Trovagene Announces Data Showing Ability of Onvansertib to Rescue Venetoclax-Resistance in AML

Trovagene announced new in-vitro and in-vivo data suggesting that onvansertib may provide a new therapeutic option for patients who develop resistance to frontline treatment with venetoclax.

The data show that onvansertib, as a single agent, inhibits tumor growth in venetoclax (Venclexta® - Abbvie) resistant in-vitro and in-vivo models. Additionally, the data also demonstrate synergy with the combination of onvansertib and venetoclax, providing further support for the ability of onvansertib to rescue patients once they show signs of resistance to venetoclax. Currently, there are no viable treatment options for patients once they develop resistance to venetoclax; the median overall survival is only 1.7 to 2.3 months and prognosis is poor. Onvansertib may represent a new therapeutic option to treat venetoclax-resistant AML and potentially increase progression-free and overall survival for these patients.

"We are very encouraged by the data suggesting that onvansertib will be able to rescue AML patients once they develop resistance to frontline treatment with venetoclax," said Dr. Mark Erlander, Chief Scientific Officer of Trovagene. "In our current Phase 2 AML trial, we are targeting venetoclax-resistant patients and treating them with the combination of onvansertib plus hypomethylating agent decitabine. We are also considering plans to conduct a future clinical trial of onvansertib in combination with venetoclax in patients showing initial signs of resistance to venetoclax to provide a new therapeutic option in an indication with significant clinical need."

AML is the most common acute leukemia in adults and is most frequently diagnosed in those 65 to 74 years of age. Prognosis is generally poor and worsens with advanced age. Current first-line treatment options for AML include induction chemotherapy; however, many older patients are not candidates for this treatment option. With the introduction of venetoclax, the treatment landscape has evolved and elderly patients who are not eligible for intensive chemotherapy are receiving venetoclax in combination with a hypomethylating agent frontline. Resistance tends to develop within approximately 11 months following initiation of treatment with venetoclax and today there are no viable therapies for these patients and their prognosis is poor. Thus, there is a significant medical need for new therapeutic options to treat patients once they develop resistance to venetoclax.

The ongoing multi-center open label Phase 2 AML trial (NCT03303339) of onvansertib in combination with decitabine will enroll a total of 32 patients. Eligible patients are either treatment naïve and not candidates for induction therapy or have relapsed/refractory disease following treatment with one prior regimen, including patients treated with venetoclax in combination with a hypomethylating agent. Patients will receive onvansertib, administered orally, on days 1 through 5 of each 21-28-day cycle in combination with decitabine. The primary efficacy endpoint of objective response (CR + CRi) will be assessed in patients who complete at least 1 cycle of treatment.

Onvansertib is a first-in-class, third-generation, oral and highly-selective adenosine triphosphate (ATP) competitive inhibitor of the serine/threonine polo-like-kinase 1 (PLK1) enzyme, which is over-expressed in multiple cancers including leukemias, lymphomas and solid tumors. Onvansertib targets the PLK1 isoform only (not PLK2 or PLK3), is orally administered and has a 24-hour half-life with only mild-to-moderate side effects reported. Trovagene believes that targeting only PLK1 and having a favorable safety and tolerability profile, along with an improved dose/scheduling regimen will significantly improve on the outcome observed in previous studies with a former panPLK inhibitor in AML.

Onvansertib has demonstrated synergy in preclinical studies with numerous chemotherapies and targeted therapeutics used to treat leukemias, lymphomas and solid tumor cancers, including irinotecan, FLT3 and HDAC inhibitors, taxanes and cytotoxins. Trovagene believes the combination of onvansertib with other compounds has the potential to improve clinical efficacy in acute myeloid leukemia (AML), metastatic castration-resistant prostate cancer (mCRPC), non-Hodgkin lymphoma (NHL), colorectal cancer and triple-negative breast cancer (TNBC), as well as other types of cancer.

Trovagene has three ongoing clinical trials of onvansertib: A Phase 2 trial of onvansertib in combination with Zytiga® (abiraterone acetate)/prednisone in patients with mCRPC who are showing signs of early progressive disease (rise in PSA but minimally symptomatic or asymptomatic) while currently receiving Zytiga® (NCT03414034); a Phase 1b/2 Study of onvansertib in combination with FOLFIRI and Avastin® for second-line treatment in patients with mCRC with a KRAS mutation (NCT03829410); and a Phase 1b/2 clinical trial of onvansertib in combination with low-dose cytarabine or decitabine in patients with relapsed or refractory AML (NCT03303339). Onvansertib has been granted orphan drug designation by the FDA in the U.S. and by the EC in the European Union for the treatment of patients with AML.

Trovagene licensed onvansertib (also known as NMS-1286937 and PCM-075) from Nerviano Medical Sciences (NMS). NMS has an excellent track record of licensing innovative drugs to pharma/biotech companies, including Array (recently acquired by Pfizer), Ignyta (acquired by Roche) and Genentech.

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