Lacklustre performance: drugs targeting β-amyloid in Alzheimer’s disease
Tuesday, August 29th, 2017
The Alzheimer’s Association International Conference (AAIC) is the largest gathering of the Alzheimer’s disease (AD) research community in the world, and provides a unique forum for the discussion of ideas and dissemination of knowledge. One of the key concepts grappled by the AD research community at AAIC 2016 in Toronto, Canada, was the validity of the amyloid hypothesis.
It is generally accepted that the accumulation of b-amyloid (Ab), particularly Ab40-42, in the extracellular spaces around neurons as amyloid plaques is central to the pathogenesis of AD. This idea is expressed in the ‘amyloid cascade hypothesis’ [1,2]. It thus follows that by reducing the production of Ab or eliminating the amyloid plaques from the brain, the progression of disease could be slowed, halted, or even reversed . Alzheimer’s disease is the most important cause of dementia, which affects a staggering 40 million people worldwide, a number which is predicted to double every 20 years until 2050 . Therefore, achieving prevention, or even just slowing of disease progression, would have a significant impact on morbidity, mortality, and burden on healthcare systems worldwide.
Hence, significant funding has been directed by both public research institutions and private pharmaceutical corporations towards the development of drugs that target Ab. Ab is produced by two steps of enzymatic processing: first by b-secretase, and then by g-secretase . The latter has been targeted by drugs collectively known as g-secretase inhibitors, most prominently avagacestat and semagacestat. Both of these drugs failed in Phase 2 and 3 trials, and notably were associated with cognitive decline, an increased risk of skin cancers, and an overall increased risk of serious adverse events [6-10]. It was suspected that the failure of g-secretase inhibitors, particularly with regards to the adverse events profile, was due to off-target inhibition of Notch, a receptor that is involved in a signalling pathway that is particularly prevalent in the skin and gastrointestinal system [9-11]. However, tarenflurbil, a g-secretase modulator that spared the active site of g-secretase and hence spared Notch, also failed to be clinically efficacious, as measured by changes in cognitive indicators such as the Mini-Mental State Examination (MMSE), Alzheimer’s Disease Assessment Scale – cognitive component (ADAS-cog), and the Clinical Dementia Rating – sum of boxes (CDR-sb) [12,13]. Hence, drug development has largely moved away from inhibition of g-secretase, and b-secretase (BACE) inhibitors are now in early development as a potential alternative.
Active and passive immunotherapeutic agents targeting Ab have also been tested, with mixed results. While bapineuzumab was successful in lowering amyloid concentrations in two Phase 3 trials, it did not cause any clinical improvement, compared to placebo, and was associated with the development of amyloid-related imaging abnormalities (ARIA) [14-17]. ARIA comprise two separate changes: vasogenic oedema and cerebral microhaemorrhages. These changes may occur due to destabilisation of amyloid in vascular walls [18,19]. While often asymptomatic, in combination with a lack of clinical efficacy this was sufficient to halt the development of bapineuzumab. Another immunotherapeutic, solanezumab, was underwhelming in its Phase 3 trial performance, but was better tolerated than bapineuzumab and showed some cognitive improvement in patients with mild AD [20-22]. Aducanumab , crenezumab , and gantenerumab  have all also shown promise and currently have Phase 3 trials in planning or underway. Hence, it appears that immunotherapy may be a more viable modality for the treatment of AD than inhibition of g-secretase.
It is possible that all trialled therapeutics have targeted AD too late in the disease course, when clinical features such as memory decline and functional impairments have become frankly apparent. Hence, some trials have now shifted towards targeting AD earlier in its disease course. Mild cognitive impairment (MCI), also known as prodromal AD, is the accepted early pre-AD stage in which it is now believed the greatest improvements can be made, by preventing further decline . Another stage prior to this, subjective cognitive impairment (SCI), in which patients report some cognitive changes but their scores on the MMSE and other indicators are unchanged, is also being recognised and may soon be targeted by therapeutic or preventive strategies .
It is also possible, of course, that the current paradigm of the amyloid cascade hypothesis is wrong. Perhaps the drugs have failed to show clinical efficacy, despite reducing cerebrospinal fluid Ab levels, because Ab is not actually central to disease pathogenesis. Another player in the game is tau – a protein that accumulates intracellularly in the classical neurofibrillary tangles. It was originally thought that tau accumulation occurred later in the disease course than that of Ab and was in some way triggered by Ab, supporting the role of Ab accumulation as the primary mediator of disease progression. However, it is now being argued that tau may actually develop concurrently and independently of Ab, and hence this may prove to be a viable target for pharmaceuticals in the future. What is certain, however, is that the pathogenesis of AD is complex, and it is unlikely that engaging with a single target will be sufficient for prevention or a cure .
Next year, when AD researchers congregate for AAIC 2017 in London, it is likely that the amyloid cascade hypothesis will further be tested by results from clinical trials of drugs targeting Ab, particularly those of immunotherapeutic agents. Whether there is a significant paradigm shift in terms of our understanding of AD pathogenesis, or a reorientation of our efforts towards prevention over treatment, will largely depend on these results over the next decade. It is certainly important that significant progress is made in the near future, lest pharmaceutical companies that fund drug development put AD in the ‘too hard’ basket and move on to simpler challenges.
