Tolremo Therapeutics Advances Oral CBP/p300 Inhibitor TT125-802 into Clinical Development Following $39M Series A Financing

Drug resistance is one of the major obstacles to long-term survival in cancer patients.

Since the approval and market launch of the first targeted therapy, Gleevec (imatinib), in 2001, more than two decades of development have yielded a vast array of drugs targeting cancer-specific molecules, leading to significant therapeutic advances in certain cancers. However, with prolonged use, cancers inevitably develop resistance to nearly all such agents, resulting in disease recurrence, metastasis, and even patient death. Current research data indicate that multidrug resistance is the primary cause of death in over 90% of cancer patients.¹。

Currently, cancer is the second leading cause of death worldwide. According to data released by the World Health Organization, there were approximately 19.3 million new cancer cases and 10 million cancer-related deaths globally in 2020. Worldwide, nearly one in six deaths is attributable to cancer. However, many cancers are curable if detected early and treated effectively. Therefore, gaining a deeper understanding of the mechanisms of cancer drug resistance and developing novel agents to overcome such resistance have become crucial strategies for breaking through the current impasse in cancer treatment.

Tolremo Therapeutics (hereinafter referred to as “Tolremo”) is a company dedicated to the development of novel drugs to combat cancer drug resistance. Established in 2017 and headquartered in Zurich, Switzerland, Tolremo is a spin-off from ETH Zurich. The company’s mission is to overcome the challenge of targeted therapy resistance by preventing the emergence of non-genetic cancer drug resistance through the early disruption of cancer’s defensive mechanisms against targeted therapies.

On September 20, TOLREMO announced the completion of a $39 million Series A financing round. The round was led by venture capital firm BioMedPartners, with participation from new investor Pierre Fabre Invest, the second-largest private pharmaceutical group in France, and existing investors. The company will use the proceeds to accelerate the clinical development of its core pipeline candidate, TT125-802.

TOLREMO is led by Dr. Stefanie Flückiger-Mangual, its Co-Founder and Chief Executive Officer. A biomedical scientist, she earned her Ph.D. in Molecular and Translational Medicine from ETH Zurich, where she also completed her postdoctoral research. Her primary focus is on developing innovative drugs to overcome cancer drug resistance, thereby improving therapeutic outcomes for cancer patients.

“Have you ever thought about starting a company?” As Flückiger-Mangual was on the verge of completing her Ph.D., her mentor posed this question, sparking in her the idea of translating scientific achievements into practical applications through entrepreneurship. Thus, six years ago, Flückiger-Mangual brought her research to fruition by co-founding TOLREMO with Wilhelm Krek, Professor of Cell Biology at ETH Zurich.

Subsequently, Flückiger-Mangual recruited industry experts to assemble a team that rapidly accelerated the company’s operations.

Chief Operating Officer Claudia Escher is a biochemist who earned her Ph.D. in Biochemistry from the University of Basel. She joined TOLREMO in 2021. Prior to this, she spent over a decade at the proteomics company Biognosys, serving as Chief Operating Officer, Head of Scientific Operations, and Scientific Project Manager, where she drove the development and commercial application of the company’s proteomics technologies.

Dr. Julie M. Cherrington, Chair of the Board, is a biomedical expert with over three decades of industry experience. Prior to joining TOLREMO, she served as President and Chief Executive Officer at multiple biotechnology companies, including QUE Oncology (a breast cancer drug developer), Arch Oncology (an oncology immunology company), Revitope Oncology (an immunotherapy company), Zenith Epi Genetics (a cancer drug developer), and Pathway Therapeutics (a small-molecule drug developer). Additionally, she held the positions of President of R&D and Executive Vice President at the CXO firm Phenomix Corporation.

Throughout her career, Dr. Cherrington has been involved in the development of multiple FDA-approved drugs, including SUTENT®, PALLADIA®, VISTIDE®, and VIREAD®. Currently, she serves as a board member for several biotechnology companies and acts as an advisor to numerous biotech firms.

In addition, Flückiger-Mangual has established a scientific advisory board composed of oncology experts. Its members include Professor Sanjay Popat, a member of The Institute of Cancer Research (UK); Professor Josep Tabernero, a member of the U.S. National Cancer Institute; and Dr. Francesco Hofmann, who previously served as Global Head of Oncology Drug Development at Novartis.

An exceptional team has fueled TOLREMO’s rapid growth and advanced the development of its core pipeline. As an emerging leader in addressing cancer drug resistance, TOLREMO was recognized in 2021 as one of Switzerland’s elite startups, ranking 17th among the top 100 Swiss startups. In recognition of this achievement, Flückiger-Mangual was honored with the “Innovator of the Year” award at the 5th Women’s Innovation Forum.

When cancer cells harbor mutations that confer insensitivity to a specific drug, they develop resistance mechanisms against the therapeutic agent. Consequently, the tumor continues to proliferate and metastasize, which can ultimately lead to patient death.

Generally, drug resistance in cancer cells typically emerges in the later stages of treatment. During the course of therapy, cancer cells develop various resistance mechanisms to counteract cytotoxic drugs, including drug inactivation, drug efflux, epigenetic alterations, DNA damage repair, inhibition of cell death, alteration of drug targets, and epithelial-mesenchymal transition (EMT). These mechanisms can act independently or synergistically and function through diverse signal transduction pathways.

