Olipudase Alfa

XENPOZYME is indicated for treatment of non–central 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 non–central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in adult and pediatric patients. ( 1 )

For injection: 4 mg or 20 mg of olipudase alfa-rpcp as a sterile, white to off white lyophilized powder in a single-dose vial for reconstitution. For injection: 4 mg or 20 mg of olipudase alfa-rpcp as a lyophilized powder in a single-dose vial for reconstitution. ( 3 )

None. None. ( 4 )

Infusion-Associated Reactions (IARs): If severe IARs occur, discontinue XENPOZYME and initiate appropriate medical treatment. ( 5.2 ) Elevated Transaminases: Assess ALT and AST within one month prior to initiation of XENPOZYME, within 72 hours prior to any infusion during dose escalation, or prior to the next scheduled XENPOZYME infusion upon resuming treatment following a missed dose. ( 5.3 ) Risk of Fetal Malformations During Dosage Initiation or Escalation in Pregnancy: 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. Advise females of reproductive potential to use effective contraception during treatment and for 14 days after the last dose if XENPOZYME is discontinued. ( 5.4 , 8.1 , 8.3 )

5.1 Hypersensitivity Reactions Including Anaphylaxis Life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in olipudase alfa-treated patients. One 18-month-old XENPOZYME-treated patient experienced an anaphylactic reaction during the sixth infusion in the dose escalation period in Trial 2 [see Adverse Reactions (6.1) ] . Additionally, a 16-month-old patient with ASMD type A, treated with a version of olipudase alfa manufactured from a different process, experienced two anaphylactic reactions during the fifth and sixth infusions in the dose escalation period; the patient received an immune tolerance induction therapy prior to treatment. In both of these pediatric patients with anaphylaxis, anti-olipudase alfa-rpcp IgE (IgE ADA) and IgG (IgG ADA) antibodies were detected [see Adverse Reactions (6.1) and Clinical Pharmacology (12.6) ] . Hypersensitivity reactions that were mild to moderate in severity occurred in 10 (33%) XENPOZYME-treated adult patients and 4 (50%) XENPOZYME-treated pediatric patients in clinical trials. Hypersensitivity reactions in adults included urticaria, pruritus, erythema, rash, rash erythematous, eczema, angioedema, and erythema nodosum. Hypersensitivity reactions in pediatric patients included urticaria, pruritus, rash, erythema, and localized edema [see Adverse Reactions (6) ] . Prior to XENPOZYME administration, consider premedicating with antihistamines, antipyretics, and/or corticosteroids. Appropriate medical monitoring and support measures, including cardiopulmonary resuscitation equipment, should be readily available during XENPOZYME administration. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue XENPOZYME immediately and initiate appropriate medical treatment. Consider the risks and benefits of re-administering XENPOZYME following a severe hypersensitivity reaction (including anaphylaxis). One patient has been rechallenged using slower infusion rates at a dosage lower than the recommended dosage. In patients with a severe hypersensitivity reaction, a tailored desensitization procedure to XENPOZYME may be considered. If the decision is made to readminister XENPOZYME, ensure the patient tolerates the infusion. If the patient tolerates the infusion, the dosage (dose and/or the rate) may be increased to reach the recommended dosage. Consider testing for IgE ADA in XENPOZYME-treated patients who experienced severe hypersensitivity reactions, including anaphylaxis [ see Adverse Reactions (6.1) ]. Testing for antibodies against olipudase alfa-rpcp are available through Genzyme Corporation (at 1-800-745-4447). Consider other clinical laboratory testing such as serum tryptase and complement activation in patients who experience anaphylaxis. If a mild or moderate hypersensitivity reaction occurs, consider temporarily holding the infusion, slowing the infusion rate, and/or reducing the XENPOZYME dose [see Dosage and Administration (2.5) ] .

