Biogen/Eisai Halt Phase 3 Aducanumab Trials
Today, Biogen and Eisai announced they would terminate the Phase 3 ENGAGE and EMERGE trials of aducanumab for early Alzheimer’s disease. A futility analysis run by an independent data-monitoring committee concluded that that trials would not reach their primary endpoint, the slowing of cognitive decline as measured by the Clinical Dementia Rating-Sum of Boxes (CDR-SB). Aducanumab is a monoclonal antibody that helps clear Aβ from the brain. The trials had recruited more than 3,200 patients around the world.
Researchers and clinicians in the field were disappointed but not wholly surprised by the news. “This is heartbreaking news for affected people, their families, and even for our colleagues at Biogen who advanced this study in an extremely thoughtful way. While this news is important for the field, we look forward to learning more from the data when it becomes available," said Eric Reiman, Banner Health, Phoenix.
“This tells us that removal of amyloid in people with disease is too late,” wrote John Hardy, University College London. “Amyloid is a disease trigger. Once the neurodegenerative disease process is up and running, it is up and running.” His thoughts were echoed by others in the field.
“Even though this trial was in the early symptomatic phase of AD, it is still in the phase when Aβ is no longer likely to be the driving process but where tau and inflammation probably are,” noted David Holtzman, Washington University, St. Louis. “I think Aβ is still a good target for the primary and maybe secondary prevention trials of AD, before tau and inflammation have started driving the disease,” he added.
Aducanumab energized the field in 2015 when researchers at the International Conference on Alzheimer’s and Parkinson’s Diseases in Nice, France, showed PET scans from the Phase 1b PRIME trial indicating the antibody all but cleared amyloid plaques from the brain. In this small trial it even appeared to slow cognitive decline as judged by the CDR-SB and the MMSE (Mar 2015 conference news). That data, including much discussion of the underpowered cognitive data, were subsequently published in Nature.
Was this the biological equivalent of “irrational exuberance,” to borrow from a retired Federal Reserve chairman? It now seems warnings at that time were prescient (Sep 2016 news and comments). “The feeling that the early reports on the clinical efficacy of aducanumab were always presented in an overoptimistic way, appears now to have been right,” wrote Bart de Strooper, Dementia Research Institute, London. “The disappointment in the field remains, however, huge,” he added. Hardy agreed. “As many people said at the time, the original Phase 1 trial should never have been published in Nature. Phase 1 trials are simply not for outcome measures. I would say that Nature should make a statement about this and learn from it,” he wrote.
What is the future now for aducanumab and similar anti-Aβ immunotherapies? “I think this solidifies the opinion that amyloid-targeted therapies do not have a clinical effect at the symptomatic stages of the disease process,” wrote Ron Petersen, Mayo Clinic, Rochester, Minnesota. “Might they work prior to the development of symptoms? Maybe, but with no symptomatic signal, it is risky to continue in that space. We clearly need other targets, and tau is the leading candidate for now.”
Biogen has halted the Phase 2 EVOLVE safety study of aducanumab and the long-term extension of PRIME. The company press release says a planned Phase 3 secondary prevention trial will be reassessed once the data from ENGAGE and EMERGE are evaluated. As of this writing, Biogen’s stock price was down 28 percent.—Tom Fagan
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USC Alzheimer’s Therapeutic Research Institute
This is terribly disappointing; a major blow to the field. Aducanumab was the leading AD therapeutic program, and a source of hope for everyone. We now need to evaluate the trial data to learn all we can and determine the implications for the field. It is our responsibility as investigators in the field to digest and interpret this new information, revise our views and plans as appropriate, and redouble our efforts to develop effective treatments for this devastating disease.
Co-Director, Brigham and Women's Hospital's Ann Romney Center for Neurologic Diseases
This morning’s news that an interim analysis by Biogen of their Phase 3 clinical trials of their anti-amyloid antibody called aducanumab showed a lack of clinical benefit is a huge disappointment for our patients and for the field of therapeutics for Alzheimer’s disease (AD). The key question is why they did not achieve clinical benefit during 18 months of monthly injections of aducanumab, an antibody that seems to clear fibrillar (mature) amyloid plaques from the brain. We do not yet have sufficient information from Biogen as to why they believe they failed to see benefit on average across the large number of AD patients they treated with the antibody. These are my thoughts about possible explanations for this failure:
Whatever the scientific explanation, and it should become clearer as Biogen makes more information available, we have no choice but to redouble our efforts to come to an effective therapeutic agent as soon as possible. My team is unwavering in its commitment to carefully re-examining our assumptions about anti-amyloid therapeutics and designing more effective drugs. Indeed, we have recently found some new antibodies and drugs distinct from aducanumab that show promise in preclinical (laboratory) testing.
