SEATTLE, WA — February 10, 2026 — Kayothera, Inc., a preclinical therapeutics company developing first-in-class, small molecule inhibitors of the retinoid nuclear receptor pathway, announced the expansion of its Clinical Advisory Board (CAB) to support its goal of creating disease-modifying therapies for type 2 diabetes, diabetic complications and other unmet medical needs.

The collective thought leadership of the clinical advisors in pancreatic islet biology and clinical trial approaches will shape Kayothera’s translational strategy as we advance the first therapy with the potential to restore dysfunctional β cells. Loss of pancreatic β cell function is the root cause of type 2 diabetes, yet no available therapy, including the most potent GLP-1 receptor agonists, has been shown to successfully restore β-cell function. By integrating insights into the mechanisms of β cell failure with expertise in clinical development, the CAB will assist in the advancement of Kayothera’s lead candidates with the potential to reverse the progression of type 2 diabetes.

Kayothera’s new CAB appointments will join Dr. Domenico Accili, the 2017 Banting Medal recipient who was the first to describe β cell dedifferentiation as the root cause of β cell dysfunction. The new appointees include:

• John Buse, MD/PhD, the Director of the Diabetes Center at the University of North Carolina and a Banting Medal recipient. Dr. Buse is recognized for his thought leadership in T2D, specifically in the design of large-scale clinical trials and the evaluation of cardiovascular outcomes in diabetes therapies.
• Francesco Giorgino, MD/PhD, a Professor of Endocrinology at the University of Bari Aldo Moro. Dr. Giorgino’s research focuses on the molecular mechanisms of β cell regeneration and survival, investigating how therapeutic targets can restore functional insulin-producing mass in metabolic disease.
• Steven Kahn, MD, a Professor of Medicine at the University of Washington and the 2025 Banting Medal recipient. Dr. Kahn’s work centers on the natural history of β cell functional loss in type 2 diabetes and his recent clinical work shows that >80% of β cell function is lost by the time a patient is diagnosed with type 2 diabetes. Dr. Kahn’s work has highlighted that restoring β cell health is the major unmet need in the type 2 diabetes landscape.

“Expanding our Clinical Advisory Board with these world-renowned experts reinforces our approach to treat and potentially reverse type 2 diabetes,” said Dr. Mark Esposito, Founder and CSO of Kayothera. “Their combined experience in β cell health and clinical development provides the necessary framework as we transition our research toward patient-focused outcomes.”

About Kayothera. Kayothera is a preclinical therapeutics company focused on the development of first-in-class, oral, small molecule inhibitors of the retinoid nuclear receptor pathway for cardiometabolic disease and other unmet medical needs. This pathway plays a critical role in a variety of serious diseases, and despite broad preclinical, clinical and real-world validation, the retinoid nuclear receptor pathway has remained undrugged. The company was founded based on discoveries from Dr. Mark Esposito’s post-doctoral research at Princeton University and professor Yibin Kang, PhD. For more information, visit www.kayothera.com.

Contact
Jessica Burback
Email: jburback@acceleratorlsp.com
Phone: 206-957-7302

One study, published in the current issue of and led by Ludwig Princeton’s and graduate student Cao Fang, describes how retinoic acid produced by the immune system’s dendritic cells (DCs) alters them to induce a dangerous tolerance of tumors. This tolerance, the researchers show, diminishes the efficacy of otherwise promising immunotherapies known as dendritic cell vaccines. They also report the design and preclinical assessment of a candidate drug that inhibits retinoic acid production by both cancer cells and DCs. The compound, KyA33, not only boosts the efficacy of DC vaccines in preclinical studies but also holds promise as an independent cancer immunotherapy.

The second study, led by a former graduate student in Kang’s lab, Mark Esposito, and recently reported in the journal, describes the rational design and preclinical development of drugs that inhibit retinoic acid production and so turn off retinoid signaling. While retinoids have been known to scientists for more than a century, efforts to develop viable drugs to block their signaling have so far met with failure. The process of drug-discovery developed in this study provided the blueprint for the design of KyA33.

“Taken together, our findings reveal the broad influence retinoic acid has in attenuating vitally important immune responses to cancer,” said Kang. “In exploring this phenomenon, we also solved a longstanding challenge in pharmacology by developing safe and selective inhibitors of retinoic acid signaling and established preclinical proof of concept for their use in cancer immunotherapy.”

A deadly tolerance

Retinoic acid is produced by an enzyme known as ALDH1a3, which is often overexpressed in human cancer cells, or by its sibling ALDH1a2 in certain subtypes of DCs.

The molecule activates a receptor in the cell’s nucleus to initiate a molecular signaling cascade that alters gene expression. Its production by DCs is known to induce the generation of immune cells known as regulatory T cells (Tregs) in the gut that restrain potentially dangerous autoimmune reactions. However, its effect on DCs themselves was not known.

DCs are perhaps best known for their critical role in orchestrating protective immune responses. DCs patrol the body looking for signs of infection and cancer. Upon detecting such threats, these itinerant cells process and present fragments of disease-associated proteins—or antigens—to activate T cells, which then target sick and cancerous cells.

