Special Reports

The Neural Frontier

Alzheimer's R&D challenge
By Robert McTiernan

China's ageing demographic profile, uniquely heightened by years of one-child policy, means that Alzheimer's disease (AD), as with all disease of old age, represents an epidemic-sized prospect for the country. With 5.7 million sufferers (2010) China's AD population is already the world's largest.1 Meanwhile, a disease that has traditionally been quietly dealt with in the community may not be so easy to ignore in a modern China where the informal care network has been critically undermined by internal migration and societal changes. The initiation of the BRAIN Initiative – a global, government-driven collaboration that aims to make genuine progress in addressing the inner workings of the brain – reflects concerns at the lack of progress in an area of medicine that has turned into a graveyard for pharmaceutical companies' drug development efforts over the last 20 years. Characterized as carrying a greater potential global economic burden – albeit often hidden within the informal care sector – than that of cancer, heart disease and stroke combined 2, unpicking the workings of this difficult, devastating and unglamorous chronic disease is set to become the focus of concerted efforts.

Un-tangling AD
Alois Alzheimer first identified what remain AD's key defining characteristics during a 1906 brain autopsy: the extracellular beta-amyloid plaques and intracellular neurofibrillary tau-protein-based tangles. Amyloid beta is a by-product from the larger amyloid precursor protein (APP), released during metabolizing by two enzymes: gamma-secretase and beta-secretase (BACE). Irregularities in the cleaving of amyloid beta from APP leads to misfolded proteins that form the plaque clusters that are toxic to the brain's neurons, and are also the vehicle for the disease's spread around the brain – a process of virus-like neuronal degeneration that has been likened to prion diseases such as mad cow's disease or Creutzfeld-Jacob disease. The tau tangles, meanwhile, are comprised of abnormally configured, excessively phosphorylated microtubule binding tau protein.

There have been significant leaps in our understanding of AD over the last 20 years, but a full picture of the underlying causes of AD and the role played by plaques and tangles will take some years of research. It is now known that while beta amyloid build-up in the brain reflect AD, levels of the protein also decrease in the spinal fluid, detectable up to 25 years before first symptoms. Tau levels are also seen to rise in the spinal fluid, up to 15 years before AD sets in, while irregular glucose patterns in the brain are evident up to 10 years before the first disease symptoms. These advances are gradually allowing more nuanced diagnoses of AD and identification of pre-dementia and preclinical asymptomatic stages of the disease – although reliably predicting who will contract AD on the basis of these biomarkers is a work in progress.

China's AD treatment reality
For Chinese patients and physicians, there remains an ongoing stigma attached to AD, in part a reflection of the Chinese term for the disease, which is based on two characters meaning 'insane' and 'idiotic'. This idiosyncracy has been the focus of concerted attempts to have the disease officially renamed. In the most recent effort to introduce a less demeaning lexicographic label, a group of psychiatrists authored an opinion piece in the June 2014 'International Psychogeriatrics' journal, calling for a name change so as to avoid "therapeutic nihilism" and patient unwillingness to seek diagnosis/treatment.3 There remains a clear potential for MNCs to work to build physician and patient understanding of the disease – although treatment guidelines have now been published, official recognition of the disease in the form of a clinical pathway for AD has not been forthcoming. A clinical trial initiated in 2012, co-sponsored by Novartis, sought to map out a path to establishing such a pathway, with poor physician adherence to the existing treatment guidelines blamed for low rates of both diagnosis and anti-dementia drug prescribing in China.

The treatment paradigms currently available offer an imperfect form of palliative care at best, with nothing able to either halt or slow the disease. The latest U.S. FDA-approved treatments are all available in China: acetylcholinesterase inhibitors (AChEIs) such as Eisai's Aricept (donepezil), which produce mainly cognitive symptomatic and weak disease-modifying effects, are indicated for use in the mild and middle stages of AD. Lundbeck's Ebixa (memantine), a non-competitive N-metil-D-aspartate (NMDA) receptor antagonist, is indicated for the middle and severe stages, and can be used in combination with AChEIs. Alongside these, nootropics (memory-enhancing drugs) may be prescribed, as well as antidepressants and antipsychotics to alleviate AD-related behavioral problems.

