XENPOZYME- olipudase alfa-rpcp_injection, powder, lyophilized, for solution

ASMD is a lysosomal storage disease that results from reduced activity of the enzyme acid sphingomyelinase (ASM), caused by pathogenic variants in the sphingomyelin phosphodiesterase 1 gene. ASM degrades sphingomyelin to ceramide and phosphocholine. The deficiency of ASM causes an intra-lysosomal accumulation of sphingomyelin (as well as cholesterol and other cell membrane lipids) in various tissues. XENPOZYME provides an exogenous source of ASM. XENPOZYME is not expected to cross the blood-brain barrier or modulate the CNS manifestations of ASMD. Plasma Ceramide Levels 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 XENPOZYME. 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 XENPOZYME and the pre-infusion levels were generally lower than the baseline level during the maintenance phase of treatment. In adult patients with ASMD in Trial 1 [see Clinical Studies (14. 2) In pediatric patients with ASMD in Trial 2 [see Clinical Studies (14. 3) Plasma Lysosphingomyelin Levels Lysosphingomyelin is substantially elevated in plasma of adult and pediatric patients with ASMD. Plasma lysosphingomyelin levels decreased after repeated administration of XENPOZYME. 3) Liver Sphingomyelin Content In adult patients, the liver sphingomyelin content, as assessed by histopathology, decreased from baseline to Week 52 in the XENPOZYME treatment group compared to an increase in the placebo group. In adult patients with ASMD, the mean (SD) maximum plasma olipudase alfa-rpcp concentration (C max max Distribution The mean (SD) volume of distribution of olipudase alfa-rpcp was 13 (2) L in adult patients with ASMD. Elimination The mean (SD) clearance of olipudase alfa-rpcp was 0. 07) L/h and the mean half-life (t 1/2 Metabolism The metabolic pathway of olipudase alfa-rpcp has not been characterized. Olipudase alfa-rpcp is expected to be metabolized into small peptides and amino acids via catabolic pathways. Specific Populations Pediatric Patients In pediatric patients (1. 5 years of age) with ASMD, the mean (SD) C max The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of olipudase alfa-rpcp or of other olipudase alfa products. Following 0. 7 years of XENPOZYME treatment in Trial 1 [see Clinical Studies (14. 2) Following 2. 2 years of XENPOZYME treatment in Trial 2 and 3 [see Clinical Studies (14. 3) Infusion-associated reactions (including hypersensitivity reactions) occurred in a higher percentage in XENPOZYME-treated patients who developed ADA compared to those who did not develop ADA [see Warnings and Precautions (5. 1) Adverse Reactions (6. 1) There was no identified clinically significant effect of ADA on pharmacokinetics of XENPOZYME.

XENPOZYME is indicated for treatment of nonen dashcentral nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in adult and pediatric patients. XENPOZYME is a hydrolytic lysosomal sphingomyelin-specific enzyme indicated for treatment of nonen dashcentral nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in adult and pediatric patients.

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 [see Warnings and Precautions (5. 3) Use aseptic technique during preparation. Reconstitute and dilute XENPOZYME in the following manner: Reconstitution and Dilution Instructions 1. [see Dosage and Administration (2. 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 4. Table 4 For patients who weigh less than 10 kg receiving 0. 03 mg/kg and 0. 1 mg/kg and patients who weigh between 10 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 (see Table 4 syringe For all other patient weights and doses, the final concentration will vary to achieve a fixed total volume (see Table 4 - syringe 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). - infusion bag 7. 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. 3) Pediatric Patients (0 to 17 years) Adult patients (18 years and older) Body Weight Body Weight Body Weight Body Weight 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 Actual volume will vary 5 mL NA 0. 1 mg/kg Actual volume will vary 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 75 mL 200 mL 100 mL 3 mg/kg 50 mL 100 mL 250 mL 100 mL Prior to administration, inspect the syringe or infusion bag for foaming. If foaming is present, let foam dissipate before administering XENPOZYME. Use a low-protein binding, 0. 