edited_gandy_US.qxp 14/1/09 10:54 am Page 57
Emerging Therapies for Alzheimer’s Disease
platform in a pool of water.
14
Phase II studies demonstrated significant immunity against amyloid plaques. Along these lines, the monoclonal anti-Aβ
effects on Alzheimer’s Disease Assessment Scale–Cognitive Subscale antibody bapineuzumab is currently the subject of phase III trials.
23
In contrast
performance and global function, as tested by the Clinical Dementia Rating to AN-1792, bapineuzumab is a humanized antibody that does not require the
Scale Sum of Boxes test.
5,15
However, phase III trials of tarenflurbil recently body to mount an immunological response to target Aβ. It is hoped that by
failed to show efficacy. Body fluid analyses are ongoing in order to using a passive approach, the adverse effects seen in the AN-1792 trial will be
determine whether the desired Aβ
42
-lowering effect was actually achieved. circumvented while simultaneously retaining the benefits. In addition, two
Many other compounds that modulate γ-secretase activity are currently other monoclonal antibodies, LY2062430 (Lilly) and RN1219 (Pfizer), are
under study, including non-steroidal anti-inflammatory drugs, which act on currently the subject of clinical trials.
γ-secretase to reduce Aβ
42
and increase the shorter, less amyloidogenic 38-
amino acid peptide.
16
Future Directions
Another interesting line of recent research involves the role of oxidative stress
Decreasing Aβ
42
Aggregation and mitochondrial dysfunction in the pathogenesis of AD. Several studies
Many researchers believe that soluble Aβ
42
molecules do not become have implicated oxidative stress in the exacerbation of plaque formation and
particularly toxic until they aggregate into fibrils and plaques.
5
This has led to the alteration of APP and Aβ metabolism.
24
It has also been shown that Aβ
therapies targeting the aggregation of Aβ
42
. Tramiprosate (Alzhemed, exerts toxic effects on mitochondria, perhaps by altering mitochondrial
Neurochem), an Aβ
42
aggregation inhibitor, has been well studied and permeability.
25
Along these lines, dimebon (Medivation), a drug believed to
showed initial promise.
17
Unfortunately, the study was ultimately halted due inhibit mitochondrial permeability, as well as being a weak cholinesterase
to the failure of large phase III trials.
18
However, Elan Pharmaceuticals is inhibitor and N-methyl-D-aspartate-receptor antagonist, has recently
currently studying a molecule known as ELND005 in a phase II safety and demonstrated encouraging results in phase II study. This randomized,
efficacy study. ELND005 is a scyllo-inositol molecule that acts as an Aβ placebo-controlled trial showed significant improvement over placebo on
aggregation inhibitor that may help to prevent or inhibit the build-up of measures of cognition, activities of daily living, and global function.
26
This
amyloid plaques in the brain. Studies of the drug using mouse models of AD effect was seen at six months, and an additional 26-week extension of the
found that the drug modified the disease process when used as a study showed maintenance of the benefits from dimebon. The drug was well
prophylactic or therapeutic.
19
In addition, phase I studies found this drug to tolerated and is now the subject of phase III trials.
be well tolerated, orally bioavailable, and with CSF concentrations in humans
that had been effective in mouse models of AD. Several other aggregation Although all of the potential therapies discussed above hold promise, many
inhibitors are in pre-clinical and clinical development. researchers hold out even greater hope for treatments that may ultimately effect
neural regeneration itself. Although the concept of neurogenesis in the adult
Increasing Clearance of Aβ
42
brain is a new one,
27
it presents researchers with perhaps the most tantalizing
A potential ‘Alzheimer’s vaccine’ has long been an interest for researchers and mode of treating patients with AD, apart from completely preventing the
a hope for patients and families. The idea of using the body’s own immunity disease. If the process of neurogenesis could be better understood, perhaps
to combat amyloid plaques has great appeal, but the most promising researchers could learn to promote the formation of new neurons in the
candidate of this approach to modifying AD ran into serious problems. The diseased portions of the brains of those with AD.
