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European Biopharmaceutical Review

Tackling Toxics


Proteins can misfold and aggregate during the process of ageing, and treatments for diseases resulting from the toxicity of these misfolded proteins require new approaches to drug discovery. A number of novel compounds are now in development that can inhibit the toxicity of soluble amyloid, as a potential disease-modifying treatment for Alzheimer’s disease.

A variety of seemingly unrelated chronic degenerative diseases, based on symptoms alone, have all been linked to a fundamental pathogenic process of protein aggregation of amyloid-like proteins (1). In each case, a specific protein or peptide aggregates to form toxic soluble oligomers and/or insoluble ‘amyloid-like’ fibres that can produce an inappropriate inflammatory response. Toxic soluble oligomers and inflammation are widely believed to cause the progressive degeneration of the cells associated with a number of these diseases. Table 1 lists some of the toxic proteins that underlie diseases resulting from amyloid-related toxicity.



Pre-eminent amongst ageing-related diseases associated with amyloidrelated toxicity is Alzheimer’s disease (AD), which affects nearly half of people over 85 and is projected to increase significantly. AD was first described by Alois Alzheimer in 1906 and is a progressive neurodegenerative disorder with characteristic clinical and neuropathological features. These degenerative effects result in the disruption of neurotransmitters carrying messages across synapses, which then leads to synaptic loss. The current treatments for mild-to-moderate AD include the use of acetylcholinesterase inhibitors to improve cognitive function and N-methyl-D-aspartate (NMDA) receptor antagonists for use in the moderate-to-severe stages of the disease. Such drugs are of relatively limited benefit to most patients because they have only modest symptomatic effects and have not yet been shown to have any significant disease-modifying properties. The effect of delaying disease onset on the prevalence of dementia are striking, and underline the enormous beneficial effect that even a modest treatment can have on the quality of life for sufferers and their carers, as well as the saving in costs. For example, it has been estimated that a two-year delay could result in a 20 per cent drop in prevalence.

Targeting Amyloid as Disease- Modifying Alzheimer’s Therapy

AD is categorised by the presence of a misfolded protein deposited as plaques in regions of the brain associated with memory. These plaques are mostly composed of amyloid-beta (). Under normal circumstances there are essentially two forms of the protein, a shorter (1-40) and longer (1-42) version comprising 40 and 42 amino acids, respectively. In the brains of AD sufferers, the concentration of Aâ rises in the areas surrounding brain cells. 1-40 and 1-42 both occur naturally in the body, but at higher concentrations misfold and then aggregate to become neurotoxic – especially 1-42. These soluble oligomers of 1-42 have been  shown to be toxic species which can have subtle, detrimental effects on synaptic function. With time, the oligomers aggregate into Aβ fibrils and eventually plaques. In an overall process that is commonly referred to as the ‘Aβ cascade’, the progressive accumulation of Aβ aggregates is believed to be fundamental to the initial development of neurodegenerative pathology and to trigger events such as neurotoxicity and synaptic loss that contribute to the progression of AD (2). The combination of Aβ’s damaging effects on the normal functioning of neurons and their eventual death causes a decline in cognition, most notably associated with memory deficits. The progressive damage caused by Aβ sets up a cycle of cell death that eventually leads to almost complete deterioration of mental function.

The amyloid cascade has been a valuable working hypothesis as the search for new treatments for AD has gathered pace. Over time our understanding of the pathological process has undergone an iterative process of modification and refinement as new evidence has been presented (2). This has spawned numerous drug discovery research programmes across a range of targets. For example, much effort has been expended on the discovery of β- and γ-secretase inhibitors to attenuate the generation of Aβ. However, some issues have surfaced regarding secretases as drug targets that can avoid mechanismbased toxicity, and it remains to be seen if this approach will provide new treatments for AD with an adequate therapeutic window. After more than a decade of research on secretases, no promising clinical data on cognition have yet emerged and trials have been stopped due to safety issues. The issue of selectivity has been raised regarding the wisdom of inhibiting γ-secretase activity and the likely consequences of also blocking a number of important physiological processes that are reliant on the function of this enzyme. A different practical challenge is presented by β-secretase which is a difficult molecular target for designing potent, brain penetrating small molecule inhibitors.

