Onconova eyes 'RASopathy' diseases as new targets for its lead drug

Onconova is planning a sideways step for its lead cancer drug rigosertib—with help from a research consortium—that could open up new opportunities in rare diseases.

Rigosertib has reached the phase 3 testing stage for myelodysplastic syndromes (MDS), although its progress through development has not been easy, punctuated with failed clinical trials in MDS and pancreatic cancer and the loss of Baxalta as its commercial partner last year.

The new collaboration focuses on 'RASopathies'—which are individually rare but together represent the largest group of genetic conditions that affect learning and development, according to RASopathies.net, a nonprofit organization devoted to bringing patients and their caregivers together with clinicians and researchers.

RASopathies involve a breakdown in the proper functioning of the RAS molecular signaling pathways that control cell activity, usually as a result of genetic mutations in pathways proteins. The mutations can be inherited or spontaneous and—even in people within the same family with the same mutation—the nature of the disease can vary.

In some cases—and these are the ones that Onconova is currently interested in—the cells can be instructed to divide on an uncontrolled fashion, causing cancers, but can have a range of other effects in the body affecting multiple organ systems.  It is thought as many as 1 in 1,000 people are affected by RASopathies.

The Philadelphia biotech reckons RASopathy research could help patients with cancer, and vice versa, and says the new collaboration will "generate supportive non-clinical data and obtain early clinical experience in the pediatric setting with rigosertib", which is thought to block downstream signaling by RAS effectors including PI3K and RAF.

Onconova says it will collaborate with the National Cancer Institute (NCI) on a broad clinical trial for pediatric patients with RASopathies, but it's not straying too far away from its care cancer focus in the first instance. Its first program will involve a RASopathy known as juvenile myelomonocytic leukemia (JMML) that has some similarities with MDS and certain other blood cancers. At the moment the only available treatment for JMML is a bone marrow transplant.

Steven Fruchtman, M.D., Onconova's chief medical officer, said the new program is "advancing research into one of the most important pediatric genetic syndromes, as we work together with families, clinicians and scientists to foster collaborative research efforts."

In the meantime, Onconova is waiting on the results of the phase 3 INSPIRE trial of intravenous rigosertib in second-line MDS—with an interim analysis due later this year—with a more selective patient population than was included in its earlier, failed ONTIME study. It's expecting a final read-out in 2018 with possible filings the following year if all goes to plan.

A phase 2 study in play looking at the combination of oral rigosertib plus azacitidine in front-line MDS and acute myeloid leukemia (AML) is also in play, with a 24% complete remission rate reported at the American Society of Hematology (ASH) meeting last month. Onconova is in the process of designing a phase 3 program for the combination.