Satralizumab

Q: What is the clinical indication for satralizumab?

A: On August 14, 2020, the FDA approved satralizumab (Enspryng) for the treatment of adults with anti-aquaporin-4 (AQP4) antibody-positive neuromyelitis optica spectrum disorder (NMOSD). It is the third medication, preceded by eculizumab (Soliris) and inebilizumab (Uplizna), to receive FDA approval for this indication.

Q: What is the mechanism of action of satralizumab?

A: Satralizumab is a humanized monoclonal antibody that targets the IL-6 receptor. Its therapeutic effect is presumed to involve inhibition of IL-6-mediated signaling, via binding to soluble and membrane-bound IL-6 receptors.

Significant elevations of the cytokine, interleukin-6 (IL-6), have been found in the serum and cerebrospinal fluid (CSF) of patients with NMOSD. Its proposed roles in NMOSD include enhancing proinflammatory T cell differentiation/activation, stimulating AQP4 antibody production, and increasing blood-brain barrier permeability.

Q: What did the clinical trials of satralizumab in neuromyelitis optica show?

A: Two phase III randomized double blind, placebo-controlled trials led to the approval of satralizumab. The first trial studied satralizumab as an adjunct to baseline immunosuppressive therapy (SAkuraSky). The second investigated satralizumab as a monotherapy (SAkuraStar).

In the SAkuraSky trial, patients with NMOSD who were seropositive and seronegative for AQP4-IgG were enrolled. All patients continued their prior immunotherapy including azathioprine, mycophenolate mofetil, or glucocorticoids in addition to the trial drug. When analyzing all patients regardless of AQP4 antibody positivity, relapse occurred in 20% of patients receiving satralizumab plus baseline immunosuppressant vs 43% in those taking placebo plus baseline immunosuppressant (HR 0.38, 95% CI 0.16 to 0.88). In the AQP4 antibody positive subgroup, a relapse occurred in 11% receiving satralizumab vs 43% receiving placebo (HR 0.21, 95% CI 0.06 to 0.75). In the seronegative subgroup, there was no significant difference; relapse occurred in 36% vs 43% (satralizumab vs placebo; HR 0.66, 95% CI 0.20 to 2.24). There was also no significant difference between satralizumab vs placebo in the assessments for pain and fatigue, nor in rates of serious adverse events or infections.

The SAkuraStar trial investigated satralizumab monotherapy. In the combined AQP4 antibody positive and negative group, relapse occurred in 30% of satralizumab treated patients vs 50% with placebo (HR 0.45, 95% Cl 0.23 to 0.89). In the AQP4 antibody positive subgroup, relapse occurred in 22% of satralizumab treated patients and 57% receiving placebo (HR 0.26, 95% Cl 0.11 to 0.63). In the seronegative group 46% vs 33% (satralizumab vs placebo; HR 1.19, 95% Cl 0.30 to 4.78) had a relapse. Although the study was not powered to detect differences in efficacy within the subgroups, these data suggest a reduced risk of relapse for AQP4-IgG seropositive patients, but insufficient evidence to support a risk reduction in seronegative patients. No new safety signals were identified.

Q: How is satralizumab administered in AQP4 antibody positive NMOSD?

A: Satralizumab is supplied in a single-dose prefilled syringe, delivering a 1 mL solution of 120 mg of satralizumab per dose. It is administered via subcutaneous injection only, with recommended sites of injection in the abdomen and thigh.

Dosing regimen consists of:

• Loading dosage of 120 mg per dose, once weekly at week 0, 2 and 4, followed by
• 120mg per dose every 4 weeks

Q: When do dosing adjustments need to be made?

A: After missed doses:

Last Dose Administered	Recommended Dosage for Delayed or Missed Doses
Less than 8 weeks during the maintenance period or missed a loading dose	Administer 120 mg by subcutaneous injection as soon as possible, and do not wait until the next planned dose. Maintenance period After the delayed or missed dose is administered, reset the dose schedule to every 4 weeks. Loading period If the second loading dose is delayed or missed, administer as soon as possible and administer the 3rd and final loading dose 2 weeks later. If the third loading dose is delayed or missed, administer as soon as possible and administer the 1st maintenance dose 4 weeks later.
8 weeks to less than 12 weeks	120 mg by subcutaneous injection at 0* and 2 weeks, followed by 120 mg every 4 weeks.
12 weeks or longer	120 mg by subcutaneous injection at 0*, 2, and 4 weeks followed by 120 mg every 4 weeks.

* “0 weeks” refers to time of the first administration after the missed dose.

During elevations in liver transaminases:

If during routine monitoring, the ALT or AST is greater than 5 times the upper limit of normal (ULN), discontinue satralizumab as follows:

• If additionally associated with any bilirubin elevation, discontinue permanently
• If there is no elevation in bilirubin above the ULN, when the ALT or AST level has returned to the normal range, following a benefit-risk assessment of the patient, and consulting Hepatology, satralizumab can be restarted per the schedule below

Last Dose Administered	Recommended Dosage for Restart of Treatment
Less than 12 weeks	Restart at a dosage of 120 mg by subcutaneous injection every 4 weeks.
12 weeks or longer	Restart at a dose of 120 mg by subcutaneous injection at Weeks 0*, 2, and 4, followed by a dosage of 120 mg every 4 weeks.