2 micron, in-line filter during administration. The following materials can be used: polyolefin or polyvinylchloride (PVC) with DEHP for infusion bags, polypropylene for syringes, polyurethane or PVC DEHP-free for infusion sets and polyethersulfone or polytetrafluoroethylene for in-line filters. Infuse XENPOZYME using the infusion rates described in Table 5 and Table 6. In absence of infusion-associated reactions, increase infusion rate per the steps of infusion as indicated (+/- 5 minutes). Each step of infusion will last for 20 minutes with the exception of the final step which should last until completion of the infusion volume. At the end of the infusion, flush the infusion line with 0. 9% Sodium Chloride Injection, USP using the same infusion rate as the one used for the last part of the infusion. Do not infuse XENPOZYME in the same intravenous line with other products. Table 5: XENPOZYME Infusion Rates for Adult Patients Dose Infusion Rate step 1 step 2 step 3 step 4 NA: Not applicable. Start infusion at step 1 and in absence of infusion-associated reaction increase infusion rate sequentially per the steps of infusion. 1 mg/kg 20 mL/hour 60 mL/hour NA NA 0. 3 to 3 mg/kg 3. 33 mL/hour 10 mL/hour 20 mL/hour 33. 33 mL/hour Table 6: XENPOZYME Infusion Rates for Pediatric Patients Dose Infusion rate step 1 step 2 step 3 step 4 NA: Not applicable. Start infusion at step 1 and in absence of infusion-associated reactions increase infusion rate sequentially per the steps of infusion. 1 mg/kg/hour for the full length of the infusion NA NA NA 0. 1 mg/kg/hour 0. 3 mg/kg/hour NA NA 0. 3 mg/kg/hour 0. 6 mg/kg/hour NA 0. 6 mg/kg/hour 1 mg/kg/hour 1 mg/kg 2 mg/kg 3 mg/kg Home Infusion Home administration under the supervision of a healthcare provider may be considered for patients on maintenance dose [see Dosage and Administration (2. 3) The dose and infusion rate used in the home setting should remain the same as were used in the supervised clinical setting and should not be changed without supervision of a physician. In case of missed dose(s) or delayed infusion, contact a physician as subsequent infusions may occur in a supervised clinical setting.">See Full Prescribing Information for important recommendations prior to XENPOZYME treatment initiation. 1 Adults: Recommended starting dose is 0. 1 mg/kg administered as an intravenous infusion. 2 Pediatrics: Recommended starting dose is 0. 03 mg/kg administered as an intravenous infusion. 3 See Full Prescribing Information for the recommended dose escalation and maintenance dosage, dosage modifications to reduce the risk of adverse reactions, and preparation and administration instructions. 7 Therapy with XENPOZYME should be directed in consultation with physicians knowledgeable in the management of ASMD. In order to avoid dosing errors including overdosage [see Overdosage (10) 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 [see Warnings and Precautions (5. 3) Verify pregnancy status in females of reproductive potential [see Use in Specific Populations (8. 3) Premedication Prior to XENPOZYME administration, consider premedicating with antihistamines, antipyretics, and/or corticosteroids [see Warnings and Precautions (5. 2) Medical Support Appropriate medical support measures including cardiopulmonary resuscitation equipment should be readily available during XENPOZYME administration [see Warnings and Precautions (5. 1) Weight-Based Dosing Information The recommended adult and pediatric dosages of XENPOZYME for the dose escalation and maintenance phases [see Dosage and Administration (2. 3) 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: 2 Dose Escalation Phase The recommended starting dose of XENPOZYME in adults is 0. In order to reduce the risk of infusion-associated reactions or elevated transaminase levels, follow the dose escalation regimen in Table 1 [see Warnings and Precautions (5. 3) Administer 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 [see Dosage and Administration (2. 1) Adult 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. Dose Escalation Phase The recommended starting dose of XENPOZYME in pediatric patients is 0. 