NXP800 / Nuvectis Pharma, Cancer Therapeutics CRC - LARVOL DELTA

Pharmacokinetic and pharmacodynamic evaluation of NXP800, a novel GCN2 activator, in a first in human clinical trial (AACR 2024) - P1 | "It is envisaged that NXP800 will need to be dosed continuously and although the protocol defined MTD at 28 days at 100 mg QD, it was decided to take a dose of range of 50 mg and 75 mg OD which caused biomarker modulation, forward for further evaluation.Conclusions A tolerable dose/schedule of continuous dosing of NXP800 has been established with biomarker modulation in blood. Patients will be randomized to two dose levels 50 and 75 mg/day in a QD schedule to evaluate response in a population of ARID1A mutated, platinum-resistant, clear cell ovarian cancer (NCT05226507)."

Clinical • First-in-human • P1 data • PK/PD data • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Ovarian Cancer • Ovarian Clear Cell Cancer • Solid Tumor • ARID1A • ATF4 • TRIB3 • ULBP1

NXP800-101: A Phase 1 Clinical Study of NXP800 in Subjects With Advanced Cancers and Expansion in Subjects With Ovarian Cancer (clinicaltrials.gov) - P1 | N=45 | Terminated | Sponsor: Nuvectis Pharma, Inc. | Active, not recruiting ➔ Terminated; Study terminated due to various reasons impacting the feasibility of future clinical development

Platinum resistant • Trial termination • Clear Cell Carcinoma • Oncology • Ovarian Cancer • Solid Tumor • ARID1A • BRCA

ME09. Paul Workman: Personalized Molecular Medicine Enabled by Multidisciplinary Approaches to Cancer Drug Discovery and Clinical Development (AACR 2025) - "Examples will include the AKT inhibitor capivasertib and the developmental GCN2 activator and HSF1 pathway inhibitor NXP800. I will also describe our recent progress towards drugging the transcription factor brachyury, the primary driver of the rare bone cancer chordoma, providing an approach that can be applied to drug other oncogenic transcription factors."

Clinical • Chordoma • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • HSF1

Discovery of ARID1A loss as a patient biomarker for NXP800 - A developmental activator of the integrated stress response (ISR) and inhibitor of the HSF1 pathway in ovarian cancer (AACR 2024) - P1 | "We propose that ARID1A loss alters the binding and recruitment of ATF4 and HSF1 leading to the altered and prolonged expression of ATF4 target genes and increased sensitivity to NXP800. NXP800 is currently in phase Ib for the treatment of ARID1A mutant platinum resistant ovarian cancer (NCT05226507)."

Biomarker • Clinical • Oncology • Ovarian Cancer • Solid Tumor • ARID1A • ATF4 • HSF1 • SMARCA4

HSF1 inhibition induces pancreatic ductal adenocarcinoma autophagy through JNK (AACR 2024) - "Objective: The objective of this study is to investigate the molecular mechanism of HSF1 inhibition in PDAC autophagy.Methods and In human PDAC cells, Western blotting analysis revealed that HSF1 inhibition via small molecular including CCT361814/NXP800, an HSF1 inhibitor in phase I clinical trials, increased autophagy marker microtubule-associated protein 1A/1B-light chain 3 (LC3) lipidation and decreased expression of phosphorylation of HSF1 at Ser326 and total HSF1 protein, conversely using HSF1 overexpression model reversed this effect... In conclusion, JNK1/2 is involved in HSF1 inhibition-induced PDAC autophagy, targeting autophagy could unveil a novel treatment strategy for pancreatic cancer through targeted HSF1 inhibition."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • HSF1 • MAP1A • MAPK8

A novel GCN2 kinase activator demonstrates therapeutic efficacy in preclinical PDX models of human cholangiocarcinoma (AACR 2024) - "We are opening a Phase 1b clinical trial investigating the effects of NXP800 use in patients with advanced CCA. Future studies determining the cellular effect of GCN2 activation utilizing NXP800 are being conducted."

Preclinical • Tumor mutational burden • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Ovarian Cancer • Solid Tumor • ARID1A • ATF4 • ATM • EIF2A • EIF2S1 • FGFR1 • TMB

Using acquired resistance to explore the mechanism of action of the integrated stress response/GCN2 activator NXP800 - A new developmental agent for platinum-resistant ARID1A mutant ovarian cancer (AACR 2024) - P1 | "We have used acquired resistance to understand the MoA of NXP800 as a potent activator of GCN2 and the ISR pathway. Further studies are underway to determine the exact proximal molecular target of NXP800 and the mechanism of GCN2/ISR activation."

