The cemetery of "unicorns"
Why investments in the fight against Alzheimer's disease so often burn out
Vladislav Rakhmanov, vc.ru
Yuri Deigin, Vice President of the Science for Life Extension Foundation, spoke about what is happening in the Alzheimer's market and why companies fail time after time.
According to the latest data from the World Health Organization (WHO), dementia and its most common type – Alzheimer's disease – ranked seventh among the top ten causes of death of people around the world. Over the past 15 years, the death rate from dementia has more than doubled, and now it claims more human lives than HIV and AIDS, which occupied the same line in 2000.
If other leaders of this gloomy rating, like cardiovascular diseases or cancer, medicine has somehow learned to prevent or put into remission, then the situation with dementia is much more deplorable, and as humanity steadily ages, it will only worsen.
Healthcare organizations around the world understand this, sound the alarm and give scientists billions of dollars in grants for research on Alzheimer's disease. In 2017, the National Institutes of Health (NIH) will allocate $1.39 billion for these purposes (which is 40% – $400 million – more than in previous years).
The ringing of the alarm is also heard by private investors, and for them it is given by the ringing of coins: they understand that drugs against this disease will be in great demand, and the remedy that will demonstrate at least minimal effectiveness will become a blockbuster with billion–dollar sales, and the company that created it will be a real "unicorn".
It is not surprising that many companies around the world – from small startups to large corporations – have got involved in this race and are trying to find, if not a cure, then at least an effective means of preventing this epidemic of the future. However, so far all the most promising projects have failed, and the Alzheimer's market is more like a cemetery of these "unicorns".
What is the reason
Cognitive abilities begin to gradually decline, and the brain begins to atrophy long before the development of a condition that could be assigned a clinical diagnosis of dementia: every ten years of life, starting at the age of 25, the volume of brain matter decreases by 5%, memory gradually deteriorates, mathematical abilities and some other cognitive functions decrease. As a result, a fairly significant percentage of older people suffer from acquired dementia.
Alzheimer's disease, during which brain neurons die, accounts for about 70% of all cases of clinical dementia. The main difficulty in dealing with it is that there is still no complete understanding of its causes.
The most common and successful approach to the treatment of this disease from the point of view of commercialization is associated with the elimination of the lack of the neurotransmitter acetylcholine in the brain, which is observed in patients. However, studies have shown that if such drugs slow down the development of the disease, it is only slightly, so they owe their popularity not to efficiency, but rather to safety. Today it is almost the only class of substances allowed for sale.
The second is memantine, an NMDA antagonist that has a nootropic and vasodilating effect, as well as stimulates the nervous system, prevents brain hypoxia and subsequent death of its cells. But it also gives only a short-term effect and does not help to slow down the disease, let alone cure it.
All these drugs "work" mainly due to the placebo effect – that is, they give hope to the patients themselves and their relatives. So the search continues.
Main targets
Now scientists are targeting several main "targets". First of all, it was noticed that amyloid plaques (from beta-amyloid peptide) and neurofibrillary tangles (from tau protein) accumulate in the brain tissues of patients. And most of the researchers are focused on combating these manifestations of the disease in the hope that they may be the cause of its occurrence.
Another target is inflammatory processes in the brain, which can be caused by hyperactive immune cells of the brain, microglia. On the one hand, these cells may try to protect the brain from amyloid plaques and neurofibrillary tangles, but on the other hand, their excessive diligence may be a "disservice" to the aging brain, since neurons also die in this war.
Another approach is related to the study of the genetic prerequisites for the development of Alzheimer's disease. It was found that one of the three alleles of the apolipoprotein E gene repeatedly increases the risk of dementia: one copy of this allele increases the risk by 3-4 times, and two – by 8-12 times. However, the disease also develops in a large number of people whose genes do not have this allele, and it is completely unclear what can be done at all to help people with these alleles, so for now this approach is on the periphery of the struggle.
Most vaccines directed against the main target, beta–amyloid, have failed clinical trials. There is less and less hope that some of the remaining ones will reach the goal, and even investors are not surprised by the next setbacks.
Loud failures
The most high-profile failure of recent times is associated with Merck, which stopped clinical trials of its drug because it was desperate to get a positive effect. Shortly before Merck, other pharmaceutical industry giants reported on the failures: Pfizer, Johnson & Johnson and Elan Pharmaceuticals.
All of them fought against beta-amyloid as part of the most popular approach today. Their failures were another blow to the positions of supporters of the "amyloid" hypothesis as the main target to be hit in the fight against Alzheimer's.
