Medicare Advantage

Medical Policy

Notification

crizanlizumab-tmca (Adakveo®)

Notification Issued Date:

This AmeriHealth New Jersey Medicare Advantage policy will become effective 01/01/2024.

Title:

crizanlizumab-tmca (Adakveo®)

Policy #:

MA08.109c

Policy

In the absence of coverage criteria from applicable Medicare statutes, regulations, NCDs, LCDs, CMS manuals, or other Medicare coverage documents, this policy uses internal coverage criteria developed by the Company in consideration of peer-reviewed medical literature, clinical practice guidelines, and/or regulatory status.

The Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition.

MEDICALLY NECESSARY

INITIAL THERAPY
Crizanlizumab-tmca (Adakveo) is considered medically necessary and, therefore, covered to reduce the frequency of vaso-occlusive crises (VOCs) in individuals aged 16 years or older with sickle cell disease, when used as monotherapy or concomitantly with hydroxyurea, when all of the following criteria, including Dosing and Frequency, are met:

Individual has a documented diagnosis of sickle cell disease confirmed by one of the following tests:
- Molecular genetic testing that reveals pathogenic variation(s) in the HBB gene causing sickle cell disease
- Hemoglobin electrophoresis
There is documentation of two or VOCs in the past 12 months that required a visit to a medical facility and/or healthcare professional and receipt of treatments for conditions such as acute pain episodes, acute chest syndrome, hepatic or splenic sequestration, priapism
There are no long-term transfusion therapies planned
Dosing and Frequency: 5 mg/kg as an intravenous (IV) infusion at Week 0, 2, and every 4 weeks thereafter

CONTINUATION THERAPY

Continuation of crizanlizumab-tmca (Adakveo) is considered medically necessary and, therefore, covered for individuals who have demonstrated a documented reduction in the annual rate of sickle cell–related VOCs.

NOT MEDICALLY NECESSARY

When molecular genetic testing reveals established benign variation(s) or wild-type genotype in the HBB gene, crizanlizumab-tmca (Adakveo) is considered not medically necessary and, therefore, not covered because the available published peer-reviewed literature does not support its use in the treatment of this disease.

EXPERIMENTAL/INVESTIGATIONAL

When molecular genetic testing reveals likely pathogenic or variations of unknown significance (VUS) in the HBB gene, the use of crizanlizumab-tmca (Adakveo) is considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

All other uses for crizanlizumab-tmca (Adakveo) are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics.

DOSING AND FREQUENCY REQUIREMENTS

The Company reserves the right to modify the Dosing and Frequency Requirements listed in this policy to ensure consistency with the most recently published recommendations for the use of crizanlizumab-tmca (Adakveo). Changes to these guidelines are based on a consensus of information obtained from resources such as, but not limited to: the US Food and Drug Administration (FDA); Company-recognized authoritative pharmacology compendia; and published peer-reviewed clinical research. The professional provider must supply supporting documentation (i.e., published peer-reviewed literature) in order to request coverage for an amount of crizanlizumab-tmca (Adakveo) outside of the Dosing and Frequency Requirements listed in this policy. For a list of Company-recognized pharmacology compendia, view our policy on off-label coverage for prescription drugs and biologics.

Accurate member information is necessary for the Company to approve the requested dose and frequency of this drug. If the member’s dose, frequency, or regimen changes (based on factors such as changes in member weight or incomplete therapeutic response), the provider must submit those changes to the Company for a new approval based on those changes as part of the utilization management activities. The Company reserves the right to conduct postpayment review and audit procedures for any claims submitted for crizanlizumab-tmca (Adakveo).

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the service.

When coverage of crizanlizumab-tmca (Adakveo) is requested outside of the Dosing and Frequency Requirements listed in this policy, the prescribing professional provider must supply documentation (i.e., published peer-reviewed literature) to the Company that supports this request.

Guidelines

There is no Medicare coverage determination addressing crizanlizumab-tmca (Adakveo®); therefore, the Company policy is applicable.

DRUG INFORMATION

Crizanlizumab-tmca (Adakveo) is administered as an intravenous (IV) infusion at Week 0, 2, and every 4 weeks thereafter. Crizanlizumab-tmca (Adakveo) may be used with or without hydroxyurea.

BENEFIT APPLICATION

Subject to the applicable Evidence of Coverage, crizanlizumab-tmca (Adakveo) is covered under the medical benefits of the Company’s Medicare Advantage products when the medical necessity criteria and Dosing and Frequency Requirements listed in this medical policy are met.