Therefore, overcoming cancer drug resistance has become an urgent issue to address. Current major strategies to overcome resistance include the development of inhibitors with unique binding modes, covalent binding inhibitors, allosteric binding inhibitors, bivalent binding inhibitors, PROTAC (Proteolysis Targeting Chimeras) products, and combination therapies.

CBP/p300 is a histone acetyltransferase (HAT) that participates in cell cycle progression, as well as cellular growth, differentiation, and development. As a crucial class of coactivators, it regulates the functions of various key transcriptional regulators. This activity is mediated by the bromodomain (BRD) of CBP/p300, which acts as an acetyl-lysine “reader,” enabling CBP/p300 to bind to acetylated histones and non-histone proteins on chromatin, thereby regulating gene transcription and driving related signal transduction pathways.

Studies have shown that p300/CBP is closely associated with various types of cancer, and it is highly expressed and activated in many different tumors2.

During pharmacological treatment, targeted therapies aim to inhibit cancer cell signal transduction pathways to achieve therapeutic outcomes. However, cancer cells can drive the development of drug resistance mechanisms through transcriptional reprogramming, thereby bypassing the inhibited signaling pathways and continuing to proliferate and spread via alternative routes. CBP/p300 serves as a key driver of this transcriptional reprogramming pathway in cancer cells.

Based on this rationale, TOLREMO has chosen to develop drugs targeting CBP/p300 to inhibit their activity, thereby blocking the signal transduction pathways that drive resistance mechanisms in cancer cells, and ultimately preventing the emergence of non-genetic cancer drug resistance.

TT125-802 is TOLREMO’s core pipeline asset. TT125-802 is a selective oral small-molecule inhibitor targeting the BRD of CBP/p300.

Preclinical studies demonstrated that TT125-802 exhibited unique selectivity for BRD with a minimal probability of off-target effects in the BROMOscan assay (a small-molecule drug screening platform) targeting a panel of 40 BRD-containing proteins. Meanwhile, TT125-802 showed selective anti-proliferative activity against the androgen receptor (AR) in castration-resistant prostate cancer (CRPC), inhibiting AR target gene expression in a dose-dependent manner.

Furthermore, in CRPC in vivo models, oral administration of TT125-802 to mice with human C4-2 xenografts inhibited tumor growth, demonstrating favorable clinical efficacy.

Currently, TOLREMO is evaluating the efficacy of TT125-802 in combination with other targeted therapies (KRAS, EGFR, and AR inhibitors) for the treatment of advanced solid tumors. The company’s clinical trials have demonstrated that the combination of TT125-802 with KRAS, EGFR, and AR inhibitors yielded favorable efficacy in preclinical models of non-small cell lung cancer, colorectal cancer, and prostate cancer.

TT125-802 is currently in the Phase I dose-escalation study to evaluate its safety, pharmacokinetics, pharmacodynamics, and early clinical efficacy. Next, TOLREMO will accelerate the advancement of the first-in-human trial of TT125-802 in patients with solid tumors.

Data released by the World Health Organization shows that in 2020, there were approximately 4.57 million new cancer cases in China, accounting for 23.7% of the global total; there were approximately 3 million cancer-related deaths, accounting for 30% of the global total. China ranks first worldwide in both the number of new cancer cases and cancer-related deaths.

According to data released by the National Cancer Center in 2020, the overall five-year survival rate for cancer patients in China was approximately 40.5%, lower than that of countries such as the United States (approximately 67%) and Japan (approximately 66.2%). The growing number of cancer patients coupled with a relatively low five-year survival rate underscores the urgent need for innovative drugs with superior therapeutic efficacy.

How to overcome the challenge of drug resistance in cancer treatment has become an urgent issue for China’s pharmaceutical industry. Currently, some companies are already attempting to break through this barrier of resistance.

Evolution Medical (the team led by Du Peng at Peking University) has discovered the broad-spectrum antitumor function and mechanism of action of the plant immune protein RDR (RNA-dependent RNA polymerase). Their research demonstrates that RDR can overcome low response rates to immunotherapy while breaking through resistance to targeted therapy. Currently, related drug development is in the preclinical stage.

In addition, PROTAC technology is regarded as a revolutionary approach to overcoming resistance to small-molecule drugs. Unlike conventional small-molecule therapeutics, PROTACs do not require tight, prolonged binding to the disease-causing target to induce its degradation, thereby mitigating drug resistance arising from target mutations to some extent.

According to the "2022 Short Report on China's PROTAC (Proteolysis-Targeting Chimera) Industry" released by LeadLeo Research Institute, domestic companies that have deployed PROTAC technology include Haisco Pharmaceutical, Kintor Pharmaceutical, BeiGene, Haichuang Pharmaceutical, IceStone Bioscience, LinkMed Pharmaceuticals, and RayzeBio, among others. Their PROTAC candidates have progressively entered clinical development stages, primarily targeting indications such as lymphoma, breast cancer, prostate cancer, hematologic malignancies, and solid tumors. However, no PROTAC products have yet received regulatory approval for market launch.

“Healthy China Action (2019–2030)” proposes that by 2030, the overall five-year cancer survival rate in China shall be no less than 46.6%. To achieve this goal, domestic pharmaceutical companies still have a long and arduous journey ahead.

References:

1. Rueff J, Rodrigues A S. Cancer drug resistance: A brief overview from a genetic viewpoint[J]. Cancer Drug Resistance: Overviews and Methods, 2016: 1-18.

2. Goodman RH, Smolik S. CBP/p300 in cell growth, transformation, and development. Genes Dev. 2000 Jul 1;14(13):1553-77. PMID: 10887150.