4 August 2008. On 31 July, the 11th International Conference on Alzheimer’s Disease, run by the Alzheimer’s Association in its hometown of Chicago, drew to a close amid a varied buzz of some good and some disheartening news. Held from 26 July on, the conference posted record attendance at more than 5,400 registrants and over 2,000 abstracts. This resulted in a conference where morning and afternoon slide talks typically required four to six parallel sessions and conference attendees increasingly had to settle on a few areas to follow.
One major take-home message from this meeting that leading scientists portrayed is that the state of the AD research field should be judged by the diversity of therapeutic approaches that are developing in preclinical science as well as wending their way through the clinical pipeline. Human trials, for example, center not only on the amyloid hypothesis, but are also beginning to test tau targets, various neurotransmitter-based targets beyond acetyl cholinesterase, neuroprotective therapies, NMDA antagonists, antioxidants, nutritional approaches, and more, as well as drugs with as yet poorly understood mixed effects, especially on mitochondria. “A marker of the field is how many trials with many different mechanisms of action are entering Phase 2 now, some entering Phase 3. The news is that there is both enough science, and will on the part of funding institutions, to push therapy development of Alzheimer disease,” Steve DeKosky of University of Pittsburgh told reporters at the meeting. Paul Aisen of University of California, San Diego agreed that the field must test a diversity of approaches for AD. “There have been many papers here on disease-modifying strategies, many around the amyloid hypothesis, but we must be open-minded to all.”
DeKosky at a news briefing urged the media and colleagues in the field not to stake too much news value on the success or failure of a single trial, especially in Phase 2. Particularly on that point, however, there was a palpable disconnect between how drug development proceeds and how it is being rated by observers in the press and investment community. For example, when Elan/Wyeth on 30 July 30 summarized data of their Phase 2 trial of bapineuzumab in a 12-minute presentation, financial analysts in the room were piping results through instantaneously to their firms, and in after-hour trading Wall Street sliced a third off Elan’s stock price and a tenth off Wyeth’s the same evening. Many scientists at the conference who interpreted the results more positively were taken aback at this swift punishment. They argued that observers should not expect too much from a single Phase 2 trial, but instead take a longer view of immunotherapy. Along the same vein, the definitive failure of Flurizan in Phase 3 to some meant a shot across the bow of the amyloid hypothesis, while others maintained the trial had not truly tested the amyloid hypothesis because the drug was too weak.
Often in medical news coverage, when the perceived frontrunner is judged to be down, another drug steals the show as a binary media looks to fill the airwaves with thumbs up-thumbs down stories. At this conference, a U.K.-Singaporean biotech company largely unknown to the field filled the void with a completed Phase 2 trial of a compound targeting tau. With its catchy name, Rember™ enjoyed a day in the sun, streaming from television networks to newspapers and online sources (see upcoming ICAD story for details.)
The Woes of Trial Design
More broadly, methodological problems of trial design, dry as that sounds, are an obstacle at this stage. Pharmaceutical and biotech companies are pushing intensely to move from symptomatic drugs (i.e., the ones on the market) to the coveted label of disease modification. Amid intense technical discussion on how to achieve this, some scientists recommended that companies not get hung up on the label and focus instead on finding a drug that shows a reasonably robust effect, period, no matter whether it is called symptomatic or disease-modifying. “Getting the dm phrase in your label for a marketed drug is not critically important,” said Aisen, and Rachelle Doody of Baylor College of Medicine in Houston agreed. Both these scientists run numerous clinical trials in AD. For their part, patients won’t care about the distinction and doctors will use a new drug so long as it has an obvious effect. Problems of trial design invariably came up in interviews with scientists no matter which particular trial was at issue; therefore, the Alzforum news coverage will summarize this topic first (it’s not that dry, really) in an effort to provide context for our subsequent summaries of individual trials.
The meeting illustrated that the field has made progress in the basic research that paves the way for drug development. A large proportion of the presentations explored the neurobiology and pathophysiology of AD, and there is by now a wealth of targets to try to attack therapeutically.
Consensus was palpable around several themes. Above all, scientists from all corners of AD research felt that trials of experimental drugs, and eventually treatment of people with AD, need to start earlier in the disease process than the mild to moderate stage defined by NINDS-ADRDA criteria that remain the standard today. “There is a focus on moving the detection threshold earlier,” Ron Petersen of the Mayo Clinic in Rochester, Minnesota, told reporters. (Petersen is the incoming chairman of the Alzheimer’s Association’s Medical and Scientific Advisory Council; he will replace Sam Gandy who currently holds this position.) Reflecting this shift toward early detection and drug testing, presentations on various aspects of fluid markers and brain imaging numbered a proud 775. Overall, data from different labs are converging on the conclusion that both CSF Aβ42/tau as well as some imaging modalities, possibly even certain cognitive tests but not the current ADAS-Cog, will be able to move detection back in the disease process and in this way improve the odds that experimental therapies will do some good.
Big Science Initiatives in AD?
Another topic that cropped up frequently at ICAD was the need to find ways to share data, standardize measurements, and conduct multisite biomarker research in such a way that results can be compared side by side. In other words, research consortia. Sticking to standard operating procedures is an anathema to the creative innovator, but without that, advances at an individual research institution tend to stay just that, and cannot pull the whole field forward. Two notable big-science initiatives are laying the groundwork in this direction. One is the Alzheimer’s Disease Cooperative Study (ADCS)), which has done much to help clinical sites of large multicenter trials standardize appropriate methods and procedures so any effect a drug might exert does not get lost amid the sites’ different ways of doing things. The other is the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (see upcoming ICAD story), a 58-site, five-year natural history study run by a public-private consortium. ADNI has carved out what is called “pre-competitive space,” i.e., areas of common ground to all drug developers in which cooperation and data sharing benefit all participants. In this case, ADNI aims to enable both companies and publicly funded drug developers to define useful antecedent biomarkers and methods that will help them as they each subsequently test their proprietary compounds individually. This study is ongoing, but preliminary data suggest that both CSF and neuroimaging markers look promising (see upcoming story.)
ICAD Every Year
One final note on the conference itself. In Chicago, the Alzheimer’s Association president, Harry Johns, announced that ICAD will from now on be held annually, in lieu of the Prevention Conference the Association previously hosted every June in Washington, DC. The next ICAD conference will take place next July in Vienna, Austria. Johns said the decision was taken in consultation with scientists, yet an utterly unscientific poll of some 40 scientists randomly collared in the hallways suggested that the field at large may still have to come around. At first blush, none welcomed the news. Many scientists in the field enjoy the European AD/PD meeting organized by Abraham Fisher of the Israel Institute for Biological Research in Ness-Ziona. AD/PD is held in the spring of what used to be ICAD off years and in 2009 will convene in Prague, Czech Republic. Many scientists also attend the Society for Neuroscience conference each fall. In addition, they travel to small, topical conferences that have no parallel sessions and facilitate the exchange of ideas in one’s own area of research, such as Keystone, Gordon, or Cold Spring Harbor conferences. “Besides creating unhelpful competition for speakers, adding yet another major conference to our travel schedule keeps us from working productively on our research,” said one scientist who did not want to offend the Association, a granting institution in the field.—Gabrielle Strobel.