OATD-02 / Molecure - LARVOL DELTA

Metabolomic reprogramming of the tumor microenvironment by dual arginase inhibitor OATD-02 boosts anticancer immunity. (PubMed, Sci Rep) - P1 | "OATD-02 is currently undergoing clinical evaluation in a phase I/II trial (NCT05759923), which will further elucidate its safety and therapeutic impact. These findings highlight the potential of arginase-targeted therapies in cancer treatment and underscore the value of MALDI-MSI as a powerful tool for tracking metabolic responses to therapy."

Biomarker • IO biomarker • Journal • Immune Modulation • Immunology • Oncology • ARG2 • CD8

Strategic update on the progress and development of Molecure's key clinical projects in 2024 (GlobeNewswire) - "Progress in the first-in-human study of OATD-02, a key oncology program in Phase I, where no dose-limiting toxicity (DLT) has been observed in patients who have received the drug (during dose escalation). Positive recommendation from the Safety Review Committee (SRC) to continue recruitment and to include additional patients at the 20 mg daily dose level. In early 2025, after another positive recommendation from the SRC, Molecure decided to modify the first-in-human study protocol and submitted a request to the relevant authorities and ethics committees to move to higher doses than initially planned for new patients."

DSMB • Solid Tumor

First-in-human Phase I Study to Evaluate Safety, Tolerability and Antineoplastic Activity of OATD-02 in Patients with Selected Advanced And/or Metastatic Solid Tumours (clinicaltrials.gov) - P1 | N=40 | Recruiting | Sponsor: Molecure S.A. | Trial completion date: Nov 2024 ➔ Dec 2025 | Trial primary completion date: Nov 2024 ➔ Dec 2025

Trial completion date • Trial primary completion date • Colorectal Cancer • Genito-urinary Cancer • Hepatology • Oncology • Ovarian Cancer • Pancreatic Cancer • Renal Cell Carcinoma • Solid Tumor

Novel orally bioavailable piperidine derivatives as extracellular arginase inhibitors developed by a ring expansion. (PubMed, Eur J Med Chem) - "Herein, we present a novel class of boronic acid-based arginase inhibitors which are piperidine derivatives exhibiting a different pharmacological profile compared to our drug candidate in cancer immunotherapy -OATD-02 - dual ARG1/2 inhibitor with high intracellular activity...Herein we describe the development and optimization of the synthesis of the new class of boronic acid-based arginase inhibitors via a ring expansion approach starting from the inexpensive chirality source (d-hydroxyproline). This upgraded methodology facilitated a gram-scale delivery of the final compound and eliminated the need for costly and time-consuming chiral resolution."

Journal • Asthma • Cardiovascular • Immunology • Oncology • Pulmonary Disease • Respiratory Diseases

An open-label, multicentre, dose-escalation, first-in-human phase I study to evaluate safety, tolerability and antineoplastic activity of OATD-02 (dual arginase 1 and arginase 2 inhibitor) in patients with selected advanced and/or metastatic solid tumors (ESMO 2023) - P1 | "The study is ongoing. Clinical trial information: NCT05759923."

Clinical • Metastases • P1 data • Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Renal Cell Carcinoma • Solid Tumor • ARG2

Molecure Announces First Half 2023 Results – Significant Financial and Operating Momentum (GlobeNewswire) - "First patient dosed in March 2023 in Phase I clinical trial to assess safety, tolerability and preliminary efficacy of OATD-02 in patients with advanced and/or metastatic solid tumors. lnitial clinical data expected at the end of 2023."

P1 data • Trial status • Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Kidney Cancer • Oncology • Pancreatic Cancer • Renal Cell Carcinoma

In-silico studies to recognize repurposing therapeutics toward arginase-I inhibitors as a potential onco-immunomodulators. (PubMed, Front Pharmacol) - "As OAT-1746 and two others are the only arginase-I inhibitors in development at the time, we have performed a QSAR-based virtual screening with 1650 FDA compounds taken from the zinc database...As a result, the current analyses were successful in locating a novel and potent hit molecule that inhibits arginase-I effectively at nanomolar concentrations. The results of this investigation can be used to develop brand-new arginase I inhibitors as an alternative immune-modulating cancer therapy."

