title: Exploring drug delivery for the DOT1L inhibitor pinometostat (EPZ-5676): Subcutaneous administration as an alternative to continuous IV infusion, in the pursuit of an epigenetic target.
abstract: Protein methyltransferases are emerging as promising drug targets for therapeutic intervention in human cancers. Pinometostat (EPZ-5676) is a small molecule inhibitor of the DOT1L enzyme, a histone methyltransferase that methylates lysine 79 of histone H3. DOT1L activity is dysregulated in the pathophysiology of rearranged mixed lineage leukemia (MLL-r). Pinometostat is currently in Phase 1 clinical trials in relapsed refractory acute leukemia patients and is administered as a continuous IV infusion (CIV). The studies herein investigated alternatives to CIV administration of pinometostat to improve patient convenience. Various sustained release technologies were considered, and based on the required dose size as well as practical considerations, subcutaneous (SC) bolus administration of a solution formulation was selected for further evaluation in preclinical studies. SC administration offered improved exposure and complete bioavailability of pinometostat relative to CIV and oral administration. These findings warranted further evaluation in rat xenograft models of MLL-r leukemia. SC dosing in xenograft models demonstrated inhibition of MLL-r tumor growth and inhibition of pharmacodynamic markers of DOT1L activity. However, a dosing frequency of thrice daily (t.i.d) was required in these studies to elicit optimal inhibition of DOT1L target genes and tumor growth inhibition. Development of an extended release formulation may prove useful in the further optimization of the SC delivery of pinometostat, moving towards a more convenient dosing paradigm for patients.
authors.affiliation: Epizyme, Inc., 400 Technology Square, Cambridge, MA 02139, United States.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Waters
authors.affiliation: Epizyme, Inc., 400 Technology Square, Cambridge, MA 02139, United States.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Daigle
authors.affiliation: Pharmadirections, 5001 Weston Parkway, Suite 103, Cary, NC 27513, United States.
authors.forename: Bruce N
authors.initials: BN
authors.lastname: Rehlaender
authors.affiliation: Epizyme, Inc., 400 Technology Square, Cambridge, MA 02139, United States.
authors.forename: Aravind
authors.initials: A
authors.lastname: Basavapathruni
authors.affiliation: Epizyme, Inc., 400 Technology Square, Cambridge, MA 02139, United States.
authors.forename: Carly T
authors.initials: CT
authors.lastname: Campbell
authors.affiliation: Epizyme, Inc., 400 Technology Square, Cambridge, MA 02139, United States.
authors.forename: Tyler B
authors.initials: TB
authors.lastname: Jensen
authors.affiliation: Epizyme, Inc., 400 Technology Square, Cambridge, MA 02139, United States.
authors.forename: Brett F
authors.initials: BF
authors.lastname: Truitt
authors.affiliation: Current address: Third Rock Ventures, 29 Newbury St. #3, Boston, MA 02116, United States.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Olhava
authors.affiliation: Current address: Warp Drive Bio, LLC, 400 Technology Square, Cambridge, MA 02139, United States.
authors.forename: Roy M
authors.initials: RM
authors.lastname: Pollock
authors.affiliation: Epizyme, Inc., 400 Technology Square, Cambridge, MA 02139, United States. Electronic address: kstickland@epizyme.com.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Stickland
authors.affiliation: Epizyme, Inc., 400 Technology Square, Cambridge, MA 02139, United States.
authors.forename: Angelos
authors.initials: A
authors.lastname: Dovletoglou
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D019175:DNA Methylation / Q000187:drug effects*; D003692:Delayed-Action Preparations; D004285:Dogs; D004334:Drug Administration Schedule; D004337:Drug Carriers; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D044127:Epigenesis, Genetic / Q000187:drug effects*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D015456:Leukemia, Biphenotypic, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D008780:Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D017207:Rats, Sprague-Dawley; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D003692:Delayed-Action Preparations; D004337:Drug Carriers; C583893:EPZ-5676; D004791:Enzyme Inhibitors; C473477:DOT1L protein, human; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase
keywords: Continuous IV; DOT1L; EPZ-5676; MLL-r; Pinometostat; Pinometostat (EPZ-5676); Subcutaneous