Chemical and Biological Therapeutic Approaches to Neurological Disorders Symposium

On Monday 18th April, the 3rd symposium on Chemical and Biological Therapeutic Approaches to Neurological Disorders took place at Burlington House in London. Dr Paul Beswick and I (Tristan Reuillon) represented the Sussex Drug Discovery Centre (SDDC) at this one day conference, organised by the Royal Society of Chemistry. Paul gave a talk on the use of structural biology for the design of ligands for glutamate ionotropic receptors, an approach which has been and is being used on different projects at the SDDC, while I presented a poster on recent developments in the field of AMPA receptor positive allosteric modulators.

Some of the leading researchers in the field of neuroscience were presenting, such as Dr Eric Karran, former head of research at Alzheimer Research UK now at AbbVie or Prof John Hardy from UCL, recent winner of the Breakthrough Prize in Life Sciences for his pioneering research into the genetic causes of Alzheimer’s disease (AD). Dementia was the major focus of the symposium, with Dr Eric Karran introducing the statistics on AD and giving a detailed overview of the different theories believed to underlie AD (amyloid-beta (Aβ) and tau pathologies). According to Dr Karran the readouts of some critical clinical trials on AD drugs within the next two years will be extremely important to understand if the drug discovery efforts have been heading in the right direction and to guide further the current research on dementia. Prof John Hardy presented the genetic causes behind AD and amyloid deposition, with an emphasis on some specific proteins, such as TREM2, which represent very attractive drug discovery targets. Prof Nigel Hooper from the University of Manchester presented research focussed on Aβ, trying to identify what forms of Aβ oligomers and fibrils are neurotoxic and trying to link the alpha-secretase ADAM10 with Aβ production. Finally Dr Suchira Bose from Eli Lilly gave an in-depth analysis of the tau pathophysiology and different modulations of this physiological pathway which could lead to novel therapeutic approaches to AD.

Other neurological disorders were also discussed during the symposium. Dr Hasane Ratni from Roche presented the discovery of RG7800, a drug currently tested in phase II clinical trials for the treatment of Spinal Muscular Atrophy, a rare neurodegenerative disease affecting mainly children. RG7800 acts as a SMN2 splicing modifier. Dr Richard Mead from the University of Sheffield talked about his current research on Motor Neuron Disease, also termed Amyotrophic Lateral Sclerosis, with a focus on the NRF2-ARE pathway, an indicator and modulator of oxidative stress in neurodegeneration. Different attempts to identify activators of this pathway, such as apomorphine, were discussed. The presentation of Dr Paul Beswick on glutamate potentiators was centred on the identification of novel drugs to treat the cognitive dysfunction associated with Schizophrenia, a major symptom, for which there is a clear unmet medical need. Finally, Prof Kristian Stromgaard from the University of Copenhagen, presented a few drug discovery approaches that his group has undertaken to disrupt protein-protein interactions in the CNS, such as the PSD-95-NMDA interaction. Owning to the lack of success in identifying small molecule hits, his research has focussed on peptidomimetics, which are surprisingly brain penetrant and are currently in preclinical development.

I found this symposium extremely interesting, with some fantastic and innovative research being disclosed, and would highly recommend it for anyone interested in neuroscience research. I hope to have given you through this blog article a flavour of the different topics which were discussed on that day and maybe tempted you to attend the 4th symposium in this series which will take place next year.


Blog written by Tristan Reuillon


Bexarotene in Alzheimer’s Disease: A case of lack of replication, lack of replication, lack of replication

In a previous blog (see here) we briefly discussed drug repositioning as an alternative approach to identifying novel therapies for Alzheimer’s disease. This strategy follows in the wake of the recent failures last year of the large Phase 3 trials with Bapineuzumab and Solineuzumab. At the forefront of drug repositioning has been Baxter International’s Gammagard which is one of a number of IVIG (intravenous immunoglobulin; obtained from the pooled plasma of healthy volunteers) treatments approved for boosting the immune system. Based on an initial small, 18-month, 24-patient study in which Alzheimer’s patients appeared to respond to the therapy (see here), Phase 3 studies were initiated. However, hopes were never especially high given that the proposed mechanism – infused antibodies would help clear amyloid peptide and/or tau protein – was vague at best and was not based upon preclinical mechanistic studies. Unfortunately these doubts proved warranted when in early May, a press release from Baxter (see here) disclosed that Gammagard had failed it’s primary endpoints and as a result it became yet another casualty in the Alzheimer drug development mine field.

