Two decades after Craig M. Crews, PhD, successfully developed cancer therapies based on degrading unwanted or harmful proteins in cells, a six-year-old startup founded by the Yale University professor and serial entrepreneur is developing oncology treatments that apply another chimera-targeting approach.
Halda Therapeutics is building a pipeline of precision therapeutics capable of selectively targeting major solid tumor cancers and directly killing cancer cells based on the company’s regulated induced proximity targeting chimeras (RIPTAC™) platform. Halda recently completed a $126 million Series B extension financing designed to advance its first two candidates into the clinic starting next year.
Unlike the proteolysis targeting chimeras or PROTACs developed by Crews’ lab in the early 2000s, RIPTACs are heterobifunctional molecules that hold two proteins together via a linker. One protein is tumor-specific, while the other performs an essential function. The resulting protein-protein interaction nullifies the essential cell function, killing the cancer cells while sparing non-cancer tissue where the cancer-specific protein is absent or minimally expressed.
It’s an approach that Halda calls “hold and kill; the company’s name is Nordic for “Hold.”
Halda says it has developed an algorithm to help select complementary pairs to begin RIPTAC therapeutic design, drawing upon hundreds of cancer selective intracellular protein markers and hundreds of proteins with essential function.
“The exciting thing about RIPTAC therapeutics is that they’re agnostic to tumor drivers,” Kat Kayser-Bricker, PhD, Halda’s chief scientific officer, told GEN Edge. “They can be oral small molecules, which is really a huge advantage over agents that have broad cell killing mechanisms like T-cell engaging bispecifics, or ADCs [antibody-drug conjugates] that are injectable therapies. Being able to have this broad efficacy with a small molecule oral therapy is a huge benefit to patients, and it’s designed to overcome the resistance that arises as patients progress on therapies.”
Halda says the financing, announced August 12, will fund the advancement of its first two RIPTAC candidates into clinical trials. During the first half of 2025, Halda plans to launch a Phase I trial assessing its lead RIPTAC candidate HLD-0915, a candidate designed to treat metastatic, castration-resistant prostate cancer (mCRPC).
No timeframe has been set for clinical study of the second RIPTAC candidate, which is designed to treat metastatic breast cancer.
Proof of mechanism and pharmacology
A week before disclosing the financing, Kayser-Bricker, Crews and 32 co-authors based at Halda and Yale published a paper in Cell Chemical Biology with data showing proof of mechanism and pharmacology of a RIPTAC therapeutic. The paper, “Regulated Induced Proximity Targeting Chimeras (RIPTACs): a Heterobifunctional Small Molecule Strategy for Cancer Selective Therapies,” detailed the creation of a chemical biology model of RIPTAC therapeutics, and illustrated their mechanism of action.
Last year, Halda emerged from stealth mode when its researchers delivered its first public presentation of data for a RIPTAC therapeutic at the 2023 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium in San Francisco.
The researchers presented preclinical data for the RIPTAC modality as applied to prostate cancer—though not specifically for HLD-0915—by demonstrating anti-tumor activity superior to the standard of care agent in prostate cancer, the Astellas Pharma/Pfizer co-marketed androgen receptor inhibitor Xtandi® (enzalutamide) in an in vivo rodent model of enzalutamide-insensitive prostate cancer. Researchers also demonstrated broad in vitro activity for the RIPTAC therapeutic across prostate cell lines.
Halda says data specific to HLD-0915 will eventually be generated but is not disclosing when. The Series B extension will enable Halda to generate clinical proof of concept for HLD-0915 “place us in a position to potentially run a registrational trial,” Kayser-Bricker said.
Also not being disclosed is how long of a financial “runway” the financing gives Halda. The Series B financing brings to $202 million the total capital raised by Halda since it was established in 2019 by Crews, whose positions at Yale include John C. Malone Professor of Molecular, Cellular, and Developmental Biology; Executive Director, Yale Center for Molecular Discovery; and a professor of chemistry, of pharmacology, and of management.
Crews’ lab pioneered the use of chemical approaches to control cellular systems by developing the hetero-bifunctional molecule approach first applied in targeted protein degradation through PROTACs. The technology served as the founding intellectual property for New Haven-based Arvinas, founded in 2013 to commercialize PROTAC-based drugs.
“Lots of Ideas”
“He was one of the first scientists to really think about bringing two molecules together to do interesting biology and to apply that to therapeutics,” Kayser-Bricker said of Crews. “Like any brilliant academic, he has lots of ideas. He invented this hetero-bifunctional molecule approach. Then, after the success of PROTACs, he really stepped back and thought, ‘What is some other biology that we could invent by bringing two proteins together and apply that to therapies to help patients?’ So, he founded Halda to do just that.”
Before focusing on RIPTACs, Halda pursued and interrogated several different hetero-bifunctional ideas during its early years, during which it moved from Branford, CT, into the former Winchester Repeating Arms Co. manufacturing site within Science Park at Yale.
Halda says it plans to use part of its proceeds to expand its staff and develop additional RIPTAC therapies for other cancer indications where there is unmet need. The company employs about 30 people and is based in New Haven, CT, where Yale is located.
“We’re focused on building out the team for downstream development activities as we’re getting ready to move into our Phase I trial,” Kayser-Bricker said. “One thing that is on our radar is continuing to build out the leadership team as well.”
Kayser-Bricker said the financing will likely allow it to bring on a full-time CEO. That role is being fulfilled, for now, by the company’s executive chair since its founding, Tim Shannon, MD, general partner with Canaan Partners.
Canaan is among Halda’s existing investors, along with Access Biotechnology, Elm Street Ventures, and Connecticut Innovations, the Nutmeg State’s strategic venture capital arm. They were joined in the Series B extension by new investors Deep Track Capital, Frazier Life Sciences, RA Capital Management, Vida Ventures, Boxer Capital, and Taiho Ventures.
In connection with the financing, representatives of four of the new investors have been appointed to Halda’s board: Rebecca Luse, Principal at Deep Track Capital; Joe Cabral, principal at Frazier Life Sciences; Nandita Shangari, PhD, managing director at RA Capital Management; and Arjun Goyal, MD, co-founder and managing director at Vida Ventures.
“The team at Halda is creating a new era for oncology treatment with a groundbreaking modality, RIPTAC therapeutics, including medicines that have the potential to deliver solutions for cancer patients,” Goyal stated.
