Bolt Hones in on ISAC programs as Toxicities Claim Preclinical Hopeful

Clinical

Immuno-oncology company Bolt Biotherapeutics announced it is dropping its preclinical BDC-2034 program and shifting its focus to prioritize two other immune-stimulating antibody conjugates (ISAC) programs: BDC-1001 and BDC-3042.

The decision to discontinue BDC-2034 was based on off-target toxicity related to the targeting antibody. The company stated that with its current cash flow position and new strategy, it can keep its doors open through 2025. 

“The second quarter was one of continued progress, highlighted by steady clinical enrollment in our BDC-1001 monotherapy and combination dose-escalation studies,” Randall C. Schatzman, Ph.D., CEO of Bolt, said in a statement. “While we are fortunate to be operating from a position of financial strength, we have implemented a pipeline prioritization and new capital allocation initiative focused on advancing BDC-1001 and BDC-3042, two drug candidates that we believe have high potential to benefit patients.”

Bolt focuses on immune-stimulating antibody conjugates, which are monoclonal antibodies conjugated to an immune-stimulatory agent. BDC-2034 uses Bolt’s Boltbody technology to target carcinoembryonic antigen cell adhesion molecule 5 (CEA). Previously, Bolt planned for BDC-2034 to enter the clinic in 2023.

BDC-1001 is a Boltbody ISAC in clinical development for HER2-expressing solid tumors, including subgroups with HER2-low tumors. It is designed as an ISAC made up of HER2-targeting biosimilar trastuzumab, conjugated to one of the company’s proprietary TLR7/8 agonists.

In this way, it stimulates anti-tumor activity in three different ways: direct tumor cell killing by trastuzumab-mediated mechanisms; localized phagocytosis; and elimination of HER2-expressing tumor cells by activated myeloid antigen-presenting cells (APC).

The company expects clinical data and recommended Phase II dosing for the drug in the second half of the year, both as a monotherapy and in combination with Bristol Myers Squibb’s checkpoint inhibitor Opdivo (nivolumab).

BDC-3042 is a myeloid modulating agonist antibody that stimulates myeloid cells to attack cancer cells. The monoclonal antibody binds to Dectin-2, a novel cell surface protein on tumor-supportive macrophages, which causes the production of pro-inflammatory cytokines. Bolt is now running IND-enabling trials for the drug and expects to enter the clinic in 2023.

Schatzman went on to say, “We are winding down spending on BDC-2034, pausing other early-stage research programs, and prioritizing ISAC programs that bring forward the latest generation of our ISAC technology — including our collaboration programs. The combination of these strategic initiatives extends our expected cash runway an additional two years through 2025.”

Bolt indicates its decision to halt the BDC-2034 program was due to off-target toxicity associated with the targeting antibody. The drug is made up of a novel antibody with selective binding to CEACAM5 (a member of the carcinoembryonic antigen, CEA, family) that demonstrated high levels of antibody-dependent cellular phagocytosis of CEA-expressing cancer cells. The company indicates it still views CEA as a viable Boltbody target if it can develop a more selective antibody.

The Boltbody ISAC platform allows researchers to both activate and recruit myeloid cells in order to reprogram the tumor microenvironment and stimulate a new anti-tumor immune response. This allows the patient’s own immune system to decide which T cells are relevant to mobilize for tumor destruction and subsequent immunosurveillance. It’s designed as an off-the-shelf immunotherapy that still delivers a personalized therapeutic outcome.

Financially, Bolt reported $1.4 million in collaboration revenue for the quarter, compared to $0 from the same quarter the previous year. This was generated from services performed under research-and-development collaborations with Genmab A/S and Innovent Biologics, Inc.

R&D expenses were $18.9 million for the quarter, down slightly from $19.7 million in the first quarter of 2021. General and Administrative (G&A) expenses were $5.5 million for the quarter compared to $4.1 for the first quarter of 2021. Loss from operations was $23.1 million for the quarter compared to $23.8 million for the same period the year before.

Bolt reports cash, cash equivalents and marketable securities of $223.6 million, which should carry it through the next few years. 

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