As it transitions from a discovery and technology platform-focused organization to a clinical stage biotech company, Critical Outcome Technologies (OTCQB:COTQF; TSX-V:COT) is approaching a critical inflection point by mid-2017 with its lead program, COTI-2, in gynaecological cancers.
COTI-2 is currently being evaluated in a Phase 1 clinical study at two premier cancer centers in the U.S.
“We’ve assembled an impressive amount of supportive preclinical data in the past for COTI-2, and are excited to be evaluating in the clinic this potentially significant therapeutic option for women suffering from debilitating gynecological cancers, such as ovarian cancer,” Alison Silva, president, says in an interview with BioTuesdays.com.
“We are focused on establishing a robust safety profile for COTI-2 in a Phase 1 study, as a primary endpoint, with secondary disease endpoints including tumor or biomarker modification, providing preliminary indication of potential improvement in disease progression,” she adds.
In addition to ovarian cancer, she says COTI-2’s specific protein target and potential for longer-term outpatient therapy, as an oral agent, represent a potentially dramatic change in the treatment of multiple susceptible gynecological and a host of other cancers.
Ms. Silva explains that in multiple preclinical animal studies, COTI-2 was able to stabilize the structure of the mutated p53 protein, allowing it to regain its normal function of tumor suppression.
“p53 is the single most important gene known to be involved in cancer,” she adds. “Mutant p53 proteins are found in more than 50% of all human cancers, and contribute to the transformation of cancer cells, metastasis and drug resistance.”
Specifically, she points out that advanced-stage, high-grade cancers have a more prevalent p53 mutation, with rates running as high as 95% in serous ovarian cancer and 75% in certain forms of squamous cell head and neck cancer patients.
Citing the company’s innovative approach to addressing difficult to treat gynecological cancers, Bharatt Chowrira, who joined the COTI board this month and is president of closely-held Synlogic, said in a statement announcing the board appointment that selective targeting of the mutant forms of p53 protein, a central switch in a number of cancers, has been the focus of intense research in the field for a number of years, with limited success.
“COTI scientists may potentially have solved this puzzle,” he added. “If this compound is able to achieve efficacy in these patients, in my opinion, this would be a major advance in this field.”
Ms. Silva points out that in addition to its novel p53-dependent mechanism of action, COTI-2 is effective at low doses, exhibited low toxicity in preclinical studies and has potential as both a single agent or combination therapy.
“In our preclinical models, COTI-2 demonstrated effectiveness when combined with many first-line therapies, including chemotherapy and possibly immunotherapy, which should be attractive to potential partners,” she adds.
The company’s IP protection includes eight issued patents in the U.S. and one each in Japan, the EU and Canada, with additional patents pending.
Ms. Silva says there are several other companies who are developing drug candidates against mutant p53 as well. “Our compound differentiates itself from the competition in three ways: in terms of potency, COTI-2 is effective at nanomolar concentrations; its specificity in targeting selectively the mutated p53 gene; and it is given orally, not intravenously.”
In July, COTI began dosing three additional patients with gynecologic cancer in the third cohort of its Phase 1 trial. There are three patients per cohort and the trial design allows the company to enroll up to 12 cohorts, or 36 patients, in the dose escalation phase. The trial is being conducted at MD Anderson Cancer Center in Houston and Lurie Cancer Center at Northwestern University in Chicago.
Ms. Silva says that later this year, the company hopes to release initial safety and pharmacokinetic results after the first four cohorts have been dosed and evaluated, and hopes to release interim data by March 2017. Final trial results are expected in mid-2017.
“When we reach a maximum efficacious dose, we plan to expand the trial and enroll an additional 10 patients with p53 mutated ovarian cancer,” Ms. Silva says. COTI plans to continue clinical development of COTI-2 in gynecologic cancer, unless an “opportunistic high-value partnership comes along.”
Also in the first half of 2017, COTI plans to begin additional early-stage clinical trials with COTI-2 in patients with recurrent head and neck squamous cell cancer and Li-Fraumeni Syndrome, a rare disorder that greatly increases the risk of developing several types of cancer, particularly in children and young adults. The company has filed an orphan drug application for Li-Fraumeni and is also studying COTI-2 as a potential candidate for acute myeloid leukemia.
The company’s next clinical candidate is COTI-219, which is expected to target KRAS mutations in oncology, and could begin clinical testing in six-to-nine months. The normal KRAS gene performs an essential function in normal tissue signaling, and the mutation of a KRAS gene is an essential step in the development of many cancers.
Ms. Silva notes that the company also is developing a highly novel antibiotic, known as COTI-MRSA1, which has been designed to prevent the occurrence of penicillin resistance, and could begin early clinical testing in nine-to-18 months.
Methicillin-resistant Staphylococcus aureus (MRSA) infection is caused by a type of staph bacteria that has become resistant to many of the antibiotics used to treat ordinary staph infections. “Ideally, we’d like to partner our MRSA program either with government or a biotech/pharma company,” she adds.