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Reeling In Biomarker Data in Young Carriers, API Rocks Staging Boat
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This is Part 2 of a three-part series. See also Part 1 and Part 3. Download a PDF of the entire series.
23 December 2011. In the second half of 2011, scientists driving the Alzheimer's Prevention Initiative have been reporting at scientific conferences the first emerging biomarker findings from their human volunteers. These data provide tantalizing glimpses of what happens in the brains of young people carrying a deterministic Alzheimer's disease mutation when they are still in their twenties and thirties. While these imaging and fluid data at present represent but small snapshots of the disease 25 years before dementia, they nonetheless suggest that a quiet drama unfolds in the Alzheimer's-bound brain years before amyloid. “At present, it looks as if functional and structural changes may occur prior to fibrillar amyloid deposition,” Adam Fleisher of the Banner Alzheimer’s Institute said in a talk at the Clinical Trials in Alzheimer’s Disease (CTAD) conference held 3-5 November 2011 in San Diego, California. If further data substantiate those initial findings, and if the findings generalize to late-onset Alzheimer’s, they would then call for a refinement of the proposed biomarker staging diagrams that have captured the imagination of Alzheimer’s disease researchers worldwide.
Fleisher belongs to a large collaborative team of scientists who have been developing the API as a program meant to pioneer secondary prevention trials in people who are at high risk of developing Alzheimer’s disease. Led jointly by Eric Reiman and Pierre Tariot at the Banner Alzheimer’s Institute in Phoenix, Arizona, and Francisco Lopera at the Universidad de Antioquia, Medellin, Colombia, the API has been doing the groundwork preparing for such trials in people who carry autosomal-dominant mutations that will give them the disease with near certainty. (The API also prepares for trials in aging people who carry the ApoE4 risk allele.) “There are many people who are at very high risk of AD who are clamoring for therapeutic trials,” Tariot said.
The Initiative’s autosomal-dominant half is complementary to the Dominantly Inherited Alzheimer Network (DIAN, ARF related story), and its late-onset half is complementary to the A4 initiative. Together, the three programs share the goal of breaking ground on secondary prevention drug trials across the AD spectrum. That is, they range from rare, deterministic AD genetics on one end to risk genetics in the middle, and to the most common forms of late-onset AD on the other end. Success in any and all of these trials could energize earlier-stage trials throughout the field, the scientists believe. However, each program is also unique in some aspects. DIAN has fewer patients than the API, but subsumes all APP and presenilin mutations; A4 is potentially the largest study, but further behind in terms of funding and driven by biomarkers, not genetics. Along the way of gathering observational data and planning their respective programs, the leaders of all three meet frequently to work out where they can coordinate to enhance each other’s goals and ensure that their respective datasets can be analyzed together.
So what’s new with API since its last update on Alzforum (see ARF API series)? In 2011, the researchers have enrolled some 1,300 relatives of the Colombian families afflicted with the E280A Paisa mutation in presenilin 1 into the observational biomarker and cognitive study phase meant to precede treatment trials. About a third are carriers. The scientists hope to bring the number of participants to 3,000 and the number of carriers close to a thousand by 2013.
That goal—as indeed all key goals of API, DIAN, and A4—hinges on new funding coming forward. In the case of API, its leaders are currently awaiting final review by the National Institute on Aging of a pending grant proposal for the first treatment trial with an identified (but undisclosed) experimental drug while simultaneously stitching together a funding coalition of company money and private philanthropy.
In the meantime, the scientists have expanded their original biomarker studies with the Colombian participants that started in 2010. In 2011, the scientists, led by Fleisher and Yakeel Quiroz, currently at Boston University, added new cohorts of cognitively older adults in age brackets from age 35 and up, all the way back to children aged eight to 17. The children are not undergoing spinal taps, but they are donating a blood sample and, importantly, lying still in the scanner for various modalities of magnetic resonance imaging.
Why children? The scientists want to chronicle the entire natural history of this form of AD from its beginning, meaning they will trace back at what age biomarker measurements begin to diverge between carriers and their non-carrying siblings. In the next-older age bracket—the 18- to 26-year-olds—mutation carriers already show distinct differences in brain function and even structure. Hence, Quiroz and colleagues reached back with the less invasive tests into even younger ages.
To date, MRI has been taken from some 200 volunteers age eight and up. This happens on a Siemens 1.5T scanner at the Hospital Pablo Tobón Uribe in Colombia. “MRI capability is very good there for API studies,” Tariot told the audience at CTAD. Plasma has been taken from some 130 volunteers age eight and up, CSF from some 90 people age 18 and older. Fluids are being drawn in Medellin following standard acquisition, preparation, storage, and shipping directions developed for DIAN. They are analyzed in the lab of Anne Fagan at Washington University, St. Louis, Missouri, to ensure that data are comparable with CSF measures in the DIAN and, indeed, the Alzheimer’s Disease Neuroimaging Study (ADNI). PET imaging with florbetapir started up in September, when the first of what will be 50 participants flew to Bogotá, and from there to Miami and then Phoenix for FDG metabolic and amyloid imaging with florbetapir (see NYT coverage). These people will travel to Phoenix in small groups to get PET studies going until a cyclotron that is currently under construction near Medellin can start providing labeled ligand for a local PET scanner that began operating in October 2011. “This travel is logistically challenging, and the team in Medellin is absolutely amazing in coordinating it,” Fleisher said.
All the above measures are also being taken in a much smaller group of relatives already affected with mild cognitive impairment or AD. The goal is to take sufficient biomarker measurements to pinpoint the earliest divergence between carrier and non-carrier for each of them, trace them forward into symptomatic AD, and integrate this information into a staged natural history of this form of Alzheimer’s. This information can then serve as a foundation for treatment trials, first in this population, but also, together with similar data from DIAN longitudinal biomarker studies of ApoE4 cohorts and ADNI and AIBL cohorts, for prevention trials in late-onset AD (LOAD). “Ultimately, we want to use treatment trials in early-onset AD as models for late-onset AD,” Fleisher said.
What are the results so far? The data for the children and adolescents are not available yet. But as shown at conferences, data for people in their twenties are trickling in, and they show functional and even subtle structural brain changes that appear to precede amyloid deposition. Specifically, carriers had abnormalities compared to their non-carrying siblings and cousins in their brain activation patterns when they performed an established fMRI task asking them to associate and subsequently remember face-name pairs (Sperling et al., 2001). Carriers performed the task as well as non-carriers, but in doing so, they activated their hippocampi more strongly and deactivated their precuneus brain area less strongly. This is essentially the same pattern of change as previously reported for the later preclinical stages of other forms of early-onset AD and, indeed, late-onset AD. Quiroz and colleagues presented these data at the Alzheimer’s Association International Conference (AAIC) in Paris in July 2011.
