FDA to alter rules for cancer drug cocktails

[gpawelski]

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

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).

[gpawelski]

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.

[gpawelski]

Synergistic Drug Combinations (Cocktails) Provide Better Outcomes for Cancer Patients

Among the most sought after attributes of chemotherapy drug combinations is drug synergy. Synergy, defined as supra-additivity wherein the whole is greater than the sum of the parts, reflects an elegant interaction between drugs predicated on their modes of action. While some synergistic interactions can be predicted based upon the pharmacology of the agents, others are more obscure.

The functional profiling platform extensively examines the synergy between classes of drugs based on known modes of action. But, in some circumstances, studies have been purely exploratory. Among their most successful findings have been:

Alkylating agent plus purine analogs (cytoxan & fludarabine)

Platin plus antimetabolites (cisplatin & 5FU; cisplatin & gemcitabine)

Dual antimetabolite combinations (gemcitabine & capecitabine)

Natural products plus anti-metabolite (Doxil & gemcitabine; vinorelbine & capecitabine)

More recently, they have explored the interaction between signal transduction inhibitors. The results of these investigations have been the subject of numerous presentations at international meetings.

The application of synergy analyses (drug cocktails) may represent one of the most important applications of the functional profiling platform, enabling the exploration of both anticipated and unanticipated favorable interactions. Equally important may be the capacity to study drug antagonism wherein two effective drugs counteract each others’ benefits. This phenomenon, characterized by the whole being less than the sum of the parts, represents a major pitfall for clinical trialists who simply combine drugs “because they can.”

These analyses are revolutionizing the way newer classes of drugs are applied and has the potential to accelerate drug development and clinical therapeutics. Good outcomes require good drugs, but better outcomes require good combinations. Intelligent combinations are a principle focus of the functional profiling platform. It strives to identify the best outcomes for patients (not populations of patients).

Source: Rational Therapeutics, Inc.