DC cancer vaccines are typically produced by generating DCs from their precursors in the blood. These immature blood cells are first isolated from a patient and then grown in lab cultures in the presence of cancer antigens from that patient’s tumor. The expectation is that such “primed” dendritic cells should elicit potent anti-tumor responses when transferred back into the patient.

Trouble is, they often do not, even though researchers have made significant   in identifying the right cancer antigens to use for such purposes. Fang, Kang and colleagues, including Esposito and Princeton Branch Director Joshua Rabinowitz, figured out why this is the case.

“We discovered that under conditions commonly employed to produce DC vaccines, differentiating dendritic cells begin expressing ALDH1a2, producing high levels of retinoic acid,” said Fang. “The nuclear signaling pathway it activates then suppresses DC maturation, diminishing the ability of these cells to trigger anti-tumor immunity. This previously unknown mechanism likely contributes to the largely suboptimal performance of DC and other cancer vaccines that has been repeatedly seen in clinical trials.”

To make matters worse, the retinoic acid secreted by DCs also favors the development of macrophages that are less efficient than DCs in combating cancer cells. The accumulation of these cells instead of DCs further undermines the efficacy of DC vaccines.

The researchers show that the genetic disruption of ALDH1a2 expression or its pharmacological inhibition with KyA33 restores the maturation and anti-tumor function of DCs. DC vaccines formulated in the presence of KyA33 elicit strong antigen-specific immune responses, delaying the onset of tumors in mouse models of melanoma and slowing their progression. When given directly to mice, the inhibitor also works independently as an immunotherapy, suppressing tumor growth.

Resolving an old paradox

The development of these ALDH1a2/3 inhibitors itself is a notable accomplishment. Of the dozen classic nuclear receptor signaling pathways, the one activated by retinoic acid was the first such pathway discovered but remains the only one that has not yet been successfully targeted by a drug.

The iScience paper describes a hybrid computational and large-scale drug screening approach Esposito, Kang and colleagues took to develop their inhibitors. With the unique tool offered by these novel compounds, the researchers were able to solve the apparent paradox of retinoid nuclear signaling in cancer.

Retinoic acid has been shown to induce the growth arrest and death of cancer cells in laboratory cell cultures, a finding that has imbued vitamin A with anti-cancer agency in the popular imagination. On the other hand, multiple lines of evidence, including the findings of major clinical trials, indicate that high intake of vitamin A actually increases the incidence of cancer (and cardiovascular disease) and related mortality. Moreover, elevated expression of ALDH1A enzymes in tumors is associated with poor survival across multiple types of cancer. To resolve this paradox, much research has attempted, with little success, to dissociate the role of ALDH1A enzymes in cells from retinoic acid production.

“Our study reveals the mechanistic basis for this paradox,” said Esposito. “We’ve shown that ALDH1a3 is overexpressed in diverse cancers to generate retinoic acid, but that cancer cells lose their responsiveness to retinoid receptor signaling, avoiding its potential anti-proliferative or differentiating effects. This explains, in part, the paradox of vitamin A’s effects on cancer growth.”

The other part, Esposito, Kang and colleagues found, is that retinoic acid does not influence the cancer cells themselves but is rather secreted into the tumor microenvironment to suppress the anti-cancer immune response. One way it does so is by disrupting T cell responses to cancer.

To demonstrate this, the researchers showed that these novel ALDH1a3 inhibitors serve as a potent immunotherapy in mouse models of cancer by stimulating the immune system to attack tumors.

“By developing candidate drugs that safely and specifically inhibit nuclear signaling through the retinoic acid pathway, we are paving the way for a novel therapeutic approach to cancer,” said Kang.

Esposito and Kang have launched a biotechnology company, Kayothera, to bring their novel ALDH1A inhibitors to the clinic for multiple diseases known to be driven by retinoic acid, including cancer, diabetes and cardiovascular disease.

The study reported in Nature Immunology was supported by the Ludwig Institute for Cancer Research, the Brewster Foundation, the Susan Komen Foundation, Metavivor Breast Cancer Research, the Breast Cancer Research Foundation and the American Cancer Society.

The study reported in iScience was supported by the Ludwig Institute for Cancer Research, the New Jersey Health Foundation, the Brewster Foundation, the Susan Komen Foundation, the Breast Cancer Research Foundation, the American Cancer Society and the National Science Foundation.

Aside from his post as a Member of the Princeton Branch of the Ludwig Institute for Cancer Research, Yibin Kang is Warner-Lambert/Parke-Davis Professor of Molecular Biology at Princeton University and an Associate Director of Rutgers Cancer Institute of New Jersey.

        # # #

About Ludwig Cancer Research

Ludwig Cancer Research is an international collaborative network of acclaimed scientists that has pioneered cancer research and landmark discovery for more than 50 years. Ludwig combines basic science with the translation and clinical evaluation of its discoveries to accelerate the development of new cancer diagnostics, therapies and prevention strategies. Since 1971, Ludwig has invested nearly $3 billion in life-changing science through the not-for-profit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers. To learn more, visit www.ludwigcancerresearch.org.

