vorbipiprant (CR6086) / Rottapharm Biotech - LARVOL DELTA

Vorbipiprant (CR6086) / Balstilimab (AGEN2034) Combination in Stage IV Refractory pMMR - MSS CRC, and Other Metastatic GI Cancers (clinicaltrials.gov) - P1/2 | N=107 | Active, not recruiting | Sponsor: Rottapharm Biotech | Recruiting ➔ Active, not recruiting

Enrollment closed • Mismatch repair • pMMR • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF

Phase I/II study of the EP4 antagonist vorbipiprant combined with anti-PD-1 immunotherapy: Safety and efficacy results in metastatic gastrointestinal non-colorectal cancers. (ASCO 2025) - P1/2 | "Pts receive oral vorbipiprant (90 mg twice daily) plus iv balstilimab (3 mg/kg every 2 weeks) until disease progression, unacceptable toxicity or death. Vorbipiprant combined with PD-1 blockade was well tolerated and showed signs of activity in non-colorectal GI cancers, thus confirming a broader spectrum of activity on top of the results in MSS CRC."

Clinical • IO biomarker • Metastases • P1/2 data • Ampulla of Vater Carcinoma • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • PD-L1

Vorbipiprant (CR6086) / Balstilimab (AGEN2034) Combination in Stage IV Refractory pMMR - MSS CRC, and Other Metastatic GI Cancers (clinicaltrials.gov) - P1/2 | N=107 | Recruiting | Sponsor: Rottapharm Biotech | N=55 ➔ 107 | Trial completion date: Sep 2026 ➔ Jun 2027 | Trial primary completion date: Mar 2025 ➔ Dec 2026

Enrollment change • Mismatch repair • pMMR • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF

The Prostaglandin EP4 Antagonist Vorbipiprant Combined with PD-1 Blockade for Refractory Microsatellite-Stable Metastatic Colorectal Cancer: A Phase Ib/IIa Trial (Clin Cancer Res) - P1b/2a | N=55 | NCT05205330 | Sponsor: Rottapharm Biotech | "No dose-limiting toxicities were observed. Of the 28 patients, seven (25%) experienced serious adverse events, but only one was attributed to vorbipiprant and one to balstilimab. The trial achieved a DCR of 50% observed across the entire cohort. In the subgroup of patients with liver metastases (n = 12), the DCR was 25%. The overall response rate was 11%, with three patients showing a partial response (median duration of response, 7.4 months). The median progression-free survival was 2.6 months, and the median overall survival was 14.2 months."

P1/2 data • Colorectal Cancer

The Prostaglandin EP4 Antagonist Vorbipiprant Combined with PD-1 Blockade for Refractory Microsatellite Stable Metastatic Colorectal Cancer: A Phase 1b/2a Trial. (PubMed, Clin Cancer Res) - "The combination of vorbipiprant and a PD-1 inhibitor (balstilimab) yielded sufficient activity in refractory pMMR/MSS mCRC, worth of confirmation in future clinical trials in biomarker-enriched populations."

IO biomarker • Journal • Metastases • P1/2 data • Colorectal Cancer • Oncology • Solid Tumor

CR6086/AGEN2034 Combination in Stage IV pMMR - MSS CRC, and Other Metastatic GI Cancers (clinicaltrials.gov) - P1/2 | N=55 | Recruiting | Sponsor: Rottapharm Biotech | Active, not recruiting ➔ Recruiting | N=28 ➔ 55 | Trial completion date: Dec 2024 ➔ Sep 2026 | Trial primary completion date: Oct 2023 ➔ Mar 2025

Combination therapy • Enrollment change • Enrollment open • Metastases • Mismatch repair • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF

Updated results and subgroup analysis by presence of liver metastases of a phase I/II study of the EP4 antagonist vorbipiprant with the anti-PD-1 balstilimab in mismatch-repair-proficient and microsatellite stable (pMMR/MSS) chemorefractory metastatic colorectal cancer (mCRC). (ASCO 2024) - P1/2 | " Adult patients (pts) with pMMR/MSS mCRC, ECOG PS ≤1 and previous exposure to fluoropyrimidines, oxaliplatin and irinotecan, received oral vorbipiprant (30, 90 or 180 mg twice daily) plus balstilimab (3 mg/kg every 2 weeks) until disease progression, unacceptable toxicity or death. Vorbipiprant combined with an anti-PD-1 (balstilimab) showed promising efficacy in this phase I/II study. Encouraging results were observed in pts with LM. This finding deserves particular attention given that the presence of LM is considered an immune resistance factor and is associated with poor outcomes of treatment with ICIs."

IO biomarker • Metastases • Mismatch repair • P1/2 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Phase I/II study of the EP4 antagonist CR6086 combined with the anti-PD-1 balstilimab in mismatch-repair-proficient and microsatellite stable (pMMR/MSS) chemorefractory metastatic colorectal cancer (mCRC) (ESMO 2023) - P1/2 | "Methods Adult pts with pMMR/MSS mCRC, ECOG PS ≤1 and previous exposure to fluoropyrimidines, oxaliplatin and irinotecan, received oral CR6086 (30, 90 or 180 mg twice daily) plus balstilimab (3 mg/kg every 2 weeks) until disease progression, unacceptable toxicity or death. Conclusions CR6086 combined with balstilimab was well tolerated and achieved durable responses in pMMR/MSS mCRC. Expansion in other gastrointestinal tumours and further clinical development in pMMR/MSS mCRC are ongoing."

