Epix Pharmaceuticals (United States)

The BRG/Brahma-associated factors (BAF or mSWI/SNF) family of chromatin remodeling complexes are critical regulators of gene expression and are major determinants of cancer and other diseases. Two paralog ATPases, SMARCA4 and SMARCA2 (BRG1 and BRM, respectively), provide the enzymatic activity required for chromatin remodeling. Here, we discover and characterize a novel series of compounds that potently and selectively inhibit SMARCA4/SMARCA2. Mutational and biochemical studies demonstrate that these inhibitors act through a unique mode of inhibition, distinct from reported SMARCA4/SMARCA2 inhibitors. Across a range of cancer cell lines, SMARCA4/SMARCA2 inhibition resulted in lineage-specific changes in chromatin accessibility at binding sites for key transcription factors (TFs). In uveal melanoma (UM), BAF inhibition resulted in loss of enhancer occupancy of SOX10 and MITF, two essential TFs, leading to down-regulation of the melanocytic gene expression program. In a mouse xenograft model of UM, SMARCA4/SMARCA2 inhibition was well tolerated and resulted in dose-dependent tumor regression correlating with pharmacodynamic modulation of BAF-target gene expression. These data provide the foundation for first-in-human studies of BAF ATPase inhibition as a novel therapeutic to treat TF-dependent cancers.

This case study demonstrates the use of Habit Reversal Training (HRT) combined with Relaxation Training (RT) in addressing trichotillomania. The subject, a 28-year-old woman, reported experiencing stress and frequent lateness to work. Her hair-pulling behavior, triggered by the early appearance of grey hair, led her to spend 30 to 60 minutes each morning pulling her hair, which contributed to her tardiness. Over the course of 14 weekly therapy sessions, interventions included self-monitoring, psychoeducation, identification and modification of visual triggers, stimulus-response strategies, and restructuring daily routines. The treatment resulted in reduced stress and effective control of hair-pulling behaviors. The case suggests that incorporating a hair care regimen into therapy may further enhance positive outcomes. It also highlights the importance of considering both psychological and societal influences in the development and treatment of trichotillomania.

Abstract Metastatic non-small cell lung cancer (NSCLC) is a highly lethal cancer with limited effective treatment options. Although immune checkpoint inhibitors show some promise, they benefit only a minority of patients and often result in resistance. We have developed a novel nano-immunotherapy for NSCLC using our patented polymers-coated mesoporous silica nanoparticle, Pdx-NPTM, which co-delivers a STING (Stimulator of Interferon Genes) agonist and an anti-PDL1 antibody, forming our drug candidate STACI - STING Agonist and Checkpoint Inhibitor. STING is widely expressed across various cell types, including innate immune cells (e.g., dendritic cells, macrophages), T cells, and cancer cells. Activation of the STING pathway leads to the production of type I interferons and other cytokines, promoting an anti-cancer immune response. Leading synthetic cyclic dinucleotide (CDN)-based STING agonists, including ADU-S100 and MK-1454, have been in clinical trials. However, their use is limited to intratumoral injection to activate local immune responses in head and neck tumors and lymphoma, rather than systemic administration. Due to the short half-life of CDNs and their poor cellular uptake, their efficacy is only modest even when combined with anti-PD1 antibody. Our hypothesis is that co-delivering an anti-PDL1 and a STING agonist on our Pdx-NPTM nanoparticle platform will overcome the limitations of STING agonist delivery, reduce the required anti-PDL1 dose to improve safety, and promote a synergistic effect between anti-PDL1 and STING agonist through delivery to both cancer and immune cells. STING agonists are known to remodel tumor microenvironment, to be immunogenic, and to upregulate PDL1 expression on cancer and antigen-presenting cells, providing a strong rationale for combining it with an anti-PDL1 antibody, which serves as both a tumor homing agent and an immune checkpoint inhibitor when loaded on our Pdx-NPTM. The nanoparticles also protect CDNs from enzymatic degradation, extend their bio-availability, and promote cellular uptake and activity in cancer and immune cells. In mice, we observed the activation of 60% of DCs in lymph nodes 48 hours after a footpad injection of nanoparticles loaded with natural 3’3’-c-di-GMP or synthetic ADU-S100 (vs. 10% by saline). In mice carrying NSCLC tumors (LLC-JSP), Pdx-NPTM co-delivering anti-PD-L1 antibody, a STING agonist, and an ICD agent (volasertib) for 3 doses significantly prolonged median survival from 11 days (saline treated) to 24 days. No toxicity effect was observed. Work to further fine-tune the STACI formulation and establish safety and efficacy profiles in multiple tumor models is ongoing and will be presented. Our versatile Pdx-NP™ platform addresses the current need of cancer immunotherapy focusing on combination therapy - where complementary biological pathways are simultaneously targeted. Citation Format: Noah Crumrine, Moataz Reda, Pramod Kumar, Ruijie Wang, Tongchatra Watcharawittayakul, Victoria Gouw, Sylvia Khalil, Worapol Ngamcherdtrakul, Wassana Yantasee. Development of PD-L1 and STING-targeted nanoparticles for lung cancer treatment [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A052.

