GAPDH

Misetionamide showed broad antineoplastic activity in 15 different cancer types including multiple human cancer cell lines with no detrimental effect on normal cells Misetionamide reduces energy metabolism by inhibiting aerobic glycolysis BERWYN, PA, Feb. 01, 2024 (GLOBE NEWSWIRE) -- Panavance Therapeutics Inc. (“Panavance” or the “Company”), a clinical-stage pharmaceutical company advancing the development of a novel oncology therapeutic intended to improve the outcomes and quality of life for patients, today announced publication of positive data in the peer-reviewed Anti-Cancer Drugs in an article titled, “Antineoplastic Activity of GP-2250 In Vitro and in Mouse Xenograft Models.”1 The publication by Sofia et al. (2024) provided early research evidence that misetionamide exhibits a dose-dependent antineoplastic effect on both established cancer cell lines and xenograft models from patient tissues.2 Antineoplastic activity was tested in over 300 cancer cell lines using the OncoPanel® cytotoxicity assay and was further tested in eight human cancer xenograft models. Results included a reduction of 30-40% of tumor volume in xenograft mouse models treated with misetionamide and demonstrated a reduction in the progression of tumor cell volume in multiple cancer cell lines including pancreatic and ovarian cancer suggesting a strong antineoplastic effect. Most notably in the ovarian tumor xenograft model, misetionamide produced a regression in the original tumor volume. Concentrations for IC50 and EC50 were determined as was the concentration at which a 10-fold increase in apoptosis was induced. All these concentrations have subsequently been shown to be clinically achievable in an on-going Phase 1 clinical trial. In addition, misetionamide was also shown to induce a cancer cell cycle block that would inhibit tumor cells from replicating and thus inhibiting tumor growth. The results of these studies also reinforce the results of other studies demonstrating strong synergism with other anticancer agents, including gemcitabine, bevacizumab, and PARP inhibitors. To that end, the results support the development of misetionamide as a promising new therapeutic agent with a unique mechanism of action for human cancers. “While this paper details the early screening work in 300 human cancer lines using in vitro studies as well as 8 in vivo studies to determine if misetionamide showed any antineoplastic activity, and, if so, in which cancer cells, we were pleased that the results showed both the very broad activity in many cancer cell lines and that normal cells were not detrimentally affected, said R. Duane Sofia, PhD, Head Nonclinical Research, Panavance Therapeutics. “The results from these studies demonstrate that misetionamide has a broad mechanism of action which could be impactful in treating most cancers. While our initial focus is on pancreatic and ovarian cancers, these studies further support the potential to pursue other cancer indications with misetionamide in the future,” said Greg Bosch, Chairman and CEO. About Misetionamide (GP-2250) Misetionamide is a tumor cell selective drug that is broadly active in multiple cancer models with a unique mechanism of action that suppresses cancer by disrupting its energy metabolism, leading to cancer cell death while not affecting normal cells. This activity occurs due to misetionamide’s targeting at least 3 key enzymes in the aerobic glycolysis pathway as well as downstream effects on other enzymes, transcription factors and tumor suppressor genes. Misetionamide’s inhibition of hexokinases, GAPDH (glyceraldehyde 3-phosphate dehydrogenase), and PVD (pyruvate dehydrogenase) during aerobic glycolysis greatly inhibits ATP production for cancer cells, setting up oxidative, metabolic, and hypoxic stresses within the cancer cell. Additionally, misetionamide’s inhibition of key transcription factors such as NFkB and enzymes further impair the ability for the cancer cell to provide sufficient energy for cellular reproduction for proliferation and survival. It also induces tissue hypoxia by inhibiting new blood vessel development in tumors.3 About Panavance Therapeutics Panavance Therapeutics Inc. is a privately held, clinical-stage pharmaceutical company developing a novel oncology asset, GP-2250 (also known as misetionamide). Panavance was formed in 2021 as a US-based, wholly owned carve out of Geistlich group, a family-owned