Also at this conference, Fleisher and colleagues presented a poster suggesting that this same group of twenty-somethings already have subtle morphological changes—meaning atrophy—in their brains. In a whole-brain comparison of gray matter volume between carriers and non-carriers, the 20 carriers had less gray matter in their temporoparietal and parahippocampal brain areas than 24 non-carriers who were otherwise matched in age, sex, education, and cognitive test scores. It’s well established that atrophy accelerates three to five years before dementia onset (e.g., Ridha et al., 2006). In this earlier work, the new signature may not have come up because the group was smaller, the imaging was not generally done in people this young, and what was done used more global measures of how the boundaries of regions of interest shift. The new API research uses voxel-by-voxel comparisons independent of regions of interest in people twenty years younger than their expected age at onset.
MRI offers a growing number of increasingly sensitive measures for AD research, and the API team put one more to the test. In a cohort of 18 mutation carriers and 22 controls in their thirties to early forties, Quiroz and colleagues worked with Brad Dickerson at Massachusetts General Hospital, Boston, to look for the cortical thinning signature Dickerson had developed in four previous studies in mild LOAD, MCI conversion to AD, and cognitively normal people who have amyloid and are being followed longitudinally. Dickerson had pinpointed nine regions of interest per hemisphere and found that atrophy, as measured by a thinner cortex in those regions, predicted that a cognitively normal person would develop dementia some eight years prior (Dickerson et al., 2011).
This is the first study of cortical thinning in the API population. In this cohort, mutation carriers on average had a 4.75 percent thinner cortex in these regions, Quiroz reported at AAIC in Paris. Most shrunken, by 6 to 8 percent, were the angular gyrus, the superior parietal lobule, and the precuneus regions. All nine regions showed a trend in the same direction, though not all are statistically significant, Quiroz said. Consistent with previous studies in other populations, these results point to neurodegeneration well underway by this stage, which in this population corresponds to what is generally called pre-MCI. With the Paisa AD mutation, affected carriers generally meet MCI criteria by age 44, a bit older than this cohort. In neuropsychological testing, this cohort, whose average age was 38, performed similarly overall to the non-carriers, though trends toward subtle decrements in word recall, verbal fluency, and recall of drawings were apparent. The earliest known cognitive deficit clearly demonstrated in this form of AD—in carriers in their thirties just like the ones studied for cortical thinning—is the visual binding memory deficit reported by Mario Parra and colleagues (see ARF related news story; Acosta-Baena et al., 2011 and Parra et al., 2010).
How do all these findings on brain imaging relate to Aβ? Amyloid PET results from API are unavailable as yet, but the first CSF and plasma data are beginning to roll in. At AAIC, Reiman presented the first cut, on 10 carriers and 10 non-carriers in the 18-26 age bracket. At this age, cognitive tests detect no difference, but brain function and structure measurements do. So far, Reiman reported, it looks as if carriers have elevated plasma Aβ42 but not Aβ40, suggesting that the presenilin 1 E280A mutation raises systemic absolute levels of this more aggregation-prone form of the peptide, as well as the Aβ42/40 ratio. (To some audience members, this finding hinted that middle-age elevated plasma Aβ42 might prove to be a risk factor in the general population as well.)
In CSF at this age, Aβ42 but not Aβ40 is elevated as well in carriers over non-carriers, Reiman reported at AAIC. This is consistent with the DIAN’s prior finding of elevated Aβ42 in carriers of a variety of early-onset AD mutations in their twenties (see ARF DIAN London story; see ARF DIAN Honolulu story). Scientists generally assume that this reflects overproduction of Aβ, implying elevated levels of the peptide in the brain at an age where there is no fibrillar amyloid deposition yet. Not everything fits neatly, though: The same study finds a paradoxical reduction of CSF tau in carriers at this young age, upwards of 20 years prior to dementia, Reiman noted at AAIC.
What does this mean? It’s too early to make a strong statement, and it’s not proven that this form of early-onset AD models LOAD, both Fleisher and Reiman cautioned in separate conversations. “Even so, at present it looks as if the functional and structural brain changes precede fibrillar amyloid deposition,” Reiman said, noting that this would be consistent with published work on reduction on FDG PET or in mitochondrial glucose metabolism in young adult ApoE4 carriers. Some studies are beginning to hint that fibrillar amyloid deposition, as visible by PET, happens soon after CSF Aβ42 has begun to drop. It is tempting, then, to speculate that the early functional and structural changes that Quiroz, Fleishman, and colleagues see might be happening in a situation of years of elevated Aβ levels but prior to when the brain deposits and, presumably, sequesters. This could imply that fibrillar amyloid deposition is an attempt by the brain to mitigate damage to synapses from an overabundance of prefibrillar forms of AD, Reiman said.
Both API and DIAN are pressing to add both cross-sectional and longitudinal data so they can address at what ages CSF Aβ42 starts dropping and how all markers the studies are tracking fit together. “More data on larger numbers of volunteers will sort this out,” Fleisher said. In the process, the currently proposed staging diagrams of preclinical (e.g., Perrin et al., 2009; Jack et al., 2010; Weiner et al., 2010; Frisoni et al., 2010) may get updated as some curves change their shape and slope or even trade places.
The result will be a knowledge base on the natural history of AD as a foundation for better clinical trials. For now, the API scientists are planning a first clinical trial as outlined in its pending grant proposal to the NIA, provided they can secure an appropriate compound, funding, and regulatory and ethical approval. At CTAD, Tariot emphasized that this trial is designed without pre-formed assumptions on which biomarker patterns will prove to be good outcome markers. Instead, it is designed precisely to address this question. “We must be humble about what we know,” Tariot said at CTAD, noting that regulators had advised API in previous planning meetings that their first trial should use a cognitive endpoint and include many biomarker readouts as secondary endpoints in order to learn as much as possible about them. Because the field does not know which biomarkers will prove to be outcome measures and how they will behave in response to a drug, the current trial is primarily frequentist with some adaptive elements. “We lack sufficient natural history data to build the computer models for a true Bayesian trial, and we have to be agnostic about the ability of biomarkers to predict treatment response. This is why we are not ready to use a Bayesian model yet,” Tariot said.
