PT-112

Ongoing clinical trial has reached target enrollment of 109 patients across clinical sites in the United States and France Open-label dose optimization and proof of concept study of PT-112 monotherapy includes interim data results, with top-line read-out and conference presentations expected in late 2024 NEW YORK, March 8, 2024 /PRNewswire/ -- Promontory Therapeutics Inc., a clinical stage pharmaceutical company advancing immunogenic small molecule approaches in oncology, has completed enrollment of its Phase 2 clinical trial of lead therapeutic candidate, PT-112, reaching its target enrollment of 109 patients with late-line metastatic castration-resistant prostate cancer (mCRPC) (ClinicalTrials.gov Identifier: NCT02266745). The study is evaluating PT-112 in patients who have been treated with at least three prior life-prolonging therapies for mCRPC, and who exhibited radiographic evidence of disease progression at study entry. Patients with bone-only metastatic disease are also included in the study. These requirements create a representative treatment population following standard of care of androgen receptor signaling inhibitors, taxane chemotherapies, and any other drug approved by FDA on the basis of overall survival. The clinical trial enrolled patients across leading sites in the United States (23) and France (9). "This clinical trial is the largest study to date of PT-112 and will establish the optimal dose in line with the FDA's Project Optimus, as well as proof of concept in our late-line mCRPC patient population," said Promontory Therapeutics Chief Medical Officer Johan Baeck, MD. "Data from our earlier Phase 1/2 studies have shown that PT-112 is clinically safe and active, and promotes immunogenic cancer cell death induced by the inhibition of ribosomal biogenesis, which is a promising mechanism of action for late-stage patients with prostate cancer — an 'immune-cold' disease with no broadly approved and effective immunotherapy." Promontory Therapeutics plans for a Type C meeting with the FDA in the second half of 2024, followed by an End-of-Phase 2 meeting with FDA and further engagement with European regulatory authorities. In addition to safety and efficacy findings among late-stage metastatic patients, the study aims to generate meaningful supportive data via correlative research, including on immune activation by PT-112 monotherapy as evaluated by the propagation of new T cell populations, as well as reductions in circulating tumor cells and ctDNA. "Promontory is grateful to our clinical partners across the U.S. and France, including Gustave Roussy Paris, for completing enrollment of this critical Phase 2 study. We are confident in PT-112's potential as an effective treatment for patients with mCRPC who have progressed on androgen receptor directed therapy, chemotherapy or radioligand therapy and who lack any effective immunotherapy," said Promontory Therapeutics Chief Executive Officer Robert Fallon. "We look forward to presenting topline safety, efficacy, and correlative data at relevant research and medical conferences later this year." About PT-112 PT-112 is the first small-molecule conjugate of pyrophosphate in clinical development in oncology. PT-112 has numerous advantages — including its tolerability and inhibition of ribosomal biogenesis which leads to immunogenic cell death, through the release of damage associated molecular patterns that bind to dendritic cells and lead to downstream immune effector cell recruitment in the tumor microenvironment. PT-112 represents a highly potent inducer of this immunological form of cancer cell death. Further, PT-112 harbors a property known as osteotropism, or the propensity of the drug to reach its highest concentrations in certain areas of the bone, making it a candidate for treatment of patients with cancers that originate in, or metastasize to, the bone. The first in-human study of PT-112 demonstrated an attractive safety profile and evidence of long-lasting responses among heavily pre-treated patients and data were published in eClinicalMedicine, part of The Lancet. The combination Phase 1b dose escalation study of PT-112 with PD-L1 checkpoint inhibitor avelumab in solid tumors was reported in a mini-oral presentation at the ESMO 2020 Virtual Congress, and the Phase 2a dose confirmation cohort in non-small cell lung cancer patients was reported at ESMO I-O 2022. The Phase 1 study in patients with relapsed or refractory multiple myeloma presented at ASH 2020 is the third completed Phase 1 study of PT-112. Monotherapy Phase 2 development is ongoing in mCRPC, and includes the Phase 2 proof of concept study in thymic epithelial tumors under the company's formal CRADA with the NCI. Interim data from the NCI study were published at ASCO 2023. About Promontory Therapeutics Promontory Therapeutics Inc. is a privately held, clinical stage pharmaceutical company focused on small molecule immunotherapy, based in New York City. Clinical data generated across three Phase 1 studies have demonstrated single-agent and combination anti-cancer activity and an attractive tolerability profile, and two Phase 2 studies of PT-112 are underway. The company's research and development work has been conducted in the United States, Europe and Asia. The company sponsored the completed clinical study of PT-112 in combination with the PD-L1 inhibitor avelumab, and has an active Phase 2 trial under formal CRADA collaboration with the National Cancer Institute (NCI), utilizing PT-112 in thymic epithelial tumors, rare cancers with no FDA approved drug, where PT-112 has received Orphan Drug designation. Promontory Therapeutics is also a company member of the Paris-Saclay Cancer Cluster, Europe's emerging bio-cluster for oncology, and was a 2023 Nominee for Best Startup by the Prix Galien USA. To learn more about Promontory Therapeutics, visit the company's website here. CONTACTS: Promontory Therapeutics Brooke Raphael, MS VP, Strategy & Operations Tel: +1 (646) 974-6453 Email: [email protected] Investors: Stan Musial Tel: +1 (646) 222-6932 Email: [email protected] ICR Westwicke Media: Alexis Feinberg Tel: +1 (203) 939-2225 Email: [email protected] SOURCE Promontory Therapeutics Inc.

