The Race For A Cure For Cancer

"They don't want a cure." I can't tell you how many times I've heard this foolish statement backed by the argument "they make their millions by treating not curing." As a medical professional and biotech analyst, I can assure you "they," the large pharmaceutical companies of the world, do want a cure. Advancement in research has moved forward more in the past decade than over the last one hundred years. What is known today is that the cure lies in our own bodies' immune system. Researchers at the Wistar Institute and Universities in the US and UK have made great strides through private funding primarily by large pharmaceutical companies. In the end, the company who holds the patents to "the cure" wins the race.

The fight against cancer has been a losing battle for mankind, to say the least. Modern-day chemotherapy has its origins on the battlefields of the First World War. Military doctors noticed that soldiers exposed to mustard gas, a chemical warfare agent, died because their bone marrow was destroyed. Later, testing with nitrogen mustard in lymphoma patients showed minimal response, but the quest began for a cure.

Many years later, the first platinum derivative, cisplatin, was approved for use in cancer patients. By 1977, cisplatin, in combination with other drugs, had revolutionized the treatment of testicular cancer, and significantly improved the treatment of many other cancers.

Let's fast forward the search for a cure to the 1970s when "immunotherapy" was discovered in the UK in 1975. Doctors Georges Köhler and César Milstein, working in Cambridge, discovered how to make synthetic antibodies. They realized immunotherapy can be local or systemic. In the 1980s, another discovery was made by a Dr. Philip Thorpe, also from the UK. Dr. Thorpe discovered that a fatty lipid molecule, phosphatidylserine "PS," is preferentially expressed on cancer blood vessels where it can serve as a target to increase the specificity of drugs to the tumor, in turn harnessing the body's immune system to find and destroy the cancer cell. Dr. Thorpe realized cancer cells expose PS to avoid detection of the immune system, a trait also used by viruses to evade our immune system.

Today the race is focused on monoclonal antibodies ("mabs") to cure cancer.

Antibodies are proteins produced by the immune system. A type of white blood cell called a B-cell produces them in response to an infection. Normally, antibodies stick to foreign objects in the body and label them for destruction. Researchers have been trying to make antibodies that will attach themselves only to cancer cells. This can be useful in four ways:

  • It can stop the cancer from growing by stopping other essential "growth factors" from sticking to it.
  • It can "tag" the cancer for destruction by the immune system through PS binding.
  • If cancer drugs or radioactive particles are attached to the antibody, it can deliver them directly to the cancer cell without harming the rest of your body.
  • An enzyme (a type of protein that can promote chemical reactions) can be attached to an antibody then given to a patient along with a chemical that can be turned into a powerful drug by the enzyme. This directs the drug to the cancer and minimizes side effects. This process is known as Antibody-Directed Enzyme/Pro-drug Therapy (ADEPT).

Several antibody-based therapies are available, including the multi-billion dollar revenue cancer drugs Herceptin and Avastin made by Genentech (Private:DNA), which gained approval with the FDA through the work of Dr. Robert Garnick. Dr. Garnick continues his work today at Peregrine Pharmaceuticals (NASDAQ:PPHM) working closely with the FDA on the immunotherapy mab bavituximab, which binds to PS.

Today, a hope for a cure draws near with the immunotherapy drugs in development by Bristol Myers (NYSE:BMY), Merck (NYSE:MRK), Roche (OTC:RHHBY) and Peregrine Pharmaceuticals (PPHM). Each company has developed their own targeted antibody. Clinical trial results are showing potent and durable responses with the most advanced immune checkpoint inhibitors on the market or in clinical trials, including blocking antibodies to CTLA-4 (ipilimumab, Yervoy®), PD-1 (nivolumab), PD-L1 (lambrolizumab) and PS binding (bavituximab). A typical pattern of response to these agents is a brief disease flare as immune cells infiltrate the tumor followed by tumor shrinkage and a durable long-term response. For PD-1 and PD-L1, it is thought the most important interaction is at the tumor site rather than more broadly across the immune system, as it is with CTLA-4 and PS binding.

Bristol Myers currently is the most advanced pharmaceutical company in this race for a cure. In the Phase III trial, ipilimumab was administered to patients with relapsed/refractory metastatic melanoma and a substantial survival benefit of 3.7 months (10.1 vs. 6.4 months in the active vs. control arms, respectively) was observed. Of particular interest is the durable responses seen with ipilimumab, with a near doubling of patient survival one and two years after treatment (one- and two-year survival rates were 46% and 24%, respectively, in the ipilimumab group versus 25% and 14% in the control group). This ipilimumab trial was the first Phase III trial to demonstrate a substantial survival benefit with an immune checkpoint inhibitor. In this trial, clinically meaningful survival benefits were observed in patients who would otherwise be at the terminal stage of their melanoma. However, ipilimumab is associated with serious adverse events. Up to 23% of treated patients developed Grade 3 or 4 colitis and hypophysitis (inflammation of the colon and pituitary gland, respectively).

Recently, CTL-4, the target of Bristol Myers marketed cancer immunotherapeutic Yervoy (ipilimumab), has shown to stop tumor growth 100% in preclinical models when combined with PS binding mab (bavituximab). These results are among the greatest achievements to date in finding a cure for cancer. Dr. Hutchins of Peregrine Pharmaceuticals recently stated, "We believe the encouraging preclinical combination treatment data are due in part to the ability of bavituximab to facilitate an increase in tumor-specific cytotoxic T-cell activity, a function that appears to expand and broaden the potential of immunotherapeutic agents including anti-CTLA-4 and anti-PD-1 which prime and sustain T-cell mediated killing of tumor cells in our pre-clinical models. We are continuing to explore these and other immunotherapy combinations and look forward to reporting additional results as they become available." Just recently the FDA clinical trial website was updated with a trial listing the combined use of ipilimumab with bavituximab in a two-arm study of advanced melanoma. Bavituximab has been tested in over 450 patients to date and has been shown to be essentially void of side effects, a trait not seen in the other immunotherapies, making it the perfect partner for combo therapy. With expanded approval programs available today with the FDA, a Biologic License Application ("BLA") may be applied for a drug approval based on clinical safety and efficacy after Phase I trials. Bristol Myers looks to be the first large pharmaceutical company to engage in combo immunotherapy with bavituximab.

Bristol Myers's immunotherapy portfolio, consisting of nivolumab and ipilimumab, puts the company in a position to capture a great share of the immunotherapy market. Revenues could exceed $10 billion by 2022. If Bristol Myers acquires bavituximab, they could, in my opinion, win the race for a cure. I expect the Food and Drug Administration to approve the company's treatment, nivolumab, in late 2014.

The FDA granted nivolumab a fast-track designation for three tumor types: a form of lung cancer, renal cell carcinoma and advanced melanoma. Fast-track status gives companies extra meetings and correspondence with regulators throughout the review process, and it allows the drugmaker to submit data as it compiles it.

Today, the quest for a cure continues and as we move into 2014 we move closer to a cure with the combined use of immunotherapy agents.

Disclosure: I am long PPHM, BMY. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

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