CONFERENCE COVERAGE SERIES
American Academy of Neurology: 2007 Annual Meeting
Boston, MA, U.S.A.
28 April – 05 May 2007
Boston: Clinical Trial Results for Dimebon Unveiled
In a randomized, double-blind, placebo-controlled study conducted in Russia, the experimental Alzheimer drug Dimebon showed positive effects on all five clinical endpoints tested, according to recent presentations by Rachelle Doody of Baylor College of Medicine in Houston, Texas, a consultant to the drug’s maker and one of three U.S.-based consultants on the trial.
The trial enrolled 183 people with mild to moderate disease (MMSE 10-24), who received Dimebon as a monotherapy 20 mg three times a day or placebo for 24 weeks. The treatment resulted in statistically significant improvement over the placebo group (which declined on all scores during the study) and over baseline for five standard clinical tests of memory (ADAS-Cog), global function (CIBIC plus), cognition (MMSE), daily functioning (ADL), and behavior (NPI). The effects, which were apparent at week 12, were maintained at week 24. The difference with the placebo group grew larger over time for some measures, as the untreated patients continued to decline. Forty-four percent of patients improved on treatment, versus 19 percent on placebo.
Doody first presented the results at the 8th International Conference AD/PD in Salzburg, Austria, in March. On 3 May, at the American Academy of Neurology conference in Boston, she showed a subgroup analysis that separated patients with mild (MMSE greater than 18) or moderate (MMSE less than or equal to 18) disease. The study was not powered for subgroup analysis, but the difference in placebo and control was so significant in the whole group that some differences remained significant in the breakdown, Doody said. In particular, Dimebon produced statistically significant improvement over placebo in all five endpoints in moderate AD. In mild AD, the MMSE was significantly higher after treatment, with other measures showing increases that did not reach significance. The same proportion of patients, just over 40 percent, improved with treatment in both groups.
“This is the first trial, to my knowledge, to demonstrate such consistent positive effects,” Doody said. Given that the study was not powered for a subgroup analysis, Doody concluded that Dimebon “probably improved both mild and moderate patients in all five outcomes.”
The drug appeared safe and well tolerated. More than 80 percent of the participants completed the trial. Serious adverse events occurred in 2 percent of treated patients and 7 percent in the placebo group. Dry mouth was the major side effect, but the investigators also saw increases in depression and insomnia.
Dimebon was discovered in Russia and was marketed there in 1983 as an antihistamine. It was recently rediscovered in a screen for dual cholinesterase inhibitors/NMDA receptor antagonists at the Russian Academy of Sciences. Existing Alzheimer medicines target either acetylcholine-destroying cholinesterases or NMDA receptors. The rationale for a dual inhibitor was based on a trial that showed using both types of drugs gave additional benefit (see ARF related news story). Dimebon is reported to have additional actions to inhibit neuronal death, potentially by blocking the mitochondrial permeability pore transition, a key step in apoptosis (Bachurin et al., 2003).
The history of Dimebon partly explains the setting of the trial in Russia, Doody explained. The infrequent use of medications for dementia there was also a factor. In the U.S., it is difficult to recruit people who have no history of medication to establish the required placebo group, she said.
Dimebon has met with deep skepticism among U.S. and European Alzheimer researchers. Doody, Paul Aisen of Georgetown University in Washington, DC, and Mary Sano of Albert Einstein Medical School in New York, all worked as consultants to the drug’s maker, Medivation Inc. of San Francisco, California, on the design, data collection, and analysis of the Moscow trial. Doody said that she and Sano traveled to Moscow to train the investigators. “The study was rigorously conducted, designed, and carried out with the same high standards as a U.S. trial. I have confidence in the international sites, and confidence in the data.” Doody will be the first author on an upcoming publication of the data.
Development of the drug has begun in the U.S., as well. With an active IND registration, Medivation Inc. is planning to begin a phase 2 dose finding study this summer, according to Chief Medical Officer Lynn Seely, who spoke in a telephone conference after the AAN presentation. The drug is also in clinical trials in the U.S. for Huntington disease.
Doody could not answer the question of whether the drug effects are symptomatic, or might represent neuroprotective actions. “We can’t infer underlying mechanism by the shapes of curves," she said. “From preclinical work, it could be both, but we do not know if the compound has disease-modifying actions. The improvement over baseline is encouraging, as is the observation that at 24 weeks, the scores have not started coming back to baseline,” she said.
“Dimebon has a lot of interesting actions,” Doody said. “If all it does is work as a cholinesterase inhibitor and NMDA antagonist, then we would have one drug instead of two,” she said. “These results are encouraging, but let’s finish the work,” Doody concluded.
More data will be coming soon. Following the 6-month trial, the investigators continued with a blinded, placebo-controlled extension out to 1 year. The results of that phase will be presented on 12 June at the Alzheimer Association Conference in Washington, DC, according to David Hung, Medivation’s CEO.—Pat McCaffrey.
References
News Citations
Paper Citations
- Bachurin SO, Shevtsova EP, Kireeva EG, Oxenkrug GF, Sablin SO. Mitochondria as a target for neurotoxins and neuroprotective agents. Ann N Y Acad Sci. 2003 May;993:334-44; discussion 345-9. PubMed.
