Volasertib is a polo-like kinase 1 (PLK-1) inhibitor with demonstrated activity in leukemia (AML) and other tumor types with significant unmet medical need. We believe that by pairing volasertib with a predicted responder diagnostic (PRD), we can create a novel Presponse™ therapeutic and potentially deliver a life-changing therapy for people fighting relapsed/refractory AML (R/R AML).
Previous studies have shown that volasertib offers the advantages of compelling activity, manageable and robust tolerability, and strong performance. The volasertib safety database includes more than 1,400 patients, including multi-year responses beyond trial duration with a significant and meaningful survival increase. By pairing volasertib with our proprietary predicted responder diagnostic, we believe we can dramatically increase the clinical response rate by identifying and treating only those patients who are most likely to benefit.
Ntbl-201 (Volasertib + PRD-AML) is entering a Phase 2 trial in R/R AML. The clinical trial design is optimized through post hoc analysis of the original Boehringer Ingelheim trial and in combination with a predicted responder diagnostic that allows us to enroll only those patients who are most likely to respond. Based on the robust results of a 41-sample proof-of-concept study, we are optimistic about the potential to improve patient selection and lead to a strong Phase 2 study.
Ex vivo flow cytometry experiments evaluated the treatment of volasertib on 41 primary AML samples collected from peripheral blood or bone marrow. Dose-response profiles consistent with volasertib’s role as a cell cycle inhibitor were observed. To obtain a preliminary concentration of volasertib for patient stratification, Notable compared the ex vivo resistant blast fractions (leukemic cells surviving ex vivo treatment with volasertib) at several concentrations with the area under the curve (AUC) for volasertib dose-response, assuming that the AUC would correspond most accurately with the clinical responses.
While prior studies of volasertib demonstrated an approximately 30 percent complete response/complete response with incomplete count recovery (CR/CRi) rate in de novo AML patients in combination with cytarabine, development was halted in part due to toxicity potentially related to the use of a flat dose, rather than patient-specific, body-surface area (BSA) dosing. Notable provided an updated plan for the design of an open label Phase 2 study, including a dose optimization plan aimed at reducing toxicity while maintaining efficacy and an overview of study objectives and endpoints.
The results suggest a strong correlation between volasertib-resistant fractions treated with 31.6 and 100 nM of volasertib and AUCs, which could represent a suitable metric to stratify patients into responders and non-responders. These preliminary metrics predict that 32–33 percent of de novo patients and 25 percent of R/R AML patients would be predicted to be responders if they were treated with volasertib. We look forward to implementing a dosing optimization plan, including standardized use of best supportive care and introduction of body surface area-based dosing, to enhance patient responses and tolerability.
