With latest startup, repeat biotech founder Craig Crews tries to ‘hold and kill’ tumors

diving letter:

• Halda Therapeutics, a Connecticut-based biotechnology startup co-founded by Yale University cancer researcher and serial entrepreneur Craig Crews, surfaced on the sly Tuesday with plans to develop drugs it claims can kill tumors in unusual ways .
• The startup’s experimental drugs, dubbed “RIPTAC” therapeutics, are a variant of a type of cancer drug that uses the cell’s internal machinery to destroy troublesome proteins. Halda says his drug candidates are designed to hold two proteins in place until a reaction occurs that kills the cancer cell, an approach that could address some limitations of targeted cancer treatments.
• Halda is backed with $76 million by investors including Canaan Partners and Access Biotechnology and has two early-stage solid tumor drugs. Although the company has yet to appoint a CEO, its principal scientist is Kat Kayser-Bricker, a longtime research and development executive at Forma Therapeutics.

Dive insight:

The term “molecular glue” has become a household name in oncology, and Crews is one of the reasons why.

With his Yale lab colleagues, Crews spent decades researching ways to repurpose the cell’s so-called garbage disposal system against cancer. In 2003 he founded Proteolix, the company that discovered the cancer drug Kyprolis. By attaching itself to the cell’s protein shredder, the proteasome, Kyprolis causes a build-up of waste that destroys malignant myeloid cells.

But Kyprolis, now owned by Amgen, was just the beginning for Crews. Since then, he’s made a major contribution to a field of research known as targeted protein degradation, in which a small molecule forcibly pulls together, or “glues,” two proteins that wouldn’t normally interact, marking one for destruction. A startup he founded in 2013, Arvinas, is the most notable among a long list of biotechs that have formed over the past decade to pursue the approach seen as a way to achieve difficult drug goals. Several, including Arvinas, have partnered with larger pharmaceutical companies.

Crews hopes to take his work with Halda a step further. “Now that the industry sees the potential of these drugs,” he says, “it frees your creativity to think, what else can we do?”

Halda similarly uses a “glue” mechanism to fight cancer. But instead of tagging and discarding a problematic protein, the company aims to “choke out” proteins that are essential for a cancer cell’s survival, Crews said. To do this, it brings together a protein that is overexpressed in a tumor cell and another that is critical to its survival. Locked in place, the essential protein is suppressed and the cell killed.

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

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 an example, a preclinical prostate cancer drug, at a medical meeting later this week. This candidate targets the androgen receptor protein that is overexpressed in prostate tumors and an unspecified target involved in transcription.

Crews and Kayser-Bricker claim their approach can bypass a mechanism by which tumors develop drug resistance, which is one of the reasons they start metastatic castration-resistant prostate cancer. These tumors eventually mutate to survive without relying on the androgen receptor, rendering drugs that focus on this target ineffective.

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

Their work remains early and unproven. Halda doesn’t say 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 funding for early stage biotechs has become more difficult. The company completed its latest round, a $51 million Series B, in late 2021. Kayser-Bricker didn’t say how long the company would run or what its next financial moves might be.

“We have what we need now,” she said. “We’re in a good place and we’re really just focused on moving our programs forward.”