FDA to alter rules for cancer drug cocktails

[gdpawel]

A diagnosis of AIDS was a death sentence until the advent of drug cocktails in the 1990s, which helped patients suppress the disease indefinitely. Now researchers say a similar combination strategy may change the course of cancer.

That's the thinking at Roche Holding AG, Novartis AG and Sanofi-Aventis SA, whose latest efforts to conjure a new generation of combination medicines are spurring regulators to rewrite the rules for drug research. The guidelines may shave five years off development timelines and lead to better treatments, said Ira Mellman, head of cancer research at Roche's Genentech unit in South San Francisco.

For a decade, researchers have crafted drugs to disrupt the precise cellular processes that fuel cancer. So far, survival benefits are measured in months, not years. That's because cancer, like HIV, evolves rapidly to evade a single treatment. Rather than mixing and matching approved drugs, scientists are now developing combinations designed to work in tandem to block cancer.

Cocktails that mix drugs still in development wouldn't have been possible just five years ago. FDA rules required that the merit of each active ingredient be proven before it could be added to another. Regulators were concerned about approving a combination where one of the ingredients didn't help, or worse, caused harm.

Twenty years of work on the human genome has helped illuminate the intertwined mechanisms of cancer. Scientists have a new understanding of the cellular and genetic links among different disease pathways. As a result, the Food and Drug Administration is ready to allow innovative testing of drug cocktails, said Richard Pazdur, the agency's top cancer regulator.

The new research guidelines describe three basic principles for early combinations.

First, there should be a scientific rationale for how the drugs will work together in the body.

Second, there should be evidence from mouse tests or small human trials that the benefit of combining the drugs is more than additive (think 1+1=3).

Finally, there should be a compelling reason why each drug can't be successful independently.

If conditions are met, companies may develop components simultaneously and forgo differentiating the drugs on the last and most expensive trials needed for regulatory approval. Those studies, pivotal Phase III trials, can cost hundreds of millions of dollars and take years to complete.

The promise of targeted cocktails is already changing how companies do business. There are several approaches being pursued. Pfizer Inc.and Roche are developing the needed parts in their own labs. Roche, based in Basel, Switzerland, has a combination that began safety tests in patients last year, and New York's Pfizer has four combinations in human trials.

A second group of companies is looking outside their labs to acquire components. Novartis, of Basel, and London's GlaxoSmithKline Plc started two studies this year combining an experimental drug from each company. AstraZeneca Plc, of London, and Merck & Co. of New Jersey also began a collaborative trial.

When Sanofi's scientists had an idea for a combination, they decided that instead of developing components, they would buy them. The company licensed a molecule from South San Francisco's Exelixis Inc. that inhibits a cancer-related enzyme and an antibody from closely held Merrimack Pharmaceuticals against a separate protein target.

Collaborations and acquisitions are likely to increase as FDA regulations are clarified. In some cases, individual components may not work at all without being combined.

About 800 targeted drugs are in various stages of development in cancer, aimed at about 300 genes relevant to the disease. For each type of malignancy, six or eight genes may be active, and the trick will be identifying and aiming drugs at the two or three most vital targets to each cancer type.

Source: FDA.gov

[gdpawel]

The FDA, just recently issued draft guidelines designed to encourage companies to work in tandem to develop two or more new drugs to be used in combination to treat cancer. Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research told a group of venture capitalists, drug company executives, and foundation representatives at a meeting that if companies want to work together, they shouldn’t wait for the final guidelines to be issued.

One can't remember phase I-II trials of combinations of drugs which had not received prior FDA approval. Cocktails tha mix drugs still in development wouldn't have been possible just five years ago.

However, cell culture assay labs have always tested new drugs in combination with each other, simultaneously measuring direct antitumor activity and antivascular activity.

Cocktails have become standard treatment in many oncological protocols: concoctions of two or more powerful cytotoxic agents which supposedly will attack the tumor in different ways. The ability of various agents to kill tumor and/or microvascular cells (anti-angiogenesis) in the same tumor specimen is highly variable among the different agents. There are so many agents out there now, doctors have a confusing array of choices. They don't know how to mix them together in the right order.