For additional information please contact communications@ludwigcancerresearch.org

PRINCETON, NJ, October 14, 2025 — A paper published today in the peer-reviewed journal iScience, co-authored by researchers from Princeton University, Ludwig Institute for Cancer Research Princeton Branch and Kayothera, Inc., describes the development of the first orally available antagonists of the retinoid nuclear receptor pathway. This groundbreaking research, “Development of retinoid nuclear receptor pathway antagonists through targeting Aldehyde Dehydrogenase 1A3 (ALDH1A3),” resolves a long-standing paradox about the role of retinoids in health and highlights a key risk to consumers of high-dose Vitamin A or retinol supplements.

It has long been known that consumption of excess retinoids, including high dose retinol (Vitamin A), results in dramatically elevated mortality due to increases in both cardiovascular disease and lung cancer. This finding has been replicated in large-scale randomized clinical trials across multiple countries. In contrast, the prevailing public wisdom is that Vitamin A and other retinoids promote heart health and suppress cancer. While the anti-cancer effects of retinoids are sometimes observed in laboratory models, beneficial effects of retinoid therapy have never been conclusively shown in patients with solid cancers. The newly published research from Princeton University reveals the mechanistic basis for this paradox by demonstrating that ALDH1A3 is overexpressed in diverse cancers to generate retinoic acid, the downstream metabolite of retinol that activates the retinoid nuclear receptor pathway. Secretion of retinoic acid then suppresses the body’s anti-tumor immune response. Meanwhile, retinoic acid-producing cancer cells lose responsiveness to retinoic acid signaling, explaining why retinoid treatment has no clear positive effect in solid cancer patients. These findings help explain the seeming contradiction between a decades-old hypothesis that retinoids are beneficial and the clinical observation that retinoids worsen health outcomes.

The retinoid nuclear receptor pathway has long been a challenging therapeutic target, with many large pharmaceutical companies attempting to create antagonists in the early 2000s but failing after years of effort. There are twelve classic nuclear receptor pathways, and, despite being discovered first, the retinoid nuclear receptor pathway is the only one that has not been successfully drugged. To overcome this challenge, the researchers developed a hybrid computational and high-throughput screening approach, followed by medicinal optimization, to create first-in-class, oral, and safe antagonists of ALDH1A3. These novel inhibitors both demonstrated potent anti-tumor immunotherapeutic activity in preclinical models and possessed an optimized drug development profile, positioning them as a potential new class of cancer immunotherapies.

“Our work addresses a decades-old controversy in retinoid biology and provides a clear mechanism by which ALDH1A3 drives disease,” said Yibin Kang, Ph.D., Lead Contact for the publication and a co-author. “By developing antagonists that safely inhibit this pathway, we are paving the way for a novel therapeutic approach to cancer that was not previously possible.”

Mark Esposito, Ph.D., first author of the paper and a co-founder of Kayothera, Inc., added, “This publication highlights the foundational science behind Kayothera and our unique approach to targeting this important pathway. It provides the biochemical validation for our drug development efforts and underscores the potential for our therapies to address significant unmet medical needs in oncology and cardiometabolic diseases.”

About the Publication
The paper is available online in the journal iScience. DOI: 10.1016/j.isci.2025.113675
Title: Development of retinoid nuclear receptor pathway antagonists through targeting Aldehyde Dehydrogenase 1A3 (ALDH1A3)
Authors: Mark Esposito, Cao Fang, Yong Wei, Alfonso Pozzan, Claudia Beato, Xiaoyang Su, Josiah E. Hutton III, Tavis Reed, Xiang Hang, Enrico D. Perini, Wen Wang, Xiaobing Cheng, Yan Pan, Jianshi Yu, Maureen Kane, Malini Manoharan, John Proudfoot, Ileana M. Cristea, and Yibin Kang.

KAYO-1732 represents a new paradigm for treating T2D by targeting the retinoid nuclear receptor pathway, a pathway shown to drive cardiovascular mortality and β cell failure in patients. Preclinical data, including a recent publication in Nature Communications, demonstrates that pathogenic ALDH1A3 activity is a key driver of pancreatic β cell dedifferentiation and failure, which leads to the progressive decline in insulin secretion seen in T2D. By inhibiting ALDH1A3, KAYO-1732 blocks activation of the retinoid nuclear receptors and directly reverses the loss of pancreatic β cell function. In preclinical models, treatment with KAYO-1732 led to the conversion of dedifferentiated β cells into a functional, mature state, resulting in restored glucose control and increased insulin secretion. This disease-modifying approach stands apart from many existing therapies that primarily focus on blood glucose management without addressing the underlying cause of β cell decline. The nomination of KAYO-1732 further validates Kayothera’s approach, which was recently recognized as one of the winners at the American Diabetes Association’s Innovation Challenge.