For Medicare Advantage members, certain drugs are available through either the member's medical benefit (Part B benefit) or pharmacy benefit (Part D benefit), depending on how the drug is prescribed, dispensed, or administered. This medical policy only addresses instances when crizanlizumab-tmca (Adakveo) is covered under a member's medical benefit (Part B benefit). It does not address instances when crizanlizumab-tmca (Adakveo) is covered under a member’s pharmacy benefit (Part D benefit).

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

Crizanlizumab-tmca (Adakveo) was approved by the FDA on November 15, 2019, indicated to reduce the frequency of vaso-occlusive crises (VOCs) in adults and pediatric individuals aged 16 years and older with sickle cell disease.

The safety and effectiveness of crizanlizumab-tmca (Adakveo) for sickle cell disease have been established in pediatric individuals aged 16 years and older, supported by evidence from adequate and well-controlled studies in adults and pediatric individuals (SUSTAIN Trial), which enrolled one pediatric individual 16 years of age treated with crizanlizumab-tmca (Adakveo) 5 mg/kg. The safety and efficacy of crizanlizumab-tmca (Adakveo) in pediatric individuals below the age of 16 years have not been established.

Description

Sickle cell disease (SCD) is the most common inherited blood disorder in the United States, affecting 70,000 to 80,000 Americans. The disease is estimated to occur in one in 500 African Americans and one in 1000 to 1400 Hispanic Americans. In SCD, hemoglobin, a molecule in red blood cells (RBCs) that carries oxygen to cells throughout the body, distorts RBCs from a round shape into a sickle, or crescent shape, which becomes hard and sticky. The sickle cells die early, which causes a constant shortage of RBCs. Symptoms of SCD can vary among individuals in type and severity, and consist of anemia, episodic pain requiring hospitalization (due to blood vessel occlusion), repeat infections, and more serious chronic complications, such as stroke. The episodic pain occurs when the distorted RBCs occlude small blood vessels and deprive the tissues and organs of oxygen-rich blood; this can lead to multiorgan dysfunction and early death. Sickle cell–related pain crises are the primary cause of health care encounters in individuals with sickle cell disease. These crises result in a decrease in quality of life and an increase in the risk of death.

SCD is caused by mutations in the HBB gene, diagnosed during prenatal screening for hemoglobinopathies. Hemoglobin consists of four protein subunits, typically two subunits called alpha-globin and two subunits called beta-globin. The HBB gene provides instructions for making beta-globin. Individuals with SCD have at least one of the beta-globin subunits in hemoglobin replaced with hemoglobin S. Common genotypes of SCD include:

HbSS (homozygous SCD): Most severe form of SCD, commonly known as sickle cell anemia. Individuals inherit two sickle cell genes "S", one from each parent.
HbSβ⁰-thalassemia, or HbSβ⁺-thalassemia: Individuals inherit one sickle cell gene “S” from one parent, and one gene for beta thalassemia, another type of anemia, from the other parent (compound heterozygous). There are two types of beta thalassemia: “0” and “+”. Those with HbSβ⁰-thalassemia usually have a severe form of SCD; those with HbSβ⁺-thalassemia tend to have a milder form of SCD.
HbSC (sickle cell hemoglobin C disease): Moderate form of SCD. Individuals inherit one sickle cell gene "S" from one parent, and a gene for an abnormal hemoglobin called "C" from the other parent.

P-selectin is a molecule on the surface of endothelial cells and platelets in the blood vessels that promotes the inflammation and adhesion involved in vaso-occlusive crises (VOCs). Crizanlizumab-tmca (Adakveo) is a US Food and Drug Administration (FDA)–approved humanized monoclonal antibody that binds to and blocks the effects P-selectin, therefore preventing RBC occlusion in small blood vessels and maintaining blood flow, and thus reducing the occurrence and severity of pain crises.

The treatment of SCD VOCs includes chronic transfusions or oral agents such as hydroxyurea or L-Glutamine (Endari). Both oral agents have different mechanisms of action to treat SCD and are sometimes used in combination. Hydroxyurea has been the standard of care for SCD for many years, with efficacy outcomes that include the ability to decrease the annual rate of SCD pain crises and acute chest syndrome, increase hemoglobin levels, decrease transfusion rates, and prevent primary and secondary stroke in pediatric individuals at risk. There are limitations of these agents, including noncompliance, variable efficacy, as well as the need to monitor for hematologic toxicity in those receiving hydroxyurea. The only cure for SCD is a stem cell transplant; however, transplant-related morbidity and mortality remain high.

