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SPOTLIGHTS
Finding the cure in the mind
There is currently no cure for Alzheimer’s disease (AD) and only a handful of approved treatments, with the success rate for approval of new compounds the lowest of any therapeutic area. In this interview with Dr Charles Stacey, we find out what causes the poor success rates, current treatments on the market, and a new type of therapy giving hope to AD patients.

Alzheimer’s disease (AD), the most common form of dementia, is an age-associated, neurodegenerative disease characterised by the progressive decline in memory and language, and pathologically by accumulation of amyloid plaques and neurofibrillary tangles in the brain and progressive regional declines in cerebral glucose metabolism.

Despite significant advances in research and development, AD is one of the largest unmet clinical needs and consequently one of the most important in the pharmaceutical sector. Currently affecting 48.6 million patients around the world, the global Alzheimer’s drugs market was valued at US$3.6 billion in 2017 and is predicted to reach US$5.6 billion by 2024.

Current treatments for AD in the market

There is currently no cure for AD and just a handful of approved treatments, says Dr Charles Stacey, president and CEO of Cerecin. The success rate for approval of new compounds is the lowest of any therapeutic area.

According to Cerecin’s Scientific Advisory Board member Jeff Cummings’ 2014 publication in the journal Alzheimer’s Research Therapy looking at clinical trials in Alzheimer’s disease between 2002 to 2012, the failure rate was 99.6 percent. No new drug has been approved since 2003, when memantine was approved. Whilst the statistics may sound bleak, there have been some positive progress.

Current treatments available in the market include cholinesterase inhibitors and NMDA receptor antagonist. These drugs have been approved by most regulatory authorities worldwide, however most users acknowledge the effects are modest and temporary. Other treatments used but without the same level evidence to support their use, include Vitamin E, Omega-3 fatty acids, coconut oil, generic medium chain triglycerides, Coenzyme Q10, Coral Calcium, Nootropics like Gingko Biloba, Huperzine A, Phosphatidylserine and Tramiprosate.

Poor success rate

Even though there has been some progress with research in understanding AD, the road to developing a cure is less bright. Dr Stacey shares several reasons for this poor success rate.

First, AD remains to this day poorly understood by many researchers in terms of what the earliest changes are and why they occur.

Second, AD is difficult to diagnose prior to subjects developing symptoms and the growing realisation that if treatment is going to be successful in slowing or preventing the condition, the agent needs to be administered in these pre-symptomatic stages.

Third, the bluntness of the instruments we use to measure improvement in cognition may fail to pick up early signals of efficacy.

Fourth, there are difficulties in defining who is likely to respond to treatment.

Fifth, traditional drug development has investigated therapies that can lead to significant toxicity.

Sixth, developing drugs in AD takes many years unlike developing drugs for acute conditions where results can be seen more quickly. This has led to some sense of despondency in the field and cautiousness from investors. Undeniably, the impact on patients and their families is devastating.

New versus conventional approaches

Many pathological processes are observed in Alzheimer’s Disease and therefore many targets are being investigated to address this condition.

One target is a particular brain protein called amyloid-beta. Many theories suggest that AD is linked to a build-up of amyloid-beta in the brain and so conventional approaches in developing AD therapies aim to disrupt the production of this protein. But the results have not been very positive, with no new drugs in the pipeline for more than a decade.

Instead of acting on amyloid-beta, Dr Stacey says Cerecin will focus on the fuel source for the brain. They found out that in the early AD process, certain brain cells become insensitive to glucose, their main source of fuel. When brain cells are unable to access glucose, a series of processes ensue that lead to cell degeneration, as glucose is critically important as a source of fuel to very active brain cells. Cerecin’s approach entails providing an alternative source of fuel in the form of ketone bodies to ‘rescue’ these cells and allow them to function. Ketone bodies have long been known as the body's last resort of stored fuel and they could cross the blood-brain barrier and replenish starved brain cells. The idea is that this restoration would then hold off or even reverse losses in people's cognition.

Dr Stacey said, “We feel that intervening with metabolic therapies that are distinct to the anti-amyloid therapies and anti-tau therapies that other groups are developing will lead to new insights and progress”.

New therapy: Tricaprilin

Cerecin has developed new formulations of tricaprilin, a small molecule structured lipid which has GRAS (Generally Recognised As Safe) status and aims to address the metabolic defect that is known to be characteristic of Alzheimer’s. The drug formulation addresses the issue of deficient glucose metabolism in Alzheimer’s by inducing a mild form of ketosis (generating ketones) for use in neurons. These ketones have the potential to restore the supply of adenosine triphosphate, improving neuronal metabolism, and in turn cognition and function in patients with Alzheimer’s. Tricaprilin is delivered as a powder that is mixed with a liquid and consumed orally.

