Bapineuzumab Phase 3: Target Engagement, But No Benefit
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Bapineuzumab prevents accumulation of Aβ in the brain of patients with mild to moderate Alzheimer’s disease and lowers phospho-tau (p-tau) in their cerebrospinal fluid (CSF), according to analysis presented September 11 at the European Federation of Neurological Societies (EFNS) annual meeting in Stockholm, Sweden. Reisa Sperling, Brigham and Women’s Hospital, Boston, and Stephen Salloway, Brown University, Providence, Rhode Island, reviewed much-anticipated biomarker data from Phase 3 clinical trials of the passive immunotherapy in 1,121 ApoE4 carriers and 1,331 non-carriers, respectively. Despite the positive biomarker results reported yesterday, clinical data released August 6 showed the drug failed to protect patients in these trials from cognitive and functional decline (see ARF related news story). Clinical development of intravenous bapineuzumab in mild to moderate AD patients will end with these trials.
“While we are disappointed with the clinical data, the biomarker evidence indicates target engagement and downstream effects on secondary markers of neurodegeneration without serious safety issues,” Salloway told Alzforum after the meeting. Niels Prins, VU University Medical Center, Amsterdam, The Netherlands, who chaired the session, considers this a positive sign. “It says there might be role for immunotherapy [in Alzheimer’s treatment], but that in order to be effective we may have to give it in the prodromal phase, and maybe even earlier,” he said in an interview with Alzforum. Sperling, Salloway, and other researchers in the field echoed this sentiment. Other researchers had a different interpretation, expressing caution about the safety data. Yet others thought the positive Aβ effects spurious.
Sperling reported that over the 71 weeks of the trial, bapineuzumab, given only once every 13 weeks at 0.5 mg/kg, reduced CSF p-tau. It also kept brain amyloid burden steady in ApoE4 carriers as it gradually increased in the placebo group. The researchers measured amyloid in a subset of patients using PIB PET imaging. In the ApoE non-carrier trial, 1.0 mg/kg of the antibody lowered CSF p-tau and showed a tendency to reduce brain Aβ compared to placebo. Some researchers contacted by Alzforum cautioned that the effect seen in the ApoE4 carrier trial might be due to an uncharacteristic jump in amyloid burden in the last six months of the trial in the untreated group. Most data suggest that amyloid accumulates gradually and has neared its peak by the time patients are symptomatic (see ARF Webinar). The drug sponsors made webcasts of Sperling’s and Salloway’s presentations slides of the two talks freely available on the EFNS website.
With the exception of vasogenic edema (also called ARIA-E or amyloid-related imaging abnormalities due to edema or effusion) and stroke, treated ApoE non-carriers had no more adverse events than untreated controls. However, safety data for the ApoE4 trial showed that 1.8 percent of the treated patients died during the course of the trial, compared to 0.7 percent of untreated patients. That one percent difference would equate to 10,000 additional deaths if one million patients were to be treated. “That is extremely concerning,” said Murali Doraiswamy, Duke University Medical Center, Durham, North Carolina, who is an investigator on the trials. Most of the deaths in the treated ApoE4-positive group resulted from cancer. No more cancer deaths than in the placebo group were seen in the ApoE4-negative trial, however. In her talk, Sperling said that the data monitoring safety board deemed the cancer deaths unrelated to the therapy. “Nonetheless, we would have to be very careful to consider the reasons for that difference before bapineuzumab could be administered to a normal cohort of ApoE4 carriers,” Doraiswamy told Alzforum. Researchers have suggested that bapineuzumab might prove effective if given earlier.
Salloway noted that analysis of PIB PET data in the ApoE4 non-carriers may be subject to strong outlier effects since the number of patients included in the analysis was smaller than expected. More than one third of patients fell below the threshold for amyloid positivity at baseline, and another 25 patients did not come for their planned follow-up scans. Patients not meeting threshold levels for amyloid were a major talking point after the presentations. “Some of these patients are likely misdiagnosed, but there may be other factors involved,” suggested Sperling. Salloway thought there might be technical issues. “We want to look more carefully at that data. Some had CSF taken, so we want to look at that to see if it is non-AD like, as well,” he said. Prins considered misdiagnosis the most likely explanation. Sperling said the figures were actually not that surprising given that, on autopsy, 15-20 percent of AD patients are found to not have had AD, after all. “That’s in the general population. In ApoE4 non-carriers you might expect that number to be higher,” she said. Among the ApoE4 carriers, 95 percent of trial participants tested reached the threshold on PIB PET scans for brain Aβ.