“The nomination of KAYO-1732 as a development candidate is a pivotal moment for Kayothera and for the tens of millions of people living with type 2 diabetes,” said Dr. Mark Esposito, CSO and Co-founder for Kayothera. “For years, the retinoid nuclear receptor pathway has been an impossible target to drug in a safe and selective manner, but our unique approach and the compelling preclinical data give us confidence that we are developing a truly first-in-class therapy with the potential to fundamentally change the course of type 2 diabetes.”

About Kayothera, Inc. Kayothera is a preclinical therapeutics company focused on the development of first-in-class, oral, small molecule inhibitors of the retinoid nuclear receptor pathway. This pathway plays a critical role in a variety of serious diseases, including cardiometabolic diseases and cancer. The company was founded based on discoveries from Dr. Mark Esposito’s post-doctoral research at Princeton University and professor Yibin Kang, PhD. For more information, visit www.kayothera.com.

The ADA’s Innovation Challenge seeks to accelerate the path from concept to commercialization for novel ideas with the potential to transform diabetes care. Kayothera’s presentation focused on its proprietary approach to inhibit the retinoid nuclear receptor pathway, a signaling mechanism that has been clinically validated to play a significant role in chronic cardiometabolic and cardiovascular diseases, including type 2 diabetes.

Kayothera’s pipeline is based on extensive preclinical research findings that show antagonists of this nuclear receptor pathway could offer compelling new therapeutic options for high-need patients. This work was validated in a recent study published in Nature Communications, which demonstrated that inhibiting the enzyme Aldehyde dehydrogenase 1a3 (ALDH1A3)—a key component of the retinoid nuclear receptor pathway—can reverse β cell failure in diabetic preclinical models and human β cells. The research showed that targeting ALDH1A3 not only lowers blood glucose levels but also reactivates β cell differentiation and regeneration, addressing the underlying pancreatic decline associated with type 2 diabetes.

“We are honored to be selected as a winner of the ADA Innovation Challenge,” said Dr. Esposito. “This recognition is a powerful validation of our belief that targeting the retinoid nuclear receptor pathway offers a novel, disease-modifying approach to treat type 2 diabetes. We are committed to advancing our therapies with the goal of providing patients with a medicine that can restore pancreatic function and reverse the ever-increasing prevalence of type 2 diabetes in the United States.”

This award underscores Kayothera’s commitment to developing safe and effective therapies that go beyond symptom management to treat the fundamental mechanisms of type 2 diabetes pathology.

• ADA – 2025 Innovation Challenge
• The American Diabetes Association Announces Winners of the Innovation Challenge to Transform Diabetes Care

About Kayothera. Kayothera, Inc. is an early-stage therapeutics company focused on the development of first-in-class, oral, small-molecule inhibitors of the retinoid nuclear receptor pathway. This pathway is pathogenically activated in several cancers as well as multiple cardiometabolic diseases, including diabetes and obesity. Kayothera is developing three distinct therapies, with KAYO-1732 in development as a disease-modifying treatment that controls blood glucose and lipid levels to prevent multiorgan degeneration in cardiometabolic syndrome and diabetes. KAYO-1609 has completed IND-enabling studies and is in development to treat late-stage and metastatic cancers, including pancreatic, prostate, gastric, and multiple other cancers. Kayothera is also developing a next-generation obesity therapy based on a genetically validated target in the retinoid nuclear receptor pathway. The company was founded based on discoveries from Dr. Mark Esposito’s post-doctoral research at Princeton University and Professor Yibin Kang, PhD. For more information, visit www.kayothera.com.

Seattle, WA — October 22, 2024, Kayothera, Inc., a preclinical-stage therapeutics company developing first-in-class, oral, small molecule inhibitors of the retinoid nuclear receptor pathway, announced the expansion of its Scientific Advisory Board (SAB) to support the development of its first-in-class, oral, small molecule inhibitors of the retinoid nuclear receptor pathway. 

Chaired by Yibin Kang, PhD, Warner-Lambert/Parke-Davis Professor of Molecular Biology at the Ludwig Institute of Princeton University, the SAB will work closely with Kayothera’s executive team to provide strategic guidance and expert insights to advance its mission of creating the best therapies to treat serious and life-threatening diseases.

Kayothera’s SAB includes the following members:

• Domenico Accili, MD, the Russell Berrie Foundation Professor of Diabetes at Columbia University and the Director of the Columbia University Diabetes Research Center. Dr. Accili is the 2017 Banting Medal Recipient and is highly recognized for his pioneering work on beta cell failure in type 2 diabetes. Dr. Accili pioneered the theory of pancreatic islet dedifferentiation and identified ALDH1a3 as a key marker of diseased pancreatic islets. 
• Shridar Ganesan, PhD/MD, a prominent physician-scientist and medical oncologist at the NYU Perlmutter Cancer Center, where he serves as the Director for the Center for Molecular Oncology and Professor of Medicine. Dr. Ganesan is well-known for pioneering breast cancer research and guides Kayothera’s early clinical program in oncology.
• Suzanne George, MD, a renowned clinical expert in sarcoma, serving as the clinical director of the Center for Sarcoma and Bone Oncology at Dana-Farber Cancer Institute and an associate professor of Medicine at Harvard Medical School; Dr. George has extensive expertise in soft tissue sarcoma, bone sarcomas, and gastrointestinal stromal tumors (GIST); and
• Kendall Mohler, PhD, was previously co-founder and chief scientific officer at Trubion Pharmaceuticals, the founding CSO at Juno Therapeutics, and a senior leader at Immunex, where he played a key role in the development of Enbrel (etanercept).

