An Open-label, Single-arm, Phase Ib/IIa Trial to Evaluate the Safety and Efficacy of the EP4 Receptor Antagonist CR6086 in Combination With the PD-1 Inhibitor Balstilimab (AGEN2034), in Patients With Pretreated Mismatch-repair-proficient and Microsatellite Stable Metastatic Colorectal Cancer, and Other Metastatic GI Cancers.

This Phase Ib/IIa study comprises a Main Study and a Study Extension.
The Main Study has been designed according to a 3+3 dose escalation/dose expansion design in MSS mCRC patients. A dose expansion will be conducted at both the intermediate and high dose levels, if tolerated, with the purpose of generating additional and more robust safety and preliminary efficacy data.
The Study Extension explores in other metastatic GI cancers the CR6086 recommended dose for expansion (RDE) obtained in the Main Study.
No control arm was included, as the target patient population of this study consists of patients in whom the overall survival is less than 6 months and treatment options are very limited and often poorly tolerated, making unlikely that the study results can be significantly biased.

Start Date23 Nov 2021

Sponsor / Collaborator

Rottapharm Biotech SRL

[+1]

NCT03163966 / CompletedPhase 2

A Randomized, Double Blind, Placebo-controlled, Dose Response, Phase II, Multicentre Trial to Evaluate the Efficacy, Safety and Pharmacokinetics of Oral CR6086 Administered at the Doses of 30, 90 or 180 mg Bid for 12 Weeks in Combination With Methotrexate, in DMARD-naïve Patients With Early Rheumatoid Arthritis

CR6086 is a new, potent and selective, orally available, small molecule prostaglandin EP4 receptor antagonist, endowed with immunomodulatory properties. The pharmacological properties of CR6086, along with its oral bioavailability, predictable pharmacokinetics and good safety, make it the ideal candidate to be tested alone or in combination with methotrexate (MTX) in patients with early Rheumatoid Arthritis who are naïve to Disease-Modifying Antirheumatic Drugs (DMARDs). The compound has indeed the potential to provide a safer and more effective treatment than MTX (or other conventional synthetic DMARDs - csDMARDs), and could significantly improve the proportion of responder patients and avoid/delay the recourse to biological DMARDs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs).

Start Date05 Oct 2017

Sponsor / Collaborator

Rottapharm SpA

100 Clinical Results associated with Vorbipiprant

100 Translational Medicine associated with Vorbipiprant

100 Patents (Medical) associated with Vorbipiprant

Literatures (Medical) associated with Vorbipiprant

01 Dec 2018·Arthritis research & therapyQ2 · MEDICINE

Pharmacological characterisation of CR6086, a potent prostaglandin E2 receptor 4 antagonist, as a new potential disease-modifying anti-rheumatic drug

Q2 · MEDICINE

ArticleOA

Author: Giambelli, Roberto ; Letari, Ornella ; Ferioli, Cristian ; Di Luccio, Elena ; Mennuni, Laura ; Lanza, Marco ; Rovati, Lucio Claudio ; Zerbi, Silvia ; Persiani, Stefano ; Piepoli, Tiziana ; Perrella, Marco ; Comi, Eleonora ; Zanelli, Tiziano ; Bonazzi, Albino ; Colovic, Milena ; Maggioni, Daniele ; Caselli, Gianfranco ; Ferrari, Flora

BACKGROUND:

Prostaglandin E₂ (PGE₂) acts via its EP4 receptor as a cytokine amplifier (e.g., interleukin [IL]-6) and induces the differentiation and expansion of inflammatory T-helper (Th) lymphocytes. These mechanisms play a key role in the onset and progression of rheumatoid arthritis (RA). We present the pharmacological characterisation of CR6086, a novel EP4 receptor antagonist, and provide evidence for its potential as a disease-modifying anti-rheumatic drug (DMARD).

METHODS:

CR6086 affinity and pharmacodynamics were studied in EP4-expressing HEK293 cells by radioligand binding and cyclic adenosine monophosphate (cAMP) production, respectively. In immune cells, IL-6 and vascular endothelial growth factor (VEGF) expression were analysed by RT-PCR, and IL-23 and IL-17 release were measured by enzyme-linked immunosorbent assay (ELISA). In collagen-induced arthritis (CIA) models, rats or mice were immunised with bovine collagen type II. Drugs were administered orally (etanercept and methotrexate intraperitoneally) starting at disease onset. Arthritis progression was evaluated by oedema, clinical score and histopathology. Anti-collagen II immunoglobulin G antibodies were measured by ELISA.

