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Crenezumab Update: Baseline Data from Colombian Prevention Trial

Series - Alzheimer's Association International Conference 2019:

A subset of the world’s largest known kindred of autosomal-dominant Alzheimer’s disease, near the Colombian city of Medellin, have enrolled in the Banner Alzheimer Prevention Initiative Autosomal Dominant Alzheimer’s Disease trial. It is treating presymptomatic mutation carriers with crenezumab or placebo (May 2012 news). It also represents the last ongoing trial for this anti-Aβ antibody (May 2019 conference news). At the AAIC conference held July 14–18 in Los Angeles, researchers presented the baseline demographic, cognitive, and biomarker data on 242 trial participants in this ongoing trial. At the start, carriers were on average five years younger than noncarriers but already performed worse on cognitive tests and also showed more variability.

Pierre Tariot of the Banner Alzheimer’s Institute kicked off a series of four data presentations from this trial. It evaluates whether crenezumab, which binds monomeric and non-fibrillar aggregates of Aβ, can stave off cognitive decline in asymptomatic E280A mutation carriers. People with genetic forms of AD make perfect subjects to study prevention, but there are so few of them in the world that they are hard to find. As the world’s largest characterized ADAD kindred at this time, the Colombian families offer a chance to find out whether early intervention can prevent disease, and do it in a trial large enough that it could lead directly to an approved therapy, Tariot said.

Desired Distribution. Amyloid burden at baseline in mutation carriers and noncarriers in the API Colombian ADAD trial. Half of the carriers (red) exceed the SUVR cutoff 1.1 for amyloid positivity. [Courtesy of Pierre Tariot.]

The trialists needed a design that did not compel participants to learn whether they inherited the dreaded mutation. To do that, the API team aimed to enrolled 200 mutation carriers, randomized equally to treatment or placebo, and 100 noncarriers, all of whom receive placebo (Tariot et al., 2018). DIAN trials do this, too. In total, the scientists in Colombia screened 365 people and randomized 252, including 169 mutation carriers and 83 noncarriers, somewhat less than the goal of 300.

Even though the researchers in Colombia had built a large prescreening registry containing more than 5,000 people, trial recruitment was difficult because many people who otherwise met inclusion criteria were either already mildly symptomatic or unable to take as much time off from work as the trial required, or delay pregnancy for the duration of the trial (Rios-Romenets et al., 2018). Even so, the trial maintained its statistical power because retention is high, at 92 percent, and because it was changed to end in a “common-close” design. The common close means that all participants will stop receiving treatment or placebo five years after the last person is randomized, which adds about 25 percent more observations to the primary analysis. The trial began in December 2013, the last person was randomized in February 2017, and the placebo-controlled treatment period will end in 2022.

API had contracted with crenezumab’s maker, Roche/Genentech, to share data and biological samples from the trial after it was completed. The agreement was subsequently tweaked to include baseline data, consistent with the principles set forth by the Collaboration for Alzheimer’s Prevention (July 2016 news). Tariot said it took years to work out exactly how to share the baseline data among the trial partners without unmasking the identities or genotypes of participants, or accidentally revealing who was receiving placebo or active treatment. When it came for public release, the trials’ small sample size presented a danger that simply knowing age and sex could be enough for individuals to identify which group they were in.

In the end, scientists pruned data on 10 participants older than 54, to allow age-range matching across groups and to avoid the risk of giving away anyone’s genetic status. Tariot showed data on the remaining 242, comprising 167 carriers and 75 noncarriers between the ages of 30 and 53. At baseline, carriers averaged 37 years old, younger than noncarriers, who averaged 42. The reason for this is that the trial enrolled cognitively normal carriers, and aging is strongly associated with MCI and dementia in carriers. Sex, education, and ApoE4 carriage were similar across groups. In general, all participants had fewer years of education than some other research cohorts, with an average of 8.5 years in school. In DIAN, that average is 14 years. No one had ARIA at baseline, per trial criteria.

Carriers and noncarriers had similar clinical dementia rating (CDR) global scores, but CDR Sum of Boxes and functional assessment staging were both worse in carriers. Tariot called the differences “small, but suggestive of something.” Carriers did worse than noncarriers on the MMSE and on many cognitive tests. By definition, they still fell in the normal range, because those who met criteria for MCI were excluded. Notably, carriers showed greater variation in scores, especially on measures of memory. Carriers and noncarriers did not differ on neuropsychiatric or depression measures.

Natalia Acosta-Baena, Universidad de Antioquia, scrutinized the baseline cognitive data in detail to try to understand age-related cognitive changes in this group. Looking at how age affected this cross-sectional analysis, she discovered that memory declined first, with mutation carriers demonstrating slippage by age 35. This confirms her earlier analyses for the onset of cognitive symptoms in this group (Acosta-Baena et al., 2011). 

