VHL

PRESS RELEASE Amphista Therapeutics announces new data demonstrating in vivo efficacy and CNS activity of its mechanistically differentiated targeted protein degraders First demonstration of efficacy in disease-relevant in vivo models for an orally delivered bifunctional non-cereblon / non-VHL-based protein degrader Deep degradation of target protein is achieved in a rapid, sustained, and highly selective manner Successful achievement of efficient CNS delivery for multiple degraders and demonstration of significant degradation of target protein in the brain Cambridge, UK, January 24th, 2024 – Amphista Therapeutics (“the Company” or “Amphista”), a leader in next generation targeted protein degradation (TPD) approaches, today announces the achievement of two compelling new data sets with its next generation bifunctional degraders demonstrating in vivo efficacy and the ability to target and degrade proteins in the central nervous system (CNS). Amphista’s degraders, which leverage a novel protein degrading mechanism, with advantages beyond first generation cereblon or VHL-based approaches, have demonstrated: Sustained degradation of target protein and anti-tumor efficacy: once daily oral dosing led to statistically significant reduction in tumor burden and survival advantage in multiple in vivo disease models.Rapid degradation of target protein: significant levels of degradation were induced rapidly after dosing.Highly selective degradation of target protein: statistically significant degradation of target protein vs >8000 other proteins, including closely related homologs, when dosed at 100x DC50. Amphista also discloses significant progress in the advancement of its technology for the treatment of neurodegenerative diseases, a key focus of the Company. These data show: Amphista degraders can be rationally designed to achieve CNS penetrance with examples achieved across multiple targets. Rapid degradation of target protein achieved in the brain in vivo (dog and non-human primate, and in multiple brain regions) when dosed intravenously. Louise Modis, Chief Scientific Officer of Amphista Therapeutics, said: “We are delighted by the progress we have made in advancing our pipeline and demonstrating the potential of our unique TPD technology. To our knowledge, this is the first time an orally delivered bifunctional non-cereblon / non-VHL-based protein degrader has shown efficacy in disease-relevant in vivo models. Combined with our progress in demonstrating in vivo degradation of targets within the CNS, we are extremely excited to have achieved these key preclinical development milestones and we look forward to providing additional updates across our pipeline throughout the year.” Beverley Carr, Interim Chief Executive Officer of Amphista Therapeutics, said: “The last six months have been transformative for Amphista and these new compelling in vivo data strengthen our belief that our technology has the potential to deliver differentiated protein degrader molecules with class-leading physicochemical properties, enabling us to target a wider tissue and indication scope than traditional protein degrader approaches. These data are testament to the strength of our scientific team and we are on track with our portfolio priorities, exploring the tremendous potential of our platform across multiple indications in CNS and oncology.” About Amphista Therapeutics Amphista Therapeutics is focused on transforming the lives of patients with severe diseases including cancer. The company is applying its proprietary Amphista degrader platform to advance new approaches in targeted protein degradation (TPD). They aim to address the challenges faced by earlier stage TPD research and to realise the full therapeutic potential of this transformational approach. Founded by Advent Life Sciences, Amphista is a spin-out of TPD expert Professor Alessio Ciulli’s laboratories at the University of Dundee. The Company has raised over $60M to date and is funded by leading life science investors including Forbion, Gilde Healthcare, Novartis Venture Fund, Advent Life Sciences, Eli Lilly & Company and The Dementia Discovery Fund. For more information, please visit: www.amphista.com Amphista and the Amphista logo are all trademarks of Amphista Therapeutics Limited. For more information please contact: Amphista Therapeutics Beverley Carr, Interim CEO info@amphista.com ICR Consilium Amber Fennell, Namrata Taak Email: Amphista@consilium-comms.com Tel: +44 (0)20 3709 5813