By contrast, an alternative strategy that comes under the broad description of ‘Aâ aggregation inhibition’ or ‘antiaggregation therapies’ has been to target Aβ itself rather than its production, However, there have been relatively few good quality chemical starting points for this approach. Nonetheless, this is an area which could hold considerable promise, particularly with the rapid development in our scientific understanding of toxic amyloid assemblies that now provides further impetus for this alternative approach. Progressive accumulation of Aβ assemblies is generally considered to be fundamental to the development of the neurodegenerative pathology and inflammation that contribute to AD.

Accumulating evidence increasingly supports a cogent argument that compounds preventing the generation of toxic Aβ assemblies could provide successful new treatments for AD (3). Unlike current therapies, which only treat the symptoms of the disease, disease-modifying interventions that prevent the generation of toxic Aβ assemblies may have the potential to slow or even halt AD progression.

The consensus is that AD severity correlates more closely with soluble forms of Aβ rather than with fibrillar forms of the peptide, and suggests an important role for soluble oligomers of Aβ. Therefore, strategies to block Aβ aggregation at the initial stages of oligomerisation, for example small molecules that bind to and stabilise Aâ monomer to prevent oligomerisation and allow neurophysiological clearance mechanisms to effect natural removal areparticularly attractive (4,5). In addition, compounds that are capable of binding to toxic Aâ assemblies/oligomers could neutralise their effects and facilitate their elimination (see Figure 1).



AD is believed to result from initial synaptic failure, which precedes any significant neuronal degeneration, and this Aâ-induced dysfunction of synaptic plasticity then appears to contribute to early memory loss (6). Long-term potentiation (LTP), a well-established electrophysiological model of synaptic plasticity, involves a sustained increase in excitatory synaptic transmission, and inhibition of LTP by Aβ may mimic an early manifestation of AD. In normal adult rats and mice, Aβ oligomers have been found to potently inhibit hippocampal LTP in vitro and in vivo.

It has been established that low-n oligomers of Aβ are composed of N- and C-terminally heterogeneous human Aβ peptides, including the Aβ1-40 and Aβ1-42 species that occur in the human brain and extracellular fluids. Support for the role of low-n Aβ oligomers as key toxic species has come from work by Cleary et al which demonstrated that defined molecular species of the Aβ protein cause acute cognitive deficits in the rat (7). Specifically, Cleary et al and others have shown that soluble oligomeric forms of Aβ, including dimers and trimers, are both necessary and sufficient to disrupt learned behavior. Furthermore, Aβ dimers have been identified as the smallest synaptotoxic species in AD brains (8). Therefore, therapies based on directly targeting soluble Aβ oligomers are an increasingly attractive approach for treating AD.

Antibodies or Small Molecules?

There are a number of antibody-based approaches that directly target Aβ, but antibodies have significant limitations with regard to bioavailability in the brain, and may also have immunogenicity problems with chronic administration. A vaccine (AN-1792) did demonstrate some benefit in neuropsychological test battery tasks in a small number of patients in a Phase 2 trial (9). However, six per cent of the patients developed encephalitis and the trial was halted: this severe inflammation caused by the vaccine would, of course, preclude its therapeutic use. Passive immunisation strategies may hold more promise and bapineuzumab, a humanised monoclonal antibody against Aβ, is now in Phase 3 trials and is the most advanced of a number of antibody products in the clinic. Like all antibody approaches, however, brain penetration issues may limit their therapeutic benefits.

Small molecule approaches, however, allow much better bioavailability in the brain to be achieved. Therefore, a number of compounds are in clinical development that interfere with the effects of Aβ. For example, Tramiprosate, which is orally bioavailable, is thought to inhibit the binding of Aβ to heparin sulfate, thereby blocking the formation of toxic Aβ aggregates (10). A Phase 2 study with Alzhemed showed positive effects in attenuating the disease in patients with mild AD. However, Tramiprosate did not demonstrate significant cognitive benefit in Phase 3 trials. In spite of this early disappointment, a number of new candidate Aβ-binding small molecules are emerging as potential diseasemodifying therapies.

