Setbacks in Alzheimer research demand new strategies, not surrender


In this month’s editorial, the PLOS Medicine Editors discuss the challenges of addressing a growing population with Alzheimer disease and dementia amidst disappointing news from the pharmaceutical industry.


Published in the journal: . PLoS Med 15(2): e32767. doi:10.1371/journal.pmed.1002518
Category: Editorial
doi: 10.1371/journal.pmed.1002518

Summary

In this month’s editorial, the PLOS Medicine Editors discuss the challenges of addressing a growing population with Alzheimer disease and dementia amidst disappointing news from the pharmaceutical industry.

Those hoping for new treatments for Alzheimer disease (AD) are unfortunately used to receiving disappointing news, but this year began on a particularly sobering note when Pfizer announced that it was shutting down its drug-discovery efforts for the disease [1]. A pharma giant giving up on such a huge potential market—globally, 47 million people are affected by AD and related dementias, and the number is predicted to double every 20 years [2]—is a telling acknowledgment of how barren the AD drug-discovery landscape is.

The path to a drug that can halt AD is beset by difficulties, as several pharmaceutical companies have experienced. Trials for such drugs have, in most instances, failed—many at later stages of clinical evaluation, after considerable financial investment. For instance, Eli Lilly abandoned development of the injectable drug solanezumab, which targets β-amyloid protein but in clinical trials failed to improve cognition or function in patients with mild-to-moderate AD, for those receiving the drug compared to those on placebo [3,4]. Similarly, TauRX experienced discouraging results with their drug LMTM, which targets tau protein [5].

AD presents a unique combination of challenges to drug-discovery efforts. Treating any brain disease requires getting drugs across the blood—brain barrier and avoiding toxicity from off-target effects in the complex network of cerebral activity. Treating diseases of aging carries the added complication of managing comorbidities. In the case of AD, the extracellular deposits of amyloid-β peptide and the intracellular accumulation of abnormally phosphorylated tau neurofibrillary tangles (NFT) that define the disease are often accompanied by other neurological insults that also affect cognition, such as cerebrovascular disease, Lewy bodies, frontotemporal lobar degeneration, or hippocampal sclerosis [68]. It is estimated that 16% or more of people believed by their physician to have probable AD are in fact misdiagnosed and have another type of neurocerebral pathology [9]. Difficulty identifying the early stages of AD also means that many trial participants with accurately diagnosed AD are at an advanced stage of the disease, with neurological damage that may not benefit even from a drug that can effectively prevent further amyloid plaque or tangle formation.

The slow progression of AD, coupled with the costly cognitive and imaging tests used to establish clinical end points and monitor safety, makes trials lengthy and expensive. With promising results now coming from trials of cancer therapies—especially immunomodulatory approaches—one can see how pharma companies might find it more attractive to turn their attention to drugs that generally cost less to test: Phase III Alzheimer trials cost hundreds of millions of dollars to conduct, whereas a cancer trial costing closer to US$50 million may have a better chance of success. Nonetheless, the burden of AD and other forms of dementia cannot be ignored, and this area continues to be a funding priority for governments (the United States National Institutes of Health budget for AD and AD-related disease research is currently US$1.4 billion per year) and nonprofits (e.g., US$385 million from the Alzheimer’s Association International Research Grant Program). We hope that these investments will result in a better understanding of the mechanisms and biomarkers in AD, and perhaps a drug-discovery landscape with greater certainty will convince companies like Pfizer to recommit resources.

While it may be tempting to focus on results of drug trials with the implicit hope of imminent clinical benefit, meaningful success against dementia must remain a longer-term project. Bruce Miller and Carol Brayne, co-guest editors of PLOS Medicine’s 2017 Special Issue on Dementia, note that the focus on single biological targets to treat such a complex disease may have sown the seeds for clinical failure. “Drug development researchers have been ignoring what population data and the more detailed work from subsets of rarer dementia have been telling us for a long time,” says Brayne. Miller agrees that “targeted approaches on smaller cohorts with better understood biology will be a better approach,” noting also that “Pfizer and others took an overly simplistic approach thinking essentially that all dementia—whatever age—would respond to amyloid-lowering therapies.”

