CONFERENCE COVERAGE SERIES
Alzheimer's Association International Conference 2007
Washington, DC, U.S.A.
09 – 12 June 2007
CONFERENCE COVERAGE SERIES
Washington, DC, U.S.A.
09 – 12 June 2007
See also treatment stories for other phase 2 results: 1, 3, 4, and 5.
At the second Alzheimer’s Association International Conference on Prevention, which concludes today in Washington, D.C., the statistical woes of the first phase 3 trial of an anti-amyloid drug (see related story) have left a vacuum that other therapeutic approaches were only too happy to fill. With an explicit reminder to take good news from phase 2 trials with the appropriate caution that they inevitably raise hope without offering an actual drug to most people for a few more years to come, here’s one summary.
Dimebon Still Going Strong
A drug that was definitely NIH (i.e., not invented here) is delivering basically the same strong effect in a blinded 6-month continuation that was already reported for the initial 6-month treatment period at recent conferences. Alzforum has published a detailed story of the prior data on this Russian drug (see ARF related news story), so today’s update merely summarizes the news since last month.
At the Prevention Conference, Rachelle Doody of Baylor College of Medicine in Houston, Texas, reported that at 12 months, the researchers still noted a clinical improvement above baseline in the treated group on the ADAS-Cog and the MMSE. This was a net improvement, not a slowing of decline. It was smaller than at the 6-month point, but still present. On activities of daily living and behavior problems, the treated patients had returned to baseline after an initial improvement at 6 and 9 months, but the placebo group deteriorated. Global function as measured by the CIBIC-plus scale stayed stable or improved in 69 percent of treated patients by 12 months. On all five endpoints measured, Dimebon maintained an improvement over placebo, Doody reported. (This trial included no biomarker readouts.) The drug’s good safety profile was unchanged. Whether the drug effect is symptomatic or also modified aspects of the underlying disease is unclear as yet, though mechanistic studies are ongoing, Doody added. Other scientists at the conference, on the whole, were puzzled as to how this drug could possibly have such a strong effect given that it is not linked to any of the major AD hypothesis.
The buzz among scientists was that this drug actually shows a more robust effect than either of the approved drugs do, but data for direct side-by-side comparisons are not available. When asked if Dimebon is better than the combination of an acetylcholinesterase inhibitor plus memantine, Doody said that she believed it might be but could only speculate at this point. According to Medivation Chief Medical Officer Lynn Seely, the patients are now on an open-label extension. Continuing the blinded phase further would have been unethical to the placebo group, who declined for a year while their fellow trial participants improved or stayed stable. As happens after positive phase 2 data, shares of the sponsoring company Medivation, Inc. in San Francisco rose after the news was disclosed even before Doody gave the formal scientific presentation on Tuesday morning. This flow of cash helps the company finance future trials, but no U.S. or European trial has begun yet or is scheduled for 2007. It’s important to note that this was a small trial with only 183 patients . Even if Dimebon survived phase III in the U.S., it would be years before the drug could hit the market.—Gabrielle Strobel.
See other treatment stories 1, 2, 3, and 5.
A novel therapeutic approach captured attention at the second Alzheimer’s Association International Conference on Prevention, which wound down today in Washington, D.C. Lauren Costantini of the biotechnology company Accera in Broomfield, Colorado, presented data of a short phase 2b trial of a milkshake to be taken with breakfast. The active ingredient in this beverage is a compound that the liver converts to ketone bodies. These then enter the brain and provide an alternative source of energy for neurons that no longer metabolize glucose effectively.
That cerebral glucose metabolism wanes years before AD is diagnosed is fairly well established scientifically. The question here is whether an alternative, downstream entry point into the metabolic cascade that eventually generates the cellular fuel ATP can restore the neuron’s metabolism enough to noticeably help people with AD. This is a treatment that is not by itself specific to AD. Rather, it would prop up ailing mitochondria and tackle the energy deficit that plagues the brain in several neurodegenerative diseases. If all goes well, it could become part of a combination therapy for AD, Costantini said.
A previous double-blind, placebo-controlled study in an aged dog model of dementia indicated that the compound, called AC-1202 and trademarked Ketasyn, made the old dogs more active and moved some readouts of mitochondrial efficiency and oxidative damage in the desired direction, Costantini said. A subsequent single-dose phase 2a study in 20 people with mild to moderate AD showed that ketone body concentration in people’s blood rose; it also showed an uptick on the ADAS-cog scale in people who do not carry the ApoE4 allele.
At the conference yesterday, Costantini described the latest phase 2b study of 152 people aged 50 and older who had mild to moderate AD and also took a cholinesterase inhibitor, conducted at 25 sites in the U.S. They were randomized to drug or placebo, took it for 3 months, had it washed out for 2 weeks, and then continued in an open-label extension for another 6 months.
