Current status of vaccination therapies in Alzheimer's disease
Version of Record online: 11 OCT 2012
© 2012 International Society for Neurochemistry
Journal of Neurochemistry
Volume 123, Issue 5, pages 647–651, December 2012
How to Cite
J. Neurochem. (2012) 10.1111/jnc.12009
- Issue online: 7 NOV 2012
- Version of Record online: 11 OCT 2012
- Manuscript Accepted: 4 SEP 2012
- Manuscript Received: 3 SEP 2012
positron emission tomography
Alzheimer's disease (AD) is a major health and societal problem and is the predominant cause of dementia. Age is the major risk factor for AD, and with the predicted demographic change to an increasingly elderly population, the prevalence of the disease will reach a staggering 100 million by 2050. Acetylcholinesterase inhibitors such as donepezil, rivastigmine and galantamine offer a modest symptomatic relief for a short period of time in mild-to-moderate AD, and memantine, a low-affinity N-methyl d-aspartate receptor antagonist, is licensed for use in moderate-to-severe AD. However, none of the current therapies is able to alter the course of the disease. The health care burden of dementia is equivalent to the gross domestic product of several mid-size countries (Wimo and Prince (2011) and unless treatments are found for AD that delay either disease onset or slow down disease progression, the cost to health care services around the world will be punitive.
Compared with other diseases of the mind, such as schizophrenia, there is, in fact, a very solid body of evidence that provide insights into some of the key pathological processes in the disease. The autosomal dominant mutations to the amyloid precursor protein (APP), presenilin 1 and presenilin 2 that cause early-onset AD clearly point to the key role that Abeta deposition plays. The similarities of the intracellular tau abnormalities seen in AD and the autosomal dominant forms of fronto–temporal lobar degeneration mediated by mutations to the tau gene strongly support the case that tau is implicated in neuronal death, and is likely downstream of Abeta deposition. These observations have been formulated in the ‘amyloid cascade hypothesis’, which while having its opponents, nevertheless incorporates much of the key data in a logical and compelling manner (Hardy et al. 1998; Hardy and Selkoe 2002; Karran et al. 2011). And yet, and yet. The AD research field has recently been rocked by three phase 3 failures: semagecestat, a gamma secretase inhibitor that inhibits the production of the Abeta peptide failed its primary end points in 2011; and now, within a few weeks of each other, the news that both the anti-Abeta monoclonal antibodies, bapineuzumab (Pfizer/Janssen Alzheimer Immunotherapy) and solanezumab (Lilly), that were being tested in phase 3 trials have failed to meet their primary end points; an improvement in cognition and activities of daily living. These last three disappointments come after the other phase 3 failures of tramiprosate in 2007 (Aisen et al. 2011) and tarenflurbil in 2008 (Green et al. 2009) that were also ‘amyloidocentric’ – that is, they targeted the Abeta peptide so as to reduce (via different mechanisms) its deposition in brain parenchyma (Table 1). However, the field acknowledges that the pre-clinical data and human biomarker data for these latter two molecules were not compelling (Golde et al. 2011).