A more personalized approach to AD will require acknowledging the combinations of dementia pathologies that contribute to cognitive deficits in people with AD and treating these entities in parallel with amyloid- and NFT-directed or novel AD-specific interventions. Such an approach will likely require earlier diagnosis and more sophisticated understanding of each individual’s disease etiology. Genetic studies using large databases are leading to more individualized risk prediction [10] for cognitive decline and dementia than was previously possible using only the established marker, apolipoprotein E genotype and have implicated novel targets for possible treatment, such as inflammatory pathways [11]. This kind of investigation may lead to novel and more sensitive biomarker screens to identify trial participants at an earlier stage of disease, when effective interventions may be more easily demonstrated.

However, a targeted approach will require substantial time and resources to develop, and even if it achieves some clinical success, it will be difficult to implement on a global scale. Costly screens and personalized treatments may be feasible in high-income countries (HICs) but may offer minimal relief to the growing proportion of people living with dementia in low- and middle-income countries (LMICs). In the meantime, a more accessible approach can be to address the lifestyle and environmental factors that contribute to dementia risk. Says Brayne, “Trials and drug development have to be done in parallel with societal thinking about cost and implications of taking this approach versus life-course optimization of brain health.” Epidemiological evidence suggests that late-life resilience to cognitive decline may be influenced by factors such as physical exercise, social and intellectual stimulation, and socioeconomic circumstances decades earlier as well as late in life [1214]. Moreover, evidence is accumulating that long-term effects of traumatic brain injury [15,16], including concussive and potentially even subconcussive events, may represent an avenue for prevention, not only for professional athletes or soldiers exposed to head injury into their adulthood but also for people who play contact sports as children or adolescents.

Even an optimistic forecast shows little current likelihood of disease-modifying treatment for those already affected by dementia and few clear approaches to prevention for older populations at risk of progressive cognitive decline. For these people and those who care for them, the pressing concern is not eliminating risk or developing treatments for the next generation but how to manage established disease and prepare long-term care plans for the time when dementia care becomes too much to handle without help. As with targeted therapies, care options differ across socioeconomic strata. For people in care homes, new person-centered psychosocial interventions [17,18] may provide benefit to quality of life and decreased reliance on medications. However, for most in LMICs (and many people in HICs), care is delivered by overstretched institutions or directly by families, which may both be lacking the capacity to provide the personal attention and high-level care that people with dementia require and deserve. This is the current crisis: the human and economic costs of dementia each year far outweigh the research investments that any pharmaceutical company is willing to stake on effective interventions. The response will no doubt differ among countries and depend on local resources and disease burden, but pending a more effective research agenda, it will surely demand the best forms of humane, supportive care that our family ties, social consciences, and economic systems can provide.


Zdroje

1. “Pfizer ends research for new Alzheimer’s, Parkinson’s drugs” https://www.reuters.com/article/us-pfizer-alzheimers/pfizer-ends-research-for-new-alzheimers-parkinsons-drugs-idUSKBN1EW0TN Accessed Feb 8, 2018.

2. Prince M, Wilmo A, Guerchet M, Ali G, Wu Y, Prina M. World Alzheimer Report 2015: The global impact of dementia: an analysis of prevalence, incidence, cost and trends. Alzheimer’s Disease International. 2015. http://www.alz.co.uk/research/world-report-2015 Accessed Feb 8, 2018.

3. Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014 Jan 23;370(4):311–21. doi: 10.1056/NEJMoa1312889 24450890

4. Honig L, Vellas B, Woodward M, Boada M, Bullock R, Borrie M, et al. Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease. N Engl J Med 2018; 378:321–330 doi: 10.1056/NEJMoa1705971 29365294

5. Gauthier S, Feldman HH, Schneider LS, Wilcock GK, Frisoni GB, Hardlund JH, et al. Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer’s disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial. Lancet. 2016 Dec 10;388(10062):2873–2884. doi: 10.1016/S0140-6736(16)31275-2 Epub 2016 Nov 16 27863809

