Are Anti-Amyloid Therapies Still Worth Being Developed As Treatments For

Viewpoints Are Anti-amyloid Therapies Still Worth Being Developed as Treatments for Alzheimer’s Disease? Despite limited pharmaceutical success thus far, amyloid peptides may yet prove useful in the treatment of Alzheimer’s and delay disease progression. By Laurent Lecanu, DPharm, PhD rug discovery in the domain of Alzheimer’s obstacle lies in the multiplicity of the deleterious disease is essentially benchmarked by clinical pathways that are activated during the progression trial failures (dimebon, tramiprosate, taren- of the disease, probably at distinct time points. Dflurbil, semagacestat, the vaccine AN1752).1-6 These multiple pathways explain the limited efficacy Difficulty in finding an AD treatment arises from of the classical single-target drugs. Future treatments lack of knowledge of the origin of this disease. for AD will necessarily include drugs aimed at dif- Although the etiology of the familial form of AD is ferent targets. Alternatively, in accord with the cur- known, that of the sporadic form, which represents rent trend, they will evolve toward the development 95 percent of the cases, remains unidentified.7 of compounds8 that target several mechanisms lead- Consequently, most animal models currently used in ing to different pathological endpoints. the proof-of-concept stage of preclinical studies in For a long time, the scientific community has pri- AD R&D were developed based on knowledge marily focused on improving cholinergic network acquired from studying the familial form of AD. dysfunction for the treatment of AD. This led to the This represents a second obstacle in finding AD development of the therapeutic class of acetyl- treatments, as these models have limited usefulness cholinesterase inhibitors (AchEI), with tacrine as the for studying the sporadic form of the disease and as class leader. The clinical benefits of tacrine were an investigational tool in drug development. A third modest and hampered by its significant liver toxicity. 22 | Practical Neurology | November/December 2010 Anti-amyloid Therapies for AD? Beta-amyloid ligands The new generation of AchEI represented by galant- unclear, years of research continuously provided amine, rivastigmine, and donepezil did not improve compelling evidence that some of the amyloid forms the delay in symptom onset compared to tacrine, present in the brain are detrimental to the neuronal and the true benefit of these AchEI for the treatment cells’ survival. This situation rationalized the devel- of mild, moderate, and severe Alzheimer’s disease as opment of drugs meant to reduce the amyloid bur- well as mild cognitive impairment remains contro- den in the diseased brain, the so-called anti-amy- versial.9-14 A 2006 Cochrane review of efficacy of loid. As of today, three main approaches have been donepezil, the leading AchEI on the market, in AD used. The first approach was the inhibition of pep- treatment concluded that, although this AchEI is tide synthesis. The amyloid peptide is generated clinically effective, the treatment effects are small through the cleavage of the transmembrane protein and not always apparent in practice.15 In addition, Amyloid Precursor Protein by two proteases, the the long-term cost effectiveness of donepezil is beta-secretase or BACE-1 and the gamma-secretase. unknown,16,17 and the scientific relevance of the use The development of BACE-1 inhibitors is still at the of AchEI to treat AD has been questioned.18,19 discovery or early pre-clinical stage due to their Nevertheless, except for AchEI, no major advances challenging peptide-like structure that prevents in AD drug development have been made. Even the them from crossing the blood-barrier.23 In addition, beneficial effects of the low-affinity N-methyl-D- recently generated BACE1-/- mouse strains exhibited aspartate (NMDA) receptor antagonist are still a high mortality rate and the survivors were much unclear. Recent Cochrane reviews confirm a small smaller than their wild-type littermates,24 and adult beneficial effect of the NMDA receptor antagonist, BACE1-/- mice displayed hyperactive behaviors that memantine, at six months in moderate to severe were related to the inactivation of voltage-gated AD.20,21 On the other hand, they rule out any benefi- sodium channels and a modification of the synaptic cial effect of this agent in mild to moderate AD.21 current. Therefore, it appears that although com- Other studies reported that memantine has no bene- pelling evidence supports the development of beta- fit as a monotherapy in Alzheimer’s disease but secretase inhibitors, a broader, more cautious, and proved to be beneficial when associated to better understanding of BACE1 is necessary prior donepezil. Memantine was also shown to induce to seriously