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.


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.