Other tests for language, attention, and visuospatial acumen, as well as RBANS total scores, showed no significant age-related differences between carriers or noncarriers at baseline. Further analysis is needed, with adjustment for education and ApoE status. Even so, Tariot said, “While generally confirming what has been seen before, I found it sobering to see the inescapable consequences of having this mutation.”

Yi Su, Banner Institute, presented data on brain imaging with florbetapir PET for amyloid, FDG PET to track hypometabolism, and structural MRI. As a group, the mutation carriers had more amyloid than noncarriers. At baseline, 46 percent of carriers exceeded the threshold for Aβ positivity on PET scans. This hit a benchmark the investigators had set of trying to enroll a carrier group who were not all amyloid-positive already, but spanned a range of SUVRs. None of the noncarriers were amyloid-positive.

Yakeel Quiroz, Massachusetts General Hospital, Boston, checked Aβ burden against memory performance in this group. She reported that cerebral amyloidosis correlated with lower episodic memory scores in the mutation carriers, even after adjusting for age. In other words, trial participants with more brain amyloid did worse on the CERAD word list and other memory measures.

Along with higher amyloid burden, the mutation carriers had on average lower FDG uptake than noncarriers, but similar hippocampal volume, Su reported. As a function of age, amyloid became abnormal first, then glucose uptake, then hippocampal volume. The time line largely matched previous work from this group, and DIAN data (Benzinger et al., 2013). 

That said, changes in metabolism and hippocampal atrophy appeared later than expected. This could have been due to methodology, or this particular mutation. There may also have been selection bias, Su said. Because the current study excluded cognitively impaired participants, it may be enriched for people with protective factors, Su speculated.

Some of the baseline data is accessible via GAAIN. Researchers can apply to collaborate on analyses or seek access to the data at APIData@bannerhealth.com. For new results on plasma NfL in the larger Colombian ADAD cohort, see next story in this series. —Pat McCaffrey

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References

Therapeutics Citations

  1. Crenezumab

News Citations

  1. NIH Director Announces $100M Prevention Trial of Genentech Antibody
  2. Keep Your Enthusiasm? Scientists Process Brutal Trial Data
  3. CAP Articulates Plan for Sharing Data from Trials of Preclinical Alzheimer’s Disease
  4. Colombian Cohort Delivers Data on Blood NfL

Paper Citations

  1. Tariot PN, Lopera F, Langbaum JB, Thomas RG, Hendrix S, Schneider LS, Rios-Romenets S, Giraldo M, Acosta N, Tobon C, Ramos C, Espinosa A, Cho W, Ward M, Clayton D, Friesenhahn M, Mackey H, Honigberg L, Sanabria Bohorquez S, Chen K, Walsh T, Langlois C, Reiman EM, Alzheimer's Prevention Initiative. The Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease Trial: A study of crenezumab versus placebo in preclinical PSEN1 E280A mutation carriers to evaluate efficacy and safety in the treatment of autosomal-dominant Alzheimer's dise. Alzheimers Dement (N Y). 2018;4:150-160. Epub 2018 Mar 8 PubMed.
  2. Rios-Romenets S, Acosta-Baena N, Lopez L, Madrigal-Zapata L, Street H, Jakimovich L, Langbaum JB, Cho W, Reiman EM, Tariot PN, Lopera F. Adherence/Retention Alzheimer's Prevention Initiative Colombia Plan. Alzheimers Dement (N Y). 2018;4:283-287. Epub 2018 Jul 14 PubMed.
  3. Acosta-Baena N, Sepulveda-Falla D, Lopera-Gómez CM, Jaramillo-Elorza MC, Moreno S, Aguirre-Acevedo DC, Saldarriaga A, Lopera F. 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.
  4. Benzinger TL, Blazey T, Jack CR Jr, Koeppe RA, Su Y, Xiong C, Raichle ME, Snyder AZ, Ances BM, Bateman RJ, Cairns NJ, Fagan AM, Goate A, Marcus DS, Aisen PS, Christensen JJ, Ercole L, Hornbeck RC, Farrar AM, Aldea P, Jasielec MS, Owen CJ, Xie X, Mayeux R, Brickman A, McDade E, Klunk W, Mathis CA, Ringman J, Thompson PM, Ghetti B, Saykin AJ, Sperling RA, Johnson KA, Salloway S, Correia S, Schofield PR, Masters CL, Rowe C, Villemagne VL, Martins R, Ourselin S, Rossor MN, Fox NC, Cash DM, Weiner MW, Holtzman DM, Buckles VD, Moulder K, Morris JC. Regional variability of imaging biomarkers in autosomal dominant Alzheimer's disease. Proc Natl Acad Sci U S A. 2013 Nov 19;110(47):E4502-9. Epub 2013 Nov 5 PubMed.

Other Citations

  1. APIData@bannerhealth.com

External Citations

  1. GAAIN

Further Reading

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