From anti-parasitic to anti-cancer: a repositioning success story
When the DDU began in 2006 its focus was on delivering pre-clinical candidates for Human African trypanosomiasis (HAT). HAT is caused by the protozoan parasites Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense and transmitted by the bite of an infected tsetse fly. The disease, fatal unless treated, has two stages: an initial peripheral infection and a second stage when parasites enter the central nervous system, causing the classic symptoms of HAT, eventually leading to coma and death. Back in the early 2000s available treatments were poor, with unacceptable efficacy and safety profiles, particularly in the second stage of the disease.
T. brucei N-Myristoyltransferase (TbNMT) was identified as potential drug target for HAT through genetic approaches by collaborators of the DDU. Following a small molecule diversity screen and subsequent optimisation programme, the DDU validated TbNMT as a good drug target in a mouse model of HAT (Nature, 2010, 464, 728-732). One of the resulting proprietary small molecule lead compounds (DDD86481) rapidly killed trypanosomes both in vitro and in vivo and cured trypanosomiasis in mice. However, DDD86481 was not blood brain barrier penetrant and therefore not a suitable candidate for taking forward to treat stage 2 HAT in humans. DDD86481 otherwise had good drug properties for a peripheral indication and given that NMT plays a role many cellular functions its potential as a target in many diseases including cancer has been greatly explored.
The DDU began a programme to reposition DDD86481 by providing the compound to collaborators with appropriate NMT-driven disease models however, the story in cancer was not straight forward and it was unclear which cancer types to target in the clinic. A serendipitous meeting between Prof David Gray at the DDU and Dr Luc Berthiaume, from the University of Alberta changed that. Luc had evidence that low NMT2 expression is highly prevalent in leukaemias and lymphomas. By targeting the remaining NMT1 enzyme in these cancers with DDD86481 the DDU and Luc showed that you could selectively kill cancer cells over healthy cells (which retained both NMTs isoforms). 19 types of cancer have the loss of one NMT at a prevalence of 5%- 80%. Dundee licenced DDD86481 (and other related compounds) to Luc’s spin-out company, Pacylex, in 2017 where it became known as PCLX-001.
A key enabling step by Pacylex to take PCLX-001 to the clinic was the development of a companion diagnostic test to identify patients with cancers sensitive to NMT inhibition. Excitingly for the DDU, on the 22nd November 2022, Pacylex announced that PCLX-001 had been awarded Fast Track Designation for the treatment of adult patients with relapsed or refractory acute myeloid leukaemia (AML) by the FDA. On the 18th May 2023, Pacylex announced that in the expansion study, the first patient with Relapsed/Refractory Non-Hodgkin Lymphoma had been dosed in a Phase 2a Study with PCLX-001 and published the results of the phase 1 trial ((doi.org/10.1200/JCO.2023.41.16_suppl.e15094). 2023 ended with the publication of the Phase 1 safety and efficacy results for PCLX-001, now called Zelenirstat which showed excellent bioavailability, half-life, safety profile, and drug exposure. Zelenristat has also shown potent in vitro radiosensitization in human glioblastoma models and unexpected prolonged progression free and overall survival in colorectal and appendiceal cancers (Phase 1). Zelenirstat has also shown potent in vitro radiosensitization in human glioblastoma models.
Zelenirstat, is a first-in-class, once daily, oral cancer therapy with a novel mechanism of action and offers a potent alternative to classic therapies to kill cancer cells. In line with the Pacylex diagnostic test for sensitivity biomarkers, the company continues to generate data to support the use of Zelenirstat in other cancer indications. Now in Phase 2 trials DDD86481 has come a long way, and the DDU is thrilled that it is now treating patients with an unmet medical need