A First-in-Class, 3rd Generation Polo-like Kinase 1 (PLK1) Inhibitor with Best-in-Class Attributes
Onvansertib is a first-in-class, 3rd generation, oral and highly-selective adenosine triphosphate (ATP) competitive inhibitor of the serine/threonine Polo-like-Kinase 1 (PLK 1) enzyme. The compound was tested against more than 260 kinases with PLK1 being the only active target with an IC50 of 2nM.
Polo-like Kinase 1 (PLK1)
- Belongs to a family of kinases (PLK1,2,3,4,5)
- Dysfunction leads to cancer formation and progression
- Over-expressed in dividing cancer cells
- Inhibition leads to cancer cell death
A Phase 1 clinical trial of onvansertib in patients with advanced or metastatic solid tumor cancers was completed and published in the journal Investigational New Drugs in 2017. This was an open-label dose escalation trial to assess the safety of onvansertib and determine the maximum tolerated dose and recommended Phase 2 dose. A total of 19 patients were administered treatment with onvansertib given orally, once daily for 5 consecutive days in a 21-day cycle. 16 of the 19 patients were evaluable and showed 30% stable disease. Only mild to moderate side effects were reported and there were no gastrointestinal disorders, mucositis or alopecia (hair loss).
We are benefiting from work that was performed with prior 1st and 2nd generation PLK inhibitors that has helped us to optimize our clinical development program for onvansertib. While earlier PLK inhibitors demonstrated significant clinical activity in combination with standard-of-care, major drawbacks unrelated to efficacy of the drug class resulted in discontinuation of their development. Drawbacks include lack of selectivity for PLK1 only, significant toxicities not related to the mechanism of action, intravenous administration, fixed dose and dosing schedule and a long half-life of up to 5 days.
Previous clinical trials with 1st and 2nd generation PLK inhibitors have shown that inhibition of polo-like- kinases can lead to tumor cell death, including a Phase 2 study in Acute Myeloid Leukemia (AML) where response rates of up to 31% were observed when combined with a standard therapy for AML (low-dose cytarabine-LDAC) versus treatment with LDAC alone with a 13.3% response rate. And in a randomized Phase 3 clinical trial, an increase in remission rate of 25% was seen, but with a negative overall survival trend attributed to a combination of factors, including serious adverse events not related to the mechanism of action, an intravenous formulation and fixed dose and regimen, as well as lack if prophylactic administration of anti-infectives to proactively manage serious infections.
The onvansertib product attributes combined with our clinical development program effectively addresses the drawbacks associated with 1st and 2nd generation PLK inhibitors and we believe that onvansertib will demonstrate clinical efficacy along with favorable safety and tolerability.