COX on board since APRIL
Calling on Guardian Angels to Fight Cancer
By Patrick Cox | April 14, 2011 |
In this month’s issue, I have a very exciting company for you. Although the company is very early-stage, with no human clinical data yet, I believe the science is sound. This company has discovered a compound that modifies a well-studied cellular process implicated in a broad range of cancers. For many years, it has been a holy grail of cancer researchers.
Tens, if not hundreds, of millions of dollars have been spent by pharmaceutical companies in the quest to find a therapy to hit this molecular target — but in vain. The tiny biotech we’re presenting this month, however, truly appears to have discovered the compound that does so successfully.
Obviously, preclinical biotechnology innovators make for more speculative investments than those that have reached the stage of clinical trials. With greater risk, however, also comes the potential for greater reward. The biggest yields in pharmaceuticals come from picking winners before human data verify the safety and efficacy of a drug in humans. Of course, the flip side of that coin is the possibility that clinical trials will fail.
Most investors and analysts, therefore, tend to rely solely on human clinical studies as the only means of judging a drug candidate. This is simply because most people lack the time, background or confidence to study and grasp the core scientific platforms of preclinical companies. This creates opportunities for investors who are willing to do their homework and buy into companies before clinical results drive share prices up.
Fortunately, we’re not living in the 20th century anymore. With Google Scholar and a little patience, you can instantaneously access information that could be found only in large university libraries just a few decades ago.
So I would like to tell you about a number of factors that indicate this company’s pipeline has transformational potential. Beyond the core science, which I’ll describe below, there is also the reputation and decades of experience of its founder and chief scientist. Additionally, strong preclinical data and outside interest lead me to believe the probability of success justifies adding this company to your watch list of transformational technologies. However, I encourage you to consider this technology carefully.
P53, The Guardian Angel of the Genome
Before addressing the company, though, I would like to talk about cancer and the “guardian angel gene.” Known to geneticists as TP53, this gene encodes the transcription factor p53. Lately, you’ve been hearing the term “transcription factor” in this publication quite a lot. There’s a reason for that. As the human genome and the proteins expressed by genes are understood, more and more breakthroughs will be enabled.
When this protein was discovered in 1979, the tools did not exist to fully analyze and understand the TP53 gene or its protein transcription factor p53. The scientific community assumed, in fact, that p53 was causing cancers. Later research revealed a much more complex and interesting story.
P53 is, in fact, a cancer-suppressing transcription factor, rather than a cancer-causing one. After discoveries revealed its role in preventing cancers, the journal Science named p53 “Molecule of the Year” for 1993.
Additional discoveries are still being made about p53. This protein clearly operates as a transcription factor, controlling the conversion of DNA information to messenger RNA, or mRNA. It also, however, seems to act in a pharmacological manner. Regardless, p53 plays an extremely important role in guarding cell health.
Specifically, p53 monitors the DNA and activates cellular gene repair processes when a cell sustains genetic damage. If genetic damage proves too extensive for repair, p53 triggers the cell’s built-in self-destruct process, apoptosis.
For this reason, the p53 protein has been called the master watchman of the genome. As such, it prevents the mutations that turn healthy cells into cancer cells.
There is an Achilles’ heel to this process, however. If the p53-encoding gene, TP53, itself receives damage, there is no mechanism to repair it as p53 repairs other genes. Its tumor-suppressing functionality is curtailed. Similarly, if some other factor interferes with p53's normal functioning, the TP53 gene can no longer prevent cancers.
This is the reason that human papillomavirus (HPV) leads to an increased risk of cancer. When HPV infects a cell, it causes it to manufacture a protein that binds to p53, inactivating the master watchman. For some cancers, such as cervical cancers, HPV is believed responsible for 70% of cases.
In more than half of all human cancers, p53 is suppressed by mutations of the TP53 gene itself. The other cancers directly inhibit p53's molecular signaling pathway. P53 suppression, therefore, is implicated in almost all cancers. If some molecule could restore p53's activity in cancer cells, it is believed that the cancers would be naturally and nontoxically eliminated. Such a molecule would be a powerful new oncology drug. This is exactly what this month’s watch list company, Beverly, Mass.-based Cellceutix (PINK SHEETS: CTIX), has discovered.
