The clinical relevance of donanemab was demonstrated through a slowing of clinical decline, stability of clinical symptoms, lowered risk of advancement to next clinical stage, and lower risk of meaningful within-patient change.
At the 2023 Alzheimer’s Association International Conference (AAIC), held June 16-20, in Netherlands, Amsterdam, full data from the pivotal, phase 3 TRAILBLAZER-ALZ 2 trial (NCT04437511) highlighted donanemab’s (Eli Lilly) impact on disease progression in individuals with early symptomatic Alzheimer disease (AD).1,2
The results, which were simultaneously published in JAMA, showed that donanemab, an antiamyloid therapy, was effective across all cognitive and functional secondary end points, and across multiple analysis methods. When the initial topline results of the study were announced in May 2023, Eli Lilly noted it will proceed with global regulatory submissions as soon as possible, with a potential FDA submission occurring this quarter.
TRAILBLAZER-ALZ-2, a multicenter trial, included 1736 patients who received donanemab (n = 860) or placebo (n = 876) administered intravenously every 4 weeks for up to 72 weeks. Spanning across 277 medical sites in 8 countries, the primary outcome of the study was least-squares mean (LSM) change in integrated Alzheimer Disease Rating Scale (iADRS) score, with lower scores indicating greater impairment. Among trial participants, 68.1% (n = 1182) had low/medium tau pathology and 31.8% (n = 552) had high tau pathology.
Mark A. Mintun, MD, vice president of Pain and Neurodegeneration Research, and Clinical Development Chief Medical Officer at Avid Radiopharmaceuticals, a subsidiary of Eli Lilly, and several other investigators, presented the data. In the low/medium tau population, LSM change from baseline in the iADRS score at 76 weeks was –6.02 (95% CI, –7.01 to –5.03) in the donanemab group and –9.27 (95% CI, –10.23 to –8.31) in the placebo group, otherwise a 35.1% (95% CI, 19.90-50.23) slowing of disease progression. The impacts were less pronounced in the overall population, with between-group score differences of 2.92 (95% CI, 1.51-4.33; P <.001), representing a 22.3% (95% CI, 11.38-33.15) slowing of disease progression.
In the low/medium tau population, investigators observed between-group differences of –0.67 (95% CI, –0.95 to –0.40; 36.0% slowing of clinical progression) for CDR-SB, 1.83 (95% CI, 0.91-2.75; 39.9% slowing of clinical progression) for ADCS-iADL, and –1.52 (95% CI, –2.25 to –0.79; 32.4% slowing of clinical progression) for ADAS-Cog13, at week 76. In this same cohort, donanemab-treated patients had a 38.6% (HR, 0.614; 95% CI, 0.471-0.800; P <.001) lower risk of progression to the next clinical stage on CDR-Global over the 76-week treatment time frame.
At 76 weeks, brain amyloid plaque levels decreased by 88.0 centiloids (95% CI, –90.20 to –85.87) with donanemab treatment and increased by 0.2 centiloids (95% CI, –1.91 to 2.26) in the placebo group in the low/medium tau population. In this group, 80.1% (95% CI, 76.12-83.62) of donanemab-treated patients achieved amyloid clearance by week 76 whereas no patients on placebo achieved the same.
In terms of plasma phosphorylated tau (p-tau)217, an exploratory outcome, investigators observed differences of –0.25 (95% CI, –0.28 to –0.22; P <.001) tau standardized uptake value ratio (SUVR) in the low/medium tau population relative to placebo and –0.22 (95% CI, –0.24 to –0.20; P <.001) in the combined population at 76 weeks. In total, there was a 39% relative decrease in plasma p-tau217 by donanemab in the low/medium tau population and a 35% decrease by donanemab at the conclusion of the trial.
Across statistical approaches and outcome measures, donanemab treatment resulted in 4.4-7.5 months saved at 18 months in the low/medium tau population. In addition, over the 76-week treatment period, the low/medium tau populations and combined populations on donanemab had 21% and 19% decreases in plasma glial fibrillary acidic protein, respectively, in comparison to increases of 8.9% and 11.4% from those on placebo. There was no clear pattern observed in neurofilament light change, as some treated patients saw decreases in levels from weeks 24 to 52, but slight increases following that.
In a post-hoc analysis, those with the lowest baseline p-tau217 had better disease slowing by iADRS and CDR-SB. In the lower, middle, and higher tertiles at week 76, disease progression was slowed by 36% (P = .011), 30% (P = .002) and 21% (P = .001), respectively, on iADRS. Using solely patients with high baseline tau levels (n = 552), the difference between the donanemab and placebo groups in the LSM change at 76 weeks was 1.26 (95% CI, –1.77 to 4.28; P = .42) for the iADRS score and –0.69 (95% CI, –1.19 to –0.20; P = .006) for the CDR-SB score.
In terms of safety, the therapy showed a profile that was similar to the phase 2 findings and consistent with class effects observed with amyloid plaque-lowering therapies. Mean changes in clinical laboratory values, vital signs, and ECGs were similar across treatment groups. Treatment discontinuation because of adverse events (AEs) occurred more frequently in the donanemab group, including infusion-related reactions (3.6%), amyloid-related imaging abnormalities (ARIA)-edema (2.5%), ARIA-microhemorrhages/hemosiderin deposits (0.8%), and hypersensitivity (0.5%).
Among the cohort, 3 participants in the donanemab group with serious ARIA subsequently died. Of them, non were prescribed anti-coagulants or anti-platelet medications. Two patients developed severe ARIA-E, one following re-treatment after resolution of severe ARIA-E and stabilization of severe ARIA-H. One patient had superficial siderosis at baseline and later developed a large intracerebral hemorrhage.
In total, 24% of donanemab-treated patients experienced ARIA-E. In a summary of ARIA and macrohemorrhage, ARIA-E events were found to be largely mild to moderate radiographically (94%). In terms of timing, ARIA-E first occurred after receiving up to 3 donanemab infusions in most cases (58%). First ARIA-E events radiographically resolved in 98% of participants, with a mean resolution time of around 10 weeks. Of note, 6% of patients on active treatment experienced recurrent ARIA-E.
Antithrombotic use was permitted in the study, with 9.8% of treated patients who used anticoagulants and 38.8% of those used antiplatelets during the double-blind period. Results showed that ARIA events occurred at a similar frequency with and without antithrombotic use. In terms of immunogenicity, 87% and 84% of donanemab-treated patients, respectively, had treatment-emergent antidrug antibodies or were positive for neutralizing antibodies.
In January, when the FDA issued its CRL for donanemab, the agency felt as though there was not enough sufficient, longer-term evidence to approve the agent, considering its application was supported by the phase 2, 12-month TRAILBLAZER-ALZ study (NCT03367403). Because patients met the goal and subsequently stopped dosing as early as 6 months in, less than 100 patients ended up receiving at least 12 months of the therapy. The FDA indicated that the data to meet the exposure expectation would likely need to include the unblinded controlled safety data from TRAILBLAZER-ALZ 2 upon completion.3