5.2 Infusion-Associated Reactions IARs occurred in approximately 75% of pediatric and 50% of adult XENPOZYME-treated patients in the clinical trials; a severe IAR occurred in one (12.5%) of the pediatric patients. The most frequent IARs in: ≥10% of adult patients were headache, pruritus, vomiting, and urticaria >20% of pediatric patients were urticaria, erythema, headache, nausea, pyrexia, and vomiting Acute phase reaction (APR), an acute inflammatory response accompanied by elevations in inflammatory serum protein concentrations, was observed in one XENPOZYME-treated adult and one XENPOZYME-treated pediatric patient. Most of the APRs occurred at 48 hours post infusion during the dose escalation period. Elevations of C-reactive protein, calcitonin, and IL-6, and reduction of serum iron were observed. The most common clinical symptoms associated with APRs were pyrexia, vomiting, and diarrhea. Acute phase reactions were managed similar to other IARs. In the postmarketing setting, 24 hours after receiving XENPOZYME at a higher than recommended initial dose, a 2-year-old male patient with ASMD, experienced fever, respiratory distress, hypotension, and death [see Overdosage (10) ] . Prior to XENPOZYME administration, consider pre-medicating with antihistamines, antipyretics, and/or corticosteroids to reduce the risk of infusion-associated reactions (IARs). However, IARs may still occur in patients after receiving pre-treatment. Follow the dose escalation regimen to minimize IARs [see Dosage & Administration (2.2 & 2.3) ] . If a severe IAR occurs, discontinue XENPOZYME immediately and initiate appropriate medical treatment. Consider the risks and benefits of re-administering XENPOZYME following a severe IAR. One patient has been rechallenged using slower infusion rates at a dosage lower than the recommended dosage. If the patient tolerates the infusion, the dosage (dose and/or the rate) may be increased to reach the recommended dosage. If a mild or moderate IAR occurs, consider temporarily holding the infusion, slowing the infusion rate, and/or reducing the XENPOZYME dosage [see Dosage and Administration (2.5) ] .

5.3 Elevated Transaminase Levels XENPOZYME may be associated with elevated transaminases (ALT, AST, or both) within 24 to 48 hours after infusion. Elevated transaminase levels were reported in 4 (13%) XENPOZYME-treated adults and 1 (13%) XENPOZYME-treated pediatric patient during the dose escalation phase in clinical trials. At the time of the next scheduled infusion, these elevated transaminase levels generally returned to levels observed prior to the XENPOZYME infusion [see Adverse Reactions (6.1) ] . To manage the risk of elevated transaminase levels, assess ALT and AST within one month prior to initiation of XENPOZYME, within 72 hours prior to any infusion during dose escalation, which includes the first 3 mg/kg dose outlined in Tables 1 and 2, or prior to the next scheduled XENPOZYME infusion upon resuming treatment following a missed dose. If either the baseline or pre-infusion transaminase level (during the dose escalation phase) is >2 times the ULN, repeat transaminase levels within 72 hours after the end of the infusion. If the pre-infusion transaminase levels are elevated above baseline and >2 times the ULN prior to the next scheduled administration, the XENPOZYME dose can be reduced (repeat prior lower dose or reduce the dose) or XENPOZYME can be temporarily withheld until the liver transaminases return to the patient's baseline value. Upon reaching the recommended maintenance dose, transaminase testing is recommended to be continued as part of routine clinical management of ASMD.

5.4 Risk of Fetal Malformations During Dosage Initiation or Escalation in Pregnancy There is no evidence that olipudase alfa-rpcp crosses the human placenta. However, published literature reports that early embryonic exposure to a metabolite of sphingomyelin (ceramide) or the S1P receptor modulator fingolimod can produce exencephaly in chicks and mice, respectively. […]

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. ( 6.1 ) 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genzyme Corporation at 1-800-745-4447 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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. 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) ] . The median exposure duration was 2.5 years (range: 0.4 to 3.7 years) in adult patients and 2.7 years (range: 2.5 to 3.2 years) in pediatric patients. 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 N=13 Placebo N=18 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) ] . After 64 weeks, all pediatric patients entered into Trial 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. and Trial 3 for an Overall Observation Period of 2.5 to

3.2 Years Adverse Reactions XENPOZYME N=8 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) and 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 (5.1) ] .

8.1 Pregnancy 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) ] . 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 (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. 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. 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 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.

8.2 Lactation 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 ) . When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for XENPOZYME and any potential adverse effects on the breastfed infant from XENPOZYME or from the underlying maternal condition. 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.

8.3 Females and Males of Reproductive Potential 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.

8.4 Pediatric Use 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) and Clinical Studies (14.2 , 14.3 , 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) ] . 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 [see Warnings and Precautions (5.1) ] .

8.5 Geriatric Use 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.

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.