We must avoid throwing up our hands and assuming it is impossible to treat Alzheimer’s. Nothing could be further from the truth. Rather, we must make even more strenuous efforts in laboratories and clinics around the world to achieve this crucial goal. We owe it to all of our patients and their families never to give up in our quest.
Arizona Alzheimer's Consortium
This is heartbreaking news for affected persons and their families, our valued research participants, and all stakeholders in the fight against AD. It is also heartbreaking for our Biogen colleagues, who have advanced the development of this drug in an extremely thoughtful way, and for all stakeholders in the fight against AD.
When findings from the evaluation of this demonstrably plaque-busting treatment become available, they are likely to help the field consider a) the potential roles of different kinds of anti-amyloid treatments, alone or in combination, in clinically affected persons, b) the opportunities to give these and other promising treatments their best chance to demonstrate a beneficial effect in prevention trials, and c) what more can be done in the effort to discover a more diversified portfolio of promising treatments.
As I noted when Biogen reported its early phase trial results, confirmation of a cognitive benefit in the Phase 3 trials would have been a game-changer for the field. But refutation of the amyloid hypothesis would also require failure of different anti-Aβ treatments in unimpaired persons with and without pre-existing Aβ plaques (Reiman, 2016). More needs to be done to put this hypothesis to the test in prevention trials, and more needs to be done to advance the discovery and evaluation of other treatment approaches.
Alzheimer’s disease trials are not easy, and they are not fast. Given the stakes, all of us need to do our part to help in this effort, remain thoughtful and steadfast, and do what we can to find the best ways to treat and prevent this terrible disorder as soon as possible.
We look forward to learning from the findings and data when they become available.
Reiman EM. Alzheimer's disease: Attack on amyloid-β protein. Nature. 2016 Aug 31;537(7618):36-7. PubMed.
Banner Alzheimer's Institute
This is obviously disappointing news for all stakeholders.
Some things that we are reflecting on include the fact that, for drugs of this type, there is the conundrum of having to have elevated brain amyloid (and thus having had AD pathology for many years, likely with established neurodegeneration) to be eligible for the drug. The question about earlier intervention with anti-amyloid therapies, before symptoms, before neurodegeneration, and perhaps even before extensive amyloid deposition, remains entirely open and I believe must be answered by preclinical trials.
Since the interim analysis prompted the decision and they said no safety issues, it implies there was not enough slowing of cognitive decline. It will be difficult to comment in detail until the data are revealed. However, even though this trial was in the early symptomatic phase of AD, it is still in the phase of AD when Aβ is no longer likely to be the driving process but where tau and inflammation probably are. I think Aβ is still a good target for the primary and maybe secondary prevention trials of AD before tau and inflammation have started driving the disease.
Harvard Medical School and Brigham&Women's Hospital
It's important to remember not only that the most compelling evidence for Aβ as a driver of Alzheimer's disease is, as Dennis mentions, the human genetic data, but that this is most relevant to the genetic form of AD. The driver(s) of the more common sporadic form, which has been the subject of most of the clinical trials, are not well established. Preclinical animal data are also obtained in models that, if they are relevant to anything at all, are again most relevant to familial AD. One might conclude from these considerations that the anti-amyloid antibody trials most likely to show efficacy would be those of the Colombian presenilin cohort, but it remains possible that, even in the familial disease, there are underlying cellular dysfunctions that must be corrected for a treatment to work.
It is also interesting to recall that in 1911 Alzheimer himself concluded, from studying familial cases, "We now come to the further question of whether these plaques, or as FISCHER calls them 'Sphärotrichia,' can be considered as the cause of a quite specific, classifiable and clinically diagnosable psychosis. There are cases of indubitable Dementia senilis, in which the plaques are not very numerous. Moreover, as FISCHER himself stresses, they dislocate the nervous structures more than they destroy them. So the loss of cortical tissue due to the plaques cannot be very considerable. Furthermore, in addition, in places where plaques are not found in the cerebral cortex, we see the well-known widespread senile sclerotic changes, the lipid-pigmented and granular degenerations of ganglion cells with alterations of their fibrils which BRODMANN and BIELSCHOWSKY have described in detail, the fibre-formation of the glia, pigment-accumulation in the glia and the degenerative phenomena in the vessel walls which it is impossible to believe were caused by plaques. These changes are found in the basal ganglia, the medulla, the cerebellum and the spinal cord, although there are no plaques at all in those sites or only isolated ones. So we have to come to the conclusion, that the plaques are not the cause of senile dementia but only an accompanying feature of senile involution of the central nervous system. However, as they seem to occur regularly in larger numbers in presbyophrenic dementia, while only occasional single ones are to be found in advanced age without dementia, they must have as decisive an importance as the diffuse infiltration of the lymphoid vessels with plasma cells. This latter cannot be considered as the cause of paralytic disease but of the paralytic disease process, and is an important diagnostic aid for its recognition." (Alzheimer A. Über eigenartige Krankheitsfälle des späteren Alters. Z Ges Neurol Psychiatr. 1911;4:356–385, translated in Alzheimer, Forstl and Levy, 1991).
