Ep165: Zach Hornby on Tackling Cancer Drug Resistance

Episode Summary

Executive Summary: Zach Hornby, CEO of Boundless Bio, discusses how the company is targeting cancer’s extra-chromosomal DNA (ecDNA)—a mechanism that can drive oncogene amplification and resistance to targeted therapies. He explains Boundless Bio’s diagnostics-driven patient selection strategy, two oral small-molecule programs in the clinic, and why slower enrollment and public-market skepticism are part of the long biotech development path.

Main Topics: Origin story and personal background (Priority: 3/5): Hornby describes growing up in Cape Elizabeth, Maine, the influence of his parents, and how early exposure to debate, service, and curiosity shaped his career path toward science and biotech leadership. Education and shift from science to biotech business (Priority: 4/5): He recounts studying biology/neuroscience at Stanford, considering medicine and research, then pivoting toward biotech business roles after realizing he preferred strategy, experimentation design, and analysis over bench work. Career path through biotech operations and commercialization (Priority: 4/5): Hornby traces his career through TKT, L.E.K. Consulting, Harvard Business School, Neurocrine, and Halozyme, highlighting how regulatory, commercial, and strategic experience prepared him for general management. Boundless Bio’s ecDNA-focused scientific platform (Priority: 5/5): The company is developing ecDNA-directed therapeutics to address cancer drug resistance caused by oncogene amplifications on extra-chromosomal DNA loops outside chromosomes. ECHO diagnostic and patient identification strategy (Priority: 5/5): Boundless Bio’s ECHO assay analyzes standard next-gen sequencing BAM files to detect ecDNA signatures and identify which oncogene is amplified, with validation performed through partners and central labs to fit clinical workflows. Clinical pipeline and combination strategy (Priority: 5/5): Hornby discusses two ongoing Phase 1/2 programs: a checkpoint-related program (BBI-355) for amplified tumors and an RNR inhibitor (BBI-825) aimed at ecDNA biology and MAPK-driven resistance, both tested in combination with standard agents. Public-company realities, enrollment delays, and long-term vision (Priority: 4/5): He addresses slower-than-expected enrollment, the rationale for a smaller R&D layoff, the need for a larger data readout in 2H 2025, and his belief that ecDNA-directed drugs could become a new therapeutic class for patients with few or no options.

Key Arguments: ecDNA is a clinically important mechanism of resistance because oncogene amplifications can let tumors evade targeted therapies and later rebound. A diagnostic that uses standard sequencing data is strategically preferable because it avoids forcing clinicians to adopt a new workflow. Partnering with a specialized diagnostics company and central lab improves regulatory readiness and enables prospective trial enrollment. BBI-825’s RNR inhibition is rational because cancer cells have a heightened need for de novo nucleotide synthesis, creating synthetic lethality in ecDNA-bearing cells. The company’s programs are designed to be used in combination with existing standards of care rather than as isolated monotherapies. Although enrollment has been slower than expected, the team is prioritizing stronger, more interpretable data rather than releasing small underpowered datasets. Boundless Bio’s long-term goal is to define ecDNA-directed therapeutics as a new class for a large unmet-need patient population. Small-molecule oral drugs are attractive because they are easier to manufacture, distribute, and eventually scale globally, including in lower-resource settings.

Data Points: Town population: 5,000 - Hornby’s hometown, Cape Elizabeth, Maine. Bio company acquisition value: $1.7 billion - Ignita was acquired in late 2017 after developing Entrectinib (Roslitrec). Year of Harvard Business School MBA: 2005 - Hornby attended HBS after several years in industry. Neurocrine partnership: One of the richest partnerships in industry history - He references the Pfizer alliance around insomnia drug Indiplon. Public offering proceeds: $100 million - Boundless Bio raised this amount in its IPO earlier in the year. Expected proof-of-concept timing: End of 2024 originally; now shifted to 2H 2025 - Due to slower enrollment and desire for a larger dataset. MSK patient database: 70,000 sequenced patients - Memorial Sloan Kettering is using ECHO on its IMPACT-sequenced cohort. Amplification prevalence: 25% of all cancer patients, aside from HER2 - Hornby cites this as a broad unmet-need population lacking standard options. Current clinical trial phase: Phase 1/2 - Both core programs are in ongoing first-in-human dose-escalation studies. Targeted resistance fraction: About 50% - He says resistance in KRAS G12C colorectal can be attributable to amplifications of KRAS or other MAPK genes.

Pivotal Quotes: "“You don’t want to try to convince physicians or pathologists to do something outside of their workflow.”" — Zach Hornby: Explaining why Boundless Bio designed its diagnostics around standard sequencing data. "“Patients with amplification, 25% of all cancer patients, aside from HER2, they have zero standard of care, zero options.”" — Zach Hornby: Describing the unmet need Boundless Bio hopes to address. "“We’re hopeful that we’ll prove that multiple different ECDNA-directed therapeutics work.”" — Zach Hornby: Stating the company’s vision for a new therapeutic class built around ecDNA biology.

Implications: The episode highlights ecDNA as an emerging cancer-resistance target and shows how diagnostics plus combination therapy may create a new precision-oncology category. It also underscores the patience required for biotech execution in public markets.