Eli Lilly's New Alzheimer's Drug, KISUNLA: Breakthrough or Bust?

Introduction

The FDA approved Eli Lilly’s KISUNLA (donanemab-azbt) injection for IV infusion on July 02, 2024 for mild and/or early cases of dementia caused by Alzheimer’s Disease. Early media reports, including those published by PBS (4) , suggest that KISUNLA is the second drug of its kind on the US market demonstrating a "convincing" delay in cognitive decline. How does KISUNLA compare to the already available treatment options? What's good about it - and what's bad about it?

Is KISUNLA a breakthrough in Alzheimer's treatment, or is it a well-funded bust? Let's dive in...

Background Information

Estimates vary, but experts suggest that more than 6 million Americans, most of them age 65 or older, may have Alzheimer’s. Alzheimer’s is currently ranked as the seventh leading cause of death in the United States and is the most common cause of dementia among older adults.

Dementia is defined as the loss of cognitive functioning (thinking, remembering, and reasoning) and behavioral abilities to such an extent that it interferes with a person’s daily life and activities.

The causes of dementia can vary depending on the types of brain changes that may be taking place. Other forms of dementia include Lewy body dementia, frontotemporal disorders, and vascular dementia. It is common for people to have mixed dementia — a combination of two or more types of dementia.

This NIH - National Institutes of Aging (NIA) infographic is an incredible resource for differentiating types of dementia:

understanding-types-dementia_0.pdf

Download PDF • 2.09MB

Current Alzheimer's treatment options include, but are not limited to:

• Cholinesterase Inhibitors: donepezil, galantamine, rivastigmine

• Glutamate Agonist: memantine

• Monoclonal Antibodies: lecanemab

KISUNLA (donanemab-azbt)

The approval of KISUNLA (donanemab-azbt) follows last year’s approval of a similar drug, LEQEMBI (lecanemab) by Japanese manufacturer Eisai.

• Mechanism of Action: KISUNLA (donanemab-azbt) is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against insoluble N-truncated pyroglutamate amyloid beta. KISUNLA has been shown to reduce amyloid beta plaques in clinical trials.

• Available Products (USA): Injection 350 mg/20 mL (17.5 mg/mL) clear to opalescent, colorless to slightly yellow to slightly brown solution in a single-dose vial.

• Approved Indication(s): KISUNLA is indicated for the treatment of Alzheimer’s disease. Treatment with KISUNLA should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in the clinical trials
  

• Dosing: The recommended dosage of KISUNLA is 700 mg every four weeks for three doses, then 1400 mg every four weeks (see Table 1). KISUNLA is administered every four weeks as an intravenous infusion over approximately 30 minutes. KISUNLA must be diluted prior to administration.

Safety Considerations / Warnings

1. Amyloid Related Imaging Abnormalities (ARIA): KISUNLA can cause amyloid related imaging abnormalities -edema (ARIA-E) and -hemosiderin deposition (ARIA-H)
   

• Monoclonal antibodies directed against aggregated forms of beta amyloid, including KISUNLA, can cause amyloid related imaging abnormalities (ARIA), characterized as ARIA with edema (ARIA-E), which can be observed on MRI as brain edema or sulcal effusions, and ARIA with hemosiderin deposition (ARIA-H), which includes microhemorrhage and superficial siderosis. ARIA can occur spontaneously in patients with Alzheimer’s disease

• ARIA usually occurs early in treatment and is usually asymptomatic, although serious and life-threatening events, including seizure and status epilepticus, rarely can occur. When present, reported symptoms associated with ARIA may include, but are not limited to, headache, confusion, visual changes, dizziness, nausea, and gait difficulty. Focal neurologic deficits may also occur. Symptoms associated with ARIA usually resolve over time
  

• Monitoring for ARIA Obtain a recent baseline brain magnetic resonance imaging (MRI) prior to initiating treatment with KISUNLA. Obtain an MRI prior to the 2nd, 3rd, 4th, and 7th infusions. If a patient experiences symptoms suggestive of ARIA, clinical evaluation should be performed, including an MRI if indicated.

  • Confirm the presence of amyloid beta pathology prior to initiating treatment.

• Incidence: s tudies show symptomatic ARIA occurred in 6% (52/853) of patients treated with KISUNLA

1. Intracerebral Hemorrhage: Brain bleeds with a diameter greater than 1 centimeter have occurred in patients treated with KISUNLA.
   

   • Fatal events of intracerebral hemorrhage in patients taking KISUNLA have been observed.

   •  Risk Factors for ARIA and Intracerebral Hemorrhage:

     • Concomitant Antithrombotic or Thrombolytic Medication

     • ApoE ε4 Carrier Status

     • Radiographic Findings of Cerebral Amyloid Angiopathy (CAA)

     • Radiographic Severity

   • Incidence: Intracerebral hemorrhage greater than 1 cm in diameter was reported in 0.5% (4/853) of patients on KISUNLA compared to 0.2% (2/874) of patients on placebo in clinical trial.