Conflicts of interest
- Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256(5054):184-5.
- Selkoe DJ. Towards a comprehensive theory for Alzheimer’s disease. Hypothesis: Alzheimer’s disease is caused by the cerebral accumulation and cytotoxicity of amyloid beta-protein. Ann N Y Acad Sci. 2000;924:17-25.
- Scheltens P, Blennow K, Breteler MMB, de Strooper B, Frisoni GB, Salloway S, et al. Alzheimer’s disease. The Lancet. 2016;388(10043):505-17.
- Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and meta-analysis. Alzheimers Dement. 2013;9(1):63-75.
- Tolia A, de Strooper B. Structure and function of gamma-secretase. Semin Cell Dev Biol. 2009;20(2):211-8.
- Penninkilampi R, Brothers HM, Eslick GD. Pharmacological agents targeting γ-secretase increase risk of cancer and cognitive decline in Alzheimer’s disease patients: a systematic review and meta-analysis. J Alzheimers Dis. 2016;53(4):1395-404.
- Coric V, Salloway S, van Dyck CH, Dubois B, Andreasen N, Brody M, et al. Targeting prodromal Alzheimer disease with avagacestat: a randomized clinical trial. JAMA Neurol. 2015;72(11):1324-33.
- Coric V, van Dyck CH, Salloway S, Andreasen N, Brody M, Richter RW, et al. Safety and tolerability of the gamma-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol. 2012;69(11):1430-40.
- Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med. 2013;369(4):341-50.
- Henley DB, Sundell KL, Sethuraman G, Dowsett SA, May PC. Safety profile of semagacestat, a gamma-secretase inhibitor: IDENTITY trial findings. Curr Med Res Opin. 2014;30(10):2021-32.
- Proweller A, Tu L, Lepore JJ, Cheng L, Lu MM, Seykora J, et al. Impaired Notch signaling promotes de novo squamous cell carcinoma formation. Cancer Res. 2006;66(15):7438-44.
- Green RC, Schneider LS, Amato DA, Beelen AP, Wilcock G, Swabb EA, et al. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA. 2009;302(23):2557-64.
- Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA. Efficacy and safety of tarenflurbil in mild to moderate Alzheimer’s disease: a randomised phase II trial. Lancet Neurol. 2008;7(6):483-93.
- Blennow K, Zetterberg H, Rinne JO, Salloway S, Wei J, Black R, et al. Effect of immunotherapy with bapineuzumab on cerebrospinal fluid biomarker levels in patients with mild to moderate Alzheimer disease. Arch Neurol. 2012;69(8):1002-10.
- Liu E, Schmidt ME, Margolin R, Sperling R, Koeppe R, Mason NS, et al. Amyloid-beta 11C-PiB-PET imaging results from 2 randomized bapineuzumab phase 3 AD trials. Neurology. 2015;85(5):692-700.
- Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370(4):322-33.
- Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2009;73(24):2061-70.
- Panza F, Frisardi V, Imbimbo BP, Logroscino G, Seripa D, Pilotto A, et al. Amyloid-related imaging abnormalities associated with immunotherapy in Alzheimer’s disease patients. Future Neurol. 2012;7(4):395-401.
- Sperling R, Salloway S, Brooks DJ, Tampieri D, Barakos J, Fox NC, et al. Amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol. 2012;11(3):241-9.
- 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;370(4):311-21.
- Farlow M, Arnold SE, van Dyck CH, Aisen PS, Snider BJ, Porsteinsson AP, et al. Safety and biomarker effects of solanezumab in patients with Alzheimer’s disease. Alzheimers Dement. 2012;8(4):261-71.
- Siemers ER, Sundell KL, Carlson C, Case M, Sethuraman G, Liu-Seifert H, et al. Phase 3 solanezumab trials: secondary outcomes in mild Alzheimer’s disease patients. Alzheimers Dement. 2016;12(2):110-20.
- Sevigny J, Chiao P, Williams L, Chen T, Ling Y, O’Gorman J, et al. Randomized, double-blind, placebo-controlled, phase 1b study of aducanumab (BIIB037), an anti-Abeta monoclonal antibody, in patients with prodromal or mild Alzheimer’s disease: interim results by disease stage and ApoE e4 status. 67th Annual Meeting of the American Academy of Neurology; Washington, DC; 2015.
- Cummings J, Cho W, Ward M, Friesenhahn M, Brunstein F, Honigberg L, et al. A randomized, double-blind, placebo-controlled phase 2 study to evaluate the efficacy and safety of crenezumab in patients with mild to moderate Alzheimer’s disease. Alzheimers Dement. 2014;10(4):P275.
- Ostrowitzki S, Deptula D, Thurfjell L, Barkhof F, Bohrmann B, Brooks DJ, et al. Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch Neurol. 2012;69(2):198-207.
- Gauthier S, Reisberg B, Zaudig M, Petersen RC, Ritchie K, Broich K, et al. Mild cognitive impairment. The Lancet. 2006;367(9518):1262-70.
- Stewart R. Subjective cognitive impairment. Curr Opin Psychiatry. 2012;25(6):445-50.
- Herrup K. The case for rejecting the amyloid cascade hypothesis. Nat Neurosci. 2015;18(6):794-9.