Important Safety Information

 

Infusion-Related Reactions (IRRs)

In the SUSTAIN clinical trial, IRRs (occurring during/within 24 hours of infusion) were observed in 2 (3%) patients treated with ADAKVEO

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Indication


ADAKVEO® (crizanlizumab-tmca) is indicated to reduce the frequency of vaso-occlusive crises (VOCs) in adults and pediatric patients, aged 16 years and older, with sickle cell disease.

Efficacy

Reduced VOC Frequency

In the 52-week SUSTAIN study, ADAKVEO was proven to reduce the frequency of VOCs1

ln a prespecified subgroup analysis of the per-protocol population

Patients who received at least 12 of the 14 planned doses of ADAKVEO showed a 52% reduction in the median annual rate of VOCs2,3

  • Patients on ADAKVEO® (crizanlizumab-tmca) experienced a 52% reduction in VOCs vs placebo (1.04 vs 2.18; HL=-1.02; 95% CI: -2.00, -0.03)

Per-protocol population is a subset of the ITT patient population who received at least 12 of the 14 planned doses of ADAKVEO (n=40) or placebo (n=41), completed a visit at least 14 days after final dose of study drug, and had no major protocol violations. The per-protocol population was analyzed according to the randomized treatment arm and not powered to show statistical significance.2,3

 

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Reduction in the frequency of VOCs was seen even in those who typically experienced few VOCs2,3†

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The majority of patients in the SUSTAIN trial had low VOC baseline frequency2,3†

ln a prespecified, noncomparative subgroup analysis

Patients who experienced 2-4 VOCs in the previous 12 months (63%, n=42)

had a 43% reduction in the median annual rate of VOCs with ADAKVEO (n=42) vs placebo (n=41) (1.14 vs 2.00, HL=-0.05; 95% CI: -1.56, 0.01)

Patients who experienced 5-10 VOCs in the previous 12 months (37%, n=25)

had a 63% reduction in the median annual rate of VOCs with ADAKVEO (n=25) vs placebo (n=24) (1.97 vs 5.32, HL=-2.74; 95% CI: -5.00, -0.83)

 

ln a prespecified, noncomparative subgroup analysis
VOC frequency was reduced regardless of hydroxyurea use1-3†

Patients already on HU who still experienced VOCs in the previous 12 months showed a

32% reduction in the median annual rate of caso-occlusive crises (VOCs) for patients already on HU
in the median annual rate of VOCs

ADAKVEO with HU (n=42) vs placebo with HU (n=40) (HL=-1.01; 95% CI: -2.44, 0.00)

Patients not on HU who experienced VOCs in the previous 12 months showed a

50% reduction in the median annual rate of vaso-occlusive crises (VOCs) for patients not on HU
in the median annual rate of VOCs

ADAKVEO without HU (n=25) vs placebo without HU (n=25) (HL=-1.02; 95% CI: -2.00, 0.00)

 

*Annual rate of VOCs leading to a health care visit (ER, clinic, hospital, or local physician visit).1,4

The subgroup analyses should be interpreted with caution because the data are from a prespecified, noncomparative subgroup analysis of the primary end point and are not powered to detect statistical significance or superiority of ADAKVEO over placebo.3

VOCs, vaso-occlusive crises; ITT, intent to treat; HL, Hodges-Lehmann; CI, confidence interval; ER, emergency room.

 

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The Power of VOC Protection

Watch Nirmish R. Shah, MD, describe the clinical data for ADAKVEO and a hypothetical patient case study.

Important Safety Information

Infusion-Related Reactions (IRRs)

In the SUSTAIN clinical trial, IRRs (occurring during/within 24 hours of infusion) were observed in 2 (3%) patients treated with ADAKVEO 5 mg/kg. Postmarketing cases of IRRs, including severe pain events requiring hospitalizations, have been reported. The majority of these IRRs occurred during the first and second infusions. The management of pain events included acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, antihistamines, intravenous fluids, and/or oxygen therapy. Some patients have also experienced subsequent complications such as acute chest syndrome and fat embolism, particularly those treated with steroids.

Monitor patients for signs and symptoms of IRRs, which may include pain in various locations, headache, fever, chills, nausea, vomiting, diarrhea, fatigue, dizziness, pruritus, urticaria, sweating, or shortness of breath or wheezing.

