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Insight & Intelligence™ : Mar 27, 2014

The Promise of Combination Therapies

Recent technical advances, new business strategies, and FDA policies will speed combination therapy development.
  • Lynn C. Klotz, Ph.D.

A number of diseases are complex multigene or multifactor diseases. Some major ones are cancer, neuropsychiatric conditions such as schizophrenia and depression, obesity, and bacterial infections. All these diseases extract a heavy financial toll on society. For instance, neoplasms (cancer and related abnormal cell growth) cost $217 billion per year in the U.S. in 2009, second only to cardiovascular diseases. Combination drugs for cancer and bacterial infections are the focus here. Cancer therapies often don’t work, cancer cells often develop resistance to drug therapies, and many bacterial pathogens resist a wide range of antibiotics.

Advantages of Combination Therapies

Successful combination therapies often target proteins in different pathways involved in cell proliferation and disease spread in the body. Combination therapies should increase the likelihood that the disease will be arrested or cured, reduce the likelihood that drug resistance will develop, and slow the rate of drug resistance.

Unsuccessful first-round, single-drug therapy could be a disaster as it may be too late to save the patient in the second round, so it is important to arrest or cure cancer and infections as quickly as possible. A potential disadvantage of combination therapies is toxicity, especially for cancer drugs if high doses of each drug in the combination are necessary; cancer drugs are usually highly toxic to begin with.

Drug Combinations for Cancer and Bacterial Infections

Hodgkin’s lymphoma combination therapy is one of the great success stories in cancer therapy. Before the 1960s, Hodgkin’s lymphoma was almost always fatal. In the mid-1960s, a four-drug combination was developed called MOPP for the first letter in the names of the four drugs. It cured almost 70% of patients with advanced-stage disease. MOPP had a big problem, however: It was fairly toxic. In the mid-1970 a different four-drug combination, ABVD, was shown to increase effectiveness to well over 80% five-year survival in patients under sixty years old and with less toxicity. The four cancer drugs in this combination are Adriamycin, Bleomycin, Vinblastine, and Dacarbazine.

Thomas Roberts, co-chair of the department of cancer biology at the Dana-Farber Cancer Institute, points out that in the 60’s and 70’s there were relatively few cancer therapies and hence a limited number of combinations. There are now a very large number of possible two, three, and four drug combination therapies for cancer. To be precise, based on today’s 365 therapies from the National Cancer Institute’s list of cancer therapies, there are 736 million two, three, and four drug combinations, a staggeringly large number. At present, there are only 38 combination therapies on the NCI list, so we have barely scratched the surface.

The World Health Organization has identified antibiotic resistance as one of the greatest threats to human health. No new antibiotics were approved by the FDA in 2013, only one monoclonal antibody drug for anthrax in 2012, and none in 2011. Moreover, the clinical trial pipeline is nearly dry as there are only two new classes of antibiotics in late-stage trials. We desperately need new antibiotics to combat bacterial infections. Unless we find some way around widespread antibiotic resistance, we may find ourselves back to the days before antibiotics when serious infections often caused deaths of people of all ages.

Combination antibiotic therapies should kill bacterial pathogens more effectively and, just as important, slow the rate of antibiotic resistance. If p1 and p2 are the probabilities that resistance develops for antibiotics 1 and 2, the probability that resistance develops for the two-antibiotic combination is the much smaller product p1 x p2. When antibiotic resistance develops in a few bacterial cells during infection, the resistant bacteria will multiply and survive. It is important to kill them all to slow the development of antibiotic resistance in that pathogen.

The status of combination therapies for several diseases and various research approaches are reviewed in “Multi-target therapeutics: when the whole is greater than the sum of the parts.

Speeding Cures for Complex Diseases

Two developments—precompetitive partnerships to understand disease pathways and to identify targets for drugs, and FDA policies to expedite clinical trials—will speed combination therapies for complex diseases to market.

Why precompetitive partnerships? When the human genome project was completed, many researchers thought all that was now needed to cure disease was to find out which of the 25,000 human proteins were implicated in which diseases, then make drugs to manipulate the proteins. But identifying the proteins is not nearly enough.

An analogy may help explain where we were then. If you had a map of New York’s subway system and a schedule of train arrivals at stations, you might think you know all there is to know about the subway system. But your train doesn’t show up one day. Did it stall at the station just before yours? Is there a labor strike, shutting down the whole system? You realize you really know very little about the system. The subway map and schedule is analogous to the completed human genome project. The train not arriving is analogous to being ill. And depending on the illness, to cure it you may need to know only a little bit more or you may need to know a lot more.

Understanding the complicated pathways to disease and how pathways and their molecules interact requires the work of many kinds of experts: molecular biologists, chemists, materials engineers, computer scientists and so on, all contributors to systems biology. This is a big undertaking best achieved with many partners.

