EP2

Tumors actively prevent the formation of immune responses by so-called cytotoxic T cells, which are essential in combating cancer. Researchers have now uncovered for the first time how this exactly happens. The study provides rationales for new cancer immunotherapies and could make existing treatments more effective. Tumors actively prevent the formation of immune responses by so-called cytotoxic T cells, which are essential in combating cancer. Researchers at the Technical University of Munich (TUM) and the Ludwig-Maximilians-Universität München (LMU) Hospital have now uncovered for the first time how this exactly happens. The study in the journal Nature provides rationales for new cancer immunotherapies and could make existing treatments more effective. A second paper in Nature confirms the findings. In cancer, tumors often impair the body's immune response. For example, they can prevent immune cells from perceiving cancer cells as a threat or render them inactive. Immunotherapies aim to overcome these mechanisms and stimulate the immune system, in particular the T cells. However, such therapies do not work for a large number of cancer patients. Researchers around the world are looking for the causes and new counter-strategies. Messenger substance stops effector development of T cells in tumors A team led by Dr. Jan Böttcher, research group leader at the Institute of Molecular Immunology at TUM, and Prof. Sebastian Kobold, Deputy Director of the Department of Clinical Pharmacology at LMU Klinikum München, has now discovered that tumors use a messenger substance to influence immune cells in an early phase of the immune response. Many cancer cells show increased secretion of the messenger substance prostaglandin E2. The researchers were able to show that prostaglandin E2 binds to EP2 and EP4, two receptors on the surface of certain immune cells. These so-called stem-like T cells migrate from other areas of the body into the tumor. If the immune response is successful, they multiply in the tumor and develop into cytotoxic T cells that attack the cancer. "This whole process is strongly limited when tumors secrete prostaglandin E2 and this factor binds to EP2 and EP4 receptors," says Jan Böttcher. "The T cell response collapses and the tumor can progress." If the researchers prevented the interaction of messenger substance and receptor in tumor models, the immune system was able to fight tumors effectively. Current therapies address a later point of the immune response "We have discovered a mechanism that influences the body's immune response in a crucial phase," says Jan Böttcher. "Many tumors prevent the stem-like T cells from generating cytotoxic T cells in the tumor that could attack the cancer." Current immunotherapies aim to prevent the cancer from switching off immune responses at a later phase. Checkpoint inhibitor therapies, for example, aim to release the blockade of fully differentiated cytotoxic T cells and "switch them back on." Before the dreaded T cell exhaustion sets in, which other researchers are trying to prevent, differentiated T cells must also be present. Increase the effectiveness of existing therapies "Current treatment approaches would probably be more effective if the effects of prostaglandin E2 on stem-like T cells is blocked to enable their unhindered differentiation within tumor tissue," says Sebastian Kobold. This similarly applies to recent approaches that rely on the protein IL-2 to stimulate T cells. The current study shows that as soon as the prostaglandin E2 binds to the two receptors, T cells can no longer respond to IL-2. "We suspect that even the body's own IL-2 signals may be sufficient to enable T cells to successfully fight cancer once the effects of prostaglandin E2 have been stopped," says Sebastian Kobold. Second study in "Nature" confirms results A second research publication in Nature investigates the effects of prostaglandin E2 on the immune system. For this study, the authors, researchers from the University Hospital of Lausanne, collaborated with the Munich team. In their laboratory, they among other things examined T cells from human tumor tissue. When they blocked the release of prostaglandin E2 in cancer tissue, the T cells showed better expansion and were thus able to fight human cancer cells more effectively. Search for counter-strategies begins "We now have a concrete starting point for significantly improving immunotherapies," says Jan Böttcher. "Researchers around the world must now develop strategies to overcome the tumors' defense. We need to stop the effects of prostaglandin E2 -- either by preventing tumors from producing the molecule or by making immune cells resistant to it."