The proposed API trial, then, would use a change in a composite cognition measure as the primary outcome, looking for a slower rate of decline on drug versus placebo. Jessica Langbaum at the Banner Institute and colleagues elsewhere are developing this measure (see ARF related news story). Because this change will emerge slowly, the trial needs to be large and long. As proposed, the trial would enroll 300 participants. Two hundred carriers would be randomized 1:1 to treatment or placebo so no one would have to find out his or her mutation status; 100 non-carriers would be on placebo. The trial would feature an interim analysis after two years, guided by rules that assume biomarkers will change before cognition does. If the trial shows a positive biomarker pattern and/or clinical trends, then it will continue to five years, long enough to learn whether favorable cognitive changes are detectable.
Overall, the Alzheimer’s research field went from thinking a few years ago that this is too out-of-the-box to multiple groups now doing the same thing. In particular, industry scientists previously pointed to the absence of a regulatory path (see ARF eFAD essays). That path is clearer now, and involvement and support on the part of regulators have been evident. “The feedback from the regulatory scientists to API and DIAN has been incredibly valuable,” Tariot told the audience at CTAD (see ARF related news story; ARF news story). With an emerging regulatory path, the patients, the protocols, the tools, and some biomarker data in hand, researchers know the fate of those initial trials at this point would seem to lie squarely in the hands of funders.—Gabrielle Strobel.
This is Part 2 of a three-part series. See also Part 1 and Part 3. Download a PDF of the entire series.
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Comments on Related News |
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Related News: DIAN Dispatch from Hawaii: Glimpse at Data, Push for Trials
Comment by: Vincent Marchesi, ARF Advisor
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Submitted 20 July 2010
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Posted 23 July 2010
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One can only applaud the courage and commitment of the investigators involved in this study. It is surely a wise move to follow people with dominant mutations who are clearly at risk for clinical AD, and the markers to be studied are probably the best available.
But I'd still like to ask two questions: How sure are we that the accumulation of amyloid seen by scanning and the CSF levels of Aβ and tau that are being measured do indeed reflect the earliest pathogenic mechanisms that lead to symptomatic AD?
Secondly, is this the best time to couple this study with a battery of untested experimental therapies? No one is more aware than I of the desperate need for effective treatments, and the pressure on the investigators to add them to the study must surely be suffocating. My concerns are these: Although the evidence linking amyloid Aβ to AD is overwhelming, we still don’t know how or when it becomes toxic, and, equally important, whether other factors, such as inflammation, oxidative damage, and vascular injury are just as critical to the development of clinical disease....
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One can only applaud the courage and commitment of the investigators involved in this study. It is surely a wise move to follow people with dominant mutations who are clearly at risk for clinical AD, and the markers to be studied are probably the best available.
But I'd still like to ask two questions: How sure are we that the accumulation of amyloid seen by scanning and the CSF levels of Aβ and tau that are being measured do indeed reflect the earliest pathogenic mechanisms that lead to symptomatic AD?
Secondly, is this the best time to couple this study with a battery of untested experimental therapies? No one is more aware than I of the desperate need for effective treatments, and the pressure on the investigators to add them to the study must surely be suffocating. My concerns are these: Although the evidence linking amyloid Aβ to AD is overwhelming, we still don’t know how or when it becomes toxic, and, equally important, whether other factors, such as inflammation, oxidative damage, and vascular injury are just as critical to the development of clinical disease. Does this overwhelming focus on amyloid as the primary culprit divert attention and resources away from the study of these other factors? If we continue to ignore them, the best designed therapies for the control of amyloid may be rendered ineffective.
 View all comments by Vincent Marchesi |
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Related News: London: What Regulators Say About Trials in Familial AD
Comment by: René Spiegel
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Submitted 9 December 2010
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Posted 9 December 2010
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Placebo or Historical Controls: Mathematical Model Offers a Better Choice
I read this informative series about the expert conference organized by EMA with interest. Among the issues discussed, this meeting touched on the question of whether studies with potential therapeutic agents in carriers of autosomal-dominant AD mutations could serve as a model for simplified clinical testing of new medications against pre-symptomatic stages of the more common sporadic forms of AD. My comment pertains to Part 3 of this series, which addresses the topic of placebo-controlled studies as part of clinical trials of new medications. I notice that this discussion, which comprised primarily questions by participants and answers by regulators, failed to distinguish between early and late clinical development phases of new medications. However, this differentiation is essential, because Phases 1, 2, and 3 of clinical development tackle different questions based on quite different knowledge bases about the therapy at hand.
My colleagues and I take the view that long-term use of placebo...
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Placebo or Historical Controls: Mathematical Model Offers a Better Choice
I read this informative series about the expert conference organized by EMA with interest. Among the issues discussed, this meeting touched on the question of whether studies with potential therapeutic agents in carriers of autosomal-dominant AD mutations could serve as a model for simplified clinical testing of new medications against pre-symptomatic stages of the more common sporadic forms of AD. My comment pertains to Part 3 of this series, which addresses the topic of placebo-controlled studies as part of clinical trials of new medications. I notice that this discussion, which comprised primarily questions by participants and answers by regulators, failed to distinguish between early and late clinical development phases of new medications. However, this differentiation is essential, because Phases 1, 2, and 3 of clinical development tackle different questions based on quite different knowledge bases about the therapy at hand.
My colleagues and I take the view that long-term use of placebo in studies of new compounds that are in advanced development, typically Phase 3, is highly ethically problematic. The Declaration of Helsinki (Seoul, 2008, paragraph 32) allows use of placebo instead of the best current proven intervention in situations “where no current proven intervention exists; or where for compelling and scientifically sound methodological reasons the use of placebo is necessary to determine the efficacy or safety of an intervention and the patients who receive placebo or no treatment will not be subject to any risk of serious or irreversible harm. Extreme care must be taken to avoid abuse of this option.“
With regard to long-term treatment of pre-symptomatic stages of all forms of AD, the first condition (i.e., lack of current proven treatments) is met; however, this is not true for the second condition. Without doubt, patients with autosomal-dominant AD face a high risk of serious or irreversible harm if treated with placebo for extended periods of time (18 months or longer, depending on the mechanism of action of the intervention studied). The same applies to patients with amnestic MCI who show specific neuropsychological, neurochemical, or brain imaging markers of pre-symptomatic AD. In the spirit of the Declaration, it is therefore unacceptable to knowingly expose such trial participants for extended periods of time to an ineffective intervention (placebo) when studying a treatment that in prior clinical trials has shown clear potential for clinically relevant efficacy and acceptable tolerability. These latter elements are customarily established in Phase 1 and early Phase 2 trials, which are shorter in duration and do require placebo control. For pre-registration trials, so-called pivotal studies, however, the scientific community and regulatory authorities would be well advised to consider novel study designs. Such designs should combine maximal protection of patients against ineffective treatments with the ability to foster scientifically valid testing of new candidate drugs.