“I am truly excited to collaborate with this exceptional team at Kayothera,” said Dr. Kang. “The collective expertise and experience of our Scientific Advisory Board members will be crucial as we push the frontiers of innovation. Together, we are set to make significant progress in developing first-in-class, oral, small-molecule inhibitors of the retinoid nuclear receptor pathway. I eagerly anticipate the profound impact we will have on treating serious and life-threatening diseases.”

About Kayothera. Kayothera, Inc. is an early-stage therapeutics company focused on the development of first-in-class, oral, small-molecule inhibitors of the retinoid nuclear receptor pathway. This pathway is pathogenically activated in several cancers as well as multiple cardiometabolic diseases, including diabetes and obesity. Kayothera is developing three distinct therapies, with KAYO-1732 in development as a disease-modifying treatment that controls blood glucose and lipid levels to prevent multiorgan degeneration in cardiometabolic syndrome and diabetes. KAYO-1609 has completed IND-enabling studies and is in development to treat late-stage and metastatic cancers, including pancreatic, prostate, gastric, and multiple other cancers. Kayothera is also developing a next-generation obesity therapy based on a genetically validated target in the retinoid nuclear receptor pathway. The company was founded based on discoveries from Dr. Mark Esposito’s post-doctoral research at Princeton University and Professor Yibin Kang, PhD. For more information, visit www.kayothera.com.

Recent board additions highlight Kayothera’s evolution into pipeline-focused organization with meaningful translational efforts

Seattle, WA — October 14, 2024, Kayothera, Inc., a preclinical-stage therapeutics company developing first-in-class, oral, small molecule inhibitors of the retinoid nuclear receptor pathway, announced the appointment of Bruce L.A. Carter, PhD (Chairman), and Paul Sekhri to its Board of Directors.

“We are pleased to welcome Dr. Bruce Carter and Paul Sekhri to the Board of Kayothera,” stated Thong Q. Le, President & CEO. “Bruce and Paul bring substantial drug development expertise and have demonstrated a commitment to advancing therapeutic innovations that benefit patients in need. We look forward to their contributions, which will help ensure Kayothera’s long-term success.”

Bruce Carter, PhD, was the Chairman of the Board and former Chief Executive Officer of ZymoGenetics Inc., USA. He has also served as the Corporate Executive Vice President and Chief Scientific Officer for Novo Nordisk A/S, the former parent company of ZymoGenetics. From 1982 to 1986, Dr. Carter held various positions of increasing responsibility at G.D. Searle & Co., Limited, including Head of Molecular Genetics. He was a lecturer at Trinity College, University of Dublin, from 1975 to 1982. Dr. Carter holds directorship in Enanta Pharmaceuticals, TB Alliance, and Aurigene Discovery Technologies Limited (India). Dr. Carter received his BS with Honors in Botany from the University of Nottingham, England, and his PhD in Microbiology from Queen Elizabeth College, London University, UK.

“I am thrilled to chair the Kayothera Board,” said Dr. Carter. “This is an exciting time as Kayothera’s KAYO-1732 candidate for type 2 diabetes progresses to IND and its candidate for solid tumors, KAYO-1609, enters Phase 1 trials. I look forward to working closely with Kayothera’s board and executive team as the company progresses its promising drug candidates.”

Paul Sekhri has over 30 years of experience in the Life Science Industry. His experience encompasses senior management in large corporate pharmaceutical and biotechnology companies and private equity and venture capital. Mr. Sekhri is currently President and Chief Executive Officer and Chairman of vTv Therapeutics, Inc., a clinical-stage biopharmaceutical company focused on diabetes. He most recently held the positions of President, CEO, and Chairman at eGenesis, Inc., from 2019 to 2022. Prior to eGenesis, he was President and CEO of Lycera Corp. from 2015 to 2019. Prior to Lycera, he served as Senior Vice President, Integrated Care for Sanofi from 2014-2015. Previously, he served as Chief Strategy Officer and Group Executive Vice President, Global Business Development for Teva Pharmaceutical Industries, Ltd. Prior to joining Teva, Mr. Sekhri spent five years as Operating Partner and Head of the Biotechnology Operating Group at TPG Biotech, the life sciences venture capital arm of TPG Capital. From 2004-2009, Mr. Sekhri was Founder, President, and Chief Executive Officer of Cerimon Pharmaceuticals, Inc. Before founding Cerimon, Mr. Sekhri was President and Chief Business Officer of ARIAD Pharmaceuticals, Inc. Previously, Mr. Sekhri spent five years at Novartis as Senior Vice President, and Head of Global Search and Evaluation, Business Development and Licensing for Novartis Pharma AG.