Announced positive randomized first-line HCC data showing superiority of TPST-1120 combination therapy across multiple study endpoints compared to standard of careReported new biomarker data in two important subpopulations, PD-L1 negative and b-catenin mutant patients, consistent with MoA of TPST-1120Preparing to move TPST-1120 into a pivotal Phase 3 trial in HCC and TPST-1495 into a Phase 2 in FAP BRISBANE, Calif., March 19, 2024 (GLOBE NEWSWIRE) -- Tempest Therapeutics, Inc. (Nasdaq: TPST), a clinical-stage biotechnology company developing first-in-classi targeted and immune-mediated therapeutics to fight cancer, today reported financial results for the year ended 2023 and provided a corporate update. “2023 was a transformative year for Tempest. We announced strong positive randomized data showing the benefit of TPST-1120 combination therapy compared to standard-of-care in first-line liver cancer,” said Stephen Brady, president and chief executive officer of Tempest. “These data also showed the predicted positive effect of TPST-1120 in two subpopulations that are common in liver cancer, i.e., patients with PD-L1 negative and cold tumors, as well as patients with a b-catenin mutation, and we believe set up the program for a pivotal Phase 3 trial. We look forward to 2024 as the year Tempest evolves towards becoming a late-stage clinical organization.” 2023 Accomplishments TPST-1120 (clinical PPARα antagonist): Reported positive interim data in April 2023 from the ongoing randomized Phase 1b/2 clinical study evaluating TPST-1120 in combination with the standard-of-care regimen of atezolizumab and bevacizumab in previously untreated patients with advanced unresectable or metastatic hepatocellular carcinoma (“HCC”), compared to patients treated with the standard of care regimen alone. The data demonstrated clinically meaningful improvement in multiple categories and signaled the potential superiority of the TPST-1120 arm in the primary analysis planned for later in the year.Reported updated positive data from the ongoing randomized study in October 2023 demonstrating clinical superiority of TPST-1120, when combined with atezolizumab and bevacizumab, as compared to the standard-of-care regimen, across multiple study endpoints in first-line HCC. Data from 40 patients randomized to the TPST-1120 arm and 30 patients randomized to the control arm, with a median follow-up of 9.2 and 9.9 months, respectively, showed: Confirmed objective response rate (“cORR” or “confirmed ORR”) of 30% for the TPST-1120 triplet arm (an increase from 17% in the earlier interim analysis), as compared to 13.3% for the atezolizumab + bevacizumab control arm; duration of response (“DoR”) not yet reached.Hazard ratio favors the TPST-1120 arm for key survival endpoints Progression free survival (“PFS”): median PFS of 7 mo (5.6 mo, 13.8 mo) for TPST-1120 arm versus 4.27 mo (2.8 mo, 7.3 mo) for the control arm; HR of 0.7 favors TPST-1120 arm and is not yet matureOverall survival (“OS”): median OS not reached for the TPST-1120 arm (10.84 mo, NE) versus 15.1 mo (7.49 mo, NE) for the control arm; HR 0.59 favors TPST-1120 arm and is not yet mature 40% of the patients in the TPST-1120 arm were on treatment (16/40) compared to 16.7% in the atezolizumab + bevacizumab control arm (5/30)72.5% of the patients on the TPST-1120 arm were on study (29/40), compared to 46.7% on the atezolizumab + bevacizumab control arm (14/30)TPST-1120 remains well tolerated, with safety data comparable between the two arms Presented new translational biomarker findings at the 2023 American Association for Cancer Research (AACR) Annual Meeting from the completed monotherapy and nivolumab combination therapy dose escalation Phase 1 trial in patients with advanced solid tumors, which showed on-target changes in gene signatures in the peripheral blood that were dependent upon drug exposure levels. In addition, distinct on-target changes in both lipid profile and NF-κB pathway regulated immune response gene signatures were observed in patients who achieved a RECIST response, compared with non-responders, following treatment with TPST-1120 and nivolumab.Presented data at the Society for Immunotherapy of Cancer (SITC) 2023 Spring Scientific Meeting highlighting biomarker data from the Phase 1 trial showing an association between observed clinical benefit of TPST-1120 and fatty acid oxidation perturbations and gene expression.TPST-1495 (clinical dual EP2/4 prostaglandin receptor antagonist) Presented