Crizanlizumab

Risk Summary

Based on data from animal studies, crizanlizumab has the potential to cause fetal harm when administered to a pregnant woman. In an animal reproduction study, intravenous administration of crizanlizumab-tmca to pregnant cynomolgus monkeys from the onset of organogenesis through delivery resulted in a non-dose related increased fetal loss (abortions/stillbirths) at doses approximately 2.8 times the exposure at the recommended clinical dose at 5 mg/kg/dose once every 4 weeks (see Data).

There are insufficient human data on crizanlizumab use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Advise pregnant women of the potential risk to a fetus. Crizanlizumab should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is approximately 14% and up to 43%, respectively. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Women with sickle cell disease have an increased risk of adverse pregnancy outcomes for the mother and the fetus. Pregnant women are at greater risk for VOCs, pre-eclampsia, eclampsia, and maternal mortality. For the fetus, there is an increased risk for intrauterine growth restriction, preterm delivery, low birth weight, and perinatal mortality.

Data

Animal Data

In an enhanced pre- and postnatal development study in cynomolgus monkeys, pregnant animals received intravenous doses of crizanlizumab-tmca at 10 and 50 mg/kg once every 2 weeks during the period of onset of organogenesis through delivery. No maternal toxicity was observed. Maternal exposures at doses of 10 and 50 mg/kg were between 2.8 and 16 times, respectively, the human clinical exposure based on area under the curve (AUC) in patients with sickle cell disease at 5 mg/kg/dose once every 4 weeks. There was an increase in fetal loss (abortions or still births) at both crizanlizumab-tmca doses which was higher in the third trimester.

There were no effects on infant growth and development through 6-months postpartum that were attributable to crizanlizumab-tmca.

Measurable crizanlizumab-tmca serum concentrations were observed in the infant monkeys at postnatal Day 28, confirming that crizanlizumab crosses the placental barrier.

Risk Summary

There is no data on the presence of crizanlizumab-tmca in human or animal milk, the effects on the breastfed child, or the effects on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to crizanlizumab-tmca are unknown.

The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for crizanlizumab and any potential adverse effects on the breastfed child from crizanlizumab or from the underlying maternal condition.

No carcinogenicity or genotoxicity studies have been conducted with crizanlizumab-tmca.

In the 26-week repeat-dose toxicity study, cynomolgus monkeys were administered crizanlizumab-tmca once every 4 weeks at doses up to 50 mg/kg (at least 13.5 times the human clinical exposure based on AUC in patients with sickle cell disease at 5 mg/kg once every 4 weeks). There were no adverse effects of crizanlizumab-tmca on male or female reproductive organs.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Infusion-related reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Sickle Cell Disease

The safety of crizanlizumab was evaluated in the SUSTAIN trial [see Clinical Studies (14.1)]. Eligible patients were diagnosed with sickle cell disease (any genotype including HbSS, HbSC, HbS beta⁰-thalassemia, HbSbeta⁺ thalassemia, and others). Patients received crizanlizumab 5 mg/kg (N = 66) or 2.5 mg/kg (N = 64) or placebo (N = 62) administered by intravenous infusion on Week 0, Week 2, and every 4 weeks thereafter. The safety evaluation below is limited to the patients who received the recommended dose of 5 mg/kg.

Among the 66 patients that received the recommended dose (5 mg/kg), 83% were exposed for 6 months or longer and 61% were exposed for approximately one year; forty-two (64%) patients were treated with crizanlizumab in combination with hydroxyurea.

Serious adverse reactions were reported in 2 patients (3%) treated with crizanlizumab 5 mg/kg; both reactions were pyrexia.

Two deaths (3%) occurred in the crizanlizumab 5 mg/kg treatment group. None of the deaths were considered to be related to crizanlizumab.

The most common adverse reactions (≥10%) were nausea, arthralgia, back pain, and pyrexia.

Table 1 summarizes the adverse reactions in the SUSTAIN trial.

Table 1. Adverse Reactions (≥10%) in Patients Receiving crizanlizumab With a Difference Between Arms of >3% Compared to Placebo in SUSTAIN:

Clinically relevant adverse reactions (all Grades) that were reported in less than <10% of patients treated with crizanlizumab 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.

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other crizanlizumab products may be misleading.

The immunogenicity of crizanlizumab was evaluated using a validated bridging immunoassay for the detection of binding anti-crizanlizumab-tmca antibodies. In a single arm, open label multiple dose study, 0 of the 45 patients with sickle cell disease treated with crizanlizumab 5 mg/kg tested positive for treatment-induced anti-crizanlizumab-tmca antibodies. In a single-dose study of healthy subjects, 1 of the 61 (1.6%) evaluable subjects tested positive for a treatment-induced anti-crizanlizumab-tmca antibodies.