2. Hypersensitivity Reactions: anaphylaxis and angioedema have occurred in patients who were treated with KISUNLA.

   1. Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with a hypersensitivity reaction and initiate appropriate therapy. KISUNLA is contraindicated in patients with a history of serious hypersensitivity to donanemab-azbt or to any of the excipients of KISUNLA.
      

3. Infusion-Related Reactions: chills, erythema, nausea/vomiting, difficulty breathing/dyspnea, sweating, elevated blood pressure, headache, chest pain, and low blood pressure

   1. In clinical trial, infusion-related reactions were observed in 9% (74/853) of patients treated with KISUNLA compared to 0.5% (4/874) of patients on placebo.

   2. Infusion reactions typically occur during infusion or within 30 minutes post-infusion.

   3. Infusion-related reactions were mostly mild or moderate in severity.

      1. Infusion-related reactions resulted in discontinuations in 4% (31/853) of patients treated with KISUNLA.

   4. In the event of an infusion-related reaction, the infusion rate may be reduced, or the infusion may be discontinued, and appropriate therapy initiated as clinically indicated. Pre-treatment with antihistamines, acetaminophen, or corticosteroids prior to subsequent dosing may be considered

Comparative Efficacy & Safety

Where KISUNLA exists in place in therapy, who should consider this novel treatment approach.

comparative efficacy analysis - oral options (donepezil, memantine, rivastigmine, galantamine) vs. KISUNLA

comparative safety analysis - oral options vs. KISUNLA

• Comparative Efficacy

  • Oral Medications:

    • Donepezil: Zhang, et. al determined efficacy with Mini-Mental Status Exam (MMSE), Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog), and Montreal Cognitive Assessment (MoCA). The study determined that compared to the control group, patients who received donepezil showed statistically significant improvement across MMSE (standardized mean difference [SMD] 0.85, 95% CI: 0.40-1.31) and MoCA (SMD: 1.88, 95% CI: 0.32-3.45)

    • Rivastigmine: Hansen et al. compared rivastigmine with donepezil, highlighting that the patients who received rivastigmine had a statistically significant cognitive function as indicated by the reduction of Alzheimer's Disease Cooperative Study/Activities of Daily Living Inventory (ADCS-ADL) score (−14.9 vs. −12.8, respectively; P < 0.05

    • Galantamine: Richarz et al. - results show galantamine significantly improved cognitive function as ADAS-cog at 12 months showed an improvement from 2.2 to 3 points (P < 0.05). However, after 18-24 months, the ADAS-cog score returned to baseline, and at three years, patients showed an average decline of 2.9 scores, indicating galantamine's efficacy in improving or slowing cognitive impairment

    • Memantine: A study assessed the reports of memantine delays on cognitive and global function decline using the Clinician’s Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) and Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory modified for severe dementia (ADCS-ADLsev).

      • The CIBIC-Plus' assessment at baseline, indicated as “no change,” was set at 4.00, with higher values illustrating the worsening of the condition. Compared to the baseline, the endpoint for the observation of memantine was 4.5 + 1.12 (95% CI: -0.51 to 0.02, P = 0.06), and the last observation carried forward at 28 weeks was 4.4 + 1.13 (95% CI: -0.51 to 0.02, P = 0.06). Compared to the placebo, it was 4.8 + 1.09 (95% CI: -0.51 to 0.02, P = 0.03) at the endpoint and 4.7 + 1.13 (95% CI: -0.51 to 0.02, P = 0.03) after 28 weeks, indicating the changes from baseline
        

  • KISUNLA Study

    • The primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range, 0-144; lower scores indicate greater impairment).

      • Results: The least-squares mean (LSM) change in iADRS score at 76 weeks was −6.02 (95% CI, −7.01 to −5.03) in the donanemab group VS −9.27 (95% CI, −10.23 to −8.31) in the placebo group (difference, 3.25 [95% CI, 1.88-4.62]; P < .001) in the low/medium tau population

      • Secondary outcomes: In the low/medium tau population, the differences between treatment groups in the LSM change from baseline at 76 weeks was −0.67 (95% CI, −0.95 to −0.40) (36.0% [95% CI, 20.76%-51.15%] slowing of clinical progression) for CDR-SB, 1.83 (95% CI, 0.91-2.75) (39.9% [95% CI, 19.15%-60.58%] slowing of clinical progression) for ADCS-iADL, and −1.52 (95% CI, −2.25 to −0.79) (32.4% [95% CI, 16.55%-48.35%] slowing of clinical progression) for ADAS-Cog13

    • Summary: Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population.

• Comparative Safety

  • Oral Medications:

    • Donepezil: patients taking donepezil reported statistically significant adverse effects such as nausea, vomiting, diarrhea, fatigue, headache, and dizziness.

    • Rivastigmine: patients reported mild to moderate nausea. The patch form of rivastigmine can cause some mild skin irritation and might not be suitable for sensitive skin. In patients who cannot tolerate oral administration of rivastigmine, an immediate switch to the skin patch should be considered as an alternative route of administration.