Phase 1 clinical trial data at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting showing that in a diverse and treatment-refractory patient population, treatment with TPST-1495 as a monotherapy and in combination with pembrolizumab resulted in tumor shrinkage and prolonged stable disease in certain patients, as well as a durable confirmed partial response in a combination therapy patient with microsatellite stable colorectal cancer, an indication not normally responsive to immunotherapy.Announced publication in Cancer Research Communications of data highlighting the increased potency of TPST-1495 against prostaglandin-driven tumor models by blocking EP2 and EP4 together.Continued enrollment of an endometrial cancer-specific arm investigating the two highest doses of TPST-1495 in combination with pembrolizumab. Potential Future Milestones TPST-1120 (clinical PPARα antagonist) Expect to announce updated data from the ongoing randomized study in first-line liver cancer patients in 2024.Plan to advance TPST-1120 into a registrational study in first-line liver cancer patients, subject to obtaining feedback from the FDA. TPST-1495 (clinical dual EP2/4 prostaglandin receptor antagonist) Plan to advance TPST-1495 into a Phase 2 study in patients with Familial Adenomatous Polyposis (“FAP”) under the auspices of the Cancer Prevention Clinical Trials Network and funded by the National Cancer Institute (“NCI”) Division of Cancer Prevention in 2024, subject to final approval of NCI.Expect to report data from the combination arm at the two highest TPST-1495 doses in patients with advanced endometrial cancer in 2024. Financial Results Year End 2023 Tempest ended the year with $39.2 million in cash and cash equivalents, compared to $31.2 million on December 31, 2022. The increase was primarily due to proceeds from the issuance of common stock of $35.6 million from the at-the-market offering program, offset by cash used in operating activities.Net loss and net loss per share for the year were $29.5 million and $1.91, respectively, compared to $35.7 million and $3.09, respectively, for the same period in 2022.Research and development expenses for the year were $17.5 million compared to $22.5 million for the same period in 2022. The $5.0 million decrease was primarily due to a decrease in costs incurred from contract research organizations and third-party vendors.General and administrative expenses for the year were $11.7 million compared to $12.1 million for the same period in 2022. The $0.4 million decrease was primarily due to a decrease in consulting and professional services.Based on current cash and operating plan, Tempest expected to have sufficient resources to fund operations into the second quarter of 2025. About Tempest Therapeutics Tempest Therapeutics is a clinical-stage biotechnology company advancing a diverse portfolio of small molecule product candidates containing tumor-targeted and/or immune-mediated mechanisms with the potential to treat a wide range of tumors. The company’s novel programs range from early research to later-stage investigation in a randomized global study in first-line cancer patients. Tempest is headquartered in Brisbane, California. More information about Tempest can be found on the company’s website at www.tempesttx.com. Forward-Looking Statements This press release contains forward-looking statements (including within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended, and Section 27A of the Securities Act of 1933, as amended (the “Securities Act”)) concerning Tempest Therapeutics, Inc. These statements may discuss goals, intentions, and expectations as to future plans, trends, events, results of operations or financial condition, or otherwise, based on current beliefs of the management of Tempest Therapeutics, as well as assumptions made by, and information currently available to, management of Tempest Therapeutics. Forward-looking statements generally include statements that are predictive in nature and depend upon or refer to future events or conditions, and include words such as “may,” “will,” “should,” “would,” “could”, “expect,” “anticipate,” “plan,” “likely,” “believe,” “estimate,” “project,” “intend,” and other similar expressions. All statements that are not historical facts are forward-looking statements, including any statements regarding: the design, initiation, progress, timing, scope and results of clinical trials; anticipated therapeutic benefit and regulatory development of the