Ask Dr. Danter: In your March 2nd press release you indicated that COTI-2 development was progressing and that the IND would be filed by the end of March. As the end of March is here, can you provide any update?
Thank you for this timely question. First, our COTI-2 program continues to progress. We have put in place a very experienced, high profile scientific advisory board to advise on the clinical development of COTI-2 and other assets. We continue to pursue opportunities for multiple clinical trial indications. We have also hired a very experienced clinical trial manager to oversee the clinical trials planned to begin later this year with the first trial at MDACC in women with gynecological cancers. Our IND application is a substantial high quality document of over 5,000 pages and is currently in the final step, called publishing, before the actual electronic IND application can be formally filed with the FDA. Publishing means that the various preclinical test reports and other materials such as scientific articles referenced in the IND application must be loaded into the FDA’s electronic data room and then hyperlinked from the IND application to these data room documents. This publishing process typically takes 2-3 weeks depending upon the size and complexity of the IND application with the average IND application containing from 3,000 to 5,000 pages. Generally speaking, the larger the submission the greater the number of references, which in turn impacts the extent of document hyperlinking and quality assurance required. With some recent publishing difficulties overcome we now anticipate the filing to be completed by mid-April.
Ask Dr. Danter: Who manufactures COTI-2? Is the manufacturing site certified by the United States FDA?
Delmar Chemicals based in Montreal has manufactured the GMP (good manufacturing practices) quality COTI-2. We have a long-standing contractual relationship with Delmar Chemicals as we do not have internal synthetic chemistry capabilities. The cost to add such overheads and fixed costs cannot be justified at this time for the amount of COTI-2 production required.
The COTI-2 is manufactured in kilogram quantities. We currently have about six kilograms of GMP material. The HCl COTI-2 salt can also be made in kilogram quantities as needed.
The United States Food and Drug Administration has already visited the manufacturing facilities and deemed them compliant.
The filing of your IND has been delayed a number of times since the early fall of 2014. What is causing the delays in filing your IND application with the FDA for COTI-2?
Thank you for the question and the opportunity to provide an update regarding our IND filing in support of a Phase 1 clinical study for COTI-2 in gynecological cancers at MD Anderson Cancer Center. We wish also to thank our many followers and investors for their patience and support in recent months.
Since the latter part of January, we have revised our target for filing the IND to the end of the first quarter of 2015 and we wish to assure you that we are on track to achieve that goal. That being said, as noted in your question, we are several months behind our original schedule for filing this important application, and there have been two main unanticipated issues that have caused this delay.
The first issue arose when we scaled up our GMP (good manufacturing practices) chemistry to produce the kilogram quantities of COTI-2 required for the Phase I material to be given to patients. When scaled up, the original standard preparation route, which worked well for the small quantities used in our preclinical studies, produced impurities that were unacceptable. A new synthetic route had to be found which took time to develop. Our new method for preparing the COTI-2 is very clean with very low levels of any contaminants and is actually much cleaner than with our original small quantity method. Although this issue was resolved, it did result in an approximately three month delay.
The second issue arose more recently when we were finalizing the COTI-2 oral suspension to be given to patients. We made a slight adjustment to the suspending material in order to improve its taste and thus patient compliance. While we were advised that this should not produce any issues, the formulation change did result in a degradation of COTI-2 over time in this suspension material that was deemed unacceptable in maximizing patient outcomes. We were forced to return to our original formulation of COTI-2 in a commonly used suspension, OraPlus. This change has resulted in good stability and purity over time. This final chemistry issue is resolved but resulted in a further delay of two months.
The IND is now in the final writing of the chemistry section and formatting of the document. In spite of the delays, we have consistently avoided rushing the process in order to assure that the highest quality document will be submitted and thus improve the timing of approval with the FDA. To be clear, we are on track for an IND submission by the end of the first quarter of 2015.
I would also like to add that we are planning on filing a Health Canada CTA once the IND has been filed in the U.S., and we are very close to finalizing a very experienced and prestigious Scientific Advisory Board to guide and consult on the clinical development of COTI-2 in multiple cancer indications.