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 [see Warnings and Precautions (5. Table 2: XENPOZYME Dose Escalation Regimen for Pediatric Patients Use actual body weight for patients with a BMI less than or equal to 30. 1) Pediatric 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 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. 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. 6 mg/kg, administer that dose twice as per Table 1 and 2. Consecutive Missed Doses In: 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 1 for adult patients or Table 2 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 1 for adults or Table 2 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 1 for adult patients or Table 2 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. In the event of a severe severe [see Warnings and Precautions (5. 2) In the event of a mild to moderate mild to moderate [see Warnings and Precautions (5. 2) 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 [see Warnings and Precautions (5. 3) Use aseptic technique during preparation. Reconstitute and dilute XENPOZYME in the following manner: Reconstitution and Dilution Instructions 1. [see Dosage and Administration (2. 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 4. Table 4 For patients who weigh less than 10 kg receiving 0. 03 mg/kg and 0. 1 mg/kg and patients who weigh between 10 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 (see Table 4 syringe For all other patient weights and doses, the final concentration will vary to achieve a fixed total volume (see Table 4 - syringe 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). - infusion bag 7. 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. 3) Pediatric Patients (0 to 17 years) Adult patients (18 years and older) Body Weight Body Weight Body Weight Body Weight 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 Actual volume will vary 5 mL NA 0. 1 mg/kg Actual volume will vary 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 75 mL 200 mL 100 mL 3 mg/kg 50 mL 100 mL 250 mL 100 mL Prior to administration, inspect the syringe or infusion bag for foaming. If foaming is present, let foam dissipate before administering XENPOZYME. Use a low-protein binding, 0. 2 micron, in-line filter during administration. The following materials can be used: polyolefin or polyvinylchloride (PVC) with DEHP for infusion bags, polypropylene for syringes, polyurethane or PVC DEHP-free for infusion sets and polyethersulfone or polytetrafluoroethylene for in-line filters. Infuse XENPOZYME using the infusion rates described in Table 5 and Table 6. In absence of infusion-associated reactions, increase infusion rate per the steps of infusion as indicated (+/- 5 minutes). Each step of infusion will last for 20 minutes with the exception of the final step which should last until completion of the infusion volume. At the end of the infusion, flush the infusion line with 0. 9% Sodium Chloride Injection, USP using the same infusion rate as the one used for the last part of the infusion. Do not infuse XENPOZYME in the same intravenous line with other products. Table 5: XENPOZYME Infusion Rates for Adult Patients Dose Infusion Rate step 1 step 2 step 3 step 4 NA: Not applicable. Start infusion at step 1 and in absence of infusion-associated reaction increase infusion rate sequentially per the steps of infusion. 1 mg/kg 20 mL/hour 60 mL/hour NA NA 0. 3 to 3 mg/kg 3. 33 mL/hour 10 mL/hour 20 mL/hour 33. 33 mL/hour Table 6: XENPOZYME Infusion Rates for Pediatric Patients Dose Infusion rate step 1 step 2 step 3 step 4 NA: Not applicable. Start infusion at step 1 and in absence of infusion-associated reactions increase infusion rate sequentially per the steps of infusion. 1 mg/kg/hour for the full length of the infusion NA NA NA 0. 1 mg/kg/hour 0. 3 mg/kg/hour NA NA 0. 3 mg/kg/hour 0. 6 mg/kg/hour NA 0. 6 mg/kg/hour 1 mg/kg/hour 1 mg/kg 2 mg/kg 3 mg/kg Home Infusion Home administration under the supervision of a healthcare provider may be considered for patients on maintenance dose [see Dosage and Administration (2. 3) The dose and infusion rate used in the home setting should remain the same as were used in the supervised clinical setting and should not be changed without supervision of a physician. In case of missed dose(s) or delayed infusion, contact a physician as subsequent infusions may occur in a supervised clinical setting.

