Epizyme’s first-in-class DOT1L inhibitor EPZ-5676 disappoints investors

On November 6, Epizyme (NASDAQ: EPZM) reported clinical data from the Phase I study of DOT1L inhibitor EPZ-5676 in ASH2014 Annual Meeting (Abstract #387). Of the 28 patients with mixed lineage leukemia (MLL), two patients in the 54 mg/m2 dosing cohort achieved complete responses and another two patients achieved partial responses. Epizyme shares dropped 25.7% to $19.76 in the morning, and closed at $23.56.

MLL is an aggressive subtype of acute leukemia characterized by the presence of MLL fusion proteins. Current treatment is limited to chemotherapy and stem cell transplantation. The five-year event-free survival rate in pediatric patients with MLL is approximately 27%. According to Epizyme, the total annual incidence of MLL in major pharmaceutical markets is approximately 4,900 patients (rare disease).

Wildtype MLL gene, located at 11q23, encodes a histone methyltransferase which modifies histone H3 on lysine 4. Rearrangements result in oncogenic MLL-fusion proteins in which the native methyltransferase domain is replaced by partner proteins (e.g., AF4, AF9, AF10, and ENL). MLL-fusion proteins gain the ability to recruit histone methyltransferase DOT1L[1] which modifies histone H3 on lysine 79. Hypermethylation at H3K79 results in increased expression of genes causing leukemia (e.g., HOXA9, MEIS1).

Epizyme developed EPZ-5676, a small molecule inhibitor of DOT1L (Ki=0.08 nM), for the treatment of MLL. EPZ-5676 inhibits cellular H3K79 methylation, HOXA9 and MEIS1 expression with IC50 of 2.7 nM, 67 nM, 53 nM, respectively[2]. The most sensitive cell line is MV4-11 with MLL-AF9 fusion, which gave an IC50 of 3.5 nM. At the dose of 70 mg/kg, complete responses in rat xenograft model were achieved.

EPZ-5676 was the first histone methyltransferase to enter clinical development. Epizyme is currently conducting two Phase I trials in adult and pediatric MLL patients. To date, 36 relapsed/refractory patients had received at least one dose of EPZ-5676. Two patients discontinued treatment due to drug-related adverse reactions. Only two of the 28 patients who were evaluable for efficacy achieved complete responses.

Just as Adam Feuerstein said, not nasty, but nothing to cheer about. Epizyme plans to explore further the efficacy of EPZ-5676 at the dose of 54 mg/m2. Don’t expect higher doses with more complete responses. Preliminary PD data demonstrated that the inhibition of H3K79 methylation by EPZ-5676 in mononuclear cells ranges from 0 to 81% at doses above 36 mg/m2. The overall response rate of 14% is not unthinkable.

Epizyme is a biotech company focusing on first-in-class histone methyltransferases (e.g., DOT1L, EZH2) inhibitors. Two lead candidates, EPZ-5676 (DOT1L inhibitor, co-developed with Celgene) and EPZ-6438 (EZH2 inhibitor, co-developed with Eisai), have entered human clinical development. The establishment of PoC (proof of concept) is never easy. God bless Epizyme.

[1] Cancer Cell. 2011, 20(1), 66-78.

[2] Blood. 2013, 122(6), 1017-1025.

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