In an attempt to realize an alternative to placebo-based study designs that is both ethically and scientifically sound, our group has developed mathematical models to reliably forecast clinically relevant endpoints and disease trajectories of AD patients in pre-symptomatic stages (MCI subjects). Our models make use of medical history, biological, and neuropsychological measures that are routinely established at baseline of every therapeutic study. Model-based forecasted endpoints and trajectories of decline constitute the background—the “simulated placebo group”—against which potential drug effects can be contrasted. We call this alternative study design the Placebo Group Simulation Approach (PGSA). Our ideas about it were presented at the recent CTAD congress in Toulouse (Poster 25, Abstract in J Nutrition Health & Aging 14: S16, 2010; we will gladly send a PDF file of the poster to colleagues interested in our concept).
First results using data from the ADNI database clearly demonstrate that empirically established and mathematically modelled endpoints and disease trajectories show high concordance in large samples of pre-symptomatic AD patients. We are currently attempting to validate our models using several independent datasets. Based on the first encouraging findings, we hope that the PGSA will replace placebo-controlled long-term studies in advanced stages of development of new anti-AD drugs. Needless to say, trials offering treatment with active drug to all participants are also easier to perform and less costly.
(Previously at Novartis, the author was a project leader in the development of the cholinesterase inhibitor drug rivastigmine; see, e.g., Spiegel, 2002 and Almqvist et al., 2004.)
View all comments by René Spiegel
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Related News: Mark Your Calendars: Powerful CNN Documentary on Alzheimer’s
Comment by: John Keitzer
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Submitted 28 January 2011
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Posted 28 January 2011
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As a caregiver for seven years and counting to my wife of 64 years, I find this encouraging. I am currently trying to get her into a trial.
Thank God for the new research.
View all comments by John Keitzer |
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Related News: Mark Your Calendars: Powerful CNN Documentary on Alzheimer’s
Comment by: Terrence Town
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Submitted 27 January 2011
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Posted 28 January 2011
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I look forward to watching what promises to be an interesting and thought-provoking documentary. I am fairly certain that I echo the thoughts of the AD research community in stating the incredible importance of raising public awareness to this tragic disease.
I don't think it is hyperbole to state that AD is the public health crisis of our time. Unfortunately, right at the time when we should be focusing our efforts on AD prevention and treatment, we face NIH budget shortfalls that have a choke hold on our research efforts.
I truly hope that documentaries such as this raise awareness of the scope and breadth of this problem, and prompt a re-evaluation of research priorities from public health leadership.
View all comments by Terrence Town |
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Related News: Colombians Come to Fore in Alzheimer’s Research, Mass Media
Comment by: Dina Grutzendler
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Submitted 11 March 2011
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Posted 13 March 2011
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I am Colombian, and have family near the town of Yarumal. I think even if the treatment fails, many new things will be discovered, so it is worthwhile.
I think Alzheimer’s due to old age is different from the early-onset autosomal-dominant Alzheimer’s disease in Yarumal. There is the possibility that the treatment works, at least partially, but that it won’t necessarily be effective for old age Alzheimer’s, considering that a lot is still unknown about the process of the illness. Still, partial success would be a lot for the people with ADAD.
View all comments by Dina Grutzendler |
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Related News: News Flash: Colombian Families Come to Phoenix for Amyloid PET
Comment by: Jessica Langbaum, Eric M. Reiman, ARF Advisor, Pierre Tariot (Disclosure)
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Submitted 5 October 2011
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Posted 5 October 2011
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We are so grateful for the interest of the New York Times in the efforts of the Alzheimer's Prevention Initiative. Their coverage also means a great deal to Dr. Francisco Lopera, the pioneer who has identified the families afflicted with early-onset Alzheimer’s in Colombia, to Dr. Ken Kosik, who has supported this project throughout, to the families themselves, and to Dr. Adam Fleisher, who is directing the specific imaging project that was covered. At the end of the last trip to Phoenix, William, who was identified in the Times article as having symptomatic Alzheimer’s, stood at our farewell dinner, gestured to the people assembled, and said, “This proves that nothing is impossible.”
We hope to clarify that it is not certain that any of the experimental treatments that we are considering will fail in symptomatic patients. We hope they won't and will look at any available data carefully. The overriding point is that, regardless of which agents are selected, there is a strong and testable scientific rationale to assume that some of them may have a more profound effect when...
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We are so grateful for the interest of the New York Times in the efforts of the Alzheimer's Prevention Initiative. Their coverage also means a great deal to Dr. Francisco Lopera, the pioneer who has identified the families afflicted with early-onset Alzheimer’s in Colombia, to Dr. Ken Kosik, who has supported this project throughout, to the families themselves, and to Dr. Adam Fleisher, who is directing the specific imaging project that was covered. At the end of the last trip to Phoenix, William, who was identified in the Times article as having symptomatic Alzheimer’s, stood at our farewell dinner, gestured to the people assembled, and said, “This proves that nothing is impossible.”
We hope to clarify that it is not certain that any of the experimental treatments that we are considering will fail in symptomatic patients. We hope they won't and will look at any available data carefully. The overriding point is that, regardless of which agents are selected, there is a strong and testable scientific rationale to assume that some of them may have a more profound effect when administered earlier in the course of illness. And, while it would be ideal to start the first treatment trial in late 2012, it could be a bit later, depending on funding, regulatory approval, and so on. Between now and then, we will do whatever it takes to get the design and all requisite conditions right.
View all comments by Jessica Langbaum
View all comments by Eric M. Reiman
View all comments by Pierre Tariot |
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Related News: The EMA Deems Brain Atrophy Valid Trial Selection Measure
Comment by: Philip Scheltens
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Submitted 18 October 2011
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Posted 18 October 2011
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I applaud the EMA for taking this, and the previous, initiative, since they clearly may boost industry to use these markers in future clinical trials. Further, both EMA guidelines clearly underline the rationale of the concept reflected in the Dubois set of criteria. I would concur with Paul Aisen that MR hippocampal atrophy is too much a downstream marker to be used in the very early stage for selecting (future) AD cases. Amyloid markers are better suited for this, and within the amyloid-positive individuals, MRI may indicate the patients who are already further on the path to clinical AD. View all comments by Philip Scheltens |
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Related News: DIAN Forms Pharma Consortium, Submits Treatment Trial Grant
Comment by: Luis Salguero
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Submitted 26 December 2011
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Posted 4 January 2012
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Related News: Anti-Amyloid Treatment in Asymptomatic AD Trial
Comment by: Elena Galea
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Submitted 9 January 2012
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Posted 9 January 2012
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If one defines "AD prevention" broadly, then there already has been a
recent prevention trial using biomarkers, namely, one led by Bruno Dubois
of donepezil in people who met the new diagnostic criteria for prodromal
AD. While the trial differs in that it used an approved drug and enrolled
symptomatic patients essentially at the MCI stage, it is still worth
amending this news story with discussion of that trial (see also ARF related news story). Of particular
interest in this context are the
endpoints used and how they affect the design of clinical trials in
very early Alzheimer's such as A4, which aims at testing anti-amyloid
treatments at preclinical stages. Dubois reported a 45 percent
reduction in hippocampal atrophy in donepezil-treated patients
versus the placebo group, with no changes in cognitive measures. That
is, they detected protection when using a surrogate biomarker but not
in clinical signs. This means that brain atrophy may be a more
sensitive marker of AD-related neurodegeneration than current...