envisioning a clinical trial. On the subtle psychotic symptoms in an AD patient,22 rais- other hand, many small molecules specific ing concerns about this treatment. inhibitors of gamma-secretases were developed and In the endeavor to find a cure for Alzheimer’s several clinical trials have been launched. disease, many efforts have been devoted to targeting Unfortunately, tarenflurbil and semagacestat, the the once considered main actor of the disease, first gamma-secretase inhibitors/modulators tested namely the amyloid peptide. Although the real con- in clinical trials, failed in phase III at demonstrat- tribution of amyloid peptide to the disease remains ing any therapeutic efficacy. November/December 2010 | Practical Neurology | 23 Anti-amyloid Therapies for AD? A second approach developed was the vaccine nosed by Alois Alzheimer in 1907,28 amyloid plaques against amyloid peptide, also called active immuniza- were described as playing a major role in the disease tion. The rationale was to have the patients’ immune progression. Although amyloid plaques are common- system target the amyloid peptide. However, the ly present in otherwise healthy subjects and some- widely reported failure of the vaccine AN1792 in times in higher amounts than in patients suffering phase I studies for safety reasons represented a from Alzheimer’s disease, the thought that they con- major setback for the development of this type of tribute to the disease still carries some weight and treatment. The meningoencephalitis cases observed dissolving these insoluble structures remains a cur- during the AN1792 clinical trial were attributed to rent therapeutic concept. Kinetic studies showed the nature of the epitope used, which led to the that amyloid peptide has to self-assemble to form development currently ongoing of vaccines based on oligomers as a preliminary step towards plaque for- different epitopes meant to not trigger such dramatic mation. Interestingly, the Amyloid Derived immune reaction. Nevertheless, regardless of the epi- Diffusible Ligands (ADDLs), another amyloid species tope to be used, the risk of inducing an autoimmune that also results from the self-aggregation of the disease with a vaccine targeting a native protein has monomeric amyloid peptide into oligomers contain- never really been debated, leaving open the question ing 4 to 24 monomers,29 is known as a highly neuro- of what will happen to the physiological functions of toxic molecular entity and has been purported to A‚1-42 following vaccination. bear most of the deleterious effects of the amyloid An alternative to the active immunization is the peptide described in Alzheimer’s disease. Both administration of humanized immunoglobulins plaques’ purported deleterious role and ADDLs pro- specifically raised against the amyloid peptide. vided at the time the rationale and justification for Several clinical trials are currently being or have the development of small molecules inhibitors of already been conducted to assess safety/tolerability amyloid aggregation as a potential treatment for and clinical efficacy of such concept (Bapineuzumab, Alzheimer’s disease. Many pharmaceutical compa- solanezumab and PF-04360365).25-27 First reports nies as well as academia were extremely creative in showed that either the immunoglobulin treatment developing various compounds that showed remark- did not lead to any cognitive improvement or the able anti-Alzheimer properties in vitro and in vivo but effect of the treatment on the ADAS-cog score has for which clinical data are still lacking. not been recorded, which at best questions the clini- Unfortunately, the conjunction of concurring cir- cal efficacy of humanized monoclonal antibody in cumstances threw an undeserved shade over the the treatment of Alzheimer’s disease. The high per- development of aggregation inhibitors: the complexity centage (9.5 percent) of vasogenic edema reported and multifactorial origin of the disease that makes it after one single injection of bapineuzumab, although difficult for a monotherapy to be clinically relevant, reversible, raises the question of long-term treatment the discovery of pathological pathways seemingly safety on the blood-brain barrier integrity in particu- offering a more drugable potential, and finally the lar. The mechanism of action of these humanized amyloid plaques themselves whose neurotoxicity IgGs is poorly understood; since immunoglobulins ceased to look so evident as the lack of correlation do not cross the blood-brain barrier, the common between amyloid load and cognitive was established. assumption is that they would trigger an output flow However, it may be discussed that, under the light of of amyloid from the brain across the blood-brain new discoveries, restricting the therapeutic

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