Crizanlizumab-tmca (Adakveo) Form

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

Adakveo is indicated to reduce the frequency of vasoocclusive crises (VOCs) in adults and pediatric patients aged 16 years and older with sickle cell disease.

Crizanlizumab-tmca is available as Adakveo (Novartis Pharmaceuticals Corporation). Crizanlizumab-tmca is a humanized IgG2 kappa monoclonal antibody that binds to P-selectin and blocks interactions with its ligands, including P-selectin glycoprotein ligand 1 (PSGL-1). Crizanlizumab-tmca can also dissociate preformed Pselectin/PSGL-1 complex. Binding P-selectin on the surface of the activated endothelium and platelets blocks interactions between endothelial cells, platelets, red blood cells, and leukocytes (Novartis, 2021).

The Prescribing Information for Adakveo includes warnings and precautions for infusion-related reactions, in which the label recommends to monitor for and advise patients of signs and symptoms. Adakveo infusion should be discontinued for severe reactions and manage medically. and temporarily interrupt or slow the rate of infusion for mild or moderate infusion-related reactions and initiate symptomatic treatment. It is recommended to exercise caution with corticosteroids in patients with sickle cell disease unless clinically indicated (e.g., treatment of anaphylaxis). Warnings and precautions also include interference with automated platelet counts (platelet clumping), in which it is recommended to run test as soon as possible or use citrate tubes (Novartis, 2021). The most common adverse reactions (incidence greater than 10 %) include nausea, arthralgia, back pain, abdominal pain, and pyrexia.

Sickle Cell Disease

Sickle cell disease (SCD) is a Mendelian recessive disorder comprised of a group of disorders that affects hemoglobin, the molecule in red blood cells that delivers oxygen to cells throughout the body. People with this disorder have atypical hemoglobin molecules called hemoglobin S, which can distort red blood cells into a sickle, or crescent shape. Clinically, sickle cell disease is manifested most often by acute painful episodes or "crises" but with many other acute and chronic complications including a variety of serious organ system complications, life-long disabilities and even death. When red blood cells sickle, they break down prematurely, leading to hemolytic anemia. Vaso-occlusion (previously called sickle cell crisis) occur when the stiff and inflexible sickled red blood cells get stuck in small blood vessels, resulting in recurrent painful episodes (previously called sickle cell crisis) and a variety of serious organ system complications which can lead to life-long disabilities and even death. According to the Centers for Disease Control and Prevention, sickle cell disease affects approximately 100,000 Americans. The disease occurs most often in African-Americans, where 1 out of every 365 babies born have the disease. The management of acute pain in individuals with SCD is divided into prevention of pain, treatment of acute pain episodes, and management of chronic pain. Prophylactic pain management includes reducing pain triggers such as exposure to cold temperature or respiratory triggers, dehydration, and overexertion. Hydroxyurea and L-glutamine are the two main pharmacotherapy options for reducing pain episodes. Other pain management options include non-opioid (e.g., acetaminophen and NSAIDs) and opioid treatment.

On November 15, 2019, the FDA approved Adakveo (crizanlizumab-tmca) for patients age 16 years and older to reduce the frequency of VOC, a common and painful complication of sickle cell disease that occurs when blood circulation is obstructed by sickled red blood cells. Crizanlizumab-tmca is the first targeted therapy approved for sickle cell disease. Crizanlizumab-tmca is a selectin blocker humanized IgG2 kappa monoclonal antibody that binds to P-selectin and blocks interactions with its ligands including P-selectin glycoprotein ligand 1. Binding P-selectin on the surface of the activated endothelium and platelets blocks interactions between endothelial cells, platelets, red blood cells, and leukocytes.