Company’s product candidates; the Company’s ability to deliver on potential value-creating milestones; the Company’s ability to advance into a late-stage clinical company; and the Company’s ability to achieve its operational plans. Forward-looking statements are based on information available to Tempest Therapeutics as of the date hereof and are not guarantees of future performance. Any factors may cause differences between current expectations and actual results, including: unexpected safety or efficacy data observed during preclinical or clinical trials; clinical trial site activation or enrollment rates that are lower than expected; changes in expected or existing competition; changes in the regulatory environment; and unexpected litigation or other disputes. Other factors that may cause actual results to differ from those expressed or implied are discussed in greater detail in the “Risk Factors” section of the Company’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2023 and other documents filed by the Company from time to time with the Securities and Exchange Commission. Except as required by applicable law, Tempest Therapeutics undertakes no obligation to revise or update any forward-looking statement, or to make any other forward-looking statements, whether as a result of new information, future events or otherwise. These forward-looking statements should not be relied upon as representing Tempest Therapeutics’ views as of any date subsequent to the date of this press release and should not be relied upon as prediction of future events. In light of the foregoing, investors are urged not to rely on any forward-looking statement in reaching any conclusion or making any investment decision about any securities of Tempest Therapeutics. TEMPEST THERAPEUTICS, INC. Consolidated Balance Sheets (in thousands) December 31, 2023 December 31, 2022 Assets Current assets Cash and cash equivalents$39,230 $31,230 Insurance recovery of legal settlement - 450 Prepaid expenses and other current assets 1,133 1,270 Total current assets 40,363 32,950 Property and equipment, net 840 1,060 Operating lease right-of-use assets 9,952 11,650 Other noncurrent assets 448 429 Total assets$51,603 $46,089 Liabilities and Stockholders' Equity Current liabilities Accounts payable$845 $1,108 Accrued legal settlement - 450 Accrued expenses and other 1,673 2,961 Current loan payable, net 4,285 - Current operating lease liabilities 952 1,413 Accrued compensation 1,543 1,248 Interest payable 113 97 Total current liabilities 9,411 7,277 Loan payable, net 6,264 10,371 Operating lease liabilities 9,160 10,330 Total liabilities 24,835 27,978 Stockholders' equity Common stock 22 11 Additional paid-in capital 192,009 153,872 Accumulated deficit (165,263) (135,772)Total stockholders' equity 26,768 18,111 Total liabilities and stockholders' equity$51,603 $46,089 TEMPEST THERAPEUTICS, INC. Consolidated Statements of Operations (in thousands, except per share amounts) Year ended Year ended December 31, 2023 December 31, 2022 Expenses: Research and development$17,498 $22,527 General and administrative 11,659 12,113 Operating loss (29,157) (34,640) Other income (expense), net: Interest expense (1,449) (1,618)Interest and other income, net 1,115 549 Net loss$(29,491) $(35,709)Net loss per share$(1.91) $(3.09) Investor Contacts: Sylvia WheelerWheelhouse Life Science Advisorsswheeler@wheelhouselsa.com Aljanae Reynolds Wheelhouse Life Science Advisorsareynolds@wheelhouselsa.com i If approved by the FDA

New data package reveals improvements in multiple categories for TPST-1120 combined with atezolizumab + bevacizumab versus standard of care atezolizumab + bevacizumab in a global Phase 1b/2 study 30% confirmed ORR achieved in TPST-1120 arm compared to 13.3% for atezolizumab + bevacizumab in the control arm, a substantial increase specific to the TPST-1120 arm compared to the previous data cut of 17.5% versus 10.3% in the control arm Results show a favorable PFS and OS hazard ratio for TPST-1120 arm versus atezolizumab + bevacizumab control arm Biomarker data for the TPST-1120 arm demonstrate: increased confirmed ORR of 43% and DCR of 100% in subpopulation of patients with a beta catenin mutation; and consistent confirmed ORR of 27% in PD-L1 negative patients, as compared to 7% in the atezolizumab + bevacizumab control arm 40% of patients on the TPST-1120 arm remain on treatment, as compared to 16.7% for atezolizumab + bevacizumab control arm Tempest Therapeutics, Inc. (Nasdaq: