Donanemab

Donanemab, sold under the brand name Kisunla, is a monoclonal antibody used for the treatment of Alzheimer's disease.[1] Donanemab was developed by Eli Lilly and Company.[2]

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 people taking donanemab and 14.9% of people taking placebo.[3] 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.[4][5][6]

Adverse effects

The US Food and Drug Administration (FDA) label for donanemab contains a boxed warning about amyloid-related imaging abnormalities.[1]

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).[4]

Donanemab can cause serious side effects. The most common side effects of donanemab include ARIA, headache, and infusion-related reactions.

ARIA refers to temporary swelling in areas of the brain (ARIA-E), or small spots of bleeding in or on the surface of the brain (ARIA-H). The swelling in areas of the brain usually resolves over time, while the small spots of bleeding in or on the surface of the brain may not resolve. Most people who develop ARIA do not get symptoms; however, some people, especially those with swelling in the brain, may have symptoms such as headache, confusion, dizziness, vision changes, nausea, seizures, and difficulty walking. Some of these symptoms may be serious and life-threatening. ARIA can be fatal. While ARIA may occur any time during treatment with donanemab, it has most frequently been observed during the first 24 weeks of treatment.

Some people may also develop larger areas of bleeding in the brain while taking donanemab which may also be serious and life-threatening. Some people may be at a higher risk of developing bleeding in the brain if they are taking medicines to reduce blood clots from forming (antithrombotic medicines) while receiving donanemab.

Some people have a genetic risk factor (homozygous apolipoprotein E [ApoE] ε4 gene carriers) that may cause an increased risk for ARIA.

Allergic reactions associated with donanemab include swelling of the face, lips, mouth, or eyelids, difficulty breathing, and hives. Infusion-related reactions may also occur. Symptoms of infusion-related reactions include chills, irritation of skin, nausea, vomiting, sweating, headache, chest pain, and problems breathing.[9]

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)[10] in participants with Alzheimer's disease.[4] 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.[4] 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.[4]

Donanemab has shown positive results in its first trials.[11][12]

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.[13]

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.

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 participants 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

Trailblazer-alz

The phase II trial methodically differed from phase I, altering the duration, the amount of donanemab, and the number of participants. There was an increase in the amount of donanemab infused into the blood every month for 72 weeks. The participants infused with donanemab and infused with the placebo became equal, creating close to a 1:1 ratio with 257 participants in total.[11] 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.[14]

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.[14] This BACE inhibitor was administered orally compared to donanemab which is intravenously injected. To effectively see the comparison between participants only taking donanemab and participants 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 participants infused with donanemab. After phase II, the trial was stopped.[14]

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 participants seen in phase I.[11] 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.

type	mab
mab type	mab
source	zu/o
target	Amyloid beta
tradename	Kisunla
medlineplus	a624048
dailymedid	Donanemab
routes of administration	Intravenous
atc prefix	N06
atc suffix	DX05
legal us	Rx-only
legal eu	Rx-only
cas number	1931944-80-7
drugbank	DB16647
unii	1ADB65P1KK
kegg	D11500
synonyms	LY3002813, donanemab-azbt
c	6452
h	10038
n	1708
o	2013
s	42

Medical uses

Adverse effects

Cerebral edema

History

Phase I

First study

Side effects

Society and culture

Legal status

Economics

Names

Research

References

Second study

Side effects

First study

Side effects

Second study

Side effects

Trailblazer-alz

Results

Side effects

Results

Side effects

Phase III