New blood test speeds Alzheimer’s diagnosis

The fight against Alzheimer’s disease has long been hampered by lack a simple diagnostic test for patients. Recently, an international team of researchers announced that they have a developed a blood test for the disease.

To learn more about the efforts to find a cure and see why a better way to test is so important, read the following article on this topic.

Alzheimer’s: Frustrating search for a cure

Drug makers have been working hard — and spending enormous sums — in the search for effective new Alzheimer's disease (AD) treatments. For the past 20 years the most important avenue of research has been concerned with what is called the amyloid hypothesis.

In an earlier article we mentioned that one of the characteristics of patients with AD is the presence in the brain of the sticky substance called amyloids. Normally, the cerebrospinal fluid in the brain washes away harmful waste proteins such as beta-amyloids during sleep.¹ The amyloid hypothesis posits that in AD patients beta-amyloid protein accumulate: first in small clusters, then in larger mats and finally in dense plaques. Eventually, this disrupts communication between neurons and activates immune cells, which cause inflammation and the destruction of brain cells.²

The solution, or so everyone seemed to believe, was a class of investigational drugs called BACE inhibitors. BACE inhibitors are supposed to reduce the amount of amyloid beta in the brain. In theory, by doing so, they aim to restore the normal function of nerve cells.³

Unfortunately, things don’t seem to be turning out the way the theory predicted. Indeed, it became something of a pattern in recent years to hear of encouraging new trial results for some new BACE inhibitor drug, only to have those hopes dashed upon further review.⁴

This unfortunate cycle took a turn for the worse in 2018, to the extent that important players have concluded that the BACE inhibitors may be a dead end in the search to cure AD. In February, Merck announced it was discontinuing a Phase 3 study into a BACE inhibitor called verubecestat.⁵ In May, Janssen said they were stopping clinical trials for their BACE inhibitor due to safety concerns.⁶ In June, Eli Lilly and Co and AstraZeneca Plc said they would abandon efforts to jointly develop a BACE inhibitor.⁷

All of this was preceded by perhaps the worst news for AD research, which came out in January. After another hugely expensive, high-profile AD drug fizzled out in clinical trials, Pfizer said it would end research for Alzheimer’s drugs entirely, in the process closing their AD facility and laying off hundreds of highly experienced PhD. scientists.⁸

In and of themselves, these setbacks are not especially surprising, as drug candidates for AD have a 99.6% failure rate.⁹ However, taking into account that all, or most of these setbacks revolved around the amyloid hypothesis, more researchers are now concluding that a different path will need to be taken to find care.

For example, skeptics of the amyloid hypothesis can now cite studies based on recent advancements in positron emission tomography (PET) which show how the spread of different proteins, called tau can also damage neurons.¹⁰ The studies indicate that not only is it possible for a person to have AD without significant amyloid plaque deposits but that it’s also possible for a person to have significant buildup of plaques without contracting AD.¹¹

Now what?

Do these new insights, coupled with the clinical trial failures, disprove the amyloid hypothesis? Not entirely.

Recently drug makers EISAI and Biogen announced positive results of a Phase 2 clinical study for an anti-amyloid antibody known as BAN2401. Trial participants with mild cognitive impairment (MCI) or mild to moderate dementia due to AD who were given the antibody for 18 months saw the progression of symptoms slowed.¹² Moreover, positron emission tomography (PET) scans of participants showed a statistically significant reduction of brain amyloid load compared to a placebo.

While these results are encouraging, many long-time watchers of AD drug development raise questions about the novel trial design and statistical methodology used in this study.¹³ Other observers have concluded that the EISAI/Biogen results are at least faintly encouraging. They will need to be supplemented with full-scale phase 3 results before any conclusions can be reached.¹⁴ So, to this extent, the amyloid hypothesis lives on.

Skeptics of the amyloid hypothesis continue to note that many treatments exhibiting promise in Phase 2 have failed in Phase 3.¹⁵ Indeed, we may already be seeing a shift away from the amyloid hypothesis, as is evident in the pipeline. While amyloid drugs make up a third of all prospective AD drugs in Phase 3 trials, they account for only 18% of the drugs in Phase 2 trials.¹⁶

A reason for hope

Considering the current lack of an effective treatment, is there cause for optimism around AD?

