Dual Inhibitor for Diffuse Large B-Cell Lymphoma Receives Orphan Drug Designation

A small molecule drug that targets two different types of enzymes in development for diffuse large B-cell lymphomas (DLBCL) and multiple myeloma, has received an orphan drug designation from the US Food and Drug Administration (FDA). The drug, CUDC-907 (Curis, Inc.), is an oral inhibitor of histone deacetylases (HDACs) and three different isoforms of the phosphoinositide 3-kinase, alpha, beta, and delta.

Several HDACs are approved for hematological malignancies, including the just approved panobinostat (Farydak, Novartis) for previously treated advanced multiple myeloma in combination with two other therapies: belinostat (Beleodaq, Spectrum Pharmaceuticals) for relapsed or refractory peripheral T-cell lymphoma, vorinostat (Zolinza, Merck) for cutaneous T-cell lymphoma, and romidepsin (Istodax, Gloucester Pharmaceuticals, Inc.) for cutaneous T-cell lymphoma patients who have received at least one prior systemic therapy.

The first PIK3 inhibitor approved by the FDA was idelalisib (Zydelig, Gilead), a first-in-class compound approved in combination with rituximab for chronic lymphocytic leukemia (CLL). Idelalisib is also approved for follicular B-cell non-Hodgkin lymphoma and relapsed small lymphocytic lymphoma (SLL), also a type of non-Hodgkin lymphoma.

CUDC-907 is an oral, dual inhibitor of histone deacetylase (HDAC) and phosphoinositide 3-kinase (PI3K) enzymes that is currently under investigation in phase I clinical studies in patients with relapsed or refractory lymphomas or multiple myeloma. It is also being used in patients with advanced/ relapsed solid tumors, including hormone receptor (HR)-positive and HER2-negative breast cancer, or midline carcinoma with certain nuclear protein in testis (NUT) gene rearrangements.

DLBCL is an aggressive form of non-Hodgkin lymphoma (NHL) and the largest subtype of NHL, accounting for about one-third of all NHL patients in the US. According to the American Cancer Society, there will be approximately 71,850 new cases of NHL in the United States and 19,790 people will die of this disease.

"We are pleased to receive orphan drug designation for CUDC-907 in DLBCL, which represents an area of significant unmet need, especially in the relapsed/ refractory setting," said Ali Fattaey, PhD, President and Chief Executive Officer of Curis, in a statement. "We are continuing to treat DLBCL patients with CUDC-907 in the expansion stage of our Phase I study, and anticipate initiating a Phase II trial in this indication in the second half of the year."

The FDA orphan drug designation is a way to incentivize drug makers to develop drugs for rare diseases that affect fewer than 200,000 people in the US.

At the 2013 annual American Society of Hematology (ASH) meeting, Curis presented interim data on 13 patients from the hematological malignancy phase I dose finding trial. Dose-limiting toxicities included grade 3 diarrhea and grade 4 hyperglycemia in one patient at the 60 mg, once daily dose. Frequent high-grade adverse events in two or more patients included neutropenia, thrombocytopenia, and diarrhea. Of the 13 patients, 11 could be evaluated for response to therapy. Of these patients, one with mixed follicular lymphoma/ diffuse large B-cell lymphoma had a partial response (70% reduction of a single lesion) that was treated at the 30 mg, once daily dose. Seven additional patients had stable disease. Additional data from a different subset of patients showed that of eight patients with DLBCL who could be evaluated, seven had tumor shrinkage, including one complete response and two partial responses.

According to Massachusetts-based Curis, the company developing CUDC-907, the full data from this dose escalation study is likely to be presented at a medical meeting this year.

References:

• Curis, Inc. (2015). CUDC-907 (dual PI3K and HDAC inhibitor).