Onconova Therapeutics Inc.’s lead candidate in myelodysplastic syndromes took a major hit Monday as the small-molecule I.V. rigosertib failed to meet the primary endpoint of significantly improved survival vs. best supportive care in higher-risk patients.

The Newtown, Pa.-based company’s stock (NASDAQ:ONTX) took the failure’s brunt as shares opened about 70% down and ended up closing 66% downward at 34 cents each.

The phase III INSPIRE study compared I.V. rigosertib plus best supportive care to physician's choice (PC) plus best supportive care in patients who had progressed on, failed to respond to, or relapsed after previous treatment with a hypomethylating agent (HMA) within nine cycles in the course of one year after initiation of HMA treatment.

In the intent-to-treat analysis, patients randomized to I.V. rigosertib achieved overall survival of 6.4 months vs. 6.3 months for PC (p=0.33) in the overall higher-risk patient population. Overall survival in the prespecified very high risk subgroup of patients was also not significantly different between the two study arms.

The study showed an increase in overall survival analysis that the company said it had not expected in the PC arm post-interim. Additional analyses into the results are ongoing. A safety analysis indicates I.V. rigosertib was generally well-tolerated with adverse events similar to those seen in previous clinical studies with I.V. rigosertib in myelodysplastic syndromes patents.

Serious adverse events were uncommon, the company noted, with a similar profile of such events in both study arms.

Myelodysplastic syndromes patients are broadly classified into lower- and higher-risk groups, each with different treatment goals and approaches, according to DRG. Lower-risk patients are treated to delay disease progression and improve quality of life. Higher-risk patients are treated to extend their overall survival and improve quality of life. Hematopoietic stem cell transplantation is the only curative option available.

H.C. Wainwright analyst Joseph Pantginis wrote Monday that the study’s failure is “a major hit” to the overall thesis for rigosertib and Onconova, which, he added, must now rebuild itself. However, he continued, Onconova is in “the fortunate position to have meaningful pipeline opportunities in hand already.”

Pantginis wrote that while he expects the rigosertib program to further expand into solid tumors, investors will need to see meaningful data from solid tumor studies prior to increasing confidence on the drug again.

Onconova is conducting preclinical studies with rigosertib to treat COVID-19. The data suggest rigosertib inhibited SARS-CoV-2 replication in verso cells. Onconova has applied to several government agencies for funding and the chance to participate in clinical trials with the NIH. CEO Steven Fruchtman told investors Monday that he expects more clarity on the opportunity before the year ends.

A significant nondilutive funding event for this potential COVID-19 opportunity could help reverse the company’s misfortune, Pantginis wrote.

Fruchtman suggested turning to oral rigosertib and ON-123300, a dual inhibitor of CDK4/6 + ARK 5, for strengthening the now weakened pipeline. Both target “meaningful cancer pathways,” he said. As a RAS pathway inhibitor, oral rigosertib could address a number of oncology settings outside of hematology, he told investors Monday morning. He also said there would be continued expansion of the company’s investigator-initiated study program with oral rigosertib beyond the ongoing phase I/IIa study in KRAS-mutated lung adenocarcinoma into additional solid tumors.

In April, Onconova reported an advance in its preclinical development and the presentation of new data for ON-123300. Along with Hanx Biopharmaceuticals, its greater China collaboration partner for ON-123300, the firm completed the FDA pre-IND consultation, providing guidance for the manufacturing of the product and a preclinical development plan for the submission of an IND application.

Data from preclinical studies demonstrated a differential metabolism of ON-123300 in male vs. female rodents. As a result, the drug exposure is almost two- to threefold higher in female rats, an effect that appears to be limited to rodents and is not observed in preclinical studies with human liver microsomes.

Based on the metabolism data from other species, relevant species have been selected along with the dosing strategy to be implemented in GLP toxicological studies to be conducted by Hanx.

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