Swiss company, to focus on GP-2250 and the oncology business. GP-2250 is a tumor cell selective and broadly active small molecule with a unique dual mechanism of action of selectively disrupting the energy metabolism of cancer cells leading to cancer cell death as well as impacting nuclear factor-κB (“NFκB”) which effects cancer cells’ ability for protein synthesis and DNA transcription thereby restricting cancer cell growth and proliferation. The Company is advancing towards the initiation of two registration directed clinical studies expected: a Phase 2/3 study of GP-2250 for the treatment of platinum resistant ovarian cancer and a pivotal Phase 3 clinical trial as a first-line maintenance therapy for non-BRCA mutated pancreatic cancer patients. Extensive preclinical studies have demonstrated that GP-2250’s broadly anti-neoplastic MOA has the potential to be effective in additional indications, including for example melanoma, squamous cell, breast, and colorectal cancers. For more information, please visit panavance.com and connect with the Company on Twitter, LinkedIn, and Facebook. ________________________________________ 1Sofia, R. Duane; Martin, Kathryn M.b; Costin, James C.c. Antineoplastic activity of GP-2250 in-vitro and in mouse xenograft models. Anti-Cancer Drugs 35(2):p 183-189, February 2024. | DOI: 10.1097/CAD.0000000000001550 2Buchholz, M; Majchrzak-Stiller, B; Hahn, S.; Vangala, D; Pfirrmann, RW; Uhi, W; et al. Innovative substance 2250 as a highly promising anti-neoplastic agent in malignant pancreatic carcinoma – in vitro and in vivo. MGC Cancer 2017; 17:216. 3Majchrzak-Stiller, B.; Buchholz, M.; Peters, I.; Waschestjuk, D.; Strotmann, J.; Höhn, P.; Hahn, S.; Braumann, C.; Uhl, W.; Müller, T.; et al. GP-2250, a novel anticancer agent, inhibits the energy metabolism, activates AMP-Kinase and impairs the NF-kB pathway in pancreatic cancer cells. J. Cell. Mol. Med. 2023, 27, 2082–2092. Corporate and Investor Relations Contact Lisa DeScenza LaVoieHealthScience (978) 395-5970 ldescenza@lavoiehealthsceince.com Media Contact Sara Krane LaVoieHealthScience (617) 865-2197 skrane@lavoiehealthscience.com

Misetionamide is effective in targeting and killing BRAF-mutated melanoma cells while preserving normal cellsBRAF-mutated melanoma accounts for approximately 50% of all melanomas BERWYN, PA, Nov. 21, 2023 (GLOBE NEWSWIRE) -- Panavance Therapeutics Inc. (“Panavance” or the “Company”), a clinical-stage pharmaceutical company advancing the development of a novel oncology therapeutic intended to improve the outcomes and quality of life for patients, today announced publication of positive data in the peer-reviewed International Journal of Molecular Sciences in a manuscript titled, “In Vitro Experiments on the Effects of GP-2250 on BRAF-Mutated Melanoma Cell Lines and Benign Melanocytes.”1 The publication by Gambichler, et al. (2023) details the anti-tumor activity of the GAPDH inhibitor misetionamide (GP-2250) in BRAF-mutated melanoma cell lines and benign melanocytes. Mutated BRAF is a potent oncogene involved in sending signals inside cells which are involved in directing cell growth and is overexpressed in melanomas, non-small cell lung cancer, and other tumor types. Misetionamide is a tumor cell selective drug that is broadly active in multiple cancer models with a unique mechanism of action that suppresses cancer by disrupting its energy metabolism, leading to cancer cell death while not affecting normal cells. This activity occurs due to misetionamide’s targeting at least 3 key enzymes in the aerobic glycolysis pathway as well as downstream effects on other enzymes, transcription factors and tumor suppressor genes. Misetionamide’s inhibition of hexokinases, GAPDH (glyceraldehyde 3-phosphate dehydrogenase), and PVD (pyruvate dehydrogenase) during aerobic glycolysis greatly inhibits ATP production for cancer cells, setting up oxidative, metabolic and hypoxic stresses within the cancer cell. Additionally, misetionamide’s inhibition of key transcription factors such as NFkB and enzymes further impair the ability for the cancer cell to provide sufficient energy for cellular reproduction for proliferation and survival. It also induces tissue hypoxia by inhibiting new blood vessel development in tumors.2 This study demonstrated that misetionamide may be a promising add-on therapy in BRAF-mutated melanomas, which account for approximately 50% of