PEER-REVIEWED LITERATURE
Summary

The safety and efficacy of crizanlizumab-tmca (Adakveo) was studied in a Phase 2, placebo-controlled, double-blind trial (SUSTAIN) of 198 adolescents and adults 16 to 65 years of age who were diagnosed with SCD of any genotype (HbSS, HbSC, HbSβ⁰-thalassemia, HbSβ⁺-thalassemia, and others) and had, out of two to 10 sickle cell–related pain crises in the past 12 months, appropriate symptoms to require a visit to a medical facility and/or healthcare professional, plus receipt of pain medication for the crises. Approximately 70% all participants had HbSS, the most severe genotype. Approximately 62% of all participants were receiving hydroxyurea prior to the trial and were able to continue its use, as long as they remained on a stable dose. Key exclusion criteria included planned transfusions, hemoglobin less than 4 g/dL, or planned initiation, termination, or dose alteration of hydroxyurea. Participants were randomly assigned 1:1:1 to receive one of three protocols as an IV infusion every 4 weeks through Week 52 (after two loading doses 2 weeks apart): crizanlizumab-tmca (Adakveo) 5 mg/kg or 2.5 mg/kg, or placebo. The primary outcome of this study was the annual rate of sickle cell–related pain crises leading to a healthcare visit, with high-dose crizanlizumab-tmca (Adakveo) versus placebo. This trial demonstrated a reduced median annual rate of sickle cell pain crises (SCPCs) by 45.3% compared to placebo (1.63 vs 2.98; P=0.01), regardless of concomitant hydroxyurea use or SCD genotype. There was a 35% reduction in the median annual rate of SCPCs among participants with the HbSS genotype (1.97 in the high-dose crizanlizumab-tmca (Adakveo) group, as compared with 3.01 in the placebo group, and a 51% reduction in the median annual rate of SCPCs among participants with genotypes other than HbSS (0.99 in the high-dose crizanlizumab-tmca (Adakveo) group, as compared with two in the placebo group). Adverse events with crizanlizumab-tmca (Adakveo), occurring in 10% or more of participants and at a rate at least twice as high as placebo, were arthralgia, diarrhea, pruritus, vomiting, and chest pain.

The pharmacokinetics, pharmacodynamics, safety and efficacy of crizanlizumab-tmca (Adakveo) was studied in a Phase 2, single-arm, open label study (SOLACE-adults) of 57 adolescents and adults 16 to 70 years of age who were diagnosed with SCD of any genotype and had at least one VOC in the past 12 months that lead to a healthcare visit. The majority of all participants had HbSS, the most severe genotype. Approximately 65% of all participants were receiving hydroxyurea prior to the trial and were able to continue its use, as long as they remained on a stable dose. Participants received crizanlizumab-tmca (Adakveo) 5 mg/kg (for about 4 years) or 7.5 mg/kg (for about 3 years). For the efficacy endpoint, there was a sustained reduction (from baseline) in annualized rate of VOCs leading to healthcare visit after at least 1 year of treatment. There was a median absolute reduction of 0.79 and 0.98 VOC events from baseline with crizanlizumab 5.0 and 7.5 mg/kg doses, respectively, over the course of the study. The author stated that both arms were enrolled sequentially, so they cannot be compared as they were not matched for sample size or baseline characteristics. Thus, no conclusions should be drawn as to the relative efficacy.

The safety and efficacy of crizanlizumab-tmca (Adakveo) was also studied in a Phase 3, randomized, double-blind trial (STAND) of 252 adolescents and adults aged 12 to 84 years of age who were diagnosed with SCD of any genotype and had at least two VOCs in the past 12 months that lead to a healthcare visit. The majority of all participants had HbSS, the most severe genotype; although there was a higher incidence of Sβ+-thalassemia (10%), which generally induces a milder phenotype than that reported in SUSTAIN trail (5%). Approximately 72% of all participants were receiving hydroxyurea prior to the trial and were able to continue its use, as long as they remained on a stable dose. Participants were randomly assigned 1:1:1 to receive one of three protocols as an IV infusion every 4 weeks through Week 52 (after two loading doses 2 weeks apart): crizanlizumab-tmca (Adakveo) 5 mg/kg or 7.5 mg/kg, or placebo in addition to standard of care, for 1 year. The primary endpoint was the annualized rate of VOCs leading to a healthcare visit over the first year postrandomization. The primary analysis concluded that there was no significant difference in the adjusted annualized rate of VOCs between crizanlizumab-tmca (Adakveo) 5 mg/kg (n=84; rate, 2.49) and placebo (n=85; rate, 2.30; RR, 1.08; 95% CI, 0.76–1.55); nor crizanlizumab-tmca 7.5 mg/kg (n=83; rate, 2.04) and placebo (n=85; rate, 2.30; RR, 0.89; 95% CI, 0.62–1.27). The overall incidence of adverse events was similar across treatment groups. The safety profile of crizanlizumab-tmca (Adakveo) in STAND was consistent with that reported in SUSTAIN, with no indication of increased risk of clinically significant events. These outcomes are preliminary data, as the trial is ongoing, to be completed December of 2026. Because crizanlizumab-tmca (Adakveo) is FDA-approved, providers may have been reluctant to expose individuals with severe disease to a trial with a placebo arm.