The GenomeNet website provides pathway diagrams for many diseases including a generalized cancer pathway, pathways for specific cancers, and infection pathways for many bacterial pathogens. Clicking on the generalized-cancer-pathway hyperlink reveals how complicated the cancer process is. The pathway diagram leaves an impression that a very lot is known about the cancer process, giving us many choices for combination drug targets. Moreover, pathways and drug targets are being discovered continually. 

A general flow diagram for precompetitive partnerships is presented in the Figure. The basic idea is that a large group of partner research institutions and companies contribute their resources to discover pathways and drug targets for complex diseases. With this knowledge in hand, each partner is free to develop and market its own proprietary drugs and drug combinations.

In a thoughtful analysis of cancer research strategy, the funding organization Cancer Research UK places considerable emphasis on partnerships and combination drugs.

For bacterial pathogens, a major new precompetitive partnership was announced in February 2014. The partnership called “European Gram Negative Antibacterial Engine (ENABLE), will bring together 32 partners in 13 countries, led by GlaxoSmithKline and Sweden’s Uppsala University.” An article from the Lancet Infectious Disease Commission, “Antibiotic resistance—the need for global solutions,” details approaches for addressing antibiotic resistance, again with a heavy emphasis on partnerships.

The FDA policies for drug development include three programs, two newer ones and an older one, to help support developers and speed clinical trials. The new program is Breakthrough Therapy Designation. In the FDA’s words, “A breakthrough therapy is a drug: intended alone or in combination with one or more other drugs to treat a serious or life threatening disease or condition, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies.” A breakthrough therapy designation speeds the development and approval of promising therapies and provides FDA guidance for conducting clinical trials efficiently.

The FDA Fast-Track Program is designed to aid the development and speed review of new drugs that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs. The FDA decision to fast track a drug candidate is based on preclinical data, whereas the breakthrough designation is based on early clinical trials.

The old program is the Orphan Drug Act of 1983, which provides a number of benefits to developers of drugs for “orphan” diseases, those with less than 200,000 victims in the U.S. Benefits include seven years of exclusive marketing regardless of patent status, tax incentives for clinical research, possible grant funding for Phase I and II clinical trials.

Calls for FDA reform such as doing away with Phase III clinical trials would bring drugs to market three years faster and reduce clinical trial costs by 25%. Of course, such a radical reform would require intensive post-market surveillance for the drug’s safety and efficacy in patients. 

A Business Opportunity Illustration

Small biotechnology and big drug companies alike will find many ways to take advantage of these recent activities to speed development of combination drugs. As an illustration, let’s look at a hypothetical small cancer drug-discovery company that had researched a new pathway, found promising targets, and now has drug candidates for an orphan cancer. In addition to entering clinical trials with a lead drug candidate for single-drug therapy, our company should look at companion drug(s) for combination therapy, focusing on companion drugs that are either expensive FDA-approved drugs with minimal efficacy and so have poor pharmacoeconomics or on drugs that failed in Phase III clinical trials for unclear efficacy. Combination therapies could “rescue” these marginal drugs.

There are many signs that pharmacoeconomic considerations are beginning to affect decisions on whether to use particular drugs. In a New York Times Op Ed titled “In Cancer Care, Cost Matters”, physicians from Memorial Sloan-Kettering Cancer Center wrote “we are not going to give a phenomenally expensive new cancer drug to our patients.” The particular drug that prompted their decision was Zaltrap for metastatic colorectal cancer. The drug is priced around $11 thousand for a month of treatment and median survival is about twelve months. A quick cost-effectiveness calculation yields CE = (12 x $11,000) /1 lys = $132,000 per life-years-saved, well above the $50,000 to $70,000 maximum for acceptable cost-effectiveness. (Basic pharmacoeconomic measures are covered in an earlier GEN article.) Cost utility is even less favorable since the saved life-years are most likely to be of low quality.

Our hypothetical company’s drug combinations would then be screened in cell culture to find combinations that are noticeably better than the drugs singly. Going further could be a lot to handle for a small company. At this point, it could negotiate a partnership with the patent holder of the companion drug(s), or it could seek the help of the National Cancer Institute’s long-established cancer drug-screening program for further screening, identifying the best combination candidate, and taking the combination through animal testing ready to enter clinical trials.

The NCI's screening program is massive. About 80,000 cancer-drug candidates have been screened since 1990. The NCI accepts drug candidates from government laboratories, research institutes, academic institutions, and companies throughout the world. For small biotechnology companies with proprietary or expert knowledge of novel pathways and targets, the NCI program could be a valuable resource. 

What has our company gained by this strategy? By picking an orphan cancer, our company would be eligible for orphan drug benefits. Since the combination therapy appears to be a significant advance, it should be eligible for fast-track or breakthrough therapy designations. By taking advantage of NCI’s screening program, the combination therapy should be well positioned for clinical trials and for a partnership with the developers of the other drugs in the combination.