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Tempest is a clinical-stage oncology company focused on leveraging its deep scientific understanding of cancer biology and medicinal chemistry to
develop and advance novel, orally available therapies for the treatment of solid tumors. Tempest s philosophy is to build a company based upon not only creative science and thoughtful management, but also upon the efficient translation of those
ideas into therapies that will improve patient s lives. To this end, Tempest is advancing TPST-1495 and TPST-1120, two product candidates in clinical trials that it believes are the first clinical-stage molecules designed to treat their
respective targets; and a third program in preclinical studies that could be the first to target TREX-1, a key cellular enzyme that regulates the innate immune response in tumors. TPST-1495 is a dual
antagonist of EP2 and EP4, receptors of prostaglandin E2, and is currently in a Phase 1 trial in solid tumors. Tempest s second program, TPST-1120, is a selective antagonist of peroxisome proliferator-activated receptor alpha, or PPAR ,
and is also in a Phase 1 trial in solid tumors. Tempest expects to report initial data from both these programs in the first half of 2022. Additionally, Tempest is advancing a third program targeting the three prime repair exonuclease, or TREX-1, for which Tempest expects to select a development candidate in the first half of 2022. Beyond these three ongoing programs, Tempest plans to leverage its drug development and company-building experience,
along with academic relationships, to identify promising new targets that may feed new programs into Tempest s pipeline.
Tempest has developed a diversified pipeline of small molecule product candidates that Tempest believes are innovative and target scientifically
validated pathways. These product candidates are designed to target tumor cells directly, modulate the immune system to kill cancer cells, or a combination of both. Tempest selected targets that are expressed in a diverse set of tumor types, with
the intention to address unmet medical needs or improve existing standards of care. Tempest s product development programs consist of the following:
HCC: hepatocellular carcinoma; RCC: renal cell carcinoma; CCA: cholangiocarcinoma; CRC: colorectal cancer; FPI: First Patient In; RP2D: Recommended Phase 2
Dose; DC: Development Candidate; ORR: Objective Response Rate. Note that the primary anti-tumor activity readout is ORR by RECIST v. 1.1 criteria, and time on study treatment; additional endpoints include duration of response and progression free
survival, which may be reported at a later timepoint.
Tempest s Program Summaries
Tempest s first product candidate is TPST-1495, a novel, oral, small molecule designed to be a dual antagonist of only two of the four prostaglandin E2
(PGE2) receptors, EP2 and EP4, sparing the homologous but differentially active EP1 and EP3 receptors. To our knowledge, TPST-1495 is the first dual EP2/EP4 PGE2 receptor antagonist in the clinic. PGE2 is well understood from the
scientific literature to be an important stimulator of tumor growth in diverse cancer types of high need, and to be inhibitory to anti-tumor immune function in the tumor microenvironment. PGE2 signaling through EP2 and EP4 has been observed both to
enhance tumor progression and promote immune suppression. Tempest conducted head-to-head preclinical studies comparing TPST-1495 to single antagonists of EP4 being
developed by other companies. In these studies, Tempest observed significantly enhanced activity of TPST-1495 in both overcoming PGE2-mediated suppression of human immune cells in vitro as well as significantly increased anti-tumor activity in mouse
models of human colorectal cancer, as compared to single antagonists of EP4. Tempest is currently evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and possible anti-tumor activity of TPST-1495 in a multicenter Phase
1a/1b dose and schedule optimization study in subjects with advanced solid tumors, with a focus on prostaglandin-driven tumor types, such as colorectal cancer, or CRC. Tempest is observing dose-proportional exposure, and Tempest is encouraged by
early signs of activity of TPST-1495 monotherapy, as shown by on-target pharmacodynamic changes, disease control, and reduction of tumor-specific biomarkers in the ongoing dose optimization clinical study. The
TPST-1495 Phase 1 clinical trial is ongoing in the schedule and dose optimization stage and Tempest expects to establish the RP2D for expansion and the preliminary safety profile and ORR in first half of 2022. Tempest also expects to initiate
monotherapy combination studies with an anti-PD-1/L1 immune check point inhibitor, prior to the end of 2021.