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If one defines "AD prevention" broadly, then there already has been a
recent prevention trial using biomarkers, namely, one led by Bruno Dubois
of donepezil in people who met the new diagnostic criteria for prodromal
AD. While the trial differs in that it used an approved drug and enrolled
symptomatic patients essentially at the MCI stage, it is still worth
amending this news story with discussion of that trial (see also ARF related news story). Of particular
interest in this context are the
endpoints used and how they affect the design of clinical trials in
very early Alzheimer's such as A4, which aims at testing anti-amyloid
treatments at preclinical stages. Dubois reported a 45 percent
reduction in hippocampal atrophy in donepezil-treated patients
versus the placebo group, with no changes in cognitive measures. That
is, they detected protection when using a surrogate biomarker but not
in clinical signs. This means that brain atrophy may be a more
sensitive marker of AD-related neurodegeneration than current measures of
cognitive
decline.
However, the trial may not have a clinical application in the
short term because regulatory agencies only accept treatments with
proven beneficial effects on cognition. This is probably why in the A4
trial, the investigators plan to use very subtle changes in cognitive
decline as the
main endpoint. An important consequence of this strategy is that the
A4 trial will require 300-500 patients per arm and run for three years
to achieve enough power. This is an incredibly costly design. For this
reason, it
is not realistic that the A4 trial becomes the paradigm to
test preclinically the currently existing long list of drugs that await
trial.
Note that
the donepezil trial required approximately 100 patients per arm and ran
for
a year. One solution is to validate as soon as possible brain atrophy
as a biomarker of presymptomatic AD progression by developing
longitudinal studies to establish the conversion into MCI of
cognitively normal people at high risk according to PET and CSF
amyloid-β measurements. This, however, may take many years.
For the
time being, another solution, as proposed by Pieter Jelle Visser, is to
start screening drugs first in small trials with surrogate markers,
and move to larger trials with cognitive endpoints only with
successful candidates
(Sperling et al., 2011). Looking at
time projections, it is probable that by the time the short trials are
finished, the regulatory agencies will have accepted surrogate markers
to support drug approval for preclinical AD. There will then be no need
to follow up in longer trials.
In conclusion, it appears that the
right strategy is to combine preclinical trials using surrogate
biomarkers as endpoints with longitudinal trials to validate these
biomarkers.
View all comments by Elena Galea |
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Related News: NIH Director Announces $100M Prevention Trial of Genentech Antibody
Comment by: Peter Davies
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Submitted 18 May 2012
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Posted 18 May 2012
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This is interesting from several points of view. I wonder if these studies in AD mutation carriers will be considered a better test of the amyloid hypothesis than previous or ongoing studies with amyloid antibodies. This year should see the data released on bapineuzumab and solanezumab. My guess is that these two antibody trials will show evidence of reduction of brain amyloid deposition (measured through amyloid imaging in PET scans), but little or no evidence of effects on rate of decline of cognitive function. The excuse will be offered that treatment was not initiated early enough—this has rapidly become dogma in the field. Will the Genentech antibody, administered earlier in the course of disease, before symptoms are obvious, show similar results? If, in this trial, there is evidence for reduced amyloid deposition without an impact on rate of cognitive decline, will this finally be accepted as strong evidence...
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This is interesting from several points of view. I wonder if these studies in AD mutation carriers will be considered a better test of the amyloid hypothesis than previous or ongoing studies with amyloid antibodies. This year should see the data released on bapineuzumab and solanezumab. My guess is that these two antibody trials will show evidence of reduction of brain amyloid deposition (measured through amyloid imaging in PET scans), but little or no evidence of effects on rate of decline of cognitive function. The excuse will be offered that treatment was not initiated early enough—this has rapidly become dogma in the field. Will the Genentech antibody, administered earlier in the course of disease, before symptoms are obvious, show similar results? If, in this trial, there is evidence for reduced amyloid deposition without an impact on rate of cognitive decline, will this finally be accepted as strong evidence against the amyloid hypothesis?
Perhaps it is time to start locating families with tau mutations for presymptomatic treatment with antibodies to tau, or one of the new agents shown to reduce pathology in mice transgenic for a mutant human tau (1-3). I am eager to see the field diversify its efforts, rather than continue to spend hundreds of millions of dollars flogging the amyloid horse.
References:
1. Boutajangout A, Ingadottir J, Davies P, Sigurdsson EM. Passive immunization targeting pathological phospho-tau protein in a mouse model reduces functional decline and clears tau aggregates from the brain. J Neurochem. 2011; 118: 658-667. Abstract
2. Chai X. Wu S. Murray TK. Kinley R. Cella CV. Sims H. Buckner N. Hanmer J. Davies P. O'Neill MJ. Hutton ML. Citron M. Passive immunization with anti-tau antibodies in two transgenic models: Reduction of tau pathology and delay of disease progression. J. Biol. Chem. 2011; 286):34457-34467. Abstract
3. Zhang B, Carroll J, Trojanowski JQ, Yao Y, Iba M, Potuzak JS, Hogan AM, Xie SX, Ballatore C, Smith AB 3rd, Lee VM, Brunden KR. The microtubule-stabilizing agent, epothilone D, reduces axonal dysfunction, neurotoxicity, cognitive deficits, and Alzheimer-like pathology in an interventional study with aged tau transgenic mice. J Neurosci. 2012 Mar 14;32(11):3601-11. Abstract
View all comments by Peter Davies |
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Related News: NIH Director Announces $100M Prevention Trial of Genentech Antibody
Comment by: William Klunk, ARF Advisor (Disclosure)
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Submitted 17 May 2012
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Posted 18 May 2012
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The anti-amyloid trial in presymptomatic carriers of an AD-causing presenilin 1 mutation just announced for API, and actively being planned by DIAN, are milestones to be applauded.
