Donanemab-azbt (Kisunla)

Number: 1066

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses donanemab-azbt (Kisunla) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification: 

Precertification of donanemab-azbt (Kisunla) is required of all Aetna participating providers and members in applicable plan designs. For precertification of donanemab-azbt (Kisunla), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

Note: Site of Care Utilization Management Policy applies. For information on site of service for donanemab-azbt (Kisunla), see Utilization Management Policy on Site of Care for Specialty Drug Infusions.

1. Exclusions 

   Coverage will not be provided for members with any of the following conditions:

   1. Suspected neurodegenerative etiology of cognitive impairment other than Alzheimer’s disease (AD), including but not limited to frontotemporal lobar degeneration (FTLD) or Lewy body disease (i.e., meeting consensus criteria for possible or probable dementia with Lewy bodies). 
   2. History of transient ischemic attacks (TIA), stroke, or seizures within the past 12 months.
   3. Bleeding disorder that is not under adequate control (including a platelet count less than 50,000 or international normalized ratio [INR] greater than 1.5).
   4. Kisunla will not be used in combination with any other amyloid beta-directed antibodies (e.g., aducanumab, lecanemab). 

2. Prescriber Specialties

   This medication must be prescribed by or in consultation with a geriatrician, neurologist, psychiatrist, or neuropsychiatrist.

3. Criteria for Initial Approval

   Aetna considers donanemab-azbt (Kisunla) medically necessary for treatment of Alzheimer's Disease (AD) [except as outlined in Section I for exclusions] when all of the following criteria are met:

   1. Member must meet one of the following criteria:

      1. Member is 50 years of age or older; or
      2. If less than 50 years of age, member has a genetic mutation in amyloid precursor protein (APP), presenilin-1 (PSEN1), or presenilin-2 (PSEN2), or other clinical documentation to support early  onset AD; and
   2. Member must have mild cognitive impairment due to AD or mild AD dementia; and
   3. Member must have objective evidence of cognitive impairment at baseline (Appendix A); and
   4. Member must have one of the following scores at baseline on any of the following assessment tools:
      
      
      1. Clinical Dementia Rating-Global Score (CDR-GS) of 0.5 or 1 (Appendix B); or
      2. Mini-Mental Status Examination (MMSE) score of 21 - 30  (Appendix C); or
      3. Montreal Cognitive Assessment (MoCA) score of greater than or equal to 16 (Appendix D); and

   5. Member must meet one of the following criteria:

      1. Have a positron emission tomography (PET) scan confirming the presence of amyloid pathology; or
      2. Have results from a lumbar puncture confirming at least one of the following:
         
         
         1. Presence of elevated phosphorylated tau (P-tau) protein and/or elevated total tau (T-tau) protein, and reduced beta amyloid-42 (AB42); or
         2. Low AB42/AB40 ratio; or
         3. Elevated P-Tau/AB42 ratio; or
         4. Elevated T-tau/AB42 ratio; and
   6. Member must have a recent brain magnetic resonance imaging (MRI) within one year prior to initiating treatment to evaluate for pre-existing Amyloid Related Imaging Abnormalities (ARIA); and
   7. Member meets one of the following regarding apolipoprotein E ε4 (ApoE ε4) status:
      
      
      1. Genotype testing for ApoE ε4 status has been performed prior to initiation of treatment to inform member of the risk of developing ARIA; or
      2. Genotype testing has not been performed and the prescriber has informed the member that it cannot be determined if they are ApoE ε4 homozygous and may be at higher risk for ARIA; and
   8. If there is concurrent use of antithrombotic medications (aspirin, other antiplatelets, or anticoagulants), the member has been on a stable dose for at least 4 weeks prior to initiation of the requested medication; and
   9. Member and/or provider must currently be participating in a provider-enrolled patient registry that collects information on treatments for Alzheimer’s disease (e.g., Alzheimer’s Network for Treatment and Diagnostics [ALZ-NET]).

   Aetna considers all other indications as experimental, investigational, or unproven.

