Healthcare challenges and sanitary threats: biosimulation might help

In our central nervous system disorders themed month, Dr. Serge Bischoff and Prof. Michel Baudry explore the healthcare challenges associated with CNS disorders and query whether biosimluation could aid in drug discovery in this space.

'Alzheimer's disease affects around 26 million people across the world and, in 2010 alone, cost $604 billion to treat. The number of sufferers is expected to triple by 2050 as populations age' (Reuters, April 7th, 2011).

Alzheimer's disease is one of the most threatening neurodegenerative diseases today. While it involves multiple stakeholders, such as drug producers, research scientists, caregivers, governmental organizations / institutions, and politicians, those who suffer most are the patients and their caregivers. This situation rings clear-cut alarm bells, leading us to create a company that would provide some concrete answers and solutions to these challenges.

Anticipate the challenges: more patients, higher healthcare costs and very few treatments

The fast progression of the number of patients affected by neurodegenerative diseases, such as Alzheimer's and Parkinson's, often associated with mood or mental disorders appears ineluctable. A major aggravating or precipitating factor is the aging of the population, not necessarily because brain aging leads to these diseases, but maybe also because humans and their brains are exposed over a longer period of time to neurotoxic agents. In particular, a consensus is emerging about a cause-effect relationship between exposure to some pesticides and incidence of Parkinson's disease.

"Alzheimer's disease is one of the most threatening neurodegenerative diseases today"

In addition to these diseases affecting large patient populations, more and more rare diseases are being discovered thanks to the development of novel genetic, genomic and proteomic technologies. Although relatively limited numbers of patients are affected, these are still very numerous (25 million Americans, for example). As a consequence, the costs of these diseases to society are exploding. As an example, according to the European Brain Council, 'the total European 2010 costs of brain disorders was €798 billion' (Olesen et al., 2012). And even if it is possible that new medications and treatments may relieve the patients from disabling symptoms, and possibly cure the diseases, there is, unfortunately, little hope that the exponential increase in healthcare costs will slow down in the next 10–15 years.

A major reason for cost escalation is a surprisingly high rate of failures, especially in the area of Alzheimer's disease (Carroll, 2012). It is so high, that there is little hope of cure for the next few years. Thus, 'through all the twists and turns of Alzheimer's theorizing over the past three decades, one stark fact has remained constant: Drugs that aim to stop the disease process have always failed in large-scale clinical trials' (Schnabel, 2013). This backdrop makes the healthcare challenges even tougher as major stakeholders are giving up.

Disengagement of main stakeholders?

The trend is alarming for two of the main stakeholders, the drug makers and the investors. The main reason that pushes them out of this field is always the same: the ROI (return on investment) – too risky, too expensive, and too long.

If the real costs of R&D are taken into consideration, and especially the failures, the numbers are staggering, ranging from $1 to $4 billion and possibly even higher (Forbes). Consequently many major pharmaceutical players are reducing their activities in the CNS field (Miller, 2010), and even more so in specific areas, such as Alzheimer's disease. "I think we have to do a lot more basic science work to understand what's going on," C. Viehbacher (CEO of Sanofi) said in an interview at an industry event in San Diego. "We really, at best, partially understand the cause of the disease. It's hard to come up with meaningful targets."(Bloomberg). At the investor end, there are also signs of moving away from diseases like Alzheimer's. The consequences will be dramatic, and may leave societies and governments to solve the major problems.

Need for new approaches, new tools, and new technologies

'Innumerable complexities and obstacles' may account for the high rate of failures. Recent studies also raised the question of the reproducibility of published scientific results (Vasilevski et al., 2013). Tackling the complexity of CNS functions and the multifactorial nature of brain diseases needs more appropriate approaches.