In preparing this issue, my associate Ray Blanco and I had the pleasure of interviewing Dr. Krishna Menon, Cellceutix’s president and chief scientific officer, as well as Leo Ehrlich, CEO and CFO.
Important Scientist at the Helm
I have, by the way, been familiar with the work of Dr. Menon and Leo Ehrlich for quite some time. In addition to being the founder of Cellceutix, Dr. Menon is the chief regulatory officer for one of the most exciting companies in our portfolio, NanoViricides (OTCBB: NNVC). Formerly, Ehrlich helped found NanoViricides and served as its CFO. Dr. Menon also runs KARD Scientific, a contract research organization (CRO). KARD Scientific has been instrumental in testing and developing NanoViricides’ breakthrough antiviral nanovesicle technology.
CROs are an important and growing part of the drug discovery process. Because they specialize in performing tests and validation, pharmaceutical and biotech companies have found advantages and saving by outsourcing various aspects of the research process to these important organizations.
Pharmas have increasingly turned to CROs as a way to cut costs and manage the complexity of bringing new products to market. Since 2002, KARD Scientific has successfully helped its clients file eight investigative new drug applications with the FDA, thus launching them into human clinical trials.
Researchers at CRO facilities, therefore, see a wide range of platform technologies and candidate compounds from all over the industry. For CRO researchers, exposure to a large variety of different drug candidates can lead to a uniquely broad biotech perspective and expertise. As the head of his own CRO, Dr. Menon has been in the position to develop a very good sense of what will eventually make it to market and what won’t.
Dr. Menon, who has been described as a “lab workaholic,” also has decades of his own experience developing important anti-cancer compounds. His Ph.D. work, for example, laid the foundation for Eli Lilly’s blockbuster cancer drug Alimta. He was also a key developer for Gemzar, another billion-dollar cancer drug. For this and other contributions, he was honored with Eli Lilly’s President’s Award in 1999.
Therefore, his confidence in Cellceutix’s leading candidate, a first-in-class p53-activating cancer compound, has considerable significance. The genesis of the compound, in fact, has roots reaching back many years in Dr. Menon’s long professional career.
As a young man, before earning graduate degrees in medicine and pharmacology, Dr. Menon was the chief veterinarian for a Jamaican parish, which is comparable to an American state. On one occasion, he was called to do a postmortem analysis following the mysterious death of an expensive prize bull. The investigation revealed that the animal had been treated with an agent designed to kill external parasites, a common problem in tropical countries.
During the postmortem analysis, Dr. Menon discovered that the tick-and-mite-killing product acted as a cytotoxic agent, causing organ failure. More importantly, however, he also observed that the bull had suffered from subcutaneous tumors, but many had been eliminated by the product.
The event marked the beginning of his quest to develop anti-cancer compounds that combine low toxicity with high efficacy. This theme has marked much of his career, and has already led to the creation of breakthrough cancer drugs. It is now reaching its culmination in Cellceutix’s leading compound, called Kevetrin.
Kevetrin, a Potential P53-Activating Blockbuster
Discovered by Dr. Menon, Kevetrin is a pharmaceutical-grade salt of a molecule belonging to a class of chemicals known as thioureal compounds. Though widely used in industrial chemical processes, this class of compounds has never before been considered a promising source of drug candidates. The compound on which Kevetrin is based has been used for some time as a chemical intermediary for synthesizing more complex compounds. Before Menon began looking at it, however, its potential as a therapeutic drug was never considered.
Originally, Kevetrin was considered by Cellceutix’s scientific team to be a very interesting candidate for treating head and neck cancers. Follow-up research conducted at Boston’s Dana-Farber Cancer Institute revealed that it had a much broader potential, however.
Further tests performed on cancer-resistant cell lines grown in animal models revealed astonishing results. Tumor growth was delayed in many different kinds of cancers. In many cases, tumor shrinkage was observed. Seeking independent verification, Cellceutix sent its compound to bioscience giant Millipore. Millipore’s screening panels revealed strong data for Kevetrin in cancers ranging from leukemia to solid tumors.
