Bold Therapeutics Inc. presented compelling late-breaking data at the American Association for Cancer Research (AACR) Annual Meeting 2025 demonstrating BOLD-100's unique dual mechanism of action: direct anticancer activity combined with significant neuroprotective effects against oxaliplatin-induced peripheral neuropathy (OIPN). The findings, presented by Sr. Director of Preclinical Development Mark Bazett, PhD, could transform first-line treatment for metastatic colorectal cancer.
Clinical Evidence of Neuroprotective Benefits
The company's global Phase 1b/2a trial (BOLD-100-001, NCT04421820) evaluated BOLD-100 in combination with FOLFOX across 109 patients with advanced gastrointestinal cancers, including colorectal, gastric, biliary tract, and pancreatic cancers. While the study was designed to assess efficacy and safety, investigators observed an unexpected and profound reduction in both frequency and severity of OIPN.
"In each patient cohort, rates of neuropathy were dramatically lower than those typically seen in historical benchmarks for FOLFOX alone," the company reported. Trial investigators noted the unexpectedly low incidence of neuropathy, particularly in heavily pretreated patients receiving FOLFOX again, where high incidence and severity would normally be expected.
Preclinical Validation Confirms Mechanism
To validate these clinical observations, Bold Therapeutics developed a preclinical rat model of cold allodynia, a common OIPN symptom. Rats treated with high or low doses of oxaliplatin received BOLD-100 every three days for 17 days. The results confirmed clinical findings: animals receiving BOLD-100 showed significantly less neuropathic pain. Importantly, when BOLD-100 treatment ceased, neuropathy symptoms rapidly returned, providing strong evidence for its protective mechanism.
Addressing Critical Unmet Medical Need
Peripheral neuropathy represents one of the most significant toxicities of oxaliplatin, the gold-standard chemotherapy for metastatic colorectal cancer. Up to 85% of patients receiving oxaliplatin develop some degree of neuropathy, with 30-50% experiencing persistent, chronic symptoms severely impacting quality of life. The condition manifests as pain, tingling, numbness, and extreme cold sensitivity affecting hands, feet, and oral cavity.
For many patients, peripheral neuropathy becomes the primary reason for dose reductions, treatment interruptions, or early discontinuation of oxaliplatin-based therapy, directly compromising therapeutic outcomes and survival benefits. With no approved treatments to prevent or reverse OIPN, oncologists face difficult trade-offs between maintaining treatment efficacy and preserving long-term quality of life.
Commercial and Clinical Implications
According to an independent analysis by a leading U.S. life science investment bank supported by extensive physician and payer interviews, BOLD-100's expanded clinical positioning could result in a potential multibillion-dollar commercial opportunity starting in 2030. The drug could potentially treat up to 85% of first-line metastatic colorectal cancer patients, representing a significant market expansion.
BOLD-100's dual benefits could allow patients to complete full treatment cycles without dose modifications, maintain better functional independence and quality of life, avoid long-term irreversible nerve damage, and enhance overall treatment adherence and clinical outcomes.
Ongoing Development and Future Plans
Bold Therapeutics is currently enrolling FOLFOX-naïve second-line metastatic colorectal cancer patients in a multinational randomized clinical study comparing FOLFOX versus FOLFOX plus BOLD-100 across various efficacy, safety, and quality-of-life endpoints. The company anticipates this trial will further demonstrate BOLD-100's potential as a transformative therapy in early-line colorectal cancer, biliary tract cancer, and other solid tumor indications.
The findings pave the way for a pivotal Phase 3 clinical trial and an accelerated pathway to approval in first-line metastatic colorectal cancer. BOLD-100 is a first-in-class selective GRP78 inhibitor that results in stress-induced apoptosis, representing a novel mechanism of action in oncology treatment.