6. White LR, Edland SD, Hemmy LS, Montine KS, Zarow C, Sonnen JA, et al. Neuropathologic comorbidity and cognitive impairment in the Nun and Honolulu-Asia Aging Studies. Neurology. 2016 Mar 15;86(11):1000–8. doi: 10.1212/WNL.0000000000002480 Epub 2016 Feb 17 26888993

7. Honda H, Sasaki K, Hamasaki H, Shijo M, Koyama S, Ohara T, et al. Trends in autopsy-verified dementia prevalence over 29 years of the Hisayama study. Neuropathology. 2016 Aug;36(4):383–7. doi: 10.1111/neup.12298 Epub 2016 Mar 14 26989005

8. Grinberg LT, Nitrini R, Suemoto CK, Lucena Ferretti-Rebustini RE, Leite RE, Farfel JM, et al. Prevalence of dementia subtypes in a developing country: a clinicopathological study. Clinics (Sao Paulo). 2013;68(8):1140–5. doi: 10.6061/clinics/2013(08)13 24037011

9. Beach TG, Monsell SE, Phillips LE, Kukull W. Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005–2010. J Neuropathol Exp Neurol. 2012 Apr; 71(4): 266–273. doi: 10.1097/NEN.0b013e31824b211b 22437338

10. Desikan RS, Fan CC, Wang Y, Schork AJ, Cabral HJ, Cupples LA, et al. Genetic assessment of age-associated Alzheimer disease risk: development and validation of a polygenic hazard score. PLoS Med. 2017;14(3):e1002258. doi: 10.1371/journal.pmed.1002258 28323831

11. Steele NZ, Carr JS, Bonham LW, Geier EG, Damotte V, Miller ZA, et al. Fine-mapping of the human leukocyte antigen (HLA) locus as a risk factor for Alzheimer’s disease: A Case-Control Study. PLoS Med. 2017;14(3):e1002272. doi: 10.1371/journal.pmed.1002272 28350795

12. Wang H, MacDonald S, Dekhtyar S, Fratiglioni L. Association of lifelong exposure to cognitive reserve-enhancing factors with dementia risk: A community-based cohort study. PLoS Med. 2017;14(3):e1002251. doi: 10.1371/journal.pmed.1002251 28291786

13. Rusmaully J, Dugravot A, Moatti JP, Marmot MG, Elbaz A, Kivimaki M, et al. Contribution of cognitive performance and cognitive decline to associations between socioeconomic factors and dementia: A cohort study. PLoS Med. 2017;14(6):e1002334. doi: 10.1371/journal.pmed.1002334 28650972

14. Clare L, Wu Y-T, Teale JC, MacLeod C, Matthews F, Brayne C, et al. Potentially modifiable lifestyle factors, cognitive reserve, and cognitive function in later life: A cross-sectional study. PLoS Med. 2017;14(3): e1002259. doi: 10.1371/journal.pmed.1002259 28323829

15. Mendez MF. What is the Relationship of Traumatic Brain Injury to Dementia? J Alzheimers Dis. 2017;57(3):667–681. doi: 10.3233/JAD-161002 28269777

16. Nordström A and Nordström P. Traumatic brain injury and the risk of dementia diagnosis: A nationwide cohort study. PLoS Med. 2018;15(1):e1002496. doi: 10.1371/journal.pmed.1002496 29381704

17. Ballard C, Corbett A, Orrell M, Williams G, Moniz-Cook E, Romeo R, et al. Impact of person-centred care training and person-centred activities on quality of life, agitation, and antipsychotic use in people with dementia living in nursing homes: A cluster-randomised controlled trial. PLoS Med. 2018;15(2):e1002500. doi: 10.1371/journal.pmed.1002500 29408901

18. Possin KL, Merrilees J, Bonasera SJ, Bernstein A, Chiong W, Lee K, et al. Development of an adaptive, personalized, and scalable dementia care program: Early findings from the Care Ecosystem. PLoS Med. 2017;14(3):e1002260. doi: 10.1371/journal.pmed.1002260 28323819

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PLOS Medicine


2018 Číslo 2

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