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...  Read more

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

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...  Read more

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

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...  Read more

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

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

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

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...  Read more

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

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...  Read more

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

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...  Read more

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