PTT-4256 / Pathios Therap - LARVOL DELTA

RAISIC-1: First-in-human Phase 1/2 study of PTT-4256, a first-in-class GPR65 inhibitor, in advanced solid tumors: Safety, tolerability, PK/PD results. (ESMO 2026) - No abstract available

Clinical • First-in-human • Metastases • P1/2 data • PK/PD data • Oncology • Solid Tumor

Updated Safety, Tolerability, and Translational Biomarker Results from RAISIC-1: A Phase 1/2 Study of the GPR65 Inhibitor PTT-4256 in Advanced Solid Tumors (EORTC-NCI-AACR 2026) - "Abstract will be available as of 4 November (with consent of the author)"

Biomarker • Clinical • Metastases • P1/2 data • Oncology • Solid Tumor

GPR65 in cancer: expression heterogeneity, invasion and metastasis, the tumor immune microenvironment, and translational implications. (PubMed, Int Immunopharmacol) - "The oral inhibitor PTT-4256 is undergoing Phase 1/2 evaluation in RAISIC-1, with updated first-in-human data providing preliminary pharmacokinetic, pharmacodynamic, biomarker, safety, and early signals of clinical activity...The optimal dose, overall safety profile, and definitive clinical antitumor efficacy remain to be established. Further single-cell, spatial, and biomarker-guided studies will be essential to define the therapeutic value of GPR65."

First-in-human • Heterogeneity • Journal • Review • Brain Cancer • Colorectal Cancer • Glioma • Lung Cancer • Melanoma • Metabolic Disorders • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • CD8

GPR65 is a Novel Therapeutic Target Associated with Immune Exhaustion in Clear Cell Renal Cell Carcinoma (KCRS 2026) - P1/2 | "GPR65-High status did not predict improved outcomes with either atezolizumab/bevacizumab or avelumab/axitinib but did portend significantly prolonged progression free survival with nivolumab compared to GPR65-Low in HCRN-GU16-260 (HR=0.49, p=0.009). The ongoing phase I/II RAISIC-1 trial (NCT06634849) is investigating a novel GPR65 inhibitor, PTT-4256, as monotherapy or in combination with anti-PD-1 ICI in patients with solid tumors, including dose expansion cohorts for patients with RCC. Keywords GPR65; Immunosuppression; Clear Cell; Immunotherapy"

IO biomarker • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CXCL10 • IL10 • IL2RG • PD-L1

RAISIC-1: A phase 1/2 clinical trial of the GPR65 inhibitor PTT-4256—Preliminary safety, tolerability, pharmacokinetic, and pharmacodynamic results. (ASCO 2026) - P1/2 | "Enrollment at dose levels ≥ 300 mg is ongoing. Phase 2 (Module B) as PTT-4256 monotherapy or in combination with anti-PD1 in RCC and head & neck squamous cell cancer (HNSCC) will commence upon identification of RP2D."

Clinical • IO biomarker • P1/2 data • PK/PD data • Genito-urinary Cancer • Head and Neck Cancer • Hypertension • Nasopharyngeal Carcinoma • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

An Open Label Dose Finding Study of PTT-4256 in Patients With Solid Tumours (RAISIC-1). (clinicaltrials.gov) - P1/2 | N=30 | Recruiting | Sponsor: Pathios Therapeutics Pty Ltd | N=95 ➔ 30

Enrollment change • Breast Cancer • Colorectal Cancer • Gastric Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor • Triple Negative Breast Cancer

An Open Label Dose Finding Study of PTT-4256 in Patients With Solid Tumours (RAISIC-1). (clinicaltrials.gov) - P1/2 | N=95 | Recruiting | Sponsor: Pathios Therapeutics Pty Ltd | N=25 ➔ 95

Enrollment change • Breast Cancer • Colorectal Cancer • Gastric Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor • Triple Negative Breast Cancer

PTT-4256-01: An Open Label Dose Finding Study of PTT-4256 in Patients With Solid Tumours (RAISIC-1) (clinicaltrialsregister.eu) - P1/2 | N=25 | Not yet recruiting | Sponsor: Pathios Therapeutics Limited

New P1/2 trial • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

An Open Label Dose Finding Study of PTT-4256 in Patients With Solid Tumours (RAISIC-1). (clinicaltrials.gov) - P1/2 | N=95 | Recruiting | Sponsor: Pathios Therapeutics Pty Ltd

New P1/2 trial • Breast Cancer • Colorectal Cancer • Gastric Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor • Triple Negative Breast Cancer

Low pH, High Stakes: A Narrative Review Exploring the Acid-Sensing GPR65 Pathway as a Novel Approach in Renal Cell Carcinoma. (PubMed, Cancers (Basel)) - P1/2 | "The first-in-class GPR65 inhibitor, PTT-4256, is now under evaluation in the Phase I/II RAISIC-1 trial (NCT06634849) in solid tumours, including RCC. Targeting acid-sensing pathways represents a novel and promising therapeutic strategy in RCC, aiming to remodel the TME and overcome ICI resistance. Integrating GPR65 inhibition with existing immunotherapies may define the next era of RCC management, warranting continued translational and clinical investigation."