RESULTS:

CR6086 showed selectivity and high affinity for the human EP4 receptor (K_i = 16.6 nM) and functioned as a pure antagonist (half-maximal inhibitory concentration, 22 nM) on PGE₂-stimulated cAMP production. In models of human immune cells in culture, CR6086 reduced key cytokine players of RA (IL-6 and VEGF expression in macrophages, IL-23 release from dendritic cells, IL-17 release from Th17 cells). In the CIA model of RA in rats and mice, CR6086 significantly improved all features of arthritis: severity, histology, inflammation and pain. In rats, CR6086 was better than the selective cyclooxygenase-2 inhibitor rofecoxib and at least as effective as the Janus kinase inhibitor tofacitinib. In mice, CR6086 and the biologic DMARD etanercept were highly effective, whereas the non-steroidal anti-inflammatory drug naproxen was ineffective. Importantly, in a study of CR6086/methotrexate, combined treatment greatly improved the effect of a fully immunosuppressive dose of methotrexate.

CONCLUSIONS:

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.

News (Medical) associated with Vorbipiprant

31 May 2024

·rottapharmbiotech.com

Updated results and subgroup analysis of the phase I/II study of CR6086 (vorbipiprant) and balstilimab in advanced colorectal cancer presented at ASCO 2024

Press Release Poster May 31, 2024 Monza (Italy) – Rottapharm Biotech, a research company dedicated to the discovery and development of innovative drugs, today announces that updated results and subgroup analysis by presence of liver metastases of the phase I/II study of the EP4 antagonist CR6086 (vorbipiprant) with the anti-PD-1 antibody balstilimab (Agenus Inc, Nasdaq: AGEN) in mismatch-repair-proficient and microsatellite stable (pMMR/MSS) chemorefractory metastatic colorectal cancer (mCRC) will be presented at the American Society of Clinical Oncology (ASCO) Annual Meeting on June 1, 2024. The analysis indicates that vorbipiprant combined with an anti-PD-1 showed promising efficacy also in patients with liver metastases, a particularly challenging patient population since the presence of liver metastases is considered an immune resistance factor and is associated with poor outcomes of treatment with immune checkpoint inhibitors (ICIs). Presentation Details Abstract Title: 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) Abstract Number: 3560 Presenting Author: Filippo Pietrantonio, MD, Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy Poster Board Number: 223 Presentation Session Date and Time: Saturday, June 01, 2024, 1:30 PM-4:30 PM CDT The poster will be available to view in this website page following the ASCO congress. About CR6086 (vorbipiprant) CR6086 (vorbipiprant) is a novel targeted immunomodulator acting as an antagonist at the prostaglandin E2 (PGE2) receptor EP4 subtype. EP4 receptors have an important role in the altered immune response observed in autoimmune diseases. PGE2-EP4 signalling plays a major immunosuppressive role in the tumour microenvironment, and as such it favours cancer immune escape and tumour progression. Consistently, experimental evidence suggests that EP4 receptor antagonists may improve the response to immune checkpoint inhibitors (ICIs). A Phase I/II clinical trial to evaluate the safety and efficacy of CR6086 in combination with the PD-1 inhibitor balstilimab in patients with pretreated mismatch-repair-proficient and microsatellite stable metastatic colorectal cancer provided promising results presented at the European Society for Medical Oncology (ESMO) annual congress in 2023. Study expansion in other gastrointestinal tumors is ongoing. About Rottapharm Biotech Rottapharm Biotech is a research company dedicated to the discovery and development of innovative drugs. It is located in Monza (Italy). The company expertise in research and development includes medicinal/computational chemistry for small molecules, development of biologics and advanced therapies, new targets validation, pharmacological and pharmacokinetic characterization of new drug candidates, original formulations, and design of innovative clinical trials. The company strategy is to develop its own pipeline independently and then seek partnerships with pharmaceutical companies, as well as investing in alliances on innovative projects of other biotech companies or university spin-offs. Rottapharm Biotech Contact Federica Girolami, Business Development Director Tel. +39 346 4131428 federica.girolami@rottapharmbiotech.com About Agenus Agenus is a leading immuno-oncology company targeting cancer and infectious diseases with a comprehensive pipeline of immunological agents. The company’s mission is to expand patient populations benefiting from cancer immunotherapy through combination approaches, using a broad repertoire of antibody therapeutics, adoptive cell therapies (through MiNK Therapeutics) and adjuvants (through SaponiQx). Agenus is headquartered in Lexington, MA. For more information, visit www.agenusbio.com or @agenus_bio. Information that may be important to investors will be routinely posted on our website and social media channels. About balstilimab Balstilimab (Agenus, Inc.) is an investigational monoclonal antibody inhibitor of programmed cell death 1 (PD-1) protein. It has been evaluated in >900 patients to date and has demonstrated strong clinical activity and an excellent safety profile in several tumour types. Agenus Cautionary Statement Regarding Forward-Looking Statements This press release contains forward-looking statements that are made pursuant to the safe harbor provisions of the federal securities laws, including statements regarding clinical development and regulatory plans and timelines, anticipated corporate milestones, new clinical data and program updates to be presented. These forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially. These risks and uncertainties include, among others, the factors described under the Risk Factors section of our most recent Quarterly Report on Form 10-Q or Annual Report on Form 10-K filed with the Securities and Exchange Commission. Agenus cautions investors not to place considerable reliance on the forward-looking statements contained in this release. These statements speak only as of the date of this press release, and Agenus undertakes no obligation to update or revise the statements, other than to the extent required by law. All forward-looking statements are expressly qualified in their entirety by this cautionary statement. Agenus Inc. Media 781-674-4784 communications@agenusbio.com

