Updated 21 May 2012

On May 21, the New York Times editorial page commented on this upcoming trial.

 On 15 May at the Alzheimer’s Disease Research Summit 2012, a conference hosted by the National Institute on Aging, Francis Collins announced that $16 million of federal funds would go toward the first-ever therapeutic prevention trial in cognitively healthy people. The decision is part of the National Plan to Address Alzheimer’s Disease, said Collins, who directs the National Institutes of Health in Bethesda, Maryland. The unprecedented trial will be run by an international collaboration of researchers in academia and industry. The news came as Kathleen Sebelius, Secretary of the Department of Health and Human Services, formally introduced the long-awaited plan (see ARF related news story). Funding from a public-private partnership gives the green light to what is widely considered the cutting edge in the field of AD clinical research today, that is, the drive to evaluate mechanism-based experimental treatments in people who are on the path to Alzheimer’s but have not developed the disease’s neurodegeneration or symptoms yet.

The Alzheimer's Prevention Initiative is led by Eric Reiman, Pierre Tariot, and Jessica Langbaum at the Banner Alzheimer’s Institute in Phoenix, Arizona, and Francisco Lopera and his colleagues at the University of Antioquia in Colombia. Over the past two years, these scientists and other colleagues have enrolled members of the world’s largest kindred afflicted with a deterministic presenilin 1 mutation into a broad-based observational biomarker and cognition study while simultaneously laying the groundwork for secondary prevention trials. They consulted leading academic, biotech, and pharma researchers, regulators, and funders on the best approach. They navigated the legal and ethical challenges inherent in giving unapproved drugs to outwardly healthy people. The researchers got to know, and wrestled with finding, the most respectful ways of working with a vulnerable population living primarily outside of the U.S. (For background on API, see ARF related news story; ARF news story.)

Last fall, the scientists submitted to the National Institute on Aging a grant proposal for a first presymptomatic treatment trial in this population, as well as in people with autosomal-dominant AD mutations living in the U.S. The grant is being funded through $50 million from the 2012 NIH budget. In February, Sebelius had pledged that this money would be directed to select research projects this year (see ARF related news story). Slicing money out of the current fiscal year budget “is rarely done but was merited, given the urgency of this disease,” Collins said.

Scientists following the API’s progress have been curious about which investigational treatment the API scientists would choose as the most promising one to start with. Likewise, they wondered which pharma company would commit to making their leading experimental medicine available for a five-year trial in a genetically defined population while developing the drug for the much larger market of late-onset AD. The match eventually came to pass with Genentech of South San Francisco, a member of the Roche group.

A press release issued jointly by the Banner Alzheimer’s Institute and Genentech quotes its executive VP for Research, Richard Scheller, as saying: “Genentech is very excited to be a part of this landmark effort. If the study demonstrates that we can prevent the disease in this special group of patients, it may pave the way to preventing Alzheimer’s in the general population.”

Genentech licensed crenezumab from the Swiss biotech company AC Immune SA. Similar to bapineuzumab, solanezumab, and gantenerumab, three AD immunotherapies currently in Phase 3 and 2 trials, respectively, crenezumab is a humanized monoclonal antibody that binds the Aβ peptide. It differs in its technical details, such as which species of Aβ it binds and how strongly it activates microglial cells (see Alzforum Q&A with Ryan Watts). Watts is the lead scientist at Genentech on this project.

“The dominant mutations are definitely a model worth pursuing, as you can identify patients early,” said Rusty Katz, who directs the Food and Drug Administration’s Division of Neurology Products. Katz has advised the general process preparing for API trials over the years. Regulatory approval of this particular trial by the FDA and the Colombian drug regulatory agency Invima will take some months, putting the estimated start date for the trial into the first half of 2013, said Reiman.

Besides the NIH bolus, the $100 million trial gets $15 million of philanthropic funding coming through the Banner Alzheimer’s Institute, and Genentech will put up the rest. The company will also provide clinical and operational expertise to finalize design and conduct the study. Already, API scientists Langbaum, Yui Ayutyanont, and Suzanne Hendrix are collaborating with Carole Ho and others at Genentech to define a composite cognitive outcome measure and run power calculations.

Importantly, the trial is intended not as an exploratory study, but as a registration trial, meaning a positive outcome might form the basis for a new drug application, said Reiman. Toward this end, primary outcome measures will be a composite cognitive battery and other cognitive tools. Various brain imaging tests, including amyloid PET and fluid biomarkers, will be secondary outcomes.

Three hundred people in Colombia will participate in the trial. One hundred mutation carriers will receive monthly injections of crenezumab, 100 will get placebo, plus 100 non-carriers will receive placebo to ensure that study participants will not know whether they carry the pathogenic mutation or not. All participants will be asymptomatic, said Reiman.

In addition, some 24 people living in the U.S. will join the trial at five U.S. sites, said Reiman. The Banner Alzheimer’s Institute will be one; the others will be determined with the help of the Dominantly Inherited Alzheimer Network (DIAN), which collaborates with API. Genentech is a member of DIAN’s Pharma Consortium (see ARF related news story). Trial participants will be 30 years of age and older.

Conducting trials internationally can be a sensitive business, particularly in vulnerable genetic cohorts living in countries less affluent than the U.S. For his part, Lopera has been seeking a biopharma partner willing to recognize that. “We consider this a unique opportunity. These patients are a sacred group of people for Alzheimer’s research, and everything will be done with the utmost respect,” said Watts. “Genentech intends to provide study participants support for their time and efforts. We are currently working with Dr. Lopera and Banner on the details of this plan,” Ho wrote to Alzforum in an e-mail. API researchers themselves have set up a small nonprofit initiative to support the families' ongoing needs.