Side effects were minor, mostly diarrhea for the first month until the digestive system had adjusted to handling the elevated number of ketone bodies (i.e., fats) coming out of the liver.
When analyzing all patients randomized into the trial together, the treatment showed a small difference in the ADAS-cog endpoint though that was not statistically significant. The most interesting finding was a difference between patients depending on which allele of the ApoE risk gene they had inherited. People with the 2 or 3 alleles, who make up half of all AD patients nationwide, benefited from the milkshake cognitively and on the overall clinical assessments, while people who carry the 4 allele did not. This is the second time this pharmacogenomic effect has turned up in an AD application of what is primarily a metabolic drug. The diabetes drug rosiglitazone also appears to help people with ApoE2 or 3, but not 4 (Risner et al., 2006; also see ARF related conference news on insulin and AD), and the pharmaceutical company GSK is currently testing that in large phase 3 trials.
If such differences become firmly established, and the requisite drugs approved for AD, doctors may begin recommending ApoE genotyping for some patients, as that knowledge would help them assign a therapy that is likely to help and at the same time avoid exposing ApoE4 carriers to unnecessary risk of side effects. Right now, doctors have no such way of distinguishing which drug is more likely to work in which patient. The Alzforum is hosting a Webinar on the topic of ApoE genotyping this Friday, June 15.
Lastly, on a basic science note, the mechanism of this drug brings up an intriguing similarity with what the ketogenic diet does for severe cases of pediatric epilepsy. There, kids are fed a high-fat diet. They are asked to eat large helpings of mayonnaise, for example. The children understandably dislike the diet, but it controls their seizures better than drugs. Mechanistic research by Gary Yellen at Harvard Medical School has begun describing how it works. Reportedly, the ketone bodies enhance a normal gating function of normal potassium channels, which serves to limit the rate of spontaneous firing (Ma et al., 2007; see also Gasior et al., 2006). AD and epilepsy are very different diseases, to be sure. Yet some AD researchers are beginning to develop an interest in epileptiform activity in AD mouse models, and it centers around the regulation of synaptic transmission. People with AD, especially the early onset familial forms, have been reported to have seizures. This is still a poorly understood area of science. For example, there is some data linking epilepsy drugs to increased risk for developing dementia (Carter et al., 2007). It’s unclear whether in AD, one would want to dampen dysregulated synaptic transmission or boost transmission of dysfunctional synapses, and how that could be done with regional specificity.—Gabrielle Strobel.
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See also treatment stories 2, 3, 4, and 5.
For most people in AD research, a conference is the best place to pick up the latest and greatest on treatment trials, because those data are either published with long delays or not at all. The second Alzheimer’s Association International Conference on Prevention, held 9-12 June in Washington, D.C., had a fair amount of trial data to offer. The research comes not a minute too soon. Worldwide, 26.6 million people have Alzheimer disease today and projections put the number of cases at 100 million by the year 2050, according to estimates presented at the conference by Ron Brookmeyer of Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland. Here are selected tidbits of trial data.
Alzhemed
If you were on the edge of your seat about the much-anticipated results of the first phase 3 trial of Alzhemed, which is, after all, the first anti-amyloid and purportedly disease-modifying drug for AD that has gotten this far, you can safely slide back, exhale, and prepare to wait a little longer. Paul Aisen of Georgetown University yesterday faced a standing-room-only press room packed with reporters and even some curious senior scientists from competing companies who did not want to await the formal scientific presentation scheduled for 2 hours later. But Aisen had to tell them that he had no data to show even though the company Neurochem of Laval, Quebec, had previously said that they would present the results of this pivotal trial at this conference. The problem? The 67 centers participating in this U.S.-Canadian trial had sent raw data that varied so greatly from one center to the next that the variability essentially rendered the statistical model by which the data were going to be analyzed unworkable. “The data is a poor fit to the statistical model,” Aisen said. Hence, the statisticians are now trying to modify the statistical model to better fit the data, and only then will they be able to analyze the endpoints. Aisen said that he expected this process to take another month.
It is important to realize that this does not mean that the trial is known to have failed to reach its primary endpoints and that its scientists are conducing a post-hoc analysis to find some promising hints amid the data. The changes to the statistical method happen while the data remains blinded. It simply means that there is no efficacy or safety data at this point.
