26th July 2023, Dr Chee L Khoo
First it was aducanumab then lecanemab. Now it’s donanemab. All of them purportedly showed statistically significant improvement in clinical outcomes although the “significance” is hotly debated. Although aducanumab was the first to be approved by FDA (June 2021), the limited clinical improvement together with the increased risk of severe adverse effects meant that aducanumab is no longer used these days. We explored lecanemab in December 2022 when the CLARITY AD trial published. Both aducanemab and lecanemab were both granted accelerated approval by the FDA although lecanemab have since received approval via the standard pathway. It is expected donanemab will similarly be granted in due course. Let’s have a look at donanemab in the TRAILBLAZER -ALZ 2 trial.
One school of thought theorised that the accumulation of soluble and insoluble aggregated amyloid-beta (Aβ) is involved in the pathologic processes in Alzheimer disease. Thus, abnormal β-amyloid is thought to be a key pathological hallmark of Alzheimer disease defined by the 2018 National Institute on Aging and the Alzheimer’s Association Research Framework and is one of the major targets in Alzheimer disease research and drug development (1).
Over the past decade, considerable advances occurred in testing the amyloid cascade hypothesis in Alzheimer disease clinical trials. Previous amyloid-targeting therapy trials failed to show appreciable slowing of clinical disease progression (2-5); however, aducanumab, lecanemab, and donanemab recently showed promising amyloid plaque clearance, potentially benefitting patients (6-8). These are monoclonal antibodies directed at brain beta-amyloid.
TRAILBLAZER-ALZ 2 was a 76-week, phase 3, randomised, double-blind, parallel, multi-centre, placebo-controlled trial (9). Eligible participants aged 60 – 85 years with early symptomatic Alzheimer disease (mild cognitive impairment or Alzheimer disease with mild dementia). Screening involved MMSE (scores 20-28), amyloid pathology on PET (>37 Centiloids) and MRI scans to exclude oedema, effusion or microhaemorrhages or white matter disease. Randomised participants received either donanemab (700 mg for the first 3 doses and 1400mg thereafter) or placebo.
The primary outcome of the trial was a change in the iADRS score between the groups. The integrated Alzheimer’s Disease Rating Scale (iADRS) is a cognitive/functional composite of two widely accepted measures, the Alzheimer Disease Assessment Scale – Cognitive Subscale 13-item version (ADAS-Cog13) and the Alzheimer Disease Cooperative Study – instrumental activities of daily living (ADCS-iADL) scale. The iADRS (score range, 0–144) is a linear combination of its two components, the ADAS-Cog13 (range, 0–85; higher scores indicating greater deficit of global cognition) [23] and the ADCS-iADL (instrumental items of the ADCS-ADL scale [items 6a and 7–23]; range, 0–59; lower scores indicating greater impairment). Since worse outcomes are indicated by higher scores on the ADAS-Cog13, the ADAS-Cog13 score is multiplied by -1 when adding the composite score.
The possible scores on the iADRS range from 0 to 144 (lower scores indicate greater impairment), and the meaningful within-patient change (MWPC) is a change of 5 points for those with Alzheimer disease with MCI and 9 points for those with Alzheimer disease with mild dementia.
The Findings
1736 were enrolled (mean age, 73.0 years; 996 [57.4%] women) and 76% completed the trial: 860 were assigned to receive donanemab and 876 were assigned to receive placebo. As expected, the combined population had higher tau biomarkers at baseline due to the inclusion of participants with high tau pathology and showed greater impairment across baseline clinical assessments.
Primary outcomes
In the low/medium tau population, compared with baseline, there was a 35.1% reduction in disease progression at 76 weeks in patients on donanemab. Sounds impressive but the real absolute change from baseline in the iADRS score was −6.02 in the donanemab group vs −9.27 in the placebo group (p < .001). Remember, the iADRS ranged from 0 – 144 and the difference between the groups was -3.2.
In the combined population, the reduction in progression was only 22.3% (-10.19 in the donanemab group vs -13.11 in the placebo group (p<0.001).