PT-112's mechanism of action inhibits ribosomal biogenesis, promoting immunogenic cancer cell death through cancer cell organelle stresses Data presented at the Society for Immunotherapy of Cancer's 38th Annual Meeting NEW YORK, Nov. 4, 2023 /PRNewswire/ -- Promontory Therapeutics Inc., a Phase 2 stage biotech company advancing immunogenic small molecule approaches in oncology, today presented data demonstrating the molecular mechanism of its lead therapeutic candidate, PT-112, and its ability to induce immunogenic cell death (ICD) in cancer cells. Data suggest that PT-112-induced ICD is mediated by endoplasmic reticulum (ER) and mitochondrial stresses, which are specific intra-cellular events that comprise part of the larger ICD mechanism. The presentation was made at the Society for Immunotherapy of Cancer's (SITC) 38th Annual Meeting, taking place November 1-5, 2023 in San Diego. The work was designed in collaboration with the Galluzzi Lab at Weill Cornell Medical College in New York, in order to elucidate the sequence of events – beginning with inhibition of ribosomal biogenesis and culminating in selective ICD – underlying PT-112's immune effects. Analyzing a panel of mouse cell lines engineered to lack specific genes involved in mitochondrial apoptosis (Bcl2, Bax and Bak1), flow cytometry, immunoblotting, RT-PCR, and immunofluorescence microscopy were used to determine the impact of PT-112 on ER and mitochondrial stress, as well as immunogenic signaling. "Our continued studies of PT-112 provide mechanistic insights for this promising immunogenic small molecule, which has shown clinical activity in patients with a variety of cancers," said Promontory Therapeutics Senior Vice President of Research and Development Tyler Ames, PhD. "This particular work sheds light on how PT-112 encourages the immunogenic cell death of cancerous cells through ER stress and mitochondrial dysfunction, both of which are known to contribute to immune signaling." Study findings include: PT-112 drives ER stress and mitochondrial dysfunction, which promote ICD. PT-112 effects on mitochondria included increases in mitochondrial mass and reactive oxygen species, changes in membrane polarization, and the release of mitochondrial DNA into the cytosol, a potent immunogenic signal. Some of these effects were impacted by the absence of Bax and Bak1. PT-112 elicits the phosphorylation of eukaryotic translation initiation factor 2 subunit alpha (EIF2S1, best known as eIF2α), indicating ER stress and the activation of the integrated stress response (ISR). There is an increase in the levels of Ifnb1 mRNA after PT-112 exposure, indicating PT-112 induces type 1 interferon responses. PT-112 is the subject of ongoing Phase 2 clinical trials for metastatic castrate-resistant prostate cancer and thymic epithelial tumors, and a completed Phase 2a trial in non-small cell lung cancer. In previous mechanism of action research, data showed that PT-112 causes ribosomal biogenesis inhibition and nucleolar stress, which is the likely driver of PT-112-induced cancer organelle stresses and ICD. For more information about Promontory Therapeutics and PT-112, visit . About PT-112 PT-112 is a novel inhibitor of ribosomal biogenesis, which leads to selective immunogenic cancer cell death (ICD). PT-112's mechanism of action governs intracellular events that cause the release of damage associated molecular patterns, known to bind to dendritic cell and natural killer cell receptors, prompting an anti-cancer immune response. PT-112's potential best-in-class ICD effects may create the conditions for effective and durable responses to treatment. The first in-human study of PT-112 demonstrated an attractive safety profile and evidence of long-lasting responses among heavily pre-treated patients and data were published in eClinicalMedicine, part of The Lancet. The company's Phase 2 study of PT-112 in late-stage metastatic castration-resistant prostate cancer patients is underway in the United States and France. An active Phase 2 trial is also on-going with the National Cancer Institute utilizing PT-112 in thymic epithelial tumors, a rare disease with no FDA approved drug, for which PT-112 has received FDA Orphan Drug designation. An additional Phase 2a study has been successfully completed for non-small cell lung cancer in combination with PD-L1 inhibition. About Promontory Therapeutics Promontory Therapeutics Inc. is a privately held, clinical stage drug development company focused on small molecule immunotherapy in cancer. The company's lead therapeutic candidate PT-112 has demonstrated single-agent and combination anti-cancer activity and an attractive tolerability profile across three Phase 1 studies. PT-112 is the subject of ongoing Phase 2 clinical trials for metastatic castration-resistant prostate cancer in the United States and France, thymic epithelial tumors with the National Cancer Institute, and a completed Phase 2a trial in non-small cell lung cancer. As part of its recent research and development expansion into France, Promontory was selected as the first international company member of the Paris-Saclay Cancer Cluster, Europe's emerging biotech hub for oncology. To learn more about Promontory Therapeutics, visit the company's website here. CONTACTS: Promontory Therapeutics: Brooke Raphael, MS VP, Strategy & Operations Tel: +1 (646) 974-6453 Email: [email protected] Investors: Stan Musial Chief Financial Officer Tel: +1 (646) 222-6932 Email: [email protected] Media: Alexis Feinberg ICR Westwicke Tel: +1 (203) 939-2225 Email: [email protected] SOURCE Promontory Therapeutics Inc.