On February 14, 2023 Halda Therapeutics, a biotechnology company developing a novel class of cancer therapies called RIPTAC (Regulated Induced Proximity TArgeting Chimeras) therapeutics, reported the first public presentation of data for a RIPTAC therapeutic from its pipeline at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Genitourinary (ASCO GU) Cancers Symposium being held in San Francisco on February 16-18 (Press release, Halda Therapeutics, FEB 14, 2023, View Source [SID1234627223]). The poster presentation will describe preclinical data of an orally-available RIPTAC therapeutic for the treatment of prostate cancer, demonstrating anti-tumor activity superior to the standard of care agent in prostate cancer, enzalutamide, in an in vivo rodent model of enzalutamide insensitive prostate cancer, as well as demonstrating broad in vitro activity across prostate cell lines.
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Halda has raised $76 million to date from investors, including Canaan Partners, Access Biotechnology, Elm Street Ventures, and Connecticut Innovations, to pioneer the new RIPTAC drug modality to treat cancer. Proceeds from the funding have enabled the company to build a robust platform and pipeline of small molecule, anti-cancer drug candidates, including two lead programs for major solid tumor types to overcome common drug resistance and to address significant unmet treatment needs for cancer patients.
The company’s scientific founder, Craig Crews, PhD, Professor of Molecular, Cellular, and Developmental Biology at Yale University, is a pioneer of induced proximity biology that led to the invention of PROteolysis Targeted Chimeras (PROTAC), a class of heterobifunctional small molecule protein degrader therapeutics. Professor Crews is scientific founder of multiple biopharmaceutical companies, including Proteolix, Inc. (acquired by Onyx Pharmaceuticals) and Arvinas, Inc. Crews subsequently set the vision for RIPTAC therapeutics as another class of heterobifunctional small molecules which were invented by Halda.
"Halda’s new RIPTAC modality is an evolution of my lab’s multi-decade interest in heterobifunctional drugs," said Professor Crews. "RIPTAC therapeutics address a shortcoming shared by most current pharmaceutical modalities, namely, the reliance on oncogenic driver proteins which can result in drug resistance. This modality offers an oral, selective, and widely applicable cancer cell-killing mechanism that can overcome drug resistance and can be used in advanced cancer where resistance has emerged, as well as potentially in early-stage cancer."
RIPTAC therapeutics work by a novel "hold and kill" mechanism, bringing together two proteins, a cancer-specific protein, and a protein with essential function, resulting in abrogation of the essential cell function, and subsequently, cancer cell death. The two proteins targeted with Halda’s prostate cancer program are Androgen Receptor (AR) as the tumor-specific protein to selectively deliver the RIPTAC therapeutic to tumors, and an essential protein involved in transcriptional regulation. This therapeutic induces a prostate cancer specific protein-protein interaction between AR and a protein with essential function, which abrogates an essential function and results in cancer cell killing. The novel mode of action is designed to overcome the known bypass mechanisms of resistance that evolve during a course of therapy, which is a common limitation of today’s precision oncology medicines.
"We are excited to unveil the first data for our lead pipeline candidate demonstrating the unique mechanism of the RIPTAC modality, as well as preclinical activity in models of prostate cancer," said Kat Kayser-Bricker, PhD, Chief Scientific Officer of Halda Therapeutics. "Novel drug mechanisms are desperately needed to better address prostate cancer and the emergence of resistance to standard of care. The cancer cell-killing mechanism of our prostate cancer RIPTAC therapeutic is uniquely designed to leverage AR as a targeting protein, independent of its driver status, while overcoming limitations of the current prostate cancer treatments and the heterogeneity of resistance."
The poster presentation, with lead author Kanak Raina, Senior Director of Biology at Halda, entitled "An Oral RIPTAC Therapeutic for Prostate Cancer," will take place on Thursday, February 16 at 11:30 a.m.-1:00 p.m. PT and at 5:45-6:45 p.m. PT in Poster Session A: Prostate Cancer in Level 1 West Hall. The abstract for the ASCO (Free ASCO Whitepaper) GU poster presentation can be found here. Highlights from the presentation include the following results:
In castrated mice bearing VCaP xenografts, the prostate cancer RIPTAC therapeutic resulted in tumor growth inhibition superior to enzalutamide, the standard of care agent for prostate cancer as well as broad in vitro activity across prostate cell lines.
In castrated mice bearing VCaP xenografts, the prostate cancer RIPTAC therapeutic induced AR:RIPTAC:EP ternary complex formation in the tumor at a low oral dose, resulting in tumor‑specific abrogation of the essential protein.
The RIPTAC therapeutic demonstrated pharmacokinetic properties suitable for oral administration.
Lead molecules utilizing AR as a tumor protein formed a ternary complex between AR and an essential protein involved in transcriptional regulation across prostate cancer cell lines, leading to abrogation of the essential protein and consequent cancer cell killing.
About Prostate Cancer and mCRPC
Prostate cancer is the most common non-skin cancer in men. In the U.S., 1 in 8 men will be diagnosed with prostate cancer in his lifetime.1 Prostate cancer depends on the androgen receptor (AR), a transcription factor critical for prostate cancer growth and progression. Treatment initially relies on androgen deprivation therapy, as well as AR signaling inhibitors (ARSIs). However, resistance to antiandrogen interventions eventually emerges, and is driven by many heterogenous bypass mechanisms including genomic alterations in AR. The long-term prognosis for patients with metastatic castration resistant prostate cancer (mCRPC) is poor, with a relatively short overall survival. In the mCRPC form of the disease, more than 80% of patients harbor amplifications of the AR gene or the upstream enhancer region of DNA.2 AR remains expressed in tumors even if they are no longer AR dependent, dramatically reducing effectiveness of ARSIs, thus representing a vast unmet need.