Donanemab

Last updated

Donanemab
Monoclonal antibody
Type Whole antibody
Source Humanized (from mouse)
Target Amyloid beta
Clinical data
Other namesLY3002813
ATC code
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
UNII
KEGG
Chemical and physical data
Formula C6452H10038N1708O2013S42
Molar mass 145087.70

Donanemab (USAN; development code LY3002813) is a biological drug in Phase III clinical trials to determine whether it slows the progression of early Alzheimer's disease. Donanemab has shown positive results in its first trials. [1] [2] Donanemab was developed by the Eli Lilly and Co. and is under clinical development as a possible treatment for Alzheimer's disease. [1] [3] There is currently no approved cure or disease-modifying treatment for Alzheimer's disease except for lecanemab.

Contents

Donanemab, also known as N3pG, is an antibody produced in mice that targets an abnormal protein, amyloid beta (Aβ). Although the cause of Alzheimer's disease remains unknown, advances in understanding amyloid pathology have revealed a possible relationship between the quantity of amyloid plaques deposited in the brain and the development of Alzheimer's disease. Donanemab targets amyloid plaque, potentially reducing the excess protein which may be a factor in Alzheimer's disease.

Development

Transgenic mice were used to source the humanized antibodies, as DNA was injected during the embryotic stage. [4] The mice used had a modified genetic sequence more similar to humans, leading to antibodies that are genetically similar to ones produced by humans. [5] To produce the antibody to create donanemab, mice were injected with a specific antigen, a non-self-cell, which induces an immune response. White blood cells are produced to destroy the antigen. B cells, which are a type of white blood cell, produce antibodies to bind and destroy the antigen. Antibodies produced are then harvested from the mice to be fused with cancer B cells. [4] This hybrid cell produces monoclonal antibodies used as the drug donanemab having the function of a B cell. [4] [5]

Donanemab and Aβ peptide

The recent improvements in amyloid imaging technology have linked the excess Aβ peptide outside the cell with the development of Alzheimer's disease. [3] The overproduction of the Aβ peptide creates a plaque in certain parts of the brain, disrupting neurotransmission. [6] Donanemab attacks the soluble and insoluble plaque buildup, slowing down the progression of the disease. [7]

Trials

Phase I

First study

In the United States and Japan, Lilly's company ran the Phase I study from May 2013 to August 2016. [8] The study was conducted on patients with mild Alzheimer's disease shown through a positive amyloid PET scan that was conducted on each patient. 100 participants were injected intravenously with donanemab up to 4 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 patients 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. [4]

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. [8] 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. [8] 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. [8]

Side effects

The increase in dosage led to a larger percentage of patients experiencing symptomatic ARIA-E, rising to 1 in 4 participants. Auto-antibodies were also becoming problematic for donanemab, recognising 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. Whilst this trial showed a positive outcome for patients taking monthly doses for 16 months as the amyloid PET scan became negative, the trial ended in August 2019. [1]

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. [1] 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. [8]

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 was. [8] 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 analysing 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. [8]

Side effects

There was an overview on the adverse drug reactions (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. [1] 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 AD; 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. [8]

In May 2023, the company reported its Phase III study showed the drug could slow the pace of Alzheimer's disease by 35%. [9] 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. [2]

FDA review

In March 2024, the FDA convened an expert panel to further review the efficacy and safety of donanemab. [10]

Cerebral edema

In the 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. [2] A large percentage of symptomatic patients discontinued the drug because they experienced nausea. [1]

See also

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References

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  2. 1 2 3 Sims JR, Zimmer JA, Evans CD, et al. (17 July 2023). "Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial". JAMA. 330 (6): 512–527. doi: 10.1001/jama.2023.13239 . PMC   10352931 . PMID   37459141.
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  6. ↑ Demattos RB, Lu J, Tang Y, Racke MM, Delong CA, Tzaferis JA, Hole JT, Forster BM, McDonnell PC, Liu F, Kinley RD, Jordan WH, Hutton ML (December 2012). "A plaque-specific antibody clears existing β-amyloid plaques in Alzheimer's disease mice". Neuron. 76 (5): 908–20. doi: 10.1016/j.neuron.2012.10.029 . PMID   23217740. S2CID   16620402.
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  8. 1 2 3 4 5 6 7 8 "Donanemab Confirms: Clearing Plaques Slows Decline—By a Bit". ALZFORUM. 2021. Retrieved 23 April 2021.
  9. ↑ "Eli Lilly Alzheimer's treatment donanemab slowed disease progression in clinical trial". CNBC. 3 May 2023. Retrieved 3 May 2023.
  10. ↑ Tirrell M (8 March 2024). "Eli Lilly says Alzheimer's drug approval delayed as FDA seeks input from advisers". CNN. Retrieved 8 March 2024.
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