OFF-LABEL INDICATION

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.

References

Abboud MR, Cançado RD, De Montalembert M, et al. Crizanlizumab with or without hydroxyurea in patients with sickle cell disease (STAND): primary analyses from a placebo-controlled, randomised, double-blind, phase 3 trial. Lancet Haematol. 2025;12(4):e248-e257.

American Hospital Formulary Service (AHFS). Crizanlizumab. AHFS Drug Information 2025. AHFS Drug Information. [UpToDate Lexidrug Web site]. 09/25/2023. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed May 5, 2025.

Angelucci E, Matthes-Martin S, Baronciani D, et al. Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel. Haematologica. 2014;99(5):811-820.

Ataga KI, Kutlar A, Kanter J, et al. Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease. N Engl J Med. 2017;376(5):429-439.

Bradt P, Spackman E, Synnott P, et al. Crizanlizumab, Voxelotor, and L-Glutamine for Sickle Cell Disease: Effectiveness and Value. Institute for Clinical and Economic Review (ICER). March 12, 2020.

Brandow AM, Carroll CP, Creary S, et al. American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain. Blood Adv. 2020 Jun 23;4(12):2656-2701.

Centers for Disease Control and Prevention (CDC). Sickle Cell Disease: About sickle cell disease. 02/21/2025. Available at: About Sickle Cell Disease | Sickle Cell Disease (SCD) | CDC. Accessed May 5, 2025.

Charache S, Terrin M, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crisis in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med. 1995;332(20):1317-1322.

Crizanlizumab-tmca (Adakveo®). [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 06/2024. Available at: ADAKVEO® (crizanlizumab-tmca) for Sickle Cell Pain Crises. Accessed May 5, 2025.

Elsevier’s Clinical Pharmacology Compendium. crizanlizumab-tmca (Adakveo®). 07/17/2024. [Clinical Key Web site]. Available at: https://www.clinicalkey.com/pharmacology/ [via subscription only]. Accessed May 5, 2025.

Fitzhugh C. Investigational therapies for sickle cell disease. [UpToDate Web Site]. Updated 01/24/2025. Available at: Investigational pharmacologic therapies for sickle cell disease - UpToDate [via subscription only]. Accessed May 5, 2025.

Gardner RV. Sickle Cell Disease: Advances in Treatment. Ochsner J. 2018;18(4):377-389.

George A. Prevention of stroke (initial or recurrent) in sickle cell disease. [UpToDate Website]. 01/21/2025. Available at: https://www.uptodate.com/contents/prevention-of-stroke-initial-or-recurrent-in-sickle-cell-disease#H1305585422. Accessed May 5, 2025.

Hankins JS, McCarville MB, Rankine-Mullings A, et al. Prevention of conversion to abnormal transcranial Doppler with hydroxyurea in sickle cell anemia: a phase III international randomized clinical trial. American Journal of Hematology. 2015;90(12):1099-1105.

Jain DL, Sarathi V, Desai S, Bhatnagar M, Lodha A. Low fixed-dose hydroxyurea in severely affected Indian children with sickle cell disease. Hemoglobin. 2012;36(4):323-332.

Kanter J, Mennito S, Nair SM, et al. Pharmacokinetics, pharmacodynamics, safety, and efficacy of crizanlizumab in patients with sickle cell disease: final results from the phase II SOLACE-adults study. Ther Adv Hematol. 2024; Nov 3;15:20406207241292508.

Lexi-Drugs Compendium. Crizanlizumab-tmca (Adakveo®). 05/02/2025. [Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed May 5, 2025.