I believe the entire paper is worth reading by everyone concerned with finding treatments for this disease.
It is also worth noting that tau, gaining popularity as a driver for the sporadic disease, has never been linked to familial AD; its mutations case diseases that are quite distinct, both phenotypically and, more importantly, anatomically. Finally, I would urge the community to consider the brilliant insights of Scott Small, who has focused on the critical question of why AD starts in the entorhinal cortex. Any explanation of its pathogenic mechanism must account for this anatomical specificity.
The tendency of many scientists towards Manichean dualism will cause them to dismiss the amyloid hypothesis as completely wrong. My conclusion is that would be a mistake. The amyloid hypothesis was a great advance, as it provided the first molecular hypothesis for the origins of the disease. To dismiss it totally would be ignore the genetic and other evidence cited by Dennis for its involvement. It would seem to me more profitable to consider that it is likely to be incomplete, and to think about how it fits into a more comprehensive picture that may allow for more effective therapeutic strategy.
Alzheimer A, Förstl H, Levy R. On certain peculiar diseases of old age. Hist Psychiatry. 1991 Mar;2(5 Pt 1):71-101. PubMed.
Goizueta Institute @ Emory Brain Health
Was this the right drug at the wrong time? Or another "wrong" drug? (See Golde et al., 2018).
This is a critical question for the field to answer. There is evidence that this antibody reduces the amyloid PET ligand signal in many trial participants (at least in the Phase 1B study). However, the data, at least those images presented in Sevigny et al. (2016), shows lowering of the signal not just in the cortex but in the white matter as well. So is this antibody truly lowering amyloid in the brain or just altering the amyloid PET (aPET) ligand signal in some other way? Of course the data in the Nature paper was just a few cases which may not be representative. …
As a field we have not yet proven that a reduction in amyloid ligand signal following a treatment equates to a reduction of amyloid in the brain. We need autopsy data to evaluate this relationship. If such data were to reveal a strong correlation between reduction in Aβ accumulation and aPET ligand reduction, that for me would be critical data supporting a move into a secondary prevention trial (API, DIAN-TU, A4/5, etc.). If, however, such pathology data does not provide clear-cut evidence for reduction of amyloid, then we will all need to think critically about a path forward. First, a lack of correlation of pathology with aPET following treatment would call in to question the utility of aPET for target engagement. Second, such data would suggest that aducanumab may not actually be engaging its target as effectively as we presume based on aPET. If the later scenario proves to be the case, then there needs to some serious thinking about additional studies with this drug, until one can prove target engagement in humans. Indeed data from the Bacskai laboratory (Kastanenka et al., 2016) does not provide evidence for amyloid reduction in a preclinical amyloid deposition model.
I have raised this issue about the critical need for autopsy enrollment of trial participants, and I know that there has been some progress in this regard, but this should be a standard part of clinical trial protocol, at least when we are evaluating drugs that are thought to target a pathology. Trial participants are heavily invested in these studies; I think if asked after a few months many will consider brain donation. But we would still need much better coordination between the trial sponsor and the sites that might do autopsies to insure that the clinical data can be synchronized with the autopsy.
Until we have such data all we can do is speculate about right drug at wrong time or wrong drug.
Like many who have commented already, many years ago I wrote, "The medical community should be cautious in evaluating the efficacy of anti-Aβ drugs, as they may not show such disease-modifying effects when given in therapeutic trials. To restate the analogy to atherosclerotic disease, by the time a patient is experiencing angina, the patient needs a bypass or angioplasty, not a cholesterol-lowering agent (although after intervention such an agent would be appropriate). Similarly, in AD, by the time a patient is symptomatic, Aβ-lowering therapies may not be effective." (Golde, 2003.)
So, here we are some 15 years later and that caution looks well-warranted. We need to test the right drugs at the right time and ensure that trials are run in such a way that we get information on how to design a better drug or a better trial with each iteration.
Golde TE, DeKosky ST, Galasko D. Alzheimer's disease: The right drug, the right time. Science. 2018 Dec 14;362(6420):1250-1251. PubMed.
Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, O'Gorman J, Qian F, Arastu M, Li M, Chollate S, Brennan MS, Quintero-Monzon O, Scannevin RH, Arnold HM, Engber T, Rhodes K, Ferrero J, Hang Y, Mikulskis A, Grimm J, Hock C, Nitsch RM, Sandrock A. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature. 2016 Aug 31;537(7618):50-6. PubMed.
Kastanenka KV, Bussiere T, Shakerdge N, Qian F, Weinreb PH, Rhodes K, Bacskai BJ. Immunotherapy with Aducanumab Restores Calcium Homeostasis in Tg2576 Mice. J Neurosci. 2016 Dec 14;36(50):12549-12558. Epub 2016 Nov 3 PubMed.