ALAMEDA, Calif. and HAYWARD, Calif.--( BUSINESS WIRE )-- Exelixis, Inc. (Nasdaq:EXEL) and Arcus Biosciences (NYSE:RCUS) today announced that the companies have entered into a clinical trial collaboration for STELLAR-009, a phase 1b/2 trial evaluating zanzalintinib, Exelixis’ next-generation tyrosine kinase inhibitor (TKI), in combination with AB521, an inhibitor of the transcription factor HIF-2⍺, in patients with advanced solid tumors, including clear cell renal cell carcinoma (ccRCC). Exelixis is sponsoring STELLAR-009, and Arcus is co-funding the study and providing AB521 for use in the trial. Patient enrollment for STELLAR-009 is expected to begin before the end of 2023. “ We are excited to learn more about the potential effects of zanzalintinib plus Arcus’ HIF-2⍺ inhibitor, as these two molecules approach the inhibition of cancer cell proliferation and tumor angiogenesis from differing angles, and combination therapy may provide better outcomes than either therapy alone,” said Amy Peterson, M.D., Executive Vice President, Product Development & Medical Affairs, and Chief Medical Officer, Exelixis. “ We have a long-established commitment to advancing treatment options in kidney cancer, and we are eager to maximize the potential of zanzalintinib through this collaboration with Arcus and look forward to advancing the combination in the clinic.” “ We are excited to partner with Exelixis on the STELLAR-009 study to determine the best-in-class potential of AB521 in combination with zanzalintinib and look forward to generating a robust set of data to move this combination into full development,” said Dimitry S.A. Nuyten, M.D., Ph.D., Chief Medical Officer of Arcus Biosciences. “ The STELLAR-009 study is an important step in the development of AB521 and enables a cost-effective path to evaluating our HIF-2⍺ inhibitor with a next-generation TKI.” The dose-finding stage of this open-label study will determine a recommended dose for zanzalintinib in combination with AB521 in patients with advanced solid tumors and in patients with advanced ccRCC. Expansion cohorts will further evaluate the tolerability and activity of this combination in ccRCC as well as investigate the contribution of components, supported by activity data generated from monotherapy studies in ccRCC patients, to support full development. More information about this trial will be available soon on ClinicalTrials.gov. About Zanzalintinib Zanzalintinib is a next-generation oral TKI that inhibits the activity of receptor tyrosine kinases implicated in cancer growth and spread, including VEGF receptors, MET, AXL and MER. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis and resistance to multiple therapies, including immune checkpoint inhibitors (ICIs). With zanzalintinib, Exelixis sought to build upon its extensive experience with the target profile of cabozantinib, the company’s flagship medicine, while improving key characteristics, including pharmacokinetic half-life. Zanzalintinib is currently being developed for the treatment of advanced solid tumors, including genitourinary, colorectal and head and neck cancers. About AB521 AB521 is a small molecule inhibitor of HIF-2⍺, a transcription factor involved in oxygen sensing in multiple organs as well as in tumors. Clear cell RCC is almost universally associated with HIF-2⍺ dysregulation as a result of genetic abnormalities in the VHL pathway. This creates a situation of pseudohypoxia and the abnormal increase in HIF-2⍺-mediated expression of a wide array of proteins involved in cancer cell proliferation and survival, treatment resistance and angiogenesis. Arcus is currently evaluating AB521 in ARC-20, a phase 1/1b study in cancer patients. Enrollment for the dose-expansion stage in ccRCC patients is complete for the target dose of 100 mg, and efficacy data from this stage are expected in 2024. In the dose-escalation stage up to 100 mg, as of December 1, 2023, pharmacokinetic and pharmacodynamic data were consistent with the data generated in healthy volunteers, and no dose-limiting toxicities were observed. AB521 has the potential to achieve substantially greater HIF-2⍺ inhibition than the approved dose of the marketed competitor. About RCC Kidney cancer is among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S. 1 An estimated 81,800 Americans will be diagnosed with kidney cancer in 2023. 1 Clear cell RCC is the most common type of kidney cancer in adults. 2 If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 15%. 3 In 2022, approximately 32,200 patients with advanced kidney cancer required systemic therapy in the U.S., with over 20,000 patients receiving first-line treatment. 