The Medicines and Healthcare products Regulatory Agency (MHRA) has approved donanemab (Kisunla) for use in the early stages of Alzheimer’s disease. This decision follows a thorough review of the drug's benefits and risks, marking a significant step forward in the treatment of this debilitating condition.
Mechanism of Action
Donanemab is a monoclonal antibody designed to target and remove beta-amyloid plaques, which are believed to be a primary cause of Alzheimer’s disease. By binding to these plaques, donanemab helps to reduce their presence in the brain, thereby slowing the progression of the disease.
Clinical Trial Results
The approval was based on data from the Phase III TRAILBLAZER-ALZ 2 study, which involved 1,736 patients with early Alzheimer’s disease characterized by mild cognitive impairment, mild dementia, and evidence of amyloid pathology. The study assessed changes in cognition and function using tools like the integrated Alzheimer’s Disease Rating Scale (iADRS).
Patients were administered either 700 mg of donanemab every four weeks for the first three doses, followed by 1400 mg every four weeks (860 patients), or a placebo (876 patients) for up to 72 weeks. Results showed that patients treated with donanemab experienced statistically significant less clinical progression of Alzheimer’s disease compared to those on the placebo. Specifically, patients with low to medium levels of tau protein showed a 35% slowing of clinical progression, equivalent to a 4.4-month delay in disease progression. In the overall population, donanemab treatment resulted in a 22% slowing of clinical progression, or a 1.4-month delay.
ApoE4 Gene Considerations
The approval specifies that donanemab is intended for adults in the early stages of Alzheimer’s disease who have either no copies or one copy of the apolipoprotein E4 (ApoE4) gene. Patients will undergo testing to determine their ApoE4 gene status before starting treatment. The Commission on Human Medicines (CHM) advised that the risk-benefit profile of donanemab is favorable for ApoE4 non-carriers and heterozygotes but not for homozygotes, who are at a higher risk of developing Amyloid Related Imaging Abnormalities (ARIAs).
Dosage and Administration
The recommended dose of donanemab is 1400mg, administered intravenously every four weeks. The initial treatment involves 700mg doses weekly for the first three rounds. Each infusion should last at least 30 minutes, and the total treatment duration should not exceed 18 months.
Safety and Monitoring
The most common side effects include infusion-related reactions, headaches, and ARIA. The incidence of ARIA was notably higher in ApoE4 homozygotes compared to non-carriers and heterozygotes. Symptomatic ARIA-E occurred in 4.1% of non-carriers and 6.1% of heterozygotes, compared to 7.7% of homozygotes. Serious ARIA events occurred in approximately 0.7% of non-carriers, 1.7% of heterozygotes, and 3% of homozygotes.
Contraindications include the use of anticoagulants or a diagnosis of cerebral amyloid angiopathy (CAA) prior to treatment, as the risks in these patients are considered to outweigh the benefits. A post-authorization safety study will be conducted to further investigate the safety and benefit-risk profile of donanemab in routine clinical practice, with a focus on the incidence and severity of ARIAs and intracerebral hemorrhage.
Risk Minimization
To ensure safe and effective use, treatment initiation will be managed through a central registration system as part of a controlled access program. Additional risk minimization activities include educational materials for prescribers and radiologists, and a patient card to enhance awareness of safety concerns and inform physicians of ARIA differential diagnoses in emergency settings.
