New Initiative AMPs Up Alzheimer’s Research

A new initiative called the Accelerating Medicines Partnership (AMP) will contribute $129.5 million toward the search for biomarkers and therapeutic targets for Alzheimer’s disease, the National Institutes of Health announced February 4. The goal is to speed up the discovery of treatments in critical and underserved areas of medicine. In addition to funding AD, another $100 million will be spent on Type 2 diabetes and the autoimmune disorders rheumatoid arthritis and lupus, with other diseases to be funded later. About half the money will come from the National Institutes of Health (NIH), and 10 industry partners will donate the rest. Several nonprofit organizations, including the Alzheimer’s Association and USAgainstAlzheimer’s, will help guide the research in collaboration with the Food and Drug Administration. All data and analyses from AMP projects will be made publicly available. The AMP website provides more information, including a list of industry and not-for-profit partners.

For Alzheimer’s disease, the new effort intends to fill two gaps in the present state of the research, said George Vradenburg of USAgainstAlzheimer’s. One is for better biomarkers to track disease in preclinical populations and show if a drug is working. The second is for validated therapeutic targets beyond amyloid and tau. “That will increase the number of shots on goal,” said Vradenburg. Most Alzheimer’s drug candidates have failed in clinical trials, and none have been approved in the last decade. The NIH estimates about a 95 percent failure rate for new drugs for any disorder, and AMP aims to improve this average.

Current AD biomarkers, such as PET amyloid imaging and cerebrospinal fluid (CSF) Aβ and tau, identify people on course to develop the disease, but do not track well with clinical outcomes (see Nov 2012 conference story). Researchers would like to find a surrogate biomarker because that would speed up clinical trials, lower costs, and might allow more drugs to be tested. PET tau tracers, which label neurofibrillary tangles in the brain, show promise in this regard (see Nov 2013 conference story). In addition, some researchers think that electroencephalography (EEG), which directly measures synaptic activity, might reflect cognitive status better than do current biomarkers (see Nov 2012 conference story). 

To more fully test these two markers, AMP will fund the addition of PET tau imaging and EEG to three existing prevention trials: the Dominantly Inherited Alzheimer Network trial, the Alzheimer’s Prevention Initiative ApoE4 trial, and the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) trial. EEG and tau imaging may also be added to a Phase 2 AD study of the approved cancer drug sargramostim. This recombinant granulocyte macrophage colony-stimulating factor pumps up the innate immune system, said Neil Buckholtz, who directs the neuroscience division at the National Institute on Aging. The sargramostim trial received $2.2 million in NIH funding in 2013, and is run by Sanofi Aventis, Cambridge, Massachusetts, one of the AMP partners, in collaboration with scientists at Baylor College of Medicine, Houston. The 24-week trial will test the drug in people with mild cognitive impairment to see if it clears amyloid deposits and slows cognitive decline.

While the biomarker portion of the project will receive the bulk of AMP funding, some money will also support three studies that are searching for new therapeutic targets by developing network models of AD (see Sep 2013 news story). These studies, led by Philip De Jager at Brigham and Women’s Hospital, Boston; David Bennett at Rush University Medical Center, Chicago; Eric Schadt at the Icahn School of Medicine at Mount Sinai, New York; and Todd Golde at the University of Florida, Gainesville, were funded by the NIH in 2013. AMP support will enable the creation of a shared database and help coordinate the efforts of the three groups, Buckholtz said.—Madolyn Bowman Rogers

Comments

  1. The devil is in the details

    The NIH is investing $67.6 million and the pharmaceutical industry is committing $61.9 million to launch the AMP initiative to "speed up the discovery of AD treatment." This is certainly good news for the AD field and NIH director Francis Collins, the Alzheimer’s Association, and USAgainstAlzheimer’s deserve our heartfelt thanks. At a time of severe funding restrictions overall, with the NIA payline dropping to the seventh percentile in 2013, the new funds will be expected to invigorate research activity and boost the morale of AD researchers.

    Unfortunately, the emerging details of the plan dampen such expectations. While awaiting more details, it seems that bulk of the NIH money will be used to add additional biomarkers (tau tracers, EEG measurements, and unspecified biomarkers) to the ongoing anti-amyloid prevention trials.