Six to seven years ago, there was no choice but to begin anti-amyloid trials in symptomatic populations. Regulators and most in pharma were not ready to consider anything else. But even then, many in the field openly discussed concerns that targeting Aβ this late in the course of the disease would not be effective due to the extensive neurodegeneration already present.
The concept of prevention trials, along with their lengthy timeframe, large subject numbers, and associated expense, was daunting to pharma and the NIH, and was resisted by regulators. The side effects that emerged from the active and passive immunotherapy trials made the situation even more difficult to navigate. The hope was simply that the formidable challenges posed by prevention trials could be avoided because the trials in mild to moderate AD would work. Unfortunately, they haven’t—as of yet, anyway.
Perhaps the...
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The anti-amyloid trial in presymptomatic carriers of an AD-causing presenilin 1 mutation just announced for API, and actively being planned by DIAN, are milestones to be applauded.
Six to seven years ago, there was no choice but to begin anti-amyloid trials in symptomatic populations. Regulators and most in pharma were not ready to consider anything else. But even then, many in the field openly discussed concerns that targeting Aβ this late in the course of the disease would not be effective due to the extensive neurodegeneration already present.
The concept of prevention trials, along with their lengthy timeframe, large subject numbers, and associated expense, was daunting to pharma and the NIH, and was resisted by regulators. The side effects that emerged from the active and passive immunotherapy trials made the situation even more difficult to navigate. The hope was simply that the formidable challenges posed by prevention trials could be avoided because the trials in mild to moderate AD would work. Unfortunately, they haven’t—as of yet, anyway.
Perhaps the cliché, “Desperate times call for desperate measures,” is too extreme for the current state of affairs, but the lack of trial success definitely led to more open-mindedness and serious consideration of the API and DIAN (and A4) proposals. In addition, scientific advances with a variety of biomarkers over the past five to 10 years produced surrogate markers that could be assessed for target engagement in a presymptomatic population, making study design more feasible.
Thus, a combination of failures and successes has brought us to the verge of the first convincing human test of the amyloid cascade hypothesis. This is a door that I firmly believe our field needs to pass through before real therapeutic success can be achieved.
It should not go unnoticed that, despite the field evolving to a somewhat receptive point, the initiation of these trials has required inspired leadership and painstaking work. Regardless of the outcome of these trials, the field already owes a debt to Reiman, Tariot, Langbaum, and Lopera of API; Morris, Bateman, and others of DIAN; and Aisen, Sperling, and colleagues of A4. These individuals faced many hurdles to get their respective programs to the point where they are today, and dedicated an immense amount of effort with no guarantee of any reward at all. At least the API study has produced the satisfaction that it will be initiated, and hopefully the DIAN and A4 trials will soon follow.
View all comments by William Klunk |
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Related News: NIH Director Announces $100M Prevention Trial of Genentech Antibody
Comment by: Sanjay W. Pimplikar
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Submitted 23 May 2012
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Posted 23 May 2012
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The news that Genentech is providing major funding to support the upcoming prevention trial in the Paisa mutation cohort is a milestone event, especially since other pharmaceutical companies seem to be reducing their commitment to Alzheimer’s disease therapeutic trials in the face of continuing failures. It is doubly heartening to learn from Ryan Watts (in his interview with Gabrielle Strobel, see Q&A) that “...We have an entire strategy for AD. We are going after several different molecular pathways besides Aβ.” The AD field should congratulate Richard Scheller of Genentech for this bold initiative.
The details of the API/NIH/Genentech prevention study are sketchy at the moment, but the choice of crenezumab warrants comment. This is a new antibody and is relatively unknown to the AD field. Having an IgG4 backbone, crenezumab should not elicit a strong proinflammatory response (which is the likely cause of vasogenic edema and microhemorrhage seen in the passive immunotherapy trials), and should be an improvement...
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The news that Genentech is providing major funding to support the upcoming prevention trial in the Paisa mutation cohort is a milestone event, especially since other pharmaceutical companies seem to be reducing their commitment to Alzheimer’s disease therapeutic trials in the face of continuing failures. It is doubly heartening to learn from Ryan Watts (in his interview with Gabrielle Strobel, see Q&A) that “...We have an entire strategy for AD. We are going after several different molecular pathways besides Aβ.” The AD field should congratulate Richard Scheller of Genentech for this bold initiative.
The details of the API/NIH/Genentech prevention study are sketchy at the moment, but the choice of crenezumab warrants comment. This is a new antibody and is relatively unknown to the AD field. Having an IgG4 backbone, crenezumab should not elicit a strong proinflammatory response (which is the likely cause of vasogenic edema and microhemorrhage seen in the passive immunotherapy trials), and should be an improvement over the antibodies in use in current trials.
However, the IgG4 subtype is unique in that it rapidly undergoes Fab-arm exchange (a phenomenon by which a "heavy chain and attached light chain" half-molecule of a dimeric IgG4 antibody is swapped for another "half-molecule" of an IgG4 dimer of a different antigen specificity), creating a bispecific antibody (1). It is not publicly known how effective such a "monomeric" anti-Aβ antibody (crenezumab) will be in removing Aβ, although one can assume that Genentech has strong supporting data.
Nonetheless, there is a growing realization of "IgG4-related" diseases, which are often associated with elevated serum IgG4 antibodies (2). With a normal serum range of 0.01 to 1.4 mg IgG4/ml in healthy individuals, a single dose of 900 mg of crenezumab in a 60 kg individual (15 mg/kg, see the interview above) could instantly increase the serum IgG4 levels in some individuals by 10-fold. One can be sure that the Genentech scientists and the regulatory authorities have considered the potential side effects of long-term administration of high amounts of IgG4.
Regarding the point raised by Ryan Watts and Bill Klunk about "this study being a key clinical trial to test the amyloid hypothesis," I see myself agreeing with the views expressed by Peter Davies. Should this prevention trial fail to stop cognitive decline despite the biomarkers moving in the right direction, would that be strong evidence for the academic community to seriously entertain alternative mechanisms of AD pathogenesis?
