Veru Advances Oral Sabizabulin After Preclinical Data Show Potent Activity in Daraxonrasib-Resistant Pancreatic Cancer
核心洞察
Veru announced preclinical data showing sabizabulin overcomes daraxonrasib resistance with an IC50 of 18.2 nM in a resistant human pancreatic cancer (搜索) cell line, a concentration achievable with current human dosing.
The company will advance oral sabizabulin into a planned Phase 2b trial for metastatic KRAS (搜索)-driven pancreatic cancer (搜索) that has progressed on the recently FDA-approved daraxonrasib.
Sabizabulin demonstrated collateral sensitivity (resistance index of 0.25) in daraxonrasib-resistant pancreatic cancer (搜索) cells, with prior Phase 1b/2 data showing a favorable safety profile in 80 prostate cancer patients.
Veru Inc. (NASDAQ: VERU) announced new preclinical data demonstrating that its oral microtubule-targeting agent sabizabulin can overcome drug resistance to daraxonrasib (RASONQUE™, Revolution Medicines) with potent anticancer efficacy (IC50 = 18.2 nM) in a daraxonrasib-resistant human pancreatic cancer (搜索) cell line — a drug concentration achievable with current sabizabulin human dosing with good safety. Based on these findings and prior supportive preclinical and clinical studies, the company has made the strategic decision to advance oral sabizabulin as an innovative treatment for patients who develop metastatic pancreatic cancer progression that has become resistant to daraxonrasib.
Preclinical Evidence of Overcoming Daraxonrasib Resistance
Preclinical studies used a 2D proliferation assay to evaluate sabizabulin efficacy in parental and daraxonrasib-resistant KRAS (搜索)-driven pancreatic cancer (搜索) cell line AsPC-1 (G12D KRAS mutation) and colon cancer HCT-116 cell line (G13D KRAS mutation). Investigators confirmed that the mechanism of daraxonrasib resistance was reactivation of the KRAS signaling pathway in both resistant cell lines.
The resistance index (RI) — the ratio of drug concentration required to inhibit 50% cell growth (IC50) in the resistant cell line compared with its parental (sensitive) line — was used to quantify drug tolerance. An RI greater than 1 indicates resistance, while an RI below 1 indicates increased sensitivity. As expected, daraxonrasib-resistant cell lines were resistant to daraxonrasib, with an RI of 68 for the pancreatic cancer (搜索) cell line and an RI of greater than 128 for the colon cancer cell line. In contrast, daraxonrasib-resistant pancreatic cancer cells became more sensitive (collateral sensitivity) to sabizabulin, with an RI of 0.25, while the resistant colon cell line retained sensitivity with an RI of 1.
These data indicate that sabizabulin retained highly potent anticancer efficacy in daraxonrasib-resistant pancreatic and colon cancer cell lines characterized by reactivation of the KRAS (搜索) signaling pathway, and may support sabizabulin as a treatment for daraxonrasib-resistant cancer types beyond pancreatic cancer (搜索).
Clinical Rationale and Prior Safety Data
"The recent FDA approval of Revolution Medicines' daraxonrasib was a major breakthrough in the treatment of KRAS (搜索)-driven metastatic pancreatic cancer (搜索)," said Mitchell Steiner, M.D., Chairman, President, and Chief Executive Officer of Veru Inc. "Unfortunately, resistance to daraxonrasib occurs as the median time to cancer progression was 7.2 months in patients receiving daraxonrasib. The primary mechanism that leads to daraxonrasib reactivation is reactivation of the KRAS signaling pathway. As sabizabulin targets downstream components of the KRAS signaling pathway, we explored and confirmed in recently completed preclinical studies that sabizabulin has the potential to treat metastatic pancreatic cancer that has become resistant to daraxonrasib."