Our very own Dr. Wayne Danter was recently interviewed by Ken Evseroff of New to the Street while attending investor conferences in New York City. Here is the interview:
New to the Street is a television show that profiles public companies and provides business news. New to the Street offers a blend of business and financial services news reporting and in-depth interviews relating to new products, economic analysis and public company profiles. New to the Street is produced by FMW Media Works Corp.
Researchers from the MD Anderson Cancer Center recently conducted preclinical experiments on COTI-2. What were the aims of these experiments?
The aim of these experiments was twofold. First, Dr. Mills at MDACC wanted to confirm that COTI-2 was preferentially killing cancer cells with p53 mutations. Secondly he wanted to identify the range of different mutations in the p53 gene that were responsive to COTI-2.
Dr. Mills first evaluated the activity of COTI-2 in a number of human cancer cells lines that we had not previously studied. He was able to evaluate the killing activity of COTI-2 in the context of p53 mutations since the p53 mutation status of these cells was known. He then went on to introduce 32 different types of p53 mutations into mouse embryonic fibroblasts (MEFs), a cell-based system for studying the effect of gene mutations. Once the p53 gene mutations were established in the MEFs the effect of COTI-2 on those cells was evaluated.
Changes in normal p53 protein levels together with changes in other proteins known to be direct cellular targets of normal p53 protein were also evaluated for each of 32 different types of p53 mutations following treatment with COTI-2.
Extensive data from the experiments have demonstrated that COTI‐2 restores p53 protein to its normal function in human cancer cells with a wide range of common p53 gene mutations.
What would be the impact on cancer patients if COTI-2 proves to be effective in people with p53 mutant tumors?
Given the central role of p53 mutations in human cancers, COTI-2 could represent a breakthrough therapy for many cancer patients if clinical trials confirm its’ activity in people. If we consider a specific disease such as ovarian cancer, p53 mutations are found in more than 90% of these tumors. Preclinical animal experiments with a human ovarian cancer known to have a p53 mutation and be resistant to conventional chemotherapy demonstrated that treatment with COTI-2 as a single agent either completely halted tumor growth or lead to dramatic tumor regression depending on the dose. COTI-2 was associated with no observable toxicity in these experiments.
Unlike nearly every other cancer treatment in existence today, 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.
Traditional cancer treatments have been largely unfocused in that they indiscriminately kill dividing cells, cancer or otherwise, which often leads to significant toxic side effects in patients. Targeted therapies on the other hand, try to inhibit one or more abnormal proteins that are found in proliferating cancer cells resulting in programmed cell death.
One or more mutations in the p53 gene are found in at least 50% of all human cancers. These mutations begin a sequence of events that leads to loss of control of cell growth and proliferation. Due to its central importance in many human cancers, drugs that restore function to mutated p53 proteins have been described as one of the three holy grails of cancer research.
Targeting specific abnormal proteins found only in cancer cells could be expected to be associated with less toxicity in normal healthy cells.
The following is an abbreviated transcript from an interview Dr. Danter had with Juan Costello of The Wall Street Analyst, providing an overview of our business, our lead cancer drug candidate, COTI-2, and milestones we are working towards. Click here to listen to the interview in its entirety.
Juan Costello: Thanks for joining us today Dr. Danter.
Dr. Wayne Danter: You are very welcome. Thanks for the opportunity.
Juan Costello: Certainly. Now, starting off, give us a brief history and overview of the company for some of the listeners that are new to your story.
Dr. Wayne Danter: Sure, the company was formed around a core technology based on Artificial Intelligence. So, the principle was very simple--If you start off with better starting points you will likely end up with higher quality products at the end of the drug discovery process. So, following that concept we took a partly traditional drug discovery process, created computer simulations of each one of those individual elements, validated the simulations on external data, and then put it back together into a platform that we currently are applying to drug discovery and preclinical drug development.
Juan Costello: In terms of COTI-2 can you talk about some of the positive results there?
