XENPOZYME

Olipudase alfa is recombinant human acid sphingomyelinase.

It is the first and only enzyme replacement therapy in the world for the treatment of Acid Sphingomyelinase Deficiency (ASMD), also known as Niemann–Pick disease.

ASMD is a rare lysosomal storage disease caused by mutations in the SMPD1 gene, leading to a deficiency in acid sphingomyelinase and the abnormal accumulation of the primary ASM substrate, sphingomyelin.

Olipudase alfa works to hydrolyze sphingomyelin accumulated in body tissues, such as the lungs, liver, spleen, kidneys, and bone marrow.

Olipudase alfa gained its first global approval in Japan on March 28, 2022.

It was later approved by the European Commission on June 28, 2022 6 and by the FDA on August 31, 2022.

Olipudase alfa is indicated as an enzyme replacement therapy for the treatment of non–central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in adult and pediatric patients.

Olipudase alfa is an enzyme replacement therapy that works to ameliorate the signs and symptoms of ASMD by reducing the amount of sphingomyelin that accumulates in organs and causes tissue damage in patients with ASMD.

It works to reduce the extent of non-neurological manifestations of ASMD, such as splenomegaly and hepatomegaly.

Ceramide is elevated in plasma of adult and pediatric patients with ASMD.

Plasma ceramide levels showed a transient increase after each administration (post infusion) of olipudase alfa.

In the dose escalation phase, plasma ceramide levels were substantially increased compared to the baseline level.

Plasma ceramide levels gradually decreased following repeated administration of olipudase alfa and the pre-infusion levels were generally lower than the baseline level during the maintenance phase of treatment. 9.

• In adult patients with ASMD in Trial 1, the mean (standard deviation, SD) pre-infusion plasma ceramide concentration was 3.7 mg/L at baseline and decreased to 2.2 mg/L at Week 52 following treatment with olipudase alfa. 9.

• In pediatric patients with ASMD in Trial 2, the mean (SD) pre-infusion plasma ceramide concentration was 4.7 mg/L at baseline and decreased

to 1.8 mg/L at Week 52 following treatment with olipudase alfa.

Lysosphingomyelin is substantially elevated in plasma of adult and pediatric patients with ASMD.

Plasma lysosphingomyelin levels decreased after repeated administration of olipudase alfa. 9.

• In adult patients with ASMD in Trial 1, the mean (SD) pre-infusion plasma lysosphingomyelin concentration was 379 mcg/L at baseline and decreased to 99 mcg/L at Week 52 following treatment with olipudase alfa. 9.

• In pediatric patients with ASMD in Trial 2, the mean (SD) pre-infusion plasma lysosphingomyelin concentration was 625 mcg/L at baseline and decreased to 80 mcg/L at Week 52 following treatment with olipudase alfa.

In adult patients, the liver sphingomyelin content, as assessed by histopathology, decreased from baseline to Week in the olipudase alfa treatment group compared to an increase in the placebo group.

is an autosomal recessive genetic disorder caused by different mutations in the SMPD1 gene that encodes acid sphingomyelinase.

Historically, ASMD has been called Niemann-Pick disease (NPD), with different classifications based on disease onset and severity.

NPD type

A (NPD-A) refers to the severe early-onset form, infantile neurovisceral ASMD and NPD type B (NPD-B) is referred to as the later-onset, chronic visceral form of ASMD.

Chronic neurovisceral

ASMD (NPD-A/B) is a phenotype with intermediate severity.

ASMD has a broad spectrum of disease severity and neurological and non-neurological manifestations; thus, it is difficult to classify different types of ASMD using the former classification system of ASMD (A, B, A/B).

Acid sphingomyelinase typically breaks down metabolically-related lipids such as sphingomyelin in various cell types, such as the monocytes, macrophages, and hepatocytes.

The deficiency of acid sphingomyelinase thus leads to the accumulation of these lipids in body tissues, causing progressive cell and tissue damage and impairing organ functioning.

Olipudase alfa is recombinant human acid sphingomyelinase that hydrolyzes sphingomyelin (SM), preventing its accumulation in body organs.

As an enzyme replacement therapy, it is an exogenous source of acid sphingomyelinase.

Target Actions Organism U Pyruvate kinase PKLR activator Humans.

In adult patients with

ASMD, the mean (SD) maximum plasma olipudase alfa-rpcp concentration (C max ) and area under the concentration-time curve (AUC) at steady state were 30 mcg/mL and 607 mcg∙h/mL, respectively, at the recommended maintenance dose of 3 mg/kg administered once every 2 weeks. over a dose range of 0.1-3 mg/kg (0.03-1 times the approved recommended maintenance dose).