Platinum resistant • Preclinical • Oncology • Ovarian Cancer • Ovarian Clear Cell Cancer • Solid Tumor • ARID1A • ATF4 • EIF2A • EIF2B4 • EIF2S1 • HSF1

Modeling response prediction to a novel GCN2 kinase activator (NXP800) in patient-derived xenograft cholangiocarcinoma models using a multi-omics approach (AACR 2025) - "Multi-omics analysis revealed a sensitivity mechanism structured around EGFR signaling, providing insights into which patients should be selected for treatment with NXP800. A Phase 1b clinical trial investigating the effects of NXP800 use in patients with advanced CCA is open and currently accepting patients."

Clinical • Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor • ARID1A • ATF4 • ATM • BRAF • EIF2A • EIF2S1 • FGFR1

The Novel HSF1 Inhibitor NXP800 Exhibits Robust Antitumor Activity in Hepatocellular Carcinoma. (PubMed, Int J Mol Sci) - "Furthermore, NXP800 antitumor properties were significantly augmented when NXP800 was coupled with the DNA-damaging agent doxorubicin or the PARP inhibitor olaparib. Our investigation indicates that NXP800 has significant antitumor activity and might represent a promising therapeutic agent for the treatment of human HCC."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • E2F1 • HSF1

Activating GCN2 and subsequently the Unfolded Protein Response with the small oral molecule NXP800 delays tumor growth in osteosarcoma. (PubMed, Cell Death Discov) - "Finally, NXP800 delays tumor growth in preclinical OS model by promoting apoptosis. This study is a preclinical proof-of-principle of therapeutic efficacy of NXP800 both in vitro and in vivo, highlighting the relevance of targeting GCN2, and consequently activating the ISR and UPR, to induce apoptosis and inhibit tumor progression in OS."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • ATF4

Clinical candidate drug NXP800 inhibits HSF1 pathway and activates the Integrated Stress Response (ISR) via GCN2 in ARID1A mutant ovarian cancer (LCC 2026) - "In addition, previous studies suggest that actin depolymerization can lead to GCN2 activation. Further studies are underway to explore the potential link between alteration of actin dynamics and GCN2 activation in response to NXP800."

Clinical • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • ARID1A • HSF1

NXP800 for the Treatment of Patients With Advanced or Metastatic Cholangiocarcinoma (clinicaltrials.gov) - P1 | N=7 | Terminated | Sponsor: Mayo Clinic | Active, not recruiting ➔ Terminated | Trial primary completion date: May 2026 ➔ Aug 2025 | N=30 ➔ 7 | Trial completion date: May 2026 ➔ Sep 2025; study sponsor phasing out drug supply

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor

Advances in Prostate Cancer Treatment: Exploring Molecular Targets and New Strategies in Castration-Resistant Disease. (PubMed, Cureus) - "Key developments include next-generation AR pathway inhibitors, such as darolutamide, with improved safety profiles; PARP inhibitors for patients with DNA repair gene mutations; and PSMA-targeted radioligand therapy. The therapeutic landscape is also expanding to include novel targets such as the heat shock response, with HSF1 inhibitors like NXP800 in clinical trials for treatment-refractory disease. By targeting this molecular heterogeneity, ongoing research aims to deliver more effective, personalized treatments to improve survival and quality of life for men with advanced prostate cancer."

Journal • Review • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • HSF1

NXP800 for the Treatment of Patients With Advanced or Metastatic Cholangiocarcinoma (clinicaltrials.gov) - P1 | N=30 | Active, not recruiting | Sponsor: Mayo Clinic | Recruiting ➔ Active, not recruiting

Enrollment closed • Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor

NXP800-101: A Phase 1 Clinical Study of NXP800 in Subjects With Advanced Cancers and Expansion in Subjects With Ovarian Cancer (clinicaltrials.gov) - P1 | N=45 | Active, not recruiting | Sponsor: Nuvectis Pharma, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Platinum resistant • Clear Cell Carcinoma • Oncology • Ovarian Cancer • Solid Tumor • ARID1A • BRCA

A Phase 1 study of the novel GCN2 kinase activator NXP800 in patients with advanced cholangiocarcinoma. (PubMed, Future Oncol) - P1 | "www.clinicaltrials.gov identifier is NCT06420349."

Journal • P1 data • Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor

Nuvectis Pharma Provides Final Clinical Data Update from the NXP800 Phase 1b Study in Ovarian Cancer… (GlobeNewswire) - P1b | N=61 | NCT05226507 | Sponsor: Nuvectis Pharma, Inc. | "Available data from 13 patients with recurrent, platinum resistant, ARID1a-mutated ovarian cancer treated with 75 mg/day in the NXP800 Phase 1b study includes 2 partial responses and 3 stable diseases; thrombocytopenia successfully managed with intermittent dosing schedule; observed clinical activity warrants exploration of potential development opportunities in other cancer types....The company will not pursue further development of NXP800 in ovarian cancer but, in the coming months, will evaluate the feasibility of development opportunities for NXP800 in other cancer types, such as endometrial and prostate cancers, in which the patients’ performance status and other characteristics may allow treatment with NXP800 to be more impactful."