Previously, they were shaken by meningoencephalitis (brain inflammation), which occurred in 6% of patients during studies of one of the anti-amyloid vaccines, and subsequent analysis, which showed that even in those patients in whom the vaccine successfully cleared the brain of amyloid plaques, this did not lead to noticeable cognitive improvements.
A few years earlier, another promising drug, Dimebone, developed in the Soviet Union, also failed. Initially, it was positioned as an anti-allergenic agent, but unexpectedly showed its effectiveness in the fight against Alzheimer's disease.
American investors became interested in him, who created the Medivation company specifically for his clinical research. The drug passed the first two "rounds" with brilliance: it not only slowed down the process of developing the disease, but also turned it around. The company's shares jumped against this background, then the pharmaceutical giant Pfizer bought the rights to the drug for $ 225 million, guaranteeing payment of another $ 500 million if the drug successfully enters the market.
Everyone was looking forward to the results of the final tests, but the effectiveness of the drug was not confirmed in them, and twice – first in 2010, and then in 2012. In 2011, the third phase of Dimebone against Huntington's disease, a genetic neurodegenerative disease known to many fans of the TV series "Doctor House", also failed.
Big Pharma's Plans
"Big Pharma" does not give up: research continues. In 2019, Merck plans to complete clinical trials of its drug and test its effectiveness in the earlier stages of Alzheimer's disease.
Eli Lilly and AstraZeneca are testing a similar drug – the companies plan to report on the results achieved in August. Roche and Biogen are also conducting research – they also do not give up trying to defeat beta-amyloid.
In addition, against the background of failures with beta-amyloid, studies of tau protein, which may also be one of the key drivers of the disease, are attracting increasing attention. At the end of last year, encouraging results of the first phase of trials of a vaccine directed against tau protein were published: according to the researchers, 29 out of 30 patients had a favorable immune response without any serious side effects.
The hope remains that some of the drugs may work. However, it is rather weak, considering the statistics of failures. So, in the period from 2002 to 2012, only one of 244 candidates for a drug for Alzheimer's disease received FDA approval and joined the ranks of acetylcholinesterase inhibitors – safe, but ineffective.
At the same time, the "price of dementia" continues to grow: the costs associated with it in one way or another amounted to $818 billion in 2015 (approximately 1.09% of global GDP), and by 2018 this figure will reach a trillion US dollars.
Alternative approach
Years of failures and burned-out investments in the fight against Alzheimer's disease make us think that perhaps a completely different approach to its prevention is needed.
Michael Fossel, professor of clinical medicine at the University of Michigan and head of Telocyte, believes that the reason for the defeats in the battle with Alzheimer's disease is that researchers are struggling with individual symptoms of the disease, and not with its root cause – cell aging, which causes both the gradual accumulation of the ill-fated beta-amyloid and the loss of neurons characteristic of the disease Alzheimer's.
His team relies on gene therapy using telomerase, a special enzyme that, according to Fossell, can affect one of the main biological processes of aging – shortening of telomeres (areas at the ends of chromosomes).
This enzyme allows you to "complete" short telomeres and thereby rejuvenate cells. According to Fossel, it is gene therapy that will finally defeat Alzheimer's disease.
Fossel is not alone in his view of the aging of the body as the root cause of all diseases that we call age–dependent - the risk of getting sick with them increases exponentially with age. At some point, the human body ceases to cope with pathogenetic processes, and a person either gets cancer, or he has cardiovascular diseases, or Alzheimer's disease.
Despite the fact that at the official level, WHO does not yet recognize aging as a disease, more and more research organizations are turning to the study of this process. These are the California Salk Institute and the Buck Institute for Aging Research, and the American scientific grant agency National Institutes of Health, a division of which – the National Institute on Aging – is engaged in funding research on age-dependent diseases and aging itself.
There are already encouraging results of experiments on mice to slow down the central aging program – the epigenetic "clock". They were rolled back with the help of "Yamanaka factors", for which the scientist Shinya Yamanaka received the Nobel Prize, and thus were able to prolong the life of rapidly aging mice by at least 33%, and even by 50% compared to one of the three control groups. By the way, other researchers have shown that Yamanaki factors also lengthen telomeres.
Learning to return the body to a younger state, in which the functioning and repair systems are at a higher level, is the main goal of specialists who deal with aging problems.
Success in this field will make it possible to fight for a healthy and long human life not only symptomatically, infinitely eliminating individual diseases, which are becoming more and more with age, but also to cope with their root cause – aging – and therefore with Alzheimer's disease.
I think that this approach has the greatest potential to give investors new "unicorns". After all, aging therapy with proven effectiveness will be sold for hundreds of billions of dollars – the pharmaceutical market has not seen such a "blockbuster" yet.
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29.06.2017