Rencofilstat inhibits cyclophilin to reduce hepatic inflammation and fibrosis, which, in turn, could improve liver function and reduce portal-systemic shunting. Since HepQuant quantifies liver function and portal-systemic shunting, it was used to measure the hepatic effects of rencofilstat treatment of MASH with advanced fibrosis. Seventy subjects with suspected ≥ F3 MASH, defined from liver biopsy or AGILE 3+ ≥ 0.53, were randomised to rencofilstat 75 mg/d (n = 24), 150 mg/d (n = 23) or 225 mg/d (n = 23), and tested by HepQuant at baseline, 60 and 120 days. The DuO version included oral dosing of d4-cholate and two blood samples (20 and 60 min). DuO's disease severity index (DSI) and portal-systemic shunting fraction (SHUNT%) were evaluated for changes from baseline at 60 and 120 days of rencofilstat treatment. Across all subjects, there was a significant decrease in SHUNT% both at Day 60 (-1.67%, p = 0.0156) and Day 120 (-1.55%, p = 0.0441). In the 225 mg rencofilstat arm, 56% of subjects (10/18) were responders by Day 120 (p = 0.0549), and their DSIs improved with a mean change of -1.61 (p = 0.0190). Across all treatment arms, subjects with DSI > 18.3 at baseline had the greatest improvement with treatment (ΔDSI = -2.59, p = 0.0053). Although further studies are warranted, the decreases in DSI and SHUNT% suggest that rencofilstat 225 mg/d improves hepatic function and portal-systemic shunting. HepQuant DuO is simple to administer, well-tolerated and a useful tool for detecting the hepatic effects of treatment. The study was registered at ClinicalTrials.gov, NCT05461105.

Purpose[99mTc]Tc-HYNIC-iPSMA is a novel technetium-99m-labelled small molecule inhibitor of the prostate-specific membrane antigen (PSMA) for detecting prostate cancer (PC). The objective of this registry was to collect and evaluate [99mTc]Tc-HYNIC-iPSMA patient data and images to establish the safety and tolerability, and clinical utility of this agent in imaging at different stages of PC.MethodsPatients 18 to 80 years old with primary staging and metastatic PC were eligible. Patients unable to perform prescribed examinations, undergo a [99mTc]Tc-HYNIC-iPSMA planar and SPECT or SPECT/CT (when available), or sign a patient informed consent form were excluded from the registry. All eligible patients underwent a screening and baseline visit before imaging with [99mTc]Tc-HYNIC-iPSMA. The primary safety endpoint was assessed by collecting and grading all treatment-related adverse events using the Common Terminology Criteria for Adverse Events. Patients were followed until disease progression, death, serious or intolerable adverse events, registry termination by the sponsor, patient withdrawal, or lost to follow-up. Analysis was planned for when data was available from 40 enrolled patients.Results40 patients enrolled in 6 countries and received [99mTc]Tc-HYNIC-iPSMA tracer administration followed by planar and SPECT imaging. Of the 40 patients included, investigators reported a change in management due to the [99mTc]Tc-HYNIC-iPSMA imaging in 17/40 of patients (42.5%). No adverse events were reported.Conclusions[99mTc]Tc-HYNIC-iPSMA is a promising option to identify PSMA-positive prostate cancer on SPECT and could improve patient access to PSMA imaging worldwide.

DNA-encoded chemical library (DEL) technology provides a time- and cost-efficient method to simultaneously screen billions of compounds for their affinity to a protein target of interest. Here we report its use to identify a novel chemical series of inhibitors of the thioesterase activity of polyketide synthase 13 (Pks13) from Mycobacterium tuberculosis (Mtb). We present three chemically distinct series of inhibitors along with their enzymatic and Mtb whole cell potency, the measure of on-target activity in cells, and the crystal structures of inhibitor-enzyme complexes illuminating their interactions with the active site of the enzyme. One of these inhibitors showed a favorable pharmacokinetic profile and demonstrated efficacy in an acute mouse model of tuberculosis (TB) infection. These findings and assay developments will aid in the advancement of TB drug discovery.

A glioblastoma (GBM) is one of the most aggressive, infiltrative, and treatment-resistant malignancies of the central nervous system (CNS). The current standard of care for GBMs include maximally safe tumor resection, followed by concurrent adjuvant radiation treatment and chemotherapy with the DNA alkylating agent temozolomide (TMZ), which was approved by the FDA in 2005 based on a marginal increase (~2 months) in overall survival (OS) levels. This treatment approach, while initially successful in containing and treating GBM, almost invariably fails to prevent tumor recurrence. In addition to the limited therapeutic benefit, TMZ also causes debilitating adverse events (AEs) that significantly impact the quality of life of GBM patients. Some of the most common AEs include hematologic (e.g., thrombocytopenia, neutropenia, anemia) and non-hematologic (e.g., nausea, vomiting, constipation, dizziness) toxicities. Recurrent GBMs are often resistant to TMZ and other DNA-damaging agents. Thus, there is an urgent need to devise strategies to potentiate TMZ activity, to overcome drug resistance, and to reduce dose-dependent AEs. Here, we analyze major mechanisms of the TMZ resistance-mediated intracellular signaling activation of DNA repair pathways and the overexpression of drug transporters. We review some of the approaches investigated to counteract these mechanisms of resistance to TMZ, including the use of chemosensitizers and drug delivery strategies to enhance tumoral drug exposure.