Beer versus Alzheimer!


While casually browsing for updates on Alzheimer’s Disease (AD), apolipoprotein E4 (ApoE4) genotype and amyloid beta (Aβ) burden, one title strongly caught the attention of the author of this blog:

Beer Drinking Associates with Lower Burden of Amyloid Beta Aggregation in the Brain: Helsinki Sudden Death Series.

Beer drinking against dementia? This study, published by Kok and colleagues (1) in Alcoholism: Clinical & Experimental Research, at least deserved reading! The authors investigate in this paper the association between the consumption of different alcoholic beverages (spirits, wine, beer) and Aβ aggregation in the brain. Their results rather surprising: beer drinking decreased the prevalence of Aβ-immunoreactivity in brain sections of autopsy cases investigated.

Before looking into details of the study, first a brief background on Aβ and AD. Amyloid plaques or senile plaques are extracellular deposits of the Aβ peptide and are one of the microscopically hallmarks of AD. The Aβ peptide is derived by sequential proteolytic cleavage of the β-amyloid precursor protein (APP) and plaques seem to spread hierarchically throughout the brain in patients with AD (figure 1). AD is a complex disease and little is known about its pathophysiology and cause. Also studies have shown a substantial genetic component in AD, the pattern of inheritance seems far more complex in which genetic risk factors such as ApoE4 work together with environmental factors and life exposure (i.e. life style).

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Figure 1: Characteristic progression of Aβ deposition. Senile plaques (left) seem to spread hierarchically throughout the brain in patients with AD (right). Modified from Jucker et al(2)

Kok et al (1) investigated on how alcohol consumption may influence Aβ burden and analysed for this brain sections (frontal cortex) of 125 cases that were known to consume alcohol and of which Aβ data was available. Only beer drinking was negatively associated with the presence of Aβ-immunoreactivity (figure 2); spirits and wine did not show any correlation, and age, as well as ApoE4 genotype were, as expected, strongly associated with Aβ burden.

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Figure 2: Aβ-immunoreactivity prevalence in beer drinkers versus non-beer drinkers (unadjusted analyses, n= 125).

The mechanism on how beer consumption may influence Aβ aggregation remains speculative. Regular beer consumers were shown to have increased levels of B vitamins and folate, as well as reduced levels of total homocysteine. High blood levels of homocysteine (hyperhomocysteinemia) seem to increase the risk for endothelial cell injury that may result in stroke and are associated with a wide range of diseases including thrombosis and AD (for review see (3)). However, how this links to Aβ burden clearly needs further investigation. Nevertheless, the study by Kok et al (1) is unique and is the first study that assesses the effects of alcohol consumption on post-mortem Aβ aggregation.

The author of this blog wants to emphasize that after reading this blog it is not advisable to drink more beer now. As most are surely aware, excessive use of alcohol can lead to cognitive impairment and many other undesirable things.

 

Blog written by: Lucas Kraft

References

  1. Kok, E. H., Karppinen, T. T., Luoto, T., Alafuzoff, I., and Karhunen, P. J. (2016) Beer Drinking Associates with Lower Burden of Amyloid Beta Aggregation in the Brain: Helsinki Sudden Death Series. Alcohol. Clin. Exp. Res. 10.1111/acer.13102
  2. Jucker, M., and Walker, L. C. (2013) Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature. 501, 45–51
  3. Morris, M. S. (2003) Homocysteine and Alzheimer’s disease. Lancet. Neurol. 2, 425–8

 

 

#sharetheorange


The Alzheimer’s Research UK (ARUK) conference 2016 took place in Manchester on the 8th and 9th of March. Researchers mostly from the UK, but also guest speakers from Germany and the US, presented their research that covered different fields of study related to Alzheimer’s disease (AD). However, the conference for the author of this blog already started the day before with the PhD day. This day was just for PhD students working on AD or AD related topics and gave them the opportunity to present their work in a more informal environment. The students presented their results in the form of posters or presentations and to the blog author’s delight also negative (or less “good looking”) results were presented which promoted vibrant discussion. Tea and lunch breaks were used to browse posters which pushed PhD students to get in touch with each other. The day was completed by presentations of academic and industrial representatives that gave insight into different career paths.

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Figure 1 | Sussex PhD students who participated in the conference. From left to right: Mahmoud, Karen, Saskia, Devkee, Lucas, Rebecca, Joanne and Luca.

With the PhD day already being a great success, the following days were sure to turn out to be as good. While more basic AD-related concepts and research were covered during the first day, the second day provided talks about new treatment approaches for dementia, as well as AD drug discovery and development. Two talks were in particular interesting:

