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 (β–amyloid 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.