Mr. Sekhri has been a director on more than 35 private, public company, and non-profit boards and is currently a member of the Board of Directors of AdhereTech, Spring Discovery, and Veeva Systems Inc. Mr. Sekhri is also the Chairman of the Boards of Directors of Resolution Therapeutics, Compugen Ltd., Longboard Pharmaceuticals, and Kaerus Bioscience. Additionally, he is on the Board of Directors of The Metropolitan Opera, The English Concert in America, and was a member of the Board of Trustees of Carnegie Hall. Most recently, he was nominated as Chairman of the Board of Trustees of Young Concert Artists, Inc.

“I look forward to collaborating with the Kayothera Board to guide the development of innovative medicines that address underserved patients in need,” stated Mr. Sekhri. “Kayothera’s focus on developing novel, first-in-class antagonists of the retinoid nuclear signaling pathway and dedication to bringing best-in-class drug candidates forward is a mission that I look forward to supporting.”

About Kayothera. Kayothera, Inc. is an early-stage therapeutics company focused on the development of first-in-class, oral, small-molecule inhibitors of the retinoid nuclear receptor pathway. This pathway is pathogenically activated in several cancers as well as multiple cardio-metabolic diseases, including diabetes and obesity. Kayothera is developing three distinct therapies, with KAYO-1732 in development as a disease-modifying treatment that controls blood glucose and lipid levels to prevent multiorgan degeneration in cardiometabolic syndrome and diabetes. KAYO-1609 has completed IND-enabling studies and is in development to treat late-stage and metastatic cancers, including pancreatic, prostate, gastric, and multiple other cancers. Kayothera is also developing a next-generation obesity therapy based on a genetically validated target in the retinoid nuclear receptor pathway. The company was founded based on discoveries from Dr. Mark Esposito’s post-doctoral research at Princeton University and Professor Yibin Kang, PhD. For more information, visit www.kayothera.com.

 Company expects to file IND application with the U.S. Food & Drug Administration (FDA) by the end of 2024

Seattle, WA — September 18, 2023, KayoThera, Inc. (“KayoThera”), an early-stage therapeutics company developing first-in-class, oral, small molecule inhibitors of the retinoid pathway, today announces that it has selected KAYO-1609 as its first drug development candidate. KAYO-1609 has demonstrated a differentiated safety profile across a variety of species with ideal drug-like properties. Preclinical studies in multiple models of cancer support the potential of KAYO-1609 in the treatment of genetically-defined cancers based on the molecule’s mechanism of action. With the nomination of KAYO-1609 as the development candidate, KayoThera is well-positioned for IND-enabling studies, clinical planning, and partnering activities.

Retinoid signaling is known to both inhibit helper CD4 T cells that mediate tumor cell destruction, and cause maturation of regulatory T cells that dampen the immune system’s response to cancer. Retinoid signaling further forces differentiation of monocytes into tumor-associated macrophages that can promote tumor growth and metastasis. Collectively, these activities reduce the immune system’s ability to detect and eliminate malignant cells. Inhibition of the amplified retinoid signaling found in unique tumor types could potentially restore or enhance the anti-tumor immune activity, enabling a unique approach to cancer immunotherapy in patients with few therapeutic options.

“Despite its known roles in blunting the body’s anti-tumor immune defense, previous efforts to develop retinoid signaling antagonists have failed due to unacceptable toxicity in preclinical development,” said Mark Esposito, Ph.D., vice president of R&D, and co-founder of KayoThera. “The discoveries on which KayoThera was founded enable the development of orally available, small molecule inhibitors of this important signaling pathway that have very favorable safety profiles. The preclinical safety and efficacy data generated to date in studies of KAYO-1609 are exceptionally promising, and we intend to move as rapidly as possible toward initiating human clinical trials of this novel molecule in genetically-defined cancers.”

KAYO-1609 has demonstrated excellent safety and tolerability, with no dose-limiting toxicities observed in studies across five different species. Preclinical studies also have identified a dose-responsive biomarker for target engagement that is expected to facilitate the IND-enabling studies. KayoThera expects to initiate IND-enabling studies of KAYO-1609 in the third quarter of 2023 and anticipates filing an IND application with the FDA by the end of 2024. Following acceptance of the IND, the company plans to initiate a human clinical trial of KAYO-1609 in patients with genetically-defined cancers that are most likely to demonstrate clinical benefit based on the mechanism of action of KAYO-1609.

“The selection of KAYO-1609 as our lead oncology development candidate is the most recent demonstration of the significant progress, we have made over the past few months to position KayoThera for success,” said Kendall Mohler Ph.D., chief development officer and board member of KayoThera. “In May we announced the expansion of our pipeline into the cardiometabolic disease space, with a focus on Type 2 diabetes and in July we strengthened our financial position with multiple grants and the expansion of our Series A financing. Taken together, we now have the financial resources to advance exciting and differentiated candidates in cancer and Type 2 diabetes, diseases with significant unmet clinical need that are associated with significant mortality and morbidity. We are committed to developing retinoid signaling pathway inhibitors as novel therapeutic modalities that can improve outcomes for patients living with these and other serious diseases.”