Another key point of discussion at EFNS centered on what to do going forward. “Why do we see evidence of an effect on downstream markers of neurodegeneration but still do not see a clinical effect?” asked Sperling. She suggested that perhaps the treatments are being given too late or the effects are too weak. On the latter, vasogenic edema forced the study sponsors, Janssen Alzheimer Immunotherapy and Pfizer, to drop the highest doses from the trials. Some immunotherapy trials deliver antibody monthly, not every 13 weeks. Other researchers suggested that combination therapy, perhaps with a gamma-secretase inhibitor, might be a better approach. Prins said it will be interesting to see subgroup analysis of the bapineuzumab data. Salloway told Alzforum that additional data will be presented at the American Neurological Association meeting in Boston in October. “We’d like to see an analysis specifically of the mild patients and also see behavioral data,” he told Alzforum. “That is yet to come.”—Tom Fagan.
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Comments
McGill University Faculty of Medicine
The absence of clinical benefits is disappointing, but not surprising at this point, and the adverse events (AEs) are disconcerting. Notwithstanding the AEs, I agree with the investigators' speculation that earlier interventions may be required for benefit, but I am concerned that the next round of trials appears mostly to be aimed at individuals with MCI. As is well known, many such people already have advanced AD pathology in their brains. Hence, I won't be surprised if it proves necessary to go even "further upstream." But how? And with what endpoints?
I have thought for some time that biomarkers will be our last best hope at that stage. At least a positive treatment effect on biomarker endpoints would provide preliminary data to help justify the expense and time commitment for Phase 3 prevention trials. But in this last regard, the disjunction in the bapineuzumab results between biomarker and clinical effects is worrisome. By the time people have established AD dementia, at least, it seems that "target engagement" and biomarker effects don't correlate with clinical benefit. Will the same be true at earlier disease stages? Let us humbly hope not!
Genentech, Inc.
The bapineuzumab biomarker data are modest and confirm the conclusion that this is not a thorough test of the amyloid hypothesis. It is good to see that there appears to be some target engagement, but it is likely the case that both dose levels and frequency were too low to show robust amyloid removal. This means that it is still unclear if mild to moderate AD is too late, or if there was simply not enough drug activity. In other words, it is hard to draw any solid conclusions from these data beyond the point made above (the amyloid hypothesis still needs to be tested in any patient population).
Michigan State University
One concern I have with the bapineuzumab trials is that the doses had to be reduced due to the issue of vasogenic edema (ARIA-E). Although it is uncertain if this is related to the microhemorrhage found in the mouse models and the active vaccine trial, if it is, one might anticipate that other approaches with antibodies lacking effector functions, such as crenezumab, might have better outcomes (due to greater efficacy of higher doses). While it's getting trite to say this, hitting amyloid in cases that are already Braak stage 4-5 (early clinical AD) is unlikely to halt the self-propagating tau pathology. Like every disease, AD will be best approached from a prevention perspective, and it is presymptomatically that the anti-amyloid therapies are most likely to have impact. The reported biomarker changes encourage use of these agents at the earliest stages of the disease.
Independent Consultant (retired)
Viewing the presentations by Reisa Sperling and Stephen Salloway on the Web (many thanks to the EFNS organizers, by the way!), I find it difficult to draw firm conclusions—perhaps apart from the rather worrying thought that we may need to question the suitability of these CSF biomarkers as potential surrogates for clinical effects. In this context, it was surprising that results for total tau levels were not mentioned. It would have been highly interesting to see whether effects on p-tau and t-tau are consistent or not. I hope we will see these results at a later point in time.