TPST), a clinical-stage oncology company developing first-in-class1 therapeutics that combine both targeted and immune-mediated mechanisms, today announced new and updated positive results from the planned data analysis of an ongoing global randomized Phase 1b/2 clinical study in which TPST-1120, Tempest’s PPAR⍺ antagonist, shows clinical superiority in multiple study endpoints when combined with atezolizumab and bevacizumab in a randomized comparison to atezolizumab and bevacizumab in the first-line treatment of patients with unresectable or metastatic hepatocellular carcinoma (“HCC”). “This comprehensive analysis of more mature clinical data shows an even greater benefit than the earlier interim analysis of the TPST-1120 triplet therapy over standard of care alone, both for the entire study population and in subpopulations of patients, the latter of which was predicted by TPST-1120’s proposed mechanism of action,” said Stephen Brady, president and chief executive officer of Tempest. “First-line HCC remains an indication with substantial opportunity to improve patient outcomes and, based upon these data, we are excited about the opportunity to move TPST-1120 into a pivotal study. Given these new data and the Phase 1 evidence of activity beyond HCC, we look forward to advancing discussions with potential partners who share our vision for TPST-1120.” These new data were provided by F. Hoffman La-Roche (“Roche”) from a clinical collaboration pursuant to which Roche managed the study operations for this multicenter trial. Tempest retains all product rights to TPST-1120. Data from 40 patients randomized to the TPST-1120 arm and 30 patients randomized to the control arm, with a median follow-up of 9.2 and 9.9 months, respectively, show: Confirmed objective response rate (“cORR” or “confirmed ORR”) of 30% for the TPST-1120 triplet arm versus 13.3% for the atezolizumab + bevacizumab control arm; duration of response (“DoR”) has not yet been reached Hazard ratio (“HR”) favors the TPST-1120 arm for key survival endpoints Progression free survival (“PFS”): median PFS of 7 mo (5.6 mo, 13.8 mo) for TPST-1120 arm versus 4.27 mo (2.8 mo, 7.3 mo) for the control arm; HR of 0.7 favors TPST-1120 arm and is not yet mature Overall survival (“OS”): median OS not reached for the TPST-1120 arm (10.84 mo, NE) versus 15.1 mo (7.49 mo, NE) for the control arm; HR 0.59 favors TPST-1120 arm and is not yet mature New biomarker subpopulation findings are consistent with the mechanism of action of TPST-1120 Patients with b-catenin activating mutations (21% in this study (n=7)) showed a cORR of 43% and a disease control rate (“DCR”) of 100% in the TPST-1120 arm Distinct from the control arm, the TPST-1120 arm was consistently active across both PD-L1 positive and PD-L1 negative tumors, with a cORR of 27% in the TPST-1120 arm compared to 7% for the control arm in PD-L1 negative tumors 40% of the patients in the TPST-1120 arm were on treatment (16/40) compared to 16.7% in the atezolizumab + bevacizumab control arm (5/30) 72.5% of the patients on the TPST-1120 arm were on study (29/40), compared to 46.7% on the atezolizumab + bevacizumab control arm (14/30) TPST-1120 remains well tolerated, with safety data comparable between the two arms The randomized arms were generally well balanced at baseline Secondary endpoints include DoR, PFS, and OS, which are not fully mature as of the data cut. In Roche’s IMbrave150 Phase 3 trial, confirmed ORR benefit correlated with overall survival (OS) benefit.2 Enrollment began in fall of 2021 and the cutoff date for these data was April 20, 2023. Tempest expects the data set to be jointly presented by Roche and Tempest at a medical meeting at a later date. ORR was determined by RECIST v1.1, and confirmed responses included at least two scans. Conference Call & Webcast Information Tempest will host a webcast conference call today, October 11, 2023 at 8:30am ET. To join the conference call via phone and participate in the live Q&A session, please pre-register online here to receive a telephone number and unique passcode required to enter the call. The live webcast and audio archive of the presentation may be accessed on the investor section of the Tempest website at https://ir.tempesttx.com/. The webcast will be available for replay for 30 days. About the Randomized Clinical Trial The Phase 1b/2 global randomized HCC study is part of Roche’s Morpheus program and evaluates TPST-1120 in combination with atezolizumab and bevacizumab versus