ENSPRYNG

Satralizumab is a recombinant humanized monoclonal antibody targeted against human interleukin-6 (IL-6) receptors, similar to tocilizumab, which is produced in Chinese hamster ovary cells and based on an IgG2 framework.

Satralizumab is used in the treatment of neuromyelitis optica spectrum disorder (NMOSD), a rare autoimmune inflammatory disorder of the central nervous system (CNS) involving demyelinating lesions in the optic nerve, spinal cord, brainstem, and cerebrum.

Some of the pro-inflammatory mechanisms involved in NMOSD are thought to be mediated, at least in part, by IL-6, including increased production of anti-aquaporin-4 (AQP4) autoantibodies and increased permeability of the blood-brain barrier, which allows for the passage of pro-inflammatory mediators into the CNS. 2, 3 Satralizumab is thought to exert its therapeutic benefits by blocking IL-6 receptors and, subsequently, these inflammatory responses.

Enspryng®, a satralizumab formulation developed by Chugai Pharmaceutical and Roche, 4 is uniquely formulated with "recycling antibody technology" whereby the association of satralizumab to IL-6 receptors occurs in a pH-dependent manner 3.

• this allows satralizumab to bind an IL-6 receptor until it reaches an endosome, after which the drug may dissociate from the receptor and move back into the plasma to act again.

This novel mechanism effectively increases the duration of action of satralizumab, as it allows for single drug molecules to interact with multiple endogenous IL-6 receptors prior to elimination.

Satralizumab was first approved for use in Canada in June for the treatment of AQP4 antibody-positive patients with NMOSD.

It received subsequent approvals in Switzerland and Japan, 3 and was approved for use by the FDA in August 2020, 7 becoming the 3rd treatment to receive FDA approval for NMOSD (after eculizumab in June and inebilizumab in June 2020).

Satralizumab is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive.

In Canada, it is also used in adolescent patients for the same indication.

Enspryng®, a satralizumab formulation developed by Chugai Pharmaceutical and Roche, 4 utilizes a novel "recycling antibody technology" whereby the association of satralizumab to IL-6 receptors occurs in a pH-dependent manner.

IL-6 receptors are taken up into cells and transported into endosomes, a relatively acidic environment in comparison to plasma (pH 5.5-6.0 vs. pH 7.4).

• this decrease in pH allows satralizumab to dissociate from the IL-6 receptor and be recycled back into the plasma, where it can bind to another IL-6 receptor and repeat the process.

Satralizumab has been associated with an increased risk of infection, including serious and potentially fatal infections.

It should not be administered to patients with active infections, including localized infections, until the infection resolves, and is contraindicated for use in patients with active hepatitis B or tuberculosis.

The C max and

AUC at steady-state, achieved after an 8-week loading period, were approximately 31.5 mcg/mL and 737 mcg.mL/day, respectively.

C trough concentrations were approximately 19 mcg/mL.

The bioavailability of satralizumab following subcutaneous injection has been reported to be between 78.5% and 85%. 4, 5.

Satralizumab is subject to biphasic distribution.

• the estimated volume of distribution for the central and peripheral compartments are 3.46 L and 2.07 L, respectively.

While the metabolism of satralizumab has not been studied directly, 4 monoclonal antibodies as a class are principally cleared by catabolism. 4, 1.

Monoclonal antibodies are typically eliminated via uptake into cells and subsequent catabolism via lysosomal degradation.

Due to their large size, they are only eliminated renally under pathologic conditions.

The terminal half-life of satralizumab is approximately 30 days (range 22-37 days).

The total clearance of satralizumab is concentration-dependent and is estimated to be 0.0601-0.0679 L/day. 4, 5 The inter-compartmental clearance was 0.336 L/day.

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There is no data regarding overdose of satralizumab.

No serious adverse effects were noted in healthy adults receiving a single dose of 240 mg Subcutaneous in clinical trials.

Patients experiencing a suspected overdose should be treated with symptomatic and supportive measures as clinically indicated.

is contraindicated in patients with: A known hypersensitivity to satralizumab or any of the inactive ingredients Active Hepatitis B infection Active or untreated latent tuberculosis Known hypersensitivity to satralizumab or any of the inactive ingredients Active Hepatitis B infection Active or untreated latent tuberculosis.

B virus, tuberculosis, and liver transaminase screening is required before the first dose.

Prior to every use, determine if there is an active infection.

The recommended loading dosage of

ENSPRYNG for the first three administrations is 120 mg by subcutaneous injection at Weeks 0, 2, and 4, followed by a maintenance dosage of 120 mg every 4 weeks.

Information for important preparation and administration instructions. 2.1 Assessments Prior to the First Dose of ENSPRYNG Hepatitis B Virus Screening Prior to initiating ENSPRYNG, perform Hepatitis B virus (HBV) screening.

ENSPRYNG is contraindicated in patients with active HBV confirmed by positive results for surface antigen [HBsAg] and anti-HBV tests.

For patients who are negative for HBsAg and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment with ENSPRYNG.

Tuberculosis Screening Prior to initiating

ENSPRYNG, evaluate for active tuberculosis and test for latent infection.

For patients with active tuberculosis or positive tuberculosis screening without a history of appropriate treatment, consult infectious disease experts before initiating treatment with ENSPRYNG.

Liver transaminases and serum bilirubin should be assessed prior to initiation of treatment with ENSPRYNG.

Caution should be exercised when considering initiation of ENSPRYNG treatment in patients whose aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels are greater than 1.5 times the upper limit of normal (ULN).

Because vaccination with live-attenuated or live vaccines is not recommended during treatment with ENSPRYNG, administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of ENSPRYNG for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of ENSPRYNG for non-live vaccines. 2.2 Recommended Dosage For subcutaneous use only.