Mount Sinai Medical Center
If the results from the bapineuzumab study are taken in the context of Lilly’s prespecified analysis of pooled data from the EXPEDITION and EXPEDITION2 solanezumab trials, subdivided into those with mild versus moderate impairment, it would suggest that treating patients earlier in their cognitive decline could prove beneficial. I predict an interesting discussion at the upcoming ANA meeting in October, in which the solanezumab biomarker data, analyzed by the ADCS group, and further analyses of the bapineuzumab biomarker data will be presented in the same setting. The discussion may also help to answer, at least partially, the question posed by Reisa Sperling regarding why “we see evidence of an effect on downstream markers of neurodegeneration, but still do not see a clinical effect.” Personally, I think this reflects the fact that in the natural course of events, there is a time lag between biomarker and clinical changes. This is similar to what happens in the evolution of the clinical syndrome of Alzheimer’s, and perhaps any neurodegenerative disease, when biomarker changes may precede the onset of the clinical syndrome by years or even decades.
University of Oslo
Yet another devastating result. It seems that there is an important piece in the puzzle missing. All these immunological studies aim for plaque disintegration and measure CSF Aβ. However, intracerebral accumulation of oligomeric Aβ during plaque disintegration could not be revealed so far.
Three years ago, we published our hypothesis about this issue (1). It seems that the blood-brain barrier (BBB) is insufficient in clearing the disintegrated plaque-related Aβ, which thus leads to an accumulation of the more toxic species. Recently, it has become evident that export of Aβ via the BBB is reduced in patients (2), and that ABC transporters may play an important role in the clearance (3,4). Additionally, these transporters exhibit important functions in the regeneration processes in the hippocampus (5).
Do we face here a fundamental problem? Disturbed clearance and regeneration? Both mechanisms are regulated by mitochondrial ATP-production and may also explain the elevation of the disease risk when the "mother was a sufferer" (6).
References:
Pahnke J, Walker LC, Scheffler K, Krohn M. Alzheimer's disease and blood-brain barrier function-Why have anti-beta-amyloid therapies failed to prevent dementia progression?. Neurosci Biobehav Rev. 2009 Jul;33(7):1099-108. PubMed.
Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, Yarasheski KE, Bateman RJ. Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science. 2010 Dec 24;330(6012):1774. PubMed.
Krohn M, Lange C, Hofrichter J, Scheffler K, Stenzel J, Steffen J, Schumacher T, Brüning T, Plath AS, Alfen F, Schmidt A, Winter F, Rateitschak K, Wree A, Gsponer J, Walker LC, Pahnke J. Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice. J Clin Invest. 2011 Oct;121(10):3924-31. PubMed.
Pahnke J, Wolkenhauer O, Krohn M, Walker LC. Clinico-pathologic function of cerebral ABC transporters - implications for the pathogenesis of Alzheimer's disease. Curr Alzheimer Res. 2008 Aug;5(4):396-405. PubMed.
Schumacher T, Krohn M, Hofrichter J, Lange C, Stenzel J, Steffen J, Dunkelmann T, Paarmann K, Fröhlich C, Uecker A, Plath AS, Sommer A, Brüning T, Heinze HJ, Pahnke J. ABC transporters B1, C1 and G2 differentially regulate neuroregeneration in mice. PLoS One. 2012;7(4):e35613. Epub 2012 Apr 24 PubMed.
Scheffler K, Krohn M, Dunkelmann T, Stenzel J, Miroux B, Ibrahim S, von Bohlen und Halbach O, Heinze HJ, Walker LC, Gsponer JA, Pahnke J. Mitochondrial DNA polymorphisms specifically modify cerebral β-amyloid proteostasis. Acta Neuropathol. 2012 Aug;124(2):199-208. PubMed.
Maastricht University; VU University Medical Centre
The observation that bapineuzumab lowers CSF phospho-tau (p-tau) levels is intriguing. It is consistent with the finding from the AN1792 study that immunization with aggregated β amyloid is associated with a reduction of CSF total tau levels (1). Both p-tau and total tau are released during axonal degeneration. The trial findings provide in-vivo evidence for the idea that aggregated Aβ is neurotoxic, and that the neurotoxicity can be partly reversed by removal of the aggregated Aβ. Moreover, they suggest that the removal of Aβ and any associated inflammatory reaction itself is not neurotoxic, as tau levels would then be expected to increase. This is in line with neuropathological data from the AN1792 study (2). So removal of aggregated Aβ could be a good thing, but may not be sufficient to improve patients clinically, at least if they have mild to moderate AD. Prevention of aggregated Aβ rather than clearance may therefore be preferred, either by starting immunotherapy in a very early stage of the disease or by using alternative treatment strategies.