4 About Exelixis Exelixis is a globally ambitious oncology company innovating next-generation medicines and regimens at the forefront of cancer care. Powered by bi-coastal centers of discovery and development excellence, we are rapidly evolving our product portfolio to target an expanding range of tumor types and indications with our clinically differentiated pipeline of small molecules, antibody-drug conjugates and other biotherapeutics. This comprehensive approach harnesses decades of robust investment in our science and partnerships to advance our investigational programs and extend the impact of our flagship commercial product, CABOMETYX® (cabozantinib). Exelixis is driven by a bold scientific pursuit to create transformational treatments that give more patients hope for the future. For information about the company and its mission to help cancer patients recover stronger and live longer, visit www.exelixis.com , follow @ExelixisInc on X (Twitter), like Exelixis, Inc. on Facebook and follow Exelixis on LinkedIn. About Arcus Biosciences Arcus Biosciences is a clinical-stage, global biopharmaceutical company developing differentiated molecules and combination medicines for people with cancer. In partnership with industry partners, patients and physicians around the world, Arcus is expediting the development of first- or best-in-class medicines against well-characterized biological targets and pathways and studying novel, biology-driven combinations that have the potential to help people with cancer live longer. Founded in 2015, the company has expedited the development of multiple investigational medicines into clinical studies, including new combination approaches that target TIGIT, PD-1, the adenosine axis (CD73 and dual A2a/A2b receptor), HIF-2a, CD39 and AXL. For more information about Arcus Biosciences’ clinical and preclinical programs, please visit www.arcusbio.com or follow us on X. Exelixis Forward-Looking Statements This press release contains forward-looking statements, including, without limitation, statements related to: the therapeutic potential of zanzalintinib in combination with AB521 to improve outcomes for patients with advanced solid tumors, including ccRCC, and for the combination to provide better outcomes than either therapy alone; Exelixis’ expectation that patient enrollment for STELLAR-009 will begin before the end of 2023; Exelixis’ plans to continue studying the therapeutic potential of zanzalintinib in kidney cancer, as well as in other advanced solid tumors; and Exelixis’ scientific pursuit to create transformational treatments that give more patients hope for the future. Any statements that refer to expectations, projections or other characterizations of future events or circumstances are forward-looking statements and are based upon Exelixis’ current plans, assumptions, beliefs, expectations, estimates and projections. Forward-looking statements involve risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in the forward-looking statements as a result of these risks and uncertainties, which include, without limitation: complexities and the unpredictability of the regulatory review and approval processes in the U.S. and elsewhere; Exelixis’ and Arcus Biosciences’ continuing compliance with applicable legal and regulatory requirements; the potential failure of zanzalintinib in combination with AB521 to demonstrate safety and/or efficacy in STELLAR-009 and in future clinical testing; uncertainties inherent in the product development process, including evolving regulatory requirements, slower than anticipated patient enrollment or inability to identify a sufficient number of clinical trial sites; the costs of conducting clinical trials, including the ability or willingness of Exelixis’ clinical collaboration partners to invest in the resources necessary to complete the trials; Exelixis’ dependence on third-party vendors for the development, manufacture and supply of zanzalintinib; Exelixis’ ability to protect its intellectual property rights; market competition; changes in economic and business conditions; and other factors affecting Exelixis and its development programs detailed from time to time under the caption “Risk Factors” in Exelixis’ most recent Annual Report on Form 10-K and subsequent Quarterly Reports on Form 10-Q, and in Exelixis’ future filings with the Securities and Exchange Commission. All forward-looking statements in this press release are based on information available to Exelixis as of the date of this press release, and Exelixis undertakes no obligation to update or revise any forward-looking statements contained herein, except as required by law. Arcus Forward-Looking Statements This press release contains forward-looking statements. All statements regarding events or results to occur in the future contained herein are forward-looking