* “0 weeks” refers to time of the first administration after the missed dose.

Of note, if any subsequent increase in ALT/AST and/or bilirubin above the ULN occurs after restarting treatment, satralizumab should be discontinued. Further reinitiation is not recommended.

Neutropenia:

If the neutrophil count falls below 1.0 × 109/L, and is confirmed by repeat testing, satralizumab should be interrupted until the neutrophil count is > 1.0 × 109/L

Q: What are the pharmacokinetics of satralizumab?

A: The half-life of satralizumab is approximately 30 days. Steady state is achieved 8 weeks after initiating treatment. There is no data on the effects of renal or hepatic impairment on satralizumab.

Q: What are the pharmacodynamics of satralizumab?

A: The relationship between the pharmacodynamic effects of satralizumab and clinical outcomes in NMOSD is unknown.

Q: What are the major adverse effects of satralizumab?

A: The most common adverse reactions, with an incidence of at least 15%, include: nasopharyngitis, headache, upper respiratory tract infection, gastritis, rash, arthralgia, extremity pain, fatigue, and nausea. Less common, but notable events are per below.

Injection-Related Reactions: occurred in 9% of satralizumab treated vs 8% of placebo treated patients across both trials. Occurred within 24 hours; the most common systemic reaction was diarrhea, and the most common local reactions were pruritus and skin masses.

Elevated liver enzymes: in the monotherapy trial, ALT and AST elevations from baseline occurred in 43% and 25%, respectively, of satralizumab treated patients, vs 13% and 9% of those on placebo. When studied as an adjunctive therapy, these increases were 8% and 8% of satralizumab treated patients compared to 12% and 19% of those on placebo.

Decreased neutrophil count: of patients treated with satralizumab monotherapy, 10% had neutrophil counts below 1 × 109/L, compared to 9% on placebo. Of patients on satralizumab as adjunctive therapy, 15% had neutrophil counts below 1 × 109/L, compared to 4% on placebo. There was one patient in the monotherapy trial with neutrophil counts < 0.5 × 109/L, and one patient in the adjunctive trial that discontinued satralizumab because of neutropenia.

Q: What pretesting and monitoring labs are recommended for satralizumab?

A: Assessments prior to the first dose:

• Liver Function Tests
• Hepatitis Panel (Hep B core antibody, Hep B surface antibody, Hep B surface antigen, Hep C Virus antibody)
• Complete Blood Count
• Tuberculosis (TB) screening

Monitoring during treatment:

• Monitor ALT and AST levels every 4 weeks for the first 3 months, followed by every 3 months for one year, and then as clinically necessary
• Monitor neutrophil count between 4 to 8 weeks after satralizumab initiation, and then at regular, clinically determined intervals.

TB has been observed in other IL-6 receptor antagonists. Consider anti-tuberculosis treatment prior to starting satralizumab in patients with a history of latent or active TB in whom an adequate treatment could not be confirmed, and for patients with a negative test but risk factors for TB infection.

Q: What vaccines are recommended prior to starting satralizumab?

A: Live or live-attenuated vaccines should not be given while on satralizumab therapy, because clinical safety has not been established. Administer all immunizations according to immunization guidelines, at least 4 weeks before starting satralizumab for live or live-attenuated vaccines and, whenever possible, at least 2 weeks with non-live vaccines.

Q: What is the effect on pregnancy and breastfeeding?

A: The safety of satralizumab during pregnancy and lactation has not been studied in NMOSD patients. Thus, it is not routinely used in this population. Tocilizumab, another monoclonal antibody targeting the IL-6 receptor, crosses the placenta and is present in breast milk, though neonatal intestinal absorption may be unlikely. A post-marketing review of 399 women who received tocilizumab for rheumatic disease did not show an increased rate or specific pattern of congenital malformations following in utero tocilizumab exposure. This data did show an increased risk of pre-term birth and spontaneous abortion compared to the general population, but this risk may have been confounded by maternal disease.

Q: How does satralizumab compare to other therapies for antibody positive NMOSD?

A: There are no head-to-head clinical trials comparing different therapies for antibody positive NMOSD.

Prior to the FDA-approved medications for AQP4 antibody positive NMOSD, commonly used treatment options included rituximab, azathioprine, and mycophenolate mofetil. Given the addition of now multiple FDA-approved medications, factors that may influence treatment decision include route of administration, FDA approval status, frequency of administration, healthcare costs, and potential comparative efficacy.

While satralizumab can be given as a first line treatment, given the above factors, clinicians may choose to use satralizumab in patients who have experienced failure or intolerance with other treatments.

Q: How should patients be switched from one therapy to satralizumab?

A: We suggest checking immunoglobulin levels, in addition to the required liver function tests and neutrophil counts, for patients on other therapies prior to initiating satralizumab. Transfusions of IV immunoglobulins can be considered in patients who have hypogammaglobulinemia, prior to initiating treatment.

Approach last updated: March, 11 2021

References

1. FDA drug info: Satralizumab: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761149s000lbl.pdf
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