4. Continuation of Therapy

   Aetna considers continuation of donanemab-azbt (Kisunla) therapy medically necessary for treatment of Alzheimer’s Disease (AD) [except as outlined in Section I for exclusions] when the criteria outlined below are met.

   1. Continuation of therapy for 12 months (first reauthorization after the initial 7-month approval period) when all of the following criteria are met:

      1. Member has met all initial authorization criteria at the time of initial approval; and
      2. Member has been evaluated for evidence of amyloid-related imaging abnormalities (ARIA) on MRI prior to the 2nd dose, 3rd dose, 4th dose, and 7th dose (Appendix E);

         1. For members with radiographic evidence of amyloid related imaging abnormalities-edema (ARIA-E):

            1. Dosing may continue based on clinical judgement, if applicable, for members that meet the following criteria:

               1. Member has mild ARIA-E on MRI and is asymptomatic or has mild clinical symptoms; or
                  

            2. Dosing should be suspended until MRI demonstrates radiographic resolution and symptoms resolve for members that meet any of the following criteria:

               1. Member has mild ARIA-E on MRI and has moderate or severe clinical symptoms; or
               2. Member has moderate ARIA-E on MRI and is asymptomatic or has mild, moderate, or severe clinical symptoms; or
               3. Member has severe ARIA-E on MRI and is asymptomatic or has mild, moderate, or severe clinical symptoms; or

         2. For members with radiographic evidence of amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H):

            1. Dosing may continue for members that meet the following criteria:

               1. Member has mild ARIA-H on MRI and is asymptomatic; or

            2. Dosing should be suspended until MRI demonstrates radiographic stabilization and symptoms resolve for members that meet any of the following criteria:

               1. Member has mild ARIA-H on MRI and is symptomatic; or
               2. Member has moderate ARIA-H on MRI and is asymptomatic or symptomatic; or
               3. Member has severe ARIA-H on MRI and is asymptomatic or symptomatic; and

         3. Member and/or provider continues to participate in a provider-enrolled patient registry that collects information on treatments for Alzheimer's disease (e.g., Alzheimer's Network for Treatment and Diagnostics [ALZ-NET]).

   2. Continuation of therapy for 12 months (reauthorizations beyond initial 19 months of therapy) when all of the following criteria are met:

      1. Member has met all initial authorization criteria at the time of initial approval; and
      2. Member has a positive clinical response as evidenced by stabilization or slowing of disease progression as documented by any of the following (Note: Repeat assessment tool(s) must be the same tool that was submitted upon initial request):
         
         
         1. CDR-Global Score (i.e., score of 0.5 or 1); or 
         2. MMSE (i.e., decline of 3 points or less per year); or
         3. MoCA (i.e., score of greater than or equal to 16); and

         Note: Continuation requests for members with assessment scores outside of the provided ranges (i.e., mild dementia) or who have progressed greater than the provided rate of decline may be reviewed on a case-by-case basis.

      3. Member and/or provider continues to participate in a provider-enrolled patient registry that collects information on treatments for Alzheimer’s disease (e.g., Alzheimer’s Network for Treatment and Diagnostics [ALZ-NET]).

5. Related CMS Coverage Guidance

   This Clinical Policy Bulletin (CPB) supplements but does not replace, modify, or supersede existing Medicare Regulations or applicable National Coverage Determinations (NCDs) or Local Coverage Determinations (LCDs). The supplemental medical necessity criteria in this CPB further define those indications for services that are proven safe and effective where those indications are not fully established in applicable NCDs and LCDs. These supplemental medical necessity criteria are based upon evidence-based guidelines and clinical studies in the peer-reviewed published medical literature. The background section of this CPB includes an explanation of the rationale that supports adoption of the medical necessity criteria and a summary of evidence that was considered during the development of the CPB; the reference section includes a list of the sources of such evidence. While there is a possible risk of reduced or delayed care with any coverage criteria, Aetna believes that the benefits of these criteria – ensuring patients receive services that are appropriate, safe, and effective – substantially outweigh any clinical harms.

   Code of Federal Regulations (CFR):

   42 CFR 417; 42 CFR 422; 42 CFR 423.

   Internet-Only Manual (IOM) Citations:

   CMS IOM Publication 100-02, Medicare Benefit Policy Manual; CMS IOM Publication 100-03 Medicare National Coverage Determination Manual.