About KayoThera Inc
KayoThera, Inc. is an early-stage therapeutics company focused on the development of first-in-class, oral, small molecule inhibitors of the retinoid pathway. This pathway plays a critical role in a variety of serious diseases, including cardiometabolic diseases and cancer. KayoThera is developing therapies to treat diabetes and late-stage and metastatic cancers including breast, lung, pancreatic, colorectal, brain, and kidney cancers. The company was founded based on discoveries from Dr. Mark Esposito’s post-doctoral research at Princeton University and professor Yibin Kang, PhD. For more information, visit www.kayothera.com.

About Accelerator Life Science Partners

Accelerator Life Science Partners (ALSP) is an early-stage life science accelerator and investment firm that creates and builds next generation biotechnology companies centered on innovative science. ALSP catalyzes the development and commercialization of breakthrough biotechnology innovations by providing a holistic toolkit and leveraging its network and entrepreneurial expertise to accelerate the establishment and operation of early-stage biotechnology companies. ALSP’s portfolio companies are backed by renowned life science investors and are comprised of industry-leading, transformative companies, including KayoThera, Inc., Lodo Therapeutics (acquired by Zymergen, now Ginkgo BioWorks), Petra Pharma (acquired by a global pharmaceutical company), Proniras Corporation, and Rodeo Therapeutics (acquired by Amgen Inc.).  For more information, please visit www.acceleratorlsp.com.

 Additional funding will support advancement of KayoThera’s development programs in diabetes and oncology

SEATTLE, WA – July 19, 2023, KayoThera, Inc. (“KayoThera”), an early-stage therapeutics company developing first-in-class, oral, small molecule inhibitors of the retinoid pathway, today announces the strengthening of its financial resources through multiple grant awards and expansion of its previously announced Series A financing. The expanded financing was led by Accelerator Life Science Partners (ALSP), who also provided Series A funding for KayoThera. With the additional $5.2 million in new equity investments, non-dilutive grant funding, and initial seed funding from the New Jersey Health Foundation, KayoThera’s total financial support to date is $14 million.

KayoThera has received grant funding from the National Institutes of Health Small Business Innovation Research (SBIR) program^1,2 and the Andy Hill Cancer Research Endowment (CARE) Fund³. In addition, KayoThera secured additional Series A financing in an expansion round led by ALSP that also included participation from BioAdvance, Pier 70 Ventures, and WRF Capital. The additional resources secured by KayoThera will further support the Company’s therapeutic development programs.

“The grant awards are important validation of our development programs, and the expanded Series A financing reflects our investor’s confidence in our ability to innovate oral, small molecule inhibitors of the retinoid pathway,” said Mark Esposito, Ph.D., Vice President, R&D, and Co-Founder of KayoThera. “With the additional financial resources announced today, we are well-positioned to advance our lead diabetes and oncology programs, each of which has first-in-class potential in disease indications with large patient populations and significant unmet medical need.”

“Our belief that KayoThera offers a compelling investment opportunity and has the potential to transform the treatment of serious metabolic diseases and cancer was the key driver for our initial investment in the Company,” said Thong Q. Le, Senior Managing Director of ALSP and CEO of KayoThera. “Since the initial Series A financing in March 2022, KayoThera has made significant progress in advancing its core technology and development programs. The additional funding announced today will allow the Company to continue making exciting advances in innovating small molecule inhibitors of the retinoid pathway and position itself for strategic partnering activity that will further help realize the commercial and clinical value of its science.”

The retinoid pathway is known to play critical roles in several serious diseases. For example, the clinical use of retinoid activators leads to both adverse cardiometabolic events such as hyperlipidemias as well as increased cancer rates and faster cancer progression. KayoThera’s unique approach to drugging this pathway is based on biology discovered at Princeton University and represents the first platform to create drug-like retinoid inhibitors.

References
¹ NIH NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases) R43DK136420. Grant title: Development of first-in-class antagonists of the retinoid pathway as novel oral therapies for Type 2 Diabetes.
²NIH NCI (National Cancer Institute) R43CA278127. Grant title: Development of first-in-class antagonists of the retinoid pathway as novel oral immunotherapies for solid cancers.
³The Andy Hill Cancer Research Endowment (CARE) Fund FY23-LS-05. Grant title: Development of a First-in-Class Immunotherapy to Treat Advanced Solid Tumors Through IND-Enabling Safety Studies.

The content in this release is the sole responsibility of the authors and does not necessarily represent the official views or imply endorsement of the National Institutes of Health.