Prior to every use of

ENSPRYNG, advise patients to consult with their healthcare professional (HCP) if they suspect an active infection, including localized infections.

In case of active infection, delay use of ENSPRYNG until the infection is resolved.

Missed Dose If a dose of

ENSPRYNG is missed for any reason other than increases in liver enzymes, administer as described in Table 1.

Table 1 Recommended Dosage for Delayed or 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 3 rd and final loading dose 2 weeks later.

If the third loading dose is delayed or missed, administer as soon as possible and administer the 1 st maintenance dose 4 weeks later. 8 weeks to less than 12 weeks 120 mg by subcutaneous injection at 0 "0 weeks" refers to time of the first administration after the missed dose. 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. 2.3 Important Administration Instructions ENSPRYNG is intended for patient self-administration by subcutaneous injection under the guidance of a health care professional (HCP).

After proper training in subcutaneous injection technique, a patient may self-inject ENSPRYNG or the patient's caregiver may administer ENSPRYNG, if the HCP determines that it is appropriate.

ENSPRYNG " Instructions for Use " (IFU) for more detailed instructions on the preparation and administration of ENSPRYNG.

Patients or caregivers should seek immediate medical attention if the patient develops symptoms of a serious allergic reaction and should not administer further doses until evaluated by a HCP.

Prior to use, remove the prefilled syringe from the refrigerator and allow to sit at room temperature outside of the carton for 30 minutes.

Do not warm

ENSPRYNG in any other way.

Inspect visually for particulate matter and discoloration prior to administration.

ENSPRYNG solution should be clear and colorless to slightly yellow.

Do not use

ENSPRYNG if the solution is cloudy, discolored, or contains particles, or if any part of the prefilled syringe appears to be damaged.

Instruct patients to inject the full amount in the syringe (1 mL), which provides 120 mg of ENSPRYNG, according to the directions provided in the IFU.

ENSPRYNG by subcutaneous injection in the abdomen or thigh.

Rotate injection sites with each administration.

Do not give injection into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact. 2.4 Safety Monitoring During Treatment Liver Transaminases Monitor ALT and AST levels every 4 weeks for the first 3 months of treatment with ENSPRYNG, followed by every 3 months for one year, and thereafter as clinically necessary.

If an ALT or

AST elevation of greater than 5 times the ULN occurs, discontinue ENSPRYNG as follows: If associated with any bilirubin elevation, discontinue ENSPRYNG, and reinitiation is not recommended.

If not associated with any bilirubin elevation above the ULN, when the ALT or AST level has returned to the normal range and following a benefit-risk assessment of the patient, treatment with ENSPRYNG can be restarted per the schedule in Table 2.

Table 2 Recommended Dosage for Restart of Treatment After Liver Transaminase Elevation 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 "0 weeks" refers to time of the first administration after the missed dose. , 2, and 4, followed by a dosage of 120 mg every 4 weeks.

If treatment is restarted, the liver parameters must be closely monitored, and if any subsequent increase in ALT/AST and/or bilirubin above the ULN is observed, ENSPRYNG should be discontinued, and another reinitiation is not recommended.

Monitor neutrophils to 8 weeks after initiation of therapy and thereafter at regular clinically determined intervals.

If the neutrophil count is below 1.0 × 10 9 /L and confirmed by repeat testing, ENSPRYNG should be interrupted until the neutrophil count is > 1.0 × 10 9 /L.

ENSPRYNG (satralizumab-mwge) injection is available as a sterile, preservative-free, clear, colorless to slightly yellow solution in single-dose prefilled syringe (PFS) with needle safety device.

PFS is not made with natural rubber latex.

ENSPRYNG carton contains one single-dose 120 mg/mL prefilled syringe (NDC 50242-007-01). 16.2 Storage and Handling Refrigerate at 2°C to 8°C (36°F to 46°F) in original carton to protect from light.

Do not freeze.

Do not shake.

Prior to administration, ENSPRYNG, if unopened, can be removed from and returned to the refrigerator, if necessary.

The total combined time out of refrigeration should not exceed 8 days at a temperature that does not exceed 30°C (86°F).

Refrigerate at 2°C to 8°C (36°F to 46°F) in original carton to protect from light.

Do not freeze.

Do not shake.

Prior to administration, ENSPRYNG, if unopened, can be removed from and returned to the refrigerator, if necessary.

The total combined time out of refrigeration should not exceed 8 days at a temperature that does not exceed 30°C (86°F).

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ENSPRYNG during pregnancy.

Healthcare providers are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-833-277-9338.

There are no adequate data on the developmental risk associated with the use of ENSPRYNG in pregnant women.

In an animal reproduction study, no adverse effects on maternal animals or fetal development were observed in pregnant monkeys and their offspring, with administration of satralizumab-mwge at doses up to 50 mg/kg/week.

In the

U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2 – 4% and 15 – 20%, respectively.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

Fetal/neonatal adverse reactions Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester.

Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to ENSPRYNG in utero.

Weekly subcutaneous administration of satralizumab-mwge (0, 2, or 50 mg/kg) to monkeys throughout pregnancy resulted in no adverse effects on postnatal development of the offspring; however, immune function was impaired in offspring at both doses.

Plasma exposures (C ave ) in dams at the low and high doses were approximately and 100 times, respectively, that in humans at the recommended monthly maintenance dose of 120 mg.

Safety and effectiveness in pediatric patients have not been established.

Clinical studies of

ENSPRYNG did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients.

However, population pharmacokinetic analyses in patients with NMOSD did not show that age affected the pharmacokinetics of satralizumab-mwge.

In general, caution should be used when dosing the elderly, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant diseases or other drug therapy.