By: Katelyn Hoosein, PharmD Candidate c/o 2025

            Alzheimer’s disease (AD) is a neurodegenerative disorder with symptoms that progressively worsen over time, including memory loss, impairment in judgment and problem solving, language deficit, social disengagement, irritability, agitation, aggression, and psychosis. AD typically occurs in patients 60 years of age and older, but, rarely, patients younger than 60 years old can develop early-onset AD.¹ The Centers for Disease Control and Prevention (CDC) estimates that 5.8 million Americans were living with AD in 2020 and this number is expected to increase to 14 million by 2060. In addition, the number of people living with AD doubles every 5 years beyond the age of 65 years.² After diagnosis, the average life expectancy of a person with AD is between 8 to 10 years, but may range from 3 to 20 years depending on the level of impairment and age at time of diagnosis.¹ AD is thought to be the result of the formation of beta-amyloid plaques and neurofibrillary tangles. The beta-amyloid protein is created from the breakdown of a larger protein called the amyloid precursor. In AD, the beta-amyloid proteins clump together to form plaques, which disrupts cell signaling between neurons at the synapse. In addition, tau proteins bind together, leading to the formation of neurofibrillary tangles inside neurons. This disrupts cell signaling as well.³

            There is currently no treatment to cure AD. According to the Alzheimer’s Association, pharmacological therapy is aimed at maintaining quality of life and maximizing ability in performing daily activities by treating cognitive and non-cognitive symptoms and changing disease progression.⁴ Medications that treat cognitive symptoms, such as memory and thinking, include cholinesterase inhibitors (Donepezil, Rivastigmine, and Galantamine), glutamate regulators (Memantine), and a combination of both (Donepezil & Memantine (Namzaric)). Non-cognitive symptoms include sleep disturbances and agitation. Insomnia can be treated using an orexin receptor antagonist called Suvorexant (Belsomra). There is currently one FDA-approved atypical antipsychotic, Brexipiprazole (Rexulti), used to treat agitation associated with AD. Medications that change disease progression aim to remove the beta-amyloid protein and include Leqembi (Lecanemab) and Aduhelm (Aducanumab), which will be discontinued in November 2024.⁴

            On July 2, 2024, the Food and Drug Administration (FDA) approved Eli Lilly’s Kisunla (donanemab-azbt) for adults with early symptomatic Alzheimer’s disease, which includes patients with mild cognitive impairment and patients with the mild dementia stage with confirmed amyloid pathology.⁵ Kisunla is a humanized monoclonal antibody that removes beta-amyloid plaques, one of the clinical features of AD.⁶ Kisunla is a 350 mg/20 ml (17.5 mg/ml) single-dose vial with an injection solution that is sterile, preservative-free, clear to opalescent, and colorless to slightly yellow to slightly brown.⁶ It must be kept refrigerated and protected from light. If refrigeration is not available, it can be stored in room temperature conditions for up to 3 days. It should not be frozen or shaken.⁶ Prior to administration, Kisunla must be diluted with 0.9% sodium chloride. Before dilution, Kisunla should be brought to room temperature. Then, the volume of Kisunla needed is withdrawn and mixed with enough 0.9% sodium chloride injection needed to make the final concentration between 4-10 mg/ml.⁶ The diluted solution is gently inverted to mix evenly, not shaken. After dilution, it is recommended to immediately administer the solution, but it can be stored refrigerated for up to 72 hours and at room temperature for up to 12 hours.⁶ The recommended dose of Kisunla is 700 mg every 4 weeks for 3 doses, then 1400 mg every 4 weeks. It is administered as an intravenous infusion over 30 minutes.⁶ 

            A common side effect of Kisunla is headache. Kisunla has a warning for amyloid related imaging abnormalities (ARIA), which can be categorized into ARIA with edema (ARIA-E) or ARIA with hemosiderin deposition (ARIA-H). ARIA-E shows up on a brain MRI as edema or sulcal effusions, which is the leackage of fluid into the brain, and ARIA-H includes microhemorrhage and superficial siderosis, which is the deposition of hemosiderin in the brain due to blood extravasation. ARIA typically occurs within the first 24 weeks of treatment and is usually asymptomatic; however, headache, confusion, visual changes, dizziness, nausea, gait difficulty and seizures are common symptoms.⁶ The risk of ARIA is increased in patients that are apolipoprotein E ε4 (ApoE ε4) homozygotes, which accounts for about 15% of patients with AD.⁶ In addition to ARIA, Kisunla has been associated with intracerebral hemorrhages greater than 1cm in diameter.⁶ Other warnings and precautions with Kisunla include hypersensitivity reactions, including anaphylaxis and angioedema, and infusion-related reactions, including chills, erythema, nausea, vomiting, and dyspnea. Patients that develop an infusion-related reaction may have the infusion rate reduced or drug discontinued. Pre-treatment with antihistamines, acetaminophen, or corticosteroids may be useful prior to next dose to avoid an infusion-related reaction.⁶

