Important Safety Information

 

Infusion-Related Reactions

In the SUSTAIN clinical trial, infusion-related reactions (defined as occurring within 24 hours of infusion) were observed in 2 (3%) patients treated

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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

Reduction in Frequency of VOCs

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

Significant 45% (1.63 vs 2.98) reduction in the median annual rate of VOCs vs placebo1,2*
In a prespecified subgroup analysis of the per-protocol population2,3
  • Patients on ADAKVEO® (crizanlizumab-tmca) experienced a 52% reduction in vaso-occlusive crises (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

In a prespecified, noncomparative subgroup analysis, reduction in the frequency of VOCs was observed with ADAKVEO regardless of hydroxyurea use1-3

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

 

Expert Presentation: Efficacy

Watch a medical expert explain the efficacy profile of ADAKVEO from the pivotal SUSTAIN study.

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Reduction in Days Hospitalized

Patients treated with ADAKVEO were hospitalized for fewer days1

42% (4.00 vs 6.87) reduction with ADAKVEO in the median annual rate of days hospitalized vs placebo1,2

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 of 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.

Patients Who Did Not Experience a VOC

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

36% of patients treated with ADAKVEO did not experience a VOC vs 17% with placebo1

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

In a post hoc analysis6
  • 22% of patients who completed the 12-month treatment period did not experience a VOC with ADAKVEO vs 8% with placebo (15 of 67 patients vs 5 of 65 patients; OR=3.57; 95% CI: 1.20, 10.63)
  • Results are based on a noncomparative post hoc analysis and are observational in nature; as such, they are not powered to show statistical significance.

OR, odds ratio.

Delayed Time to First VOC

Time to first VOC was delayed with ADAKVEO1

>3 times delay in the median time to first VOC from randomization with ADAKVEO—4.1 months vs 1.4 months with placebo1

An early separation of the time to first VOC was observed at Week 2 with ADAKVEO.

  • Results reported at 2 weeks were not prespecified and are observational in nature; as such, there was no prespecified statistical procedure controlling for type 1 error

 

In a post hoc analysis, median time to first VOC from randomization in patients with or without hydroxyurea who still experienced VOCs7

Time to first VOC

  • In patients on ADAKVEO with hydroxyurea, time to first VOC was 2.4 months vs 1.2 months in those on placebo with hydroxyurea (HR=0.58; 95% CI: 0.35, 0.96)
  • In patients on ADAKVEO without hydroxyurea, time to first VOC was 5.7 months vs 2.9 months in those on placebo without hydroxyurea (HR=0.39; 95% CI: 0.20, 0.76)

These analyses should be interpreted with caution as the data are from a noncomparative post hoc subgroup analysis and not powered to detect statistical significance or superiority of ADAKVEO over placebo.

HR, harzard ratio.

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

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 hydroxyurea

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.
  • *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

Expert Presentation: SUSTAIN Study Design

Watch a detailed overview of SUSTAIN, the pivotal study that evaluated ADAKVEO in a clinically diverse patient population.

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ADAKVEO was evaluated in a clinically diverse patient population1

Studied across all major SCD patient types1,2§

 

SUSTAIN patient types and baseline characteristics

Genotypes

  • HbSS (70%)
  • HbSC (13%)
  • HbSß+-thalassemia (10%)
  • HbSß0-thalassemia (5%)
  • Other (2%)
SUSTAIN patient types and baseline characteristics

VOC Frequency

(during previous 12 months)
  • 2 to 4 VOCs (63%)
  • 5 to 10 VOCs (37%)
SUSTAIN patient types and baseline characteristics

Hydroxyurea Use||

  • 62% of patients were on hydroxyurea and still had experienced 2 to 10 VOCs in the previous 12 months
  • Patients were on hydroxyurea for at least 6 months and on a stabilized dose for at least 3 months prior to the study

 

Baseline characteristics1,3
  • §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; 2019. 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. 6. Data on file. Novartis Pharmaceuticals Corp; November 2019. 7. Kutlar A, Kanter J, Liles DK, et al. Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: a SUSTAIN study analysis. Am J Hematol. 2019;94(1):55-61.

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

In the SUSTAIN clinical trial, infusion-related reactions (defined as occurring within 24 hours of infusion) were observed in 2 (3%) patients treated with ADAKVEO 5 mg/kg. Monitor patients for signs and symptoms of infusion-related reactions, which may include fever, chills, nausea, vomiting, fatigue, dizziness, pruritus, urticaria, sweating, or shortness of breath or wheezing. Discontinue ADAKVEO infusion for severe reactions and institute appropriate medical care.

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%), 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, abdominal pain (abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort, and abdominal tenderness), 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 full Prescribing Information.