The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions (5. 1) Infusion-Associated Reactions (IARs) [see Warnings and Precautions (5. 2) Elevated Transaminase Levels [see Warnings and Precautions (5. 3) Most common adverse reactions in adult patients (incidence >=10%) are headache, cough, diarrhea, hypotension, and ocular hyperemia. 1 Most common adverse reactions in pediatric patients (incidence >=20%) are pyrexia, cough, diarrhea, rhinitis, abdominal pain, vomiting, headache, urticaria, nausea, rash, arthralgia, pruritus, fatigue, and pharyngitis. 1 To report SUSPECTED ADVERSE REACTIONS, contact Genzyme Corporation at 1-800-745-4447 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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. The pooled safety analysis from 3 clinical trials included a total of 38 XENPOZYME-treated patients (30 adult and 8 pediatric patients) with age range from 1. 5 to 59 years old receiving intravenous doses up to 3 mg/kg every 2 weeks [see Clinical Studies (14) Serious adverse reactions of anaphylactic reaction were reported in 2 (25%) XENPOZYME-treated pediatric patients. Most frequently reported adverse drug reactions in adults (incidence >=10%) were headache, cough, diarrhea, hypotension, and ocular hyperemia. Most frequently reported adverse drug reactions in pediatric patients (incidence >=20%) were pyrexia, cough, diarrhea, rhinitis, abdominal pain, vomiting, headache, urticaria, nausea, rash, arthralgia, pruritus, fatigue, and pharyngitis. Adult patients with ASMD type B and type A/B (Trial 1) In Trial 1, 13 adult patients received XENPOZYME once every 2 weeks for 52 weeks (primary analysis period (PAP)) at dosages escalating from 0. 1 mg/kg to a target dose of 3 mg/kg [see Clinical Studies (14. 2) Adverse reactions that occurred in at least 7% of XENPOZYME-treated adult patients during the PAP are described in Table 7. Table 7: Adverse Reactions Occurring at >7% in Adult Patients with ASMD During the 52-Week Primary Analysis Period in Trial 1 Adverse Reaction XENPOZYME Placebo Headache 7 (54%) 8 (44%) Cough 4 (31%) 2 (11%) Diarrhea 2 (15%) 2 (11%) Hypotension 2 (15%) 2 (11%) Ocular hyperemia 2 (15%) 1 (6%) Erythema 1 (8%) 1 (6%) Asthenia 1 (8%) 1 (6%) Pharyngitis 1 (8%) 1 (6%) Dyspnea 1 (8%) 0 Urticaria 1 (8%) 0 Papule 1 (8%) 0 Myalgia 1 (8%) 0 Throat irritation 1 (8%) 0 C-reactive protein abnormal 1 (8%) 0 Pediatric Patients with ASMD type B and type A/B (Trial 2 and Trial 3) In Trial 2, 8 pediatric patients less than or equal to 17 years of age received XENPOZYME intravenously once every 2 weeks for 64 weeks [see Clinical Studies (14. 3) Adverse reactions that occurred in at least 13% of pediatric patients are described in Table 8. Table 8: Adverse Reactions Occurring at >=13% in XENPOZYME-Treated Pediatric Patients with ASMD in Trial 2 Duration of treatment in Trial 2 was 64 weeks. All patients continued into Trial 3. Adverse Reactions XENPOZYME Abdominal pain includes abdominal pain and abdominal pain upper Fatigue includes fatigue and asthenia Rash includes rash and erythema Pyrexia 8 (100%) Cough 6 (75%) Diarrhea 6 (75%) Rhinitis 6 (75%) Abdominal pain 5 (63%) Vomiting 4 (50%) Headache 4 (50%) Urticaria 4 (50%) Nausea 3 (38%) Rash 3 (38%) Arthralgia 3 (38%) Pruritus 2 (25%) Fatigue 2 (25%) Pharyngitis 2 (25%) C-reactive protein increased 1 (13%) Hypotension 1 (13%) Anaphylactic reaction 1 (13%) Hypersensitivity 1 (13%) Infusion site swelling 1 (13%) Tachycardia 1 (13%) Pharyngeal swelling 1 (13%) Treatment related serious adverse reactions, hypersensitivity reactions including anaphylaxis, and IARs occurred within 24 hours of infusion and were observed in a higher percentage of pediatric patients than in adult patients. Laboratory Adverse Reaction Elevated transaminase levels ranging from 3 times to 14 times the upper limit of normal (ULN) were reported in 4 (13%) adults and 1 (13%) pediatric patient during the XENPOZYME dose escalation phase in clinical trials. Immunogenicity: Antidrug Antibody-Associated Adverse Reactions In Trial 1, infusion-associated reactions (including hypersensitivity reactions) occurred in a higher percentage in XENPOZYME-treated patients who developed IgG ADA compared to those who did not develop IgG ADA (73% versus 44%) [see Clinical Pharmacology (12. 6) Clinical Studies (14. 2) In Trial 2, one XENPOZYME-treated pediatric patient (18-months old) experienced an anaphylactic reaction during the sixth infusion and developed IgE ADA and the highest IgG ADA titers (ADA peak titer 1,600) of the patients in this trial. After treatment discontinuation, XENPOZYME was resumed four months later using a diluted drug solution and a desensitization procedure. One pediatric patient (16-months old) with ASMD type A, treated with a version of olipudase alfa manufactured from a different process, experienced anaphylactic reactions (both during the fifth and sixth infusions) and developed IgG ADA (highest titer 1,600) and IgE ADA [see Warnings and Precautions (5.