            The clinical effect of Kisunla was studied by the TRAILBLAZER-ALZ 2 trial, which was a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial performed over 18 months.⁷ Participants were from 277 medical research centers/hospitals in 8 countries (United States, Australia. Canada, Czech Republic, Great Britain, Japan, the Netherlands, and Poland). The study consisted of participants between the age of 60 to 85 years of age with early symptomatic Alzheimer’s disease, which included mild cognitive impairment or mild dementia. Participants who were eligible also had screening Mini-Mental State Examination (MMSE) scores of 20 to 28 (indicating mild to moderate dementia or normal cognitive status), amyloid pathology ≥37 centiloids (a method of measure beta-amyloid in the brain) assessed with positron emission tomography (PET), and tau pathology also assessed by PET, which was categorized as low/medium or high tau. The study did not include patients with a significant neurological or psychiatric disease affecting the central nervous system other than AD, current serious or unstable illnesses, life expectancy less than 24 months, presence of amyloid-related imaging abnormalities of edema/effusion, more than 4 cerebral microhemorrhages, more than 1 area of superficial siderosis, and any intracerebral hemorrhage greater than 1 cm or severe white matter disease on MRI.⁷ 8,240 patients were screened, but 1,736 were enrolled and 76% completed the trial.⁷

Participants in the TRAILBLAZER-ALZ 2 trial were randomly assigned in a 1:1 ratio by a computer-generated sequence with group assignments performed through baseline tau characteristics and enrollment site.⁷ 860 participants received donanemab (700 mg for the first 3 doses and 1400 mg after) and 876 received placebo, administered intravenously every 4 weeks for up to 72 weeks.⁷ Amyloid plaque level was assessed at 24 and 52 weeks and, if it was less than 11 centiloids on one PET scan or less than 25 but greater than or equal to 11 centiloids on 2 consecutive PET scans, donanemab was switched to placebo in a blinded procedure.⁷ Final adverse event and efficacy assessments were performed at 76 weeks and ARIA monitoring occurred at 4, 12, 24, 52, and 76 weeks through MRI. If ARIA was detected, the participant had imaging every 4 to 6 weeks until resolved or stabilized.⁷

            The primary outcome was change in the iADRS score, which is an assessment of cognitive and daily function, from baseline to 76 weeks in either the low/medium tau population or combined (low/medium and high tau) population. The score range for iADRS is 0 to 144, with lower scores indicating greater impairment, and the meaningful within-patient change is a change of 5 points for those with AD with mild cognitive impairment and 9 points for those with AD with mild dementia.⁷ Secondary outcomes included amyloid plaque reduction at 76 weeks, percentage of participants reaching amyloid clearance (defined as < 24.1 centiloids measured by PET at 24 weeks and 76 weeks), and adverse events.⁷ According to Figure 2 and Table 2, in the low/medium tau population, the mean change in the iADRS score from baseline to 76 weeks was -6.02 in the donanemab group and -9.27 in the placebo group (difference, 3.25 [95% confidence interval (CI), 1.88 to 4.62; P < 0.001), indicating a 35.1% slowing of disease progression with donanemab.⁷ In the combined tau population, the mean change in the iADRS score from baseline to 76 weeks was -10.19 in the donanemab group and -13.11 in the placebo group (difference, 2.92 [95% CI, 1.51 to 4.62, P < 0.001), indicating a 22.3% slowing of disease progression with donanemab.⁷ According to Figure 3a, in the low/medium tau population, brain amyloid plaque level decreased by 88.0 centiloids (95% CI, −90.20 to −85.87) with donanemab treatment and increased by 0.2 centiloids (95% CI, −1.91 to 2.26) with placebo at 76 weeks.⁷ In the combined tau population, brain amyloid plaque level decreased by 87.0 centiloids (95% CI, −88.90 to −85.17) with donanemab and decreased by 0.67 centiloids (95% CI, −2.45 to 1.11) with placebo.⁷ This indicates that donanemab cleared more amyloid plaque from the brain when compared to placebo. According to Figure 3b, in the low/medium tau population, 34.2% of patients (95% CI, 30.22%-38.34%) achieved amyloid clearance at 24 weeks and 80.1% of patients (95% CI, 76.12%-83.62%) reached it at 76 weeks in the donanemab group r56compared to 0.2% of patients (95% CI, 0.03%-1.02%) at 24 weeks and 0% of patients (95% CI, 0.00%-0.81%) at 76 weeks in the placebo group.7 In the combined tau population, amyloid clearance was achieved by 29.7% of patients (95% CI, 26.56%-33.04%) at 24 weeks and 76.4% of patients (95% CI, 72.87%-79.57%) at 76 weeks for the donanemab group and 0.2% of patients (95% CI, 0.07%-0.90%) at 24 weeks and 0.3% of patients (95% CI, 0.08%-1.05%) at 76 weeks for the placebo group.⁷ These results indicate that in both the low/medium tau population and combined tau population, donanemab had higher rates of amyloid clearance when compared to placebo.

