Btobioinnovation.com
Author: Jean-Claude Muller, 穆卓Executive Editor at BtoBioInnovation, jcm@btobioinnovation.com
Editor’s Note
In June of this Year we have announced the cessation of the weekly editing of the Biopharmaceutical Newsletter but you can still find valuable and updated information on your website: www.btobioinnovation.com under the News heading.
You will find herewith a slightly extended version of a commentary published in the November-December issue of MedNous: www.mednous.com.
Bill Gates invests into Alzheimer’s disease
To date, the only thing that can be said about experimental treatments for Alzheimer’s disease is that nothing works. None of biological hypotheses about the disease have produced drugs that give a convincing benefit to patients in controlled clinical trials. In fact, quite the opposite. Trials of some of the most promising agents continue to fail in early or late clinical settings. For years, scientists have explored various targets associated with the disease ranging from acetylcholine esterase, glutamate, nicotinic and NMDA (N-methyl D-aspartate) receptors, cyclooxygenase-1 and 2 (COX-1 and COX-2) and Monoamine Oxidase (MAO) inhibitors to beta amyloid, tau and beta secretase (BACE). Yet the relevance of these numerous targets may not be the sole issue. Different approaches including non-therapeutic ones, new thinking and strong leadership are also needed.
This leadership has now come to the fore with a commitment by the Microsoft founder and philanthropist Bill Gates to contribute directly to Alzheimer’s disease research. On 13 November, Mr. Gates announced plans to donate $50 million of his own money to the Dementia Discovery Fund (DDF), a public-private partnership organised by the pharmaceutical industry, the UK Department of Health and the charity Alzheimer’s Research UK. The fund is managed by SV Health Managers, an investment group with offices in London, UK and Boston, Massachusetts, US.
Mr Gates said progress needs to be made in five areas:
(1) understanding the disease better, particularly its early stages;
(2) detecting and diagnosing clinical signs of the disease better;
(3) broadening the range of disease targets to include more than just beta amyloid and tau, the current “mainstream” of drug development;
(4) lowering barriers for the recruitment of patients into clinical trials;
(5) making better use of data from patients’ health records.
None of Mr Gates’ proposals are entirely new and his $50 million investment is small compared with the billions already sunk by the biopharmaceutical industry and academic institutions into Alzheimer’s disease clinical research over the past 20 years. Nevertheless his personal commitment will give traction to new research effort and possibly unlock some heretofore unsolved and collateral problems.
One of the unsolved problems is how the entire network and pathways of targets involved in the appearance and the progression of Alzheimer’s disease actually works. For example, we still do not understand the sequence of events that take place in early stages of the disease. But progress is being made by several teams of scientists in Canada, France, the UK and the US who have performed integrated analyses of many genes involved in the disease. They have discovered several pathways including new unknown gene interactions and new anti-inflammatory genes. This recent research supports some already existing findings indicating that microglial functions can become dysfunctional in Alzheimer’s. This has now led to new proposals, namely to tackle Alzheimer’s and other neurodegenerative diseases with local or systemic immunotherapy. For instance, Professor Beka Solomon, at the University of Tel Aviv in Israel, has suggested several years ago, that there might be a viral component to the disease. Proclara Biosciences (formerly NeuroPhage Pharmaceuticals) is currently testing this hypothesis in man with NPT088. Rebooting the body’s immune repair mechanisms to address neuro-degeneration is highly reminiscent of the breakthroughs in cancer over the past decade.
To support the identification of accurate biomarkers or biosignatures, predictive of the progression of the disease and easily retrievable from blood or cerebrospinal fluid, researchers need more accurate in vivo imaging technologies. There is also a need to replace the current cognitive tests such as the Alzheimer’s Disease Assessment Scale –Cognitive subscale (ADAS-Cog) and the Cambridge Assessment of Memory and Cognition (CAMCOG) test. These tests are lengthy and the outcomes depend on how a patient feels at the time. Concurrently, family doctors need to be more aware of the signs of early disease such as visuoperceptual disturbances, language difficulties, mild depression, erratic behaviour and a progressive neglect in physical appearance. These weak observable traits often arrive before serious memory deficits occur and can be detected by close friends, relatives and even by colleagues at the workplace when the disease appears early in life. On the basis of data from the 2015 Rotterdam study* on the incidence and risk of dementia, scientists have identified seven risk factors for the disease: diabetes, obesity, physical and mental inactivity, smoking, low educational attainment and diet. On the basis of this study it has been modelled that addressing effectively these factors could lead to a 30% reduction in the incidence of dementia.
In clinical medicine, not enough attention has been paid to characterising early-onset Alzheimer’s disease. Some of the recent Phase 3 clinical failures may not have been due to the treatments themselves, but to their late application when neurodegeneration is far too advanced. Novartis and Amgen have announced an expansion of their ongoing collaboration with the US Banner Alzheimer’s Institute to find out if CNP520, a beta secretase 1 (BACE1) enzyme inhibitor, can prevent or delay the onset of Alzheimer’s disease. The patients selected for the study are cognitively healthy but at a genetic or high risk of the disease. Meanwhile, Paris-based Pharnext is developing a repurposed low dose combination of compounds, called PXT864, which interacts with more than one biological target. The active ingredients are baclofen and acamprosate which together appear to restore the balance between excitatory glutamate activity, inhibitory glycine and the GABA activity pathways. Last month, at the 10th Clinical Trials on Alzheimer’s Disease (CTAD) in Boston, the company reported that “Treatment with PXT864 Showed Stabilisation of Cognitive Disability in Mild Alzheimer’s Disease after 36 Weeks”, This promising approach tackles a new mechanism of action completely outside of the “mainstream” namely beta amyloid and tau.
The pharmaceutical industry and academic institutions have already gathered a huge amount of data on genetic factors as well as on other risk factors for Alzheimer’s, on the biological patterns of the disease and on some unexplained outcomes of failed or non-conclusive clinical trials. But they have not yet made this data available in a common format to bench and data scientists, physicians and care givers. An example of how available data can be analysed is the work of France-based Bio-Modeling Systems. It has published a computer assisted deductive integration (CADI) study about some unusual clinical observations from Alzheimer’s patients. Their conclusion supports the idea that amyloid beta and tau could be unspecific consequences of the disease rather than the main cause.
To expect the positive outcome, claimed at the December 2013 G8 meeting in London, with the ambition that a cure or a disease-modifying therapy should be available by 2025, there is a need to go beyond Mr Gates’ five recommendations.
More flexibility from the regulatory authorities to conduct clinical trials in early stages of the disease with combination therapies of established as well as of investigational drugs, as it is already the case for anti-infective and anti-cancer drugs, will be requested.
Stronger collaboration between several ongoing national and international initiatives, from countries where a growing elderly population is becoming a serious burden on families and healthcare systems, should become mandatory.
To tackle the multifactorial nature of the onset and progression of Alzheimer’s disease there should be strong incentives to attract input and resources from new comers from other innovative sectors, including digital medicine and artificial intelligence.
Challenges are huge, expectations are high, unmet medical need is tremendous all over the globe, but international concerted efforts focused at the heretofore unsolved issues can make a difference.
Let us leave the final words to Mr Gates who said in early November: “This is a frontier where we can dramatically improve human life. It’s a miracle that people are living so much longer, but longer life expectancies alone are not enough…. I believe there is a solution.”
*De Bruin RF, Bos MJ, Portegies ML et al. The potential for primary prevention of dementia accross two decades : the prospective, population-based Rotterdam Study; BMC Med 2015, 13: 132