Evidence is pointing towards inflammation processes that may trigger and influence AD pathology. One inflammation factor that seems involved and is activated in AD is the NLRP3 inflammasome (1). The NLRP3 inflammasome is a multiprotein complex which is formed inside macrophages and microglial cells and that catalyses the activation of caspase-1. Caspase-1 in return converts interleukin-1β (IL-1β) into its active form which is secreted and triggers an immune response. Most commonly, nonsteroidal anti-inflammatory drugs (NSAIDs) are used in the treatment of inflammatory conditions that act through inhibition of cyclooxygenase 1 and/or 2. Dr David Brough and colleagues at the University of Manchester hypothesized that NSAIDs may supress inflammation through a mechanism dependent on NLRP3 inflammasome inhibition and thus could potentially be repurposed as inflammasome inhibitors. Screening identified fenamates (fenamic acid, mefenamic acid) to be able to block NLRP3 formation by inhibition of the volume-regulated anion channel (VRAC). Other NSAIDs such as ibuprofen or diclofenac did not show any effect on NLRP3 mediated inflammation. Nevertheless, the other NSAIDs may still exert a positive effect via alternative pathways. Prof Michael Heneka from the University of Bonn (Germany), who gave a talk on targeting innate immunity in AD, demonstrated that these NSAIDs are great activators of peroxisome proliferator-activated receptor gamma (PPAR-γ). Activation of PPAR-γ was shown in transgenic APP/PS1 mice to increase Aβ removal by microglial cells (2). The activating effect of NSAIDs on PPAR- γ may also explain their efficacy in reducing the risk of AD (3). Conclusively, NSAIDs may be an interesting class of anti-inflammatory drugs that could be repurposed in the treatment and/or prevention of AD.

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Figure 2 | Activation of the NLRP3 inflammasome and production of active IL-1β. Activation of microglial cells via the Toll-like receptor (TLR) or cytokine receptors induces the production of components of the NLRP3 inflammasome, as well as pro-IL-1β. Lysosomal damage by Aβ leads to assembly and activation of the inflammasome that in turn activates caspase-1. Caspase-1 processes pro-IL-1β to its bioactive form which is released. Picture from (3)

The second talk that strongly caught the interest of the author of this blog was the introduction of the Alzheimer’s Research UK Drug Discovery Alliance – a coordinated initiative between the ARUK, Oxford University, Cambridge University and University College London that aims to accelerate the identification for new treatment for AD and other forms of dementia. The Drug Discovery Alliance is especially interested in new and unexplored biological targets and in doing so is keen to hear from researchers across the research community about potential proteins, enzymes or pathways that play a role in AD. By combining the individual strengths of all the three university institutes, the alliance hopes to drive innovation in dementia drug discovery.

 

Blog writted by: Lucas Kraft

 

References

  1.            Heneka, M. T., Kummer, M. P., Stutz, A., Delekate, A., Schwartz, S., Vieira-Saecker, A., Griep, A., Axt, D., Remus, A., Tzeng, T.-C., Gelpi, E., Halle, A., Korte, M., Latz, E., and Golenbock, D. T. (2012) NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature. 493, 674–678
  2.            Mandrekar-Colucci, S., Karlo, J. C., and Landreth, G. E. (2012) Mechanisms underlying the rapid peroxisome proliferator-activated receptor-γ-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer’s disease. J. Neurosci. 32, 10117–28
  3.            Heneka, M. T., Golenbock, D. T., and Latz, E. (2015) Innate immunity in Alzheimer’s disease. Nat. Immunol. 16, 229–236

DNA damage and repair: Let’s use our brains!


The integrity of our DNA is under constant attack from numerous endogenous and exogenous agents. The consequences of defective DNA and DNA damage responses (DDRs) have been extensively studied in fast proliferating cells, especially in connection to cancer, yet their precise roles in the nervous system are relatively poorly understood.

Two fundamental questions are still open:

What is the integrity of the genome in the adult and aging brain?

 What is the role of DNA damage in aging and neurodegenerative disorders such as Alzheimer’s disease (AD) or Parkinson’s disease (PD)?

How damaged is the genome in the adult brain?

The neurons of our nervous system are post-mitotic, meaning that once matured, they cannot rely on cell division to replace a lost or disabled neighbour. This fact has two important consequences:

  • In a long-lived species such as homo sapiens, a ‘lucky’ CNS neuron may survive for 80 years or more, potentially accumulating a lot of DNA damage.
  • Neurons are devoid of homologous recombination – the most effective way to repair DNA double stranded breaks -which takes place mainly during cell division.

The genome integrity in the adult brain is still the object of intense scrutiny but what is generally accepted is that the adult brain tolerates an unexpected degree of DNA damage and that the DDR mechanisms might be significantly different from other somatic cells.

What is the role of DNA damage in aging and neurodegenerative disorders?

As we have already observed, neurons are particularly prone to accumulating DNA defects with age, the key question here is whether these defects contribute to developing and/or sustaining neurodegeneration.

Several pieces of evidence seem to point in this direction. For example, age is the most common risk factor for most adult-onset neurodegenerative diseases with even the most aggres­sive familial forms of dementia rarely striking before the age of 40 years.

What is still unclear is how DNA damage contributes to the development of pathologies such as AD and PD that are regional by nature, e.g. involve only specific areas of the brain.

On this regard, several models and theories have been suggested but none of them has been fully validated yet with sufficient data (Fig.1).