Tempest s second product candidate is TPST-1120, an oral, small molecule designed to be a selective antagonist of PPAR and is the first PPAR
antagonist in the clinic. PPAR is a key transcription factor controlling fatty acid oxidation, or FAO. It is clear from the scientific literature that FAO can serve as a source of energy for tumor cell growth and that the PPAR
transcriptome is upregulated in many tumor types. It also is published that FAO is a preferred energy source for so-called immune suppressor cells such as regulatory
T-cells (Treg), myeloid derived suppressor cells, or MDSCs, and M2 macrophages. Tempest s preclinical data suggest that TPST-1120 can directly kill tumor cells that are dependent upon FAO, alter the tumor
microenvironment immune cell infiltrate away from a suppressor immune phenotype, and synergize with immune checkpoint inhibitor therapy in animal models. Tempest is evaluating TPST-1120 in a Phase 1a/b clinical study that has both monotherapy and
combination therapy arms in patients with advanced solid tumors that Tempest s PPAR -dependent transcriptome analysis of diverse human cancers revealed favor the usage of FAO. Tempest has been observing dose-dependent exposure and on-target pharmacodynamic changes in both monotherapy and combination TPST-1120 therapy arms. The monotherapy dose escalation phase of the clinical study has been completed, and Tempest observed clinical benefit in
10 of 20 of patients enrolled in this arm in the form of disease stabilization. Three patients with advanced cholangiocarcinoma experienced prolonged stable disease ( 21 weeks) and some reduction of tumor
burden, although not to the extent of a RECIST response. In the TPST-1120 combination arm with nivolumab, Tempest observed a deep and durable RECIST response in a patient with 4th line kidney
cancer that had previously failed to respond to, and then progressed on, the combination immune-oncology, or IO, regimen of nivolumab with ipilimumab. This patient experienced a rapid tumor reduction to -54%
by RECIST criteria on TPST-1120 + nivolumab at the first on-treatment assessment at eight weeks, which has subsequently deepened to -61% after six months of treatment and is ongoing. Tempest is encouraged by
this response as a signal of synergy between TPST-1120 and anti-PD-1 therapy in IO-resistant disease. In March 2021, Tempest
announced a clinical collaboration with Hoffman-La Roche Ltd., or Roche, to accelerate the development of TPST-1120 into a frontline, randomized study. Pursuant to the terms of Tempest s collaboration,
Roche will evaluate TPST-1120 in a global randomized phase 1b/2 clinical study in combination with the standard-of-care first-line regimen of atezolizumab and
bevacizumab in patients with advanced or metastatic hepatocellular carcinoma, or HCC, not previously treated with systemic therapy. The study will include at least 40 and up to 60 patients who will receive the TPST-1120 combination and will be
compared to the standard-of-care atezolizumab and bevacizumab regimen with primary objectives of anti-tumor activity and safety. Under the terms of the collaboration
agreement, Roche will manage the study operations for this global multicenter trial. Tempest will retain global development and commercialization rights to TPST-1120. Tempest expects the first patient in the frontline HCC study to be enrolled in mid-2021, and for ORR results of the TPST-1120 Phase 1a/1b dose finding trials to be available by early 2022.
Tempest has a third program in its pipeline against TREX-1, a target
Tempest believes may be an effective approach to modulate STING, which stands for STimulator of INterferon Genes, with a systemic therapy. The STING pathway is the focus of clinical and
pre-clinical programs at multiple pharmaceutical and biotechnology companies. TREX-1 is a double-stranded DNA exonuclease that controls activation of the cGAS/STING
pathway, which is an innate immune response pathway that induces the production of IFN- , a cytokine that is well-established to be a key factor in triggering the development of anti-tumor immunity. The
expression of TREX-1 is enhanced in tumors and inhibits activation of cGAS/STING to evade immune recognition. Because STING is expressed ubiquitously, but TREX-1
expression is increased in tumors, Tempest believes that TREX-1 may be the optimal approach to target STING with an orally available small molecule inhibitor to selectively activate this pathway in tumors.
Tempest has demonstrated proof of concept of this approach in a mouse tumor model with a TREX-1 inhibitor tool compound and expects to select a TREX-1 inhibitor
development candidate for IND-enabling studies in the first half of 2022.
