TLN-4601
TLN-4601 is a proprietary first-in-class small molecule with the potential to treat multiple cancer indications, like the well known chemotherapeutics, doxorubicin and mitomycin C. TLN-4601 is a natural product derived from a non-pathogenic micro-organism. Discovered using Thallion’s DECIPHER® technology, TLN-4601 was tested in preclinical studies conducted by the National Cancer Institute and Thallion to establish its safety and efficacy in animal and in vitro models.
Early preclinical data suggested that TLN-4601 has a novel mechanism of action with dual activity. TLN-4601 is a potent inhibitor of the RAS-mitogen-activated phosphokinase (MAPK) pathway, a validated target for a number of commercially available oncology treatments. TLN-4601 acts at the centre of the pathway, leading to the inhibition of downstream intracellular signalling events. In addition, TLN-4601 also binds selectively to the peripheral benzodiazepine receptor (PBR) that appear to be over-expressed a variety of different tumour types. This selective binding may concentrate the drug in the tumour tissue where it is most needed.
More recent data suggests that TLN-4601 may act as a broader pro-apoptotic agent, inducing cell death in cancer cells via the intrinsic apoptotic pathway. TLN-4601-induced apoptosis occurs relatively rapidly, with cytochrome C release, caspase activation and nucleosomal DNA fragmentation often occurring within four hours of treatment, and the activity appears independent of Bcl-2, Bax and Bak expression. Furthermore, differential sensitivity to TLN-4601 has been observed between cancer cell lines and normal peripheral blood lymphocytes, suggesting the potential for a therapeutic window between cancer and normal cells. Together, these data suggest that further studies pertaining to hematological malignancies are warranted.
Thallion completed a Phase I/II trial for TLN-4601, which examined the compound's safety, pharmacologic profile and anti-tumour efficacy for the treatment of advanced solid tumours. The dose-escalation part of the trial included colorectal, ovarian, duodenal and glioma patients. TLN-4601 was safe, well tolerated and the maximum tolerated dose was not attained. Of the seven patients that received at least six cycles of treatment, four demonstrated stable disease. In the second portion of the trial, 12 additional patients were treated with the highest dose, as determined in the first portion of the study, to obtain additional safety and pharmacokinetic data, as well as an early indication of the compound's clinical efficacy.
Thallion also conducted a Phase II trial evaluating TLN-4601 as a monotherapy treatment for patients with recurrent glioblastoma multiforme, an advanced from of brain cancer. In the Phase II trial, TLN-4601 was continuously administered intravenously at a dosage level of 480 mg/m2/day over 14 days, followed by 7 days off treatment (three-week cycles). The primary endpoint of the open label trial was six-month progression free survival, with secondary endpoints including tumour response, progression-free survival at 12 months, as well as overall survival. After enrolling 20 of the targeted 40 patients, a planned interim analysis was conducted and showed that only three out of seventeen evaluable patients demonstrated stable disease after two cycles (six weeks) of treatment. No stable disease was observed after four cycles of treatment. TLN-4601 was considered as generally safe and well tolerated. In the absence of any meaningful clinical response, the company decided to close the phase II trial and evaluate its options with respect to the future development of TLN-4601, including the possibility of out-licensing the compound.