Affordability concerns and existing treatments' side-effects profile and patchy reimbursement mean that tradtional Chinese medicine (TCM)-based treatments are a strong alternative choice in China. Ginkgo biloba extract is at the top of the treatment market for all-cause dementia – the TCM has been shown in studies to improve mental ability and memory. Along with Panax ginseng, Ginkgo biloba is commonly prescribed to perform the same role as a nootropic. Huperzine A is another treatment option – the alkaloid medicine, derived from the Huperzia serrate plant, is reported to have higher AChEI potency than galanthamine, and to also act as an NMDA antagonist – although clinical data to back these claims are relatively scarce.

Despite the competition from traditional remedies, MNCs' sales of Alzheimer's products in China are not insignificant: according to Eisai's financial report, Aricept earned revenues of RMB 234 million (USD 38 million) in China during 2013, with growth at 44% YOY. Ebixa's performance has also been eye-catching, Lundbeck reporting that China sales picked up 131% YOY during 2013 (although revenue figures were not disclosed), even though the drug has been on the market since 2006 and reimbursed since 2009. The Danish firm claims Ebixa is now used in around one-third of AD patients in the country.

Floundering on beta-amyloid rocks
That Alzheimer's is proving a difficult candidate for drug development is an understatement – 99.6% of AD-related clinical trials held in the U.S. over 2002-12 either failed or were discontinued; during that time, of 244 compounds assessed by the U.S. FDA, a grand total of one was approved for marketing – memantine in 2003.4 Development efforts have focused for the last 20 years on development of active and passive immunotherapies that remove amyloid beta from the brain and/or block its production, based on the (still unproven) amyloid cascade hypothesis that amyloid plaques trigger the whole cascade of events that culminates in AD. This target has produced some of Big Pharma's most high-profile and expensive Phase III failures of recent years. Eli Lilly has perhaps suffered most, having run the full gamut of gamma-secretase inhibitor (semagacestat), BACE inhibitor (LY2886721), and antibody (solanezumab) and coming out empty-handed – albeit there is hope for solanezumab in earlier stages of the disease. Pfizer and Johnson & Johnson (J&J)'s development of the passive immunotherapy bapineuzumab also crashed expensively at the Phase III stage in 2012.

The gamma-secretase and BACE enzymes responsible for cleaving the amyloid beta from APP represent no easy targets – gamma secretase has a role to play in processing the Notch protein, for example, a developmental signaling protein/pathway best avoided, as perturbations of the pathway have resulted in poor clinical outcomes. The pro-amyloid cascade lobby would argue there remains potential for development of more closely targeted molecules. However, there is no clear consensus on the veracity of the amyloid cascade theory itself, one study pointing out the essential role played by amyloid beta in regulating information transfer through the nerve cell networks in the brain, and questioning whether targeting the protein is in fact entirely counter-productive to brain functioning.5

While those not already up to their necks in AD are likely to sit on their hands until more is known about the underlying disease functions, a number of potential avenues continue to be explored, including targets such as cognition-related neurotransmitters, neuroprotection, cholesterol and energy homeostasis, or second messenger modulation. There is also a swelling wave of activity focused on the tau protein. Singapore-based firm TauRx is at the forefront of this, and is among the few firms actively testing a late-stage candidate of any kind currently, with a global Phase III study of tau aggregate inhibitor LMTX – a novel chemical form of methylene blue. Roche is also looking to get in on the tau act – signing a second licensing agreement with AC Immune for development of a multiple tau-targeting candidate, following a deal with the same firm on anti-amyloid crenezumab.

China-based R&D
China has been and remains an important testing ground for many of these candidates, including failed efforts from Pfizer with antihistamine Dimebon (latrepirdine) and Lilly with semagacestat, as well as TauRx's ongoing Phase III (see Table 3). There have also been some successes in terms of China's homegrown R&D: in June this year, U.S.-based Inovio Pharmaceuticals picked up development rights to an amyloid-targeting vaccine against senile dementia developed by Shanghai's Fudan University that it is hoped avoids the brain inflammation side-effects caused by comparable efforts. In March, meanwhile, researchers at Shanghai's Jiaotong University revealed progress on development of nanoparticles that are able to breach the blood-brain barrier before acting like high-density lipoproteins in binding and removing amyloid beta – albeit performed successfully only in mice.

