Donanemab

Donanemab, sold under the brand name Kisunla, is a monoclonal antibody used for the treatment of Alzheimer's disease. Donanemab was developed by Eli Lilly and Company.

The most common side effects include amyloid-related imaging abnormalities, which are brain hemorrhages and brain swelling, which can cause strokes, seizures, falls and trouble thinking. Brain hemorrhage and swelling occurred in 36.8% of patients taking donanemab and 14.9% of placebo patients. Headache and allergic reactions to the medication were other common side effects.

Donanemab was approved for medical use in the United States in July 2024. Most of the members of the FDA advisory panel had financial conflicts of interest. Treatment is intended for people with mild cognitive impairment or mild dementia stage of disease, which is the same population the treatment was studied in the clinical trials. Several public interest groups spoke out in FDA hearings against approval of the drug.

Medical uses

Donanemab is indicated for the treatment of Alzheimer's disease for people with mild cognitive impairment or mild dementia stage of disease.

Adverse effects

The US Food and Drug Administration (FDA) label for donanemab contains a boxed warning about amyloid-related imaging abnormalities.

Side effects may include infusion-related reactions, with symptoms such as flu-like symptoms, nausea, vomiting and changes in blood pressure, and hypersensitivity reactions, including anaphylaxis (severe, life-threatening allergic reaction) and angioedema (swelling).

Cerebral edema

In larger doses of donanemab, some people developed a form of cerebral edema (brain swelling) called "amyloid-related imaging abnormalities with edema or effusions" (ARIA-E); some of these people were asymptomatic while others displayed edema.

History

The efficacy of donanemab was evaluated in a double-blind, placebo-controlled, parallel-group study (study 1, NCT04437511/TRAILBLAZER-ALZ 2) in participants with Alzheimer’s disease. The participants had confirmed presence of amyloid pathology and mild cognitive impairment or mild dementia stage of disease. 1736 participants were randomized 1:1 to receive 700 mg donanemab every four weeks for the first three doses, and then 1400 mg every four weeks (N = 860) or placebo (N = 876) for a total of up to 72 weeks. The treatment was switched to placebo based on a pre-specified reduction in amyloid levels measured by positron emission tomography (PET) at weeks 24, 52, and 76.

Donanemab has shown positive results in its first trials.

Phase I

First study

In the United States and Japan, Eli Lilly ran the phase I study from May 2013 to August 2016. The study was conducted on people with mild Alzheimer's disease shown through a positive amyloid PET scan that was conducted on each individual. 100 participants were injected intravenously with donanemab up to four times monthly. Phase I was part of a multi-armed study that used one control group across the different trials. The positive result indicated that the participants had excess amyloid protein in the brain depicting an early sign of Alzheimer's disease. Each month, doses of 0.1 mg/kg to 10 mg/kg were injected into males and non-fertile females at an average age of 74.

Lilly revealed that there were adverse effects for the 37 people who received the treatment and 12 volunteers who received the placebo. The highest dose of donanemab reduced the effect of the plaque burden in the brain. An overall finding was that the higher dosage led to 40% reduction in protein plaques in the brain.

Side effects

Up to four injections occurred monthly until adverse effects led Lilly to alter the trial, increasing the number of injections up to 8 per month and increasing the dosage of patients from 0.1 mg/kg to 0.3 mg/kg. The change in dosages was in conjunction with the decrease in participants from 37 documented volunteers to 9 participants with results available to the public.

There were no adverse symptoms when they were given a singular dose. Donanemab was found to be highly immunogenic, creating an immune response that increases the efficiency of the original antibody infused. In the next part of the trial, where patients received multiple doses, six patients had an infusion reaction which included chills, flushing, dizziness, rash, and fever. No patients had ARIA-E, but there were cases of ARIA-H leaving small hemorrhages in the brain. The two cases with ARIA-H were asymptomatic. Most people developed anti-drug antibodies lowering the drug's effectiveness, with a short half-life of ten days.

Second study

The second phase I study was conducted in December 2015 in the United States and Japan. This trial had 150 participants, increasing the sample size by 50 people. The method was altered in comparison with the first study conducted. This trial used three different dosing regimens: one with a single dosage of 10, 20, or 40 mg/kg, another with 10 mg/kg every other week for 24 weeks, and a third with 10 or 20 mg/kg every month for 16 months. The participants were randomly selected to be a part of either the placebo group or the real trial, with a ratio of 3:1. The aim of this trial was the same as the first, primarily measuring the effectiveness on reducing amyloid brain plaques.

