Recursion Pharmaceuticals is advancing two investigational oncology drugs, REC-3565 and REC-4539, into clinical trials, targeting significant unmet needs in hematologic malignancies and small-cell lung cancer (SCLC). The UK Medicines and Healthcare Products Regulatory Agency (MHRA) has cleared a clinical trial application (CTA) for a Phase 1 clinical trial of REC-3565, a potential best-in-class MALT1 inhibitor for B-cell malignancies. Simultaneously, the U.S. Food and Drug Administration (FDA) has cleared an investigational new drug (IND) application for a Phase 1/2 clinical trial of REC-4539, a potential best-in-class LSD1 inhibitor for SCLC and other potential indications. These advancements highlight Recursion's commitment to leveraging its TechBio platform to industrialize drug discovery.
REC-3565: Targeting B-Cell Malignancies
REC-3565 is designed as a highly selective MALT1 inhibitor for B-cell malignancies, including chronic lymphocytic leukemia (CLL). The total addressable population includes approximately 41,000 relapsed and/or refractory (R/R) patients with CLL and B-cell lymphomas in the US and EU5 annually. MALT1 is a central regulator of NF-kB signaling, which supports the uncontrolled proliferation of malignant B and T cells in hematological cancers.
Combining REC-3565 with Bruton's tyrosine kinase inhibitors (BTKi) or BCL inhibitors could potentially overcome resistance and provide deeper, more durable efficacy. Current MALT1 inhibitors in clinical development have demonstrated off-target inhibition of UDP glucuronosyltransferase 1A1 (UGT1A1), leading to hyperbilirubinemia. REC-3565 does not significantly inhibit UGT1A1, potentially mitigating risks of drug-drug interaction and hyperbilirubinemia.
In preclinical in vivo studies, REC-3565 has demonstrated tumor growth inhibition in hematological xenograft models as a single agent and in combination with BTK inhibitors. Notably, durable tumor eradication was observed in combination with zanubrutinib in an ABC-DLBCL xenograft model. The first patient is expected to be dosed in the Phase 1 EXCELERIZE clinical trial in Q1 2025 to evaluate the safety/tolerability of REC-3565 and provide dosing recommendations for later combination studies.
REC-4539: Addressing Small-Cell Lung Cancer
REC-4539 is a potential best-in-class brain-penetrant LSD1 inhibitor. The initial clinical investigation will focus on SCLC while also exploring other solid tumor indications. The total addressable population in the US and EU5 for extensive-stage SCLC is approximately 45,000 patients annually. Overexpression of LSD1 occurs in several tumor types, including SCLC, driving cancer cell proliferation and survival.
REC-4539 is designed to target both peripheral disease and brain metastases, which are common in SCLC. In preclinical in vivo studies, REC-4539 showed dose-dependent tumor inhibition in an SCLC xenograft model with brain penetration and a reversible mechanism. It also demonstrated potency and selectivity to potentially reduce off-target toxicity, with a favorable ADME profile and limited platelet level effects.
The first patient is expected to be dosed in the Phase 1/2 ENLYGHT clinical trial in H1 2025. The trial will evaluate REC-4539 as a monotherapy and in combination with durvalumab in patients with SCLC.
Leadership Insights
"We are excited to add REC-4539 and REC-3565 to our clinical stage portfolio as we explore first- and best-in-class oncology medicines and build momentum and value through our pipeline," said Chris Gibson, Ph.D., Co-Founder and CEO of Recursion.
Najat Khan, Ph.D., Chief R&D Officer and Chief Commercial Officer, added, "For REC-4539, we’ve developed a reversible LSD1 inhibitor that not only targets peripheral disease but is also designed to penetrate the brain, potentially addressing a critical unmet need in small-cell lung cancer. Similarly, REC-3565 is a highly selective MALT1 inhibitor without significant off-target inhibition of UGT1A1, which could enhance combination therapy by mitigating potential risks of drug-drug interaction and hyperbilirubinemia."
