Onconova Therapeutics Inc. CEO Ramesh Kumar noted that "the more direct RAS target approaches have so far not succeeded, although a lot of work is going on," and that's why his firm chose a different route with rigosertib in myelodysplastic syndromes (MDS).

"RAS doesn't have a really nice pocket," he told BioWorld. "What our scientists have found is that there is another pocket that people have not been chasing – the RAS binding domain," or RBD. Included in the RAS universe are 15 to 20 proteins; all share the RBD as a docking site. As long ago as 2016, a paper published in Cell showed that rigosertib, proved safe so far in more than 700 patients, "basically mimics RAS and plays havoc with the entire pathway," to the benefit of cancer patients with overheated signaling. An estimated 30 percent of tumors involve RAS.

After trading as high as $2.66, Newtown, Pa.-based Onconova's shares (NASDAQ:ONTX) ended Wednesday at $1.72, down 2 cents, following news that the independent data monitoring committee (DMC) gave its nod for the firm to move forward with the phase III trial known as INSPIRE (the INternational Study of Phase III I.V. RigosErtib).

The experiment is testing intravenous (I.V.) rigosertib in patients with higher-risk MDS who have progressed on, failed to respond to or relapsed after hypomethylating agent (HMA) therapy, typically azacitidine. DMC inspectors recommended that the trial go ahead with a one-time expansion in enrollment, using a pre-planned sample size re-estimation consistent with the statistical analysis plan (SAP) agreed upon for the trial. Onconova remains blinded to interim data.

"The FDA and the EMA were very strict about what the company is allowed to know," the firm's chief medical officer, Steven Fruchtman, said. Other than the encouraging news from the DMC, "nothing has changed," he told BioWorld.

INSPIRE seeks to show a 33.5 percent improvement with rigosertib over physician's choice.

The SAP for the INSPIRE trial featured an adaptive trial design, permitting several options following the interim analysis, which included continuation of the trial as planned, discontinuation of the trial for futility, trial expansion using pre-planned sample size re-estimation, and trial continuation for only the pre-defined treatment subgroup of patients classified as very high risk (VHR), based on the Revised International Prognostic Scoring System.

INSPIRE will continue to enroll eligible patients based on the current trial design of the overall intent-to-treat (ITT) population and will increase enrollment by adding 135 patients to the original target, reaching a total sign-up of 360 patients, with the aim of increasing the power of the trial. The ITT and the VHR population will continue undergoing evaluation with regard to the primary endpoint of overall survival. With expanded enrollment, the design of the trial will be identical to the current parameters and will include the analysis of the overall survival endpoint in the ITT and the pre-specified VHR subgroup, Onconova said.

The INSPIRE study is active at about 175 trial sites in 22 countries across four continents, and has enrolled more than 170 patients. In Japan, patients have been enrolled to that study by Symbio Pharmaceuticals Ltd., of Tokyo, Onconova's partner for Japan and Korea.

No FDA-approved therapies exist specifically for MDS patients after failure of front-line HMAs.

CDK4/6 efforts underway with Hanx

An oral version of rigosertib is in the works, too. Already the company has tried it when combined with HMAs, and the plan is to start testing this year the combo for response in first-line, higher-risk MDS patients.

"We have presented some phase II data," Fruchtman said, and dose optimization is underway for the would-be pivotal study.

Earlier this month, Onconova signed a cooperative research and development agreement with the NIH's National Cancer Institute (NCI), which will conduct research, including preclinical laboratory studies and a clinical trial, with rigosertib in pediatric cancer-associated RASopathies, the name for rare diseases that share a well-defined molecular basis in expression or defects involving RAS effector pathways. Those are usually caused by germline mutations in genes that alter the RAS subfamily and mitogen-activated protein kinases that control signal transduction, and are among the most common genetic syndromes.

"We're a tiny company," CEO Kumar said. "The more diffuse we go, the less likely we'll succeed. The way we can win is by staying focused but at the same time setting up all these collaborations," he said, adding that the firm is "reaching out to investigators all over the world."

Along with the NIH pact, Onconova is working on a deal with the University of California San Francisco that targets a RASopathy called juvenile myelomonocytic leukemia, or JMML. Proposals have come from the Mayo Clinic, MD Anderson Cancer Center, and researchers in Austria, he said.

Onconova has more than rigosertib. In December, the firm inked a license and collaboration agreement with Hanx Biopharmaceuticals Inc., of Wuhan, China, for further development, registration and commercialization of ON-123300 in that country. The preclinical compound is described as a first-in-class dual inhibitor of CDK4/6 and ARK5. Under the terms, Onconova will receive an up-front payment along with regulatory and commercial milestone payments, as well as royalties on Chinese sales. Hanx will provide all funding required for Chinese IND-enabling studies performed for a CFDA IND approval. The companies also intend for those studies to comply with U.S. FDA standards. Both companies will oversee the IND-enabling studies, and Onconova maintains global rights outside of China.

"The genesis of Onconova is in the chemistry library," Kumar said. "We screen for novel inhibitors of kinases and other enzymes. Some of the kinases that really have perplexed us from the beginning are the so-called cell division kinases, or cyclin-dependent kinases." Drugs from the likes of Pfizer Inc., Novartis AG and Eli Lilly and Co. have proved successful, and Onconova with Hanx hopes to develop a second-generation approach that makes a drug active as a single agent, functional when the first-generation therapies develop resistance, and useful beyond breast and lung cancers, he said.

Hanx is developing a PD-1 checkpoint inhibitor antibody with which the CDK4/6 therapy might be synergistic. "Without us deviating from our focus, without us spending additional money, the [CDK4/6] drug hopefully will be in the clinic later this year," he said.

Aside from the academic, NIH and Symbio tie-ups, Onconova is seeking deals in geographic areas where the small company could not commercialize. "We would very much like to keep the U.S. rights in our control, but everywhere else, outside of the U.S., outside of Japan and Korea, we're looking for new partnerships," Kumar said.