Fig.1 Models to explain the relationship between age, DNA damage and neurodegeneration. (from: Chow, H-m; Herrup, K. Genomic integrity and the ageing brain’, NATURE REVIEWS NEUROSCIENCE, 2015; 16, p 672)

Alessandro 8-12-2015 Figure 1

DNA damage and the onset of specific neurodegenerative diseases. a | As we age, all of our neurons experience increasing amounts of irreparable DNA damage. The accumulating damage is induced by products of cell metabolism and other destructive activities (black arrows) coupled with a reduced capacity for DNA repair (grey arrows). Disease initiation then arises as a result of an additional insult, specific to the particular degenerative condition, which, coupled with the damage already present, precipitates the emergence of disease. Without that insult, a slow but benign descent into ageing would continue without serious clinical consequences (as indicated by the dashed line). Once the activity of DNA repair can no longer keep pace with the rate at which DNA damage is generated, damage accumulates at an increased pace and a point of no return is reached, eventually leading to neuronal death. b | An alternative, but not mutually, exclusive conceptualization involves a network-based model of DNA damage. If the relative activity levels of different circuits of neurons leads to the accumulation of specific unrepaired DNA lesions in the participating cells 42 , the predicted consequence would be regional variability in the rates of DNA damage, leading to different rates of neuronal ageing and hence to specific selections of neurodegenerative events. For instance, during the development of Alzheimer disease (AD), aberrant activities of neurons in the hippocampal network might result in the lethal accumulation of DNA damage in certain cells. Within the same brain, Purkinje cells in the cerebellum, engaged in a different pattern of physiological activity, would show minimal accumulation of such damage and be spared. After many years, the loss of genomic integrity in the most affected hippocampal neurons would lead to a pattern of cell dysfunction and death that would be more pronounced than that in the cerebellum. A similar branching network model with different initiation points could be envisioned for other diseases, including Parkinson disease (PD), Lewy body disease (LBD) and epilepsy.

 

Clearly, answering to some of these questions could open new exciting avenues in the field of neurodegeneration, an area that unfortunately is increasingly neglected by big pharma after the clinical failures of the last decade.

It is definitely time for DDR research to focus on the brain!

Blog written by Alessandro Mazzacani

Further reading:

‘Genomic integrity and the ageing brain’, Hei-man Chow and Karl Herrup, NATURE REVIEWS NEUROSCIENCE, 16, NOVEMBER 2015, p 672

 DNA Damage and Its Links to Neurodegeneration’ Ram Madabhushi, Ling Pan,and Li-Huei Tsai, Neuron, 83, July 2014, p 266

Solanezumab, the story continues… but is it good news, bad news or just news?


On the 23rd of July, the British newspapers interpreted Eli Lilly’s most recent data on Solanezumab presented at the Alzheimer’s Association International Conference in Washington DC ranging from a circumspect “Dementia Drug Shows Promise” (the i), through “Jab Will Halt Alzheimer’s” (Daily Express) to “Alzheimer’s Miracle Drug Has Saved My Life” (Daily Mirror). The BBC was at the less excitable end of the spectrum claiming that there were “Early signs that drug ‘may delay Alzheimer’s decline”. Within the scientific literature opinion was likewise divided as to whether Solanezumab does not help in Alzheimer’s disease (McCarthey, M. BMJ 2015), has “questionable potential” (Reardon, S Nat Rev Drug Discov, 2015) and or actually does demonstrate disease modifying effects (Karran, E. BMJ, 2015). So, what’s going on here? Well, the recent debate relates to data from a two-year extension study, EXPEDITION-EXT from the two earlier 18-month Phase 3 studies of Solanezumab (EXPEDITION 1 and EXPEDITION 2) that we discussed previously (Amyloid in Alzheimer’s Disease – The End of the Beginning or the Beginning of the End?). Questions can be raised about the clinical trial design, in which patients and caregivers knew that they were on the drug on the extension trial as well as the effect size (Reardon, S Nat Rev Drug Discov, 2015). Nevertheless, the key observation, which is consistent (but not proof of) a disease modifying rather than symptomatic effect, is that change in the ADAS-Cog score for subjects that were previously on placebo but then given Solanezumab in the extension trial ran parallel rather than converged with the group that received drug during the original 18-month Phase 3 study (see figure below, taken from see Reardon, S Nat Rev Drug Discov, 2015).

Picture JA blog 14-09-2015

Better placed than most to comment on the matter is Dr Eric Karran, currently the director of research at Alzheimer’s Research UK but formerly head of neuroscience research at Eli Lilly when Solanezumab first progressed into development. Dr. Karran, who recently authored an excellent article reviewing the preclinical and clinical data on a variety of Phase 3 Alzheimer’s disease drugs (Karran E. Annals of Neurology, 2014), told the BBC; “If this gets replicated, then I think this is a real breakthrough in Alzheimer’s research. Then, for the first time, the medical community can say we can slow Alzheimer’s, which is an incredible step forward. These data need replicating, this is not proof, but what you can say is it is entirely consistent with a disease-modifying effect”. The Solanezumab replication study, EXPEDITION 3, involves 2,100 patients with mild Alzheimer’s disease with results due in October 2016 and as Dr. Karran comments “if it doesn’t work, we will all be very disheartened” although the next drug stepping up to the crease/plate (depending on whether you prefer your sporting analogies with a British or American flavour) will be Merck’s B-secretase inhibitor, MK-8931 which he described as “a superlative molecule” (Karran, E. Nat Rev Drug Discov, 2015). And so, following the flurry of excitement and hyperbole we settle back down to awaiting the data from rigourously-conducted, placebo-controlled Phase 3 studies with predefined end-points and can best describe the EXPEDITION-EXT data as very interesting without making any extrapolation to the patient benefit and ultimate regulatory approval (or otherwise) of Solanezumab. However, from the patient point of view, it is perhaps best to keep our collective fingers crossed.

