In July 2015, Chipscreen BioSciences initiated a Phase III trial of chidamide in hormone receptor (HR) positive breast cancer (CTR20150456). It is the first Phase III trial to evaluate the efficacy and safety of HDAC inhibitor in Chinese patients with breast cancer.
Syndax Pharmaceuticals (NASDAQ: SNDX) is evaluating another HDAC inhibitor, entinostat, in breast cancer in a pivotal Phase III trial in breast cancer. Two years ago, the FDA granted Breakthrough Therapy Designation to the drug based on Phase IIb (ENCORE 301) results.
In September 2013, Eddingpharm licensed China rights to entinostat. Eddingpharm originally intended to participate in Syndax’s global Phase III trial. However, the IND wasn’t submitted to the CFDA until February 2015. If all goes well, Eddingpharm will commence clinical study of entinostat in 2016.
Syndax’s Phase IIb trial (NCT00676663) assigned 130 patients with HR positive breast cancer progressing on first-line therapies. Patients were randomly assigned to exemestane + entinostat (EE) or exemestane + placebo (EP). Median overall survival was improved to 28.1 months with EE versus 19.8 months with EP (p=0.036).
The Phase IIb results appear encouraging, but I still have some doubts. There is no difference in response rate (6.3% vs. 4.6%). The median progression-free survival (mPFS) of 2.3 months in the EP group was lower than the 3.8-4.1 months observed in other similar trials[2,3]. The EE group had more Grade 3/4 adverse events (50% vs. 26%).
The FDA has approved everolimus plus exemestane for the second-line treatment of HR positive breast cancer. The combination of palbociclib with fulvestrant has also shown a marked benefit in second-line treatment in a Phase III trial. Entinostat, if approved, will have to compete with everolimus and palbociclib in the second-line settings.
Entinostat (MS-275) was discovered by Japanese scientists in Mitsui Pharmaceuticals in 1990s. European Patent EP0847992 which covers entinostat expires in 2017. The patent protection for the compound relies on WO2010022988 which covers a crystalline polymorph.
Syndax licensed the program from Bayer with an upfront fee of $2 million in April 2007. The company conducted a Phase II trial of entinostat plus erlotinib in non-small cell lung cancer, but failed. Fortunately, the Phase II trial in breast cancer succeeded.
Chipscreen’s chidamide is an anolog derived from entinostat. The CFDA has approved chidamide for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) in December 2014. Chipscreen is likely to complete the breast cancer study in advance of Eddingpharm.
 J Clin Oncol. 2013, 31(17), 2128-2135.
 N Engl J Med. 2015, 373(3), 209-219.
 N Engl J Med. 2012, 366(6), 520-529.
 J Med Chem. 1999, 42(15), 3001-3003.
Chipscreen grabs CFDA approval for chidamide