This trial was a huge, expensive effort, and problems with it will harbor lessons on what to avoid in the future as other experimental drugs approach phase 3 and will have to be tested in equally large studies to have adequate power for make-or-break trials. This 18-month trial enrolled 1,052 people 50 years and older with mild to moderate AD at 50 U.S. and 17 Canadian centers. The people were randomized to take either placebo or 100 or 150 milligrams of drug twice a day of Alzhemed (aka tramiprosate), a patented variant of the amino sulfonic acid taurine that is thought to bind to the Aβ peptide and interfere with its fibrillization. All took an acetylcholinesterase inhibitor; memantine use was optional. The trial used psychometric test batteries as well as structural MRI and CSF Aβ and tau biomarkers as outcome measures. Seventy-five percent of patients completed the trial.
But when it came time to analyze, the researchers found that there was a highly significant center effect. The reasons Aisen was able to give at this point for the diverging results included that some patients were on memantine while others were not, the patients took memantine for differing lengths of time, some patients went on or off antidepressants during the time, some people changed their acetylcholinesterase inhibitor dose, and others took vitamin E (though vitamin E has been shown in a large clinical trial to have little effect, at least in amnestic MCI; see Petersen et al., 2005). The variation among sites was so great that it violated the assumptions underlying the statistical model the study set out to use. Consequently, the scientists, with input from the FDA, are currently working to identify the confounding factors and include them in the statistical model, Aisen said. Then they will enter the actual data for the treatment groups into the adjusted model.
Aisen presented no numbers. He said that preliminary analysis suggested a treatment effect on the cognitive endpoints and on the MRI, i.e., the disease-modification endpoint. The trial’s woes highlight the difficulties of conducting large, long trials. Apparently, people changed the doses and combination of their background medications during the trial. In theory, they should not do that, but of course they are patients first and trial subjects second, so their doctor will act in their best interest. These patients can be made to leave the trial, but that weakens the data even further because regulatory rules require that the analysis include all patients who are randomized into the trial, not only those who took all trial drug to the end (called intent-to-treat analysis). A large trial magnifies these problems, Aisen said. Whatever the outcome of this particular trial, Aisen said the experience with it will teach the field about how to conduct such large trials.
Neurochem scientists also presented a series of posters. One showed tramiprosate, or 3-amino-1-propanesulfonic acid, to simply be taurine elongated by a further peptide bond. (Taurine itself is a common ingredient in infant formula and energy drinks.) The posters claimed that tramiprosate is neuroprotective by interfering with various proposed pathways of Aβ toxicity in slice and cell-based assays.—Gabrielle Strobel.
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See other treatment stories 1, 2, 4, and 5.
To borrow a Twainism, news about the death of γ-secretase inhibitors proves to have been exaggerated. At the second Alzheimer’s Association International Conference on Prevention, held from June 9 to today in Washington, D.C., scientists presented results from a phase 2 trial of a compound called LY450139 (a more mellifluous name is to follow soon, promised Eric Siemers of Eli Lilly, the drug’s sponsor.) Developed by Eli Lilly and Company, the compound is hoped to prove itself as a mechanism-based AD drug because it inhibits the γ-secretase enzyme complex that generates the Aβ peptide. The Alzforum has covered this compound as an example of how drug companies use biomarkers in their preclinical research to plan their human trials (see ARF related news story). Here is a summary of the phase 2 human data.
To conduct this trial, Eli Lilly collaborated with the Alzheimer Disease Cooperative Study (ADCS), a consortium of some 90 U.S. and Canadian academic centers for the clinical testing of candidate AD drugs. The ADCS Data Core analyzed the phase 2 data independently of Lilly. Elaine Peskind of the University of Washington School of Medicine in Seattle presented the data in the scientific session, and Siemers presented the same data to reporters at a press briefing yesterday.
This trial was unusual in that it was a biomarker trial. It used as its endpoint reduction of Aβ concentration in plasma and cerebrospinal fluid, not improvement in cognitive or clinical measures. The reason for this design is, basically, that the power calculations for measuring the cognitive/clinical effect of a disease-modifying drug call for trials so large and long that they essentially turn into phase 3 efforts like the one for Alzhemed/tramiprosate (see ARF related story from this conference). (Symptomatic drugs tend to show their effect faster so are easier to test in phase 2.) To conduct a trial within the scope of phase 2, Lilly scientists decided to place their bet on a biomarker readout that has scientific support but has not been definitively shown to improve the disease. That makes this strategy faster, if risky.
The study enrolled 51 patients with mild to moderate AD, randomized 15 to placebo and 36 to treatment. Of those, 22 received the lower dose throughout the trial, and 14 were titrated up to the higher dose after 8 weeks. Treatment lasted for 14 weeks, and follow-up for 26. Three placebo patients discontinued, as did five of the treated patients.
