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 The recently published draft guidance (see pdf here and Webinar here) invited comment and that is exactly what it got.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.