Immunodeficiency Virus • Immune Modulation • Immunology • Infectious Disease • Inflammation

Recent Advances targeting CCR5 for Cancer and its Role in Immuno-Oncology. (PubMed, Cancer Res) - "Because CCR5 on Tregs serves as the co-receptor for HIV virus entry, CCR5 targeted therapeutics used in HIV, (small molecules (maraviroc, vicroviroc) and a humanized monoclonal antibody (leronlimab)), are now being repositioned in clinical trials as cancer therapeutics. As CCR5 is expressed on a broad array of tumors, the opportunity for therapeutic repositioning and the rationale for combination therapy approaches are reviewed herein."

IO Biomarker • Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Gene Therapies • Human Immunodeficiency Virus • Immune Modulation • Immunology • Infectious Disease • Inflammation • Oncology • Solid Tumor

Phase 1 Pharmacokinetic Trial of 2 Intravaginal Rings Containing Different Dose Strengths of Vicriviroc (MK-4176) and MK-2048. (PubMed, Clin Infect Dis) - "In this first study evaluating 2 doses of a combination VCV/MK-2048 VR, both rings were found to be safe and well tolerated. VCV and MK-2048 were detectable in plasma, CVF, and cervical tissue samples, and drug release and plasma drug exposure were higher for the original-dose than for the low-dose ring."

Journal • P1 data • PK/PD data

Phase 1 Safety and Pharmacokinetics Study of MK-2048/Vicriviroc (MK-4176)/MK-2048A Intravaginal Rings. (PubMed, Clin Infect Dis) - "Tissue-associated VCV and/or MK-2048 did not correlate with inhibition of HIV infection. These data highlight the need to assess adequacy of drug dosing in the VR and measuring genital tissue drug concentrations to develop more precise concentration-response relationships."

Clinical • Journal • P1 data • PK/PD data

Safety and Efficacy of Vicriviroc (MK-7690) in Combination With Pembrolizumab (MK-3475) in Participants With Advanced/Metastatic Microsatellite Stable (MSS) Colorectal Cancer (CRC) (MK-7690-046) (clinicaltrials.gov) - P2; N=40; Active, not recruiting; Sponsor: Merck Sharp & Dohme Corp.; Trial completion date: May 2020 ➔ Jun 2021; Trial primary completion date: May 2020 ➔ Jun 2021

Trial completion date • Trial primary completion date

V1 and V2 Domains of HIV Envelope Contribute to CCR5 Antagonist Resistance. (PubMed, J Virol) - "Vicriviroc (VCV) is a CCR5 antagonist that blocks the viral entry of CCR5-tropic (R5) virions by binding to and inducing a conformational change in the chemokine receptor...Genotypic and phenotypic assays demonstrated a distinct role of the variable domain V1/V2 in competitive resistance to CCR5-antagonist therapy. Thus, future studies analyzing the development of clinical resistance should focus on the relationship between the V1/V2 and V3 domains."

Journal

Vicriviroc, a CCR5 Inhibitor, Added to an Optimized Antiretroviral Therapy for Previously Treated HIV (VICTOR-E2) (Study P04285 (clinicaltrials.gov) - P3; N=0; Withdrawn; Sponsor: Merck Sharp & Dohme Corp.; N=500 ➔ 0; Terminated ➔ Withdrawn

Enrollment change • Trial withdrawal

Safety and Efficacy of Vicriviroc (MK-7690) in Combination With Pembrolizumab (MK-3475) in Participants With Advanced/Metastatic Microsatellite Stable (MSS) Colorectal Cancer (CRC) (MK-7690-046) (clinicaltrials.gov) - P2; N=40; Active, not recruiting; Sponsor: Merck Sharp & Dohme Corp.; Recruiting ➔ Active, not recruiting

Clinical • Combination therapy • Enrollment closed

ACTIVITY OF ECD4-IG AGAINST CCR5 ANTAGONIST-RESISTANT HIV-1 (CROI 2019) - "...To investigate whether eCD4-Ig can neutralize HIV-1 isolates resistant to the CCR5 antagonists maraviroc (MVC) and vicriviroc (VCV) we determined the eCD4-Ig susceptibility of infectious HIV-1 recombinants expressing env from MCV-susceptible and -resistant viruses...Susceptibility to eCD4-Ig, MVC and the CXCR4 antagonist AMD3100 was determined by a standardized drug susceptibility assay on TZM-bl cells...Recombinant HIV-1 resistant to MVC showed disparate patterns of susceptibility to eCD4-Ig, suggesting that mutations conferring resistance to small-molecule CCR5 antagonists affect interactions with the CCR5mim1 sulfonated peptide moiety of eCD4-Ig in different ways. Analysis of additional HIV-1 isolates with varying susceptibility to CCR5 antagonists and eCD4-Ig may help refine our understanding of the interaction between this promising novel HIV-1 entry inhibitor and the CCR5mim1 binding domain on gp120."