About KayoThera, Inc
KayoThera, Inc. is an early-stage therapeutics company focused on the development of first-in-class, oral, small molecule inhibitors of the retinoid pathway. This pathway plays a critical role in a variety of serious diseases, including cardiometabolic diseases and cancer. KayoThera is developing therapies to treat diabetes and late-stage and metastatic cancers including breast, lung, pancreatic, colorectal, brain, and kidney cancers. The company was founded based on discoveries from Dr. Mark Esposito’s post-doctoral research at Princeton University and professor Yibin Kang, Ph.D. For more information, visit www.kayothera.com.

About Accelerator Life Science Partners
Accelerator Life Science Partners is an early-stage life science accelerator and investment firm that creates and builds next generation biotechnology companies centered on innovative science. ALSP catalyzes the development and commercialization of breakthrough biotechnology innovations by providing a holistic toolkit and leveraging its network and entrepreneurial expertise to accelerate the establishment and operation of early-stage biotechnology companies. ALSP’s portfolio companies are backed by some of the world’s leading life science investors and are comprised of industry-leading, transformative companies, including Petra Pharma (acquired by a global pharmaceutical company), Rodeo Therapeutics (acquired by Amgen Inc.) and Lodo Therapeutics (acquired by Zymergen). For more information, please visit www.acceleratorlsp.com.

 About Andy Hill Cancer Research Endowment (CARE) Fund
The Andy Hill Cancer Research Endowment (CARE) Fund invests in public and private entities to promote cancer research in Washington. Through research grants and strategic partnerships, the CARE Fund aims to improve health outcomes by advancing transformational research in the prevention and treatment of cancer. The Washington State Legislature created the CARE Fund in 2015 and this public investment in cancer research is maximized by private and nonstate matching funds. For additional information, please visit www.wacarefund.org.

About BioAdvance
BioAdvance is a $85 million early-stage life sciences fund with a focus in the mid-Atlantic region, investing up to $1.5 million initially and up to $5 million over the lifetime of companies that have the potential to improve human health. Since making its first investments in 2003, BioAdvance has committed more than $50 million in funding to approximately 100 organizations developing more than 160 products in the therapeutics, medtech, diagnostics, research tools and digital health sectors. BioAdvance portfolio companies have leveraged $3.7 billion in subsequent capital, including proceeds from acquisitions. Eleven products have received FDA approval. For more information, please visit www.bioadvance.com.

 About Pier 70 Ventures
Pier 70 Ventures is a US-based venture capital firm investing in impact-driven innovation. The firm’s debut fund is the Pier 70 INpact Fund. Looking for brilliance beyond the usual places, Pier 70 Ventures finds and funds technologies with the potential to disrupt the future of healthcare. We invest in talented entrepreneurs pushing humanity forward with innovation. We VENTURE BOLDLY by empowering bright, enthusiastic leaders with capital, mentorship, and access to our global networks. For additional information, please visit www.pier70ventures.com.

About WRF and WRF Capital
Washington Research Foundation (WRF) supports research and scholarship in Washington state, with a focus on life sciences and enabling technologies. WRF was founded in 1981 to assist universities and other nonprofit research institutions in Washington with the commercialization and licensing of their technologies. WRF is one of the foremost technology transfer and grant-making organizations in the nation, having earned more than $445 million in licensing revenue for the University of Washington and providing over $145 million in grants to the state’s research institutions to date.

WRF Capital, the investment vehicle for Washington Research Foundation, has backed 122 local startups since 1996. Returns support the Foundation’s investment and grant-making programs. For additional information, please visit www.wrfseattle.org.

The study resolves two significant questions in diabetes research: 1) can diseased β cells be restored to healthy function and (2) whether the activity of ALDH1A3 is just a marker or if it directly contributes to β cell failure. The authors show that ALDH1A3-positive β cells can be converted back into functional, mature β cells using unique lineage tracing tools developed at Columbia University. This data suggests that no matter how severe, T2D can be reversed through β cell regeneration. Next, by using both genetic models and Kayothera’s innovative ALDH1A3 inhibitors, the paper demonstrates that ALDH1A3 inhibition can regenerate healthy β cells in both diabetic mice and, importantly, in β cells derived from human type 2 diabetic patients. The findings indicate that inhibiting ALDH1A3 offers a promising new therapeutic approach for T2D with important disease modifying potential.

“Our work demonstrates that targeting ALDH1A3 can restore the function of insulin-producing β cells, a novel concept with immense therapeutic potential,” said Thong Le, CEO of Kayothera, Inc. “The use of our innovative ALDH1A3 inhibitors was critical to these findings, confirming that this approach holds promise for significant disease modification in diabetes.”

Mark Esposito, Ph.D., a co-author and founder of Kayothera, Inc., added, “The findings published in Nature Communications are a critical step in our mission to develop first-in-class therapies for metabolic diseases. By inhibiting this key enzyme, we believe we can not only manage but potentially reverse the cellular dysfunction at the root of type 2 diabetes.”

About the Publication
The paper is available online in the journal Nature Communications.
Title: Genetic and pharmacologic inhibition of ALDH1A3 as a treatment of β-cell failure
Authors: Jinsook Son, Wen Du, Mark Esposito, Kaavian Shariati, Hongxu Ding, Yibin Kang, and Domenico Accili.