Data show conclusively that patients benefit both in terms of response and survival from drugs and drug combinations found to be 'active' in functional profiling assays even after treatment failure with several other drugs, many of which are in the same class, and even with combinations of drugs found to have low or no activity as single agents, but which are found in the assay to produce a synergistic and not merely an additive anti-tumor effect.

Source: Weisenthal Cancer Group, Huntington Beach, CA and Departments of Clinical Pharmacology and Oncology, Uppsala University, Uppsala, Sweden. Current Status of Cell Culture Drug Resistance Testing May, 2002.

[Butters Stotch :)]

What kind of drugs may be used?

[gdpawel]

The FDA had been thinking about mixing cocktails of drugs still in development. Exactly what drugs they have in mind is still up for debate. However, it has been suggested by some that perhaps Genentech/Roche should use assays like the Microvascular Viability Assay (MVA) with functional profiling to identify a potential target population of breast cancer patients that it thinks will benefit from the drug Avastin and then conduct a randomized clinical trial among this group. It's not a case of just throwing Taxol + Carboplatin in with Avastin and expect it to work for all cancer patients in all types of cancers.

Of course, this kind of strategy has been going on for years with cell culture assays, and the latest example is the Avastin controversy. Avastin combined with Carboplatin and Taxol has improved the survival of lung cancer patients. Avastin plus Carboplatin and Taxol improves the survival of some breast cancer patients. The problem is that it doesn't improve the survival of all breast cancer patients.

When the FDA rules on the clinical utility of a drug, they use a broad-brush approach that looks at the global outcomes of all patients, determining whether these glacial trends reflect a true climate change. The problem is that while Bethesda, Maryland may not be noticing significant changes in ocean levels, people who live on the Maldives are having a very different experience. As these scientists ponder the significance of Avastin, some breast cancer patients are missing out on a treatment that could quite possibly save their lives.

One breast cancer patient's life saving therapy is another's pulmonary embolism without clinical benefit. Until such time as cancer patients are selected for therapies predicated upon their own unique biology, we will confront one Avastin after another. The solution to this problem has been to investigate the VEGF targeting agents in each individual patient's tissue culture, alone and in combination with other drugs, to gauge the likelihood that vascular targeting will favorably influence each patient's outcome.

The problem with Avastin is the same thing that was a problem with AZT for HIV/AIDS. Early results, then rapid resistance. Solution is combination therapy to attack different targets. Tumor vasculature needs VEGF to survive. Avastin removes VEGF, killing blood vessels. But other proangiogenic factors can substitute: FGF, PDGF, ephrin A1, angioprotein 1, IL-8 etc.

We need to attack these other targets, as well. But "how" do you attack these other targets? If you can achieve this, then you may not need the other drugs, which really don't get into the tumor so well. But angiogenic attack provides true selective toxicity, something which is sorely lacking with all of our other treatments.

There are numerous drugs that can prolong life in breast cancer patients and slow the spread of cancer while improving quality of life, at so much less cost. In cancer medicine, it's not a case of throwing targeted drugs like Avastin at the problem. It's knowing "what" targeted drugs and "how" to use them in "individual" patients (not average populations). It is not clear that the purported mechanism is really what's happening.

The problem is that few drugs work the way oncologists think they do and it takes far more "information" to think through what it is they are using them for. I don't need to know how my laptop or television works, as long as it works and I feel the same way about anti-cancer therapies. Theory doesn't matter as much as the evidence that it does what we want it to do.

[Rich66]

In some cases, individual components may not work at all without being combined.

Now that's a paradigm shift.

[gdpawel]

According to an article in the Journal of the National Cancer Institute, it is becoming increasingly evident that cancers are dependent on a number of altered molecular pathways and can develop diverse mechanisms of resistance to therapy with single agents. Therefore, combination regimens may provide the best hope for effective therapies with durable effects (JNCI J Natl Cancer Inst Volume103, Issue16 Pp. 1222-1226).

[kykeon22]

thanks for those very interesting articles.