Alterome Therapeutics announced today that the first patient has been dosed in its Phase 1/1b clinical trial evaluating ALTA3263, a novel pan-KRAS dual ON/OFF inhibitor, in adults with KRAS-mutant solid tumors. This milestone marks a significant step forward in addressing one of oncology's most challenging targets.
ALTA3263 is an oral, KRAS-selective small molecule inhibitor specifically designed to potently inhibit the KRAS "ON" (active) state of more than 90% of all KRAS mutations while providing complete target coverage in tumors. The compound's dual inhibition mechanism potentially offers advantages over existing KRAS inhibitors that primarily target the OFF state.
A Novel Approach to a Critical Oncogenic Driver
KRAS mutations are found in more than 20% of all patients with metastatic cancer, with particularly high prevalence in non-small cell lung cancer (NSCLC), pancreatic ductal carcinoma (PDAC), and colorectal cancer (CRC). Despite recent advances in KRAS-targeted therapies, many patients with specific mutations remain underserved by current treatment options.
"With this trial, we hope to bring a breakthrough therapy to the many patients with KRAS-driven cancers who are still underserved," said Andrew Chi, M.D., Ph.D., Chief Medical Officer of Alterome. "We have shown in preclinical studies that ALTA3263 has the attributes to potentially address this significant unmet need and transform patient outcomes."
The Phase 1/1b trial (NCT06835569) is designed as an open-label, dose-escalation study with multiple cohorts. Investigators will evaluate the safety, tolerability, pharmacokinetics, and preliminary clinical activity of ALTA3263 in adults with advanced unresectable or metastatic solid tumors harboring KRAS mutations.
Addressing Limitations of Current KRAS Inhibitors
While first-generation KRAS inhibitors have shown clinical benefit for specific mutations like G12C, highly prevalent KRAS mutations such as G12D and G12V exist predominantly in the ON-state and remain difficult to target effectively. ALTA3263 aims to overcome these limitations through its dual ON/OFF state inhibition mechanism.
Anthony Tolcher, M.D., FRCPC, Founder of NEXT Oncology and primary investigator on the ALTA3263 Phase 1/1b trial, highlighted the ongoing challenges: "While progress has been made in KRAS mutant cancers, we still regularly see patients who have exhausted all available effective treatment options and also suffer from toxic side effects of current therapies. We are excited to participate in this trial, and hope that ALTA3263 will usher in the next generation of KRAS targeted therapies that promise greater efficacy and improved tolerability and safety for patients."
Promising Preclinical Profile
According to Alterome, ALTA3263 demonstrates several key pharmacological properties that distinguish it from other KRAS inhibitors in development:
- Non-covalent, orally bioavailable inhibitor with high potency
- Inhibits KRAS with picomolar to low single-digit nanomolar potency
- Targets both ON and OFF states of KRAS
- Exhibits high selectivity for KRAS over HRAS and NRAS
- Demonstrates excellent pharmacokinetic and tolerability profiles
In preclinical studies, ALTA3263 led to deep tumor regressions in multiple KRAS mutant models while being well-tolerated during prolonged oral dosing. These data were presented at the 2024 EORTC-NCI-AACR (ENA) Symposium.
Expanding Precision Oncology Portfolio
ALTA3263 represents one of two clinical-stage programs in Alterome's pipeline. The company is also developing ALTA2618, a first-in-class, oral mutation-selective inhibitor for AKT1 E17K-driven cancers, which is also in Phase 1 clinical development.
Alterome Therapeutics has raised more than $231 million in venture capital to date and is led by a team of precision oncology R&D leaders with experience in developing marketed oncology small molecule drugs.
The initiation of this clinical trial represents an important advancement in the field of KRAS-targeted therapies, potentially offering new hope for patients with limited treatment options. Results from this study will be closely watched by clinicians and researchers focused on precision oncology approaches for solid tumors.