5
Tuszynski et al. tried just such
drug in question, AN-1792, was designed to present the body with Aβproteins an approach when they implanted genetically modified nerve-growth-factor-
in order to induce active immunity against Aβ
42
and amyloid plaques. Studies secreting cells into the nucleus basalis of eight patients with early-stage AD.
5,28
of AN-1792 in mouse models of AD appeared positive, with evidence that This approach appeared safe and tolerable in these patients. This is clearly an
plaques were both prevented and reduced.
20
Unfortunately, when trials began area of development that will require many more years of study, and many
in elderly human subjects with AD, approximately 6% of patients developed molecules purported to stimulate neurogenesis are currently being studied.
aseptic meningoencephalitis, necessitating the termination of the study.
21
Conclusion
Interestingly, subsequent analysis of the data showed that subjects who Although slow in arriving, many of the approaches described above, whether
developed high titers of antibodies to Aβ
42
seemed to decline more slowly, and inhibiting Aβ production, modifying secretase activity, reducing Aβ
autopsy reports indicated that despite diagnostic neuropathological features of aggregation, or increasing clearance of Aβ, hold promise for actual
AD, these patients also had regions in the brain where amyloid appeared fully modification of the AD process itself, rather than simply managing symptoms.
cleared.
22
As a result of the serious adverse events seen in the AN-1792 study, Hopefully, these emerging treatments will provide patients and families with
many researchers have turned to immunotherapies that rely on passive new, more effective ways of combating AD in the very near future. ■
1. Cummings JL, N Engl J Med, 2004;351(1):56–67. 12. Pappolla MA, et al., Neurology, 2003;61(2):199–205. 19. www.transitiontherapeutics.com/technology/alzheimers.php
2. Archer HA, et al., Ann Neurol, 2006;60(1):145–7. 13. Arvanitakis Z, et al., Neurology, 2008;70(19 Pt 2):1795–1802. 20. Schenk D, et al., Nature, 1999;400(6740):173–7.
3. Hardy J, Selkoe DJ, Science, 2002;297(5580):353–6. 14. Kukar T, et al., BMC Neurosci, 2007;8:54. 21. Hock C, et al., Neuron, 2003;38(4):547–54.
4. Näslund J, et al., JAMA, 2000;283(12):1571–7. 15. Christensen DD, Prim Care Companion J Clin Psychiatry, 22. Nicoll JA, et al., Nat Med, 2003;9(4):448–52.
5. Christensen DD, CNS Spectr, 2008;13(2 Suppl. 2):10–14. 2007;9(1):32–41. 23. www.elan.com/News/full.asp?ID=1166655
6. Hussain I, IDrugs, 2004;7(7):653–8. 16. Vardy ER, et al., Expert Rev Neurother, 2006;6(5):695–704. 24. Karuppagounder SS, et al., Neurobiol Aging, 2008; in press.
7. Siemers ER, et al., Neurology, 2006;66(4):602–4. 17. Aisen PS, et al., Curr Alzheimer Res, 2007;4(4):473–8. 25. Bachurin SO, et al., Ann N Y Acad Sci, 2003;993:334–44.
8. Siemers ER, et al., Clin Neuropharmacol, 2007;30(6):317–25. 18. European trial of Alzhemed ends, marketing morphs to 26. Doody RS, et al., Lancet, 2008;372(9634):207–15.
9. www.athenagen.com/index.php?/athenagen/press_releases/48 supplement: Alzheimer’s Research Forum, drug news, 2007. 27. Eriksson PS, et al., Nat Med, 1998;4(11):1313–17.
10. Pangalos MN, et al., Biochem Soc Trans, 2005;33(Pt 4):553–8. Available at: www.alzforum.org/new/detail.asp?id=1691 (last 28. Tuszynsik M, et al., Neurology, 2004;62(Suppl. 5):A174–75.
11. Cordy JM, et al., Mol Membr Biol, 2006;23(1):111–22. accessed October 15, 2008).
US NEUROLOGY 57
Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84