References:
Gilman S, Koller M, Black RS, Jenkins L, Griffith SG, Fox NC, Eisner L, Kirby L, Rovira MB, Forette F, Orgogozo JM, . Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology. 2005 May 10;64(9):1553-62. PubMed.
Boche D, Denham N, Holmes C, Nicoll JA. Neuropathology after active Abeta42 immunotherapy: implications for Alzheimer's disease pathogenesis. Acta Neuropathol. 2010 Sep;120(3):369-84. PubMed.
AbbVie
One has to take conclusions about "target engagement" with a huge grain of salt.
In the 302 Study, we are talking about less than 20 percent of subjects providing CSF data, and less than 11 percent providing PIB data. No data are available on their baseline demographics or cognitive status, or on the rate of progression of these subsets of subjects to help us understand how representative these subjects are. The PIB data from the 302 Study don't show any reduction in the treated subjects. The statistical separation is due to a large increase in PIB signal in the placebo-treated subjects. With regards to the CSF data, the lack of data on the effects of treatment on CSF β amyloid levels is troubling. Additionally, the effect on p-tau is contrary to what has been predicted by the biomarker community: increases in p-tau in the placebo-treated patients and stabilization in the bapineuzumab-treated subjects.
In the 301 Study, we are talking about less than 14 percent of subjects providing CSF data, and less than 4 percent providing PIB data. The same concerns about subgroups apply to this study. The PIB data from the 301 Study suggest either absolutely no effect on Aβ (1.0 mg/kg dose) or actually increasing Aβ (0.5 mg/kg dose). In this study, the placebo-treated subjects had a large decrease in PIB signaling in the latter half of the study. The CSF data from the 301 Study are also noticeable for the absence of any data on Aβ. The p-tau data suggest no effect at the 0.5 mg/kg dose, and a reasonable effect at the 1.0 mg/kg dose.
So, at the end of the day, we are left with data from small subgroup analyses whose demographics and cognitive characteristics remain to be reported. We have inconsistent effects on PIB imaging in the placebo-treated subjects from one study to another and it's the changes in the placebo-treated subjects that are responsible for the statistical separation. We are also left with inconsistent effects on CSF p-tau and no data on CSF Aβ. I don't quite see the target engagement, at least not yet.
Over-interpretation of subgroup analyses, lack of control over bias, and using them as the rationale for pushing ahead with additional large studies are, in my humble opinion, some of the reasons we have to keep on explaining to patients that yet another promising drug has failed.
Caveat emptor.
Vice President, The Institute for Molecular Medicine
Immunotherapy is a potentially powerful strategy for reducing the level of Aβ in the brain. Antibodies specific to Aβ facilitate the clearance of amyloid deposits and improve behavioral deficits in APP/Tg mice (1-11). Based on these impressive results generated in different mouse models of AD, and the lack of adverse reactions, many companies began active or passive vaccinations trials in patients with mild to moderate AD pathology.
It is well known that the first trials with the AN1792 vaccine, which consisted of fibrillar Aβ42 as the immunogen and a strong Th1-type adjuvant, QS21, had to be halted because approximately 6 percent of the volunteers developed some degree of meningoencephalitis (infiltration of T cells and macrophages). However, from these AN1792 trials, we learned very important lessons:
1. Immunotherapy could reduce the Aβ load in AD patients who respond to vaccinations with generation of sufficient titers of anti-Aβ antibodies (responders).
2. Anti-Aβ-specific T cells may induce significant side effects in AD patients vaccinated with full-length Aβ42.
3. CSF tau, but not Aβ42, levels were reduced in responders.
4. Analysis of a neuropsychological test battery (NTB) z-score revealed differences favoring responders versus placebo.
5. The beneficial effects were observed in two patients who suffered transient attacks of meningoencephalitis, and the degree of protection was correlated with the titer of the antibodies binding to Aβ plaques.
6. Responders to AN1792 immunizations had significantly greater brain volume decreases and greater ventricular enlargements as a percentage of baseline brain volume.
Thus, published results of the AN1792 vaccine trials (12-21) demonstrated that immunotherapy could be useful for current and future human trials if we can come up with the best design of a potent vaccine and the right time for application.