For a first-hand account of the state of AD R&D in China currently, GBI this month had the privilege of speaking to one of China's leading AD researchers, Dr. Wang Jianzhi, Professor and Director of Pathophysiology at the Key Laboratory of Chinese Education Ministry within Tongji Medical College, affiliated to Wuhan's Huazhong University of Science and Technology. Dr. Wang is a confirmed "Tau-ist", with over 20 years of experience carrying out research into the tau protein. Her team's most recent paper considers the neuroprotective and neurodegenerative effects of tau hyperphosphorylation – with proper manipulation of the tau holding promise for arresting neurodegeneration in AD.6

Wang notes the paucity of government backing for AD research. While support for basic research is made available through the Natural Science Foundation of China (NSFC), "Funding for drug R&D is mainly from the Ministry of Science and Technology (MOST), specifically the 863 Project, which supports translational and development research. However, […] when they give you this support, they generally want to see a product, a drug, a treatment immediately". The lack of clear drug targets has meant that funding support for AD has been limited in China to date.

The difficulties inherent in exploring neurodegenerative diseases in the body's most inaccessible organ, weighed against the demands of drug development are underlined: "Alzheimer's disease is a very difficult, multi-factorial and chronic disease. Unlike a disease like cancer, the major symptom is loss of memory meaning that diagnosis is still a relatively subjective process. This represents a major problem for development and evaluation of drugs. The lack of very definite biomarker targets means AD research has been neglected for some time, both by government and the pharma industry".

The BRAIN Initiative
Dr. Wang views China's entry into the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, announced in June this year, as a strong positive in terms of building AD R&D's profile and funding momentum in the country. Originally launched in April 2013, the U.S.-EU BRAIN Initiative has been compared with the Human Genome Project as a strongly government/NIH backed global R&D collaboration with a target of mapping the activity of every neuron in the human brain. The U.S. government alone has promised at least USD 300 million annually to the program for the next ten years.

At the same time as the BRAIN project would be principally aimed at exploring brain imaging techniques, Dr. Wang warns of the necessity of combining these techniques with understanding of molecular markers and clinical behaviors: "Non-invasive brain imaging techniques are important, and allow us to explore the normal functioning of the brain compared with how the diseased brain operates. However, this must be combined with knowledge of molecular markers and the clinical symptoms. […] We need to find the specific factors behind the amyloid and tau pathology [that has] shown up in autopsy – the amyloid pathology is already well-defined in terms of gene mutation, but the whole AD development process needs to be explored". It is to be hoped that long-term projects like the BRAIN Initiative allow this kind of research to progress.

TCMs: herbal cures
Dr. Wang's team at Tongji Medical School view neurodegeneration generally as a specific type of chronic cell death which differs from apoptosis or necrosis, with an urgent need for development of new specific biomarkers – a process that will require patient and "very close collaboration between basic researchers, clinical neurologists and the pharmaceutical companies" to achieve. Industry collaboration is something that the Tongji team would welcome, and discussions to this end have been held with some prestigious pharmaceutical companies.

The chronic nature of AD means that Traditional Chinese medicines (TCMs) may offer a promising research avenue. Dr. Wang underlines the need to establish the right setting for this kind of research, which would require TCM practitioners boasting of achieving good results with a particular herbal formula. "If we can find the experienced TCM doctors, we have a very good team for basic research, we have established a lot of methods, cell lines and animal models for AD, with over 20 years' experience. If there is a specific company involved in this kind of research, if they can connect these three parts together, this would provide a more optimistic setting for drug development".

Hope for the future
That AD has the feel of an elephants' graveyard in terms of drug R&D at present is undeniable: the failures reflect the impatience for development in the context of one of the least understood and defined diseases in the world currently. The promise of being the first to provide a meaningful treatment for a disease that would mean a USD 5 billion to USD 10 billion a year pot at the end of the rainbow has been a sirens' song to drug developers, who have at times been guilty of ignoring warning signs that would otherwise be heeded.

Far from being a lost cause, however, the necessity of facing a global epidemic – with disease numbers forecast to quadruple by 2050, and Asia to account for 59% of that burden – makes AD a word-leading health threat.7 The scale of AD means that any progress in delaying the disease's progression would produce billions of dollars-worth of health savings globally. Breaking through one of the final frontiers in medicine through globally coordinated efforts to understand the inner-workings of the brain offers hope that the AD puzzle can eventually be pieced together, and provide a more patient momentum behind R&D efforts.

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