Dive Brief:

• Halda Therapeutics, a Connecticut-based biotechnology startup co-founded by Yale University cancer researcher and serial entrepreneur Craig Crews, emerged from stealth Tuesday with plans to develop medicines it claims can kill tumors in an unusual way.
• Dubbed “RIPTAC” therapeutics, the startup’s experimental medicines are a twist on a kind of cancer drug that co-opts the cell’s internal machinery to destroy troublesome proteins. Halda says its drug candidates are designed to hold two proteins together to cause killing of the cancer cell, an approach that could address some limitations of targeted cancer treatments.
• Halda is backed with $76 million from investors, including Canaan Partners and Access Biotechnology, and has two medicines in early development for solid tumors. Though the company doesn’t yet have a CEO appointed, Kat Kayser-Bricker, a longtime R&D executive with Forma Therapeutics, is its chief scientist.

Dive Insight:

The term “molecular glue” has become a well-known phrase in oncology, and Crews is one of the reasons why.

With his labmates at Yale, Crews has spent decades researching ways to repurpose the cell’s so-called garbage disposal system against cancer. In 2003, he formed Proteolix, the company that discovered the cancer drug Kyprolis. By locking on to the cell’s protein-shredder, the proteasome, Kyprolis causes a pileup of waste that destroys malignant myeloid cells.

But Kyprolis, now owned by Amgen, was just the start for Crews. He’s since become a key contributor to a field of research known as targeted protein degradation, in which a small molecule forcibly pulls, or “glues,” two proteins together that normally wouldn’t interact, flagging one for destruction. A startup he founded in 2013, Arvinas, is the most notable among a lengthy list of biotechs that formed in the last decade to pursue the approach, which is seen as a way to reach difficult drug targets. Several, including Arvinas, have partnered with larger pharmaceutical companies.

Crews hopes to take his work one step further with Halda. “Now that the industry recognizes” the potential of these medicines, he says, it “frees up one's creativity to think, what else can we do?”

Halda similarly uses a “gluing” mechanism to target cancer. But instead of tagging and trashing a problematic protein, the company aims to “smother” proteins essential to a cancer cell’s survival, Crews said. It does so by bringing together a protein that’s overexpressed in a tumor cell and another that’s crucial to its survival. Locked in place, the essential protein is stifled, killing the cell.

The company’s scientists outlined the approach in a manuscript uploaded in January to the pre-print server bioRxiv.

Halda believes this “hold-and-kill” strategy could be used to selectively target any overexpressed protein within a tumor, while sparing healthy tissue. The company is describing one example, a preclinical prostate cancer drug, at a medical meeting later this week. That candidate targets the androgen receptor protein, which is overexpressed in prostate tumors, as well as an unspecified target involved in transcription.

Crews and Kayser-Bricker claim their approach can sidestep a mechanism by which tumors develop drug resistance, which is one reason they’re starting with metastatic castration-resistant prostate cancer. These tumors eventually mutate to survive without relying on the androgen receptor, making drugs that focus on that target ineffective.

But the protein is still present in “large numbers” afterwards, potentially allowing Halda to use it to pursue “an alternate cell-killing mechanism,” Kayser-Bricker said.

Their work remains early and unproven. Halda isn’t saying when it expects to start human testing and didn’t describe what else it’s working on.

It’s also growing at a time when financing has become harder for young biotechs to obtain. The company closed its last round, a $51 million Series B, in late 2021. Kayser-Bricker didn’t say how long of a runway the company has or what its next financial steps might be.

“We have what we need for now,” she said. “We’re in a good place and are really just focusing on progressing our programs.”

Editor’s note: This story has been updated to clarify the mechanism by which Halda’s drugs are designed to work.