Blog written by John Atack

Novel Rat model for Alzheimer’s disease


It is stating the obvious that having good animal models is critical to the success of any drug discovery program. In many more complex diseases however, good animal models are not available. The ‘gold standard’ animal models for Alzheimer’s disease, Aβ-overproducing transgenic AD mice; do not demonstrate robust tauopathy and subsequent neuronal loss without the addition of genes not linked to familial AD.

In a recent paper Cohen et al., (1) have generated transgenic rats bearing human mutant APP (amyloid precursor protein) and PS1 (presenilin 1). These animals appear to manifest the full spectrum of age-dependent Alzheimer’s disease pathologies alongside cognitive disturbances. They have age-dependent β-amyloid deposition as well as intraneuronal Aβ1-42 and soluble Aβ oligomers. Many mouse models do present with some tauopathy, however, they do not present with neurofibrillary tangles (NFT) as observed in human AD. In this rat model however, they identified striking tauopathy. As well as hyperphosphorylated Tau, structures reminiscent to NFTs were identified close to β-amyloid plaques in aged rats. In addition immunostaining revealed structures consistent with NFTs in 16 month old rats. These NFT-like structures were also frequently observed in areas without plaques, as is found in human AD.

In concert with the molecular pathology, these transgenic rats exhibited neuronal loss and neuronal degeneration that was progressive and age-dependent. There was also an inverse correlation between the neuronal numbers and Aβ1-42 abundance. TUNEL staining indicated the presence of nicked DNA and measurements of active caspase-3 suggested the neurons were apoptosing.  This neuronal loss paralleled changes in behavioural characteristics such as novel object recognition (which is a hippocampal-dependent measure of working memory) that was significantly impaired in older transgenic animals. This was repeated in the Barnes maze, where there were no difference between wild-type and transgenic animals at 6 months, but after 15 months the transgenic animals made significantly more errors than wild-type.

With recent late-stage failures of treatments for Alzheimers this new animal model opens up the possibility to test novel therapeutics in a more human disease-like model.

FDA and New Drugs for Alzheimer’s Disease: Lowering the Bar or Circumventing a Roadblock?


A month or so ago, the Food and Drug Administration (FDA) kicked-off a bit of a kerfuffle with, depending upon your viewpoint, its innovative, radical, and/or dangerous proposals to overhaul aspects of the regulatory path to approval for new drugs for Alzheimer’s disease. The recently published draft guidance (see pdf here and Webinar here) invited comment and that is exactly what it got. On the one hand, the proposals were welcomed by clinicians and patient groups that are desperate to see new treatments come to market while on the other hand there was a degree of scepticism by those that regarded them being overly favourable towards pharmaceutical companies. But let us first reflect upon why the FDA felt the need to stir the pot in the first place.

It has been noted that of the greater than 100 drugs that entered development for the treatment of Alzheimer’s disease since 1998, only three have achieved Food and Drug Administration (FDA) approval. These drugs were the acetylcholinesterase inhibitors rivastigmine from Novartis (Exelon, approved in 2000) and galantamine from Forest/Janssen (Reminyl, 2001) along with the NMDA receptor antagonist memantine from Merz/Forest/Lundbeck (Namenda, 2003). They joined the acetylcholinesterase inhibitor donepezil (Aricept; Eisai/Pfizer), which was approved in 1996, to comprise the quartet of FDA-approved therapies for the symptomatic treatment of Alzheimer’s disease. More recently, disease-modifying rather than symptomatic-relief approaches have attracted most attention with the amyloid hypothesis predominating, although recent clinical trial failures of amyloid-related drugs have instigated  a re-appraisal of this approach (for review see here).

We have previously discussed the state of amyloid-related therapeutics for the treatment of Alzheimer’s Disease, with the focus clearly shifting to the treatment of earlier, mild forms of the disease or the prevention of the disease in susceptible populations (see here). Most notably, the Lilly antibody Solanezumab showed signs of efficacy in early (mild) Alzheimer patients in the failed Expedition 1 and Expedition 2 Phase III studies and these data have encouraged additional Phase III studies specifically targeting such patients, although it should be noted that diagnostic accuracy in such patients could be an issue. Hence, it is not unreasonable to assume that in later stages of the disease, neuronal damage may have become too widespread for effective disease-modifying intervention, particularly as regards amyloid-based therapeutics (see here).

It was the recognition that effective treatment would most likely occur in the early stages of the disease that prompted the FDA’s proposals. At the moment, regulatory requirements for a drug approval require an improvement in cognition to be accompanied by a functional improvement in an activity of daily living, such as making a cup of tea. However, in a recently-published article in New England Journal of Medicine which summarises their proposals, the FDA note that in Alzheimer patients that do not have overt dementia meaningful functional deficits are currently difficult to measure. Accordingly, they propose reducing or dropping the requirement for a functional improvement in early forms of the disease (see Figure below). Moreover, as the chronology of Alzheimer’s disease pathology becomes better defined by biomarker and imaging studies such as the Alzheimer’s Disease Neuroimaging Initiative (ADNI; for example Jack et al, 2013), early cognitive deficits plus appropriate biomarkers may be used to address the issue of accuracy of diagnosis in early Alzheimer’s Disease.