IO biomarker • Metastases • Mismatch repair • P1/2 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

A Phase Ib/IIa Study of CR6086 in Combination With Balstilimab in pMMR-MSS Metastatic Colorectal Cancer Patients (clinicaltrials.gov) - P1/2 | N=28 | Active, not recruiting | Sponsor: Rottapharm Biotech | Recruiting ➔ Active, not recruiting | Trial primary completion date: Jun 2023 ➔ Oct 2023

Combination therapy • Enrollment closed • Metastases • Mismatch repair • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF

Agenus Advances Portfolio with 6 Clinical Collaborations (GlobeNewswire) - "Targovax to conduct a clinical trial combining botensilimab and balstilimab with ONCOS-102...in patients with PD-1 relapsed/refractory melanoma; Oxford BioTherapeutics to conduct a clinical trial combining balstilimab with OBT076...in patients with solid tumors, including lung, gastric, and ovarian cancer; Immunogenesis to conduct a clinical trial combining balstilimab and zalifrelimab with evofosfamide...in patients with advanced solid tumors, including prostate, pancreatic, HPV-negative head and neck cancer; Targovax to conduct a clinical trial combining QS-21 STIMULON with TG01...in up to 3 cancer indications, including multiple myeloma; Rottapharm Biotech is conducting a clinical trial combining balstilimab with CR6086 (EP4 antagonist) in patients with pMMR-MSS colorectal cancer; Nelum is conducting a clinical trial combining zalifrelimab with NLM-001...and chemotherapy in patients with advanced pancreatic cancer."

Licensing / partnership • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Gynecologic Cancers • Head and Neck Cancer • Hematological Malignancies • Lung Cancer • Melanoma • Multiple Myeloma • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Solid Tumor

A Phase Ib/IIa Study of CR6086 in Combination With Balstilimab in pMMR-MSS Metastatic Colorectal Cancer Patients (clinicaltrials.gov) - P1/2 | N=27 | Recruiting | Sponsor: Rottapharm Biotech

Combination therapy • Mismatch repair • New P1/2 trial • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF

A Study of the EP4 Antagonist CR6086 in Combination With Methotrexate, in DMARD-naïve Patients With Early Rheumatoid Arthritis (clinicaltrials.gov) - P2; N=248; Completed; Sponsor: Rottapharm Biotech; Recruiting ➔ Completed

Clinical • Combination therapy • Trial completion • Immune Modulation • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • CRP • MRI

Agenus R&D Update & Third Quarter Financial Report (GlobeNewswire) - "iNKT cancer clinical trial expected to commence in 4Q2020; Seven AGEN programs to be presented at SITC; Partnered program MK-4830 presented at ESMO; Agenus provides balstilimab to Rottapharm for clinical testing with CR6086, a potent and selective prostaglandin EP4 receptor antagonist, in patients with advanced metastatic colorectal cancer; trial expected to commence by end of 2020"

Clinical data • New trial • Oncology

[VIRTUAL] EFFICACY AND SAFETY OF THE PROSTAGLANDIN EP4 RECEPTOR ANTAGONIST CR6086 ADDED TO METHOTREXATE IN DMARD-NAÏVE EARLY RA PATIENTS: A PHASE 2 RANDOMIZED CONTROLLED TRIAL (EULAR 2020) - P2 | "There was no benefit demonstrated for CR6086 added to MTX in the study cohort as a whole. However, in a post-hoc analysis, enhanced responses were observed with CR6086 90mg bid added to MTX in patients >6 months disease duration. This generated the hypothesis that addition of CR6086 90mg bid may benefit in RA patients initiating MTX after the window of opportunity, to be tested in further studies."

Clinical • P2 data • Immune Modulation • Immunology • Inflammation • MRI

DAS28-CRP Versus DAS28-ESR and Thresholds for Disease Activity Category: Blinded Data from the Ongoing Phase IIb Trial with the EP4 Receptor Antagonist CR6086 in DMARD-Nave Patients with Early Rheumatoid Arthritis (ACR-ARHP 2018) - P2; "This is a randomized, placebo-controlled, double-blind, dose response, Phase IIb, multicentre trial of CR6086 administered for 12 weeks in combination with methotrexate (NCT03163966). Analysis of blinded data from the ongoing Phase IIb trial with CR6086 indicated that the newly proposed DAS28-CRP thresholds for remission, low and high disease activity are consistent with the validated DAS28-ESR cut-offs, thus supporting their use in clinical trial and clinical practice. [1] Fleischmann R et al. Ann Rheum Dis."

Clinical • P2b data • Immunology • Inflammation • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology

In Vitro Effects of CR6086, a Potent ProstaglandinE2 Subtype 4 Receptor Antagonist, on Bone Erosive Pathways (ACR-ARHP 2017) - "The new potent EP4 receptor antagonist immunomodulator CR6086 directly affects bone resorption by inhibiting the expression of different mediators that induce bone erosions in RA (RANKL, IL-6 and VEGF). These results support the in vivo findings and confirm that CR6086 may potentially act as a novel DMARD. CR6086 is in Phase II clinical development in DMARD-naïve early RA patients."

Immunology • Inflammation • Rheumatoid Arthritis

Pharmacological characterisation of CR6086, a potent prostaglandin Ereceptor 4 antagonist, as a new potential disease-modifying anti-rheumatic drug. (PubMed, Arthritis Res Ther) - "CR6086 is a novel, potent EP4 antagonist showing favourable immunomodulatory properties, striking DMARD effects in rodents, and anti-inflammatory activity targeted to immune-mediated inflammatory diseases and distinct from the general effects of cyclooxygenase inhibitors. These results support the clinical development of CR6086, both as a stand-alone DMARD and as a combination therapy with methotrexate. The proof-of-concept trial in patients with RA is ongoing."

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