SyB L-1101 / SyB C-1101（Generic Name: Rigosertib） is a novel tumor specific PI-3K (phosphoinositide-3 kinase) and PLK (polo-like kinase) inhibitor targeting the Ras Binding Domain being developed by Onconova Therapeutics ("Onconova") for the treatment of hematologic malignancies and solid tumors. Late-stage clinical trials are currently being conducted in the U.S., Europe and India. In addition to the intravenous (IV) formulation in Phase III development (ONTIME) under Special Protocol Assessment (SPA) and orphan drug designation by U.S. FDA for post-hypomethylating agent (HMA) higher-risk myelodysplastic syndromes (HR-MDS), an oral formulation of rigosertib is in Phase II/III development (ONTARGET) for first-line lower-risk MDS (LR-MDS).
MDS represent a group of diverse myeloid (bone marrow) stem cell disorders with a poor prognosis that gradually affect the ability of bone marrow to produce normal red blood cells, white blood cells, and platelets. Blood stem cells fail to mature into healthy blood cells, and the immature blood cells, called blasts, do not function normally and either die in the bone marrow or enter the blood. A higher percent of blasts is linked to a higher likelihood of developing leukemia and a poorer prognosis. The risk of MDS increases with age and the disease commonly affects the elderly.
On February 19, 2014, Onconova announced that the Phase III ONTIME trial of intravenous (IV) rigosertib in patients with HR-MDS who had progressed on, failed or relapsed after prior therapy with HMAs did not meet the primary endpoint of overall survival compared to best supportive care (BSC). The ONTIME trial enrolled 299 patients. However, a post-hoc analysis demonstrated a statistically significant increase in median overall survival in the subset of patients who had progressed on or failed previous treatment with HMAs, thus demonstrating potential activity of rigosertib in these MDS patients. Onconova is in discussions with U.S. and European regulatory agencies to determine rigosertib's development path for post-HMA HR-MDS, with a development update planned in 4Q-2014.
For oral rigosertib in first-line LR-MDS (ONTARGET), Onconova's Phase II trial has enrolled >60 patients at 5 sites with encouraging transfusion-sparing activity noted. The potential genomic prognostic method has been identified, and a cohort of 20 LR-MDS patients is now being enrolled to confirm genomic signature. Recruitment continues in a second Phase II trial to explore dose and schedule optimization, with a regulatory update from FDA and European countries obtained. EU consultations are underway to determine the design of the Phase III trial, which is planned to start in H1-2015.
Oral rigosertib is also in Phase I/II development for 1st-line MDS/AML as a treatment in combination with Vidaza (azacitidine). A Phase I trial for 2nd-line Head & Neck cancer with rigosertib in combination with chemoradiotherapy has also been initiated.
In Japan, SymBio is developing rigosertib for the treatment of refractory/relapsed HR-MDS (IV form) and first-line LR-MDS (oral form), with development in additional indications to follow (e.g., first-line development in MDS/AML in combination with Vidaza).