After administration of 3 mg/kg olipudase alfa once every two weeks in adults with ASMD, the estimated mean (CV%) volume of distribution of olipudase alfa is 13.1 L (18%).

Olipudase alfa is not expected to cross the blood-brain barrier or modulate the CNS manifestations of the disease.

Olipudase alfa is a recombinant human enzyme and is expected to be eliminated via proteolytic degradation into small peptides and amino acids.

There is no information available.

After administration of 3 mg/kg olipudase alfa once every two weeks in adults with ASMD, the mean terminal half-life (t1/2) ranged from 31.9-37.6 hours.

After administration of 3 mg/kg olipudase alfa once every two weeks in adults with ASMD, the mean (CV%) clearance of olipudase alfa is 0.331 L/h (22%).

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Based on findings from animal reproduction studies, XENPOZYME may cause embryo-fetal harm when administered to a pregnant female. olipudase alfa-rpcp dosage initiation or escalation, at any time during pregnancy, is not recommended as it may lead to elevated sphingomyelin metabolite levels that may increase the risk of fetal malformations.

However, the decision to continue or discontinue olipudase alfa-rpcp maintenance dosing in pregnancy should consider the female's need for XENPOZYME, the potential drug-related risks to the fetus, and the potential adverse outcomes from untreated maternal ASMD disease.

In an embryo-fetal toxicity study in pregnant mice, a rare malformation (exencephaly) was observed in offspring at an exposure less than the exposure at the maximum recommended human dose (MRHD) of olipudase alfa-rpcp.

There are no available data on olipudase alfa-rpcp use in pregnant females to evaluate for a drug associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

Advise the pregnant female of the potential risk to the fetus.

Cases of overdosage with

XENPOZYME have been reported in pediatric patients during dose escalation.

Some patients experienced serious adverse reactions including death within 24 hours of initial dose.

The clinical findings included fever, hypotension, gastrointestinal bleeding, marked elevation in liver tests, metabolic acidosis, respiratory failure, and vomiting.

There is no known specific antidote for olipudase alfa-rpcp overdosage.

In the event of overdosage, immediately stop the infusion, and monitor the patient closely in a hospital setting for the development of hypersensitivity reactions and IARs including acute phase reactions.

Studies to evaluate the carcinogenic potential of olipudase alfa-rpcp have not been conducted.

Studies to evaluate the mutagenic potential of olipudase alfa-rpcp have not been conducted.

Intravenous administration of olipudase alfa-rpcp every other day at doses up to 30 mg/kg had no adverse effects in a combined study of fertility in male and female mice.

Exposures at this dose, based on the embryo-fetal development study, were estimated to be approximately 1.5-fold those of the MRHD of olipudase alfa-rpcp.

See Full Prescribing Information for important recommendations prior to XENPOZYME treatment initiation.

Recommended starting dose is 0.1 mg/kg administered as an intravenous infusion.

Recommended starting dose is 0.03 mg/kg administered as an intravenous infusion.

Information for the recommended dose escalation and maintenance dosage, dosage modifications to reduce the risk of adverse reactions, and preparation and administration instructions. 2.1 Important Recommendations Prior to XENPOZYME Treatment Initiation Therapy with XENPOZYME should be directed in consultation with physicians knowledgeable in the management of ASMD.

In order to avoid dosing errors including overdosage, follow all instructions for dosage and administration.

Laboratory Testing Before initiating XENPOZYME

Obtain baseline transaminase (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) levels in all patients within 1 month prior to treatment initiation.

Verify pregnancy status in females of reproductive potential.

Premedication Prior to

XENPOZYME administration, consider premedicating with antihistamines, antipyretics, and/or corticosteroids.

Appropriate medical support measures including cardiopulmonary resuscitation equipment should be readily available during XENPOZYME administration.

The recommended adult and pediatric dosages of XENPOZYME for the dose escalation and maintenance phases are based on body weight as follows for patients with a body mass index (BMI): Less than or equal to 30, the dosage is based on actual body weight (kg) Greater than 30, the dosage is based on adjusted body weight (kg).

Calculate an adjusted body weight (kg) based on height in meters as described below: Adjusted body weight (kg) = (actual height in m) 2 × 30 2.2 Recommended Dosage in Adult Patients Dose Escalation Phase The recommended starting dose of XENPOZYME in adults is 0.1 mg/kg. In order to reduce the risk of infusion-associated reactions or elevated transaminase levels, follow the dose escalation regimen in Table 1.