|Drug name and proposed mechanism of action||Phase 2 results||Phase 3 results|
|Tramiprosate Abeta aggregation inhibitor||58 mild-to-moderate AD patients randomized to four groups: placebo, 50, 100, 150 mg/kg tramiprosate bid for 3 months. Drug mediated a significant lowering of Abeta 42 in CSF samples (Aisen et al. 2006)||1052 mild-to-moderate AD patients randomized to three groups: placebo, 100, 150 mg/kg bid for 78 weeks. No significant effects on primary outcome measures of ADAS-cog and CDR-sum of boxes (Aisen et al. 2011)|
|Tarenflurbil Gamma-secretase modulator||210 mild-to-moderate AD patients randomized to placebo, 400, 800 mg bid tarenflurbil for 12 months. Some evidence for an improvement in activities in daily living at the 800 mg bid dose (Wilcock et al. 2008)||1684 mild AD patients randomized to placebo, 800 mg bid tarenflurbil for 18 months. No significant effects on primary outcome measures of ADAS-cog and ADCS-activities of daily living (Green et al. 2009)|
|Semagecestat Gamma secretase inhibitor||51 mild-to-moderate AD patients randomized to placebo, 100, 140 mg od semagecestat following dose escalation for a total duration of 18 weeks. Significant reduction in plasma Abeta 40 peptide (Fleisher et al. 2008)||Trial data currently unpublished. 2600 mild-to-moderate AD patients randomized to placebo, 100, 140 mg semagecestat od for 76 weeks in two trials (ClinicalTrials.gov identifiers NCT00594568; NTC00762411) enroled. Trials were halted after interim analysis showed increased incidence of skin cancer and worsening of cognition and activities of daily living|
Bapineuzumab humanized monoclonal antibody directed at amino acids 1–5 of Abeta peptide.
Amyloid plaque clearance mediated by microglial activation
|234 mild-to-moderate AD patients, randomized to placebo, 0.15, 0.5, 1.0 or 2.0 mg/kg bapineuzumab IV infusions every 13 weeks for 78 weeks. Some evidence for an improvement in cognitive and functional end points in study completers and ApoE4 non-carriers (Salloway et al. 2009)||Trial data currently unpublished. 4500 mild-to-moderate AD patients randomized to placebo and 0.5 mg/kg IV every 13 weeks for 18 months in ApoE4 carriers, and randomized to placebo and 0.5 and 1.0 mg/kg IV every 13 weeks for 18 months in ApoE4 non-carriers in four trials (Clinical Trials.gov identifiers lNCT00575055; NCT00574132; NCT00676143; NCT00667810.) Trials were halted after completion of two trials demonstrated a failure to meet primary outcome measures of cognition and activities of daily living|
Solanezumab Humanized monoclonal antibody directed at amino acids 16–24 of Abeta peptide
Amyloid plaque clearance mediated via peripheral sink mechanism
|52 mild-to-moderate AD patients were randomized to placebo, 100 mg every 4 weeks, 100 mg weekly, 400 mg every 4 weeks, 400 mg weekly IV solanezumab for 12 weeks. There was a significant dose-dependent increase in Abeta 42 peptide in CSF (Farlow et al. 2012)||Trial data currently unpublished. 2000 mild-to-moderate AD patients randomized to placebo and 400mg solanezumab monthly IV for 18 months (Clinical Trials.gov identifiers NCT00905372; NCT00904683). Trials failed to meet their primary outcome measures of ADAS-cog and ADCS-activities of daily living. A secondary analysis of mild AD patients pooled from both trials showed a significant effect on cognition|
The most recent findings will stimulate a number of researchers in the field who will claim that the amyloid cascade has been tested in the clinic and we can accept the null hypothesis. More worryingly for the future development of medicines, many senior executives in pharmaceutical companies will be drawing breath and considering whether they can continue to pour money into a hugely expensive endeavour that has thus far delivered no return on investment. In particular, those companies that have therapeutic approaches in earlier phases of clinical assessment (Lobello et al. 2012) that are similar in pharmacological mechanism to those that have failed will be urgently reviewing their future development strategies. In ‘big pharma’, there is a continual internal competition for resources and it could well be that neuroscience research will suffer as companies divert their funding to other debilitating diseases that require new therapies – such as cancer, diabetes and arthritis – which have all produced a flow of phase 3 clinical successes providing excellent new medicines for patients.