    • Galantamine: Patients report nausea, vomiting, dizziness, and abdominal pain.

  • KISUNLA Study

    • The incidence of death was 1.9% in the donanemab group and 1.1% in the placebo group, while the incidence of serious adverse events was 17.4% in the donanemab group and 15.8% in the placebo group

    • Treatment-emergent adverse events were reported by 759 of 853 participants (89.0%) receiving donanemab and 718 of 874 participants (82.2%) receiving placebo.

    • Treatment discontinuation due to adverse events was reported in 112 participants receiving donanemab and 38 participants receiving placebo.

    • The most common adverse events that led to treatment discontinuation were infusion-related reactions, either amyloid-related imaging abnormalities edema/effusion or microhemorrhages and hemosiderin deposits, and hypersensitivity

  • Summary: While showing promising results, KISUNLA therapy does not come without risk. Significant adverse outcomes are associated with KISUNLA use, whereas with the generic, oral medications, stomach upset is the most commonly reported adverse event. It is clear based on the results of the aforementioned studies that KISUNLA injection is significantly more risky compared to oral medication when used in the treatment of Alzheimer's Disease.
    

So... Is it Worth the Price Tag?

In my professional opinion -- not really.

I want to encourage patients and their loved ones to engage in meaningful conversations with their healthcare providers when it comes to choosing Dementia treatment modalities. Ideally, I would start a patient on a traditional oral medication, and only consider these newer, riskier modalities in the event of severe GI adverse events and intolerance/treatment failure of the oral options. In addition, KISUNLA therapy is administered by HCPs following proper dilution and preparation. Alternatively, most dementia oral medications are taken once daily, by mouth, usually in the evening time. Patients experiencing mild to moderate stomach upset should be encouraged to continue treatment and take medications with food to reduce the potential for GI effects. Patients who do not experience relief of symptoms after dose stabilization or treatment continuance may be considered as candidates for alternate therapy: rivastigmine patches or injectable medications such as KISUNLA.

I like to imagine that in these situations I am treating my own grandparent. If my grandma were seeking new treatment for Alzheimer's Disease, after reviewing the studies mentioned in this article - I would not advocate for initiating KISUNLA. Not only is the injectable treatment expensive, but despite its positive results, it also poses a high risk of severe, sometimes life-threatening adverse events. In the spirit of risk vs benefit, I strongly encourage those with loved ones newly diagnosed with Alzheimer's to consider the traditional oral medications prior to discussing injectable options such as LEQEMBI and KISUNLA. In order to improve comparative efficacy analysis, I would like to see a single study which utilizes a standardized measurement scale, rather than multiple scales, which make it incredibly difficult to compare medication outcomes directly.

If you have any questions, or would like more information on this topic - please leave us a comment below, or send us a message, and we will be more than happy to answer your questions. To request a specific drug or topic to discuss further, feel free to do the same! Stay safe, Pharmers!

Resources:

1. Dou, KX., Tan, MS., Tan, CC. et al. Comparative safety and effectiveness of cholinesterase inhibitors and memantine for Alzheimer’s disease: a network meta-analysis of 41 randomized controlled trials. Alz Res Therapy 10, 126 (2018). https://doi.org/10.1186/s13195-018-0457-9

2. (KISUNLA) Prescribing Information. Lilly USA, LLC. Revised 07/2024. Accessed online at https://pi.lilly.com/us/kisunla-uspi.pdf?s=pi

3. (KISUNLA) Medication Guide. Lilly USA, LLC. Issued 07/2024. Accessed online at https://pi.lilly.com/us/kisunla-us-mg.pdf?s=mg

4.  Alzheimer's Disease Fact Sheet. NIH: National Institute on Aging (NIA). Updated 04/05/2023. Accessible online at https://www.nia.nih.gov/health/alzheimers-and-dementia/alzheimers-disease-fact-sheet.

5. Perrone, M. FDA approves 2nd Alzheimer’s drug that can modestly slow dementia. PBS News. Published 07/02/2024. Accessed online at https://www.pbs.org/newshour/health/fda-approves-2nd-alzheimers-drug-that-can-modestly-slow-demetia#:~:text=The%20Food%20and%20Drug%20Administration,drug%20from%20Japanese%20drugmaker%20Eisai.

6. 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):512–527. doi:10.1001/jama.2023.13239

7. Eisai Global. “LEQEMBI®” (Lecanemab) Approved for the Treatment of Alzheimer’s Disease in China. Published 01/09/2024. Accessed online at https://www.eisai.com/news/2024/news202403.html

8. Thangwaritorn S, Lee C, Metchikoff E, Razdan V, Ghafary S, Rivera D, Pinto A, Pemminati S. A Review of Recent Advances in the Management of Alzheimer's Disease. Cureus. 2024 Apr 16;16(4):e58416. doi: 10.7759/cureus.58416. PMID: 38756263; PMCID: PMC11098549.