Acute promyelocytic leukemia (APL) is a specific type of acute myeloid leukemia characterized by the t(15;17) translocation which fuses the PML gene on chromosome 15 to the retinoic acid receptor (RAR) α gene on chromosome 17. APL is characterized by a distinct morphology of blast cells and is associated with specific coagulopathy. There are about 1,500 patients a year diagnosed with APL in the United States.

All-trans retinoic acid (ATRA) is the current standard of care for first-line treatment of APL in combination with chemotherapeutic agents. ATRA can cause differentiation of abnormal promyelocytes into mature granulocytes in APL. ATRA has been associated with retinoic acid syndrome, a serious and sometimes fatal complication that occurs in up to 25% of patients due to a rapid increase in white blood cells. Current National Comprehensive Cancer Network guidelines also recommend that patients undergo one to two years of maintenance therapy with ATRA following disease remission.

Unfortunately, the duration of remission induced by treatment with ATRA alone is typically short. In addition, patients often fail to respond to a second course of treatment with ATRA. Currently, patients who fail ATRA-based therapy are treated with arsenic trioxide, a compound administered intravenously and associated with significant toxicity including irregular heartbeat. There is no standard of care for patients who do not respond to ATRA and arsenic trioxide.

Tamibarotene was developed to specifically overcome resistance to ATRA. In vitro, tamibarotene is approximately 10 times more potent than ATRA at causing APL cells to differentiate and die. In addition, tamibarotene has a lower affinity for cellular retinoic acid binding protein, or CRABP, which we believe should allow for sustained plasma levels during administration. Tamibarotene does not bind the RAR-α receptor, the major retinoic acid receptor in the dermal epithelium. In clinical studies, the rate of RAS appeared to be low.

Tamibarotene is currently approved in Japan for treatment of recurrent APL. The efficacy of orally-administered tamibarotene was demonstrated in two Phase 2 studies conducted in Japan in a total of 63 Japanese subjects with APL. The overall complete response rate in these subjects was 60%. In subjects experiencing their first relapse, the overall complete response rate was 81%.

There is a Special Protocol Assessment (SPA) in place with the FDA for a Phase 2 registration clinical trial, known as STAR-1, which is evaluating the efficacy and safety of tamibarotene as a third-line treatment for APL. The FDA has granted Orphan Drug Designation and Fast Track Designation for the use of tamibarotene in patients with relapsed or refractory APL following treatment with all-trans retinoic acid (ATRA) and arsenic trioxide. The STAR-1 trial is ongoing and currently includes 30 clinical sites, 22 of which are in Europe, and one in Canada. CytRx believes that successful data from the STAR-1 trial and supporting studies, in conjunction with data from the Japanese clinical trials, potentially will form the basis for a New Drug Application (NDA) as early as 2010.

CytRx retains an option to expand its licenses for the use of tamibarotene in other fields in oncology, including multiple myeloma, myelodysplastic syndrome and certain solid tumors in the U.S., and multiple myeloma, myelodysplastic syndromes and solid tumors other than hepatocellular carcinoma in Europe. APL is diagnosed in approximately 1,500 new patients in the United States annually. The near-term market opportunity for CytRx’s tamibarotene in refractory APL in the U.S. alone is estimated to approach $20 million per year - with the market opportunity for an expanded label including refractory, maintenance and front-line therapy increasing to $150 million in potential recurring revenue in the U.S. and Europe. 

Human Clinical Trials
A Phase 2 Registration Study of Oral Tamibarotene in Acute Promyelocytic Leukemia Patients Who Have Received Prior Therapy with ATRA and Arsenic Trioxide (STAR-1) is ongoing.

Click on the link below for current clinical trial information and eligibility criteria:

clinicaltrials.gov

Bibliography
Tadasu Tobita, Akihiro Takeshita, et al. Treatment with a new synthetic retinoid, Am80, of acute promyelocytic leukemia relapsed from complete remission induced by all-trans retinoic acid. BLOOD, 1 August 1997;VOLUME 90, NUMBER 3