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What, therefore, are the implications of these proposals? Well, in a New York Times editorial (18th March, 2013), the FDA’s proposals have been described as lowering the bar for Alzheimer’s disease drug approval. The term “lowering the bar” implies a reduction in scientific rigour but this is not necessarily the case, with the FDA recognising that “innovative approaches to trial design and end-point selection are urgently needed”. Moreover, the phrase implies that the bar could be cleared if only one jumped high enough (i.e. if the drugs were good enough) but as the emphasis moves more towards treating early Alzheimer’s disease, the current requirement for cognitive improvement to be coupled with a functional improvement may be seen more as an insurmountable roadblock than a barrier (especially if there is limited, if any, evidence of a functional deficit in early Alzheimer’s disease). The New York Times Editorial further elaborated on its glass-is-half-empty viewpoint by warning that the FDA might “end up approving drugs that provide little or no clinical benefit yet cause harmful side effects in people who take the medications for extended periods.”

The viewpoint expressed by the NY Times is disputed by those in the field (see here). For example, an opposing glass-is-half-full opinion is offered by Dr. Eric Siemers, senior medical director at Eli Lilly, who commented in the March 14th edition of the New York Times article (the one that triggered the subsequent Editorial) that “This is really a huge advance” and in an era when failures in the drug discovery process can sometimes all too readily be apportioned to the regulatory authorities he added the seldom-heard comment “Kudos to the F.D.A.” There is no doubt that the proposed guidelines map out an innovative path to new treatments that if adopted could circumvent the current potential regulatory road block. Indeed, commenting on a recent article which quantifies the financial costs of dementia in the US (see here), the NY Times itself noted last week “the number of people with dementia will more than double within 30 years, skyrocketing at a rate that rarely occurs with a chronic disease”. So, as the population ages and a tsunami of dementia-related financial and emotional burden looms large, if ever there was a time to reshape the Alzheimer’s disease drug development paradigm it is surely now.

 

Amyloid in Alzheimer’s Disease – The End of the Beginning or the Beginning of the End?


In terms of drug discovery, there are four general ways of identifying new drugs: 1) there is serendipity, where a chance preclinical or clinical observation is translated into a novel therapeutic (with the initially cardiovascular Viagra being an example, the clinical utility of which you could quite literally hang your hat on); 2) Iteration, in which a new drug is an improvement upon an existing drug (e.g. reduced side effects or better pharmacokinetics); 3) repositioning, whereby a drug approved or initially evaluated for Indication A proves efficacious in Indication B and finally; 4) hypothesis-driven drug discovery, in which drugs are targeted towards a pathway or protein specifically implicated (e.g. genetically or pathologically) in a disease process. This latter process is the most rational and intellectually satisfying and forms the basis of the multiple amyloid-related approaches to treating Alzheimer’s disease since the amyloid core at the centre of the hallmark senile plaques  as well as the genetics of familial cases of AD all point the scientific finger of guilt towards the amyloid pathway.

As regards the amyloid hypothesis of Alzheimer’s Disease, it is now a few months ago that we discussed the big summer of data that lay ahead with Bapineuzumab and Solanezumab. Well, the data has now been chewed over and digested and as the year draws to a close, it is a good time to be reflective and assess where the field stands. So, in alphabetical, chronological and clarity of what-happens-next? order let us first consider Bapineuzumab. The data for the first Phase III study, Study 301, was disappointing but not surprising since the AD patients were the ApoE4-carrier subpopulation that the Phase II study suggested were less susceptible to the potential benefits. Hopes were therefore pinned on data from the ApoE4-noncarrier Study 302. However, these data were unambiguously negative (follow the links for data of Studies 301 and 302 presented at the September meeting of the European Federation of Neurological Societies) with the complete lack of ambiguity resulting in the termination of the two additional ex-US and incomplete studies (Studies 3000 and 3001). So, all-in-all, quite an emphatic end of story for i.v. Bapineuzumab.

The story for Eli Lilly’s Solaneuzumab is, however, not quite so clear cut. To recap, the EXPEDITION1  and EXPEDITION2 were pivotal Phase III studies. The EXPEDITION1 study missed its primary end-point but showed a significant effect on a secondary end-point, namely cognition in mild AD. This secondary end-point was then used as the primary end-point in the EXPEDITION2 study, but there were no significant effects of Solanezumab. However, combining data from these 2 studies – one of which showed efficacy, the other one not – showed a significant effect in mild but not more advanced moderate AD patients. This is entirely consistent with the way the field has been moving, namely that amyloid-related treatments need to be as early in the disease process as possible. There was a brief flirtation with the prospect that because of the large unmet need regulators may find a way to approving Solanezumab based on the existing data. However, subsequent to discussions with the FDA, Eli Lilly accept that approval would require a new Phase III study in mild AD patients, although their press release does note that “It is possible that different courses of action could be taken in different jurisdictions.”. Given their recent run of bad luck with neuroscience Phase III compounds (the γ-secretase inhibitor Semagacestat in 2010 and then this year the mGlu2/3 agonist pomaglumetad methionil and Solanezumab), one can only admire the depth of the company’s neuroscience financial trouser pocket and their obvious commitment to the area.

