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Temple University and Onconova Therapeutics, Inc. | Date: 2017-03-08

Substituted phenol derivatives of Formula I:


NEWTOWN, Pa., June 05, 2017 (GLOBE NEWSWIRE) -- Onconova Therapeutics, Inc. (NASDAQ:ONTX), a Phase 3 stage biopharmaceutical company focused on discovering and developing novel small molecule drug candidates to treat cancer, with a primary focus on Myelodysplastic Syndromes (MDS), today announced the results of a Phase 2 study with rigosertib as a treatment for higher risk (HR-MDS) after failure of hypomethylating agents (HMAs). The study sought to evaluate bone marrow blast (BMBL) response to rigosertib as a surrogate for overall survival (OS) in this patient population. The results showed treatment with rigosertib resulted in a reduction in BMBL count, including complete bone marrow responses, confirming findings in earlier studies. Thus, BMBL response to rigosertib is a potential surrogate marker for improvement in overall survival in this patient population. “In this new study for HR-MDS patients after failure of HMA therapy, we are excited to confirm a correlation between blast reduction and prolongation of survival in rigosertib treated patients. These results build upon our previous findings in the ONTIME trial showing improvement in overall survival in patients with the highest risk prognostic categories after failure of HMA treatment (ASH 2014 presentation),”said Ramesh Kumar, Ph.D., President and CEO of Onconova. Rigosertib is currently being tested in a randomized, global, Phase 3 INSPIRE trial for this patient population. Study Name: Relationship of Bone Marrow Blast response to Overall Survival in a Multicenter Study of Rigosertib in Patients with Myelodysplastic Syndromes with Excess Blasts Progressing on or After Treatment with a Hypomethylating Agent Summary of Data from the 04-24 Trial Following these results, all patients will be followed until death and/or progression, even if they have discontinued treatment for any reason. View the complete study poster HERE. Onconova Therapeutics, Inc. is a Phase 3-stage biopharmaceutical company focused on discovering and developing novel small molecule drug candidates to treat cancer, with a primary focus on Myelodysplastic Syndromes (MDS). Rigosertib, Onconova's lead candidate, is a proprietary Phase 3 small molecule agent, which we believe blocks cellular signaling by targeting RAS effector pathways.  Using a proprietary chemistry platform, Onconova has created a pipeline of targeted agents designed to work against specific cellular pathways that are important in cancer cells, while causing minimal damage to normal cells. Onconova has three product candidates in the clinical stage and several pre-clinical programs. Advanced clinical trials with the Company’s lead compound, rigosertib, are aimed at what the Company believes are unmet medical needs of patients with MDS. For more information, please visit http://www.onconova.com. The intravenous form of rigosertib has been employed in Phase 1, 2, and 3 clinical trials involving more than 800 patients, and is currently being evaluated in the randomized Phase 3 international INSPIRE trial for patients with higher-risk MDS, after failure of hypomethylating agent, or HMA, therapy. This formulation is intended for patients with advanced disease,  provides long duration of exposure, and ensures dosing under a controlled setting. The INternational Study of Phase III IV RigosErtib, or INSPIRE, is based on guidance received from the U.S. Food and Drug Administration and European Medicines Agency and derives from the findings of the ONTIME Phase 3 trial.  