Donanemab
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Donanemab, sold under the brand name Kisunla, is a
monoclonal antibody A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodie ...
used for the treatment of
Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
. Donanemab was developed by
Eli Lilly and Company Eli Lilly and Company, Trade name, doing business as Lilly, is an American multinational Medication, pharmaceutical company headquartered in Indianapolis, Indiana, with offices in 18 countries. Its products are sold in approximately 125 count ...
. The most common side effects include
amyloid-related imaging abnormalities Amyloid-related imaging abnormalities (ARIA) are abnormal differences seen in magnetic resonance imaging of the brain in patients with Alzheimer's disease. ARIA is associated with anti-amyloid drugs, particularly human monoclonal antibodies such a ...
, 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 In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...
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 The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(FDA) label for donanemab contains a
boxed warning In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears near the beginning of the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administratio ...
about
amyloid-related imaging abnormalities Amyloid-related imaging abnormalities (ARIA) are abnormal differences seen in magnetic resonance imaging of the brain in patients with Alzheimer's disease. ARIA is associated with anti-amyloid drugs, particularly human monoclonal antibodies such a ...
. 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 Cerebral edema is excess accumulation of fluid ( edema) in the intracellular or extracellular spaces of the brain. This typically causes impaired nerve function, increased pressure within the skull, and can eventually lead to direct compres ...
(brain swelling) called "amyloid-related imaging abnormalities with edema or effusions" (ARIA-E); some of these people were
asymptomatic Asymptomatic (or clinically silent) is an adjective categorising the medical conditions (i.e., injuries or diseases) that patients carry but without experiencing their symptoms, despite an explicit diagnosis (e.g., a positive medical test). P ...
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 Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in Metabolism, metabolic processes, and in other physiological activities including bloo ...
that was conducted on each individual. 100 participants were injected
intravenously Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...
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 effect An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term compli ...
s 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 Volunteering is an elective and freely chosen act of an individual or group giving their time and labor, often for community service. Many volunteers are specifically trained in the areas they work, such as medicine, education, or emergenc ...
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 Amyloid-related imaging abnormalities (ARIA) are abnormal differences seen in magnetic resonance imaging of the brain in patients with Alzheimer's disease. ARIA is associated with anti-amyloid drugs, particularly human monoclonal antibodies such as ...
, but there were cases of ARIA-H leaving small
hemorrhage Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, ...
s in the brain. The two cases with ARIA-H were
asymptomatic Asymptomatic (or clinically silent) is an adjective categorising the medical conditions (i.e., injuries or diseases) that patients carry but without experiencing their symptoms, despite an explicit diagnosis (e.g., a positive medical test). P ...
. 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 Beta-secretase 1, also known as beta-site amyloid precursor protein cleaving enzyme 1, beta-site APP cleaving enzyme 1 (BACE1), membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, and ASP2, is an enzyme that in humans is enc ...
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 Cerebral edema is excess accumulation of fluid ( edema) in the intracellular or extracellular spaces of the brain. This typically causes impaired nerve function, increased pressure within the skull, and can eventually lead to direct compres ...
.


Society and culture


Legal status

In July 2024, donanemab was approved for medical use in the United States. The US
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(FDA) granted the application for donanemab
fast track Fast Track, Fast track, or Fasttrack may refer to: Processes and systems * Fast track (FDA), a U.S. Food and Drug Administration expedited review program * Fast track (trade), the authority of the U.S. President to broker trade agreements with lim ...
,
priority review Priority review is a program of the United States Food and Drug Administration (FDA) to expedite the review process for drugs that are expected to have a particularly great impact on the treatment of a disease. The priority review voucher program ...
, and
breakthrough therapy Breakthrough therapy is a United States Food and Drug Administration designation that expedites drug development that was created by Congress under Section 902 of the 9 July 2012 Food and Drug Administration Safety and Innovation Act. The FDA's "b ...
designations. In October 2024, donanemab was approved for medical use in the United Kingdom by the
Medicines and Healthcare products Regulatory Agency The Medicines and Healthcare products Regulatory Agency (MHRA) is an executive agency of the Department of Health and Social Care in the United Kingdom which is responsible for ensuring that medicines and medical devices work and are accepta ...
. In March 2025, the
Committee for Medicinal Products for Human Use The Committee for Medicinal Products for Human Use (CHMP), formerly known as the Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regar ...
(CHMP) of the
European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...
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

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