If the Solaneuzumab data tells us that treating earlier is the way to go, then the ultimate extension of this approach is a prevention trial. Such a trial, which commences in the spring of 2013 and is being organised by the Banner Alzheimer’s Institute in Phoenix, is being conducted as part of the 5-year, $100 million Alzheimer’s Prevention Initiative and will focus on a family in Columbia with genetic mutation associated with on onset of Alzheimer’s disease in their late 40s. Subjects with the mutation will receive Crenezumab, an anti-amyloid antibody developed by Roche/Genentech and licensed from the Swiss company AC Immune. An additional “branch study” will also take place in the US and will include an additional 150 US mutation carriers. A second prevention trial is also due to start in early 2013 and will be conducted by the Dominantly Inherited Alzheimer Network Trials Unit (DIAN TU) and will evaluate the effects of three different drugs on subjects (160 carriers and 80 non-carriers) with AD-causing mutations.  These three drugs were selected from the more than a dozen drugs proposed by the 10 pharmaceutical companies that comprise the DIAN Pharma Consortium and include the anti-amyloid antibodies Solanezumab and Gantenerumab, a Roche antibody currently in a Phase III trial for very early, presymptomatic (prodromal) AD known exotically as SCarlet RoAD, with a third drug, the Lilly BACE inhibitor currently in Phase II, also being selected for potential inclusion.

So, there remains life in the amyloid hypothesis. But what about other approaches? Well, as we mentioned at the top of this article, drug repositioning (or drug repurposing) is an attractive potential alternative since it is a route accessible to research councils and academic centres (i.e., it lacks the huge development costs of novel therapies). Recently, a number of drugs currently in clinical use for other indications have been shown to have an effect on amyloid metabolism or the associated neuroinflammatory response in animal models, including, for instance, the anticancer (cutaneous T-cell lymphoma) drug Bexarotene, the antiepileptic drug Levetiracetam and the blood pressure drug Prazosin. Nevertheless, the extrapolation between effects in animal models and human is a large and tenuous one with, for example, Rosiglitazone producing marked effects in transgenic mice but there were no signs of efficacy in two  Phase III studies. So, despite claims that “Drug giants give up on Alzheimer’s cure” (The Independent, 19th September, 2012) it would appear that there still remains a major commitment to the development of new therapeutics for Alzheimer’s Disease and that recent developments in the field represent the end of the beginning rather than the beginning of the end.

Bapineuzumab in Alzheimer’s Disease – Keep Calm and Carry On


The news from Pfizer released on the 23rd July stating that Bapineuzumab failed the first of four Phase III studies in Alzheimer’s Disease (AD) might have induced a wailing and gnashing of teeth and Henny Penny behaviour in certain quarters but now is not the time to panic, the sky is not falling (yet). The press release stated that in a Phase III study of 18-month duration in around 1,100 mild-to-moderate Alzheimer’s Disease (AD) patients, Bapineuzumab failed to meet either of its primary endpoints which were a significant improvement relative to placebo in cognitive performance measured using the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and functional outcomes assessed using the Disability Assessment for Dementia (DAD) scale. Nevertheless, there were signs that Bapineuzumab was having some effect, albeit with respect to side effects rather than efficacy, in that the most commonly observed, treatment-related serious adverse events were the so-called amyloid-related imaging abnormalities-edema (or ARIA-E) observed by MRI.

Bapineuzumab is a humanized version of the mouse monoclonal antibody 3D6 which recognizes the N-terminus of amyloid-β and is administered by intravenous infusion. It is being co-developed by Pfizer and Janssen Alzheimer Immunotherapy (the latter of which is a division of the healthcare giant Johnson and Johnson that acquired rights from Elan – a pharmaceutical company headquartered in Dublin – to co-develop bapineuzumab in September 2009). The rationale is that the small amount of antibody that crosses the blood-brain barrier will bind to amyloid-β within the brain and facilitate its removal by microglial-mediated phagocytosis. It is therefore a passive amyloid-β immunotherapy in which the antibody is administered directly to the patient. This distinguishes Bapineuzumab from a previous active immunization approach with Elan’s AN1792 in which the synthetic, pre-aggregated 42-amino acid amyloid-β peptide was administered along with a immunogenic adjuvant (QS-21) to stimulate an immune response in patients who then themselves produced antibodies against amyloid. Unfortunately, however, 6% of patients developed meningoencephalitis (Orgogozo et al., 2003, Neurology 61:46-54), possibly as a consequence of a pro-inflammatory T-cell response.