ImmunotherapyASCOClinical Result

23 Oct 2023

·rottapharmbiotech.com

Rottapharm Biotech discloses at ESMO 2023 favourable results from the Phase 1/2 study of the EP4 receptor antagonist CR6086 combined with the anti-PD-1 balstilimab in advanced colorectal cancer - Rottapharm Biotech

Press Release Poster October 23, 2023 Monza (Italy) – Rottapharm Biotech announces favourable clinical results of CR6086, its potent and selective small molecule antagonist of the prostaglandin EP4 receptor, combined with the anti PD-1 antibody balstilimab (Agenus Inc, Nasdaq: AGEN) in advanced colorectal cancer (CRC). Study results have been presented at the European Society for Medical Oncology (ESMO) annual congress in Madrid, Spain, held from October 20-24, 2023. Patients with CRC have limited treatment options, given the aggressive behaviour of their tumours. In fact, more than 80% of CRC is classified as mismatch-repair-proficient (pMMR) and microsatellite stable (MSS), which correlates with low tumour mutation burden and poor immune cell infiltration in the tumour microenvironment (TME), and they are therefore classified as immunologically “cold” tumors. These patients generally do not benefit from Immune Checkpoint Inhibitors (ICIs) and combination strategies are needed to address immunosuppression in the TME and improve sensitivity to ICIs. The involvement of prostaglandin E2 (PGE2) in cancerogenesis has been known for decades. “PGE2, through its EP4 receptor, is a major contributor to immunosuppression in the TME and blockade of this pathway may sensitize cold tumors to ICIs.” said Dr. Lucio Rovati, CEO and CSO at Rottapharm Biotech. “CR6086 is designed to increase the activity and infiltration of several different immune cell types while reversing the immunosuppressive role of PGE2 in the TME. CR6086 is a potential best-in-class EP4 receptor antagonist and has demonstrated a strong safety profile in >250 subjects treated to date.” added Dr. Lucio Rovati. The Phase 1/2 clinical study, conducted at the National Cancer Institute (Istituto Nazionale dei Tumori) in Milan (Italy), evaluated the safety and efficacy of CR6086 combined with balstilimab in 28 patients with advanced pMMR/MSS metastatic CRC. The trial met the designated primary endpoint, with a disease control rate (DCR) of 50% associated with good safety. A DCR of 25% was observed in the difficult to treat subgroup of patients with liver metastases. The overall objective response rate (ORR) was 11%, with 3 patients having partial response (PR): one durable PR is ongoing (>1 year) in a patient with liver metastases. Disease control for all the 11 patients with stable disease lasted ≥ 12 weeks, and for 5 patients lasted ≥ 24 weeks. At a median follow-up of 8 months, the median progression-free survival (PFS) and overall survival (OS) were 2.6 months (CI 95% 1.7-3.6) and 13.7 months (CI 95% 8.8-not reached), respectively. A study expansion in other gastrointestinal tumors is ongoing. “Given the promising results, we are committed to progress CR6086 development in a randomized Phase 2 study in pMMR/MSS metastatic CRC and we look forward to advancing discussions with potential partners” concluded Dr. Lucio Rovati. Rottapharm Biotech Rottapharm Biotech is a research company dedicated to the discovery and development of innovative drugs. It is located in Monza (Italy). The company expertise in research and development includes medicinal/computational chemistry for small molecules, development of biologics and advanced therapies, new targets validation, pharmacological and pharmacokinetic characterization of new drug candidates, original formulations, and design of innovative clinical trials. The company strategy is to develop its own pipeline independently and then seek partnerships with pharmaceutical companies, as well as investing in alliances on innovative projects of other biotech companies or university spin-offs. Rottapharm Biotech Contact Federica Girolami, Business Development Director Tel. +39 346 4131428 federica.girolami@rottapharmbiotech.com About Agenus Agenus is a leading immuno-oncology company targeting cancer and infectious diseases with a comprehensive pipeline of immunological agents. The company’s mission is to expand patient populations benefiting from cancer immunotherapy through combination approaches, using a broad repertoire of antibody therapeutics, adoptive cell therapies (through MiNK Therapeutics) and adjuvants (through SaponiQx). Agenus is headquartered in Lexington, MA. For more information, visit www.agenusbio.com or @agenus_bio. Information that may be important to investors will be routinely posted on our website and social media channels. About balstilimab Balstilimab (Agenus, Inc.) is an investigational monoclonal antibody inhibitor of programmed cell death 1 (PD-1) protein. It has been evaluated in >900 patients to date and has demonstrated strong clinical activity and an excellent safety profile in several tumour types. Agenus Cautionary Statement Regarding Forward-Looking Statements This press release contains forward-looking statements that are made pursuant to the safe harbor provisions of the federal securities laws, including statements regarding clinical development and regulatory plans and timelines, anticipated corporate milestones, new clinical data and program updates to be presented. These forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially. These risks and uncertainties include, among others, the factors described under the Risk Factors section of our most recent Quarterly Report on Form 10-Q or Annual Report on Form 10-K filed with the Securities and Exchange Commission. Agenus cautions investors not to place considerable reliance on the forward-looking statements contained in this release. These statements speak only as of the date of this press release, and Agenus undertakes no obligation to update or revise the statements, other than to the extent required by law. All forward-looking statements are expressly qualified in their entirety by this cautionary statement. Agenus Inc. Media 781-674-4784 communications@agenusbio.com