Further Reading
Papers
- Takaki Y, Iwata N, Tsubuki S, Taniguchi S, Toyoshima S, Lu B, Gerard NP, Gerard C, Lee HJ, Shirotani K, Saido TC. Biochemical identification of the neutral endopeptidase family member responsible for the catabolism of amyloid beta peptide in the brain. J Biochem. 2000 Dec;128(6):897-902. PubMed.
- Iwata N, Tsubuki S, Takaki Y, Watanabe K, Sekiguchi M, Hosoki E, Kawashima-Morishima M, Lee HJ, Hama E, Sekine-Aizawa Y, Saido TC. Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat Med. 2000 Feb;6(2):143-50. PubMed.
Boston: Resting State MRI Shows Loss of Network Connectivity Early in AD
Functional imaging (fMRI) of brain activity during cognitive testing has shown that, in the downtime between tests, the resting brain is not really at rest. Instead, the scans detect coordinated activity in a distributed network of cortical regions when the brain is not engaged in a specific task. The network, commonly called the default-mode network, includes the hippocampus and other regions that are known to be impaired early in Alzheimer disease, and to be targets for early amyloid deposition (see Forum Interview with Randy Buckner). Michael Greicius and colleagues at Stanford University in Palo Alto, California, found that people with early AD displayed decreased default-mode network activity during breaks between simple motor tasks, suggesting that changes in default-mode network activity could be an early diagnostic marker (see ARF related news story). Another study found decreased default-mode network activity in patients with MCI challenged with visual or memory tasks (Rombouts et al., 2005).
Functional MRI is a complex technique that’s not widely available outside academic brain imaging centers. It requires asking patients to solve puzzles while undergoing MRI and having the expertise to analyze their responses. But diagnosing default network disconnection may be simpler than that, according to new data from Greicius. Speaking at the American Academy of Neurology meeting in Boston on 3 May, he showed that default-mode network activity was detectable by fMRI without requiring a task or stimulus. Measured in this way, the resting-state connectivity between different brain regions was weaker in people with mild cognitive impairment (MCI) than in healthy controls.
In the study, the researchers analyzed spontaneous BOLD (blood-oxygenation-level dependent) signals during 8-minute, task-free MRI scans on nine patients with mild cognitive impairment and nine healthy controls. Charles DeCarli and coworkers at the University of California at Davis performed the scans. Then, Greicius and coworkers performed an automated analysis to identify regions of correlated activity. Next, they compared how well the subjects’ network activity pattern matched a healthy pattern taken from reference scans. The scientists found significant decreases in network connectivity in the bilateral hippocampus and precuneus of the MCI group compared to the healthy controls.
The results suggest that fMRI-based detection of resting default-mode network activity could form a simple functional test for the earliest stages of AD. Because the subjects did not have to complete a task during the imaging, the measure would be easier on patients and independent of learning effects. The test could even be done on people in advanced stages of dementia. An advantage to using resting-state measures in MCI or AD is that issues of poor blood flow at baseline or regions of atrophy should not confound results, as the analysis is not looking at the magnitude of the BOLD signal or its change with a task, but instead measures the correlation between regions. The sensitivity of the test was comparable to structural measures that gauge changes in hippocampus size, Greicius said.
Greicius pointed out a recent study that reported the detection of default-mode network activity in anesthetized monkeys (Vincent et al., 2007). This data supports the idea that the default-mode network is a critical basal state of brain activity. Thus, its disruption may reveal a fundamental underlying pathology early in the course of AD.
“This work provides more evidence that important default network function is affected early in the disease process,” said Reisa Sperling from Harvard Medical School in Boston, who heard Greicius’s talk. “These functional changes will predict structural changes,” she added, but questioned whether resting-state methodology is the best way to measure network breakdown in the early stages. “You can get similar network data from task-related scans, and it’s possible that stressing the network with a task will reveal even earlier changes, like the difference between doing a cardiac stress test versus taking a resting EKG.”
While it is possible to measure network connectivity from data collected during the short rest periods in task-dependent fMRI scans, collecting a solid block of 8-minute activity gives better results, Greicius said. “I hope this data will convert some people to want to tack a resting-state fMRI to their protocols,” he said. “It would be nice if the Alzheimer Disease Neuroimaging Initiative would do it.”—Pat McCaffrey.
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References
News Citations
- Pat McCaffrey Interviews Randy Buckner
- Network Diagnostics: "Default-Mode" Brain Areas Identify Early AD
Paper Citations
- Rombouts SA, Barkhof F, Goekoop R, Stam CJ, Scheltens P. Altered resting state networks in mild cognitive impairment and mild Alzheimer's disease: an fMRI study. Hum Brain Mapp. 2005 Dec;26(4):231-9. PubMed.
- Vincent JL, Patel GH, Fox MD, Snyder AZ, Baker JT, Van Essen DC, Zempel JM, Snyder LH, Corbetta M, Raichle ME. Intrinsic functional architecture in the anaesthetized monkey brain. Nature. 2007 May 3;447(7140):83-6. PubMed.
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