Another small molecule, PBT2, is a copper/ zinc ionophore thought to bind to the Aβ-Cu (or -Zn) complex and thus prevent or attenuate the subsequent oxidative damage to neurons and inflammation. It acts to reduce levels of Aβ and neutralises its toxicity, as well as improving synaptic functioning by restoring copper/zinc sequestered by extraneuronal Aβ. It promotes memory functions such as LTP, is effective in transgenic models for AD, and improves learning and memory and clearance of Aβ. PBT2 improves cognition in animal models for AD and has shown positive initial results in Phase 2 clinical trials (11). Patients with early AD were treated with oral PBT2 in a double-blind, placebo-controlled clinical trial over 12 weeks. The drug induced a 12 per cent drop in cerebrospinal fluid (CSF) Aβ1-42 levels and produced a significant improvement in executive function on a neuropsychological test battery (NTB).

A second small molecule in clinical development is ELND005 (also known as scyllo-inositol), a potential diseasemodifying treatment for AD (12). ELND005 is a small molecule compound that inhibits the aggregation and toxic effects of Aβ; it is also thought to act by breaking down larger Aβ species. ELND005 has recently completed a Phase 2 trial. In this placebo-controlled study in 351 patients with mild to moderate AD, the co-primary cognitive endpoints did not achieve statistical significance. However, a 250mg twice daily dose showed positive clinical trends on an NTB in mild patients and also demonstrated a biological effect on Aβ1-42 levels in the CSF in the subgroup of patients who provided CSF samples. Based on the evidence from these data, ELND005 is being advanced into Phase 3 clinical development. A summary of the leading amyloid-binding drugs in clinical trials for AD is summarised in Table 2.



Exebryl-1 (13) is a compound which is reported to prevent Aâ fibrillogenesis in a number of animal models and shown to prevent accumulation of soluble and insoluble forms of Aβ. Exebryl-1 causes a reduction of Aβ load in transgenic mice and improves short-term memory in the Morris water maze test. The compound shows good brain penetration following oral administration and is currently undergoing a Phase 1 trial to determine the safety of this compound for the treatment of mild to moderate stages of AD.

A further series of small molecules are also in pre-clinical development. However, alternative small molecule starting points for inhibitors of Aβ1-42 aggregation are relatively scarce, and the vast majority of compounds claimed to be inhibitors of Aβ1-42 aggregation are unsuitable in terms of their biological profile and have poor tractability for medicinal chemistry optimisation to provide orally bioavailable, CNS-penetrating compounds with a therapeutically useful half-life. RS-0406 is a small molecule which has been shown to be an inhibitor of Aâ toxicity and is also capable of significantly inhibiting Aβ1-42 aggregation (14). It also prevents Aβ1-42- induced impairment of LTP and arrests Aβ1-42 oligomer-induced behavioural deterioration in the rat (15). Modifications to RS-0406 focused on improving its potency, introducing oral bioavailability and CNS penetrating properties of this molecule. To achieve this, selected structural changes were undertaken, which resulted in improvements in its drug-like nature. This has resulted in new analogues such as SEN1500 (16) and SEN1576 as promising compounds for clinical development. These compounds are more potent inhibitors of amyloid toxicity than RS-0406. They bind directly to Aβ1-42 monomer and oligomers, as demonstrated by surface plasmon resonance studies using a Biacore T100 instrument, they prevent the deficit in LTP caused by Aβ1-42 oligomers, and reverse Aβ-induced memory deficit in an acute model of cognition. In addition they are orally bioavailable and have good CNS penetration. Consequently, SEN1500 and SEN1576 are thought to be the first small molecules with suitable bioavailability for further development that have been shown to directly bind to Aβ1-42.

Conclusion

Small molecule inhibitors of toxic Aβ assemblies continue to be pursued as a viable anti-AD strategy. Several routes are being pursued, although the number of structural options remains limited. However, more structural types are likely to emerge as new screening approaches are applied. To date, results in the clinic have been mixed, but this is perhaps no more than might be expected for such a challenging disease and no small molecule drugs that have been shown to directly bind to Aβ have been tested in the clinic. Furthermore, it is very likely that successful treatment of AD will require patients to take a combination of drugs, rather than rely upon monotherapy, and small molecule amyloidbinding drugs could potentially be co-administered with other medication.

