23 Jul 2021

After a Phase 2 study hinted that donanemab could curb cognitive decline in people with symptomatic AD, the amyloid-targeted drug will soon be evaluated for its ability to prevent the disease. According to a July 15 announcement, trial sponsor Eli Lilly and Co. will collaborate with the Banner Alzheimer’s Institute in Phoenix to recruit participants into TRAILBLAZER-ALZ3, a Phase 3 trial that will enroll cognitively normal people at high risk for AD based on elevated concentration of plasma p-tau217. The prevention trial will begin later this year.

Donanemab is unique among the cadre of Aβ-targeted antibodies in clinical development, in that it latches onto a modified form of the peptide with a pyroglutamate residue on its N terminus. This aggregation-prone version of the peptide inhabits the dense cores of Aβ plaques. The plaque-busting power of donanemab was established in earlier trials, where the antibody reduced Aβ plaque load to virtually nil in two-thirds of participants in the Phase 2 TRAILBLAZER trial (Mar 2021 conference news). The treatment also slowed slippage on the integrated Alzheimer’s Disease Rating Scale by a third. Lilly developed this measure by combining the ADAS-Cog13 with the ADCS-instrumental Activities of Daily Living scales. In TRAILBLAZERl, both evidence of amyloid and intermediate tau tangle burden were used to select participants. Lilly is currently running a separate Phase 3 trial—TRAILBLAZER-ALZ2—using the same criteria to select participants with early AD.

If started early enough, might donanemab prevent the onset of symptoms in people at high risk for AD? This perennial question is being addressed in TRAILBLAZER-ALZ3. The trial will make use of the Alzheimer’s Prevention Registry’s GeneMatch database to help recruit ApoE4 carriers and noncarriers who are at high risk for AD. In a first for the field, concentration of plasma p-tau217 will be measured using an assay developed by Lilly and used to select participants, said Eric Reiman of the Arizona Alzheimer’s Consortium in Phoenix. Plasma p-tau217 distinguishes people who have amyloid plaques and preclinical AD from healthy controls (Jul 2020 news).

The trial will enroll a large number of participants between 55 and 80 years old, who will be randomized to receive infusions of donanemab or placebo. The study will run for three years, with a clinical primary outcome, and it will include other cognitive and biomarker measurements. Though assessments will continue for three years, Reiman told Alzforum that dosing will be short-term. He did not disclose the number of treatment doses or whether biomarker criteria would be used to determine when to stop dosing. The investigators will share trial data and samples in accordance with Collaboration for Alzheimer’s Prevention (CAP) principles.

Besides using plasma p-tau217 for selection, another unique aspect of the trial will be its use of virtual assessments and monitoring. Reiman told Alzforum that participants will undergo cognitive and clinical evaluations remotely, using tablets and video calls. They will have the option to receive infusions, and undergo physical exams, blood draws, and imaging at local centers, rather than needing to travel sometimes great distances to major medical centers. The virtual element of the trial, along with the short-term dosing phase, will relieve the overall burden on participants, and allow for greater inclusivity of underrepresented groups, Reiman said.—Jessica Shugart

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References

News Citations

1. Donanemab Confirms: Clearing Plaques Slows Decline—By a Bit 19 Mar 2021
2. Plasma p-Tau217 Set to Transform Alzheimer’s Diagnostics 29 Jul 2020

External Citations

1. TRAILBLAZER-ALZ2

Further Reading

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