Liem RI, Lanzkron S, Coates T, et al. American Society of Hematology 2019 Guidelines for sickle cell disease: cardiopulmonary and kidney disease. Blood adv. 2019;3(23):3867-3897.

Luchtman-Jones L, Pressel S, Hilliard L, et al. Effects of hydroxyurea treatment for patients with hemoglobin SC disease. Am J Hematol. 2016 Feb;91(2):238-242.

National Institutes of Health. Clinical trials: European Sickle Cell Disease Cohort - Hydroxyurea (ESCORT-HU) (NCT02516579). [ClinicalTrials Web site]. last updated 03/19/2020. Available at: https://clinicaltrials.gov/ct2/show/NCT02516579. Accessed May 5, 2025.

National Institutes of Health. Clinical trials: Study to Assess Safety and Impact of SelG1 With or Without Hydroxyurea Therapy in Sickle Cell Disease Patients With Pain Crises (SUSTAIN). (NCT01895361). [ClinicalTrials Web site]. last updated 01/31/2020. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01895361?term=NCT01895361&draw=1&rank=1. Accessed May 5, 2025.

National Institutes of Health. Clinical trials: Study of Two Doses of Crizanlizumab Versus Placebo in Adolescent and Adult Sickle Cell Disease Patients (STAND). (NCT03814746). [ClinicalTrials Web site]. last updated 04/24/2025. Available at: https://clinicaltrials.gov/ct2/show/NCT03814746?term=Crizanlizumab&rank=3. Accessed May 5, 2025.

National Institutes of Health: National Heart, Lung, and Blood Institute. Evidence Report. Evidence-based management of sickle cell disease: Expert Panel Report, 2014. Available at: https://www.nhlbi.nih.gov/health-topics/evidence-based-management-sickle-cell-disease. Accessed May 5, 2025.

National Institutes of Health (NIH). Genetics Home Reference. Sickle cell disease. Updated 03/14/2024. Available at: https://ghr.nlm.nih.gov/condition/sickle-cell-disease. Accessed May 5, 2025.

Nevitt SJ, Jones AP, Howard J. Hydroxyurea (hydroxycarbamide) for sickle cell disease. Cochrane Database Syst Rev. 2017 Apr 20;4:CD002202.

Rodgers GP, George A, Strouse JJ. Hydroxyurea use in sickle cell disease. [UpToDate Web Site]. Updated 04/16/2025. Available at: Hydroxyurea use in sickle cell disease - UpToDate [via subscription only]. Accessed May 5, 2025.

Thom H, Jansen J, Shafrin J, et al. Crizanlizumab and comparators for adults with sickle cell disease: a systematic review and network meta-analysis. BMJ Open. 2020 Sep 17;10(9):e034147.

Thornburg CD, Files BA, Luo Z, et al. Impact of hydroxyurea on clinical events in the BABY HUG trial. Blood. 2012 Nov 22;120(22):4304-10.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. crizanlizumab-tmca (Adakveo®) prescribing information and approval letter [FDA Web site]. 06/26/2024. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed May 5, 2025.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. hydroxyurea (various). prescribing information. [FDA Web site]. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed May 5, 2025.

Voskaridou E, Christoulas D, Bilalis A, et al. The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS). Blood. 2010;115(12):2354-2363.

Wang W, Brugnara C, Snyder C, et al. The effects of hydroxycarbamide and magnesium on haemoglobin SC disease: results of the multi-centre CHAMPS trial. Br J Haematol. 2011;152(6):771-776.

Wang WC, Ware RE, Miller ST, et al. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet. 2011;377(9778):1663-1672.

Ware RE, Davis BR, Schultz WH, et al. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia—TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, noninferiority trial. Lancet. 2016;387:661-670.

Ware RE, Helms RW; SWiTCH Investigators. Stroke With Transfusions Changing to Hydroxyurea (SWiTCH). Blood. 2012;119(17):3925-3932.

Yates AM, Dedeken L, Smeltzer MP, et al. Hydroxyurea treatment of children with hemoglobin SC disease. Pediatr Blood Cancer. 2013;60(2):323-325.

Coding

CPT Procedure Code Number(s)

N/A

ICD - 10 Procedure Code Number(s)

N/A

ICD - 10 Diagnosis Code Number(s)

Report the most appropriate diagnosis code in support of medically necessary criteria as listed in the policy.

HCPCS Level II Code Number(s)

J0791 Injection, crizanlizumab-tmca, 5 mg

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

Cross Reference

Policy History

Version Effective Date:

7/28/2025

Version Issued Date: