The prevalence of true "age-dependent" diseases is on the rise, due in large part to game-changing successes in modern medicine whereby previous major killers such as heart disease and certain cancers are largely survivable, today. A major outcome of such success is that we are an increasingly aging population, and inevitably, the reduction in deaths due to maladies generally associated with middle age means that we are experiencing an avalanche in the occurrence of those directly related to old age.
We are of course talking about CNS diseases, and hardly a week goes by in the news media without hearing something about cognitive decline, dementia, Alzheimer's disease or Parkinson's disease. Alzheimer's disease in particular is a very feared diagnosis which has been "spreading" explosively in the aging population - it is estimated that some 15 million people globally are afflicted - with that number predicted to rise to a massive 75 million by 2030. Houston, we have a problem!
Notwithstanding the amount of research that has gone into better understanding this devastating condition, one of the confounding aspects of developing better drugs (or in this case, any drugs that work) for Alzheimer's disease is defining a unifying mechanism underlying it's onset and progression. While we have heard much bout beta-amyloid plaques in the brains of patients suffering from the disease, as a causative phenomenon, to date any clinical trials targeting such plaques have been disappointing to say the least.
The non-baptists (beta-amyloid peptide) certainly got more attention due to the lack of any convincing proof that amyloid plaques cause the disease, but their favourite target, tau, and hyperphosphorylated tau-containing neurofibrillary tangles, has been equally problematic. Tau was eventually shown to be downstream of amyloid plaque and in fact it has been suggested that tau (and even plaque) may be a protective mechanism arising due to the brain injury underlying the disease.
After years of hearing nothing but depressing news on the subject, it was rather shocking recently to actually hear something very positive-sounding indeed, from none other than Biogen Idec. While I think we all believe that it is too much of a medical challenge to successfully treat patients in later stages of this brain-destroying disease, the hope remains that with better and earlier diagnosis, we can get to patients earlier and slow or prevent the progression of the disease, in a disease-modifying fashion - that is the holy grail for an Alzheimer's therapeutic.
Thus the announcement from Biogen that they had slowed cognitive decline in a small study of early or mild cases of Alzheimer's disease was striking - apparently in a small group of less than 200 people, Biogen's aducumab not only significantly slowed cognitive decline (a read-out directly associated with the disease) but did so in correlation with reduction in the levels of plaque in their brains! This is tremendously exciting not only because the end result is precisely what physicians and drugmakers have been desperately asking and searching for, but also because it may have finally underlined the causative role of brain plaque in the disease.
If brain degeneration is the result of plaque buildup and we can loosen and remove that plaque, then we can slow the degeneration and treat the disease. Although other major players such as Pfizer and Eli Lilly (among other) have failed to achieve this small but hugely significant success, Biogen may have gotten ahead by very carefully confirming the actual presence of the disease, and eliminating patients suffering from other forms of dementia who previously would have been diagnosed with Alzheimer's and included in clinical trial groups. Study design may be the key factor that has allowed Biogen to separate themselves from the pack.
If brain degeneration is the result of plaque buildup and we can loosen and remove that plaque, then we can slow the degeneration and treat the disease. Although other major players such as Pfizer and Eli Lilly (among other) have failed to achieve this small but hugely significant success, Biogen may have gotten ahead by very carefully confirming the actual presence of the disease, and eliminating patients suffering from other forms of dementia who previously would have been diagnosed with Alzheimer's and included in clinical trial groups. Study design may be the key factor that has allowed Biogen to separate themselves from the pack.
On the back of this extremely hopeful news, another much smaller outfit saw enormous advantage for them and weren't shy about saying it. Martin Tolar, formerly head of Pfizer's Alzheimer's disease group and current CEO of Framingham-based Alzheon, is using the Biogen data as formal proof of the amyloid hypothesis, while provocatively claiming that Alzheon is way ahead of even Biogen.
The reason? Well, Alzheon not only have an oral plaque-busting pill, as opposed to Biogen's injected biologic, but further, Alzheon are working on a molecule which has seen some very serious Phase III testing by a Canadian company, no less. The drug, tramiprosate, was yet another candidate that got buried in the Phasee III graveyard of Alzheimer's clinical trials, but Tolar points out that he knows what was wrong with it and the reformulated version of it is the real deal - he also has a dataset more than 10-fold larger than Biogen's that he can draw on, thanks to the trials sponsored by Neurochem (now Bellus Health) of Montreal.
There is a lot at stake here, and not only for the healthcare system which could be bankrupted in decades by caring for patients in the absence of any disease-modifying treatment. The fact that Biogen's market cap jumped by a massive $10B in one recent day and has increased 5-fold in five years emphasizes the aniticipated income if they get there in the end - that fiscal excitement arose in large part via the confidence evident in their move to bypass Phase II trials completely and to enter Phase III trials later this year.
It's estimated that Biogen should get to market by 2020, but Alzheon say they can get there by 2018 given that their molecule has already been in Phase III and is considered extremely safe for human use. Two years earlier is huge in the Alzheimer's market, and will not only rake in billions of dollars, but if Alzheon's pill works then it could have a serious impact on market entry of Biogen's biologic.
Unquestionably, if Alzheon can get to market, it will serve as a form of vindication for the discoverers of the drug here in Montreal, but it would be somewhat of a bitter pill to swallow at the same time. The benefit to mankind would be huge, and that's a massive payoff in an of itself, but I dare say the original investors in Neurochem/Bellus would turn in their graves in the Azlheimer's clinical trial cemetry, at the mere thought of others making billions annually from a discovery they funded. Such is life in the high stakes high risk venture of drug development in the CNS segment - the few, the proud, the brave!
[Shortly after the news from Biogen, the Mayo clinic came out with new data from the tauist side of the pews, claiming that it is tau that is most clearly associated with cognitive decline and memory loss, and it drives disease progression, not amyloid - from a study of over 3,000 post-mortem brains. It looks like the baptist versus tauist argument rages on!]
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