Sabizabulin's first-in-man study was a Phase 1b/2 clinical trial evaluating safety and efficacy in advanced metastatic prostate cancer (Markowski et al. Clin Cancer Res 28:2789-2795, 2022), conducted in 80 patients with heavily pretreated metastatic castration-resistant and taxane-resistant prostate cancer. The Phase 1b portion used a 3+3 dose escalation design with escalating daily oral doses of 4.5 mg to 81 mg, while the Phase 2 portion tested a daily dose of 63 mg in 41 patients. The maximum tolerated dose was not defined, and the recommended Phase 2 dose was set at 63 mg/day.
The most common adverse events (greater than 10% frequency) at the 63 mg oral daily dose were predominantly Grade 1-2 events. Grade ≥3 events included diarrhea (7.4%), fatigue (5.6%), and ALT/AST elevations (5.6% and 3.7%, respectively). Neurotoxicity and neutropenia were not observed at these dosage levels.
In patients treated with at least one continuous 21-day cycle of 63 mg or higher, the Kaplan-Meier median radiographic progression-free survival was estimated at 11.4 months, with durable responses lasting greater than 12 months occurring in 14.5% (n=55) of patients. The objective response rate was 20.7% in patients with measurable disease, with durable responses lasting greater than 2.75 years observed. By comparison, historical controls showed radiographic progression-free survival of only 3.6 months and an objective response rate of 2% with an alternative androgen receptor blocking agent (deBono J NEJM 382:2091, 2020).
"Sabizabulin represents a compelling candidate for Phase 2 evaluation following daraxonrasib treatment, based on its profile as an oral, targeted agent with a novel microtubule binding mechanism and its ability to downregulate TUBB3 (搜索) and other downstream effectors of the KRAS (搜索) signaling pathway," said Daniel King, M.D., Ph.D., Medical Oncologist and Director of Research and Development for Genomic Medicine at Northwell Health. "The rationale is further strengthened by reassuring safety findings from a previous Phase 1b/2 study in 80 patients, as well as preclinical data evidence that daraxonrasib resistance may potentiate sensitivity to sabizabulin."
Mechanism of Action
Sabizabulin is an orally bioavailable microtubule targeting agent that binds a novel site on microtubules, causing crosslinking of α-tubulin with the "colchicine binding site" of β-tubulin to inhibit microtubule polymerization. Based on over 12 peer-reviewed publications across a broad range of tumor types, sabizabulin treatment disrupted and fragmented microtubules, inhibited cancer cell proliferation and tumor growth, prevented cancer cell invasion and metastases, and suppressed angiogenesis. Sabizabulin also preferentially decreases transcription of βIII- and βIV-tubulin isoforms to restore chemotherapy sensitivity and induces apoptosis in nondividing cells. Notably, sabizabulin is not a substrate for multidrug resistance proteins including P-glycoprotein, MRP, and BCRP, meaning it cannot be effluxed from cancer cells.
Disease Burden and Unmet Need
Pancreatic cancer (搜索) is a highly lethal disease with one of the lowest survival rates of all major cancers, with an estimated 67,530 new cases and 52,740 deaths in the United States for 2026. The disease is predicted to become the second leading cause of cancer-related deaths in the United States by 2030. Median overall survival is 4 months, with only approximately 12.5% of patients expected to survive 5 years following diagnosis. The somatic activating KRAS (搜索) oncogene mutation is observed in more than 90% of pancreatic cancer tumors and remains active during progression from epithelial cells to invasive cancer.
Next Steps
The company plans to pursue a Phase 2b clinical study to evaluate the efficacy and safety of sabizabulin in patients who have metastatic pancreatic cancer (搜索) progression while receiving daraxonrasib (RASONQUE). Veru will first seek regulatory clarity from the FDA through a preIND meeting in calendar Q4 2026 to better understand the scope of the clinical trial. The company controls global development and commercialization rights to sabizabulin with issued patent protection until 2043. As part of this strategic decision, Veru will no longer explore sabizabulin for the treatment of chronic inflammation related to atherosclerotic cardiovascular disease.