[gdpawel]

Michka

That's a smart question! They could have. The EMILIA trial, which was sponsored by Roche, compared trastuzumab (Herceptin) emtansine used alone, to lapatinib (Tykerb) plus capecitabine (Xeloda). It was Roche who developed trastuzumab (Herceptin). It was GlaxoSmithKline who developed lapatinib (Tykerb).

Roche was one of a number of pharmaceutical companies that conjured a new generation of combination medicines and spurred regulators to rewrite the rules for drug research, to shave five years off development timelines.

For a decade, researchers have crafted drugs to disrupt the cellular processes that fuel cancer. So far, survival benefits are measured in months, not years. That's because cancer evolves rapidly to evade a single treatment. Rather than mixing and matching approved drugs, scientist 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.

The FDA has allowed innovative testing of drug cocktails. 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 changed how companies do business. There are several approaches being pursued. Pfizer Inc. and Roche are developing the needed parts in their own labs. Roche has a combination that began safety tests in patients last year, and New York's Pfizer has four combinations in human trials.

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).

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 application of synergy analyses may represent one of the most important applications of the functional profiling platform; enabling clinicians to explore both anticipated and unanticipated favorable interactions. Equally important may be the platform's 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.

Functional profiling consists of a combination of a (cell morphology) morphologic endpoint (DISC) and one or more (cell metabolism) metabolic endpoinsts (MTT, ATP, resazurin). It studies cells in small clusters or microspheroids (microclusters). The combination of measuring morphologic (structural) effects and metabolic effects constitutes the measuring of a profile at the whole cell level.

These analyses are revolutionizing the way cell-based functional profiling applies newer classes of drugs 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 functional tumor cell profiling.

Cell-based functional profiling assay labs have always tested new drugs in combination with each other, simultaneously measuring direct antitumor activity and antivascular activity.

Greg