   Medicare Coverage Determinations:

   Centers for Medicare & Medicaid Services (CMS), Medicare Coverage Database [Internet]. Baltimore, MD: CMS; updated periodically. Available at: Medicare Coverage Center. Accessed July 8, 2024.
   
   

6. Related Policies

   1. CPB 0071 - Positron Emission Tomography (PET)
   2. CPB 0140 - Genetic Testing
   3. CPB 0349 - Alzheimer's Disease Tests
   4. CPB 0788 - Alzheimer's Disease: Experimental Treatments
   5. CPB 0996 - Aducanumab-avwa (Aduhelm)
   6. CPB 1026 - Lecanemab-irmb (Leqembi)

Dosage and Administration

Donanemab-azbt is available as Kisunla and supplied for injection as 350 mg/20 mL (17.5 mg/mL) in a single-dose vial. Kisunla is administered as an intravenous (IV) infusion by a healthcare provider. 

Dosage and administration instructions outlined in the label include the following:

• Confirm the presence of amyloid beta pathology prior to initiating treatment;
• The recommended dosage of Kisunla is 700 mg administered as an IV infusion over approximately 30 minutes every 4 weeks for the first three doses, followed by 1400 mg every 4 weeks;
• Consider stopping dosing with Kisunla based on reduction of amyloid plaques to minimal levels on amyloid PET imaging;
• Obtain a recent baseline brain MRI prior to initiating treatment;
• Obtain an MRI prior to the 2nd, 3rd, 4th, and 7th infusions. If radiographically observed ARIA occurs, treatment recommendations are based on type, severity, and presence of symptoms
• Dilution to a final concentration of 4 mg/mL to 10 mg/mL with 0.9% Sodium Chloride Injection, is required prior to administration.

For additional dosing information, refer to Kisunla's Full Prescribing Information.

Source: Eli Lilly, 2024

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
0445U	β-amyloid (Abeta42) and phospho tau (181P) (pTau181), electrochemiluminescent immunoassay (ECLIA), cerebral spinal fluid, ratio reported as positive or negative for amyloid pathology
0459U	β-amyloid (Abeta42) and total tau (tTau), electrochemiluminescent immunoassay (ECLIA), cerebral spinal fluid, ratio reported as positive or negative for amyloid pathology
62270	Spinal puncture, lumbar, diagnostic
70551	Magnetic resonance (eg, proton) imaging, brain (including brain stem); without contrast material
70552	with contrast material(s)
70553	without contrast material, followed by contrast material(s) and further sequences
78608	Brain imaging, positron emission tomography (PET); metabolic evaluation
78811	Positron emission tomography (PET) imaging; limited area (eg, chest, head/neck)
78814	Positron emission tomography (PET) with concurrently acquired computed tomography (CT) for attenuation correction and anatomical localization imaging; limited area (eg, chest, head/neck)
81401	Molecular pathology procedure, Level 2 common variants (eg, R3500Q, R3500W) APOE (apolipoprotein E) (eg, hyperlipoproteinemia type III, cardiovascular disease, Alzheimer disease)
81405	Molecular pathology procedure, Level 6 full gene sequence PSEN1 (presenilin 1) (eg, Alzheimer disease)
81406	Molecular pathology procedure, Level 7 full gene sequence APP (amyloid beta [A4] precursor protein) (eg, Alzheimer disease), full gene sequence PSEN2 (presenilin 2 [Alzheimer disease 4]) (eg, Alzheimer disease)
96365 – 96368	Intravenous infusion administration
HCPCS codes covered if selection criteria are met:
J0175	Injection, donanemab-azbt, 2 mg
Other HCPCS codes related to the CPB:
A9586	Florbetapir f18, diagnostic, per study dose, up to 10 millicuries
A9598	Positron emission tomography radiopharmaceutical, diagnostic, for non-tumor identification, not otherwise classified
J0172	Injection, aducanumab-avwa, 2 mg
J0174	Injection, lecanemab-irmb, 1 mg
Q9982	Flutemetamol F18, diagnostic, per study dose, up to 5 millicuries
S3852	DNA analysis for APOE epsilon 4 allele for susceptibility to Alzheimer's disease
ICD-10 codes covered if selection criteria are met:
G30.0 - G30.9	Alzheimer's disease
G31.84	Mild cognitive impairment of uncertain or unknown etiology [due to AD or mild AD dementia]
ICD-10 codes not covered for indications listed in the CPB:
D69.0 – D69.9	Purpura and other hemorrhagic conditions
G23.0 – G23.9	Other degenerative diseases of basal ganglia
G31.01 – G31.83, G31.85 – G31.9	Other degenerative diseases of nervous system, not elsewhere classified
G32.0 – G32.89	Other degenerative disorders of nervous system in diseases classified elsewhere
R79.1	Abnormal coagulation profile
Z79.01	Long term (current) use of anticoagulants
Z79.02	Long term (current) use of antithrombotics/antiplatelets
Z86.69	Personal history of other diseases of the nervous system and sense organs [seizures]
Z86.73	Personal history of transient ischemic attack (TIA), and cerebral infarction without residual deficits

