Variability of cognitive changes after donanemab treatment

Abstract

To The Editor

In an article in this journal published recently,¹ Drs. Daly, Kepp, and Imbimbo discussed the question as to whether the anti-amyloid beta monoclonal antibodies lecanemab and donanemab effectively modify the natural history of disease in patients with early Alzheimer's disease (AD). Based on their analysis of results obtained from two large clinical trials of these drugs carried out over an 18 -month period,^{2, 3} Daly, Kepp, and Imbimbo concluded that there is not yet strong evidence for claiming a modification of the natural history of the disease by these drugs. In particular, they point out that while both drugs greatly reduced brain amyloid plaques in patients with AD as well as led to statistically significant reductions in the rate of cognitive decline in patients treated with the drugs compared to the placebo group, these clinical benefits were modest. Furthermore, both drugs are associated with significant adverse effects. In particular, donanemab was associated with increased risks of amyloid-related imaging abnormalities and brain volume loss.^{3, 4}

A further question concerning the results of these clinical trials is the degree of individual variability in the observed changes in cognition in patients treated with either drug or placebo. In the case of the study by Sims et al.,³ the integrated Alzheimer's Disease Rating Scale (iADRS) score after 76 weeks of donanemab treatment decreased by a mean of 10.2 units in the 583 patients who completed the trial, with 95% confidence limits of 11.22 and 9.16. Given that 95% confidence limits are close to ± 2 standard errors of the mean (SEM), the SEM for this group is calculated as 0.53. Further, given an n value of 583, the standard deviation (SD) is 12.69 (as calculated from the formula SEM = SD divided by the square root of n). In the placebo group, the iADRS score after 76 weeks decreased by a mean of 13.1, with 95% confidence limits of 14.10 and 12.13. There were 653 patients in this group. By the same method as above, the SD for the placebo group is calculated as 12.84. As shown in Figure 1A, there is considerable overlap between the donanemab and placebo groups in the change in iADRS score after 76 weeks.

FIGURE 1

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Comparison of the change in the cognitive impact of treatment with placebo or donanemab. A, The change (mean ± SD) in the ∆iADRS after 76 weeks of treatment with placebo or donanemab calculated from data reported by Sims et al.³ B, Normal distribution curve (red line) of ∆iADRS for all patients treated with donanemab, as calculated from data reported by Sims et al.³ Cand D, Same graphs for the subset of patients with low or medium levels of tau. The blue vertical dashed lines in (B) and (D) represent the mean change for the respective placebo group in each case. iADRS, integrated Alzheimer Disease Rating Scale; SD, standard deviation.

Given that the iADRS is a combination of the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog, which itself is the sum of several components) and the Alzheimer's Disease Cooperative Study–instrumental Activities of Daily Living (ADCS-iADL), it is reasonable to assume that the change in iADRS is normally distributed. Based on this assumption, the distribution of this variate for the donanemab group would be as shown in Figure 1B (mean value −10.2, SD 12.69). The mean score for the placebo group (−13.1) is also shown in Figure 1B. From the properties of the normal distribution, it follows that 59.0% of patients in the donanemab group would have had a better outcome than the mean outcome for the placebo group, but 41.0% would have had a worse outcome.

Sims et al.³ also examined a subset of the participants who had low or medium levels of tau. In the low/medium tau group, the mean decrease in iADRS was less for both the donanemab and placebo groups in the combined population (6.02 and 9.27, respectively; Figure 1C). Using the same procedure as for the combined group, 61.7% of patients in the donanemab group would have had a better outcome than the mean outcome for the placebo group, but 38.3% would have had a worse outcome (Figure 1D).

Donanemab has now been approved by the US Food and Drug Administration for treatment for AD. Patients receiving the drug would be informed of the potential risks associated with the drug treatment. No doubt many would also be informed of the conclusion of the TRAILBLAZER trial for donanemab, that is, that in patients with early AD donanemab treatment resulted in a statistically significant slowing of disease progression after 76 weeks of treatment.³ Many patients may then assume that they would therefore benefit from receiving the drug, whereas, as explained above, the very considerable variability in cognitive changes after drug treatment means that the probability of a benefit (i.e., better outcome than the average for the placebo group) for an individual patient would be only ≈ 60%.

I believe it is important that patients and their families be fully informed not just of the potential benefits, risks, and costs associated with donanemab treatment, but also of the very considerable variability in cognitive decline after treatment.