XENPOZYME via intravenous infusion every 2 weeks.

Table 1: XENPOZYME Dose Escalation Regimen for Adult Patients Use actual body weight for patients with a BMI less than or equal to 30.

For patients with a

BMI greater than 30, calculate adjusted body weight (kg) = (actual height in m) 2 × 30.

Patients (18 years and older) First dose (Day 1/Week 0) 0.1 mg/kg Second dose (Week 2) 0.3 mg/kg Third dose (Week 4) 0.3 mg/kg Fourth dose (Week 6) 0.6 mg/kg Fifth dose (Week 8) 0.6 mg/kg Sixth dose (Week 10) 1 mg/kg Seventh dose (Week 12) 2 mg/kg Eighth dose (Week 14) The dose escalation phase includes the first 3 mg/kg dose. 3 mg/kg (recommended maintenance dose) Maintenance Phase The recommended maintenance dosage of XENPOZYME in adults is 3 mg/kg via intravenous infusion every 2 weeks. 2.3 Recommended Dosage in Pediatric Patients Dose Escalation Phase The recommended starting dose of XENPOZYME in pediatric patients is 0.03 mg/kg. In order to reduce the risk of hypersensitivity and infusion-associated reactions or elevated liver enzyme elevations, follow the dose escalation regimen in Table 2.

Table 2: XENPOZYME Dose Escalation Regimen for Pediatric Patients Use actual body weight for patients with a BMI less than or equal to 30.

Patients (0 to 17 years) First dose (Day 1/Week 0) 0.03 mg/kg Second dose (Week 2) 0.1 mg/kg Third dose (Week 4) 0.3 mg/kg Fourth dose (Week 6) 0.3 mg/kg Fifth dose (Week 8) 0.6 mg/kg Sixth dose (Week 10) 0.6 mg/kg Seventh dose (Week 12) 1 mg/kg Eighth dose (Week 14) 2 mg/kg Ninth dose (Week 16) The dose escalation phase includes the first 3 mg/kg dose. 3 mg/kg (recommended maintenance dose) Maintenance Phase The recommended maintenance dosage of XENPOZYME in pediatric patients is 3 mg/kg via intravenous infusion every 2 weeks. 2.4 Missed Doses A dose is considered missed when it is not administered within 3 days of the scheduled date.

When a dose of

XENPOZYME is missed, refer to Table 3.

Follow the instructions in the "Escalation Phase" or "Maintenance Phase" depending on which phase the patient misses the dose.

Table 3: Dosing Recommendations for XENPOZYME Missed Doses At scheduled infusion after a missed dose, if the dose administered is 0.3 or 0.6 mg/kg, administer that dose twice as per Table and 2.

Escalation Phase Maintenance Phase 1 missed dose First dose after a missed dose: Administer last tolerated dose Second and subsequent doses after missed dose: Resume dose escalation at next infusion according to Table for adult patients or Table for pediatric patients First and subsequent doses after missed dose: Administer maintenance dose 2 consecutive missed doses First dose after missed dose: Administer 1 dose below last tolerated dose Second and subsequent doses after missed dose: Resume dose escalation according to Table for adults or Table for pediatric patients First dose after missed dose: Administer 1 dose below the maintenance dose Second and subsequent doses after missed dose: Resume the maintenance dose 3 or more consecutive missed doses For adult patients who have not completed the dose escalation phase: Reinitiate dose escalation regimen starting at 0.1 mg/kg and follow Table 1.

For pediatric patients who have not completed the dose escalation phase: Reinitiate dose escalation regimen starting at 0.03 mg/kg and follow Table 2.

First and subsequent doses after missed doses: Restart dosing at 0.3 mg/kg and follow Table for adult patients or Table for pediatric patients.

For adult patients who have missed 3 or more consecutive doses in the mainenance phase during which sphingomyelin could have reaccumulated: The treating physician may consider resuming dosing at 0.1 mg/kg and dose escalate according to Table 1.

For pediatric patients who have missed 3 or more consecutive doses in the maintenance phase during which sphingomyelin could have reaccumulated: The treating physician may consider resuming dosing at 0.03 mg/kg and dose escalate according to Table 2. 2.5 Dosage and Administration Modifications and Monitoring In the event of a severe hypersensitivity reaction (e.g., anaphylaxis) or a severe infusion-associated reaction (IAR), immediately discontinue XENPOZYME administration and initiate appropriate medical treatment.