Our Internal Discovery Capability
Tempest built an internal discovery team at Tempest to create and advance small-molecule product candidates with the ideal pharmacological
properties to target the tumor micro-environment and/or leverage the immune system. This discovery capability has enabled what Tempest believes is the rapid and efficient generation of a broad pipeline of innovative, orally available therapies, that
if approved by the FDA, will be first-in-class. Tempest s small molecule product candidates target pathways that have been validated in the scientific literature to
play key roles in promoting tumor growth and suppressing anti-tumor immunity across a diverse set of cancers.
Tempest leveraged its deep scientific
knowledge, long-term established relationships with key opinion leaders, and extensive medicinal chemistry and drug development expertise to develop its current portfolio. Dr. Peppi Prasit, a Tempest founder, serves a continuing role in the
design of Tempest s small molecule therapeutics. Dr. Prasit (see also under Scientific Advisors) has direct involvement in both Tempest s medicinal chemistry activities and synthetic chemistry activities conducted by contract research
organizations. Dr. Prasit has played a pivotal role in the discovery of multiple marketed drugs, including Vioxx and Arcoxia
while at Merck Frosst, and led the medicinal chemistry of several drugs still under clinical development. Tempest believes that the expertise that Dr. Prasit imparts on the development of its small molecule drugs is a differentiating factor of
the potential activity of its product candidates. Tempest designs its molecules to have the ideal pharmacological properties for the targeted pathway and the desired clinical effect. Small-molecule drugs against the same biological target can be
highly differentiated from each other based on their respective pharmacokinetic, pharmacodynamic and biophysical properties. For example, many small-molecule drugs are potent when tested in buffer solution but lose a significant amount of potency in
physiologically relevant media, such as blood or tumor tissue. Tempest rigorously tests its molecules in whole blood or other physiologically relevant systems and only advances molecules that retain a high degree of activity when tested under such
real world conditions.
For instance, the Tempest team leveraged Dr. Prasit s scientific insights gained from developing approved
prostaglandin signaling pathway targeted drugs, together with the published literature, to hypothesize that optimal anti-tumor inhibition and immune activation might result from blocking both EP2 and EP4 receptor signaling pathways. Tempest designed
TPST-1495 to be a first-in-class dual selective inhibitor of prostaglandin receptors EP2 and EP4 based on this scientific hypothesis. Tempest established the scientific
rationale for developing TPST-1120 after discussions with several academic investigators, including Dr. David Spaner, MD, PhD (Sunnybrook Research Institute, Toronto), who found that patients with selected advanced cancers had comparatively
elevated levels of long-chain fatty acid amides in peripheral blood that were reduced after responding to approved therapies. These findings, along with the published literature demonstrating the role of lipid metabolism on metastasis, angiogenesis
and immune evasion, led Tempest to establish an internal program to develop selective antagonists of PPAR , a transcription factor that regulates lipid metabolism. This pathway is known to be druggable, with the decades-long clinical use of
fenofibrates, a class of small molecule PPAR agonists, in patients with dyslipidemia. In addition, several members of the team at Tempest developed the
first-in-human small molecule STING agonists at a prior company. The Tempest president, Dr. Tom Dubensky, is recognized as a thought leader in drugging the STING
pathway. The insights and experience of the Tempest team, together with the rapidly expanding scientific understanding of the role of innate immunity in developing effective tumor-specific immunity, led Tempest to the scientific hypothesis that the
optimal approach to localize activation of the STING pathway to the tumor microenvironment in metastatic disease with an orally available small molecule is through a specific inhibitor of TREX-1, a dsDNA
exonuclease known to have elevated expression in tumors. The Tempest team is actively considering other innovative oncology targets that it believes have strong scientific rationale and would address specific unmet medical needs.