Some published efficacy data follows below. These two charts were presented at the 102nd annual meeting of the American Association for Cancer Research in early April 2011. Both of these charts compare Kevetrin to one of the most common chemotherapy drugs, paclitaxel. Both are xenografts grown in mice. The first chart is for lung cancer tumor line A549:
In the A549 mouse model, Kevetrin delayed tumor growth by 33–100% compared to paclitaxel. It caused only a 3–4% decrease in animal weight, which is a proxy for toxicity in mice.
The second chart below is for a drug-resistant lung cancer tumor cell line, NCI-H1975:
Here, Kevetrin showed a 44–107% delay in tumor growth compared to paclitaxel, and there was no reduction in animal weight, indicating that the compound was not producing negative metabolic effects.
As you can see, Kevetrin compares very, very favorably against paclitaxel. Similar results are observed in leukemias and cancers of the colon and breast.
Most late-stage cancers, by the way, are those that have become resistant to the current arsenal of anti-cancer drugs. Cancer cells are extremely resilient, behaving almost as autonomous organisms. They have the ability to modify and adapt to their environment through spontaneous mutation. An investigational compound showing such strong results in so many different varieties of resistant cancers is a truly big deal. Kevetrin has the potential to be a mega blockbuster. Most of the new cancer drugs on the market treat specific kinds of cancers. Kevetrin has the potential to treat many of them. This is an enormous, multibillion-dollar market.
As you can well guess, such wide-ranging efficacy prompted questions about Kevetrin’s mechanism of action and led to further experimentation. Research into Kevetrin’s mechanism of action revealed that it acts on p53 and additional pathways, interrupting cancer progression by restoring normal cancer-fighting mechanisms. Essentially, Kevetrin re-awakens the “guardian angel” of the genome and causes apoptosis in cancer cells:
As I mentioned earlier, the discovery of p53's importance in cancers has prompted Big Pharma to spend untold millions trying to therapeutically activate the transcription factor. Their research, however, has been concentrated in a different class of compounds known as nutlins. Some are promising p53 activators, but unfortunately, all nutlin-based compounds have demonstrated unacceptably high levels of toxicity.
This has not been the case for Kevetrin. Toxicology studies completed this March by Toxicon, another third-party CRO, revealed a very benign profile. This clears the way for an investigational new drug application (IND) with the FDA and human clinical trials.
The Kevetrin Game Plan
The next logical step for Kevetrin is to file an IND with the FDA for Phase I clinical trials. As you know, Phase I trials are typically performed on healthy patients with the goal of establishing a drug’s safety. If a candidate compound passes this milestone, it can move on to Phase II, where efficacy becomes the major focus.
Because Cellceutix is seeking approval for the use of Kevetrin in late-stage drug-resistant cancers, it will likely be safety tested on people who have a life-ending form of the disease. Therefore, Kevetrin has the unusual opportunity to demonstrate not only safety in Phase I, but efficacy.
Since Kevetrin has reported strong performance on drug-resistant cancers in preclinical research, its Phase I trials will probably be performed on a population of very sick, end-stage cancer patients. For these patients, there isn’t much hope with existing therapies, so there is little to lose and much to potentially gain by using Kevetrin.
Cellceutix will have an early opportunity to demonstrate the healing power of Kevetrin. In fact, if the Phase I results are strong enough, there is even a chance that Kevetrin could skip Phase II and go directly to Phase III. The FDA has programs in place, like Fast Track, Accelerated Approval and Priority Review, to expedite new drugs that have shown the potential to satisfy large unmet needs. An effective therapy for drug-resistant cancers would almost certainly qualify.
Cellceutix is gearing up for the Kevetrin IND application now. It is already in the advanced stages of preparing the application for the FDA. Leo Ehrlich expects Cellceutix to be able to file in early May, once quality control documentation for Kevetrin production is completed.
If there are no objections on the part of the FDA, the plan is to apply to begin clinical trials at Dana-Farber Cancer Institute this summer, where Dr. Menon has extensive contacts. Dr. Emil Frei, a member of Cellceutix’s scientific advisory board, is currently emeritus physician-in-chief at this institution.