IO biomarker • Journal • Review • Genito-urinary Cancer • Metabolic Disorders • Oncology • Renal Cell Carcinoma • Solid Tumor • CA9 • IL10

Preliminary safety, pharmacokinetic and pharmacodynamic analysis from the ongoing RAISIC-1 (Relief of Acidic Immune Suppression in Cancer): Phase 1/2 clinical trial of the GPR65 inhibitor PTT-4256. (SITC 2025) - "Transcriptomics data from lactic acid-stimulated blood samples and plasma proteomics (Olink® Reveal) are being analysed.Conclusions Patient enrollment at dose levels 80 mg and above is ongoing, all available clinical safety, preliminary activity, PK and PD data will be presented.Trial Registration NCT06634849Ethics Approval The study was approved by Bellberry Human Research Ethics Committee, ID number 2024-06-775, and Austin Health Human Research Ethics Committee, ID number VicTRI-19673. All participants provided informed consent prior to taking part in this clinical study."

Clinical • IO biomarker • P1/2 data • PK/PD data • Oncology • Solid Tumor

PTT-4256-01: A modular, open label, dose finding phase I/II clinical trial in patients with solid tumours to assess the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of PTT-4256 (RAISIC-1) (ESMO 2025) - P1/2 | "Legal entity responsible for the study Pathios Therapeutics Pty Ltd. Funding Pathios Therapeutics Pty Ltd."

Clinical • P1/2 data • PK/PD data • Oncology • Solid Tumor

Proffered Paper: Reversing Acidic Immune Suppression in Cancer with PTT-4256, A First-In-Class Small Molecule Inhibitor of GPR65 (EACR 2025) - "GPR65 is a key checkpoint on tumour-infiltrating immune cells that links the chronically acidic tumour microenvironment to tumour-promoting immunosuppression. Pathios' oral small molecule GPR65 inhibitor, PTT-4256, targets fundamental biology co-opted by all solid tumours with a mechanism that is orthogonal to established anti-tumour therapies including anti-PD1. An ongoing First in Human Phase 1/2 clinical trial (RAISIC-1) to establish safety and PK started in Q4'24."

IO biomarker • Oncology • Solid Tumor

Pathios Therapeutics Announces Dosing of First Patient in Phase 1/2 Clinical Study of GPR65 Inhibitor PTT-4256 in Patients with Advanced Solid Cancers (PRNewswire) - "Pathios Therapeutics...announced dosing of the first patient in the initial module of a Phase 1/2 clinical trial evaluating PTT-4256, the company's investigational first-in-class GPR65 inhibitor....The RAISIC-1 trial (Relief of Acidic Immune Suppression in Cancer) is a modular multi-part, multi-arm open-label study being conducted in Australia. The study's first module is designed to evaluate the safety, tolerability, preliminary efficacy and pharmacokinetics of PTT-4256 monotherapy in patients with a range of advanced solid tumours."

Trial status • Oncology • Solid Tumor

PTT-4256-01: An Open Label Dose Finding Study of PTT-4256 in Patients With Solid Tumours (RAISIC-1). (clinicaltrials.gov) - P1/2 | N=30 | Recruiting | Sponsor: Pathios Therapeutics Pty Ltd | Not yet recruiting ➔ Recruiting

Enrollment open • Oncology • Solid Tumor

An Open Label Dose Finding Study of PTT-4256 in Patients With Solid Tumours. (clinicaltrials.gov) - P1/2 | N=30 | Not yet recruiting | Sponsor: Pathios Therapeutics Pty Ltd

New P1/2 trial • Oncology • Solid Tumor

Pathios Therapeutics Raises $25M in First Close of Series B Financing to Advance First-in-Class Immunotherapy Approach into Clinic (PRNewswire) - "Pathios Therapeutics Limited...today announced that the company has raised $25 million in the first close of a Series B financing. The financing consists of a new strategic investment from Bristol Myers Squibb, as well as support from existing investors including Canaan and Brandon Capital. Proceeds from the raise will be used to support the continued development of Pathios' unique approach to cancer immunotherapy focused on the inhibition of GPR65, a novel target that has been genetically associated with a range of immunologically-mediated diseases. As part of these efforts, the company expects to advance PTT-4256, its lead internally discovered, oral, highly potent, and selective small molecule inhibitor of GPR65, into human clinical trials in advanced solid cancers by the end of 2024."

Financing • Oncology

PTT-4256 is a first-in-class small molecule inhibitor of GPR65 that counteracts the low pH-dependent immunosuppressive effects on immune cells and displays pronounced anti-tumor activity in mice (SITC 2023) - "Conclusions GPR65 is a key checkpoint on tumor-infiltrating immune cells that links the chronically acidic TME to tumor-promoting immunosuppression. The GPR65 inhibitor PTT-4256 restores anti-tumor immunity and demonstrates pronounced single-agent efficacy in mice, and is therefore being advanced towards clinical development."

Immune cell • IO biomarker • Preclinical • Oncology

Pathios Therapeutics Unveils PTT-4256, a Highly Potent and Selective Inhibitor of GPR65, in Presentation at American Association for Cancer Research (AACR) Annual Meeting 2023 (PRNewswire) - "Pathios Therapeutics Limited...announced the presentation of the latest preclinical data from the company's GPR65 discovery program at the American Association for Cancer Research (AACR) Annual Meeting 2023....In preclinical experiments, PTT-4256 was shown to be highly effective in counteracting the effects of low pH (i.e. high acidity) that polarizes human and mouse macrophages toward an immunosuppressive state. This PTT-4256-induced relief of immune suppression was associated with dose-dependent increases in a range of pro-inflammatory genes that are consistent with an anti-tumor immune response, evidence of an infiltration of T cells and natural killer (NK) cells into the TME, and prevention of the activation of immunosuppressive cytokines....'Based on these latest data, we are now focused on completing the toxicology program that will support initiation of clinical trials in 2024'."

Preclinical • Oncology