"...the total European 2010 costs of brain disorders was €798 billion"

Modeling and simulation (M&S), also known as 'biosimulation' represent an innovative, and perhaps inescapable way to utilize the systems biology concepts. It takes advantage of the huge amount of experimental data available, and incorporates all the advances in mathematics and computer sciences. By using mechanistic, dynamic and multiple-scale simulators, and taking into consideration the complex biological mechanisms underlying pathological processes, it is now possible to develop new drugs. M&S can identify new molecular targets, test their validity under pathological conditions, and perform the trial-and-fail approach on the computer before spending a lot of time with in vitro or in vivo animal testing.

The recent announcement of a simulator for epilepsy, which was validated experimentally, opens a new path for more efficient, cost-effective, and faster drug discovery processes. Although at an early stage, M&S might become the approach of choice for addressing major healthcare challenges in neurodegenerative disease, not only to make the drug discovery process faster, better and cheaper, but also to discover new drugs or reposition abandoned ones as we were able to do with a drug candidates to treat the rare Huntington's disease.

Conclusions: solutions can now also come from policy makers

The ball is now in the court of policy makers, not just drug producers or academic researchers. The drift towards disengagement from the larger pharmaceutical companies actually represents an opportunity for hundreds of biotechnology SME's.

At the recently held European Assembly of SMEs (Vilnius, Lithuania, November 25-26th, 2013), SMEs were identified as a priority by the European Commission. Because healthcare solutions may come from SME's, it is mandatory for policy makers to come up with measures facilitating their access to the most appropriate financing.

References

• Armstrong D., 2013, Sanofi Won't Chase Alzheimer's Therapies, Viehbacher Says. Bloomberg, April 15th, 2013 http://www.bloomberg.com/news/2013-04-15/sanofi-won-t-chase-alzheimer-s-therapies-viehbacher-says.html

• Carroll J., 2012, The Top Phase III Disasters of 2012, Fierce Biotech , http://www.fiercebiotech.com/special-report/top-phase-iii-disasters-2012/2012-10-02

• Herper M., 2012, The Truly Staggering Cost Of Inventing New Drugs, Forbes February 10, 2012 http://www.forbes.com/sites/matthewherper/2012/02/10/the-truly-staggering-cost-of-inventing-new-drugs/

• Miller G, 2010, Is Pharma running out of brain ideas? Recent cutbacks raise concerns about the future of drug development for nervous system disorders. Science 239:502-504

• Olesen et al., 2012, The economic costs of brain diseases in Europe. European J. Neurology 19:155-162.

• Schnabel J., 2013, Why Do All the Large Alzheimer's Drug Trials Fail? The Dana Farber Foundation. http://www.dana.org/news/features/detail.aspx?id=44202

• Vasilevski et al., 2013, On the reproducibility of science: unique identification of research resources in the biomedical literature. PeerJ 1:e148; DOI 10.7717/peerj.148

About the authors:

Dr. Serge Bischoff

Serge Bischoff, PhD, President and CEO, co-founded in 2007 Rhenovia Pharma (www.rhenovia.com ), a word leading biotech company in biosimulation providing services to optimize the drug discovery process of pharma and biotech companies. After having spent 5 years at INSERM in Paris, where he completed his PhD thesis in neurobiology, Serge Bischoff moved to the big pharmaceutical industry. He was a research scientist at Synthelabo-Sanofi in Bagneux for 5 years before spending 24 years at Ciba and Novartis in Basel, Switzerland, where he occupied managerial functions as Head of Drug Discovery Programs in psychiatric and neurodegenerative diseases.

Prof. Michel Baudry

Michel Baudry graduated from Ecole Polytechnique in Paris (France) in 1971 and is currently Professor of Biomedical Sciences and Dean of the Graduate College of Biomedical Sciences at Western University of Health Sciences in Pomona, CA. His previous position was Professor of Neurobiology at the University of Southern California in Los Angeles, CA. Baudry is a world-known neuroscientist and has published over 350 manuscripts in peer-reviewed journals. In 2007, he co-founded Rhenovia Pharma, where he is acting Chief Scientific Officer.

Closing thought: Can biosimulation help the healthcare challenges associated with drug discovery for CNS disorders?