The Medicines and Healthcare products Regulatory Agency (MHRA) has today, 23 October 2024, approved a license for the medicine donanemab (Kisunla) for use in the early stages of Alzheimer’s disease, following a thorough review of the benefits and risks.
Donanemab works by removing a sticky protein called beta-amyloid from the brain that is believed to cause Alzheimer’s disease, and in the trials conducted the medicine showed some evidence of efficacy in slowing its progression.
As for any new medicine, this decision was made with expert scientific advice on the benefit risk of donanemab from the Commission on Human Medicines (CHM), the government’s independent advisory body.
Licensing medicines which meet acceptable standards of safety, quality and efficacy is a key priority for us.
We’re assured that, together with the conditions of the license approval, the appropriate regulatory standards for this medicine have been met.
As with all medical products, we will keep its safety under close review, and with a safety study to be undertaken after licensing, we will ensure that the benefit risk of donanemab is closely followed up post-authorization.’’
Julian Beach, MHRA Interim Executive Director, Healthcare Quality and Access
Donanemab is approved to treat adults in the early stages of Alzheimer’s disease who have one or no copies of the apolipoprotein E4 gene (ApoE4). A person can have no copies, one copy or two of this gene. Approximately 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 also have an increased risk.
The patient’s doctor will perform testing to make sure that donanemab is right for them.
Donanemab was evaluated in a main study (Phase III Study TRAILBLAZER-ALZ 2) involving 1,736 patients with early Alzheimer’s disease who had 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 brain which is involved in Alzheimer’s disease.
The study looked at changes in patients’ brain cognition and function, measured by clinical tools such as the integrated Alzheimer’s Disease Rating Scale (iADRS). Other tools 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 start (baseline) and then throughout the study.
In this study, the patients received either 700 mg donanemab every 4 weeks for the first 3 doses, and then 1400 mg every 4 weeks (860 patients) or 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 in their Alzheimer’s disease compared to patients that were treated with the placebo. This was assessed by change in iADRS score from baseline. Patients with low to medium levels of tau protein showed 35% slowing of clinical progression which equated to 4.4 months of delay in disease progression. In the overall population treated with donanemab, there was a 22% slowing of clinical progression, translating to a 1.4-month delay in disease progression.
Donanemab treatment in both carriers and non-carriers was associated with less decline on iADRS and CDR-SB scores and a significant reduction in amyloid plaque compared with placebo (this is consistent with previous data from phase 2 for carriers but not for non-carriers which previously were not seen to benefit). However, among carriers, the reduced decline in iADRS and CDR-SB was driven by those with one ApoE4 gene. Those with two ApoE4 genes did not demonstrate a significant slowing in decline. Reduction in amyloid plaque was observed regardless of the number of ApoE4 genes an individual had, but the reduction was smaller among those with two ApoE4 genes.
ApoE4 homozygous patients who received donanemab were also at higher risk of developing Amyloid Related Imaging Abnormalities (ARIAs), which are most commonly seen as temporary swelling in one or more areas of the brain (ARIA-E) or small spots of bleeding in or on the surface of the brain (ARIA-H).
The CHM therefore advised that the risk benefit of donanemab was favorable in the patients who were ApoE4 non-carriers or heterozygous but not in the homozygous group, and that testing for the ApoE4 gene should be carried out before treatment.
Use of donanemab in patients who are on anticoagulants (blood thinners, including warfarin) or have been diagnosed with cerebral amyloid angiopathy (CAA) on MRI before starting treatment is contraindicated as the risks in these patients are considered to outweigh the benefits.
Donanemab is a monoclonal antibody which 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 reducing them, therefore slowing the progression of the disease.
The recommended dose of donanemab is 1400mg, with the patient receiving this dose once every four weeks in a healthcare setting. When starting treatment, the patient will initially receive a 700mg dose 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 medicine are infusion-related reactions (which can cause fever and flu-like symptoms), headaches and ARIA.
In placebo-controlled studies, the incidence of ARIA was lower in non-carriers (24.1% donanemab vs 11.3% placebo) and heterozygotes (37.4% donanemab vs 13.4% placebo) than in homozygotes (58.3% donanemab vs 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. Serious events of ARIA occurred in approximately 0.7% of non-carriers, 1.7% 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 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 side effects reported with this medicine is available in the patient information leaflet or from the product information published on the MHRA website.
As with any medicine, the MHRA will keep the safety and effectiveness of donanemab under close review. To promote safe and effective use and keep the safety and efficacy of donanemab under close review, initiation of treatment in any patients will be through a central registration system implemented as part of a controlled access programme.
A post-authorization safety study will be conducted to investigate the safety and benefit-risk profile of donanemab in routine clinical practice, particularly in relation to incidence and severity of ARIAs and intracerebral hemorrhage, and long-term safety.
Additional risk minimization activities will be implemented for donanemab. These activities include the following:
- educational materials 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 enhance the awareness and knowledge of patients and caregivers about the safety concerns with donanemab as well as inform physicians of ARIA differential in an emergency setting.
Anyone who suspects they are having a side effect from this medicine should to talk to their doctor, pharmacist or nurse and report it directly to the MHRA Yellow Card scheme, either through the website (https://yellowcard.mhra.gov.