Immunomodulating • Journal • Immune Modulation • Oncology • ARG1

Arginase Inhibition Mitigates Bortezomib-Exacerbated Cardiotoxicity in Multiple Myeloma. (PubMed, Cancers (Basel)) - "Bortezomib exacerbates MM-mediated LV systolic dysfunction in a mouse model of MM, while an arginase inhibitor partially prevents it. Endothelium does not mediate either these adverse or beneficial effects. This suggests that proteasome inhibitors should be used with caution in patients with advanced myeloma, where the summation of cardiotoxicity could be expected. Therapies aimed at the NO pathway, in particular arginase inhibitors, could offer promise in the prevention/treatment of cardiotoxicity in MM."

Journal • Cardiovascular • Hematological Malignancies • Multiple Myeloma • Oncology • ARG1

Arginase 1/2 inhibitor OATD-02: from discovery to first-in-man setup in cancer immunotherapy. (PubMed, Mol Cancer Ther) - "OATD-02 monotherapy had an antitumor effect in multiple tumor models and enhanced an efficacy of the other immunomodulators. Completed non-clinical studies and human pharmacokinetic predictions indicate a feasible therapeutic window and allow for proposing a dose range for the first-in-human clinical study in cancer patients."

Journal • Immune Modulation • Oncology • ARG2

First-in-human Phase I Study to Evaluate Safety, Tolerability and Antineoplastic Activity of OATD-02 in Patients With Selected Advanced and/or Metastatic Solid Tumours (clinicaltrials.gov) - P1 | N=40 | Recruiting | Sponsor: Molecure S.A.

Metastases • New P1 trial • Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Hepatology • Oncology • Ovarian Cancer • Pancreatic Cancer • Renal Cell Carcinoma • Solid Tumor

Molecure announces first patient dosed in Phase I trial with novel, first-in-class dual arginase inhibitor OATD-02 for the treatment of cancer (GlobeNewswire) - "Molecure S.A...announces today that the first patient has been dosed in a Phase I trial evaluating OATD-02 as a monotherapy in cancer patients with advanced solid tumors....We believe OATD-02 has shown a very promising pre-clinical profile, and we look forward to seeing the initial data from this first in human study in the latter part of 2023.'"

P1 data • Trial status • Oncology • Solid Tumor

Immunoregulatory CD71+ Erythroid Cells (CECs) Expand in Multiple Myeloma and Impair Control of L. Monocytogenes Infection (ASH 2022) - "10 software.Arginase inhibitorOAT-1746 arginase inhibitor (Molecure SA) was administered intraperitoneally at doses of 5 or 20 mg/kg twice daily, starting from the second or the fifth day before the bacterial challenge, respectively...Finally, ARG inhibitor decreased L. monocytogenes burden in MM-bearing mice. Altogether, our results show that accumulation of CECs during MM progression leads to impaired bacterial infection control, at least partially dependent on ARG2 activity."

IO biomarker • Anemia • Hematological Disorders • Hematological Malignancies • Immune Modulation • Infectious Disease • Inflammation • Multiple Myeloma • Oncology • Septic Shock • ARG1 • ARG2 • CD4 • CD8 • PD-L1 • TFRC • TGFB1

Molecure to begin clinical development of novel dual arginase inhibitor OATD-02 for the treatment of cancer after gaining permission to conduct first clinical trial in Poland (PRNewswire) - "Molecure S.A. ('Molecure')...announces today that the President of the Polish Office for Registration of Medicinal Products, Medical Devices and Biocidal Products granted permission to conduct the first clinical trial of OATD-02. The planned Phase I trial will be an open-label, multi-center, dose escalation study to evaluate safety, tolerability, anti-cancer activity and to establish the maximum tolerated dose of OATD-02. The study will be conducted in Poland and will enroll a maximum of 40 patients with selected advanced and/or metastatic solid tumors including colorectal cancer, ovarian cancer, pancreatic cancer or renal cell carcinoma. The study is expected to start before the end of 2022."

New P1 trial • Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Gynecologic Cancers • Kidney Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Renal Cell Carcinoma • Solid Tumor

Molecure Third Quarter 2022 Pipeline Highlights and Financial Results (PRNewswire) - "Second proprietary candidate, OATD-02, a first in class arginase inhibitor for cancer on track to enter Phase I clinical trials in late 2022, following CTA approval"

New P1 trial • Oncology • Solid Tumor

OATD-02 validates the benefits of pharmacological inhibition of arginase 1 and 2 in cancer (ESMO 2022) - "OATD-02 represents a very promising drug candidate for the combined treatment of tumours and is the only pharmacological tool, which can effectively address the benefits of arginase inhibition. OATD-02 will enter the clinical trials in 2022."