Before discussing the implications of the recently-released data on Bapineuzumab, it is worth considering the current state of AD therapeutics. Treatment of the symptoms associated with Alzheimer’s Disease is dominated by the cholinesterase inhibitors donepezil (tradename Aricept), galantamine (Reminyl or Razadyne) and rivastigmine (Exelon) plus the N-methyl-D-aspartate (NMDA) receptor antagonist memantine (Ebixa or Namenda). Although approved for the symptomatic treatment of Alzheimer’s Disease, these cognition-enhancing therapies leave a lot to be desired both in terms of efficacy and tolerability. Consequently, the Holy Grail for the treatment of Alzheimer’s Disease is the prevention or reversal of this debilitating disease of the elderly but unfortunately this remains a distant objective. However, a more achievable goal, a Grail of Significant (if not quite religious) Importance if you will, is that of slowing disease progression. In order to modify the disease process, it is necessary to  understand the underlying pathological processes. In this regard, we are fortunate (although that term always seems inappropriate for such a dreadful disease) to have clues from the pathological hallmarks of the disease which Alois Alzheimer first described over a hundred years ago, namely the extracellular deposits of amyloid that comprise the senile plaque and the intracellular accumulations of hyperphosphorylated tau (a protein that ordinarily plays an important part in maintaining the microtubules that comprise the scaffolding of the neuron).

There is much discussion over the relative importance of the role of amyloid-β peptide versus tau in the disease process, resulting in the moniker of BAPtists (βamyloid peptide-ists) for those believing that the abnormal production of the amyloid-β peptide from the amyloid precursor protein (APP) is the primary pathological process whereas those espousing the importance of the tau protein abnormalities comprise the tauist camp. Although the BAPtist and tauist labels makes for a linguistically convenient division in research activities it is clearly a gross oversimplification since the two pathologies must clearly be linked albeit in a manner that is currently unclear. Nevertheless, it would be fair to say that over the last 20 years or so, the BAPtists have taken the lion’s share of the spotlight based on the convincing genetic evidence that familial AD is associated with mutations in either APP or one of the subunits (either presenilin 1 or presenilin 2) that constitute the γ-secretase enzyme which, along with a second enzyme, the β-site APP cleaving enzyme type 1 (BACE1), plays a role in cleaving APP to produce β-amyloid.

Anyway, back to Bapineuzumab and the pressing question of what the recently-announced failure of the Phase III study with Bapineuzumab actually means for the amyloid hypothesis. Well, not a lot actually. First of all, the data relate to one of four Phase III currently underway and although Study 302 is the first for which data has been publically announced, it is not the key clinical trial. Hence, the AD patients in Study 302 had an ApoE4 genotype yet the Phase II data for Bapineuzumab (Salloway et al., 2009, Neurology, 73:2061-2070) showed that in this patient population, there was no effect; Phase II efficacy was only observed in those patients that did not possess the ApoE4 genotype and it is therefore data from the two Phase III studies with these non-carrier patients (Study 301 primarily based within the US and Study 3000 based primarily outside the US) that are of greatest interest. Data from Studies 301 and 302 will be presented at the Stockholm meeting of the European Federation of Neurological Sciences to be held from 8-11th September so within the next few weeks the future of Bapineuzumab should become clearer.

It is currently an important time for the amyloid hypothesis since Phase III data for the Eli Lilly antibody Solanezumab (also known as LY2062430) is also expected in the very near future. Amyloid antibodies are not all the same and whereas Bapineuzumab targets the N-terminal domain of the amyloid peptide, Sol recognizes the amino acids in the central region of the peptide (Aβ13-28). Moreover, Bapineuzumab binds more strongly to amyloid in plaques rather than soluble amyloid whereas Solanezumab preferentially binds to soluble amyloid-β. This distinction between antibodies can be detected clinically in so far as the fact that although Bapineuzumab produced ARIA-E, no such abnormalities were observed with Solanezumab (Farlow et al., 2012, Alz. Dementia, 8:261-271). Nevertheless, the expectations for Bapineuzumab and Solanezumab are not high. Hence, in June, the news agency Reuters reported that a survey of around 150 investors gave Bapineuzumab odds of about 5:1 for hitting its primary endpoints in the ApoE4 non-carrier Phase III studies whereas Solanezumab got the longer odds of 7:1. Although they may lack a deep scientific understanding of the underlying science, these investors nevertheless give a good indication of the expectations of the Wall Street community. Moreover, this expectation reflects the perception of Bapineuzumab and Solanezumab as being high risk, high reward assets. In other words, both antibodies have a low probability of success but if they do work, then they will justify their huge development costs not only in terms of market size but also, and more importantly, from the patient perspective.

The low expectations for Bapineuzumab and Solanezumab are related in part to the evidence emerging most notably from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) that suggests amyloid deposition occurs very early in the disease process and well before clinical signs appear (Jack et al., 2010, Lancet Neurol., 9:119-128) and that consequently amyloid-related therapeutics need to be targeted much earlier in the disease process (Karran et al., 2011, Nat. Rev. Drug Discov., 10:698-712).  In addition, the probably of success is further tempered by the difficulties inherent in the development of disease-modifying treatments for AD as highlighted by the recent Phase III failures of the Eli Lilly γ-secretase inhibitor Semagacestat (LY450139; Eli Lilly), which actually made cognition worse rather than better (plus it increased the risk of skin cancer), the Russian antihistamine latrepirdine (Dimebon or Dimebolin; Medivation/Pfizer), R-flurbiprofen (Tarenflurbil or Flurizan; Myriad Genetics/Lundbeck), for which Lundbeck signed a $350 million deal barely a month before the clinical data were released and finally homotaurine (Alzhemed or tramiprosate; Neurochem).