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications 

• 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.

Donanemab-azbt is an amyloid beta-directed antibody that is branded as Kisunla (Eli Lilly and Company). Specifically, donanemab-azbt is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against insoluble N-truncated pyroglutamate amyloid beta. The accumulation of amyloid beta plaques in the brain is a defining pathophysiological feature of Alzheimer’s disease.

Alzheimer's disease (AD) is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills, eventually resulting in the inability to carry out simple tasks. In AD, it is believed that abnormal accumulation of proteins, such as amyloid beta (which form plaques in the extracellular spaces between the neurons of the brain), and tau (which are twisted fibers that form neurofibrillary tangles inside the neurons -- intracellular), leads to loss of synapses and neurons resulting in gross atrophy of the affected areas of the brain, manifesting into progressive memory and cognitive decline (Huang, 2021). Amyloid plaques typically appear earlier in the disease process, whereas tau tangles tend to appear later in the disease. "The Amyloid Theory largely states that if you were able to prevent the accumulation of beta amyloid, or clear existing amyloid, the progress of the cognitive and memory problems associated with Alzheimer’s would be slowed or prevented" (Terry, 2021). In a pivotal phase 3 clinical trial, donanemab-azbt was found to reduce amyloid beta plaques in adults with confirmed pathology diagnosed with early symptomatic AD or mild cognitive impairment (MCI), as well those with mild dementia stage of AD. 

On July 2, 2024, the U.S. FDA approved branded Kisunla injection for the treatment of AD. FDA approval was based on the safety and efficacy data from a double-blind, placebo-controlled, parallel-group, multicenter study (TRAILBLAZER-ALZ 2; NCT04437511) in adult patients with AD. All patients had confirmed presence of amyloid pathology and mild cognitive impairment or mild dementia stage of disease. The study randomized 1736 patients in a 1:1 ratio to receive 700 mg donanemab-azbt  every 4 weeks for the first 3 doses, and then 1400 mg every 4 weeks (N = 860) or placebo (N = 876) for 72 weeks. The treatment was switched to placebo based on a prespecified reduction in amyloid levels measured by positron emission tomography (PET) at Week 24, Week 52, and Week 76. 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). The study showed that patients treated with donanemab-azbt demonstrated a statistically significant reduction in clinical decline on the iADRS compared to placebo at Week 76 in the overall population (2.92, p<0.0001), as well as on the iADRS component scales, the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog13) (-1.33, p=0.0006) and the Alzheimer’s Disease Cooperative Study – instrumental Activities of Daily Living (ADCS-iADL) scale (1.70, p=0.0001). Patients treated with donanemab-azbt also demonstrated a statistically significant reduction in clinical decline on the Clinical Dementia Rating Scale – Sum of Boxes (CDR-SB) compared to placebo at Week 76 in the overall population (-0.70, p<0.0001). 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 (FDA, 2024; Sims et al, 2023).