P1 data • Endometrial Cancer • Ovarian Cancer • Prostate Cancer

Nuvectis Pharma, Inc. Reports First Quarter 2025 Financial Results and Business Highlights (GlobeNewswire) - "On the NXP800 side, enrollment into the Phase 1b study in patients with platinum resistant, ARID1a mutated ovarian cancer continues, and we expect to provide an update from this study in a couple of months....We are excited about the upcoming months with NXP900 entering the Phase 1b portion of its clinical development and believe that with the recent financing we have working capital to take us through key clinical development milestones and into 2027.”"

Platinum resistant • Trial status • Endometrioid Carcinoma • Ovarian Cancer

Nuvectis Pharma, Inc. Reports 2024 Financial Results and Business Highlights (GlobeNewswire) - "NXP800 Phase 1b study in patients with platinum resistant, ARID1a-mutated ovarian cancer is ongoing...NXP900 Phase 1a dose escalation study continues to enroll, preparation for the start of the Phase 1b program is underway. Phase 1b program expected to begin in mid-2025....'Enrollment is ongoing in the Phase 1b clinical trial, in which patients with platinum resistant, ARID1a-mutated ovarian cancer are currently being treated with a dose of 75mg/day, on an intermittent dosing schedule. We intend to provide an update from this study in the second quarter and plan to provide the first data from the investigator-initiated study in cholangiocarcinoma later this year.'"

Enrollment status • New P1 trial • P1 data • Cholangiocarcinoma • Ovarian Cancer

Nuvectis Pharma Announces Pricing of $13.5 Million Public Offering of Common Stock (GlobeNewswire) - "Nuvectis intends to use the net proceeds from the offering to continue to advance the development programs of NXP800 and NXP900 or any future product candidate, hiring of additional personnel, capital expenditures, costs of operating as a public company and other general corporate purposes."

Commercial • Oncology

Nuvectis Pharma Announces Closing of $15.5 Million Public Offering of Common Stock and Full Exercise of Underwriter’s Over-Allotment Option (GlobeNewswire) - "Nuvectis intends to use the net proceeds from the offering to continue to advance the development programs of NXP800 and NXP900 or any future product candidate, hiring of additional personnel, capital expenditures, costs of operating as a public company and other general corporate purposes."

Commercial • Oncology

NXP800 Activates the Unfolded Protein Response, Altering AR and E2F Function to Impact Castration-Resistant Prostate Cancer Growth (Clin Cancer Res) - "We demonstrate the effects of targeting the HSF1 pathway, central to cellular stress, with an inhibitor in clinical development, namely, NXP800, in prostate cancer. Targeting the HSF1 pathway with the inhibitor NXP800 decreases HSP72 expression, activates the unfolded protein response, and inhibits AR- and E2F-mediated activity, inhibiting the growth of treatment-resistant prostate cancer models."

Preclinical • Castration-Resistant Prostate Cancer

NXP800 activates the unfolded protein response, altering AR and E2F function to impact castration-resistant prostate cancer growth. (PubMed, Clin Cancer Res) - "Overall, NXP800 has anti-tumor activity against treatment-resistant PCa models, including molecular subtypes with limited treatment options, supporting its consideration for PCa-specific clinical development."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • HSF1

New therapy hope for prostate cancer patients (PharmaTimes) - "The Institute of Cancer Research (ICR), London, found that the drug NXP800, currently in trials for ovarian and bile duct cancer, can slow prostate tumour growth and overcome hormone therapy resistance....ICR studied 439 advanced prostate cancer samples, finding higher levels of heat shock proteins linked to worse outcomes. In lab tests, NXP800 slowed growth in hormone therapy-resistant cells....Animal studies also showed promising results. In mice with resistant prostate cancers, NXP800 significantly slowed tumour growth. Without the drug, all tumours had doubled in size by 38 days; with NXP800, only 37.5% had."

Preclinical • Prostate Cancer

NXP800-101: A Phase 1 Clinical Study of NXP800 in Subjects with Advanced Cancers and Expansion in Subjects with Ovarian Cancer (clinicaltrials.gov) - P1 | N=61 | Recruiting | Sponsor: Nuvectis Pharma, Inc. | Trial completion date: Jun 2025 ➔ Dec 2025 | Trial primary completion date: Dec 2024 ➔ May 2025

Metastases • Trial completion date • Trial primary completion date • Oncology • Ovarian Cancer • Solid Tumor • ARID1A • BRCA