The Tempest senior management team, comprised of Steve Brady, CEO, Tom Dubensky, PhD, President, and Sam
Whiting, MD, PhD, CMO, possess extensive experience gained over many years in both private and public biotechnology companies in the selection of new targets, discovery of molecules to modulate pathways of interest, and the evolution of program
candidates through the full range of clinical development. The team also has substantial financing and strategic transaction experience, including private and public equity and debt financings, product and licensing collaborations, and both private
and public M&A. Tempest believes the collective and diverse experience of the team, along with Tempest s view that a company should be run in accordance with a foundational set of guiding principles, positions the company for success in
developing therapies to benefit patients living with cancer. While Tempest believes that its experienced management team represents an important competitive advantage, the historical results, past performance and/or acquisition of companies with
which members of its management team have been affiliated do not necessarily predict or guarantee similar results for its company.
clinical advisors includes thought leaders in oncology, immunology and clinical development, including: Toni K. Choueiri, MD, Director, Lank Center for Genitourinary Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute and Co-Leader, Kidney Cancer Program, Dana-Farber/Harvard Cancer Center; Drew M. Pardoll, MD, PhD, Abeloff Professor of Oncology, Director, Bloomberg Kimmel Institute for Cancer Immunotherapy, Director, Cancer
Immunology Program, Johns Hopkins University School of Medicine; Jason Luke, MD, FACP, Associate Professor of Medicine, Hematology/Oncology, and Director of the Cancer Immunotherapeutics Center within the UPMC Hillman Cancer Immunology and
Immunotherapy Program; Raymond N. Dubois, MD, PhD, Dean of the College of Medicine at the Medical University of South Carolina; Peppi Prasit, PhD, CEO Emeritus Inception Sciences; Russell Vance, PhD, Professor and HHMI Investigator, University of
California, Berkeley; and, Benjamin F. Cravatt, PhD, Professor and Gilula Chair of Chemical Biology, Department of Chemistry, The Scripps Research Institute. Tempest additionally has extensive established relationships with key opinion leaders, or
KOLs, with whom Tempest has sponsored research agreements and/or frequently consult to both gain insights on Tempest s existing pipeline and clinical development strategy and to discuss potential new target opportunities.
As of July 9, 2021, Tempest had 15 employees, including nine holding Ph.D., M.D., JD, LL.M., and/or MBA degrees, and have established internal expertise
in chemistry, biochemistry, molecular biology, immunology, pharmacology, toxicology, pre-clinical development, regulatory and quality, translational medicine, and early-to-late-stage clinical development, as well as finance, business development and strategic transactions. An important element of Tempest s strategy to date has been to utilize consultants with whom
Tempest has established relationships over several companies and in the development of multiple innovative oncology therapies, including those skilled in medicinal chemistry, pharmacology and toxicology, translational sciences, clinical operations
and medical affairs. Tempest will continue to maintain internal capabilities in R&D and clinical development areas as noted and add experienced and talented scientists in areas, such as medicinal chemistry, that Tempest believes are critical for
the discovery of highly differentiated small-molecule compounds. Additionally, while Tempest s current pipeline consists of orally-available small molecules, the Tempest team is also experienced in the conception, translation and clinical
development of simple and complex biologics.
The Tempest team has come together to build an integrated company that delivers meaningful therapies to cancer patients, through leveraging its team s
capabilities and research and development engine. Tempest expects to build value for the Tempest shareholders with the following over-arching strategy:
TPST-1495: Dual EP2/EP4 Prostaglandin
first clinical molecule is TPST-1495, a potentially first-in-class, oral, small molecule dual antagonist of the PGE2 receptors, EP2 and EP4. TPST-1495 is engineered to
inhibit only the EP2 and EP4 receptors while sparing the homologous but differentially active EP1 and EP3 receptors. There is extensive literature demonstrating that PGE2 both enhances tumor proliferation and inhibits anti-cancer immune
function; it is known from the scientific literature that many tumors express elevated levels of the cyclooxygenase enzymes that produce PGE2. The literature supports that PGE2 predominantly drives tumor proliferation by autocrine signaling through
EP2 and EP4 receptors on tumor cells and immune suppression through EP2 and EP4 receptors on lymphoid and myeloid immune cells in the tumor microenvironment. Tempest has conducted extensive preclinical studies to test and compare the anti-tumor
activities and immune activation of EP2- and EP4-specific inhibition by TPST-1495 to alternative mechanisms of PGE2 inhibition, supporting the improved activity of the
TPST-1495 approach. Tempest additionally conducted IND-enabling pharmacology and toxicology studies to support initiation of its ongoing
first-in-human Phase 1/1b study of TPST-1495 monotherapy in patients with advanced solid tumors. The company is currently evaluating the safety, tolerability,