It is helpful to reflect on some important aspects of drug discovery and development. With respect to semagecestat, it is noteworthy that a detailed biochemical analysis of the activity and selectivity of that compound (Chavez-Gutierrez et al. 2012) was published after the compound had been through its entire development and failure to show efficacy in AD patients. This study demonstrated that in a controlled biochemical, cell-free assay, semagecestat was slightly more potent as an inhibitor of notch processing compared with its activity as an inhibitor of Abeta production, in contradiction to data produced in less well-controlled cell-based assays that suggested the opposite. The liability of notch inhibition is well understood and likely contributed to some of the side effects seen in the phase 3 trials – notably, an increased incidence of skin cancer. This simple fact exemplifies that the nature of the target is hugely complex and that much scientific progress can be made in parallel to a very lengthy drug development process. This may prompt the question: why go ahead until you are absolutely sure of the profile of your drug? But, as those who work at the coalface of drug development know, if you want to wait for the perfect compound, then you will wait forever – as will the patients you seek to treat. Another key element to draw from the semagecestat story is that the clinical trial was informative – while the final data have not yet been published, the completely unexpected worsening of cognition mediated by the drug most probably closes that particular avenue down for drug hunters. With respect to bapineuzumab, here the failure, while again disappointing, may eventually be shown to be informative. First, did the antibody reach its target and exert its desired pharmacological effect – the clearance of parenchymal plaque? The dose-limiting side effects of bapineuzumab were vasogenic oedema and microhaemorrhage, mediated most probably by antibody binding to vascular amyloid (Racke et al. 2005); but what about parenchymal plaque? There were preliminary data from the phase 2 clinical trials demonstrating that bapineuzumab treatment did reduce amyloid in brain parenchyma as evidenced by reductions in the binding of 11C-PIB, an amyloid-selective positron emission tomography (PET) ligand (Klunk et al. 2004; Rinne et al. 2010). However, if this is not corroborated in the phase 3 trials, the trial will not have established a proof of mechanism and thus it would be difficult to conclude very much with respect to the viability of the approach. If the treatment was able robustly to remove amyloid plaques from the brains of patients, but with no hint of cognitive benefits, then one interpretation is that by this stage in the disease process amyloid plaques per se do not drive disease progression. Also, we have yet to discover whether the earlier findings that the treatment may have reduced the release of phospho-tau protein into the cerebrospinal fluid (CSF) – widely believed to be a marker of neuronal damage – have been confirmed (Blennow et al. 2010, 2012). If tau release has been significantly and robustly reduced, but in the absence of cognitive benefit, then the use of this particular biomarker will rightly be called into question.
With respect to solanezumab, again the failure to meet its primary end points is very disappointing, but early reports suggest that in a secondary analysis, there is a statistically significant improvement in cognition in mild AD patients. Other questions of course immediately come to mind: what was the magnitude of the improvement; was the improvement in cognition reflected in improved activities of daily living; was amyloid plaque reduced in the brain as assessed by amyloid PET brain imaging; was CSF tau lowered? Thus, if the biomarkers and end points measured in this trial point in a consistent manner to an effect in mild AD – for example, a reduction in amyloid in the brain as measured by an amyloid PET ligand; a reduction in CSF tau; the restoration of normal Abeta 42 levels in CSF, correlated with a preservation of cognitive function – then this would strongly suggest that the field has taken the first step down the path of finding an effective therapeutic for AD.