Golde TE. Alzheimer disease therapy: can the amyloid cascade be halted?. J Clin Invest. 2003 Jan;111(1):11-8. PubMed.
It is difficult to reach an educated conclusion without additional information. But, as many of the commentators agree, once Alzheimer’s disease is obvious, it may be too late, i.e., the damaging amyloid cascade already started, involving other components such as tau. Considering the numerous soluble amyloid aggregates and their diversity, it may be unlikely that a single monoclonal antibody would do the job. Perhaps a combination of neutralizing antibodies would be more effective, but such an approach would increase the cost of treatment to exorbitant levels.
The claims that this “failure” is the end of the amyloid hypothesis are premature. However, as many commentators have indicated, the idea of treating this disease is also somewhat hard to accept, considering that neural cells do not reproduce and the damage is irreversible. Thus, it would be more realistic to focus on prevention, but using the correct approach and avoiding the removal of plaque as the main goal. In fact, as some commentators have indicated, plaque is apparently a protection mechanism. Moreover, some groups have shown that dissolving plaque by solubilizing toxic aggregates increases the damage rather than improving the condition. However, prevention would still be focused on Aβ as the trigger of this disease. But a two-prong approach where Aβ and tau are considered would be advantageous. Indeed, the phosphorylation step, induced by Aβ, is an effective amplifying step for this disease. Thus, a vaccine rationally designed may be an effective way to prevent or delay the onset of disease. Yet, such a vaccine would need to be administered some time before the disease’ onset and when the individuals are still immune competent; otherwise, like the previous vaccines, it will be another failure to be added to the endless list of Alzheimer’s disease disappointments.
It was very disappointing to learn that Biogen plans to close the ENGAGE trial because of lack of efficacy on the interim analysis. We had been eagerly looking forward to the results next year and this came out of the blue. This antibody did not work for patients with early AD, but it remains to be tested if removing plaques before symptoms has a protective effect in people at risk. This outcome provides renewed impetus to explore a wide range of treatment options.
I want to thank our amazing study participants, many of whom have been part of the study for more than five years. Their courage and dedication inspire us every day to develop new treatments to delay and prevent Alzheimer’s disease.
University of Southern California Keck School of Medicine
The outcomes of the aducanumab and crenezumab Phase 3 trials are disappointing but are as expected. Neither of the antibodies showed clinical efficacy evidence in their earlier phase trials. The previous, and regularly repeated, claims of efficacy from those studies, made in presentations and publications, were without scientific or statistical support, and derived from flawed and selective subset analyses. There is no reason to expect efficacy in subsequent trials when the earlier-phase and proof-of-concept trials showed none. Indeed, the aducanumab and crenezumab Phase 3 trials used very large sample sizes aiming to detect very small effects, e.g., less than 0.4 CDR box score points. The failed futility analyses indicate how far wrong the sponsors were in their expectations for even these small effects, as less than half the planned sample would have given definitive results. In my view, these trials are driven more by hope, hubris, and a wagered business proposition than by empirical science or rational drug development.
To be clear, there is plenty of reason to appreciate and confirm the plaque-busting properties of these antibodies, as that’s what they were designed to do and do very well (so, too, did the AN-1792 Aβ vaccine, now over a decade ago). We have known for a while that clearing fibrils and plaques is unlikely to improve clinical function in humans. (Another way to phrase this is that plaques are not validated drug targets in people with early stage AD.)
The optimistic renderings of the early phase outcomes could have been tested with much smaller Phase 3 trials, getting answers more quickly, failing faster, and freeing resources and research volunteers for other therapeutic approaches, including those that target amyloid metabolism differently, and would have expanded clinical drug development knowledge.
Note by comparison, the arguably more appropriate testing of gantenerumab and crenezumab in dominantly-inherited Alzheimer disease is in very different Phase 2 secondary prevention models, and where the illness is generated by amyloid-related PS1 and APP mutations.
Maybe we now collectively take a hard look at dementia drug development and better conceptualize what we do?