The crizanlizumab-tmca approval was based on the results of a randomized clinical trial enrolling 198 patients with SCD with a history of VOC (Ataga et al; SUSTAIN Trial; NCT01895361). Ataga et al (2017) stated the up-regulation of P-selectin in endothelial cells and platelets contributes to the cell-cell interactions that are involved in the pathogenesis of VOC and sickle cell-related pain crises. The safety and efficacy of crizanlizumab, an antibody against the adhesion molecule P-selectin, were evaluated in patients with sickle cell disease. In this double-blind, randomized, placebo-controlled, phase 2 trial, patients were assigned to receive low-dose crizanlizumab (2.5 mg/kg of body weight), high-dose crizanlizumab (5.0 mg/kg), or placebo, administered intravenously 14 times over a period of 52 weeks. Patients who were receiving concomitant hydroxyurea as well as those not receiving hydroxyurea were included in the study. The primary endpoint was the annual rate of sickle cell-related pain crises with high-dose crizanlizumab versus placebo. The annual rate of days hospitalized, the times to 1st and 2nd crises, annual rates of uncomplicated crises (defined as crises other than the acute chest syndrome (ACS), hepatic sequestration, splenic sequestration, or priapism) and the ACS, and patient-reported outcomes were also assessed. A total of 198 patients underwent randomization at 60 sites. The median rate of crises per year was 1.63 with high-dose crizanlizumab versus 2.98 with placebo (indicating a 45.3 % lower rate with high-dose crizanlizumab, p = 0.01). The median time to the 1st crisis was significantly longer with high-dose crizanlizumab than with placebo (4.07 versus 1.38 months, p = 0.001), as was the median time to the 2nd crisis (10.32 versus 5.09 months, p = 0.02). The median rate of uncomplicated crises per year was 1.08 with high-dose crizanlizumab, as compared with 2.91 with placebo (indicating a 62.9 % lower rate with high-dose crizanlizumab, p = 0.02). Adverse events that occurred in 10 % or more of the patients in either active-treatment group and at a frequency that was at least twice as high as that in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain. The authors concluded that in patients with SCD, crizanlizumab therapy resulted in a significantly lower rate of sickle cell-related pain crises than placebo and was associated with a low incidence of adverse events.

Weaver and colleagues (2021) stated that SCD is a hematological disorder that primarily affects individuals of African descent from sub-Saharan Africa and along the Mediterranean. The main complications leading to hospitalizations include VOCs and ACS. These investigators examined evidence-based management and prevention of VOCs in patients with SCD. They carried out a literature search of PubMed, Medline Cochrane and Google Scholar database (January 1985 to April 2020) using the following search terms "vaso-occlusive crises", "sickle cell disease", "hydroxyurea", "L-glutamine", "voxelotor", "crizanlizumab", "treatment" and "prevention" as well as a combination of these terms. All English-language interventional studies evaluating the safety and efficacy of VOC outcomes were examined. Literature was excluded if published in a language other than English or if it was a review article. A total of 69 articles were identified and 7 met the search criteria. The majority of the studies focused on mean and median annual rates of VOCs as primary outcomes while median time to 1st sickle cell crises, median rates of hospitalizations etc. were evaluated as secondary outcomes. After reviewing the literature, many patients with VOCs will still benefit from hydroxyurea therapy since long-term efficacy data and cost is still a concern for the newer agents including L-glutamine, voxelotor and crizanlizumab. Other factors such as cost or compliance may also be taken into consideration when making recommendations for therapy.

Note

: Required Precertification:

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

Specialty Pharmacy Precertification . For Medicare Part B plans, call (866) 503-0857 or fax (844) 268-7263. Note

: Site of Care Utilization Management Policy applies. For information on site of service for crizanlizumab (Adakveo), see

Utilization Management Policy on Site of Care for Specialty Drug Infusions

.

Prescriber Specialties

This medication must be prescribed by or in consultation with a hematologist or specialist in sickle cell disease.

Criteria for Initial Approval

Aetna considers crizanlizumab-tmca (Adakveo) medically necessary for reducing the frequency of vasoocclusive crises (VOCs) in members 16 years of age or older with sickle cell disease, when

both

of the following criteria are met:

The member has experienced at least one vasoocclusive crisis within the previous 12 months;

and

The member meets

either

of the following (1 or 2):

Member has sickle hemoglobin C (HbSC) or sickle β+-thalassemia (HbSβ+) genotype;

or

Member has homozygous hemoglobin S (HbSS) or sickle β0-thalassemia (HbSβ0) genotype and meets

any

of the following:

Has experienced, at any time in the past, an inadequate response or intolerance to a trial of hydroxyurea;

or

Has a contraindication to hydroxyurea;

or

Will be using Adakveo with concurrent hydroxyurea therapy.

Aetna considers all other indications as experimental and investigational.

Continuation of Therapy

Aetna considers continuation of crizanlizumab-tmca (Adakveo) therapy medically necessary when the member has experienced a reduction in the frequency of vasoocclusive crises, or has maintained such reduction, since initiating therapy with Adakveo.

Dosage and Administration

Adakveo is supplied for injection as 100 mg/10 mL (10 mg/mL) solution in a single-dose vial.

Per the Prescribing Information, administer Adakveo 5 mg/kg by intravenous infusion over a period of 30 minutes at Week 0, Week 2, and every 4 weeks thereafter.

If a dose is missed, administer Adakveo as soon as possible. If Adakveo is administered within 2 weeks after the missed dose, continue dosing according to the patient's original schedule. If Adakveo is administered more than 2 weeks after the missed dose, continue dosing every 4 weeks thereafter.

Adakveo may be given with or without hydroxyurea.

Source: Novartis, 2021