all melanomas. “Given the anti-tumor activity observed in misetionamide as recently published from our studies in Merkel cell carcinoma cells as well as in cutaneous squamous cell carcinoma cell lines, I was eager to study the impact in BRAF-melanoma due to its GAPDH inhibition. The results demonstrated that misetionamide is able to downregulate the gene and protein expression of aberrant tumorigenic pathways in melanoma cell lines and could represent a promising therapy for tumors such as melanoma,” said Prof. Thilo Gambichler, former Head of the Skin Cancer Center of the Ruhr-University Bochum. This research was conducted at Skin Cancer Center Ruhr-University, Department of Dermatology, Venereology and Allergology, Ruhr-University Bochum, Germany with support from the Company. Results of this preclinical study showed misetionamide has anti-neoplastic effects in BRAF-mutated melanoma cell lines regarding tumor cell viability, proliferation, and apoptosis/necrosis. These findings also extend the mechanism of action activity of misetionamide to include STAT, COX2, and NOTCH 1,2, and 3 in melanoma cells in addition to the known effects on GAPDH, Hexokinases, NFkB, and others. The team studied three melanoma cell lines and one primary melanocyte cell line (Ma-Mel-61a, Ma-Mel-86a, SH-4, and ATCC-PCS-200-013, respectively) which were exposed to different misetionamide doses. All three melanoma cell lines (Ma-Mel-62a, Ma-Mel-86a, SH-4) showed a dose-dependent response to misetionamide during BrDU testing and the MTT viability assays, whereas proliferation as well as viability were drastically reduced by a misetionamide concentration of 500 μmol/L. “We are very excited to see the cancer cell killing benefits of misetionamide demonstrated in this study. These results further broaden the mechanism of action into yet another potential oncology target in BRAF-mutated melanoma. The high incidence of BRAF-mutated melanoma of approximately 50% indicates that it could be an attractive therapeutic target in addition to the company’s current focus on pancreatic and ovarian cancers,” said Greg Bosch, Chairman and CEO. About Panavance TherapeuticsPanavance Therapeutics Inc. is a privately held, clinical-stage pharmaceutical company developing a novel oncology asset, GP-2250 (also known as misetionamide). Panavance was formed in 2021 as a US-based, wholly-owned carve out of Geistlich group, a family owned Swiss company, to focus on GP-2250 and the oncology business. GP-2250 is a tumor cell selective and broadly active small molecule with a unique dual mechanism of action of selectively disrupting the energy metabolism of cancer cells leading to cancer cell death as well as impacting nuclear factor-κB (“NFκB”) which effects cancer cells’ ability for protein synthesis and DNA transcription thereby restricting cancer cell growth and proliferation. The Company is advancing towards the initiation of two registration directed clinical studies expected: a Phase 2/3 study of GP-2250 for the treatment of platinum resistant ovarian cancer and a pivotal Phase 3 clinical trial as a first-line maintenance therapy for non-BRCA mutated pancreatic cancer patients. Extensive preclinical studies have demonstrated that GP-2250’s broadly anti-neoplastic MOA has the potential to be effective in additional indications, including melanoma, squamous cell, breast, and colorectal cancers. For more information, please visit panavance.com and connect with the Company on Twitter, LinkedIn, and Facebook. Corporate and Investor Relations Contact Lisa DeScenzaLaVoieHealthScience(978) 395-5970ldescenza@lavoiehealthsceince.com Media ContactSara KraneLaVoieHealthScience(617) 865-2197skrane@lavoiehealthscience.com ________________________________________1Gambichler, Thilo & Harnischfeger, Friederike & Skrygan, Marina & Majchrzak-Stiller, Britta & Buchholz, Marie & Müller, Thomas & Braumann, Chris. (2023). In Vitro Experiments on the Effects of GP-2250 on BRAF-Mutated Melanoma Cell Lines and Benign Melanocytes. International Journal of Molecular Sciences. 24. 15336. 10.3390/ijms242015336. 2Majchrzak-Stiller, B.; Buchholz, M.; Peters, I.; Waschestjuk, D.; Strotmann, J.; Höhn, P.; Hahn, S.; Braumann, C.; Uhl, W.; Müller, T.; et al. GP-2250, a novel anticancer agent, inhibits the energy metabolism, activates AMP-Kinase and impairs the NF-kB pathway in pancreatic cancer cells. J. Cell. Mol. Med. 2023, 27, 2082–2092.