INSPIRE is a multi-center, randomized controlled study to assess the efficacy and safety of IV rigosertib in HR-MDS patients who had progressed on, failed to respond to, or relapsed after previous treatment with an HMA within the first 9 months or nine cycles over the course of one year after initiation of HMA treatment.  This time frame optimizes the opportunity to respond to treatment with an HMA prior to declaring treatment failure, as per NCCN Guidelines.  The trial will enroll approximately 225 patients randomized at a 2:1 ratio into two treatment arms: IV rigosertib plus Best Supportive Care versus Physician's Choice plus Best Supportive Care.  The primary endpoint of INSPIRE is overall survival and an interim analysis is anticipated. Full details of the INSPIRE trial, such as inclusion and exclusion criteria, as well as secondary endpoints, can be found on clinicaltrials.gov (NCT02562443). The oral form of rigosertib was developed to provide more convenient dosing for use where the duration of treatment may extend to multiple years. This dosage form also supports many combination therapy modalities. To date, 368 patients have been treated with the oral formulation of rigosertib.  Initial studies with single-agent oral rigosertib were conducted in hematological malignancies, lower-risk MDS, and solid tumors. Combination therapy of oral rigosertib with azacitidine and chemoradiotherapy has also been explored. Currently, oral rigosertib is being developed as a combination therapy together with azacitidine for patients with higher-risk MDS who require HMA therapy.  A Phase 2 trial of the combination therapy has been fully enrolled and the preliminary results were presented in 2016. This novel combination is the subject of an issued US patent with earliest expiration in 2028. Some of the statements in this release are forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, Section 21E of the Securities Exchange Act of 1934, as amended, and the Private Securities Litigation Reform Act of 1995, and involve risks and uncertainties. These statements relate to future events or Onconova Therapeutics, Inc.'s future operations, clinical development of Onconova's product candidates and presentation of data with respect thereto, regulatory approvals, expectations regarding the sufficiency of Onconova's cash and other resources to fund operating expenses and capital expenditures, Onconova's anticipated milestones and future expectations and plans and prospects. Although Onconova believes that the expectations reflected in such forward-looking statements are reasonable as of the date made, expectations may prove to have been materially different from the results expressed or implied by such forward-looking statements. Onconova has attempted to identify forward-looking statements by terminology including "believes," "estimates," "anticipates," "expects," "plans," "intends," "may," "could," "might," "will," "should," "approximately" or other words that convey uncertainty of future events or outcomes. These statements are only predictions and involve known and unknown risks, uncertainties, and other factors, including Onconova's ability to continue as a going concern, the need for additional financing and current plans and future needs to scale back operations if adequate financing is not obtained, the success and timing of Onconova's clinical trials and regulatory approval of protocols, and those discussed under the heading "Risk Factors" in Onconova's most recent Annual Report on Form 10-K and quarterly reports on Form 10-Q. Any forward-looking statements contained in this release speak only as of its date. Onconova undertakes no obligation to update any forward-looking statements contained in this release to reflect events or circumstances occurring after its date or to reflect the occurrence of unanticipated events.