References:
1. van der Neut Kolfschoten M, Schuurman J, Losen M, Bleeker WK, Martínez-Martínez P, Vermeulen E, den Bleker TH, Wiegman L, Vink T, Aarden LA, De Baets MH, van de Winkel JG, Aalberse RC, Parren PW. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science. 2007 Sep 14;317(5844):1554-7. Abstract
2. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med. 2012 Feb 9;366(6):539-51. Abstract
View all comments by Sanjay W. Pimplikar |
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Related News: NIH Director Announces $100M Prevention Trial of Genentech Antibody
Comment by: Cynthia Lemere (Disclosure)
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Submitted 23 May 2012
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Posted 23 May 2012
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I have been advocating for immunotherapy as a way to prevent Alzheimer's disease for many years. It would be absolutely wonderful if the API/DIAN studies were to establish a baseline from which to move forward in non-FAD individuals. View all comments by Cynthia Lemere |
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Related News: NIH Director Announces $100M Prevention Trial of Genentech Antibody
Comment by: Ryan Watts
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Submitted 23 May 2012
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Posted 23 May 2012
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Crenezumab is a disulfide stabilized IgG4. Thus, the point raised by Sanjay W. Pimplikar that an "IgG4 subtype is unique in that it rapidly undergoes Fab-arm exchange (a phenomenon by which a "heavy chain and attached light chain" half-molecule of a dimeric IgG4 antibody is swapped for another "half-molecule" of an IgG4 dimer of a different antigen specificity), creating a bispecific antibody (1)" is not a concern for crenezumab, as the disulfide stabilization made to the Fc backbone will ensure that it is as stable as IgG1, keeping crenezumab in a covalently "locked" bivalent conformation.
Preclinical and initial Phase I data describing MABT (crenezumab) will be published in the near future. This study outlines the rationale and initial supporting data around the unique binding properties and IgG4 backbone of crenezumab.
View all comments by Ryan Watts |
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Related News: NIH Director Announces $100M Prevention Trial of Genentech Antibody
Comment by: John Ringman
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Submitted 23 May 2012
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Posted 24 May 2012
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The public release of news regarding funding for, and the naming of the drug to be used in, an upcoming prevention study in persons at risk for PSEN1 mutations is a long-awaited landmark. We’ve been performing observational studies of persons with or at risk for familial AD (FAD) since 2001, and from the beginning, patients and at-risk subjects have been asking where this was all leading. Finally, actual treatment studies are tangibly close. Though the mutations causing FAD have been known since the early 1990s, there have been many obstacles to developing an appropriate approach to prevention in this population, some of which are still an issue.
First and foremost, there had to be an appropriate drug and an interest from a pharmaceutical company in testing it in this manner. Though it is far from certain that anti-amyloid monoclonal antibodies are going to deliver on the promise of prevention, there is ample evidence that this approach is hopeful. Although drug safety is always an issue, it becomes particularly relevant in the context of a preventative intervention, which...
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The public release of news regarding funding for, and the naming of the drug to be used in, an upcoming prevention study in persons at risk for PSEN1 mutations is a long-awaited landmark. We’ve been performing observational studies of persons with or at risk for familial AD (FAD) since 2001, and from the beginning, patients and at-risk subjects have been asking where this was all leading. Finally, actual treatment studies are tangibly close. Though the mutations causing FAD have been known since the early 1990s, there have been many obstacles to developing an appropriate approach to prevention in this population, some of which are still an issue.
First and foremost, there had to be an appropriate drug and an interest from a pharmaceutical company in testing it in this manner. Though it is far from certain that anti-amyloid monoclonal antibodies are going to deliver on the promise of prevention, there is ample evidence that this approach is hopeful. Although drug safety is always an issue, it becomes particularly relevant in the context of a preventative intervention, which will need to be given regularly to persons for the rest of their lives, starting at a young age. According to its developers, crenezumab is thought to have such a profile, but the long-term studies necessary to prove this have not been performed. Even if a drug is promising and safe, it is far from given that a pharmaceutical company will want to develop it in this fashion. Though this type of approach, if effective in preventing FAD, should also work to prevent late-onset AD, one cannot assume this, leaving open questions of approval by regulatory agencies like the FDA. Genentech is apparently willing to take this gamble.
Another major obstacle is the availability of an adequate number of appropriate subjects for such a study. Thankfully, FAD is rare. Even when you’ve identified a large number of families harboring mutations such as these, the number of at-risk persons who are the right age, have no exclusionary criteria for participation, and are willing to do so, may be much smaller. Over the years, and after what must have been an incredible amount of work, Francisco Lopera and colleagues at the University of Antioquia have collected a tremendous cohort of families with the E280A PSEN1 mutation that is large enough such that adequate numbers of study participants should easily be derived.
There are many ethical issues around a prevention trial such as this, but most critical is the fundamental fact that the majority of persons at risk for these fully penetrant mutations do not want to know their genetic status. How do you test a prevention in a population that has decided they don’t want to know if they’re eligible? One solution, as is proposed here, is to enroll all willing and appropriate at-risk persons, do the genetic testing, and give non-carriers the placebo. Though this gets around the issue of exposing non-carriers to the risk of a medication and the question of telling people their genetic status, there is the possible outcome of persons having side effects from the active drug and therefore correctly inferring their genetic status. Although this is a risk, it is not an inappropriate one as long as subjects thoroughly appreciate this possibility on entry into the study. As the education level of the persons from families with the E280A PSEN1 mutation in Colombia tends to be relatively low (50 percent with less than six years of education according to their 2011 Lancet Neurology publication; see Acosta-Baena et al., 2011), extreme caution must be taken to ensure that subjects are truly informed during the consent process. It is for this and other ethical reasons that the Colombian regulatory agency has required the study be simultaneously performed at sites in the U.S. as well.
In light of the promise of this intervention in a population that is in need, the news of this imminent study is truly heartening to me, and I'm sure to the many members of the families in which this unfortunate condition runs.
References:
1. Acosta-Baena N, Sepulveda-Falla D, Lopera-Gomez CM, Jaramillo-Elorza MC, Moreno S, Aguirre-Acevedo DC, et al. Pre-dementia clinical stages in presenilin 1 E280A familial early-onset Alzheimer's disease: a retrospective cohort study. Lancet Neurol. 2011; 10(3): 213-20. Abstract
View all comments by John Ringman |
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Related News: NIH Director Announces $100M Prevention Trial of Genentech Antibody
Comment by: William Brooks
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Submitted 24 May 2012
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Posted 24 May 2012
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This is welcome news. Families with dominantly inherited Alzheimer’s disease have largely been unable to participate in trials; symptomatic family members are sometimes too young for trials which may exclude people with younger onset age; they may live far from research centres and for a given family it is rare for several members to be affected at the same time, so sample size of a study involving family members is always a problem. Yet these families provide our best chance at understanding the Alzheimer’s disease process, since they have a known cause for their condition, and non-carrier siblings are an ideal control group since they share 50 per cent at least of the genetic background and most of their environmental influences with their brothers and sisters. The very large Colombian kindred has already contributed significantly to our knowledge of AD. It was initially thought that PSEN1 mutations, unlike APP mutations, were not influenced by APOE genotype, but a subsequent study involving this kindred showed that onset age was indeed modified by APOE.
