ExpIND process speeds Alzheimer's drug research

Researchers are actively cutting the time and cost it normally takes to develop radiopharmaceuticals by taking advantage of "Exploratory Investigational New Drug" (ExpIND), an FDA-sanctioned procedure that enhances post-discovery drug development while observing scientific and patient safety standards.

"The recent success of researchers using new imaging agents to detect amyloid plaque deposits-abnormal deposits that pile up in the brain and are thought to be a cause of Alzheimer's disease (AD)-¬has prompted a search for other similar agents that are more readily available to a wider community," said Michael Pontecorvo, Ph.D., Avid Radiopharmaceuticals, Philadelphia, Pa. "We were able to compare four drugs simultaneously and determine which provided the best images of the effects of the disease in the brain."

The drugs used in the ExpIND were first chemically combined with a radiotracer (18F-fluorine) that is detectable when used with positron emission tomography (PET) imaging. The PET scans revealed the tell-tale deposits of amyloid plaque in patients with AD as opposed to a control group of elderly individuals.

"The ability to identify subjects with elevated levels of amyloid plaque is significant," said Pontecorvo. "The success of these preliminary studies suggests that it may soon be possible to develop an 18F-labeled agent that could aid in the early diagnosis and treatment of AD."

Designed to determine a drug's pharmacokinetics (the activity of drugs in the body over a period of time including absorption, distribution and localization in tissues), ExpINDs are conducted prior to Phase I tolerance and dose escalation studies. The study uses very small doses in a few participants for a brief time.

In this case, the studies tested four 18F-labeled imaging agents in 100 patients at 10 clinical sites. Evaluation of the first agent ended after distribution to only eight subjects, allowing the researchers to concentrate on the remaining agents. After one year, a tracer was identified as the best detector of plaque deposits. The most common adverse effects were shoulder and back pain and claustrophobia, which were identified by the study physicians as likely to be procedure-related rather than drug-related effects.

"ExpINDs provide an excellent regulatory mechanism to speed the development of new radiopharmaceuticals while still assuring the safety of human subjects," said Dr. Pontecorvo. "Not only were all the agents well tolerated by the study participants, but because the development time was reduced by at least one year, the agents could potentially be available that much sooner to aid in early diagnosis of AD."

In January 2006, the FDA issued a guidance that cleared the path for drug developers in the United States to obtain important pharmacokinetic information at a much earlier stage of clinical development by using the ExpIND approach. The agency noted that ExpIND studies usually involve very limited human exposure and have no therapeutic or diagnostic intent. Although exploratory IND studies may be used during the development of products intended for any indication, it is particularly important for manufacturers to consider this approach when developing products to treat serious diseases.