The prescribing information includes a boxed warning for amyloid-related imaging abnormalities (ARIA). Monoclonal antibodies directed against aggregated forms of beta amyloid can cause ARIA, characterized as ARIA with edema (ARIA-E), which can be observed on magnetic resonance imaging (MRI) as brain swelling or sulcal effusions, and ARIA with hemosiderin deposition (ARIA-H), which includes microhemorrhage and superficial siderosis. ARIA-H can occur spontaneously in patients with AD. ARIA-H associated with monoclonal antibodies directed against aggregated forms of beta amyloid generally occurs in association with an occurrence of ARIA-E. ARIA-H of any cause and ARIA-E can occur together. ARIA 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 headache, confusion, visual changes, dizziness, nausea, and gait difficulty.

Some people have a genetic risk factor (homozygous apolipoprotein E ε4 gene carriers) that may cause an increased risk for ARIA. Thus, testing for ApoE ε4 status should be performed prior to beginning treatment to inform the risk of developing ARIA.

There is risk of 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).

Kisunla is contraindicated in patients with known serious hypersensitivity to donanemab-azbt or to any of the excipients. 

The most common adverse reactions (at least 10% and higher incidence compared to placebo) include ARIA-E, ARIA-H microhemorrhage, ARIA-H superficial siderosis, and headache.

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Appendix

Appendix A: Summary of Clinical and Cognitive Evaluation for MCI due to AD

• Cognitive concern reflecting a change in cognition reported by patient or informant or clinician (i.e., historical or observed evidence of decline over time)
• Objective evidence of impairment in one or more cognitive domains, typically including memory (i.e., formal or bedside testing to establish level of cognitive function in multiple domains)
• Preservation of independence in functional abilities
• Not demented

Source: Albert et al (2011)

Appendix B: Clinical Dementia Rating (CDR) Scale

The CDR is obtained through semi-structured interviews of patients and informants with cognitive functioning rated on a 5-point scale in the following domains: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. The score relates to the member’s level of dementia:

• 0 = Normal
• 0.5 = Very Mild Dementia
• 1 = Mild Dementia
• 2 = Moderate Dementia
• 3 = Severe Dementia

Source: Knight Alzheimer Disease Research Center; Morris (1993); O'Bryant et al (2008)

Appendix C: Mini-Mental Status Exam (MMSE)

The MMSE is scored on a 30-point scale, with items that assess orientation (temporal and spatial; 10 points), memory (registration and recall; 6 points), attention/concentration (5 points), language (verbal and written, 8 points), and visuospatial function (1 point). The score relates to the member’s level of dementia:

• 25 - 30 suggests normal cognition
• 20 - 24 suggests mild dementia
• 13 - 20 suggests moderate dementia
• Less than 12 suggests severe dementia

Source: Folstein, Folstein, and McHugh (1975)

Appendix D: Montreal Cognitive Assessment (MoCA)

Per MoCA assessment, average scores for the following ranges are:

• Mild Cognitive Impairment: 19 - 25
• Mild Dementia: 11 - 21
• Normal: 26 and above

Source: MoCA Test Inc, 2023; Nasreddine et al, 2019

Appendix E: ARIA MRI Classification Criteria

Table: ARIA MRI Classification Criteria

ARIA Type	Radiographic Severity
	Mild	Moderate	Severe
ARIA-E	FLAIR hyperintensity confined to sulcus and or cortex/subcortical white matter in one location less than 5 cm	FLAIR hyperintensity 5 to 10 cm in single greatest dimension, or more than 1 site of involvement, each measuring less than 10 cm	FLAIR hyperintensity greater than 10 cm with associated gyral swelling and sulcal effacement. One or more separate sites of involvement may be noted.
ARIA-H microhemorrhage	less than or equal to 4 new incident microhemorrhages	5 to 9 new incident microhemorrhages	10 or more new incident microhemorrhages
ARIA-H superficial siderosis	1 newFootnote1* focal area of superficial siderosis	2 new focal areas of superficial siderosis	greater than 2 focal areas of superficial siderosis

Footnote1*Includes new or worsening superficial siderosis.

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References