It is hoped that Tricaprilin will offer the best risk-benefit balance which is important when considering an agent for a chronic disease and particularly one that affects older members of society.

Dr Stacey says Tricaprilin has successfully completed phase 2a and 2b clinical trials, leading to improved cognition in subjects with AD with a particular genotype, known as APOE4 negative.

In February 2017, results of phase 3 study for the AC-1204* formulation of Tricaprilin for the treatment of mild-to-moderate AD was announced. Patients did not demonstrate a statistically significant difference at 26 weeks compared with patients treated with a placebo, although the drug was shown to be safe and highly tolerated amongst patients. Further investigation revealed that the AC-1204 formulation of Tricaprilin did not produce the levels of ketosis required to affect cognition. The results have since lead to the development of more bioavailable formulations of Tricaprilin which produce much higher levels of ketones.

These new formulations are now in clinical trials and will be conducted largely in Asia Pacific, including Singapore, Australia, Korea, and will be led by the Cerecin team in Singapore. Dr Stacey added that there are plans for a global Phase 3 study.

Move to Singapore

Singapore is home to one of the fastest-ageing populations in the Asia Pacific region, and by 2030, the number of people with dementia in Singapore is expected to more than double.

In the Asia-Pacific region, the number of people with dementia is estimated to increase from 23 million people in 2015 to 71 million people by the year 2050. East Asia and South Asia will see dementia growth rates more than double in the next 20 years.

According to Dr Stacey, the decision to relocate Cerecin’s global HQ in U.S., to Singapore was motivated by operational and strategic reasons.

Operationally, Cerecin’s lead compound, Tricaprilin, has shown to be more effective in patients with a particular genetic make-up that is more common in Asia. The clinical trial situation is also evolving in Asia-Pacific and has matured most rapidly in Singapore.

“In China, we are seeing remarkable growth due to a combination of factors: easing of regulation and policy hurdles, improving infrastructure and the development of modern neuroimaging technology in the country. Recently, Shanghai Green Valley announced that their phase 3 Study of Sodium Oligomannurarate (GV-971) Capsules in mild-to-moderate Alzheimer's disease had met its primary endpoint”, said Dr Stacey. He also highlighted China is evolving a bio-ecosystem of its own and they expect to play a key role in China from their base in Singapore

Also, the raw material from which the lead compound is made is predominantly grown in South East Asia. “We plan to centralise manufacturing of our products to the region and Singapore makes for the ideal place to do that,” he said.

Hope for AD

The field has evolved considerably, and there are now scans to diagnose subjects accurately in the earliest stages of the disease process as well as a better understanding of which patients are likely to respond to treatment.

The field is also advancing in terms of ways to measure changes with new scales being developed and in regulatory authorities approaches to evaluating drugs.

There is still much work to be done. In addition to developing treatments to slow the progression of disease or even reverse the disease process, there needs to be treatments to improve the subjects’ condition no matter what stage of disease they are in.

According to Dr Stacey, we also need to be mindful of costs. New treatments need to be affordable, safe and simple to use so they can reach the widest possible audience. The challenge is not an easy one, but with the right combination of experts in drug development, a lead agent with a proven track record, and strong financial, scientific, and community backers, there is every reason to be hopeful.

References:

  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4807045/
  • https://globenewswire.com/news-release/2018/07/26/1542579/0/en/Global-Alzheimer-s-Drugs-Market-Expected-to-Reach-USD-5-66-billion-By-2024-Zion-Market-Research.html
  • https://www.fool.com/investing/2018/07/23/5-surprising-things-you-probably-didnt-know-about.aspx
  • https://www.alz.co.uk/adi/pdf/Dementia-Asia-Pacific-2014.pdf
  • http://www.who.int/bulletin/volumes/89/3/11-020311/en/
The interview was conducted by Lim Guan Yu

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EDITORS' CHOICE  
COLUMNS  

APBN Editorial Calendar 2018
January:
Obesity / Outlook for 2018
February:
Searching for the fountain of youth
March:
Women in Science - Making a difference
April:
Digestive health in the 21st century - Trust your guts
May:
Dental health - The root to good health
June:
Cancer - Therapies and strategies for better patient outcomes
July:
Water management - Technologies for biotech and pharmaceutical industries
August:
Regenerative technology - Meat of the future
September:
Doctor Robot - The digital healthcare revolution
October:
Bones / Breast cancer
November:
Liver health / Top science research nations & institutions
December:
AIDS / Breakthrough of the year/Emerging trends
Editorial calendar is subjected to changes.
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