Clinical ResultImmunotherapyPhase 2ASCO

31 May 2022

·www.globenewswire.com

Agenus Advances Portfolio with 6 Clinical Collaborations

LEXINGTON, Mass., May 31, 2022 (GLOBE NEWSWIRE) -- Agenus Inc. (NASDAQ: AGEN), an immuno-oncology company with an extensive pipeline of therapeutics designed to activate the immune response to cancers and infections, today announced that it has entered into 3 new clinical collaborations with Targovax, Oxford BioTherapeutics, and Immunogenesis, doubling its current number of clinical collaborations. These 6 collaborations span a range of Agenus’ clinical assets, including botensilimab (Fc-enhanced anti-CTLA-4), balstilimab (anti-PD-1), zalifrelimab (anti-CTLA-4), and QS-21 STIMULON™. Agenus is pursuing partnerships with companies developing agents with complementary mechanisms, paving the way for promising immunotherapy combinations to address immunosuppression in the tumor microenvironment. The combination studies are being sponsored and executed by our collaborators, with drug supply and scientific support provided by Agenus. This strategy, enabled by in-house integrated manufacturing and scientific capabilities, positions Agenus to achieve the insights and advances needed to drive development on accelerated timelines. “These new collaborations with Targovax, Oxford BioTherapeutics, and Immunogenesis are exciting next steps in our partnership strategy to broaden combinations and indications under evaluation with our immunomodulatory antibodies,” said Dr. Steven O’Day, Chief Medical Officer at Agenus. “We believe these combinations may unlock the power of immunotherapy more broadly, potentially offering new and promising benefit to patients with treatment-resistant solid tumors.” Agenus’ new and ongoing clinical collaborations are supporting and enabling: Targovax to conduct a clinical trial combining botensilimab and balstilimab with ONCOS-102 (oncolytic virus) in patients with PD-1 relapsed/refractory melanoma. ONCOS-102 is designed to induce immune activation and immunogenic cell death to improve response to immunotherapy.Oxford BioTherapeutics to conduct a clinical trial combining balstilimab with OBT076 (CD205-targeting antibody-drug conjugate) in patients with solid tumors, including lung, gastric, and ovarian cancer. OBT076 is expected to deplete CD205+ cancer cells, and immuno-suppressive cells within the tumor microenvironment, leading to T cell activation and increased response to immunotherapy.Immunogenesis to conduct a clinical trial combining balstilimab and zalifrelimab with evofosfamide (hypoxia-reversal agent) in patients with advanced solid tumors, including prostate, pancreatic, HPV-negative head and neck cancer. Evofosfamide is anticipated to reduce tumor hypoxia and restore T cell infiltration and activity within the tumor microenvironment, increasing responsiveness to checkpoint therapy.Targovax to conduct a clinical trial combining QS-21 STIMULON with TG01 (KRAS vaccine) in up to 3 cancer indications, including multiple myeloma. TG01 is designed to induce T cells that recognize and destroy mut-RAS cancer cells; QS-21 STIMULON is expected to improve immune cell recognition, activation, and TCR diversity of the immune response.Rottapharm Biotech is conducting a clinical trial combining balstilimab with CR6086 (EP4 antagonist) in patients with pMMR-MSS colorectal cancer. CR6086 is expected to inhibit the immune suppressive role of prostaglandins in the tumor microenvironment, improving immunogenicity and responsiveness to immunotherapy. The Phase 1/2 study commenced in 2021.Nelum is conducting a clinical trial combining zalifrelimab with NLM-001 (hedgehog inhibitor) and chemotherapy in patients with advanced pancreatic cancer. NLM-001 in combination with chemotherapy is anticipated to condition the tumor microenvironment to improve T cell infiltration, activation, and