statements reflecting the current beliefs and expectations of management made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, the timing for enrollment of the study, the potential of AB521 plus zanzalintinib and the enablement of future development plans for AB521. All forward-looking statements involve known and unknown risks and uncertainties and other important factors that may cause Arcus’s actual results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Factors that could cause or contribute to such differences include, but are not limited to: difficulties or delays in initiating or conducting clinical trials due to difficulties or delays in the regulatory process, enrolling subjects or manufacturing or supplying product for such clinical trials; the emergence of adverse events or other undesirable side effects; the applicability of data resulting from the study described herein to later trials; difficulties associated with the management of the collaboration activities or expanded clinical programs; changes in the competitive landscape for Arcus’s programs; and the inherent uncertainty associated with pharmaceutical product development and clinical trials. Risks and uncertainties facing Arcus are described more fully in the “Risk Factors” section of Arcus’s most recent Quarterly Report on Form 10Q filed with the U.S. Securities and Exchange Commission. You are cautioned not to place undue reliance on the forward-looking statements, which speak only as of the date of this press release. Arcus disclaims any obligation or undertaking to update, supplement or revise any forward-looking statements contained in this press release except to the extent required by law. Exelixis, the Exelixis logo and CABOMETYX are registered U.S. trademarks of Exelixis. ____________________ 1 Key Statistics About Kidney Cancer. American Cancer Society website. Available at: https://www.cancer.org/cancer/kidney-cancer/about/key-statistics.html . Accessed December 2023. 2 What Is Kidney Cancer? American Cancer Society website. Available at https://www.cancer.org/cancer/kidney-cancer/about/what-is-kidney-cancer.html . Accessed December 2023. 3 Survival Rates for Kidney Cancer. American Cancer Society website. Available at https://www.cancer.org/cancer/kidney-cancer/detection-diagnosis-staging/survival-rates.html . Accessed December 2023. 4 Citeline’s Datamonitor Healthcare: Renal Cell Carcinoma. September 2023 (internal data on file).

Marcin Klapczynski/Getty Images Immunotherapy, or immuno-oncology, is ushering in hopes of more effective, gentler cancer care, in which the patient’s own body is programmed to destroy cancerous cells. In honor of World Cancer Research Day, Sept. 24, BioSpace spoke with leaders from Elevation Oncology, Janssen, Merck and Teclison to learn more about the latest innovations. Elevation Targets NRG1 Fusions Elevation Oncology is leveraging genomic research for true oncogenic driver alterations with a druggable pathway in the treatment of solid tumors. Shawn Leland, founder and CEO, explained his company’s approach with lead asset seribantumab, an IgG2 monoclonal antibody designed to stop the human epidermal growth factor receptor 3 (HER3) signaling that sustains tumors harboring Neuregulin 1 (NRG1) gene fusions. “These gene fusions are embedded within the cell surface,” Leland said. “They signal by secreting NRG1, which is the primary pathway for HER3, and then obviously the ER-HR3 monoclonal antibody. So, it has the ability to block NRG1 binding to HER3.” This starts a chain reaction that can prevent tumor growth. “It allows us to knock down downstream signaling through the…MAP kinase pathway which in NRG1 fusions leads to tumor growth and proliferation,” Leland said. In May, Elevation reported positive proof-of-concept data from the Phase II CRESTONE study evaluating seribantumab in patients with advanced solid tumors with NRG1 gene fusions. The study showed a 33% overall response rate across solid tumors and a 36% ORR among the cohort of non-small cell lung cancer patients, Leland said. Better still, seribantumab demonstrated a “92% disease control rate, with every patient seeing tumor shrinkage except for one patient,” he added. Long-term, “We would love to build an industry-leading precision oncology company at Elevation,” Leland said. Janssen vs. Multiple Myeloma Mark Wildgust, Ph.D., vice president of global medical affairs, oncology at Janssen, said the company has made hopeful leaps forward in the battle against multiple myeloma. With the development of two new therapeutic programs, Janssen could soon specifically target and destroy myeloma cells alone. Both teclistamab, a BCMAxCD3 bispecific