For a small biotech company like Cellceutix, a winning game plan usually involves collaboration with a large, deep-pocketed pharmaceutical company to help fund the clinical trials process. On the other side of that equation, the pharmaceutical companies have to collaborate to survive. Flagging in-house pipelines and expiring patent protections demand that they look to emerging biotechs for the next big products.
As a general rule, Big Pharmas express little interest in a compound until human data are released in Phase I or later studies. Kevetrin is an exception to this rule. Already, several big players have expressed interest, and one multibillion-dollar drug maker has even signed a nondisclosure agreement based on the strength of the preclinical data.
Ehrlich, however, tells us that Cellceutix is in no hurry to partner until the company is in a stronger position. While some investors might hope for an early Big Pharma deal, yields are maximized by taking drug candidates through the clinical trials process. This reduces risk for pharmas and increases competition among them for a partnership agreement. Phase I trials are usually the smallest and least expensive to run, and Ehrlich believes the company has the financial strength to carry it out on its own. This is good news for Cellceutix investors.
Kevetrin also has a strong intellectual property position. In the biotechnology business, strong patent protections are often the difference between success and failure. The patent for Kevetrin was published last year, and was written by Dr. Paul Ginsburg. Dr. Ginsburg, a patent attorney, has worked in senior positions at Pfizer and Schering. Among other important pharmaceutical patents, he wrote Claritin’s. It has never been challenged.
Moreover, because this class of chemicals has never been used in medicine, research into other pharmaceutical uses has barely begun. The number of potential uses is, in fact, vast. Cellceutix’s patent covers tens of thousands of possible chemical combinations for therapeutic use.
Growing Preclinical Pipeline
As promising as Kevetrin is, Cellceutix has other compounds with enormous potential waiting in the wings. Among those compounds is KM-391, which is targeted at autism.
As you know, autism is an enormous problem. In children with autism, there is a loss of brain function due to reduced brain plasticity and serotonin depletion. This, in turn, leads to various cognitive and behavioral disorders.
About 1% of the population between the ages of 3–17 is diagnosed with autism spectrum disorder. The total annual cost for autism in the United States is estimated at $60 billion, but only 5% of private research funding targets autism. Everything that is currently approved for treatment of autism addresses only symptoms, rather than the root causes.
As former director for the ALS foundation, Dr. Menon has considerable experience with neurological diseases. When he came across KM-391, originally developed in India, he saw its value and purchased the rights. He also improved the original compound.
Preclinical tests, performed in autism animal models, indicate no apparent side effects from long-term administration of KM-391. Measures of efficacy, however, are very strong. One hundred days into KM-391 trials, brain plasticity showed an 85% improvement over control in rats. Plasticity, as you know, refers to the brain’s ability to adapt to changes. Additionally, brain serotonin increased to normal levels when compared to a healthy pair-matched animal’s:
Rats treated with KM-391 also showed improvements in tests for autism-related behavioral disorders. There were marked reductions in repetitive behavior, touch sensitivity and self-induced injury, as well as improvements in group dynamics, position correction time and curiosity.
Cellceutix is preparing to file an IND for KM-391. As a small biotech with limited resources, however, Cellceutix has to concentrate on its leading compound. A successful IND and Phase I for Kevetrin will clear the path for KM-391. If KM-391 shows positive results in humans, it could completely change the way autism is treated. Like Kevetrin, this compound has multibillion-dollar potential.
Cellceutix has other candidates in its pipeline. It has preclinical and developmental-stage compounds for the treatment of psoriasis, arthritis, asthma, ALS, cancer and hypertension.
As I mentioned earlier, preclinical companies are inherently more speculative than later-stage companies, but they also have the opportunity for much greater share price appreciation. Cellceutix has a lead candidate that could be a game changer in cancer treatment. It has a world-class scientist leading research and a CEO with experience in launching new biotechnology companies. The company plans to collaborate on its candidates when it becomes appropriate, and has attracted considerable interest at an early stage based on the strength of its data.
That being said, this company is far too small for us to recommend purchasing at this time. The exciting potential of their science, however, is something I will be keeping a close watch on.
This is the most illiquid stock we have ever discussed here. If you decide to buy at this time, you are on your own — but I would encourage you to be very careful and use a strict limit order.
In the mean time, I am going to add this company to our watch list. When it is time to issue an official buy order, you will be the first to know.
