Off-target toxicity has killed off one of Bolt Biotherapeutics’ lead programs. Rather than push BDC-2034 into the clinic, the immuno-oncology startup is winding down spending on the anti-tumor candidate and focusing its $223.6 million cash pile on two other prospects.
Bolt previously planned to move BDC-2034 into the clinic next year. The candidate uses Bolt’s Boltbody immune-stimulating antibody conjugate technology to target carcinoembryonic antigen cell adhesion molecule 5 (CEA). The tumor antigen is upregulated in various solid tumors including colorectal cancer, non-small cell lung cancer, pancreatic cancer and breast cancer, some of which are immunologically “cold.”
BDC-2034 advanced to the cusp of clinical trials on the strength of evidence from a study in mice, which found the candidate was effective against pancreatic cancer. A naked anti-CEA monoclonal antibody was ineffective in the mice.
Bolt decided to stop development after seeing “off-target toxicity related to the targeting antibody.” The biotech continues to see CEA as a viable Boltbody target but thinks a more selective antibody is needed.
In an Aug. 11 note, SVB Securities senior research analyst Daina Graybosch, Ph.D., said the discontinuation of BDC-2034 is “another illustration that immunostimulatory antibody-drug conjugation (ISAC) is a difficult drug platform, and we expect extensive product iteration and back-translation will be required in this nascent stage of ISAC development.”
In light of the toxicity and a broader pipeline review, Bolt has decided to focus its cash on BDC-1001 and BDC-3042 at the expense of BDC-2034 and early-stage programs, pushing its cash runway out into 2025 in the process. The runway was previously expected to end in 2024.
BDC-1001 conjugates an HER2-targeting biosimilar copy of Herceptin to one of Bolt’s TLR7/8 agonists. The prospect is in early-phase clinical trials as a monotherapy and in combination with Bristol Myers Squibb’s checkpoint inhibitor Opdivo.
The other asset to survive Bolt’s pipeline review, BDC-3042, is still in preclinical development. BDC-3042 is an agonist antibody targeting Dectin-2, an innate immune receptor found on the surface of macrophages. The goal is to activate tumor-associated macrophages, thereby triggering the production of TNFα, IL-6, IL-1β and CCL3. Studies to ready the therapy for the clinic are underway with a view to entering human trials next year.