For severe IRRs, discontinue infusion, institute appropriate medical care, and consider permanent discontinuation of ADAKVEO. For mild or moderate IRRs, temporarily interrupt or slow the rate of infusion and initiate symptomatic treatment. For subsequent infusions, consider premedication and/or reduce the infusion rate.

Exercise caution with corticosteroids in patients with sickle cell disease unless clinically indicated (eg, treatment of anaphylaxis).

Laboratory Test Interference (Platelet Counts)

Interference with automated platelet counts (platelet clumping) has been observed following administration of ADAKVEO, in particular, when blood samples were collected in tubes containing EDTA.

Run blood samples within 4 hours of blood collection or collect blood samples in tubes containing citrate. When needed, estimate platelet count via peripheral blood smear.

Pregnancy

Based on animal data, ADAKVEO has the potential to cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. ADAKVEO should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the fetus.

Most Common Adverse Reactions

The most frequently reported adverse reactions (≥10%) in patients treated with ADAKVEO were nausea (18%), arthralgia (18%), back pain (15%), abdominal pain (12%), and pyrexia (11%).

Other Clinically Important Adverse Reactions

Clinically relevant adverse reactions (all grades) that were reported in <10% of patients treated with ADAKVEO included: oropharyngeal pain, diarrhea, vomiting, pruritus (pruritus and vulvovaginal pruritus), musculoskeletal chest pain, myalgia, infusion-site reaction (infusion-site extravasation, infusion-site pain, and infusion-site swelling), and infusion-related reaction.

Please see accompanying full Prescribing Information.

 

Fewer Days Hospitalized

Patients treated with ADAKVEO were hospitalized for fewer days1,2

The key secondary end point in the SUSTAIN study was defined as the annual rate of days a patient was hospitalized, including those related to VOCs. The range of days hospitalized for the ADAKVEO and placebo population was 0 to 131 days and 0 to 307 days, respectively.3

In a post hoc analysis, the following results were observed5
  • 46% of patients treated with ADAKVEO were not hospitalized during the trial vs 35% with placebo (31 of 67 patients vs 23 of 65 patients)
  • Median time to first hospitalization was 6.3 months with ADAKVEO vs 3.2 months with placebo

Results are based on 2 post hoc analyses of the key secondary end point and are observational in nature; as such, they were not powered to show statistical significance.

Delayed Time to First VOC

ADAKVEO delayed time to first vaso-occlusive crisis1

HR, hazard ratio.

Other end point

More than one-third of patients did not experience a VOC with ADAKVEO1

36% of patients taking ADAKVEO did not experience a VOC vs.17% of patients on placebo

Patients who did not experience a VOC that led to a health care visit during treatment: A patient was considered to not have experienced a VOC if the annualized VOC rate was zero, whether or not the patient completed the 12-month treatment period.2,3

Study Design

SUSTAIN was a 52-week pivotal SCD study that evaluated clinically meaningful end points1,2

Study description

The efficacy of ADAKVEO® (crizanlizumab-tmca) was evaluated based on the annual rate of VOCs in patients (16 to 63 years of age) with SCD in a pivotal, phase 2, 52-week, randomized, multicenter, placebo-controlled, double-blind study. The study included 198 patients evaluated at 60 study centers, the majority of which were located in the United States (51 centers with 151 study patients)1-3§

RANDOMIZATION (1:1:1)
FINAL EFFICACY ASSESSMENT
N=198
APPROVED
DOSE
ADAKVEO 5.0 mg/kg infusion (n=67)
ADAKVEO 2.5 mg/kg infusion (n=66)
Placebo (n=65)
HCP-website-study-design
WEEK 0
WEEK 52
Doses were administered over a period of 30 minutes by intravenous infusion on Week 0, Week 2, and every 4 weeks thereafter for a treatment duration of 52 weeks1
Primary end point2-4
  • Annual rate of VOCs
  • VOCs were defined as episodes that:
    • Led to a health care visit, which captured all acute episodes of pain with no other cause than a vaso-occlusive event that required a medical facility visit (ER, clinic, hospital, or local physician visit)
    • Required treatment with oral or parenteral opioids or parenteral NSAIDs
    • Included events such as acute chest syndrome, hepatic sequestration, splenic sequestration, and priapism
    • Were adjudicated by a third-party committee

Prespecified, noncomparative subgroup analysis evaluated the annual rate of VOCs with or without HU

