9 March 2007. With most drug discovery efforts ending in failure, all early-stage projects are by definition high-risk. The process of selecting candidates for advancement while mitigating that risk resembles natural selection as much as the competition on American Idol. As pathways or compounds reveal flaws—typically toxicity or lack of therapeutic effect—projects are abandoned, leaving more resources to the survivors. With more research, contenders continue to drop out until just a few future stars are left heading off to clinical development. Basic research provides the underlying knowledge of neurodegeneration to come up with the starting lineup of potential targets, said Linda Van Eldik at Northwestern University in Chicago, Illinois. From there, academics should aim to validate their new targets or compounds in vivo as rapidly as possible. Many targets or compounds are not viable because of poor pharmacokinetics, toxicity, or because patients don't tolerate the compounds, and developers want to get this information as quickly as possible. Several speakers characterized this approach as “Fail early, fail fast.”
Barbara Sahagan, from Pfizer Global Research and Development in Groton, Connecticut, reiterated this idea in her talk on target validation, which she defined as a process that increases confidence in the relationship between a target and a disease. After that, company scientists also consider the “drugability” of a target, a measure of the likelihood of finding compounds that will modulate its activity. Some targets are considered highly “druggable”—many enzymes with their substrate-binding pockets, for instance, or receptors that sit on the surface of cells. But others, such as transcription factors or adaptor proteins, present less attractive prospects for inhibition or stimulation. Finally, there is the safety of the target to consider. The overarching question in target selection is: how much do we need to know about this target to feel comfortable investing in it? Each different target is its own research project, and these smaller, high-risk projects make excellent opportunities for academic-industry collaborations, Sahagan said.
Richard Mohs from Eli Lilly in Indianapolis, Indiana explored what he called an “incredible array” of potential AD targets, gleaned from the range of neuropathology (plaques, tangles, vascular issues), to genetics (Abeta) to simply empiric data from previous drug discovery efforts. Lilly scientists are convinced that Abeta is a worthwhile target, but are less sure whether the important species is plaque or soluble amyloid, Mohs said. Other pathologies contribute to dementia and may present viable targets, as well. While Lilly plans to move ahead with its gamma- and beta-secretase inhibitors and monoclonal antibody to Abeta, in-licensing of new targets is important to the company, as well. In this regards, Mohs sees a strong demand for animal models and biomarkers. Dale Schenk, of Elan Pharmaceuticals in South San Francisco, is looking for new hypotheses and appropriate animal models to guide drug development. “We are lucky to understand 10 or 15 percent of the biology of this disease,” he said. “It’s impossible to predict what will work.” He recommended that researchers invest in model systems to get ahead. “The best groups have the best model systems,” he said.
While the only true validation of an AD target will be a clinically active drug, the gold standards for pre-clinical proof of concept are animal models. Manfred Windisch heads JSW-Research http://www.jswresearch.com/, a contract research organization in Graz, Austria, that specializes in neurodegenerative disorders. Windisch reviewed the strengths and weaknesses of animal models of AD, from mice to dogs to nonhuman primates. He concluded that each model can give part of the picture, while none gives all. He advised researchers to try to obtain quick proof of concept in animal models, but said “Don’t hassle around too long. If the compound is safe, get it into the clinic.” In the future, non-human primate models of AD will need to be used more, said Oppel Greeff, of the contract research organization Quintiles Transnational http://www.quintiles.com/. The experiments are very expensive and supplies of animals are limited, but breeding efforts by Australian and Singaporean researchers might provide many more aged primates for AD research in the coming years.
With more trials launching, patient populations could become a limiting factor, and the cost of a clinical trial depends in part on how quickly it can enroll. Both Greeff and Peter Schuler, from PRA International, another CRO, stressed the role of international trials. Both firms offer clinical trials world wide, which gives researchers and companies access to more patients, cheaper trials, and perhaps the chance to try new kinds of studies. Up-and-coming countries for clinical trials are China, South Africa, and India.
Furthermore, Greeff brought up the idea of pre-screened patient populations. Starting a trial with a well-characterized cohort that has already been followed for some time would yield faster results and improve the chance of statistical significance. Having such groups in place in the future will speed up development more than any other single factor, Greeff said. Michael Weiner of the University of California at San Francisco described a variation on this theme with a delayed start design for a phase II study. Rather than compare treatment and placebo groups as in a standard design, Weiner proposed to begin imaging on subjects a year ahead of the trial to determine rates of change off treatment. Then, the entire cohort could be treated and further monitored for alterations in their clinical course. This approach might allow for faster results, and require fewer study subjects.
In his own research, Weiner showed that he could distinguish subfields in the hippocampus by using high-resolution MRI. Moreover, he could distinguish people who were aging normally from those with MCI or AD by a characteristic pattern of changes in subfield volumes. Other recent work measuring white matter tracts by diffusion tensor imaging also reveals changes that differentiate normal aging from AD, he showed (see Zhang et al., 2007).
Weiner further updated the audience on the Alzheimer Disease Neuroimaging Initiative (ADNI). To date, 700 people have enrolled. The study is on track to enroll the remaining 100 by this May, with data collection complete by the end of 2010. Already, imaging data on 450 subjects is publicly available (see http://www.loni.ucla.edu/ADNI/). Similar efforts are starting up in Japan, Europe, and Australia, raising the prospect of a worldwide ADNI that can eventually provide tools for clinical trials. (This project, in particular, reminded scientists of the great hole Leon Thal’s death has left the field. Thal championed international collaboration on ADNI. Fillit and all conference participants honored Thal with a moment of silence at the outset.)
The Q and A session brought out the idea of enrolling late-stage patients in trials. This is a common practice in cancer, where people with advanced disease can enter chemotherapy trials. One practitioner mentioned he had 1,000 patients in his practice with single-digit MMSE scores, many of whom might participate with the consent of their caregivers. Mohs replied that the challenge is to define therapeutic objectives that are testable in modest-size studies in such a population.—Pat McCaffrey.
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- Zhang Y, Schuff N, Jahng GH, Bayne W, Mori S, Schad L, Mueller S, Du AT, Kramer JH, Yaffe K, Chui H, Jagust WJ, Miller BL, Weiner MW. Diffusion tensor imaging of cingulum fibers in mild cognitive impairment and Alzheimer disease. Neurology. 2007 Jan 2;68(1):13-9. PubMed.