Irrespective of the outcome of the Bapineuzumab and Solanezumab trials, the US National Institutes of Health (NIH) announced in May that it will help sponsor the Alzheimer’s Prevention Initiative, which constitutes probably the most rigorous test of the amyloid cascade hypothesis in that it aims to prevent the development of AD in an at-risk population that show no signs of dementia.  This clinical trial, which is scheduled to commence in 2013, is being led by the Banner Alzheimer’s Institute in Phoenix, Arizona and plans to use the Genentech antibody Crenezumab (MABT; licensed from the Swiss company AC Immune) to treat pre-symptomatic members of an extended Colombian family living in and around Medellin. Within this family, there is a high incidence of early-onset AD which is caused by a mutation, E280A, in the presenilin 1 gene that is a part of the γ-secretase complex (Acosta-Baena et al., 2011, Lancet Neurol., 10:213-220). Family members with the mutation start to show cognitive impairment at around age 45 with full dementia developing by about age 51 (New York Times, 15 May, 2012). Crenezumab was chosen in part because it is an IgG4 antibody (Bapineuzumab and Solanezumab are IgG1) that activates microglia enough to help clear β-amyloid but not enough to produce the inflammatory signal that is thought to underlie some of the edema and microhemorrhages seen with other antibodies in clinical development (Adolfsson et al., 2012, J. Neuroscience, 32:9677–9689). The approximately $100 million trial will be funded by a mixture of philanthropic (Banner Institute), public (NIH) and private (Genentech) funding in a roughly $15:$16:$65 million split. This ground-breaking trial will be carried out on 300 hundred members of the 5000-strong Colombian family, with 100 carriers of the mutation receiving drug whereas a further 100 will receive a placebo and an additional 100 non-carriers will receive a placebo, with this latter arm being included since many family members do not want to know if they carrier the genetic mutation for the disease which is called locally La Bobera – the foolishness.

While the Alzheimer’s disease community awaits the outcome of the amyloid antibody Phase III studies with Bapineuzumab and Solanezumab, and despite the challenges in developing disease-modifying drugs for AD, a recent publication describes what could essentially be viewed as clinical proof-of-concept that amyloid lowering agents could be beneficial in the treatment of AD. Thus, Jonsson and colleagues (Jonsson et al., 2012, Nature, in press doi: 10.1038/nature11283) described a mutation in APP that protects against AD in the Icelandic population. Moreover, this mutation was adjacent to the BACE1 cleavage site of APP and in a cellular model, introduction of the mutation into APP resulted in an approximate reduction of 40% in the production of β-amyloid peptide relative to non-mutated APP. These data therefore support the strategy of BACE1 inhibitors as potential therapies for treating AD and imply that a BACE1 inhibition in the region of 40% may be sufficient. This publication is especially timely given the recent description at the Alzheimer’s Association International Conference held between 14-19th July in Vancouver, Canada, at which Eli Lilly, Merck and Eisai all described Phase I clinical data with BACE1 inhibitors (designated LY2886721, MK-8931 and E2609, respectively) (http://www.alzforum.org/new/detail.asp?id=3222). Hence, after more than a decade of struggle, during which time it was considered that it might not be possible to inhibit BACE1 with small molecules that were also brain penetrant and not substrates for P-glycoprotein (which pumps drug out of the brain), it would appear that significant progress is being made.

So, in summary, the recent announcement of the failure of Bapineuzumab to demonstrate any benefit in a Phase III study in ApoE4-positive AD is consistent with the Phase II data and is therefore not unexpected. The critical data in ApoE4 non-carriers should be available in early September. These data plus the additional Bapineuzumab Phase III studies as well as the soon-to-be-announced Phase III data with Solanezumab represent a key fork in the road of AD therapeutics. If the data are positive, then it is full steam ahead down the road to a regulatory filing and the eagerly awaiting AD patient population. If, however, these collective data are negative, the discussion will turn to whether the amyloid hypothesis has actually been tested early enough in the disease process or, alternatively, have side effects limited the doses of Bapineuzumab and Solanezumab to an extent that the clinical failures can be ascribed to shortcomings in  the antibodies themselves. If it is the latter, and given that all therapeutic antibodies are not equal, then this will encourage the further development of additional antibodies such as Gantenerumab (Roche), Ponezumab (Pfizer) and Crenezumab (Genentech) as well as encourage the further development of small molecular inhibitors of BACE1. If, on the other hand, the biomarkers included in the Bapineuzumab and Solanezumab clinical trials (amyloid imaging and CSF amyloid peptide measurements) give confidence that there are significant levels of target engagement, and that modulation of amyloid is not sufficient to produce clinical benefit in AD patients with established symptoms, then there will be a pause at the fork in the road. The AD research community will then have to ponder the signpost pointing down the difficult road towards earlier diagnosis or the equally difficult and poorly lit road towards alternative, non-amyloid (e.g. tau- or ApoE4-related) disease modifying approaches. But such decisions clearly need to be data-driven and so until all the Phase III results for Bapineuzumab and Solanezumab are available, it is prudent at this stage to just keep calm and carry on.