Trovagene and Nektar have entered into a research collaboration to explore the combination of Trovagene's PLK1 inhibitor, onvansertib, and Nektar's topoisomerase I inhibitor, ONZEALD, for the treatment of metastatic colorectal cancer (mCRC). Under the collaboration, the two companies will evaluate the antitumor activity and tolerability of the combination of onvansertib and ONZEALD in two (HT29 - BRAF mutant and HCT-116 - KRAS mutant) preclinical tumor models of colorectal cancer.
ONZEALD is the first long-acting topoisomerase I-inhibitor (Topo I) designed to enhance the anti-cancer effects of topo I-inhibition while minimizing its toxicities. In a wide range of human xenograft tumors, including two colorectal models (HT29 and DLD-1), ONZEALD has shown superior antitumor activity, compared with irinotecan. ONZEALD is currently being evaluated in a Phase 3 study in patients with breast cancer who have stable brain metastases.
Onvansertib, an oral and highly-selective Polo-like Kinase 1 (PLK1) inhibitor, has shown strong antitumor activity in preclinical models of colorectal cancers, and demonstrated significant and durable synergistic antitumor activity in combination with irinotecan, and was greater than either drug alone. Trovagene has three active clinical trials: a Phase 1b/2 study in relapsed or refractory Acute Myeloid Leukemia (AML), a Phase 2 study in metastatic Castration-Resistant Prostate Cancer (mCRPC) and a Phase 1b/2 study in mCRC.
"We look forward to collaborating with Trovagene to explore a combination therapy with our respective drug candidates, ONZEALD and onvansertib, in tumor models of colorectal cancer," said Jonathan Zalevsky, PhD, Chief Scientific Officer of Nektar Therapeutics. "Importantly, this research collaboration will allow us to evaluate the efficacy of the combination in preclinical models, and potentially identify a promising treatment regimen that we would consider advancing into clinical studies."
"Our research partnership with Nektar is a key milestone achievement in the advancement of our onvansertib clinical development program," said Mark Erlander, PhD, Chief Scientific Officer of Trovagene. "We believe that the clinical data generated to date for ONZEALD, will potentially lead to an optimal treatment option, when combined with onvansertib, for patients with mCRC. Working together with Nektar will enable us to very quickly assess the potential value of the onvansertib/ONZEALD combination and our collective goal of developing an innovative and targeted treatment regimen that may have application in other cancer types beyond CRC."
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, 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, has a 24-hour drug 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 its targeted PLK1 inhibitor, 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, Triple Negative Breast Cancer (TNBC), as well as other types of cancer.
ONZEALD (etirinotecan pegol) is the first long-acting topoisomerase I-inhibitor (Topo I) designed to enhance the anti-cancer effects of topo I-inhibition while minimizing its toxicities. Nektar Therapeutics invented ONZEALD using their unique chemistry platform and is currently developing it for the treatment of advanced breast cancer patients with a history of brain metastases. In preclinical models, ONZEALD achieved a 300-fold increase in tumor concentration as compared to a first-generation topo I-inhibitor.2 Because ONZEALD is a large molecule, it is believed to penetrate the leaky vasculature within the tumor environment more readily than normal vasculature, concentrating and trapping ONZEALD in the tumor tissue.
