Pacylex Pharmaceuticals is a clinical-stage Canadian company focused on the development of a new class of targeted therapies for the treatment of hematologic and solid tumor cancers. Pacylex’s lead drug zelenirstat is a first-in-class, oral, investigational therapy for inhibiting myristoylation in cancer and autoimmune disorders.

 

Myristoylation is the addition of a fatty acid, myristate, to certain proteins allowing them to bind membranes where they interact with other proteins in critical cell functions. Myristoylation is essential for cancer cell signaling, energy production, and angiogenesis, critical to liquid and solid tumor cancer cell proliferation and survival. Zelenirstat is an N-myristoyltransferase (NMT) inhibitor which blocks the two enzymes responsible for myristoylation. Zelenirstat inhibits cancer cell signaling, energy production, and angiogenesis, and in vitro, cancer cells are 10-20-fold more sensitive to zelenirstat than normal cells (selective lethality).

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In animal cancer models, zelenirstat completely regresses hematologic cancers including clearing leukemic stem cells from the bone marrow in murine tail vein injection models. In lymphoma, zelenirstat interrupts B-cell receptor signaling; in leukemia it stops Jak/Stat signaling from FLT3/cKit. It also interrupts complex 1 assembly in mitochondria reducing energy production. Hematologic cancers are selectively killed by apoptosis. In solid tumor murine xenograft models, zelenirstat strongly inhibited small cell lung and triple negative breast cancer tumor growth. Zelenirstat is also a more effective inhibitor of angiogenesis than VEGF inhibitors sunitinib or sorafenib.

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A Phase 1 dose escalation safety and tolerability study was conducted in 29 lymphoma and solid tumor patients, who averaged 4 prior lines of therapy to which they were relapsed or refractor (R/R). The most common treatment related adverse events identified in the trial were mild to moderate gastrointestinal side effects which were self-limiting and occurred in a minority of patients. A recommended Phase 2 dose for expansion studies was established. Zelenirstat unexpectedly prolonged progression free survival in some Phase 1 solid tumor patients receiving the recommended Phase 2 dose; several patients at this dose continue zelenirstat treatment for up to 270 days and counting. Patients receiving the recommended Phase 2 dose had statistically significantly better progression free and overall survival than those receiving lesser drug doses. A Phase 2a expansion study in B-cell NHL has been initiated and an 85-year-old patient who failed 3 prior lines of therapy has already shown a response. Similar studies are ready to start in solid tumor cancers and acute myeloid leukemia (AML) patients. Zelenirstat received Orphan Drug and Fast Track designations for AML.