CAST, Center for Advanced Studies and Technologynal Medicine University “G. d’Annunzio” Chieti-Pescara
The failure of the Phase 3 aducanumab trial is another warning that the field must take a different approach. Some authors have already called for a rejection of the amyloid hypothesis, new and old players like tau-related pathology microglia activation and neuroinflammation are now looming on the horizon, but the core of the issue is that the reductionist approach that has dominated modern medicine should be abandoned. We need an epistemological leap forward, a change in paradigm, and an embrace of a complex view of the disease as a condition resulting from the converging failure of many health-controlling systems and networks, a condition that is shaped, in each subject, by the combination of the individual “omic” lookout and its modulation by the environment. Moreover, we need to leave behind the illusion that a single bullet/intervention can cure and adopt a systems-biology approach (Greene and Loscalzo, 2017). AD is a multifactorial condition in which, along with Aβ accumulation, the convergence of many genetic, environmental, vascular, metabolic, and inflammatory factors promotes the neurodegenerative process. All these conditions find fertile ground, inside and outside of the central nervous system, provided by the aging process. In that respect, converging approaches targeting co-morbidity factors represent one of the more promising areas of intervention as, at least, we need to remind ourselves that a third of AD cases are strongly dependent on the concerted activity of modifiable factors like low education, midlife hypertension, midlife obesity, diabetes, physical inactivity, smoking, and depression. Within that complex mainframe, drugs that also target the brain amyloidosis or tau-related pathology may find a place to help, but to continue in the pretense that a single drug intervention could fix the problem is futile and a great disservice to our patients and their families. It is time to take up the challenge of complexity.
Greene JA, Loscalzo J. Putting the Patient Back Together - Social Medicine, Network Medicine, and the Limits of Reductionism. N Engl J Med. 2017 Dec 21;377(25):2493-2499. PubMed.
University of Southern California
The results of the recent aducanumab trial is a major disappointment to the field, but it is not surprising. Moving forward, we can learn for the cardiovascular field. Raising HDL cholesterol (HDL-C) did not translate into cardiovascular benefit in several clinical trials despite the strong association of low HDL-C with increased cardiovascular disease risk. The failed trials led to a deeper examination of gene variants and disease risk. Variations in genes that alter HDL-C levels do not change the risk of myocardial infarctions (Voight et al., 2012). It became apparent that HDL-C is not a viable drug target.
Human genome-wide association studies (GWAS) do not identify variants for amyloid proteins as risk factors for late-onset AD. Therefore, assuming that lowering brain amyloid in late-onset AD is a viable drug target is risky. A second assumption was that the pathology in autosomal dominant AD and late-onset AD follow a similar trajectory. This assumption also lacks strong scientific evidence.
Turning to human GWAS, the findings in the recent aducanumab trial should lead us into new directions with exciting targets: APOE, ABCA7, PICALM, TREM2 and many others. The future is bright for AD as we expect more exciting discoveries and translational studies focused on recent advances in genetics.
Voight BF, Peloso GM, Orho-Melander M, Frikke-Schmidt R, Barbalic M, Jensen MK, Hindy G, Hólm H, Ding EL, Johnson T, Schunkert H, Samani NJ, Clarke R, Hopewell JC, Thompson JF, Li M, Thorleifsson G, Newton-Cheh C, Musunuru K, Pirruccello JP, Saleheen D, Chen L, Stewart A, Schillert A, Thorsteinsdottir U, Thorgeirsson G, Anand S, Engert JC, Morgan T, Spertus J, Stoll M, Berger K, Martinelli N, Girelli D, McKeown PP, Patterson CC, Epstein SE, Devaney J, Burnett MS, Mooser V, Ripatti S, Surakka I, Nieminen MS, Sinisalo J, Lokki ML, Perola M, Havulinna A, de Faire U, Gigante B, Ingelsson E, Zeller T, Wild P, de Bakker PI, Klungel OH, Maitland-van der Zee AH, Peters BJ, de Boer A, Grobbee DE, Kamphuisen PW, Deneer VH, Elbers CC, Onland-Moret NC, Hofker MH, Wijmenga C, Verschuren WM, Boer JM, van der Schouw YT, Rasheed A, Frossard P, Demissie S, Willer C, Do R, Ordovas JM, Abecasis GR, Boehnke M, Mohlke KL, Daly MJ, Guiducci C, Burtt NP, Surti A, Gonzalez E, Purcell S, Gabriel S, Marrugat J, Peden J, Erdmann J, Diemert P, Willenborg C, König IR, Fischer M, Hengstenberg C, Ziegler A, Buysschaert I, Lambrechts D, Van de Werf F, Fox KA, El Mokhtari NE, Rubin D, Schrezenmeir J, Schreiber S, Schäfer A, Danesh J, Blankenberg S, Roberts R, McPherson R, Watkins H, Hall AS, Overvad K, Rimm E, Boerwinkle E, Tybjaerg-Hansen A, Cupples LA, Reilly MP, Melander O, Mannucci PM, Ardissino D, Siscovick D, Elosua R, Stefansson K, O'Donnell CJ, Salomaa V, Rader DJ, Peltonen L, Schwartz SM, Altshuler D, Kathiresan S. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet. 2012 Aug 11;380(9841):572-80. Epub 2012 May 17 PubMed.
The next steps in curing Alzheimer’s disease
Two decades ago, the late Dale Schenk initiated studies to treat AD patients by immunotherapy. Since then, an avalanche of clinical studies followed. Unfortunately, none of these trials proceeded beyond Phase 3. Biogen/Eisai‘s decision to halt Aducanumab trials marks, in my opinion, the end of this initially attractive idea.