Almost 10 years after the AN1792 trials, we learned again, now from Pfizer/Janssen AIP's and Eli Lilly’s passive vaccination trials, a similar lesson: that immunotherapy might be safe and effective, but only when initiated very early in AD pathology. Specifically, on 6 August 2012, Pfizer announced that administration of bapineuzumab failed to improve cognitive or functional performance in patients with mild to moderate AD compared with the placebo group. These data have been generated in patients who carry or do not carry the ApoE4 genotype associated with the risk of AD. More recently, at the European National Federation of Neurological Societies annual meeting in Stockholm, we learned about biomarker results in participants of bapineuzumab trials in both ApoE4 carriers (Study 302) and non-carriers (Study 301). (Of note, I would like to thank the drug sponsors, who made it possible for us to hear and see Dr. Sperling’s and Dr. Salloway’s presentations on the meeting website.)
While no treatment differences in PIB PET have been detected in Study 301, we should mention that researchers measured amyloid only in a subset of patients (n = 12 for 1 mg/kg and n = 12 for 0.5 mg/kg vs. placebo n = 15). Even with these small numbers of participants, the researchers detected some changes in the amyloid burden at weeks 45 and 71 in patients receiving 1 mg/kg of antibody compared to placebo. Importantly, in patients who obtained this dose of bapineuzumab, the researchers showed a significant decrease of CSF p-tau (p = 0.009). These data somewhat supported previously published results from AN1792 trials and suggest that higher concentrations of antibodies (1 mg/kg vs. 0.5 mg/kg) may be needed for lowering brain amyloid and also p-tau in the CSF.
More importantly, in Study 302, administrations of 0.5 mg/kg of antibodies significantly reduced the amyloid burden (n = 75 vs. n = 40 placebo) and CSF p-tau (n = 127 vs. n = 85 placebo) in ApoE4 carriers. Here I should mention that: 1) no significant differences were detected in the amyloid burden at week 0 (baseline) and at week 71 in the bapineuzumab group; 2) the Aβ level unusually increased at week 71 in the placebo group. However, data from studies 301 and 302 still may suggest that carefully designed immunotherapy initiated at very early stages of AD, or even in asymptomatic subjects at risk of AD, may lead not only to an effective reduction in brain Aβ levels, but also to the prevention of tau pathology and improvements in cognitive function.
Information from Eli Lilly’s trials also supports this idea of early treatment: Solanezumab was not effective in two separate studies; however, analysis of pooled data across both studies showed a statistically significant slowing of cognitive decline in vaccinated patients with mild, but not moderate, AD. Thus, collectively, passive vaccination results from both Pfizer and Eli Lilly suggest that immunization should be initiated in humans as early as possible to minimize synaptic and neuronal loss.
The optimal time to initiate immunotherapy for AD has been discussed in multiple reviews written by leading scientists and published in two special issues of the CNS & Neurological Disorders-Drug Targets (22). Even in patients with the earliest stages of AD, neuropathological changes are already established, as illustrated by the prevalence of diffuse and neuritic plaques, as well as neuronal loss (23). I believe this is the reason why the AN1792 active vaccination trials and two passive immunotherapies discussed above were not ultimately efficacious. And that is why I would not be surprised if all of the currently ongoing passive and active vaccination trials (24,25) will not be effective in patients with mild to moderate AD pathology, either.
If we want to understand the efficacy of the immunotherapeutic strategy, we have to begin clinical trials before AD pathology is established. That is why the National Alzheimer’s Project recently approved anti-A clinical trials in presymptomatic FAD subjects whose disease progression is well defined and predictable, and who ultimately should succumb to the disease (see ARF related news story). Although there are a limited number of asymptomatic gene carriers available for such studies (FAD represents It is evident to me as a vaccine researcher and immunologist that a passive vaccination strategy is not useful for preventive treatment. However, if an immunologically potent active vaccine is safe, it could be used for the successful vaccination of the general population. I would like to comment that the generation of preventive vaccines is much more achievable than the generation of a therapeutic vaccine. To the best of my knowledge, only one FDA-approved therapeutic vaccine exists. This prostate cancer vaccine (sipuleucel, trade name Provenge) could only increase the median overall survival time by up to 4.5 months. Thus, all available data point us in the direction of aiming to create a safe and effective active preventive vaccination strategy for AD if pathological forms of Aβ and tau are the right targets for such a vaccine.
