The era of Alzheimer's immunotherapies is upon us

Eli Lilly just released Phase III results for their Alzheimer's immunotherapy Donanemab right after Leqembi received traditional approval. How do the two compare?

Right on the heels of Leqembi’s traditional approval pharmaceutical company Eli Lilly has come out with results of their own immunotherapy named Donanemab, published just yesterday in The Journal of the American Medical Association¹ (JAMA).

Donanemab follows along as one of many immunotherapies intended to target the plaques that form during Alzheimer’s Disease, with the assumption that targeting and removal of these plaques will lead to reduced neurodegeneration.

To provide better clarity, these immunotherapies are IgG monoclonal antibodies that bind to various portions of these plaques, which can then be targeted by immune cells within the brain for removal.

Donanemab is described as having this mechanism of action within the JAMA article:

Donanemab is an immunoglobulin G1 monoclonal antibody directed against insoluble, modified, N-terminal truncated form of β-amyloid present only in brain amyloid plaques. Donanemab binds to N-terminal truncated form of β-amyloid and aids plaque removal through microglial-mediated phagocytosis.¹¹

Again, it’s rather interesting to see that several immunotherapies have suddenly emerged within recent years given the decades of work that have come back fruitless. Readers should also be reminded that the amyloid hypothesis has come under serious scrutiny, with recent revelations suggesting a sort of racketeering occurring within the field of Alzheimer’s that have suppressed any other research endeavors into alternative causes of Alzheimer’s.

Mired in Controversy over Aducanumab, Biogen reports "positive" results over their new Alzheimer's Immunotherapy Lecanemab

There’s also serious question over the actual clinical significance of these drugs, which tend to show moderate reduction in degeneration in clinical trials. Paired with serious adverse reactions by way of ARIA and there are many reasons to be hesitant about these sudden approvals.

Eli Lilly is argued to seek approval some time this year, and so how exactly does this treatment fare relative to Aducanumab and Leqembi?

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Brief Study Overview

Visual Abstract of the study. From Sims, et al.

This clinical trial in question, named TRAILBLAZER-ALZ 2, was originally a Phase II clinical trial that was later expanded to Phase III.

The trial contained a placebo group and a Donanemab group. The Donanemab group was divided based upon tau protein levels, which were suggested to be associated with worse disease progressions, making one low/medium tau group and one high tau group. The high tau group were collected into the other groups to form the combined population as can be seen in the visual abstract above.

Donanemab was provided every 4 weeks to the treatment group in contrast to Leqembi which was provided every 2 weeks. Also, in contrast to Leqembi’s 10 mg/kg biweekly dosage Donamemab was provided as a 700 mg dosage for the first 3 treatments, which were then elevated to 1400 mg for every subsequent dose- this difference in dosing methods and levels are important to consider when looking at results.

The study took place over the course of 76 weeks (about a little over 18 months).

Now, what’s interesting is that the primary endpoints measured within Eli Lilly’s clinical trial was to look at an integrated Alzheimer Disease Rating Scale (iADRS) in contrast to the CDR-SB score considered to be the standard for these immunotherapies. Note that CDR-SB scores were a secondary endpoint measure.

iADRS is a composite score, using measures from two different Alzheimer’s assessments- the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the Alzheimer’s Disease Cooperative Study – instrumental Activities of Daily Living (ADCS-iADL). The scoring is much higher, and so it can’t be directly compared to the CDR-SB score used in the Leqembi trial.

Wessels, et al.² provides an explanation for how iADRS is calculated (emphasis mine):

The iADRS is calculated as a linear combination of total scores of the two individual components, the ADAS-Cog14 (score range 0 to 90) and the instrumental items of the ADCS-ADL (ADCS-iADL; score range 0 to 56). Because higher scores on the ADAS-Cog14 reflect worse performance, whereas higher scores on the ADCS-iADL reflect better performance, the ADAS-Cog score is multiplied by (−1) in the calculation of the integrated scale. To anchor the ADAS-Cog at 0, a constant (90) is added. The iADRS score is then computed as the sum of the transformed ADAS-Cog14 and the ADCS-iADL, as shown in the formula below:

iADRS score = [−1(ADAS - Cog14) + 90] + iADL

The iADRS score ranges from 0 to 146 with lower scores indicating worse performance.