There was a 38.6% (CDR-G hazard ratio, 0.61 [95% CI, 0.47-0.80]; P < .001) lower risk of disease progression in the low/medium tau population and a 37.4% (CDR-G hazard ratio, 0.63 [95% CI, 0.51-0.77; P < .001) lower risk of disease progression in the combined population with donanemab treatment compared with placebo over the 18-month trial
Secondary outcomes
There were dramatic reduction in brain amyloid plaque level on amyloid PET. For the low/medium tau population, there was a reduction of – 88 centiloids in the donanemab group vs +0.2 Centiloids in the placebo group while the figures for the combined population, donanemab treatment reduced amyloid by 87 centiloids vs -0.67 centiloids in the placebo group.
There were no difference in tau PET between the groups.
Adverse outcomes
The incidence of death was 1.9% in the donanemab group and 1.1% in the placebo group, while the incidence of serious adverse events was 17.4% in the donanemab group and 15.8% in the placebo group. Treatment-emergent adverse events were reported by 759 of 853 participants (89.0%) receiving donanemab and 718 of 874 participants (82.2%) receiving placebo. Treatment discontinuation due to adverse events was reported in 112 participants receiving donanemab and 38 participants receiving placebo. The most common adverse events that led to treatment discontinuation were infusion-related reactions, either amyloid-related imaging abnormalities edema/effusion or microhemorrhages and hemosiderin deposits, and hypersensitivity.
So, where are we now with anti-amyloid therapy in patients with Alzheimer Dementia? This slightly less worsening is small when looked at in absolute values. However, slowing progression by a 4-6 months as seen with donanemab does allow for someone to remain in mild cognitive impairment or mild-stage dementia for just that much longer which may have huge implications in care for that patient. In addition, 47% of participants in the low/medium tau group receiving donanemab were considered stable at 1 year compared with 29% of participants receiving placebo. For some, this can be considered clinically and personally meaningful.
There were significant adverse events with donanemab treatment including deaths.
There were further criticisms that although Alzheimer disease impacts Black and Latinx patients at rates that are 2 times and 1.5 times higher, respectively, than in White patients (12), 95% of the participants in the TRAILBLAZER ALZ 2 trial were white. So, we don’t really know how well blacks, Asians or Latino patients will respond to donanemab.
Promising new drug or another false dawn?
References:
- Jack CR Jr, Bennett DA, Blennow K, et al; Contributors. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535-562. doi:10.1016/j.jalz.2018.02.018
- Ostrowitzki S, Bittner T, Sink KM, et al. Evaluating the safety and efficacy of crenezumab vs placebo in adults with early alzheimer disease: two phase 3 randomized placebo-controlled trials. JAMA Neurol. 2022;79(11):1113-1121. doi:10.1001/jamaneurol.2022.2909
- Doody RS, Thomas RG, Farlow M, et al; Alzheimer’s Disease Cooperative Study Steering Committee; Solanezumab Study Group. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370(4):311-321. doi:10.1056/NEJMoa1312889
- Honig LS, Vellas B, Woodward M, et al. Trial of solanezumab for mild dementia due to alzheimer’s disease. N Engl J Med. 2018;378(4):321-330. doi:10.1056/NEJMoa1705971
- Salloway S, Farlow M, McDade E, et al; Dominantly Inherited Alzheimer Network–Trials Unit. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease. Nat Med. 2021;27(7):1187-1196. doi:10.1038/s41591-021-01369-8
- Budd Haeberlein S, Aisen PS, Barkhof F, et al. Two randomized phase 3 studies of aducanumab in early Alzheimer’s disease. J Prev Alzheimers Dis. 2022;9(2):197-210. doi:10.14283/jpad.2022.30
- Mintun MA, Lo AC, Duggan Evans C, et al. Donanemab in early Alzheimer’s disease. N Engl J Med. 2021;384(18):1691-1704. doi:10.1056/NEJMoa2100708
- van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9-21. doi:10.1056/NEJMoa2212948
- 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