See also:
CNS Neurol Disord Drug Targets 8, issues 1&2 (2009); and Ghochikyan, A. & Agadjanyan, M. G. CAD-106, a beta-amyloid-based immunotherapeutic for Alzheimer's disease. Thompson Reuter (2012).
References:
Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999 Jul 8;400(6740):173-7. PubMed.
Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, Duff K, Jantzen P, DiCarlo G, Wilcock D, Connor K, Hatcher J, Hope C, Gordon M, Arendash GW. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature. 2000 Dec 21-28;408(6815):982-5. PubMed.
Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt SD, Chishti MA, Horne P, Heslin D, French J, Mount HT, Nixon RA, Mercken M, Bergeron C, Fraser PE, St George-Hyslop P, Westaway D. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature. 2000 Dec 21-28;408(6815):979-82. PubMed.
Chen G, Chen KS, Knox J, Inglis J, Bernard A, Martin SJ, Justice A, McConlogue L, Games D, Freedman SB, Morris RG. A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer's disease. Nature. 2000 Dec 21-28;408(6815):975-9. PubMed.
Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen M, Soriano F, Vasquez N, Weiss K, Welch B, Seubert P, Schenk D, Yednock T. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med. 2000 Aug;6(8):916-9. PubMed.
Schenk D. Amyloid-beta immunotherapy for Alzheimer's disease: the end of the beginning. Nat Rev Neurosci. 2002 Oct;3(10):824-8. PubMed.
DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8850-5. Epub 2001 Jul 3 PubMed.
Demattos RB, Bales KR, Parsadanian M, O'Dell MA, Foss EM, Paul SM, Holtzman DM. Plaque-associated disruption of CSF and plasma amyloid-beta (Abeta) equilibrium in a mouse model of Alzheimer's disease. J Neurochem. 2002 Apr;81(2):229-36. PubMed.
Holtzman DM, Bales KR, Paul SM, Demattos RB. Abeta immunization and anti-Abeta antibodies: potential therapies for the prevention and treatment of Alzheimer's disease. Adv Drug Deliv Rev. 2002 Dec 7;54(12):1603-13. PubMed.
Movsesyan N, Ghochikyan A, Mkrtichyan M, Petrushina I, Davtyan H, Olkhanud PB, Head E, Biragyn A, Cribbs DH, Agadjanyan MG. Reducing AD-like pathology in 3xTg-AD mouse model by DNA epitope vaccine - a novel immunotherapeutic strategy. PLoS One. 2008;3(5):e2124. PubMed.
Petrushina I, Ghochikyan A, Mktrichyan M, Mamikonyan G, Movsesyan N, Davtyan H, Patel A, Head E, Cribbs DH, Agadjanyan MG. Alzheimer's disease peptide epitope vaccine reduces insoluble but not soluble/oligomeric Abeta species in amyloid precursor protein transgenic mice. J Neurosci. 2007 Nov 14;27(46):12721-31. PubMed.
Orgogozo JM, Gilman S, Dartigues JF, Laurent B, Puel M, Kirby LC, Jouanny P, Dubois B, Eisner L, Flitman S, Michel BF, Boada M, Frank A, Hock C. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology. 2003 Jul 8;61(1):46-54. PubMed.
Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med. 2003 Apr;9(4):448-52. PubMed.
Ferrer I, Boada Rovira M, Sánchez Guerra ML, Rey MJ, Costa-Jussá F. Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer's disease. Brain Pathol. 2004 Jan;14(1):11-20. PubMed.
Gilman S, Koller M, Black RS, Jenkins L, Griffith SG, Fox NC, Eisner L, Kirby L, Rovira MB, Forette F, Orgogozo JM, . Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology. 2005 May 10;64(9):1553-62. PubMed.
Fox NC, Black RS, Gilman S, Rossor MN, Griffith SG, Jenkins L, Koller M. Effects of Abeta immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology. 2005 May 10;64(9):1563-72. PubMed.
Hock C, Nitsch RM. Clinical observations with AN-1792 using TAPIR analyses. Neurodegener Dis. 2005;2(5):273-6. PubMed.
Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA. Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet. 2008 Jul 19;372(9634):216-23. PubMed.
Boche D, Denham N, Holmes C, Nicoll JA. Neuropathology after active Abeta42 immunotherapy: implications for Alzheimer's disease pathogenesis. Acta Neuropathol. 2010 Sep;120(3):369-84. PubMed.
Uro-Coste E, Russano de Paiva G, Guilbeau-Frugier C, Sastre N, Ousset PJ, da Silva NA, Lavialle-Guillotreau V, Vellas B, Delisle MB. Cerebral amyloid angiopathy and microhemorrhages after amyloid beta vaccination: case report and brief review. Clin Neuropathol. 2010 Jul-Aug;29(4):209-16. PubMed.
Kokjohn TA, Roher AE. Antibody responses, amyloid-beta peptide remnants and clinical effects of AN-1792 immunization in patients with AD in an interrupted trial. CNS Neurol Disord Drug Targets. 2009 Apr;8(2):88-97. PubMed.
Tarawneh R, Holtzman DM. Critical issues for successful immunotherapy in Alzheimer's disease: development of biomarkers and methods for early detection and intervention. CNS Neurol Disord Drug Targets. 2009 Apr;8(2):144-59. PubMed.
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Barrow Neurological Institute
The data from the bapineuzumab trial presented at EFNS has been highly informative, if not disappointing. It reinforces, conceptually, that amyloid and cognition are not related. This has been debated for over 40 years, dating back to Blessed, Tomlinson, and Roth's seminal work in the British Medical Journal (see Blessed et al., 1968). Thus, clearance of amyloid cannot and should not be tied to a cognitive measure. Underscoring that point is clear evidence from the 301 and 302 studies of target engagement in ApoE4 non-carriers and carriers, respectively. With reduction of CSF tau and reduction of PIB in the 302 study, it is quite apparent the bapineuzumab removes amyloid and potentially influences neurodegeneration. However, doing so did not result in a cognitive benefit, which means there is a disconnect between amyloid removal and stabilization of symptoms.
Many in the field are also concerned that the time of the dosing is too late. Symptomatic Alzheimer's disease might be likened to metastatic cancer, which is more treatment resistant in advanced stages. The findings from the bapineuzumab study suggest that treatment of symptomatic mild to moderate AD might be too late. Other concerns surrounding the study relate to the safety and dosing regimen. Specifically, was the choice of the dose too low because of safety concerns about ARIA E and ARIA H? Conversely, might a higher dose, which would result in more adverse events and serious adverse events (as illustrated by the 2 mg/kg arm), also be more likely to demonstrate benefit?
Many are suggesting that the amyloid theory is dead. The bapineuzumab study leaves more questions than answers.
References:
Blessed G, Tomlinson BE, Roth M. The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects. Br J Psychiatry. 1968 Jul;114(512):797-811. PubMed.
Albert Einstein College of Medicine
The simplest interpretation of the bapineuzumab results is that amyloid, and probably Aβ, are not the principal cause of dementia in AD.
Henan Academy of Innovations in Medical Science
In the cold light of day, it is clear to scientists who are not directly involved in the trials, and do not have a personal interest in this area, that the antibody treatment is not working. There is a reduction of biomarkers, but there also may be some undercurrent inflammatory response induced by the immunization, which may well explain why these people did not improve, despite the reduction in plaque load. Remember, the problem supposedly is not the plaques themselves, which are just inert junkyards of protein fragments, but the chronic inflammation response that they induce. Therefore, if the immunization increases the inflammation response, it is not really helping the patients at all. Simple biomarkers such as plaque load need to be seen in context.
I personally would not invest in the concept of active or passive immunization. The clinical trial results have been consistently disappointing, or even devastating. There are better ideas out there, for example, the use of growth factors that activate cell repair systems. I am at a loss as to why industry keeps investing in failed concepts and then complains that Alzheimer's disease is too complicated.
KULeuven
It is still amazing how many scientists in this field want to believe instead of look at facts and interpret them:
Plenty of evidence says amyloid is "bad" and involved in pathology (AD); not enough evidence says it is "good," i.e., normal function in physiology.
We have to try every trick in the book to cure AD—whether you believe in the trick or not is irrelevant.
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