In the event of a mild to moderate hypersensitivity reaction or a mild to moderate IAR, consider temporarily holding or slowing the infusion rate, and/or reducing the XENPOZYME dose.

If dose is reduced, re-escalate following dose escalation described in Tables and 2 for adult and pediatric patients, respectively.

If transaminase levels are elevated above baseline and >2 times the ULN prior to the next scheduled administration, the XENPOZYME dose can be adjusted (prior dose repeated or reduced) or treatment can be temporarily withheld until the liver transaminases return to the patient's baseline value. 2.6 Preparation Instructions Use aseptic technique during preparation.

Reconstitute and dilute XENPOZYME in the following manner: Reconstitution and Dilution Instructions 1.

Determine the number of

XENPOZYME vials to be reconstituted based on the calculated dose. 2.

XENPOZYME vials from refrigeration and set aside for approximately to 30 minutes to allow vials to reach room temperature. 3.

Reconstitute each vial with: 1.1 mL of Sterile Water for Injection, USP into the 4 mg vial 5.1 mL of Sterile Water for Injection, USP into the 20 mg vial by directing the diluent flow to the inside wall of the vial to avoid foaming. 4.

Gently roll and tilt vial(s) to reconstitute XENPOZYME and avoid foaming.

Each reconstituted vial will yield a 4 mg/mL clear, colorless solution. 5.

Visually inspect the reconstituted solution in the vials for particulate matter and discoloration.

The solution should be clear and colorless.

Discard if the solution is discolored or if visible particulate matter is present. 6.

Withdraw the required volume of

XENPOZYME from the vial(s) and dilute the XENPOZYME solution for infusion with 0.9% Sodium Chloride Injection, USP in a syringe or infusion bag depending on the volume of infusion.

For patients who weigh less than 10 kg receiving 0.03 mg/kg and 0.1 mg/kg and patients who weigh between to 20 kg receiving 0.03 mg/kg dose, the volume of infusion will vary to achieve a fixed final concentration of 0.1 mg/mL.

Prepare the required dose diluted to a final concentration of 0.1 mg/mL in a syringe for infusion.

For all other patient weights and doses, the final concentration will vary to achieve a fixed total volume.

• For total volume less than or equal to 20 mL prepare a syringe for infusion: Inject the required volume of the reconstituted XENPOZYME solution (4 mg/mL) from step 3 slowly down the inside wall of the syringe.

Add slowly the quantity sufficient of 0.9% Sodium Chloride Injection, USP to obtain the required total infusion volume (avoid foaming within the syringe).

• For a total volume of greater than or equal to 50 mL prepare an infusion bag: Add slowly the required volume of the reconstituted XENPOZYME solution (4 mg/mL) from step 3 into the appropriate size 0.9% Sodium Chloride Injection, USP infusion bag (avoid foaming within the bag) to achieve a fixed total volume per Table 4. 7.

Gently invert the syringe or the infusion bag to mix.

Do not shake.

Because this is a protein solution, slight flocculation (described as thin translucent fibers) occurs occasionally after dilution. 8.

Vials are for single dose only.

Discard any unused solution.

Storage and Handling of the Reconstituted and Diluted Solutions If the reconstituted XENPOZYME vials are not used immediately, store refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours or at controlled room temperature at 20°C to 25°C (68°F to 77°F) for up to 6 hours.

Discard the unused

XENPOZYME reconstituted solution after 24 hours if stored refrigerated or 6 hours if stored at controlled room temperature.

If the diluted solution is not used immediately, refrigerate the diluted solution at 2°C to 8°C (36°F to 46°F) for up to 24 hours or store at room temperature at 20°C to 25°C (68°F to 77°F) for up to 12 hours (inclusive of infusion time), or discard.

Do not freeze.

Table 4: XENPOZYME Infusion Volumes for Pediatric and Adult Patients Based on Body Weight Use actual or adjusted body weight per patient BMI.

Refer to section 2. .

Patients (0 to 17 years) Adult patients (18 years and older) Body Weight ≥2 kg and <10 kg Body Weight ≥10 kg and <20 kg Body Weight ≥20 kg Body Weight ≥20 kg XENPOZYME Dose Total Infusion Volume 0.03 mg/kg Actual volume will vary Volume will vary to achieve a final concentration of 0.1 mg/mL (0.6 mL to 3 mL) Actual volume will vary (3 mL to 6 mL) 5 mL NA 0.1 mg/kg Actual volume will vary (2 mL to 10 mL) 5 mL 10 mL 20 mL 0.3 mg/kg 5 mL 10 mL 20 mL 100 mL 0.6 mg/kg 10 mL 20 mL 50 mL 100 mL 1 mg/kg 20 mL 50 mL 100 mL 100 mL 2 mg/kg 50 mL.