Risk Summary 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 (see Data [see Clinical Pharmacology (12. 2) 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 (see Data 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. 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. Data Animal Data 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 10 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 0en dash24 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. Risk Summary There are no data on the presence of olipudase alfa-rpcp in human milk, the effects on the breastfed infant, or the effects on milk production. Olipudase alfa-rpcp is present in animal milk. (see Data Data Olipudase alfa-rpcp was administered as a single intravenous dose (3 mg/kg) to lactating CD1 mice on post-partum day 7. Milk was not evaluated until post-partum day 9, at which time concentrations of olipudase alfa-rpcp detected were approximately 1. 3% the estimated maximal maternal plasma concentration. XENPOZYME may cause embryo-fetal harm when administered during the first trimester of pregnancy [see Use in Specific Populations (8. 1) Pregnancy Testing Verify the pregnancy status in females of reproductive potential prior to initiating XENPOZYME. Contraception Females Advise females of reproductive potential to use effective contraception during treatment and for 14 days after the last dose if XENPOZYME is discontinued. 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 2 and Trial 3) [see Adverse Reactions (6. 1) Clinical Studies (14. 4) 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 [see Adverse Reactions (6. 1) [see Warnings and Precautions (5. 1) Of the total number of XENPOZYME-treated adult patients in these trials, 1 (3%) was 65 to 74 years of age, and none were 75 years of age and older [see Clinical Studies (14) 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.

OVERDOSAGE
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 [see Warnings and Precautions (5.2) There is no known specific antidote for XENPOZYME 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. For the management of adverse reactions, see Warnings and Precautions (5.1 5.2 5.3) Adverse Reactions (6.1)
NONCLINICAL TOXICOLOGY
Carcinogenesis Studies to evaluate the carcinogenic potential of olipudase alfa-rpcp have not been conducted. Mutagenesis Studies to evaluate the mutagenic potential of olipudase alfa-rpcp have not been conducted. Impairment of Fertility 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. In acid sphingomyelinase knockout (ASMKO) mice (a disease model of ASMD), mortality was observed after a single dose >=10 mg/kg administered as an IV bolus injection. Observations (lethargy, coolness to touch, and unwillingness to move), combined with the adrenal hemorrhage, suggested that hypotensive shock may be the cause of death. These findings were accompanied by necrosis and apoptosis in the liver and adrenal gland, elevations of ceramide, sphingosine and sphingosine 1-phosphate in the serum, catabolites of accumulated sphingomyelin as well as elevations in the serum concentrations of inflammatory mediators, such as cytokines and acute phase proteins. In ASMKO mice, a dose-dependent reduction in heart rate accompanied by a decrease in motor activity and followed by a slow decline in blood pressure was noted after a single IV administration at 3, 10, and 20 mg/kg. After 2 doses of olipudase alfa-rpcp at 3 and 10 mg/kg to ASMKO mice, a slight decline in heart rate was noted following the second administration. Repeated dose studies in adult ASMKO mice show that administration of olipudase alfa-rpcp via a dose escalation regimen, (3 mg/kg administered IV every other day, followed by a single IV dose of 20 mg/kg 3 days later) did not result in toxicity. The lack of adverse findings in BALB/c, C57BL/6 mice, rats, dogs, and monkeys at comparable olipudase alfa-rpcp doses suggested that the dose-related toxicity observed in ASMKO mice may be due to the rate and amount of substrate degradation.