Again, note this very large range of scoring for iADRS. In contrast, CDR-SB has a total score range from 0-18 (0-3 across 6 domains which are added together for an overall score). Also, note that higher CDR-SB scores are associated with worsening of disease whereas a higher iADRS score is associated with better disease progression. Put another way, one should expect a lower decline in iADRS scores if Donanemab is expected to be better than placebo.

In a similar fashion to Leqembi, note that graphical representation of disease progression starts at a baseline value which is noted as a “0”. Again, this 0 does not mean that participants start off with a iADRS score of 0, but instead keeps track of score reduction over time.

Baseline iADRS scores for patients hovered around 103-105, with CDR-SB scores hovering around 3.7-4, which is slightly above Leqembi’s Phase III baseline CDR-SB scores which were around a low 3 (check Table 1 for more on baseline characteristics).

The overall results mapping both iADRS and CDR-SB scores can be seen below:

Figure 2. Clinical outcomes for those given Donanemab compared to placebo. For comparisons in scores the caption for this figure notes the following: “A, 35.1% slowing (95% CI, 19.90%-50.23%) of clinical progression. B, 22.3% slowing (95% CI, 11.38%-33.15%) of clinical progression. C, 36.0% slowing (95% CI, 20.76%-51.15%) of clinical progression. D, 28.9% slowing (95% CI, 18.41%-39.44%) of clinical progression.”

Remember that results are interpreted based on the reduction in iADRS scores compared to baseline. Given that it is argued that early treatment is best we will only take a look at the low/moderate tau group results here. Note that greater tau protein aggregation does not infer later disease progression as the tau aggregation could be due to quicker disease progression, although it does appear that Donanemab is least effective in those with greater tau levels. Please look at the study for the combined results.

Here, it appears that the early/moderate tau group provided Donanemab showed an average decline of around 6.02 relative to baseline at the 76 week mark. This is in contrast to iADRS score decline of around 9.27 for placebo with early/moderate tau, suggesting around a 3.25 reduction in iADRS score reduction with the use of Donanemab for this group.

Given that the iADRS score uses a much larger scoring rubric this may seem to be hard to interpret. If we look at the CDR-SB change, we can see that the Donanemab group showed a CDR-SB score increase relative to baseline of around 1.16 while the placebo group saw an increase of around 1.84, resulting in a CDR-SB difference between the two groups of around 0.68.³ Again, this is when comparing the low/moderate tau groups.

This score is more comparable to Leqembi’s, and if we look back we can see that the difference in CDR-SB with Leqembi was around 0.451 which was argued to be a difference in decline of around 27%. For Donanemab, the difference in CDR-SB score is more around 36%.

On the surface, these results would suggest that Donanemab at least shows greater reductions in cognitive decline relative to Leqembi. However, given the differences in doses one may consider whether Leqembi may be underdosed relative to Donanemab or if Donanemab uses a higher dosage overall, leading to the greater improvements shown. Keep in mind that both are argued to target the same plaque, and so there is a question of whether one monoclonal antibody is better at targeting relative to another.

Also, it’s worth noting that the placebo group in the Leqembi trial showed a lower CDR-SB score difference by the primary endpoint. In comparison to Donanemab’s results, the Leqembi treatment group had an endpoint CDR-SB score of around 1.21 whereas the placebo group had a score of around 1.66.⁴

There’s a lot that would need to be discussed when comparing these numbers, but that may fall outside of my capabilities. For now, I will argue that these results aren’t too different from one another.

However, I should note that the JAMA article notes that around 47% of Donanemab participants showed no decline in cognition by the 1 year mark, relative to 29% within the placebo group. Leqembi doesn’t appear to have any reference to a “no change” group, and so this again raises further issues of lack of data stratification in these clinical trials.

Is Donanemab Safer?