References

  1. Selkoe DJ, Folding proteins in fatal ways, Nature 426, pp900-904, 2003
  2. Hardy J and Selkoe DJ, The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics, Science 297: pp353-356, 2002
  3. Amijee H and Scopes DIC, The quest for small molecules as amyloid inhibiting therapies for Alzheimer’s disease, Journal of Alzheimer’s Disease 17: pp33-47, 2009
  4. Golde TE, Disease modifying therapy for AD, Journal of Neurochemchemistry 99: pp689-707, 2006
  5. Walsh DM and Selkoe DJ, Aβ oligomers – a decade of discovery, Journal of Neurochemistry 101: pp1,172-1,184, 2007
  6. Haass C and Selkoe DJ, Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide, Nature Reviews Molecular Cell Biology 8: pp101-112, 2007
  7. Cleary JP, Walsh DM, Hofmeister JJ, Shankar GM, Kuskowski MA, Selkoe DJ and Ashe KH, Natural oligomers of the amyloid-β protein specifically disrupt cognitive function, Nature Neuroscience 8: pp79-84, 2005
  8. Shankar GM et al, Amyloid-β protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory, Nature Medicine 14: pp837-842, 2008
  9. Gilman S et al, Clinical effects of Aβ immunisation (AN1792) in patients with AD in an interrupted trial, Neurology 64: pp1,553- 1,562, 2005
  10. Gervais F et al, Targeting soluble Aβ peptide with Tramiprosate for the treatment of brain amyloidosis, Neurobiology of Aging 28: pp537-547, 2007
  11. Lannfelt L et al, Safety, efficacy, and biomarker findings of PBT2 in targeting Aβ as a modifying therapy for Alzheimer’s disease: a Phase 2a, double-blind, randomised, placebo-controlled trial, Lancet Neurolology 7: pp779-786, 2008
  12. McLaurin J et al, Cyclohexanehexol inhibitors of Aβ aggregation prevent and reverse Alzheimer phenotype in a mouse model, Nature Medicine 12: pp801-808, 2006
  13. Snow AD, Cummings JA, Lake TP, Esposito LA, Hudson FM, Hu Q, Cam JA and Aker JR, Exebryl-1: A novel small molecule drug that markedly reduces amyloid plaque load and improves memory, enters clinical trials, Alzheimers & Dementia 4 (S2), P2-310, 2008
  14. Nakagami Y et al, A novel β-sheet breaker, RS-0406, reverses amyloid â-induced cytotoxicity and impairment of long-term potentiation in vitro, British Journal of Pharmacology 137:, pp676-682, 2002
  15. O’Hare E, Scopes DI, Treherne JM, Norwood K, Spanswick D and Kim EM, RS-0406 arrests amyloid-beta oligomerinduced behavioural deterioration in vivo, Behavioural Brain Research 210:, pp32-37, 2010
  16. Amijee H et al, SEN1500, an inhibitor of Aâ oligomer toxicity protects memory in models of Alzheimer’s disease, Alzheimers & Dementia 7 (S450), P2-443, 2011

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Mark Treherne is CEO at Senexis. Mark has a PhD in Pharmacology from Cambridge University, and has over 25 years experience in the discovery of novel treatments for diseases of the central nervous system, including Alzheimer’s disease. Mark was formerly at Pfizer UK until 1997, when he set up Cambridge Drug Discovery, which was acquired by BioFocus in 2001. Mark then joined Senexis in 2002. Email: info@senexis.com

David Scopes is Chief Scientific Officer at Senexis. David has a PhD in Chemistry from the University of Manchester and joined Glaxo UK in 1976, where he became a research manager focusing on central nervous system disorders, before taking up the position of Head of Medicinal Chemistry at GlaxoWellcome in France. He moved to Oxford GlycoSciences in 1996 as Director of Chemistry, later becoming Vice-President of Drug Discovery and then joined Senexis in 2004. Email: info@senexis.com
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