Alzheimer's Disease Year-in-Review 2016

With 2017 upon us, many Alzheimer’s Disease (AD) stakeholders may look back at the year that was with a sense of dismay, given the failure of several important clinical trials aimed at translating putative mechanisms into FDA approved drugs. In this brief year-in-review, I say despair not. First, you could be suffering the January blues. The New Year can make even the most spirited among us feel down in the dumps. Second, you may be looking at the glass half-empty rather than half-full. Hidden among the spectacular clinical study failures was a wholesome year of scientific achievements and strides in public funding. So "chin up" and journey with me through this mini and wholly incomplete 2016 year in review.

First, a brief reminder of the enormity of the task ahead. Alzheimer’s Disease is an irreversible progressive neurodegenerative disorder characterized by impairment of cognitive, behavioral and functional abilities, including memory loss, and a decline in language and motor skills. According to the Alzheimer’s Association, more than 5 million people in the U.S. are afflicted, including a staggering one in nine over age 65, and one in three over age 85. In 2016, health care costs for dementia were estimated at $236 billion, with almost half borne by Medicare. In addition, unpaid caregivers contributed time with an estimated economic value of $221 billion (Alzheimer’s & Dementia, 2016). What makes AD so devastating is that it lacks a cure or even a treatment that slows its progression. Furthermore, the underlying mechanisms of the disease are still elusive. Pathological hallmarks of AD include oxidative stress, extracellular aggregation of beta-amyloid peptides and intracellular inclusions of tau-protein aggregates. In addition, there is a deficit of the neurotransmitter acetylcholine in selective regions of the brain that mediate learning and memory. There are also alterations in serotonin and dopamine which may contribute to some of the behavioral changes.

 There are presently three FDA-approved drugs, donepezil (Aricept®), galantamine (Razadyne® ER) and rivastigmine (Exelon®) that provide symptom relief by increasing the amount of acetylcholine in the brain. In addition, one FDA-approved drug, memantine (Namenda® XR) counteracts the effects of excitatory neuronal circuits and prevents the toxic effects of excessive glutamate. There is also a combination product containing donepezil and memantine (Namzaric®), which reduces the pill burden and improves medication adherence in patients with AD. Unfortunately, the approved drugs provide only modest symptom relief and none cure, halt or delay AD.  

Drugs targeted at beta-amyloid and tau-protein aggregates have been largely unsuccessful in providing a cure, slowing the progression of the disease or providing symptom relief. In July 2016, TauRx Pharmaceuticals reported that its tau aggregation inhibitor LMTX® failed to show benefit over placebo after a 15-month clinical trial in almost 900 patients with mild or moderate Alzheimer's disease. In November 2016, Eli Lilly announced that a Phase 3 study of the anti-amyloid drug solanezumab did not show a significant slowing of cognitive decline when compared with placebo in over 2000 patients with mild AD. Two previous trials of solanezumab in Alzheimer's disease had also been negative or inconclusive.

On February 14, 2017. Merck announced that it was prematurely discontinuing its clinical trial of the anti-amyloid drug verubecestat in patients with mild or moderate AD since there was “virtually no chance of finding a positive clinical effect.” However, Merck is continuing its ongoing trial of verubecestat in patients with mild cognitive impairment or "prodromal AD".

Some have argued that it is time to abandon the amyloid hypothesis as a model for developing treatment for AD since amyloid deposition begins well before patients show clinical signs of dementia, some patients with significant amyloid deposits show no signs of dementia and most amyloid deposits are in areas of the brain not associated with dementia. Similar skepticism has been expressed about pursuing therapies aimed at reducing neurofibrillary tangles (intracellular tau-protein aggregates). 

It isn’t all bad news in the field of AD over the past year. For example, drugs targeted at beta-amyloid and tau-protein aggregates could still work if used early enough. In addition to the ongoing Merck trial of verubecestat in AD patients with only mild cognitive impairment verubecestat, other anti-amyloid drugs are being evaluated in early AD, including Johnson & Johnson’s JNJ-54861911 in patients who are asymptomatic and at risk for developing AD and Novartis’ CAD106 and CNP520 in patients who are homozygous for APOE4, the largest known genetic risk factor for late-onset sporadic AD.

Significant good news came in November 2016 when Dr. Kenneth Langa and colleagues from the University of Michigan University, Ann Arbor reported that dementia prevalence among Americans 65 years or more decreased from 11.6% in the year 2000 to 8.8% in 2012 (AD accounts for 60 to 80% of dementia cases). This decline in dementia occurred despite a significant increase in the cardiovascular risk profile among older adults over the same period. An increase in education was associated with some of the decline in dementia. Additional positive news for AD stakeholders came in December 2016 with the enactment of the 21st Century Cures Act, which authorized $6.3 billion in funding, including $4.8 billion to the NIH for precision medicine and biomedical research. In part, the 21st Century Cures Act directs $1.6 billion to the BRAIN Initiative over a 10-year period.

Although the failure of solanezumab, verubecestat and LMTX call for a re-examination of the primacy of beta-amyloid and tau in the pathogenesis of Alzheimer's disease, they also serve as a necessary wake-up call for us to look elsewhere for a solution to dementia. Prudence would suggest we hold off on a definitive judgment until completion of the ongoing AD studies of verubecestat in patients with mild cognitive impairment, J&J’s JNJ-54861911 in asymptomatic patients and Novartis’ CAD106 and CNP520 in patients with a genetic risk for late-onset sporadic AD. In the meanwhile, the inexorable march towards methods aimed at prevention, identification and reduction of the risk of dementia, and treatments that provide more effective symptom relief, and that delay, halt or cure of AD continues.  Najib Babul, PharmD, MBA