July 2, 2024
Today the U.S. Food and Drug Administration approved donanemab for the treatment of people living with early symptomatic Alzheimer’s disease, which includes mild cognitive impairment and the mild dementia stage of Alzheimer’s disease, with confirmed amyloid plaques.
“Once again, we see the tide turning in our ability to treat Alzheimer’s disease. With the second clinically effective medication now approved, we have a new class of medications to choose from with our goal of slowing the progression of the disease with the hope of extending higher quality cognitive function for patients and families living with this disease. Now that we have the infrastructure and experience we have developed in beginning to treat patients with lecanemab, we hope to be able to roll out donanemab therapy more quickly so that patients and families can work with us to select the best option if this type of treatment is appropriate for them. We have a tremendous amount of work to do to determine how best to use these medications in clinical practice and how best to monitor outcomes, but the success of donanemab represents another important milestone for patients and families living with this illness and for the field.” – Brad Dickerson, MD
Details are as follows:
The efficacy of donanemab was evaluated in a double-blind, placebo-controlled, study in patients with Alzheimer’s disease (patients with confirmed presence of amyloid pathology and mild cognitive impairment or mild dementia stage of disease, consistent with Stage 3 and Stage 4 Alzheimer’s disease). In Study 1, 1736 patients were treated every 4 weeks with the drug (N = 860) or placebo (N = 876) for a total of up to 72 weeks. The treatment was switched to placebo based on amyloid PET levels measured at Week 24, Week 52, and Week 76. If the amyloid plaque level was <11 Centiloids on a single PET scan or 11 to <25 Centiloids on 2 consecutive PET scans, the patient was eligible to be switched to placebo. Tau PET was also examined. Of the total number of patients randomized, 68% had low/medium tau level and 32% had high tau level; 71% were ApoE ε4 carriers and 29% were ApoE ε4 noncarriers.
The primary efficacy endpoint was change in the integrated Alzheimer’s Disease Rating Scale (iADRS) score from baseline to 76 weeks. The iADRS is a combination of two scores: the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog13) and the Alzheimer’s Disease Cooperative Study – instrumental Activities of Daily Living (ADCS- iADL) scale.
There were two primary analysis populations based on tau PET imaging with flortaucipir: 1) low/medium tau level population (defined by visual assessment and SUVR of ≥1.10 and ≤1.46), and 2) combined population of low/medium plus high tau (defined by visual assessment and SUVR >1.46) population.
Patients treated with donanemab demonstrated a reduction in clinical decline on iADRS compared to placebo at Week 76 in the combined population with a slightly larger effect in the low/medium tau population. Patients treated with donanemab demonstrated a 29% reduction in clinical decline on CDR-SB compared to placebo at Week 76 in the combined population. There were also differences between treatment groups as measured by ADAS-Cog13 and ADCS-iADL at Week 76.
Dosing was continued or stopped in response to observed effects on amyloid imaging. The percentages of patients eligible for switch to placebo based on amyloid PET levels at Week 24, Week 52, and Week 76 timepoints were 17%, 47%, and 69%, respectively. Amyloid PET values may increase after treatment with donanemab is stopped. There is no data beyond the 76-week duration of Study 1 to guide whether additional dosing with may be needed for longer-term clinical benefit.