Now, the real question comes to the rate of adverse reactions. In a more similar comparison to Leqembi, adverse reactions were relatively high in the Donanemab group. Note that the number of deaths in both groups were made out to be somewhat comparable (1.9% vs 1.1%), although 3 of the deaths in the Donanemab group are argued to be related to Donanemab:

In the donanemab group, 3 participants with serious amyloid-related imaging abnormalities subsequently died (2 APOE ε4 heterozygous carriers and one noncarrier; none were prescribed anticoagulant or anti-platelet medications; one resumed treatment after resolution of severe amyloid-related imaging abnormalities edema/effusion that was accompanied by severe amyloid-related imaging abnormalities microhemorrhages and hemosiderin deposits and one had superficial siderosis at baseline) (eTable 9 in Supplement 3).

Again, rates of ARIA appear to be far greater in the Donanemab group, and appear to be associated with APOE4 status:

And so many of these concerns with Leqembi are shared with Donanemab, noting serious adverse reactions for an otherwise comparable drug.

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Welcome to a New Age

A greater analysis of Donanemab’s results may be saved for later. For now, it appears that Donanemab may be seen as slightly better than Leqembi. But remember that Leqembi’s questionable approval should tell us that we shouldn’t be using that as a benchmark of efficacy. All things considered, Donanemab appears to show only moderate reductions in cognitive decline. Keep in mind that patients provided Donanemab still showed a CDR-SB score increase of slightly above 1. Using the same rubric outlined by CDR-SB scoring, an increase in one dimension from 0-0.5 is a move from not impaired to impaired, and a move from 0-1 is a move from not impaired to dependent. Thus, these patients are still showing cognitive decline.

And so sentiments around Donanemab appear mixed⁵, but only this time the approval of Leqembi has likely allowed Donanemab possible approval pathways that were not there before. More drugs within this same vein are likely to follow, thus solidifying the ever-controversial amyloid hypothesis even with all of the controversies surrounding this hypothesis in particular.

Thus, we are entering a new age. More of these drugs, with unknown clinical efficacy and yet seriously concerning side effects will be pushed through with ease, meaning more profits for the manufacturers and greater unknowns for patients.

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1. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. Published online July 17, 2023. doi:10.1001/jama.2023.13239

2. Wessels, A. M., Siemers, E. R., Yu, P., Andersen, S. W., Holdridge, K. C., Sims, J. R., Sundell, K., Stern, Y., Rentz, D. M., Dubois, B., Jones, R. W., Cummings, J., & Aisen, P. S. (2015). A Combined Measure of Cognition and Function for Clinical Trials: The Integrated Alzheimer's Disease Rating Scale (iADRS). The journal of prevention of Alzheimer's disease, 2(4), 227–241. https://doi.org/10.14283/jpad.2015.82

3. There’s some discrepancy in which data is used when reporting these results. Statistical analyses of these results seem to be reported as either a NCS2 or a MMRM score as shown in Table 2. Given my lack of statistics knowledge I can’t tell why one score would be used over the other. It appears that the in-text results for the iADRS reporting used the NCS2 score, while the difference provided for the CDR-SB score in-text seems to draw from the MMRM results (it’s the only difference that shows 0.67 while the NCS2 difference shows 0.68).

4. van Dyck, C. H., Swanson, C. J., Aisen, P., Bateman, R. J., Chen, C., Gee, M., Kanekiyo, M., Li, D., Reyderman, L., Cohen, S., Froelich, L., Katayama, S., Sabbagh, M., Vellas, B., Watson, D., Dhadda, S., Irizarry, M., Kramer, L. D., & Iwatsubo, T. (2023). Lecanemab in Early Alzheimer's Disease. The New England journal of medicine, 388(1), 9–21. https://doi.org/10.1056/NEJMoa2212948

5. JAMA has allowed some opinion pieces which highlight these sentiments of questionable efficacy and concerning side effects. Here’s an example of one of these pieces:

Widera EW, Brangman SA, Chin NA. Ushering in a New Era of Alzheimer Disease Therapy. JAMA. Published online July 17, 2023. doi:10.1001/jama.2023.11701