            The TRAILBLAZER-ALZ 2 trial also reported adverse events within both the donanemab and placebo groups. According to Table 3, the incidence of death was 1.9% (16 participants) in the donanemab group and 1.1% (10 participants) in the placebo group.⁷ The incidence of serious adverse events was 17.4% in the donanemab group and 15.8% in the placebo group.⁷ Treatment-emergent adverse events (ARIA-E, ARIA-H, COVID-19, headache, fall, infusion-related reaction, dizziness, diarrhea, fatigue, arthralgia, urinary tract infection, and superficial siderosis of the central nervous system) occurred in 759 or 89% of participants treated with donanemab and 718 or 82.2% of participants treated with placebo, with ARIA-E and ARIA-H having the highest incidence.⁷ ARIA occurred in 314 or 36.8% of participants receiving donanemab and 130 or 14.9% of participants receiving placebo.⁷ Of those cases, ARIA-E occurred in 205 or 24% of participants in the donanemab group and 18 or 2.1% of participants in the placebo group, and ARIA-H occurred in 268 or 31.4% of participants in the donanemab group and 119 or 13.6% of participants in the placebo group.⁷ 112 or 13.1% of participants in the donanemab group and 38 or 4.3% of participants in the placebo group discontinued treatment due to adverse events, the most common being ARIA, infusion-related reactions, or hypersensitivity reaction.⁷ Infusion-related reactions were occurred in 74 participants (8.7%) in the donanemab group and 4 participants (0.4%) in the placebo group.⁷ Anaphylaxis occurred in 3 patients in the donanemab group, but they were mild to moderate reactions.⁷

            Alzheimer’s disease is a progressive neurological disease which can be devastating for patients and their loved ones. The FDA’s approval of Kisunla is a significant advancement in the management of Alzheimer’s disease. Although there is no cure for Alzheimer’s, Eli Lilly’s Kisunla slows disease progression, allowing for improved quality of life and maximization of ability and independence for patients.

References:

1. Wolk D, Dickerson B. Clinical Features and Diagnosis of Alzheimer Disease. Published online October 8, 2021. Accessed September 16, 2024. https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-alzheimer-disease?csi=42ee0e80-fd36-452c-80de-50fa2e1af9ce&source=contentShare
2. Centers for Disease Control and Prevention. What is alzheimer’s disease? www.cdc.gov. Published 2020. https://www.cdc.gov/aging/aginginfo/alzheimers.htm#:~:text=Alzheimer
3. What Happens to the Brain in Alzheimer’s Disease? National Institute on Aging. https://www.nia.nih.gov/health/alzheimers-causes-and-risk-factors/what-happens-brain-alzheimers-disease#:~:text=Amyloid%20plaques&text=In%20the%20Alzheimer
4. Alzheimer’s Association. Medications for Memory, Cognition and Dementia-Related Behaviors. Alzheimer’s Association. Published 2019. https://www.alz.org/alzheimers-dementia/treatments/medications-for-memory
5. Lilly’s Kisunla^TM (donanemab-azbt) Approved by the FDA for the Treatment of Early Symptomatic Alzheimer’s Disease | Eli Lilly and Company. Eli Lilly and Company. Published 2024. https://investor.lilly.com/news-releases/news-release-details/lillys-kisunlatm-donanemab-azbt-approved-fda-treatment-early
6. Kisunla (donanemab-azbt). Prescribing Information. Eli Lilly; 2024. Accessed September 18, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761248s000lbl.pdf
7. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023;330(6). doi:https://doi.org/10.1001/jama.2023.13239

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Published by Rho Chi Post