Payers Following FDA Effort To Integrate Pharmacogenomics into Drug Development

Pharmacogenomic Data Submissions, the U.S. Food and Drug Administration’s preliminary Guidance for Industry,* has received a great deal of attention from drug makers — and unnerved them a bit — since its release late last year.

To some extent, the biotech and pharmaceutical industries are skittish about sharing pharmacogenomic data; the field is so young, their preliminary data may or may not be accurate. But Lawrence J. Lesko, PhD, director of the Office of Clinical Pharmacology and Biopharmaceutics in the Center for Drug Evaluation and Research, reminds industry that the document is not binding. More importantly, he suggests that it could have the effect of giving the science of pharmacogenomics a little shove.

“Guidances are the main way we communicate with the industry,” explains Lesko, who chaired the working group that wrote the document. “A guidance usually reflects the agency’s current thinking on a topic, especially newer topics or those that aren’t understood as well as established issues.”

Pharmacogenomics is among those newer topics — one that has the potential to revolutionize drug therapy and drug development if it can do what its proponents envision, namely, resolve the problem of variability in drug response. If pharmacogenomic data could identify in advance patients who are likely to respond positively to a drug, it could save the costs of giving the drug to nonresponders and also prevent adverse events. Herceptin, approved in 1998 as a breast cancer therapy, is an example of a drug that works only for certain patients — those with a specific genomic biomarker, the HER-2/neu protein overexpressed by the tumor.

PAYERS PAYING ATTENTION

For payers struggling to develop a strategy for managing biologics, the spirit of the FDA’s pharmacogenomics document very likely could wind up at the heart of P&T committees’ work. Expect manufacturers to explore MCOs’ interpretations of the guidance document as a fundamental part of an overall marketing approach.

The advantages for industry, too, would seem clear. Incorporating pharmacogenomic data into drug development could reduce the attrition rate of drugs in the pipeline and the failure rate of clinical trials, not to mention shave the size of clinical trials, increase the probability of success, and significantly reduce development time and costs. The test that identifies responders for the trials would be codeveloped with the drug to help doctors optimize therapy by identifying patients who would benefit from the drug once it reaches the market.

“The FDA sees huge potential and wants to encourage industry to move forward in this area,” says Lesko.

“The FDA guidance tries to encourage companies to integrate pharmacogenomic information into drug development,” says Lawrence J. Lesko, PhD, director of the Office of Clinical Pharmacology and Biopharmaceutics at CDER.

Some early applications of pharmacogenomics are encouraging.

For instance, 30,000 children are diagnosed with acute lymphocytic leukemia. For some patients, mercaptopurine effects a therapeutic response; a handful of others taking it have formed toxic metabolites and ended up in the hospital for months. It all depends on the gene that controls the production of thiopurine S-methyltransferase (TPMT), a liver enzyme that metabolizes the drug. Doctors now routinely use a genetic test to measure enzyme activity and adjust the dosage of mercaptopurine for optimal therapeutic response.

In short, says Lesko, “You have basic science that you want translated into clinical applications so that the public benefits from it.”

Approvals, Denials, FDA Actions

Seattle-based Cell Therapeutics received U.S. Food and Drug Administration fast track designation for its non-Hodgkin’s lymphoma drug, pixantrone. The anthracenedione treatment is being investigated for potential use in aggressive recurrent cases of the disease. In clinical trials, pixantrone has demonstrated ease of administration and has been responsible for less cardiac damage than other anthracyclines, making it a potential element of frontline combination therapies for non-Hodgkin’s lymphoma.

HIV drug fosamprevanir (Telzir, in Europe; Lexiva, in the United States), a protease inhibitor developed by GlaxoSmithKline and Vertex, has been approved for marketing by the European Union. Approved by the FDA last October, Telzir demonstrated substantial HIV virus suppression over a two-year period when used in combination with other therapies.

Acting on the recommendation of its science advisory panel, the FDA declined approval of Allergan’s oral psoriasis drug tazarotene (Tazoral). The advisory panel, which voted 9–3 against approval, cited risks of birth defects, loss of bone density, and the drug’s 20 percent efficacy as major concerns, and asked Allergan to conduct more studies on the drug’s long-term safety and its effect on women.

Coratus Genetics has received FDA approval to begin its phase 2b trial to test the safety and efficacy of vascular endothelial growth factor-2, a treatment for severe cardiovascular disease.

The FDA has created a new office dedicated to the review and approval of new cancer drugs. The purpose is to streamline the regulatory process and to get drugs on the market faster.

Clinical Trials/Drug Development

Roche’s AIDS drug enfuvirtide (Fuzeon), a fusion inhibitor that is effective in some patients who have developed resistance to other treatments, has proven to increase immune cell counts over a 96-week period. The European Union granted Roche approval to market the drug, and FDA approval is expected later this year.

Alameda, Calif.-based Avigen has reduced its work force and will focus on developing AV201, a Parkinson’s disease therapy. Disappointing results led the company to end its trial of human coagulation factor-9 (Coagulin-B) — a hemophilia drug and its flagship product that Avigen spent $140 million to develop and test.

Gaithersburg, Md.-based Panacos Pharmaceuticals’ anti-HIV maturation inhibitor PA-457 is in a multiple-dose phase 1 study to examine its safety and pharmacokinetics in uninfected healthy volunteers. Phase 2 testing in HIV-infected patients is expected to begin later this year.

GeoPharma subsidiary Belcher Pharmaceuticals reports that its lead candidate, MF5232, is effective in treating mucositis. The condition afflicts over 400,000 people in the U.S., including cancer patients who undergo radiation therapy or chemotherapy and people, such as HIV/AIDS patients, who are immunocompromised.

CancerVax will develop three experimental drugs discovered by researchers in Havana, Cuba. In the first known deal of its kind, CancerVax will pay Cuba in food and medicine, due to restrictions on trade between the U.S. and Cuba.

InKine Pharmaceutical announced positive results from a phase 2 study of its purgative, which is to be used by colonoscopy patients…. In phase 2 trials, Mountain View, Calif.-based Vivus’s libido enhancer, alprostadil (Alista), significantly increased the sexual satisfaction of premenopausal women with female sexual arousal disorder…. Alameda, Calif.-based Peninsula Pharmaceuticals has initiated a phase 3 trial of doripenem, a beta-lactam antibiotic for the treatment of patients with ventilator-associated-pneumonia…. D-D4FC (Reverset), Incyte’s once-a-day nucleoside analog reverse transcriptase inhibitor (NRTI) therapy component, significantly reduced viral load among patients in a phase 2 clinical trial.

Miscellaneous

In a development that has potentially far-reaching implications, Zuoshang Xu, MD, PhD, of the University of Massachusetts Medical School and a CytRx research collaborator, has discovered a way to silence the mutated SOD1^G93A gene that causes familial ALS. Using RNAi technology, Xu made the discovery in a mouse model. CytRx says the development is a vital step toward the development of a biopharmaceutical product to treat ALS.

Zuoshang Xu, MD, PhD