Secondary and other end points2
  • Annual rate of days hospitalized
  • Time to first VOC
  • Number of patients who did not experience a VOC
SCD, sickle cell disease; NSAIDs, non-steroidal anti-inflammatory drugs; HU, hydroxyurea.
  • All efficacy analyses were conducted using the ITT population, which included all patients randomized to ADAKVEO 5 mg/kg (n=67) or placebo (n=65). An additional sensitivity analysis was performed using the per-protocol population, which included all patients who underwent randomization, received 12 to 14 planned doses of ADAKVEO (n=40) or placebo (n=41), and had no major violations of protocol.2
  • §Other study sites included: 8 in Brazil (n=40); 1 in Jamaica (n=7).2
  • Stratified by HU use (Y/N) and number of VOCs in the previous 12 months (2 to 4, 5 to 10).1

 

 

ADAKVEO was evaluated in a clinically diverse patient population1

Studied across all major SCD patient types

 

Baseline characteristics1,3
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SUSTAIN studied the efficacy of ADAKVEO in all major SCD patient types over the course of 52 weeks, regardless of VOC BASELINE FREQUENCY1

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  • §Baseline characteristics of patients were balanced across study arms.1
  • #With or without hydroxyurea.1
  • ||Patients who were receiving hydroxyurea must have been receiving the drug for ≥6 months, including an optimized dose for the most recent ≤3 months prior to Day 1 of the study; no dose adjustments were permitted during the 52-week treatment phase of the study, except for safety reasons.2

References: 1. Adakveo [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2021. 2. 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. 3. Data on file. Study NCT01895361. Novartis Pharmaceuticals Corp; 2016. 4. Data on file. Novartis Pharmaceuticals Corp; July 2013. 5. Data on file. Novartis Pharmaceuticals Corp; February 2020.

Next: Safety

Indication

ADAKVEO® (crizanlizumab-tmca) is indicated to reduce the frequency of vaso-occlusive crises (VOCs) in adults and pediatric patients, aged 16 years and older, with sickle cell disease.

Important Safety Information

Infusion-Related Reactions (IRRs)

In the SUSTAIN clinical trial, IRRs (occurring during/within 24 hours of infusion) were observed in 2 (3%) patients treated with ADAKVEO 5 mg/kg. Postmarketing cases of IRRs, including severe pain events requiring hospitalizations, have been reported. The majority of these IRRs occurred during the first and second infusions. The management of pain events included acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, antihistamines, intravenous fluids, and/or oxygen therapy. Some patients have also experienced subsequent complications such as acute chest syndrome and fat embolism, particularly those treated with steroids.

Monitor patients for signs and symptoms of IRRs, which may include pain in various locations, headache, fever, chills, nausea, vomiting, diarrhea, fatigue, dizziness, pruritus, urticaria, sweating, or shortness of breath or wheezing.

For severe IRRs, discontinue infusion, institute appropriate medical care, and consider permanent discontinuation of ADAKVEO. For mild or moderate IRRs, temporarily interrupt or slow the rate of infusion and initiate symptomatic treatment. For subsequent infusions, consider premedication and/or reduce the infusion rate.

Exercise caution with corticosteroids in patients with sickle cell disease unless clinically indicated (eg, treatment of anaphylaxis).

Laboratory Test Interference (Platelet Counts)

Interference with automated platelet counts (platelet clumping) has been observed following administration of ADAKVEO, in particular, when blood samples were collected in tubes containing EDTA.

Run blood samples within 4 hours of blood collection or collect blood samples in tubes containing citrate. When needed, estimate platelet count via peripheral blood smear.

Pregnancy

Based on animal data, ADAKVEO has the potential to cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. ADAKVEO should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the fetus.

Most Common Adverse Reactions

The most frequently reported adverse reactions (≥10%) in patients treated with ADAKVEO were nausea (18%), arthralgia (18%), back pain (15%), abdominal pain (12%), and pyrexia (11%).

Other Clinically Important Adverse Reactions

Clinically relevant adverse reactions (all grades) that were reported in <10% of patients treated with ADAKVEO included: oropharyngeal pain, diarrhea, vomiting, pruritus (pruritus and vulvovaginal pruritus), musculoskeletal chest pain, myalgia, infusion-site reaction (infusion-site extravasation, infusion-site pain, and infusion-site swelling), and infusion-related reaction.

Please see accompanying full Prescribing Information.