antibody and talquetamab, an off-the-shelf T cell redirecting bispecific antibody, work by identifying malignant antigens in plasma cells. In clinical tests, both have shown the ability to identify B-cell maturation antigens (BCMAs), on the surface of T cells. “This means we’re able to bring the T cell right to the proximity of myeloma cells that express BCMA, resulting in T cell activation and then subsequently the killing of those myeloma cells,” Wildgust said. Janssen is excited about the company’s positive results in targeting the lineage target antigen GPRC5D, Wildgust added. This antigen also expresses itself on the surface of T cells and is a telltale indicator of the presence of myeloma. “In preclinical studies, we've seen really effective killing of myeloma cells that express GPRC5D,” he shared. “We're also seeing really encouraging data, even to the point that FDA has now granted talquetamab breakthrough [therapy] designation as well.” Janssen received conditional marketing authorization in Europe for teclistamab in relapsed or refractory multiple myeloma in August. “We're now seeing response rates of 60% or more in this in this refractory setting. On top of that, I think we're also seeing really good progression-free survival rates as well. I think in the future it’s going to become a really important clinical option for patients," Wildgust said. Merck’s Work with VHL Pathways With more than 20 novel mechanisms, Merck’s pipeline has the potential to serve up multiple breakthrough cancer treatments. Some of these products could bring a sea change from traditional chemotherapy treatments to less toxic immunotherapy treatments. Eric Rubin, senior vice president, clinical oncology, said Merck took care to observe diverse mechanisms in the lab, making note of any activity on compounds. “This led to observing both immune targeted treatments as well as non-immune, and we let the science lead us as to what to pursue,” Rubin said. Specifically, Rubin said Merck’s research on the dysregulation of von Hippel-Lindau (VHL) pathways, which ultimately led to a Nobel Prize for the company, helped uncover new treatments for certain kidney cancers. From there, Merck was able to develop treatments for other VHL-associated cancers. “That’s why following the science, understanding how cancer is caused, can lead to very effective treatments that are not classical chemotherapy-based treatments,” Rubin said. Rubin shared that Merck is excited about Anti-TIGIT therapy vibostolimab, which has been shown to improve upon the efficacy of blockbuster Keytruda, an immunotherapy that blocks certain cancers from using the PD-1 pathway. The combination is currently being assessed in combination with concurrent chemoradiotherapy vs. concurrent chemoradiotherapy with durvalumab in patients with Stage III NSCLC. “I think as the field moved to where we had a better understanding of what drives cancer, it enabled us to try to pick agents that were more specific for the cancer and maybe less toxic,” Rubin said. Teclison’s TATE Therapy Teclison’s platform for targeting cancer is, so far, one of a kind. The New Jersey-based company is working on a compound which induces necrosis in solid tumors and activates the body’s immune system in the process. Ray Lee, M.D., Ph.D., founder and CEO, explained how the compound has a unique mechanism called a hypoxia-activating agent. “In order to do this, we actually create a so-called ‘synthetic lethality,” he said. “By depriving the tumor of oxygen, a hypoxic reaction (oxygen deprivation) sets in and the tumor begins to necrotize. Once that happens, this also triggers the body to send macrophage dendritic cells to destroy the necrotized cancer cells." Teclison published a peer-reviewed study in June demonstrating the safety, tolerability and preliminary efficacy of its trans-arterial tirapazamine chemoembolization (TATE) therapy. The TATE therapy and lead therapeutic agent, TEC-001, are being studied in combination with FDA-approved immune checkpoint inhibitors in Phase II for the treatment of liver, colorectal and lung cancer. “It works in a kind of synergistic way,” Lee continued. “One is the synergy between our compound and then the procedure embolization. The second synergy involves converting the tumor into a therapeutic vaccine so that we'll be able to enhance immunotherapy.” Lee is hopeful the approach will someday help revolutionize cancer treatment. “I really don't see that chemotherapy is the answer for (treatment),” he said. “We’re hoping what works is an immune checkpoint inhibitor. That’s why we're hoping we can use our strategy to enhance immune checkpoint inhibitors in the future.”