Because this class of drug has caused toxicity primarily in the immune and gastrointestinal systems before, the scientists laid out all side effects in detail. Five people had a skin rash, and three people saw their hair turn lighter. Seven people on the lower drug dose and three people on the higher dose, but also two people on placebo, reported diarrhea, nausea, and vomiting. Eight people on the lower dose, six on the higher dose, and two on placebo reported sleepiness, lethargy, and weakness. These side effects are quite possibly related to the drug, Siemers said, and warrant close monitoring. He also said that they were mild, lasted for a week or two, and then disappeared on their own. He noted that when a drug is overtly toxic, typically the sponsor hears of this during the trial because the local investigators see something is amiss and report back informally. This did not happen in this case, Siemers said. One patient withdrew from the trial because of diarrhea. This at first rings alarm bells because prior γ-secretase inhibitors cause serious side effects in the gut of mice (Wong et al., 2004). But Peskind told scientists that this man, who was enrolled at her site, had been at a potluck with his wife the night before and the couple both got diarrhea. The man did not want to discontinue, but the study rules required that he do, Peskind said.
Chemistry lab data indicated a marked drop in uric acid, which led Peskind to quip that the drug might work for gout, if nothing else. It also caused a small but statistically significant reduction in CD 19 white blood cells. This was not accompanied by increased infection rates or other clinical signs in this study but needs close monitoring, Siemers said. Likewise, there was a slight elongation of the QT interval on electrocardiograms that requires monitoring, but no clinical cardiovascular events.
On efficacy, Siemers and Peskind reported a decrease of plasma Aβ 40 concentrations, 58 percent at the lower 100 mg dose and 65 percent at the higher 140 mg dose. “That is the most robust plasma effect of any drug in development that I have seen,” Siemers said. Dose ranging studies showed that plasma effects become detectable starting at 40 mg of inhibitor. CSF Aβ40 levels showed a smaller decrease. Plasma Aβ42 were low to begin with and dropped below the level of detectability in treated patients, Siemers said. Changes in CSF were not statistically significant. One open question is whether the drug might have a marked effect in the body but less so in the brain.
In response to a question about what Aβ lowering means anyway when it is already low in AD, Siemers said that they cannot know for sure at this point. The working hypothesis is that CSF Aβ levels drop in advance of AD as amyloid deposits in the brain and less Aβ comes out of the brain. A further CSF reduction in response to a γ-secretase inhibitor would be due to a different biological reason, i.e., less Aβ production, but there is no data to show this in humans at this point.
The company has decided to launch a phase 3 trial, which is expected to start enrolling this fall and winter, quite possibly at some of the same sites that will also enroll patients into the phase 3 trial of Elan/Wyeth’s bapineuzumab (see ARF related news story). At least at some clinics, then, patients will have a choice of taking a pill once a day or getting an antibody infusion. Like Lilly, Elan/Wyeth made an unconventional decision in phase II. In their case, the sponsor decided to start a phase III even before the phase II trials were completed. This illustrate how pressing the need is, but also just how much of a race it is to get to the market first with a disease-modifying treatment and try to become the standard of care. —Gabrielle Strobel.
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See other treatment stories 1, 2, 3, and 4.
After a Phase 2 trial of the AD experimental immunotherapy AN1792 ended prematurely because 6 percent of the patients developed encephalitis, scientists called on the sponsoring companies Elan/Wyeth to continue following the 376 patients. They had, after all, received one or two of a planned six shots of the first active vaccine in AD research. The late Leon Thal of University of California, San Diego, who headed the Alzheimer Disease Cooperative Study consortium of clinical centers, played a leading role in initiating this study, and he presented some initial data of the study at the ICAD conference last July in Madrid, Spain.
Since then, the study has gathered more data. Michael Grundman of Elan Pharmaceuticals in San Diego presented a fuller account at the second Alzheimer’s Association International Prevention Conference, which drew to a close yesterday in Washington, D.C. This space has covered the goals of the study and trends in its initial data before (see ARF Madrid news story), so here is only a brief update. These are people who have aged 4.5 years since receiving their injections and still have AD. Grundman reported that the people who responded to the antibody still showed low but measurable antibody titers. The rating of clinical activities they were still able to perform indicated that the responders had declined about half as much as the people who received placebo. Responders were slightly less dependent on caregivers, and more responders than placebo recipients still lived at home. They showed a trend toward better memory, though it has to be said that most trial participants were no longer able to complete a full psychometric test battery. A subgroup agreed to an MRI scan and they no longer showed the shrinkage that had taken the field by surprise at the 1-year follow-up point (see ARF related Philadelphia news story). No further encephalitis cases popped up as a delayed reaction to the vaccine.
The Alzforum already reported that Elan/Wyeth has decided to forge ahead with their second-generation immunotherapy (see Phase 3 trial of bapineuzumab). This data contributed to this decision, Grundman said.—Gabrielle Strobel.
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