Patent
Onconova Therapeutics, Inc. | Date: 2015-05-15

An aqueous pharmaceutical solution composition comprising between about 20 mg/ml to about 100 mg/ml of a radioprotective ,-unsaturated aryl sulfone, a cosolvent comprising polyethylene glycol (PEG), polypropylene glycol, polyglycerol, DMA, propylene glycol, glycerol, ethanol, sorbitol, isopropyl alcohol, or a combination thereof in an amount between about 25% and about 90% w/v, and a water soluble Vitamin E derivative, wherein the composition has a pH within the range of about 7.0 to about 9.5.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 275.86K | Year: 2011

DESCRIPTION (provided by applicant): The recent success of imatinib for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia has made tyrosine and serine/threonine kinases as major targets for cancer therapy. Currently, since only a small fraction of the human kinome has been targeted by reasonably selective and potent inhibitors, there is an urgent need to develop strategies for efficient discovery and optimization of new inhibitors. Towards this goal, we have recently developeda compound library of candidate ATP-competitive kinase inhibitors. We screened our collection of novel small molecules (approximately 2,000) against a panel of 16 cultured tumor cell lines for the ability to induce cell death. This search revealed one compound, ON 1231320, with remarkable cytotoxicity against the entire panel of 16 tumor cell lines. Kinase inhibition assays against a panel of 285 kinases revealed that this compound had a remarkable specificity towards Polo-like kinase 2 (Plk2 or Snk), a kinase involved in centrosome duplication and mitotic progression. As expected, tumor cells treated with ON 1231320 arrest in mitosis due to abnormal microtubule spindle development. Plk2 has recently been implicated as one of the kinases that links cellularmetabolism to the cell cycle. Mitochondrial dysfunction, with resulting increased dependence on glycolysis, is frequently observed in cancer cells (known as the Warburg effect). Identification of pathways that promote cell survival under conditions of mitochondrial dysfunction has therapeutic implications. In a recent study, it has been shown that targeted ablation of the SCO2 gene in HCT116 human colon cancer cell line results in the ablation of mitochondrial respiration and that PLK2 is the most highly expressed gene in SCO2-/-cells. Furthermore, even a modest reduction in Plk2 levels in human cancer cells with defects in mitochondrial respiration results in the elimination of their ability to form xenografts in mice. In this proposal, we plan to furtherexamine this potent and selective Plk2 inhibitor in order to determine important chemical characteristics and biological activity necessary for advanced pre-clinical development. We propose to study the effects of this compound on tumor growth in vitro andin vivo to determine how ON 1231320 will serve as a novel cancer chemotherapeutic. The aims of this proposal are to: (1) Prepare an optimal formulation of ON 1231320 for stability and parenteral delivery; (2) Characterize the pharmacokinetic and pharmacodynamic properties of ON 1231320 in non-tumor and tumor-bearing mice; and (3) Evaluate anti-tumor efficacy of ON 01231320, determine the degree of inhibition of Plk2 required for inhibition of human tumor growth in xenograft models, and assess how ON 1231320 doses and schedules are related to the anti-tumor activity of the compound. PUBLIC HEALTH RELEVANCE: This application describes the discovery of a novel cancer therapeutic, ON 1231320, which could find a wide application in the treatment of someof the most difficult-to-treat cancers that are traditionally resistant to chemotherapy. ON 1231320 has a unique and targeted anti-cancer mechanism of action. In this application, we propose to develop optimal formulation, preclinical pharmacology, and anti-cancer efficacy profiles for ON 1231320 in preparation for a Phase I study in cancer patients.


The invention discloses a diagnostic method for predicting the therapeutic efficacy of a broad specificity kinase inhibitor in a subject with refractory cancer comprising determining the locus-specific DNA methylation profile of the subject, wherein the locus-specific DNA methylation profile predicts the therapeutic efficacy of a broad specificity kinase inhibitor for treatment of a subject with refractory cancer.


Patent
Onconova Therapeutics, Inc. | Date: 2011-03-24

The present invention provides compositions and methods for promoting rapid healing and/or regeneration of damaged tissue resulting from a wound comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of (E)-4-carboxystyryl-4-chlorobenzylsulfone, or a functional derivative thereof, and a pharmaceutically acceptable excipient.


Patent
Onconova Therapeutics, Inc. | Date: 2011-03-24

An aqueous pharmaceutical solution composition comprising between about 20 mg/ml to about 100 mg/ml of a radioprotective ,-unsaturated aryl sulfone, a cosolvent comprising polyethylene glycol (PEG), polypropylene glycol, polyglycerol, DMA, propylene glycol, glycerol, ethanol, sorbitol, isopropyl alcohol, or a combination thereof in an amount between about 25% and about 90% w/v, and a water soluble Vitamin E derivative, wherein the composition has a pH within the range of about 7.0 to about 9.5.


Patent
Onconova Therapeutics, Inc. | Date: 2015-04-29

Solution and suspension formulations are provided for administration prior to or after exposure to ionizing radiation for reducing toxic effects of the radiation in a subject which comprises an effective amount of at least one radioprotective , unsaturated aryl sulfone wherein the composition has a pH within the range of about 8 to about 9.


Patent
Onconova Therapeutics, Inc. | Date: 2014-08-27

Solution and suspension formulations are provided for administration prior to or after exposure to ionizing radiation for reducing toxic effects of the radiation in a subject which comprises an effective amount of at least one radioprotective , unsaturated aryl sulfone wherein the composition has a pH within the range of about 8 to about 9.


Patent
Onconova Therapeutics, Inc. and Columbia University | Date: 2013-12-06

The invention discloses a method of treating cancer refractory to an anticancer agent comprising administering to a cancer patient a pharmaceutical composition comprising at least one compound of Formula 1 Where R_(1 )is selected from the group consisting of NH_(2), NHCH_(2)COOH, NHCH(CH_(3))COOH, NHC(CH_(3))_(2)COOH, NHCH_(2)CH_(2)OH and N(CH_(2)CH_(2)OH)_(2 )or a pharmaceutically acceptable salt of such a compound, and an anticancer agent.

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