Dr. Wayne Danter: COTI-2 is the first commercial project out of our core technology, which is now heading towards the clinic and should be Phase I ready by the end of this year. It was originally discovered in a project done for a big pharma company looking at treatment for small cell lung cancer. They subsequently lost interest in that project, and based on the early results we took it internally as our first commercial project. We have had a lot of success in the preclinical development of COTI-2. It has behaved very much like the computer simulations have predicted and the most recent data that appeared in our press release [June 11, 2013] has to do with the mechanism of action of the drug candidate based on experiments carried out at MD Anderson Cancer Center in Houston. We have done a lot of work in cell lines and animals and we are pointed in one direction towards a slightly different pathway but with the help of Dr. Gordon Mills from MD Anderson we have focused in on p53 gene mutations. P53 is particularly important because mutations of that gene are found in at least 50% of all human cancers. Finding a drug that will impact that particular gene mutation has a great potential-- it will benefit a lot of people.
Juan Costello: Can you expand on some of the recent trends right now in this sector and how you are positioning the company to capitalize on them?
Dr. Wayne Danter: The trend nowadays is moving more and more towards gene-based types of therapies and by that I mean focusing in on gene mutations that are common in different cancers and trying to find small molecule solutions to mitigate those gene mutations. The basic concept is that the gene mutation ends up producing abnormal protein and that abnormal protein, either through increased signaling or decreased signaling in the cell, tends to lead to a cancer like transformation in many cells. The trend I think used to be trying to find blockbuster drugs for organ type tumors. Everybody has heard about the blockbuster drugs for lung cancer, colon cancer and breast cancer, but I think the trend really is away from that and towards drugs that specifically target gene mutations in a number of different types of cancers. For example, there is a wide range in the presence of p53 mutations across all human cancers. It may go from 10% to 20% in some types of lung cancer up to more than 90% in ovarian cancer. Most of the human cancers would be scattered in between that 20% and 90% in terms of the prevalence of a p53 mutation.
Juan Costello: What do you feel makes COT unique from some of the other players in the sector?
Dr. Wayne Danter: Well, I think it’s primarily our underlying technology, which has many applications. While we use it currently for internal projects we also have a number of co-development projects with external pharma and biotech partners to help them discover new compounds with a higher probability of success against their targets that they think are important internally.
We have other avenues that we are also exploring right now and I think the long term for us sees us heading towards more of an intellectual property technology type of company that right now is focused in the pharmaceutical space.
Juan Costello: What are some of the specific goals and milestones that you and the team are hoping to accomplish over the course of the next year?
Dr. Wayne Danter: The first goal is to partner our lead asset COTI-2 with a pharma biotech partner and that’s going very well. We’re looking to out-license that asset in the next 6-8 months. Behind that we have our second program, which is an AML project which has partial funding from Canadian government and we will be bringing that along as our next commercial asset. In addition to that we will be doing more research and development, co-development type projects with universities, pharmas and biotechs and we have three of those ongoing right now and another one in the works that we hope to announce shortly. We are also at present filing patents around new intellectual property that includes a computer simulation of a programmable cancer cell.
Juan Costello: And as far as investors in the financial community are concerned Dr. Danter do you believe that the Critical Outcome story and your message and upside are completely understood and appreciated by them? And if not, what do you wish investors better understood about the company?
Dr. Wayne Danter: Well, I think that one of the main things to understand about our company is that we are not a one-trick-pony. The technology allows us to have multiple projects, both external and internal going on simultaneously. And most of our investors have been aware that if one project for whatever reason doesn’t come to fruition there is one or two or three other projects that are going on simultaneously. So, it’s a much different type of investment than the traditional biotech investment around one or two assets, they either fail or they are successful.
We have a very robust core technology and given the non-sustainable nature of the traditional approach to drug discovery, we think that we are very well positioned for the future.
Juan Costello: Well, we certainly look forward to continue and attract the company’s growth and report on your upcoming progress and we would like to thank you for taking the time to join us today.
Dr. Wayne Danter: You are welcome and thank you for the opportunity.
Dr. Wayne Danter is a co-founder of Critical Outcome Technologies Inc. and a pioneer in the evolving interface between artificial intelligence (“AI”) and pharmacotherapeutics. Dr. Danter will use this page to answer questions about Critical Outcome's drug compounds, the company's proprietary, artificial intelligence-based drug discovery technology platform, and various related topics. Check back regularly or subscribe to this page by RSS.