The Food and Drug Administration has granted an Orphan drug designation to EPZ-5676, a small molecule inhibitor of DOT1L for the treatment of acute leukemias in which the MLL (ALL1) gene, located at 11q23, is rearranged due to a chromosomal translocation (MLL-r).

Due to the translocation, DOT1L is recruited to specific locations in the chromosome where it would not normally be present. As a result, DOT1L causes inappropriate methylation at these locations, which results in the increased expression of genes causing leukemia.The drug is being developed by Epizyme,a clinical stage biopharmaceutical company creating innovative personalized therapeutics for patients with genetically defined cancers and usesEpizyme’s proprietary product platform.


…the five-year overall survival rate for adult patients with the MLL-r subtype of AML ranges from approximately 5 to 24%


An aggressive disease
Mixed Lineage Leukemia or MLL-r is an aggressive subtype of two of the most common forms of acute leukemia, acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL). At this time, there is no approved therapies specifically indicated for ML-r leukemia.

The disease predominantly occurs in two age ranges – an infant/pediatric as well as adult populations – each with a similarly poor prognosis. Although both age ranges share a common genetic driver, the adult disease is frequently a secondary leukemia resulting from prior chemotherapy for a different, unrelated cancer, while the pediatric disease is sporadic in nature.

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According to research published in the journal Blood in December 2002, the five-year overall survival rate for adult patients with the MLL-r subtype of AML ranges from approximately 5 to 24%. The five-year event-free survival rate in pediatric patients with the most common MLL-r subtype of ALL is approximately 27%, as identified in research published in the New England Journal of Medicine in 2004. The total annual incidence of MLL-r in all patients (adult and pediatric, AML and ALL) in major pharmaceutical markets is approximately 4,900 patients, according to a report by Clarion Healthcare. Patients with MLL-r are routinely diagnosed today with existing tests that are commonly used in clinical settings, and there is high awareness of MLL-r among oncologists.

Difficult to detect
The translocation of MLL-r is generally difficult to detect with conventional chromosome analysis and more sophisticated analytic techniques may be needed to detect it. To meet this unmet need, Epizyme signed an agreement with Abbott Diagnostics to develop a molecular companion diagnostic test for use with EPZ-5676. Under the agreement, Abbott will utilize its proprietary fluorescence in situ hybridization (FISH) technology to design a test to detect MLL genetic alterations that lead to the oncogenic (cancer causing) function of DOT1L. Epizyme will use Abbott?s FISH-based test to help identify eligible patients for its DOT1L inhibitor.

Orphan drug designation
Criteria for orphan drug designation requires that the product be intended for treatment of a rare disease or condition, classified as affecting fewer than 200,000 people in the United States. TheOrphan drug designation allows special incentives for sponsors planning to test a product for use in a rare disease or condition. These incentives include tax credits, research and development grant funding and reduced filing fees during development or at the time of application for marketing approval. Once approved, the product may qualify for seven years of marketing exclusivity independent of any other intellectual property

Clinical trials
In September 2012, Epizyme initiated a Phase I clinical trial for EPZ-5676. The company believes EPZ-5676 is the first HMTi to enter human clinical development. As of August 2013, this program is in the dose escalation phase and is expected to initiate an expansion phase in the second half of 2013 that will exclusively enroll MLL-r patients.

Collaboration with Industry partners
Epizyme retains all U.S. rights to EPZ-5676 and has granted Celgene an exclusive license to EPZ-5676 outside of the United States. Epizyme has partnered with Abbott to develop a companion diagnostic to identify MLL-r patients.

For more information
Daigle SR, Olhava EJ, Therkelsen CA, Basavapathruni A, Jin L, Boriack-Sjodin PA, Allain CJ, Klaus CR,et al. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood. 2013 Aug 8;122(6):1017-25. doi: 10.1182/blood-2013-04-497644. Epub 2013 Jun 25.[Article][PubMed]

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