Results showed antineoplastic activity in pancreatic tumor cell lines Metabolic and transcriptional findings demonstrate a molecular basisto reduce tumor cell proliferation and induce apoptotic cell death Phase 1 study underway for the treatment of pancreatic cancer on track to potentially advance directly into a Phase 2/3 clinical trial in 2024 BERWYN, PA, Sept. 12, 2023 (GLOBE NEWSWIRE) -- Panavance Therapeutics Inc. (“Panavance” or the “Company”), a clinical-stage pharmaceutical company advancing the development of a novel oncology therapeutic intended to improve the outcomes and quality of life for patients, today announced publication of positive data in the peer-reviewed Journal of Cellular and Molecular Medicine in a manuscript titled, “GP-2250, a novel anticancer agent, inhibits the energy metabolism, activates AMP-Kinase and impairs the NF-kB pathway in pancreatic cancer cells1.” The publication by Majchrzak-Stiller, et al. (2023) details the multiple sites of action of GP-2250 in the disruption of energy production of cancer cells and the downregulation of tumor promoting transcription factors. GP-2250 is a highly selective yet broadly active cancer therapeutic with a unique mechanism of action that suppresses cancer by disrupting its energy metabolism, leading to cancer cell death through several validated mechanisms. Cancer cells depend on aerobic glycolysis to generate energy (ATP). The inhibition of the key enzymes (hexokinases and GAPDH) in aerobic glycolysis by GP-2250 reduces the ATP that cancer cells require, and this induces oxidative, metabolic, and hypoxic stresses in the cancer cells. Normal cells are not affected since they can depend on the much efficient production of ATP through oxidative phosphorylation as well, which cancer cells have lost. In addition, critical enzymes and transcription factors downstream from these initial enzymes’ inhibitions cause multiple deleterious effects on cancer cells, including growth suppression, inhibition of proliferation, and cell death by apoptosis. A key tumor promotor, the transcription factor NF-kB, is inhibited directly by GP-2250, which causes a reduction in the rate of cancer cell growth and proliferation and apoptosis induction. GP-2250 is currently being studied in a Phase 1 clinical trial for pancreatic cancer. “This publication represents an important milestone for the development of GP-2250. Our team is impressed by these key findings which further support the anticancer activity of GP-2250 because of disruption of energy metabolism and inhibition of tumor promotion by NF-κB. Importantly, these data bolster our understanding of the mechanism of action and deepen our confidence in its potential ability to improve the effectiveness of cancer treatments and quality of life for patients,” said Greg Bosch, Chairman and CEO. This research was conducted at St. Josef-Hospital, Ruhr-University Bochum, Germany with support from the Company. The team studied the hypothesis that GP-2250 induces an energy deficit, which was tested by measuring the level of ATP in two human pancreatic cancer cell lines BxPC314 (ATCC—LGC Standards GmbH) and Panc TuI (ATCC—LGC Standards GmbH). Results of the preclinical study showed that at the lowest dose of GP-2250 tested (250 μM), a significant decrease in ATP was apparent at 6 hours in both pancreatic cancer cell lines. The decrease in ATP preceded the loss of cell viability. A further decrease in ATP was apparent at the same time point with 500 μM of GP-2250 in both cell lines. These findings of a drug-induced deficit of ATP show an inhibition of energy metabolism by GP-2250. Similarly, the transcription factor NF-κB was inhibited at the same early time point of 6 hours in both cell lines demonstrating the impact of GP-2250 on downregulating tumor promoting genes. “As GP-2250 has shown antineoplastic activity in pancreatic cancers (both ductal and neuroendocrine tumors) as well as in other tumor cell lines, we expected GP-2250 to target a common feature of cancer cells such as aerobic glycolysis, a hallmark of cancer metabolism. We are pleased with the results GP-2250 demonstrated, and the metabolic and transcriptional findings provide molecular targets for GP-2250. We look forward to further evaluating GP-2250 and its potential as an important treatment for a broad range of cancers,” added Prof. Dr. med. Chris Braumann, Chief of General, Visceral & Vascular Surgery, University of Duisburg-Essen, Germany; Head of Molecular and Clinical Research at Ruhr-University of Bochum, Germany; and Scientific Advisor to Panavance. About Panavance Therapeutics Panavance Therapeutics Inc. is a privately-held, clinical-stage pharmaceutical company developing a novel oncology platform focused on improving the outcomes and quality of life for cancer patients. Panavance, a US Delaware company, is located in Berwyn, PA. It was founded in 2021 and is a subsidiary of Swiss privately held Ed. Geistlich Söhne AG für Chemische Industrie. Panavance’s lead program, misetionamide (also known as GP-2250), is a tumor cell selective and broadly active small molecule with a unique dual mechanism of action of selectively disrupting the energy metabolism of cancer cells leading to cancer cell death as well as impacting nuclear factor-κB (“NFκB”) which effects cancer cells’ ability for protein synthesis and DNA transcription thereby restricting cancer cell growth and proliferation. The Company is advancing towards the initiation of two registration directed clinical studies expected to start in 2024: a Phase 2/3 study of GP-2250 for the treatment of ovarian cancer and a pivotal Phase 3 clinical trial as a first-line maintenance therapy for non-BRCA mutated pancreatic cancer patients, a population for which there are no FDA approved agents. GP-2250’s unique mechanism of action and extensive preclinical data supports broad oncology utility with the potential to be effective in additional indications, including melanoma, squamous cell, breast and colorectal cancers. For more information, please visit panavance.com and connect with the Company on Twitter and LinkedIn. Corporate and Investor Relations Contact Lisa DeScenza LaVoieHealthScience (978) 395-5970 ldescenza@lavoiehealthsceince.com Media Contact Nick Hennen LaVoieHealthScience (929) 462-9479 nick@lavoiehealthscience.com 1 Majchrzak-Stiller, B, Buchholz, M, Peters, I, et al. GP-2250, a novel anticancer agent, inhibits the energy metabolism, activates AMP-Kinase and impairs the NF-kB pathway in pancreatic cancer cells. J Cell Mol Med. 2023; 00: 1- 11. doi:10.1111/jcmm.17825