The Medicines and Healthcare products Regulatory Agency (MHRA) has today, October 23, 2024, approved a license for the medicine donanemab (Kisunla) for use in the early stages of Alzheimer’s disease, following a thorough review of its benefits and risks.
Donanemab works by removing a sticky protein called beta-amyloid from the brain that is thought to cause Alzheimer’s disease. The studies conducted showed that the drug was effective in slowing its progression.
As with any new medicine, this decision was made based on expert scientific advice on the benefits and risks of donanemab from the Commission on Human Medicines (CHM), the government’s independent advisory body.
Licensing medicines that meet acceptable standards of safety, quality and efficacy is a top priority for us.
We are confident that, together with the terms of the marketing authorization, the applicable regulatory standards for this medicinal product have been met.
As with all medical products, we will closely monitor its safety, and with a safety study to be conducted post-licensure, we will ensure that the benefits and risks of donanemab are closely monitored post-licensure.”
Julian Beach, MHRA Interim Director, Quality and Access to Healthcare
Donanemab is approved for the treatment of adults in the early stages of Alzheimer’s disease who have one or no copies of the apolipoprotein E4 (ApoE4) gene. A person can have no copies, one or two copies of this gene. About 15% of those diagnosed with Alzheimer’s disease have two copies of this gene, known as homozygous patients, and are at increased risk of developing Alzheimer’s disease, while people with one copy are also at increased risk .
The patient’s doctor will perform tests to make sure donanemab is right for him or her.
Donanemab was evaluated in a pivotal study (Phase III trial TRAILBLAZER-ALZ 2) in 1,736 patients with early-stage Alzheimer’s disease, mild cognitive impairment, mild dementia and evidence of amyloid pathology. The patients in the study also had evidence of a protein called ‘tau’ in their brains, which is involved in Alzheimer’s disease.
The study looked at changes in patients’ brain cognition and function, measured with clinical tools such as the Integrated Alzheimer’s Disease Rating Scale (iADRS). Other instruments used included the Clinical Dementia Rating Scale – Sum of Boxes (CDR-SB), ADAS-Cog13 and ADCS-iADL. These tools are used by doctors to measure Alzheimer’s disease and were measured at the beginning (baseline) and then throughout the study.
In this study, patients received donanemab 700 mg every 4 weeks for the first 3 doses, and then 1400 mg every 4 weeks (860 patients) or a placebo (a dummy infusion, 876 patients) for up to 72 weeks.
At week 76 of the study, patients treated with donanemab had statistically significantly less clinical progression of their Alzheimer’s disease compared to patients treated with the placebo. This was assessed by the change in iADRS score from baseline. Patients with low to moderate levels of tau protein showed a 35% delay in clinical progression, which equated to a 4.4 month delay in disease progression. In the overall population treated with donanemab, there was a 22% delay in clinical progression, which translated into a 1.4 month delay in disease progression.
Treatment with donanemab in both carriers and non-carriers was associated with less decline in iADRS and CDR-SB scores and a significant reduction in amyloid plaque compared to placebo (this is consistent with previous phase 2 data for carriers, but not for non-carriers those from which no benefit was previously derived). However, in carriers, the reduced decline in iADRS and CDR-SB was driven by those with one ApoE4 gene. Those with two ApoE4 genes showed no significant slowing of decline. A reduction in amyloid plaque was observed regardless of the number of ApoE4 genes an individual had, but the reduction was smaller in those with two ApoE4 genes.
ApoE4 homozygous patients receiving donanemab were also at higher risk of developing amyloid-related imaging abnormalities (ARIAs), which are usually seen as temporary swelling in one or more areas of the brain (ARIA-E) or small areas of bleeding in or on the brain. the surface of the brain (ARIA-H).
The CHM therefore recommended that the risk benefit of donanemab was favorable in patients who were ApoE4 non-carriers or heterozygous, but not in the homozygous group, and that testing for the ApoE4 gene should be performed before treatment.
The use of donanemab in patients taking anticoagulants (blood thinners, including warfarin) or who have been diagnosed with cerebral amyloid angiopathy (CAA) on MRI before starting treatment is contraindicated as the risks are believed to be greater in these patients are then the advantages.
Donanemab is a monoclonal antibody that binds to a protein called amyloid beta in Alzheimer’s disease, where clumps of amyloid beta protein form plaques in the brain. Donanemab works by binding to these clumps and shrinking them, slowing the progression of the disease.
The recommended dose of donanemab is 1400 mg, with the patient receiving this dose once every four weeks in a healthcare setting. When starting treatment, the patient will initially receive a dose of 700 mg every week for the first three rounds of treatment. Donanemab is administered intravenously, with each infusion lasting at least 30 minutes. The total duration of treatment should not exceed 18 months.
The most common side effects of the drug are infusion-related reactions (which can cause fever and flu-like symptoms), headache and ARIA.
In placebo-controlled trials, the incidence of ARIA was lower in non-carriers (24.1% donanemab versus 11.3% placebo) and heterozygotes (37.4% donanemab versus 13.4% placebo) than in homozygotes (58.3% donanemab versus 21.3% placebo).
Among patients treated with donanemab, symptomatic ARIA-E occurred in 4.1% of non-carriers and 6.1% of heterozygotes, compared with 7.7% of homozygotes. Severe cases of ARIA occurred in approximately 0.7% of non-carriers, 1.7% of heterozygotes and 3% of homozygotes. Among patients treated with donanemab, the rate of severe radiographic ARIA-E was lower in non-carriers (1.0% (3/291) and in heterozygotes 2.1% (11/522) compared to homozygotes 4.2% (7 /168). The rate of severe radiographic ARIA-H was lower in non-carriers 4.5% (13/291) and heterozygotes 9.2% (48/522) compared to homozygotes 24.4% (41/168).
A full list of all reported side effects with this medicine is available in the patient information leaflet or in the product information published on the MHRA website.
As with any medicine, the MHRA will closely monitor the safety and effectiveness of donanemab. To promote safe and effective use and to closely monitor the safety and efficacy of donanemab, initiation of treatment in patients will occur through a central registration system implemented as part of a controlled access program.
A post-authorisation safety study will be conducted to investigate the safety and benefit-risk profile of donanemab in routine clinical practice, particularly in relation to the incidence and severity of ARIAs and intracerebral haemorrhage, and long-term safety.
Additional risk minimization activities will be implemented for donanemab. These activities include the following:
- educational material for prescribers and radiologists on important safety risks related to the use of donanemab such as ARIA-E ARIA-H and intracerebral hemorrhage >1 cm
- a patient card designed to increase awareness and knowledge of patients and healthcare providers about the safety issues with donanemab and to inform physicians about the difference in ARIA in an emergency situation.
Anyone who suspects they are having a side effect from this medicine should speak to their doctor, pharmacist or nurse and report it directly to the MHRA Yellow Card system either via the website (https://goldcard.mhra.gov.