Should this trial work and the antibody eventually be approved, how will these families be able to afford a U.S.-made biologic therapy? “Genentech is committed to patients having access to our therapies. We have a number of patient access programs for our other therapies and will likewise ensure that the appropriate access to crenezumab is obtained after completion of the trial. We have discussed this with both Dr. Lopera and Banner,” Ho wrote to Alzforum.

Once the trial is complete, information will be made available to researchers worldwide. “We want to help develop faster ways for everybody to evaluate potential prevention drugs. It’s not just about testing this drug. It’s more broadly about helping the field link biomarker changes to clinical outcomes, and stimulating more prevention studies,” Reiman said. Ho confirmed that clinical data as well as placebo samples will be made available in an ADNI-like format after the trial is completed.

“In addition, Genentech and Banner intend to provide access to biomarker samples from treatment patients within 18 months of the completion of the five-year treatment period,” Ho wrote. This pledge is a highly unusual step. Companies generally refuse to share patient samples that contain their proprietary investigational drug. At this point, the prospect remains some seven years off into the future.

While this trial is gearing up, the API scientists are planning for the next one, which aims to test investigational drugs in ApoE carriers at elevated risk of developing Alzheimer’s. They also hope that this initial trial will stimulate more presymptomatic treatment trials throughout the field. They have developed an online registry as a tool to enable people to express their interest to join such trials in the future, and to help sponsors enroll the needed participants for such trials. Alzforum provides a quarterly newsletter in partnership with this registry.

The crenezumab trial was one of two announced as part of the National Plan to Address Alzheimer’s Disease. The other one is a five-year, $7.5 million trial headed by Suzanne Craft at the University of Washington, Seattle, to test whether an intranasal insulin spray improves cognition in 240 people diagnosed with mild cognitive impairment.

Secretary Sebelius came to present the historic plan on her birthday; she began her remarks after being serenaded by an auditorium full of conference attendees. Congressman Ed Markey (D) of Massachusetts was there as well. Markey cared for his mother when she had Alzheimer’s. He co-sponsored the National Alzheimer’s Project Act (NAPA), which mandates the implementation of a national plan. The plan is available for download.

However, aside from the trial news, the long-awaited unveiling of the plan felt a tad anticlimactic to scientists at the summit because it came without additional funds beyond those announced earlier this year. The scientific community is hoping for $1 billion to $2 billion to implement the plan’s stated goal of stopping Alzheimer’s by the year 2025. For now, speakers are limited to professing their resolve to making the plan more than a document. Ron Petersen, Mayo Clinic, Rochester, Minnesota, who chaired the NAPA advisory council, spoke about ways of monitoring progress and ensuring accountability. “Today marks a momentous occasion, but the work has just begun,” Petersen said. For her part, Sebelius concluded, “We look forward to the day when Alzheimer’s becomes another disease that hard work and partnership have beaten.”—Gabrielle Strobel.

This is Part 1 of a two-part series. See also Part 2.

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  1. 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:

    . Passive immunization targeting pathological phospho-tau protein in a mouse model reduces functional decline and clears tau aggregates from the brain. J Neurochem. 2011 Aug;118(4):658-67. PubMed.

    . Passive immunization with anti-Tau antibodies in two transgenic models: reduction of Tau pathology and delay of disease progression. J Biol Chem. 2011 Sep 30;286(39):34457-67. PubMed.

    . 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. PubMed.

  2. 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.

  3. 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:

    . Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science. 2007 Sep 14;317(5844):1554-7. PubMed.

    . IgG4-related disease. N Engl J Med. 2012 Feb 9;366(6):539-51. PubMed.

  4. 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.

  5. 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.

  6. 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:

    . Pre-dementia clinical stages in presenilin 1 E280A familial early-onset Alzheimer's disease: a retrospective cohort study. Lancet Neurol. 2011 Mar;10(3):213-20. PubMed.

  7. 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:

    . Apolipoprotein Eepsilon4 modifies Alzheimer's disease onset in an E280A PS1 kindred. Ann Neurol. 2003 Aug;54(2):163-9. PubMed.

  8. 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.

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References

News Citations

  1. News Brief: Sebelius Gives Report on U.S. Alzheimer's Plan
  2. Colombians Come to Fore in Alzheimer’s Research, Mass Media
  3. Reeling In Biomarker Data in Young Carriers, API Rocks Staging Boat
  4. New Shot in Arm for Alzheimer's Research Announced Today
  5. Q&A With Ryan Watts, Genentech Lead Scientist on API Trial
  6. DIAN Grows, Gets Ready for Therapeutic Trials

External Citations

  1. editorial page
  2. National Plan to Address Alzheimer’s Disease
  3. bapineuzumab
  4. solanezumab
  5. gantenerumab
  6. Invima
  7. nonprofit initiative
  8. online registry
  9. available for download

Further Reading

News

  1. News Brief: Sebelius Gives Report on U.S. Alzheimer's Plan
  2. Colombians Come to Fore in Alzheimer’s Research, Mass Media
  3. Reeling In Biomarker Data in Young Carriers, API Rocks Staging Boat
  4. New Shot in Arm for Alzheimer's Research Announced Today
  5. DIAN Grows, Gets Ready for Therapeutic Trials