CLINICAL STUDIES
The efficacy of XENPOZYME for the treatment of nonen dashcentral nervous system manifestations of acid sphingomyelinase deficiency (ASMD) has been evaluated in 3 clinical trials involving a total of 61 patients with ASMD: Trial 1 in adult patients (NCT02004691), Trial 2 in pediatric patients (NCT02292654), and Trial 3 a long-term trial in pediatric patients (NCT02004704). Trial 1 was a multicenter, randomized, double-blinded, placebo-controlled, repeat-dose phase II/III trial in adult patients with ASMD (clinical diagnosis consistent with ASMD type B and A/B). In this trial, patients received either XENPOZYME or placebo. Treatment was administered in both groups as an intravenous infusion once every 2 weeks. XENPOZYME was dosed as follows: 0. 1 mg/kg (Day 1, Week 0), 0. 3 mg/kg (Weeks 2 and 4), 0. 6 mg/kg (Weeks 6 and 8), 1 mg/kg (Week 10), 2 mg/kg (Week 12), and then a maintenance dose of 3 mg/kg (Week 14 onwards). The trial was divided into 2 consecutive periods: a randomized placebo-controlled, double-blinded primary analysis period (PAP) which lasted to Week 52, followed by an extension treatment period (ETP) for up to 4 years. Patients randomized to the placebo arm in the PAP crossed over to receive XENPOZYME treatment in the ETP to reach the targeted dose of 3 mg/kg, while patients in the original XENPOZYME arm continued treatment. Patients enrolled in the trial had a diffusion capacity of the lungs for carbon monoxide (DLco) <=70% of the predicted normal value and a spleen volume >=6 multiples of normal (MN) measured by magnetic resonance imaging (MRI). The trial population included 87% White, 7% Asian, and 7% other; for ethnicity, 32% identified as Hispanic/Latino, 65% as non-Hispanic/Latino, and 3% were not reported. Five males and 13 females with a median age of 34 years (range: 18 to 66) were included in the placebo arm and 8 males and 5 females with a median age of 34 years (range: 20 to 59) were included in the XENPOZYME arm. The XENPOZYME and placebo groups included 1 patient (8%) and 2 patients (11%) with mild renal impairment (60 mL/minute <= creatinine clearance <90 mL/minute), respectively. There were no patients with moderate or severe renal impairment. Key efficacy endpoints included assessment of % predicted DLco, spleen volume, liver volume, and platelet count. At Week 52 during the PAP, an increase of 21% in the mean percent change in % predicted DLco was observed in the XENPOZYME-treated patients compared to the placebo-treated patients (Table 9). A reduction in spleen volume of 39% was observed in the XENPOZYME-treated patients compared to the placebo-treated patients. The changes in % predicted DLco and spleen volume were noted at Week 26 of treatment, the first post-dose endpoint assessment (Figures 1 and 2). A decrease in mean liver volume and an increase in mean platelet count were noted in the XENPOZYME-treated patients compared to the placebo-treated patients at Week 52 (Table 9). Table 9: Observed Value and Percentage Change from Baseline to Week 52 in Key Endpoints in Adult Patients with ASMD Type B, A/B on XENPOZYME or Placebo (Trial 1) Placebo XENPOZYME Difference Nominal p value: DLco n 18 13 Mean % predicted DLco at baseline (SD) 48. 7) NA n 17 12 Mean % predicted DLco at Week 52 (SD) 49. 6) NA n 17 12 LS Mean Percent change in % predicted DLco at Week 52 (SE) 3. 0) p value = 0. 0003; Spleen volume n 18 13 Mean Spleen Volume (MN) at baseline (SD) 11. 7) NA n 17 13 Mean Spleen Volume (MN) at Week 52 (SD) 11. 9) NA n 17 13 LS Mean Percent change in Spleen Volume (in MN) at Week 52 (SE) 0. 0) p value <0. 0001; Liver volume n 18 13 Mean Liver Volume (MN) at baseline (SD) 1. 3) NA n 17 12 Mean Liver Volume (MN) at Week 52 (SD) 1. 2) NA n 17 12 LS Mean Percent change in Liver Volume from baseline to Week 52 (SE) -1. 2) Platelet count n 18 13 Mean Platelet Count (10 9 115. 6) NA n 16 13 Mean Platelet Count (10 9 120. 0) NA n 16 13 LS Mean Percent change in Platelet Count from baseline to Week 52 (SE) 2. 7) p value= 0. 0280 Seventeen of 18 patients previously receiving placebo and 13 of 13 patients previously treated with XENPOZYME for 52 weeks (in the PAP) started or continued treatment with XENPOZYME, respectively, for up to 4 years. At Week 104, patients initially randomized to placebo had received XENPOZYME for 52 weeks and demonstrated the following LS mean (SE) percent changes in clinical parameters from baseline (before first administration of XENPOZYME): increase in % predicted DLco was 26. 