responsiveness to immunotherapy. The Phase 1/2 study commenced in 2021. About AgenusAgenus is a clinical-stage immuno-oncology company focused on the discovery and development of therapies that engage the body's immune system to fight cancer. The Company's vision is to expand the patient populations benefiting from cancer immunotherapy by pursuing combination approaches that leverage a broad repertoire of antibody therapeutics, adoptive cell therapies (through its subsidiary MiNK Therapeutics), and adjuvants (through its subsidiary SaponiQx). The Company is equipped with a suite of antibody discovery platforms and a state-of-the-art GMP manufacturing facility with the capacity to support clinical programs. Agenus is headquartered in Lexington, MA. For more information, please visit www.agenusbio.com and our Twitter handle @agenus_bio. Information that may be important to investors will be routinely posted on our website and Twitter. Forward-Looking StatementsThis press release contains forward-looking statements that are made pursuant to the safe harbor provisions of the federal securities laws, including statements relating to the use of therapeutic candidates botensilimab, balstilimab, zalifrelimab, and QS-21 STIMULON, for instance, statements regarding therapeutic benefit and efficacy, mechanism of action, potency, durability, and safety profile of the therapeutic candidates, both alone and in combination with each other and/or other agents; future clinical and regulatory development plans and commercialization plans for botensilimab, balstilimab, zalifrelimab, and QS-21 STIMULON; and any other statements containing the words "may," "believes," "expects," "anticipates," "hopes," "intends," "plans," "will" and similar expressions are intended to identify forward-looking statements. These forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially. These risks and uncertainties include, among others, the factors described under the Risk Factors section of our most recent Quarterly Report on Form 10-Q or Annual Report on Form 10-K filed with the Securities and Exchange Commission and available on our website: www.agenusbio.com. Agenus cautions investors not to place considerable reliance on the forward-looking statements contained in this release. These statements speak only as of the date of this press release, and Agenus undertakes no obligation to update or revise the statements, other than to the extent required by law. All forward-looking statements are expressly qualified in their entirety by this cautionary statement. Contact Ethan Lovell, Chief External Affairs & Communications OfficerAgenus Inc.339-927-1763ethan.lovell@agenusbio.com

CollaborateAntibodyCell TherapyVaccineImmunotherapy

100 Deals associated with Vorbipiprant

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Indication	Highest Phase	Country/Location	Organization	Date
Rheumatoid Arthritis	Phase 2	CZ	Rottapharm SpA	05 Oct 2017
Osteoarthritis	Phase 2	-	Rottapharm SpA	-
Neoplasms	Phase 1	IT	Rottapharm Sl	30 Jan 2022

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05205330 (ESMO2023) Manual	Phase 1/2	Microsatellite instability-high colorectal cancer pMMR \| MSS	28	CR6086+balstilimab	cvwwnjqgsj(lfqxbbummp) = CR6086-related AEs were grade 1 (G1), except for a serious G4 duodenal ulcer which led to consideration of proton pump inhibitors prophylaxis in all pts.Balstilimab-related AEs were ≤G2 and one was serious (pneumonitis) etqmtskvwg (wciktchjpt )	Positive	22 Oct 2023
				CR6086+balstilimab (liver metastases)
NCT03163966 (CREATIVE study, ACR2018)	Phase 2	Rheumatoid Arthritis	146	CR6086 + methotrexate	vpgmucgpxr(sszemyjedr) = gkusxaydkn wvqwfgaqfx (shlhxsuxja )	Positive	21 Oct 2018
				Placebo + methotrexate	vpgmucgpxr(sszemyjedr) = tefcllxwkc wvqwfgaqfx (shlhxsuxja )

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