Alzheimer's study shows mixed results for Lilly's donanemab on secondary outcomes

Eli Lilly shared more details from the much-anticipated Phase II TRAILBLAZER-ALZ trial testing its modified β-amyloid-targeting antibody donanemab in patients with early symptomatic Alzheimer's disease (see ViewPoints: What to watch for from Eli Lilly's big donanemab reveal). Preliminary data in January showed that donanemab achieved the primary endpoint of significantly slowing decline on the integrated Alzheimer's Disease Rating Scale (iADRS), a composite measure of cognition and daily function, sending Eli Lilly shares up as much as 14% at the time.

The company says the new findings, which were presented Saturday at the Alzheimer's & Parkinson Diseases (AD/PD) conference and simultaneously published in the NEJM, support the earlier results. According to Eli Lilly, donanemab "consistently slowed" cognitive and functional decline for all secondary endpoints, "with nominal statistical significance at multiple times compared to placebo." However, in the NEJM report, the study's authors described the secondary outcome results as "mixed," with most showing "no substantial difference" compared to placebo. They also called for longer and larger trials to better understand the drug's benefits and side-effect profile.

Enrolment based on tau pathology

The 18-month TRAILBLAZER-ALZ trial enrolled 272 patients from 60 to 85 years of age with early symptomatic Alzheimer's disease who had tau and amyloid deposition on PET imaging. Researchers selected patients with high amyloid burden and intermediate levels of tau – the aim being to study those who were not too late in the disease to treat, yet were affected enough to show a benefit if the drug worked, explained Daniel Skovronsky, president of Lilly Research Laboratories.

Participants were randomised to receive intravenous donanemab or placebo every four weeks for up to 72 weeks. The primary efficacy outcome evaluated change on the iADRS from baseline to week 76. The composite tool combines the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog13) and the Alzheimer's Disease Cooperative Study - instrumental Activities of Daily Living (ADCS-iADL).

Slowed decline on dementia rating scales

Top-line results unveiled in January demonstrated that donanemab slowed disease progression on iADRS by 32% relative to placebo, which was significant. Starting from baseline iADRS scores of 106 in both arms of the study, patients who received donanemab saw a change of −6.86, versus a change of −10.06 in the placebo group, for an absolute benefit of 3.20 points on the scale at the end of 76 weeks, according to results reported Saturday.

Key secondary goals looked at how patients fared in terms of ADAS-Cog13, ADCS-iADL, Mini-Mental State Examination (MMSE), and Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores. Eli Lilly said donanemab slowed worsening on the CDR-SB measure by 23% at the 76-week mark, which was not statistically significant, although there was a wider gap between the two groups at weeks 36 and 52. Biogen and Eisai used CDR-SB to serve as the main efficacy endpoint in the analysis of their anti-amyloid antibody aducanumab, which is currently under priority review at the FDA with a decision due June 7.

Meanwhile, other TRAILBLAZER-ALZ data demonstrated that donanemab slowed declines on the MMSE scale by 21%, on ADCS-iADL by 23% and on ADAS-Cog13 by 39%.

Amyloid plaque levels reduced

In addition, results showed that treatment with donanemab reduced amyloid plaque by 85 centiloids at 76 weeks compared with placebo. By targeting a type of beta amyloid known as N3pG, Eli Lilly believes donanemab, formerly known as LY3002813, may be able to rapidly and completely clear amyloid plaques. The company said 40% of participants who received donanemab in the study attained amyloid-negative status as early as six months after starting treatment, and 68% reached this target by 18 months. There was no significant change in global tau load, but Eli Lilly said that in exploratory analyses, donanemab slowed the pace of tau accumulating across key brain regions.

On the safety front, Eli Lilly noted that donanemab's profile was consistent with observations from Phase I data. In the donanemab treatment group, amyloid-related imaging abnormalities – oedema (ARIA-E) occurred in 26.7% of treated participants, with an overall incidence of 6.1% experiencing symptomatic ARIA-E. The majority ARIA-E cases occurred within the first 12 weeks after initiation of treatment, the drugmaker said. Meanwhile, the rate of symptomatic ARIA-E was 0.8% in the placebo group.

Treatment discontinuations due to adverse events (AEs) also occurred more frequently in the donanemab group at 30.5%, and there were more study drop-outs as well as a result of AEs, at 15.3%. For the placebo arm, those rates were about 7% and 5%, respectively.

Looking ahead to TRAILBLAZER-ALZ 2

Commenting on the results, Skovronsky said "we slowed the disease down by about a third. In an 18-month study we've given them six months of less decline. Of course it's a 10-year disease. The question is, over 10 years, could you give them back three years." He also suggested that the "constellation" of benefits seen with donanemab indicates the drug may have "potential for long-term disease modification." Eli Lilly has said it wants to confirm its findings in the ongoing pivotal TRAILBLAZER-ALZ 2 trial, which has a targeted enrolment of 500 patients, and in a statement Saturday indicated that "discussions with regulators are ongoing."

Last month, AC Immune announced positive data for its experimental liposomal anti-pTau vaccine ACI-35.030 in older patients with early Alzheimer's disease, and said it planned to advance the candidate into Phase II/III development.

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