2) (Figure 1); reduction in spleen volume (MN) was 36. 5) (Figure 2); reduction in liver volume (MN) was 29. 6); and increase in platelet count was 19. Patients in the previous XENPOZYME group demonstrated improvement from baseline to Week 104 in the following parameters: LS mean (SE) percent increase in % predicted DLco was 34. 9) (Figure 1); LS mean (SE) percent reduction in spleen volume (MN) was 48. 9) (Figure 2); LS mean (SE) percent reduction in liver volume (MN) was 31. 9); LS mean (SE) percent increase in platelet count was 24. Figure 1: Plot of the LS Means (95% CI) of the Percentage Change in DLco (% predicted) from Baseline to Week 104 in Adult Patients with ASMD (Trial 1) The vertical bars represent the 95% CIs for the LS means. The LS means and 95% CIs are based on a mixed model for repeated measures approach, using data up to Week 104. Patients in placebo/XENPOZYME group received placebo by Week 52 and switched to XENPOZYME thereafter. Figure 2: Plot of the LS Means (95% CI) of the Percentage Change in Spleen Volume (MN) from Baseline to Week 104 in Patients with ASMD (Trial 1) The vertical bars represent the 95% CIs for the LS means. Figure 1 Figure 2 Trial 2 was a multi-center, open-label, repeated-dose trial of XENPOZYME administered intravenously once every 2 weeks (via infusion) for 64 weeks in pediatric patients aged <18 years with a clinical diagnosis consistent with ASMD type B and A/B. Exploratory efficacy endpoints related to organomegaly, pulmonary and liver functions, and linear growth were evaluated at Week 52. 03 mg/kg (Day 1, Week 0), 0. 1 mg/kg (Weeks 2), 0. 3 mg/kg (Weeks 4 and 6), 0. 6 mg/kg (Week 8 and 10), 1 mg/kg (Week 12), 2 mg/kg (Week 14), and then a maintenance dose of 3 mg/kg (Week 16 onwards). In Trial 2, 8 patients (7 patients from 2 to <12 years old, and 1 patient <2 years old) received an initial dose of 0. 03 mg/kg XENPOZYME and all but one completed the dose escalation up to the maintenance dose of 3 mg/kg within 22 weeks. All patients were White and of non-Hispanic/Latino ethnicity. Patients enrolled in the trial had a spleen volume >=5 MN measured by MRI. Age of patients treated with XENPOZYME ranged from 1 to 10 years old, with both sexes equally represented. Treatment with XENPOZYME resulted in improvements in mean percent change in % predicted DLco, spleen and liver volumes, platelet counts, and linear growth progression (as measured by height Z-scores) at Week 52 as compared to baseline (Table 10). Table 10: Efficacy Results in XENPOZYME-Treated Pediatric Patients with ASMD (Trial 2) Baseline Values Week 52 Values (n=3) (n=3) Mean % predicted DLco (SD) 48. 7) LS Mean Percent change in % predicted DLco* (SE) 45. 7) 95% CI -12. 3 (n=8) (n=8) Mean Spleen Volume (MN) (SD) 18. 4) LS Mean Percent change in Spleen Volume (in MN) (SE) -46. 6) 95% CI -55. 9 (n=8) (n=8) Mean Liver Volume (MN) (SD) 2. 3) LS Mean Percent change in Liver Volume (in MN) (SE) -38. 9) 95% CI -44. 0 (n=8) (n=7) Mean Platelet Count (10 9 136. 2) LS Mean Percent change in Platelet Count (SE) 37. 7) 95% CI 8. 7 (n=8) (n=7) Mean height Z-scores (SD) -1. 0) LS Mean Change in height Z-scores (SE) 0. 1) 95% CI 0. 8 The 8 pediatric patients 2 to <12 years of age from Trial 2 continued treatment in an open label long term trial (Trial 3) and were treated with XENPOZYME for 2. Efficacy analyses showed continued improvements in the 3 patients evaluated for % predicted DLco, 6 patients evaluated for platelet counts, and all 8 patients evaluated for spleen and liver volumes, compared to baseline, during the additional 6 months extension. In addition, the height Z-score increased by 1. 3 from baseline when evaluated through 24 months of XENPOZYME treatment. Bone age, as assessed by hand x-ray, was delayed by a mean of 26. 4 months at baseline in the 7 pediatric patients enrolled in Trial 2 with a bone age measured at Month 24 in Trial 3. The bone age improved to within a mean of 12 months of the chronological age when assessed at Month 24 in these 7 patients.

Genzyme Corporation

• Address:

  ONE KENDALL SQUARE, 02139 CAMBRIDGE, EXTERIOR - EX

XENPOZYME- olipudase alfa-rpcp_injection, powder, lyophilized, for solution Product manual source documgent