Of course, BAN2401 and gantenerumab studies are still in the oven and tau immune therapy trials have started. However, here again one can wonder if this makes sense, as the initiation of AD starts much earlier, before the appearance of this specific pathology.
So what’s next?
We suggest the focus should now shift to the cellular phase of AD, as Bart de Strooper and Eric Karran proposed (De Strooper and Karran, 2016), without dismissing the relevance of Aβ deposition.
We followed this reasoning earlier when we discovered ubiquitin mutants in AD patient brains, hinting at an important role for ubiquitin in AD pathogenesis (Van Leeuwen et al., 1998). Indeed, there is crosstalk between the ubiquitin-proteasome system (UPS) and AD pathology (Verheijen et al., 2018). So, in my view, greater focus should be placed on protein quality control (PQC), first by the UPS, hand in hand with autophagy. We hypothesize that if cellular PQC does not work efficiently, this will result in the accumulation and seeding of toxic molecules.
Apart from an emphasis on PQC, much more attention and funding is needed for studies on glia, peripheral factors, removal of senescent cells, a variety of somatic mutations (Verheijen et al., 2018; Lee et al., 2018), RNA biology (Gout et al., 2017), microbiome, etc. Using the rapidly emerging array of new and smart techniques such as specific proteolysis-targeting chimeras, or PROTACs (Scudellari, 2019), we expect much progress in understanding the early cell biological effects initiating AD and related neurodegenerative diseases. This will undoubtedly result in the development of new therapeutic strategies.
De Strooper B, Karran E. The Cellular Phase of Alzheimer's Disease. Cell. 2016 Feb 11;164(4):603-15. PubMed.
van Leeuwen FW, de Kleijn DP, van den Hurk HH, Neubauer A, Sonnemans MA, Sluijs JA, Köycü S, Ramdjielal RD, Salehi A, Martens GJ, Grosveld FG, Peter J, Burbach H, Hol EM. Frameshift mutants of beta amyloid precursor protein and ubiquitin-B in Alzheimer's and Down patients. Science. 1998 Jan 9;279(5348):242-7. PubMed.
Verheijen BM, Stevens JA, Gentier RJ, van 't Hekke CD, van den Hove DL, Hermes DJ, Steinbusch HW, Ruijter JM, Grimm MO, Haupenthal VJ, Annaert W, Hartmann T, van Leeuwen FW. Paradoxical effects of mutant ubiquitin on Aβ plaque formation in an Alzheimer mouse model. Neurobiol Aging. 2018 Dec;72:62-71. Epub 2018 Aug 18 PubMed.
Verheijen BM, Vermulst M, van Leeuwen FW. Somatic mutations in neurons during aging and neurodegeneration. Acta Neuropathol. 2018 Jun;135(6):811-826. Epub 2018 Apr 28 PubMed. Correction.
Lee MH, Siddoway B, Kaeser GE, Segota I, Rivera R, Romanow WJ, Liu CS, Park C, Kennedy G, Long T, Chun J. Somatic APP gene recombination in Alzheimer's disease and normal neurons. Nature. 2018 Nov;563(7733):639-645. Epub 2018 Nov 21 PubMed.
Gout JF, Li W, Fritsch C, Li A, Haroon S, Singh L, Hua D, Fazelinia H, Smith Z, Seeholzer S, Thomas K, Lynch M, Vermulst M. The landscape of transcription errors in eukaryotic cells. Sci Adv. 2017 Oct;3(10):e1701484. Epub 2017 Oct 20 PubMed.
Scudellari M. Protein-slaying drugs could be the next blockbuster therapies. Nature. 2019 Mar;567(7748):298-300. PubMed.
Technical University of Denmark
It was no surprise to me in the field that aducanumab would fail. The reasons are predicted and well-described, for example in the papers listed below.
It has been known for many years that the amyloid hypothesis cannot be correct; the reason it survives is because it is appealingly simple and offers a one-sided treatment strategy that pharma can pursue easily by antibodies and inhibitors.
The main evidence for the role of Aβ in AD was 1) PSEN and APP mutations causing AD relating to Aβ, 2) plaques in the brain consisting of Aβ; 3) toxicity of Aβ in cell and mouse models.
These observations are equally well, I believe better, explained as a stress/loss of the normal function of the peptide. For example, most of the mutations that cause familial AD (PSEN mutations) actually lower total levels of Aβ, just like these drugs do. And already the first toxicity studies showed that Aβ has a therapeutic range, being beneficial at nanomolar concentrations but harmful at micromolar concentrations. In cells, it is present at nanomolar concentrations or below. The toxicity studies used to develop anti-Aβ medicine are mostly acting at micromolar levels.