    Without getting into the merits and weaknesses of the prevention trials, this development is disconcerting. If well-characterized biomarkers such as amyloid imaging, CSF-tau, hippocampal volume, hypometabolism, etc., did not behave in the predicted manner in clinical trials (1, 2), it is even less likely that non-AD specific biomarkers will provide a more positive outcome (neither tau pathology nor abnormal EEGs are specific for AD). This is not to say that the idea of testing tau tracers or EEG as valid AD biomarkers lacks merit. However, adding these biomarkers to ongoing prevention trials—without having established their validity in independent studies—may be akin to putting the cart before the horse. Moreover, contrary to the dogma, it is possible that the premise of anti-amyloid intervention may be wrong and identification of the SNAP patient population (3) and that of impaired brain immune networks as an underlying basis of LOAD (4) would suggest this is the case. Thus, it is clear that there is lot more to AD than amyloid plaques (5) and there is acknowledgement that contradictory responses of established biomarkers in the solaneuzumab and bapineuzumab trials suggest that we don't really understand the underlying pathogenic basis (6). 

    This realization should make us think twice before diverting resources to test non-validated biomarkers in ongoing trials. History teaches us that cures for diseases mostly arise through basic research. When viewed through that prism, it is difficult to see how the NIH money committed to AMP initiative will accelerate AD drug discovery. It is said that prevention trials, which are expected to be completed by 2018, are the best way to test the amyloid hypothesis. Should these trials fail to protect patients from developing dementia, knowledge that the amyloid hypothesis was wrong will be of little solace to patients or caretakers. Only through sustained funding for basic research that examines alternative hypotheses will we draw closer to an effective comprehensive treatment. 

    References:

    Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Ferris S, Reichert M, Ketter N, Nejadnik B, Guenzler V, Miloslavsky M, Wang D, Lu Y, Lull J, Tudor IC, Liu E, Grundman M, Yuen E, Black R, Brashear HR, Bapineuzumab 301 and 302 Clinical Trial Investigators. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N Engl J Med. 2014 Jan 23;370(4):322-33. PubMed.

    Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, Raman R, Sun X, Aisen PS, Siemers E, Liu-Seifert H, Mohs R, Alzheimer's Disease Cooperative Study Steering Committee, Solanezumab Study Group. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med. 2014 Jan 23;370(4):311-21. PubMed.

    Jack CR, Knopman DS, Weigand SD, Wiste HJ, Vemuri P, Lowe V, Kantarci K, Gunter JL, Senjem ML, Ivnik RJ, Roberts RO, Rocca WA, Boeve BF, Petersen RC. An operational approach to National Institute on Aging-Alzheimer's Association criteria for preclinical Alzheimer disease. Ann Neurol. 2012 Jun;71(6):765-75. PubMed.

    Zhang B, Gaiteri C, Bodea LG, Wang Z, McElwee J, Podtelezhnikov AA, Zhang C, Xie T, Tran L, Dobrin R, Fluder E, Clurman B, Melquist S, Narayanan M, Suver C, Shah H, Mahajan M, Gillis T, Mysore J, MacDonald ME, Lamb JR, Bennett DA, Molony C, Stone DJ, Gudnason V, Myers AJ, Schadt EE, Neumann H, Zhu J, Emilsson V. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease. Cell. 2013 Apr 25;153(3):707-20. PubMed.

    Pimplikar SW, Nixon RA, Robakis NK, Shen J, Tsai LH. Amyloid-independent mechanisms in Alzheimer's disease pathogenesis. J Neurosci. 2010 Nov 10;30(45):14946-54. PubMed.

    Karran E, Hardy J. Antiamyloid therapy for Alzheimer's disease--are we on the right road?. N Engl J Med. 2014 Jan 23;370(4):377-8. PubMed.

    View all comments by Sanjay Pimplikar

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References

News Citations

  1. CTAD: New Data on Sola, Bapi, Spark Theragnostics Debate
  2. CTAD: EEG Gains Luster as More Trials Incorporate Biomarkers
  3. NIH Funds Prevention Trials and Translational Studies

External Citations

  1. AMP website
  2. Nov 2013 conference story

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