Side effects

The increase in dosage led to a larger percentage of participants experiencing symptomatic ARIA-E, rising to 1 in 4 participants. Auto-antibodies were also becoming problematic for donanemab, recognizing the drug as a non-self cell leading to the body fighting against the drug. Anti-drug antibodies, which fall under auto-antibodies were produced in nearly every patient. While this trial showed a positive outcome for participants taking monthly doses for 16 months as the amyloid PET scan became negative, the trial ended in August 2019.

Trailblazer-alz

The phase II trial methodically differed from phase I, altering the duration, the amount of donanemab, and the number of patients. There was an increase in the amount of donanemab infused into the blood every month for 72 weeks. The patients infused with donanemab and infused with the placebo became equal, creating close to a 1:1 ratio with 257 patients in total. For the first three doses 700 mg was infused and 1400 mg of donanemab for every dose after that. A PET scan was also used to measure the amount of plaque in the brain. TRAILBLAZER-ALZ was the method used to improve the placebo-controlled group as it was randomised. It assessed the safety and efficacy of donanemab.

It consisted of a trial combining two experimental drugs under Lilly that target separate parts of the amyloid cascade. The goal of this phase II trial was to see how safe, tolerable, and effective an 18-month term of donanemab alone and in combination with Lilly's BACE inhibitor LY3202626. This BACE inhibitor was administered orally compared to donanemab which is intravenously injected. To effectively see the comparison between patients only taking donanemab and patients taking both of Lily's drugs was effectively achieved by studying three separate groups. One group had donanemab injections and orally received Lilly's BACE inhibitor, another had only donanemab injections, and the third was the placebo group. It planned to enroll 375 people whose memories had been deteriorating for at least six months and who scored above a certain threshold on the CogState Bridging Test but ended up with 257 participants.

Results

There was a reduction in plaque level which was highlighted through improved cognition and ability to perform daily activities. Phase II showed promising results at the beginning without analyzing its effects and the data in detail. It was concluded that there was no substantial difference in the results between the placebo group and the patients infused with donanemab. After phase II, the trial was stopped.

Side effects

There was an overview on the Integrated Alzheimer's Disease Rating Scale (iADRS) when taking donanemab and the scores were similar to the placebo group, showing no significant difference. There were cases of ARIA-E but only asymptomatic which is an improvement from the symptomatic patients seen in phase I. Lilly decided to continue trials for donanemab but discontinue the trials with the BACE inhibitor in October in 2018. In 2021 the TRAILBLAZER-ALZ trial was completed, indicating the current success of donanemab as it slows down the development of Alzheimer's disease; but with the side effects still being problematic, further investigation was needed.

Phase III

In October and November 2020, Lilly extended the TRAILBLAZER-ALZ to have a second study. It was run with 87 sites across Canada, the Netherlands, and Poland.

In May 2023, the company reported its phase III study showed the drug could slow the pace of Alzheimer's disease by 35%. The 35% slowing is a relative reduction based on a subgroup analysis, which is considered an hypothesis, not proof of the claim. Several experts have criticized the use relative values, calling it "misleading". In July 2023, results from 1,736 people treated with donanemab showed slowing of Alzheimer's progression at 76 weeks, with 24% of the people displaying cerebral edema.

Society and culture

Legal status

In July 2024, donanemab was approved for medical use in the United States. The US Food and Drug Administration (FDA) granted the application for donanemab fast track, priority review, and breakthrough therapy designations.

In October 2024, donanemab was approved for medical use in the United Kingdom by the Medicines and Healthcare products Regulatory Agency.

In March 2025, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency recommended the refusal of a marketing authorization for Kisunla, a medicine intended for the treatment of early Alzheimer's disease. In June 2025, the CHMP started a re-examination of its refusal.

Economics

The list price for donanemab is for a course of therapy lasting a year.

Names

Donanemab is the international nonproprietary name.

Research

Improvements in amyloid imaging technology have linked the excess Aβ peptide outside the cell with the development of Alzheimer's disease. The overproduction of the Aβ peptide creates a plaque in certain parts of the brain, disrupting neurotransmission. Donanemab attacks the soluble and insoluble plaque buildup, slowing the progression of the disease.

References

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Anti-amyloid monoclonal antibodies
Drugs developed by Eli Lilly and Company