If you did the same to NaCl (1,000-fold physiological concentration) you would also find that salt is toxic.
It is common in diseases that a symptom (here: plaques) reflects an underlying imbalance. The assumption that the plaques of Aβ are pathogenic ignores the other possibility, that the brain tries to protect itself from an underlying cause and that the plaques reflect this.
We have reviewed the evidence in favor of gain or loss of Aβ function in 2016 and 2017 where we also explain how and why drugs like aducanumab will fail. Its failure was self-evident except to those who have invested money or scientific prestige in a paradigm that has been proven wrong more than any other theory that comes to mind. Unfortunately, these people include, because of the paradigm's previous popularity, major opinion-leaders and big pharma with a responsibility for listening to only some key opinion makers of the dominating paradigm in the time of its sunset.
The multibillion dollar loss reflects yet another sad misplacement of funding and effort in this field, a new clinical proof that emphasis on Aβ as a "bad" molecule is a wrong hypothesis, and a new tragic day for tens of millions of people waiting for an effective treatment of this terrible disease.
Lee HG, Casadesus G, Zhu X, Takeda A, Perry G, Smith MA. Challenging the amyloid cascade hypothesis: senile plaques and amyloid-beta as protective adaptations to Alzheimer disease. Ann N Y Acad Sci. 2004 Jun;1019:1-4. PubMed.
Obrenovich ME, Joseph JA, Atwood CS, Perry G, Smith MA. Amyloid-beta: a (life) preserver for the brain. Neurobiol Aging. 2002 Nov-Dec;23(6):1097-9. PubMed.
Kepp KP. Ten Challenges of the Amyloid Hypothesis of Alzheimer's Disease. J Alzheimers Dis. 2017;55(2):447-457. PubMed.
Kepp KP. Alzheimer's disease due to loss of function: A new synthesis of the available data. Prog Neurobiol. 2016 Aug;143:36-60. Epub 2016 Jun 18 PubMed.
Siemers Integration LLC
Alzheimer’s patients and their families suffered yet another blow when Biogen announced that the EMERGE and ENGAGE Phase 3 trials of aducanumab were being stopped for futility. A more complete understanding of the potential causes of yet another negative trial will await presentation of the data; however, a few general points can be made regarding what the field has learned from an increasing number of negative studies.
First, inhibition of proteases in the brain, both γ-secretase and BACE, is less straightforward than originally hoped. Whether this is related to multiple substrates for these secretases has yet to be determined. Additionally, reduction of plaque burden, at least the neuritic plaques visible by PET, does not guarantee efficacy in patients with cognitive impairment. A corollary finding is that ARIA-E does not predict clinical efficacy.
While results of the Phase 3 crenezumab studies are not yet available, given the relatively high dose of this antibody used in the CREAD studies, targeting monomeric forms of Aβ does not appear to slow cognitive decline in people who have already progressed to having cognitive deficits.
As noted by Dr. Selkoe, other species of Aβ such as oligomers and protofibrils have not thus far been tested as targets in Phase 3 trials. The Phase 3 studies of BAN2401 to be initiated by Eisai will provide a test of protofibrils as a target. Other compounds, both antibodies and small molecules, targeting Aβ oligomers are earlier in development.
Mother Nature unquestionably hides her secrets well, but only by refining the species of Aβ being targeted, and by continuing to move earlier in the disease, can the amyloid hypothesis be sufficiently tested.
I like the important point Todd Golde stresses that it is not yet proven that a reduction in amyloid ligand PET signal following a treatment equates to a reduction of amyloid in the brain. Using in vivo 2-Photon imaging in a preclinical amyloid model (Tg 2576) we revealed that anti-amyloid immunotherapy with a oligomer-specific (A-887755) or a conformation-unspecific (6G1) antibody has absolutely no effect on fibrillar plaque growth and density (Dorostkar et al. 2014). Indeed, we need more autopsy data to evaluate this relationship
Dorostkar MM, Burgold S, Filser S, Barghorn S, Schmidt B, Anumala UR, Hillen H, Klein C, Herms J. Immunotherapy alleviates amyloid-associated synaptic pathology in an Alzheimer's disease mouse model. Brain. 2014 Dec;137(Pt 12):3319-26. Epub 2014 Oct 3 PubMed.
I agree with Todd Golde's and Jochen Herms’s comments. As I mentioned a while ago, there is very little evidence that compact amyloid plaques can be effectively removed. As Jochen said, this would have been easy to demonstrate using longitudinal optical in vivo imaging in mice showing the gradual erosion and removal of plaques following immunotherapy, however, no one has convincingly done so. With regard to the Biogen human PET data showing marked reduction in signal following immunotherapy, I previously raised the concern that the reported decrease in signal is at least partly an imaging artifact. For example, one possibility is that after antibody treatment there is a change in the microenvironment around plaques, such as microglial and astrocyte activation leading to increased plaque encapsulation by glial cells, as shown in the Biogen Nature paper a few years ago (Sevigny et al., 2016) and initially by us (Condello et al., 2015). Could this lead to a change in the pharmacodynamics of the probe, the binding affinity, or elimination of the probes, such that it would lead to overall diminished plaque binding, or a change in the temporal course of binding, resulting in reduced signal, which is erroneously interpreted as a decrease in amyloid plaques?