Chronic Myeloid Leukemia • Colorectal Cancer • Hematological Malignancies • Kidney Cancer • Leukemia • Oncology • Renal Cell Carcinoma • Solid Tumor • ARG2

OATD-02 Validates the Benefits of Pharmacological Inhibition of Arginase 1 and 2 in Cancer. (PubMed, Cancers (Basel)) - "OATD-02 is a potent small-molecule arginase inhibitor with optimal drug-like properties, including PK/PD profile. Excellent activity against intracellular ARG2 significantly distinguishes OATD-02 from other arginase inhibitors. OATD-02 represents a very promising drug candidate for the combined treatment of tumours, and is the only pharmacological tool that can effectively address the benefits of ARG1/ARG2 inhibition. OATD-02 will enter clinical trials in cancer patients in 2022."

Journal • Colorectal Cancer • Genito-urinary Cancer • Hematological Malignancies • Immune Modulation • Inflammation • Kidney Cancer • Leukemia • Oncology • Renal Cell Carcinoma • Solid Tumor • ARG2

OncoArendi Therapeutics Reports Continued Strategic and Operational Momentum for 12 Months ended 31 December 2021 (PharmiWeb) - "...'We have also successfully completed preclinical development of our novel dual acting first-in-class arginase inhibitor OATD-02, which is scheduled to begin Phase 1/2 clinical trials in 2022 for patients with different types of cancer, further validating our world leading medicinal capabilities and translational expertise'."

New P1/2 trial • Preclinical • Oncology

A Novel Oral Arginase 1/2 Inhibitor Enhances the Antitumor Effect of PD-1 Inhibition in Murine Experimental Gliomas by Altering the Immunosuppressive Environment. (PubMed, Front Oncol) - "Treatment with OAT-1746 modified the TME resulting in reduced glioma growth and increased antitumor effects of the anti-PD-1 antibody. Our findings provide the evidence that inhibition of ARG1/2 activity in tumor cells and myeloid cells in the TME unblocks antitumor responses in myeloid cells and NK cells, and improves the efficacy of the PD-1 inhibition."

IO biomarker • Journal • Preclinical • Brain Cancer • Glioblastoma • Glioma • Immune Modulation • Immunology • Inflammation • Oncology • Solid Tumor • ARG2 • ITGAM

"W dniach 15-17.01 odbyło się sympozjum @ASCO, na którym zaprezentowano wstępne dane dot. inhibitora arginazy INCB001158 firm Calithera/Incyte. Wyniki potwierdziły m. in. słuszność kierunku badań obranego przez #OncoArendi dla #OATD02. https://t.co/6HDUpeQEtx" (@oncoarendi)

Novel arginase inhibitor alone and in combination with an immune check point inhibitor reduces tumour growth in murine experimental gliomas (ESMO-IO 2019) - "These results demonstrate that arginase is a key mediator of immuno suppression in gliomas, and inhibiting Arg1 shifts the immune response toward a pro-inflammatory environment. Our results suggest that combining OAT-1746 with other immunotherapies may improve responses in glioblastoma.Legal entity responsible for the study: Molecular Neurobiology, Nencki Institute of Experimental Biology. Funding: Project DIMUNO: “Development of new cancer therapies based on selective antitumour immunomodulators”, co-financed by the National Centre for Research and Development."

Combination therapy • IO Biomarker • Preclinical

Targeting ARG2 as a novel therapeutic approach for cancer (ESMO 2019) - "OATD-02, a potent ARG1 and ARG2 inhibitor, exerts its antitumor efficacy not only by the reactivation of the immune response but also by directly suppressing the ARG2-dependent proliferation of cancerous cells. Thus, OATD-02 is a very promising compound for the treatment of hypoxic tumors which are particularly resistant to therapies. Legal entity responsible for the study: OncoArendi Therapeutics SA."

IO Biomarker

"Na konferencji Europejskiego Towarzystwa Onkologii Klinicznej #ESMO19 w Barcelonie (27.09 – 1.10) dr Marcin Grzybowski z @oncoarendi zaprezentuje niepublikowane dotąd dane dotyczące naszego klinicznego kandydata, inhibitora arginazy – cząsteczki OATD-02 https://t.co/G0pzj5ZSeH" (@oncoarendi)