On July 23, 2020 Onconova Therapeutics, Inc. (NASDAQ: ONTX), a Phase 3-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer, with an initial focus on myelodysplastic syndromes (MDS), reported the publication (Molecular Cell 79, 180-190, 2020) of in vitro data further supporting rigosertib’s role in modulating RAS cellular signaling (Press release, Onconova, JUL 23, 2020, View Source [SID1234562301]).
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"We believe this data sheds light on the capacity of Onconova’s targeted anti-cancer agent rigosertib to modulate the RAS pathway," said Steven M. Fruchtman, M.D., President and CEO. "Mutations of the RAS pathway are the most common mutations observed in cancer. In our opinion this paper confirms the rationale to investigate rigosertib in the treatment of RAS-driven malignant diseases which continue to have a high unmet medical need. Onconova looks forward to further showcasing efforts with this novel compound, including our virtual presentation at the 2nd Annual RAS-Targeted Drug Development Summit September 14-16, 2020."
The study compared the composition and activity of non-clinical grade rigosertib with clinical grade rigosertib that is approved for investigational use in humans. The authors found that non-clinical grade rigosertib used in in vitro studies by others contained impurities and degradation products in sufficient quantities to impact cellular function. In contrast, clinical grade rigosertib, which has been used in all clinical studies to-date, is free of this impurity. Using vincristine as a control, the ability of both compounds to bind tubulin (a mechanism of action seen in less targeted chemotherapy agents) was then measured. In vitro assay results indicated that both non-clinical grade rigosertib and the vincristine control showed tubulin binding activity, while clinical-grade rigosertib did not exhibit detectable tubulin-binding activity. Furthermore, cell lines expressing mutant beta-tubulin remained sensitive to rigosertib.
"We believe that the impurities found in non-clinical grade rigosertib, but not clinical-grade rigosertib, are responsible for the cellular effects observed such as tubulin disruption. Impurities are often found in non-clinical grade products and hence the reason these materials are not permitted in clinical trials," said Richard C. Woodman, M.D., Chief Medical Officer. "The peer-reviewed data reported in Molecular Cell provide new detail on how these impurities can influence chemical properties, cellular functions and subsequently, potential anticancer pathways. It is our opinion that this data supports rigosertib’s mechanism of action as a modulator of RAS signaling."
"Rigosertib is a RAS mimetic that binds to RAS binding domains of RAS effectors and inhibits growth of tumor cells in pre-clinical models. Our studies showed that clinical grade rigosertib does not exhibit tubulin binding activity. Clinical studies conducted by Onconova Therapeutics are expected to provide further insights into the clinical potential of this novel compound," added E. Premkumar Reddy, PhD, Professor of Pharmacological and Oncological Sciences, The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, who is also on Onconova’s Board of Directors.
About Rigosertib
Rigosertib, Onconova’s lead candidate, is a proprietary Phase 3 small molecule. A key publication in a preclinical model reported rigosertib’s ability to block cellular signaling by targeting RAS effector pathways (Divakar, S.K., et al., 2016: "A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling." Cell 165, 643). Onconova is currently in the clinical development stage with oral and IV rigosertib, including clinical trials studying single agent IV rigosertib in second-line higher-risk MDS patients (pivotal Phase 3 INSPIRE trial) and oral rigosertib plus azacitidine in HMA-naive and refractory higher-risk MDS patients (Phase 2). Investigator-initiated study (IIS) programs exploring oral rigosertib in a variety of cancers with mutations of RAS and its pathway are ongoing in solid tumors. Patents covering oral and injectable rigosertib have been issued in the US and are expected to provide coverage until at least 2037.