In contrast to Gammagard, for which there is a marked absence of preclinical data to support its use in Alzheimer’s disease, a paper from Cramer and colleagues made quite a splash when it was published in Science in early 2012 (see here). They described how the Eisai skin cancer drug Bexarotene (marketed as Targretin) enhanced the clearance of amyloid and improved cognitive performance in preclinical animal models. Bexarotene was approved by the FDA in December of 1999 for the treatment of refractory cutaneous T-cell lymphoma and in the aftermath of the Science publication, doctors were inundated with requests for “off-label” prescriptions of Bexarotene for the treatment of Alzheimer’s patients (see here, for example). Although perfectly legal, the off-label prescribing of Bexarotene raises separate issues of patient safety and ethics (as discussed in the New England Journal of Medicine), especially since the clamour for Bexarotene was based on preliminary evidence from a single study. Indeed, recent studies have failed to replicate important aspects of the initial report (see here, here, here and here, with the authors response here). Most notably, although some inconsistent effects on amyloid peptide concentrations and cognitive improvements were observed, there was a failure to replicate the reduction in amyloid plaques reported in the initial study. These studies highlight the difficulty in reproducing preclinical data, a topic illustrated very well by the Bayer group (see here). Obviously, the publication of a single article, albeit in an august journal such as Science, should be treated with caution until it is replicated. Nevertheless, clinical studies have commenced and the effects of Bexarotene are being studied in the clinic in a Phase Ib biomarker study in healthy young adults as well as in Alzheimer’s disease patients in a Phase 2 [18F]AV-45 amyloid imaging trial. It is a sobering reflection on the large unmet need in Alzheimer’s disease that despite all the caveats and with the limitations highlighted even within the popular press (e.g. “A huge caveat here is that many promising drugs seem to work in mice but fail when used in humans”, Forbes magazine, 10th of February, 2012), a single publication can create a demand for the off-label use of a drug that is has significant side-effects but for which there is, as yet, no evidence of clinical efficacy in Alzheimer’s disease.

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.


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.

Modelling CNS with inducible pluripotent stem cells

The challenges of accurately modelling diseases in vitro are great. A prime example is found in the central nervous system (CNS), where the complexities of the multicellular systems increase the difficulty in obtaining primary cells, especially those from patients. The use of stem-cell derived cultures is changing this, enabling neurons to be cultured from progenitor cells. More recently it has been possible to obtain human induced pluripotent stem cells (iPSC) derived from patients, effectively opening up a new source of patient cells. A number of publications have come out using these cells, and a recent double-publication from a group in Cambridge looking at Alzheimer’s disease illustrate not only the technical process, but how well the disease state can be modelled using this technology.

The first, published in Nature Neuroscience (2), describes the multi-step differentiation of human cerebral cortical neurons from pluripotent stem cells. The authors describe how they developed a multistep process for the differentiation of human cortical cells from embryonic stem (ES) and induced pluripotent stem cells (iPSC). The publication goes into some depth regarding the different phases these cells undergo during this differentiation, but critically after two months, these cells form multicellular cultures including both cortical neurons as well as astrocytes. These neurons form glutamatergic synapses that contain NMDA and AMPA receptors and whole cells patch clamp demonstrating? they have mature electrical properties and form functional excitatory synapses.

As though it wasn’t enough to publish the technical achievement differentiating? a cortical neuronal culture from iPSC and ES, the group went on to publish a follow-up in Science Translational Medicine (1), immediately demonstrating the application of this technology. They used the iPSC derived from Down syndrome patients from early Alzheimer’s pathology to model the neuronal cortex of a patient with Alzheimer’s disease.

The classic pathological hallmarks of Alzheimer’s disease are amyloid plaques composed of the amyloid Aβ (Aβ) peptide, (formed from the amyloid precursor protein) and neurofibrillary tangles comprising hyperphosphorylated forms of Tau. The amyloid precursor protein (APP) gene is encoded on chromosome 21 and therefore patients with Down syndrome (caused by trisomy of chromosome 21) develop early onset Alzheimer’s, commonly by 35 years of age.

The group took iPSC from a patient with Down syndrome (DS) and using the method set out in the neuroscience paper differentiated them into cortical neurons in the same way as they did in the first paper with control iPSCs and ES.  The group proceeded to measure whether there was Alzheimer’s pathology in these cultures.

They measured levels of Aβ40 and Aβ42 peptide production from 2-4 weeks after the onset of neuronal differentiation. In DS cultures, the levels of both Aβ40 and Aβ42 were significantly higher than in control iPSC.  In the DS cultures, these Aβ peptides also form amyloid aggregates that are not visible in the control cultures. They also measured the abundance of Tau phosphorylated at Ser202 and Thr205. This demonstrated that although phosphorylated Tau was expressed in both DS and control neurons, in control cultures phospho Tau was diffusely localised in the primary axons whereas in DS neurons it was aberrantly localised into linear foci in the cell bodies and dendrites in the DS cells. This matched the distribution found within the patient CNS.

The recent failure of so many late-stage Alzheimer’s drugs highlights the need to bring new compounds through the pipeline. Being able to elegantly model such a complex disease is perfect for a drug screening program, or phenotypic screen, to either hit Aβ or phosphorylated Tau. However, the screen can also be used for basic science to monitor disease progression potentially unravelling new targets, e.g. to elucidate the link between Aβ aggregation and hyperphosphorylated Tau. The development of such an elegant in vitro culture system such as this makes all of these more possible.


1.           Shi Y, Kirwan P, Smith J, MacLean G, Orkin SH, Livesey FJ. A human stem cell model of early Alzheimer’s disease pathology in Down syndrome. Science translational medicine 4: 124ra29, 2012.

2.           Shi Y, Kirwan P, Smith J, Robinson HPC, Livesey FJ. Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses. Nature neuroscience 15: 477–86, S1, 2012.

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) ( 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.