One positive sign is that easier and more predictive ways to test for AD may be on the horizon. Researchers are working on blood-based tests to screen for increased levels of amyloid, eliminating the need to access spinal fluid.¹⁷ Elsewhere, better biomarkers could improve the sensitivity of PET scans, directly measuring synaptic loss, a precise indicator of cognitive decline.¹⁸

Given the prospect of improved means of detection, one hope is that therapies could be administered sooner, as studies suggest that AD can start damaging brain tissue more than a decade before the onset of symptoms.¹⁹ Early this year, the FDA released draft guidelines proposing to approve drugs targeting pre-symptomatic AD patients. This would permit treating patients with no outward signs of Alzheimer’s, who are “identified through the use of sensitive cognitive screening, imaging tests, or biomarkers.”²⁰

Proponents of this approach see it as an effort to modernize AD drug development and approval and a prudent step necessary to halt the progression of AD before it starts. Others, however, see the opportunity for moral hazard. As the demand for any new AD drug is so overwhelming, they worry that regulators may yield to pressure from desperate patients and families and eventually approve a drug that confers little real world benefit.²¹

Elsewhere, innovative business models are bringing new capital and new ideas to the race to cure AD. OptumRx's parent company UnitedHealth Group recently invested $10 million alongside drug makers and the Gates foundation in the Dementia Discovery Fund, a specialist venture capital fund that invests in novel science to cure AD.²²

Lastly, even Alzheimer’s researchers are exhibiting new optimism. At the recent Alzheimer’s Association International Conference a group of researchers released a report showing that the number of drugs in Phase 2 clinical trials has increased 17% over just the past year, from 58 to 68 drugs.²³ This widening pipeline of Phase 2 drugs provides more opportunities to potentially treat Alzheimer's disease sometime in the next decade.

“There are numerous drugs, primarily biologic, that are in development for the treatment of Alzheimer's disease,” says OptumRx Chief Pharmacy Officer David Calabrese. “With the aging of the population, increased prevalence of disease, and limited array of effective treatment options, these drugs also hold the potential for significant market penetration should clinical data prove positive.”

Sources

1. Science. Sleep Drives Metabolite Clearance from the Adult Brain. Accessed Sept. 14, 2018. 
2. Alzheimer’s Association. Beta-amyloid and the amyloid hypothesis. Accessed Sept. 14, 2018. 
3. Alzheimer’s Research & Therapy. BACE1 inhibitor drugs in clinical trials for Alzheimer’s disease. Accessed Sept. 14, 2018. 
4. Drug Development Technology. Another BACE inhibitor fails in phase 3 trials. Accessed Sept. 14, 2018. 
5. Merck. Press release. Accessed Sept. 14, 2018. 
6. Janssen. Press release. Accessed Sept. 14, 2018. 
7. Reuters. Lilly-AstraZeneca latest to abandon Alzheimer's drug trials. Accessed Sept. 14, 2018. 
   
8. Reuters. Pfizer ends research for new Alzheimer's, Parkinson's drugs. Accessed Sept. 14, 2018. 
9. Alzheimer’s Research & Therapy. Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Accessed Sept. 14, 2018. 
10. BRAIN. Tau burden and the functional connectome in Alzheimer’s disease and progressive supranuclear palsy. Accessed Sept. 14, 2018. 
11. Frontiers in Neuroscience. Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer's Disease. Accessed Sept. 14, 2018. 
12. Biogen. Eisai and Biogen Announce Detailed Results of Phase II Clinical Study of BAN2401… Accessed Sept. 14, 2018. 
13. Forbes. Biogen And Eisai Say Alzheimer's Drug A Success, Reversing Earlier Result. Accessed Sept. 14, 2018. 
    
14. Stat. Alzheimer’s study sparks a new round of debate over the amyloid hypothesis. Accessed Sept. 14, 2018. 
    
15. Science. Biogen and Eisai: Let the Alzheimer’s Arguing Commence. Accessed Sept. 14, 2018. 
    
16. Usagainstalzheimers.org. 2018 Alzheimer’s Drug Pipeline. Accessed Sept. 14, 2018. 
    
17. Washington University School of Medicine in St. Louis. Blood test IDs key Alzheimer’s marker. Accessed Sept. 14, 2018. 
    
18. Yale News. Yale-developed test for Alzheimer’s disease directly measures synaptic loss. Accessed Sept. 14, 2018. 
    
19. MIT Tech Review. An Alzheimer's Warning 25 Years Before Symptoms Show. Accessed Sept. 14, 2018. 
    
20. FDA. Early Alzheimer’s Disease: Developing Drugs for Treatment Guidance for Industry. Accessed Sept. 14, 2018. 
    
21. Science. More Rough Alzheimer’s News. Accessed Sept. 14, 2018. 
    
22. Alzheimer's Association. Alzheimer's Association Applauds AARP's $60 Million Investment in the Dementia Discovery Fund. Accessed Sept. 14, 2018. 
    
23. Usagainstalzheimers.org. New Analysis Provides Insights into Late-Stage Alzheimer’s Drug Pipeline. Accessed Sept. 14, 2018. 

STATEMENT REGARDING FINANCIAL INFLUENCE:
This article is directed solely to its intended audience about important developments affecting the pharmacy benefits business. It is not intended to promote the use of any drug mentioned in the article and neither the author nor Optum Rx has accepted any form of compensation for the preparation or distribution of this article.