Selective and potent anti-cancer activity
Extensive preclinical studies demonstrated COTI-2’s ability to restore mutant p53 function and thus induce cancer cell death in many common p53 mutations. In those studies, COTI-2 as a single agent either completely halted tumor growth or led to dramatic tumor regression depending on the dose amount and p53 mutation type. Moreover, there was no observable toxicity in those preclinical studies. >> OVCAR-3 xenograft model
Unlike nearly every other cancer treatment in existence today, it appears through our preclinical studies that COTI-2 is non-genotoxic. Conventional chemotherapy involves the killing of all growing and dividing cells in the body (cancer or otherwise), which often leads to significant toxic side effects in patients. By contrast, COTI-2 specifically targets and primarily destroys tumor cells.
We commenced our Phase 1 clinical trial of COTI‐2 at the end of 2015, with COTI-2 initially being evaluated for the treatment of gynecologic cancers (including ovarian cancer). The Phase 1 clinical trial is being carried out at the MD Anderson Cancer Center at the University of Texas and the Lurie Cancer Center at Northwestern University. Dosing of women in the third cohort of the ongoing clinical trial commenced in July 2016.
Clinical trials of COTI-2 are also planned in the U.S. and Canada for the treatment of patients with recurrent head and neck squamous cell cancer.
Kevetrin, which is being developed by Beverly, Massachusetts-based Cellceutix Corporation, is a small molecule that belongs to a different class of compounds known as thioureals. Kevetrin's mechanism of action revealed the compound's ability to induce cell cycle arrest and apoptosis in a non-genotoxic way in wild type p53 and mutant p53.
A Phase 1 study evaluating Kevetrin in advanced solid tumors commenced in August 2012. Preliminary findings from Cellceutix’s Phase 1 trial showed Kevetrin to be well-tolerated in patients at increasingly higher dosing levels and that the drug activated p53 by inducing p21 expression. Additional efficacy data released earlier in 2016 showed two-thirds of patients, regardless of tumor type, had increases in p21 expression relative to pre-treatment levels, and that this appeared to be both a time-dependent and dose-dependent response among patients.
In February 2016, Cellceutix concluded its Phase 1 trial in solid tumors and is now moving Kevetrin into mid-stage trials, including, in the near-term, ovarian cancer. Other Phase 2 trials are planned for pancreatic cancer, acute myelogenous leukemia (AML), retinoblastoma and renal cell carcinoma.
In comparison, COTI-2 has a big advantage in terms of efficacy. Based on preclinical experiments, COTI-2 is the more potent activator of mutant p53 with IC50s (a measure of the effectiveness of a substance in inhibiting a specific biological or biochemical function, with lower being better) in the low nanomolar range in multiple human cancer cell lines, whereas Kevetrin is active at greater than 100 micromolar level.
Another p53-focused company is privately held Aprea AB, based out of Stockholm, Sweden. Aprea AB’s lead compound, Aprea-246, also activates mutant p53. Unlike COTI-2, Aprea-246 functions in a more limited way by inducing wild type conformation in a smaller number of p53 mutations. Additionally, APR- 246 is active only at a high micromolar range. Aprea 246 would be the most like COTI-2 of these two compounds.
The main differences between these three drugs are: (1) potency – COTI-2 is effective at nanomolar concentrations, (2) COTI-2 is effective against a wider range of p53 mutations and (3) COTI-2 is given orally not intravenously.
Drugs like COTI-2 have the potential to revolutionize outpatient cancer therapy. COTI-2’s specific protein target, low toxicity, combination effectiveness with standard agents and potential for longer term outpatient therapy as an oral agent support a dramatic change in the treatment of susceptible cancers.