We all hope that this...
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This is welcome news. Families with dominantly inherited Alzheimer’s disease have largely been unable to participate in trials; symptomatic family members are sometimes too young for trials which may exclude people with younger onset age; they may live far from research centres and for a given family it is rare for several members to be affected at the same time, so sample size of a study involving family members is always a problem. Yet these families provide our best chance at understanding the Alzheimer’s disease process, since they have a known cause for their condition, and non-carrier siblings are an ideal control group since they share 50 per cent at least of the genetic background and most of their environmental influences with their brothers and sisters. The very large Colombian kindred has already contributed significantly to our knowledge of AD. It was initially thought that PSEN1 mutations, unlike APP mutations, were not influenced by APOE genotype, but a subsequent study involving this kindred showed that onset age was indeed modified by APOE.
We all hope that this trial will result in the development of a successful treatment, however, even if this does not eventuate, the trial has an excellent chance of answering a vital question about amyloid, namely whether preventing amyloid deposition early enough, before significant neurodegeneration has occurred, will modify the course of the disease and prevent dementia. Because cognitive change occurs insidiously over years, some more sensitive and reliable biomarker of disease activity will make such trials much easier to interpret. Biomarkers are still not at the stage of being accepted as clinically useful in most countries, but this trial incorporates CSF markers and amyloid PET scans among other outcomes. CSF biomarkers look like being the best candidates for measuring disease activity, with decreasing A-beta levels occurring a decade before symptoms and increased tau levels (indicating neurodegeneration) being detected 5 years out. These measures are being studied in DIAN, which has its own therapeutic trials planned to commence shortly, with a major funding boost from the Alzheimer’s Association. DIAN differs from the Colombia/crenezumab study in that it enrolls families with a variety of FAD mutations in APP, PSEN1 and PSEN2.
Now that a determined effort has been made to recruit FAD kindreds to two thoroughly well planned and comprehensive studies, definite answers to some of the more elusive questions in Alzheimer’s disease research are within sight of being answered. This could almost certainly not have been done without US leadership and funding. These studies give long-awaited hope to families who have carried the burden of this disease, often for generations. We are grateful to them for their participation in research, which involves time away from work and family, as well as sometimes confronting and uncomfortable testing procedures. We are also grateful that funding bodies and pharmaceutical companies like Genentech have made this important investment.
References: Pastor P, Roe CM, Villegas A et al. Apolipoprotein E epsilon 4 modifies Alzheimer's disease onset in an E280A kindred. Ann Neurol 2003;54:163-9. View all comments by William Brooks |
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Related News: NIH Director Announces $100M Prevention Trial of Genentech Antibody
Comment by: Hans Basun, Martin Ingelsson, ARF Advisor, Lars Lannfelt, ARF Advisor
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Submitted 30 May 2012
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Posted 30 May 2012
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It is great news that Genentech and the NIH are taking the bold initiative to start a prevention trial on the large Colombian family with a presenilin-1 mutation. One hundred presymptomatic mutation carriers will receive monthly injections with crenezumab, Genentech’s antibody against Aβ, whereas 100 will get placebo. In addition, 100 non-carriers will also receive placebo in order to ensure that the participants will be blinded as to their mutation status.
Some comments and questions:
1. From an ethical perspective, it is crucial that both family members and staff are blinded as to the mutation status of the participants. The study seems to be very well designed in this respect.
2. At which point in time will the treatment be initiated for the individual subject? It is described that each participant should be treated for five years, but has the age at onset in the actual Colombian family been well defined? Some mutations are known to cause disease at very variable ages. For example, in the Swedish mutation family, we found an age at onset difference of more than...
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It is great news that Genentech and the NIH are taking the bold initiative to start a prevention trial on the large Colombian family with a presenilin-1 mutation. One hundred presymptomatic mutation carriers will receive monthly injections with crenezumab, Genentech’s antibody against Aβ, whereas 100 will get placebo. In addition, 100 non-carriers will also receive placebo in order to ensure that the participants will be blinded as to their mutation status.
Some comments and questions:
1. From an ethical perspective, it is crucial that both family members and staff are blinded as to the mutation status of the participants. The study seems to be very well designed in this respect.
2. At which point in time will the treatment be initiated for the individual subject? It is described that each participant should be treated for five years, but has the age at onset in the actual Colombian family been well defined? Some mutations are known to cause disease at very variable ages. For example, in the Swedish mutation family, we found an age at onset difference of more than 15 years among the mutation carriers. With the current design, treatment should be initiated fewer than five years before the expected onset of symptoms, which for the individual case might be quite difficult to decide.
3. The mutation cases are likely to have a biochemical process that drives the amyloidosis much more aggressively. Thus, the pathogenic process could be more difficult to inhibit than in late-onset sporadic disease. Therefore, it is important to keep in mind that a negative outcome should not be interpreted as a definitive failure for Aβ to serve as a therapeutic target for Alzheimer’s disease.
4. Crenezumab has an interesting profile. It is an IgG4 antibody, which does not activate microglia very well. Moreover, it binds oligomers and fibrils with high affinity and monomers with lower affinity. Monomers of Aβ might have a physiological function that should not become disturbed. Targeting fibrils in the vessel walls could be the cause of vasogenic edema observed in previous trials. We therefore believe that an ideal anti-Aβ drug should avoid both monomers and fibrils as well as the vascular amyloid deposits.
View all comments by Hans Basun
View all comments by Martin Ingelsson
View all comments by Lars Lannfelt |
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Related News: API Echoes DIAN: Biomarker Changes Precede Symptoms by 20 Years
Comment by: Jon Valla
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Submitted 8 November 2012
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Posted 9 November 2012
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This is fantastic work, but care should be taken not to conflate the common biomarker changes between the Colombian kindred described above and those at risk for late-onset sporadic AD (ApoE4 carriers). In the paper (Valla et al., 2010, cited above), we presented evidence that young adult ApoE4 carriers do not show any amyloid-related changes (increases in soluble amyloid or increased deposition), even though they show functional changes via glucose PET at that age (Reiman et al., 2004, also cited above) and cytochrome oxidase histochemistry. The "common" changes discussed in this article refer to the PET-measured functional changes, not amyloid levels or amyloid deposition. These "common" changes between familial and sporadic AD may be linked by amyloid, but the current evidence suggests they are not.
View all comments by Jon Valla |
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