atezolizumab and bevacizumab, the standard of care, in patients with unresectable or metastatic HCC not previously treated with systemic therapy. The trial enrolled 70 patients to the TPST-1120 arm and contemporaneous control arm at approximately 25 sites worldwide, including in the United States, Europe, and Asia, who received either the TPST-1120 combination or atezolizumab and bevacizumab with primary efficacy endpoint of objective response rate, and key secondary endpoints including PFS and OS. Under the terms of the clinical collaboration agreement, Roche is managing the study operations for this global, multicenter trial and Tempest retains all product rights. About TPST-1120 TPST-1120 is an oral, small molecule, selective PPAR⍺ antagonist wholly-owned by Tempest. Tempest’s data suggest that TPST-1120 treats cancer by targeting tumor cell metabolism directly, as well as by modulating immune suppressive cells and angiogenesis in the tumor microenvironment. In a Phase 1 clinical trial in patients with heavily-pretreated advanced solid tumors, TPST-1120 as monotherapy and in combination with the PD-1 inhibitor nivolumab demonstrated tumor reduction (including according to RECIST criteria), as well as biomarker modulation. TPST-1120 was well-tolerated both as a monotherapy and in combination with nivolumab. About Hepatocellular Carcinoma HCC is an aggressive cancer with rising mortality and is projected to become the third leading cause of cancer death by 2030.3 Every year, more than 900,000 people worldwide are diagnosed with HCC.4 Incidence and mortality are highest in East Asia and are increasing in parts of Europe and the US.5 In the US, HCC represents the fastest-rising cause of cancer-related death.3 Nine out of ten cases of HCC are caused by chronic liver disease, which includes chronic hepatitis B and C infection, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcohol-related liver disease (ALD) and cirrhosis resulting from these conditions.6 Even if diagnosed in the early stage, an estimated 70-80% of people with early-stage HCC experience disease recurrence following surgery.7 Early recurrence is associated with poorer prognosis and shorter survival.5,8 Tumor size, number of tumors, and portal vein invasion are associated with an increased risk of recurrence.6 About Tempest Therapeutics Tempest Therapeutics is a clinical-stage oncology company advancing small molecules that combine both tumor-targeted and immune-mediated mechanisms with the potential to treat a wide range of tumors. The company has a diverse portfolio of novel programs ranging from early research to investigation in a randomized global study in first-line cancer patients. The company’s two novel clinical programs, TPST-1120 and TPST-1495, target PPARα and EP2/EP4, respectively, and are advancing through trials designed to study the agents as monotherapies and in combination with approved agents. Tempest is also developing an orally available inhibitor of TREX1, a target that controls activation of the cGAS/STING pathway. Tempest is headquartered in Brisbane, California. More information about Tempest can be found on the company’s website at www.tempesttx.com. 1 If approved by the FDA 2 Ducreux, et. al., Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021) 3 Rahib, L. et al. Projecting cancer incidence and deaths to 2030: the undexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 74, 2913-2921 (2014). 4 World Health Organization. Liver Cancer Factsheet. Globocan. 2020. Available at: https://gco.iarc.fr/today/data/factsheets/cancers/11-Liver-fact-sheet.pdf. Last accessed: April 2023. 5 Llovet, J. M., Kelley, R. K., Villanueva, A., et al. Hepatocellular carcinoma. Nature Reviews Disease Primers. 2021, 7(1), 6. 6 Office for Health Improvement & Disparities. Liver disease profiles: November 2021 update. Available at: https://www.gov.uk/government/statistics/liver-disease-profiles-november-2021-update/liver-disease-profiles-november-2021-update. Last accessed: April 2023. 7 Hack SP, Spahn J, Chen M et al. IMbrave 050: a Phase III trial of atezolizumab plus bevacizumab in high-risk hepatocellular carcinoma after curative resection or ablation. Future Oncology. 2020 May;16(15):975-989. 8 Saito A, Toyoda H, Kobayashi M et al. Prediction of early recurrence of hepatocellular carcinoma after resection using digital pathology images assessed by machine learning. Modern Pathology. 2021. 34, 417-425. 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