Finally, a full analysis and comparison of the two antibody trials should be very helpful to the field, as these monoclonal antibodies are quite dissimilar in affinity, proposed mechanism of action and were administered using different regimens. The affinity of solanezumab for its epitope in the mid-domain of the Abeta peptide is in the picomolar range (DeMattos et al. 2001), that of bapineuzumab for the N-terminal epitope in the Abeta peptide is in the nanomolar range (Bard et al. 2000). At its most fundamental level, this will mean that solanezumab will capture Abeta and sequester it for a significantly longer period of time than will bapineuzumab. Solanezumab does not bind to deposited amyloid plaque, either in the vasculature or the parenchyma, only to soluble Abeta (Racke et al. 2005). This explains why solanezumab did not cause an increased incidence of vasogenic oedema and microhaemorrhage. It is designed to mediate clearance of Abeta from the brain according to the peripheral sink hypothesis, by shifting the equilibrium of Abeta in favour of transit out of the brain of soluble Abeta (DeMattos et al. 2002). Recent data from the phase 2 studies indeed confirm that levels of the uncomplexed Abeta 40-amino acid peptide were decreased in the CSF of patients in a solanezumab dose-related fashion, with a concomitant increase in the levels of uncomplexed Abeta 42-amino acid peptide – this being the type of profile expected if the more insoluble and plaque-prevalent Abeta 42 peptide was being mobilized from an insoluble to a soluble compartment (Farlow et al. 2012). Bapineuzumab, on the other hand, binds both soluble and deposited plaque. This mechanistic difference could prove to be very relevant to data interpretation. For example, if both antibodies were able to remove approximately equivalent amounts of amyloid plaque from the brain as assessed by amyloid PET imaging, but only solanezumab has shown a statistically significant effect on preserving cognitive performance in mild AD patients, then one might argue that the microglial activation that is thought to underlie at least some of the plaque-clearing efficacy of bapineuzumab (Schenk et al. 1999) might have caused collateral damage that obscured any potential benefit. Bapineuzumab was administered to patients who were apolipoprotein E4 (ApoE4) carriers at 0.5 mg/kg, and in ApoE4 non-carriers at 0.5 mg/kg, 1 mg/kg and 2 mg/kg initially, with the 2 mg/kg dose being abandoned, again because of concerns regarding vasogenic oedema and microhaemorrhage. Bapineuzumab was given via intravenous infusion every 13 weeks for 18 months. Solanezumab was also administered via an intravenous infusion every month at a dose of 400 mg per patient (i.e., approximately 5–6 mg/kg) for 80 weeks. For both monoclonal antibodies, a comparison of the minimal effective doses defined in the pre-clinical studies with those used in humans will be instructive to interpreting the pre-clinical to clinical translation. Thus, if the final doses selected for human studies fall well short of the pre-clinical minimum effective dose, allowing for allometric differences, then a failure to show proof of mechanism in man may not be too surprising.
Despite the wealth of new data that these trials provide, the ineluctable truth is that they failed their primary end points. So, should we retreat from amyloidocentric therapies? My view is unequivocally ‘no’. We now know that amyloid deposition precedes the presentation of cognitive deficits in AD by about 15 years (Rowe et al. 2010). While there are robust data that Abeta deposition is a key component of the disease process, we are much less sure about when and how Abeta mediates its deleterious effects. Much of the data support the notion that Abeta deposition triggers the disease – there are less data to suggest that it drives the disease in a continuous fashion (Karran et al. 2011). The recent phase 3 clinical trials were of 18 months duration, which may be just too short a period over which to see a beneficial effect on the primary end points. The field needs to persevere with amyloidocentric therapies, but to invest more resource into understanding the earliest phase of the disease process so as to identify individuals that are on the cusp of Abeta deposition. If individuals can be reliably, and relatively inexpensively, identified at this juncture, then credible anti-amyloid therapeutics have a good chance of demonstrating efficacy. Indeed, mutations to the APP gene that have the effect of modestly reducing the production of Abeta peptide from the APP holoprotein have recently been shown significantly to protect carriers from AD – a natural, genetic proof of concept (Jonsson et al. 2012). However, in this case, the reduction in Abeta production occurs from birth, and whether a much later therapeutic intervention would have the same effect remains unknown. A longitudinal study that takes repeated measures of relevant biomarkers in a large cohort of subjects in their mid-sixties could provide critical data to help identify individuals at risk of early AD pathology –and potentially well-defined cohorts for clinical trials. Also, work on other treatment modalities should continue apace: for example, approaches to ameliorate tau pathology. It is very likely that no single treatment approach will prove to be fully efficacious.
In summary, although the clinical landscape currently looks bleak, now is not the time to falter. Each failed study provides additional data on which to build better clinical programmes. And, more importantly, as a society we simply cannot afford to give up.
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