Regardless of the cause of the decreased PET signal, a broader question is whether it even makes sense to aim at removing amyloid plaques. In our experience with imaging plaques and neuronal dystrophy around them, neuronal pathology is almost fully developed at the initial stages of plaque formation. Therefore, if antibodies are truly able to remove plaques, it is unlikely that they can reverse the damage associated with them, and they may even have deleterious inflammatory effects.
Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, O'Gorman J, Qian F, Arastu M, Li M, Chollate S, Brennan MS, Quintero-Monzon O, Scannevin RH, Arnold HM, Engber T, Rhodes K, Ferrero J, Hang Y, Mikulskis A, Grimm J, Hock C, Nitsch RM, Sandrock A. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature. 2016 Aug 31;537(7618):50-6. PubMed.
Condello C, Yuan P, Schain A, Grutzendler J. Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques. Nat Commun. 2015 Jan 29;6:6176. PubMed.
University of Oxford
Several members have pointed out that the disappointing outcome of the aducanumab trial was not totally unexpected. As Kasper Kepp wrote, there are other hypotheses to account for the association of Aβ with AD. Nine years ago, I asked why we don't reconsider the hypothesis of a causal link in view of failed trials (Smith, 2010) and that question is even more appropriate now (Regland and McCaddon, 2019).
It is disappointing that so little consideration is given to an alternative approach, that of prevention (Smith and Yaffe, 2014), which has been so successful in the cardiovascular field. Many putative risk factors for AD have been identified and trials are urgently needed to see if modifying these will slow disease progression (Peters et al., 2019). For example, raised homocysteine might account for up to 20 percent of dementia (Smith et al., 2018) and lowering homocysteine by B vitamin treatment in MCI markedly slows regional brain atrophy (Douaud et al., 2013) and cognitive and clinical decline (De Jager et al., 2012; Oulhaj et al., 2016). These results are consistent with the criteria for modification of disease progression (Smith and Refsum, 2017) and should encourage others to do trials on other risk factors. Ideally, such trials should be in people with MCI, not at a later stage of the disease. However, it is noteworthy that lowering homocysteine in patients with mild AD did slow cognitive decline (Aisen et al., 2008), although it had no effect in those with moderate AD.
Smith AD. Why are drug trials in Alzheimer's disease failing?. Lancet. 2010 Oct 30;376(9751):1466. PubMed.
Regland B, McCaddon A. Alzheimer's Amyloidopathy: An Alternative Aspect. J Alzheimers Dis. 2019;68(2):483-488. PubMed.
Smith AD, Yaffe K. Dementia (including Alzheimer's disease) can be prevented: statement supported by international experts. J Alzheimers Dis. 2014;38(4):699-703. PubMed.
Peters R, Booth A, Rockwood K, Peters J, D'Este C, Anstey KJ. Combining modifiable risk factors and risk of dementia: a systematic review and meta-analysis. BMJ Open. 2019 Jan 25;9(1):e022846. PubMed.
Smith AD, Refsum H, Bottiglieri T, Fenech M, Hooshmand B, McCaddon A, Miller JW, Rosenberg IH, Obeid R. Homocysteine and Dementia: An International Consensus Statement. J Alzheimers Dis. 2018;62(2):561-570. PubMed.
Douaud G, Refsum H, de Jager CA, Jacoby R, Nichols TE, Smith SM, Smith AD. Preventing Alzheimer's disease-related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci U S A. 2013 Jun 4;110(23):9523-8. PubMed.
de Jager CA, Oulhaj A, Jacoby R, Refsum H, Smith AD. Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial. Int J Geriatr Psychiatry. 2011 Jul 21; PubMed.
Oulhaj A, Jernerén F, Refsum H, Smith AD, de Jager CA. Omega-3 Fatty Acid Status Enhances the Prevention of Cognitive Decline by B Vitamins in Mild Cognitive Impairment. J Alzheimers Dis. 2015;50(2):547-57. PubMed.
Smith AD, Refsum H. Dementia Prevention by Disease-Modification through Nutrition. J Prev Alzheimers Dis. 2017;4(3):138-139. PubMed.
Aisen PS, Schneider LS, Sano M, Diaz-Arrastia R, van Dyck CH, Weiner MF, Bottiglieri T, Jin S, Stokes KT, Thomas RG, Thal LJ, . High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA. 2008 Oct 15;300(15):1774-83. PubMed.
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