XENPOZYME (olipudase alfa-rpcp) for injection is supplied as a sterile white to off-white lyophilized powder for reconstitution in a single-dose vial.

XENPOZYME does not contain any preservatives.

XENPOZYME is available supplied as

Carton containing one 20 mg single-dose vial (NDC 58468-0050-1) Carton containing one 4 mg single-dose vial (NDC 58468-0051-1) Storage and Handling Store refrigerated at 2°C to 8°C (36°F to 46°F).

Do not freeze.

For storage of reconstituted and diluted solution.

Store refrigerated at 2°C to 8°C (36°F to 46°F).

Do not freeze.

For storage of reconstituted and diluted solution.

Based on findings from animal reproduction studies, XENPOZYME may cause embryo-fetal harm when administered to a pregnant female.

XENPOZYME dosage initiation or escalation, at any time during pregnancy, is not recommended as it may lead to elevated sphingomyelin metabolite levels that may increase the risk of fetal malformations, .

However, the decision to continue or discontinue XENPOZYME maintenance dosing in pregnancy should consider the female's need for XENPOZYME, the potential drug-related risks to the fetus, and the potential adverse outcomes from untreated maternal ASMD disease.

In an embryo-fetal toxicity study in pregnant mice, a rare malformation (exencephaly) was observed in offspring at an exposure less than the exposure at the maximum recommended human dose (MRHD) of olipudase alfa-rpcp.

There are no available data on

XENPOZYME use in pregnant females to evaluate for a drug associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

Advise the pregnant female of the potential risk to the fetus.

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

All pregnancies have a background risk of birth defect, miscarriage, or other adverse outcomes.

In the

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

In an embryo-fetal development study in pregnant mice, olipudase alfa-rpcp was administered intravenously at doses of 3, 10, or 30 mg/kg daily from gestation day (GD) 6 through GD 15.

Exencephaly was observed in 1 litter at each of the and 30 mg/kg dose groups (2 and 3 fetuses, respectively).

These data are consistent with published literature reports that brief embryonic exposures to sphingomyelin metabolites or a sphingosine-1-phosphate (S1P) receptor modulator produced neural tube defects, including exencephaly, in chicks and mice.

The developmental No Observed Adverse Effect

Level (NOAEL) is 3 mg/kg. The AUC associated with this dose is 0.14-fold the clinical exposure at the MRHD.

The developmental Lowest-Observed-Adverse-Effect

Level (LOAEL), 10 mg/kg, is also associated with an exposure that is less than the clinical exposure at the MRHD.

In an embryo-fetal development study in pregnant rabbits, olipudase alfa-rpcp was administered intravenously at doses of 3, 10, or 30 mg/kg daily from GD 6 through GD 19.

There was no maternal or developmental toxicity.

The developmental

NOAEL was 30 mg/kg; the AUC 0–24 at this dose is approximately 10.5-fold the exposure at the MRHD.

In a study of pre.

• and postnatal development in mice, olipudase alfa-rpcp was administered intravenously every other day from GD 6 through GD 18; then resumed every other day after parturition, from Lactation Day (LD) 1 through LD 19.

Olipudase alfa-rpcp did not induce any effect on maternal reproductive function or on developmental and reproductive parameters of male and female offspring.

Therefore, the maternal and developmental NOAELs are 30 mg/kg. Exposures at this dose, based on the embryo-fetal development study, were estimated to be approximately 1.5-fold the MRHD of olipudase alfa-rpcp.

The safety and effectiveness of

XENPOZYME for the treatment of non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) have been established in pediatric patients down to birth.

Use of

XENPOZYME for this indication is supported by evidence from an adequate, and well-controlled trial (Trial 1) in adults with supportive efficacy, safety, and tolerability data in pediatric patients (Trial and Trial 3) .

Compared to adults, a higher percentage of pediatric patients experienced treatment related serious adverse reactions, anaphylaxis, hypersensitivity reactions, and IARs that occurred within 24 hours of infusion.

Two pediatric patients, an 18 month old receiving XENPOZYME and a 16 month old with ASMD type A that received a version of olipudase alfa manufactured from a different process developed anaphylaxis.

Of the total number of

XENPOZYME-treated adult patients in these trials, 1 (3%) was to 74 years of age, and none were 75 years of age and older.

Clinical trials of

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