Olipudase Alfa for Genetic Brain Disorders

INDICATIONS AND USAGE 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 )

DOSAGE AND ADMINISTRATION See Full Prescribing Information for important recommendations prior to XENPOZYME treatment initiation. ( 2.1 ) Adults: Recommended starting dose is 0.1 mg/kg administered as an intravenous infusion. ( 2.2 ) Pediatrics: Recommended starting dose is 0.03 mg/kg administered as an intravenous infusion. ( 2.3 ) 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. ( 2.2 , 2.3 , 2.5 , 2.6 , 2.7 ) 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 [see Overdosage (10) ] , 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 [see Warnings and Precautions (5.3) ] . Verify pregnancy status in females of reproductive potential [see Use in Specific Populations (8.1 , 8.3) ] . Premedication Prior to XENPOZYME administration, consider premedicating with antihistamines, antipyretics, and/or corticosteroids [see Warnings and Precautions (5.1 , 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 (2.2 , 2.3) ] 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 [see Warnings and Precautions (5.1 , 5.2 , 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 × 30 [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. 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 [see Warnings and Precautions (5.1 , 5.2 , 5.3) ] . Administer XENPOZYME via intravenous infusion every 2 weeks. Table 2: XENPOZYME Dose Escalation Regimen for Pediatric 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 [see Dosage and Administration (2.1) ] . 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 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 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. 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 [see Warnings and Precautions (5.1 , 5.2) ] . 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 1 and 2 for adult and pediatric patients, respectively [see Warnings and Precautions (5.1 , 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) ] . 2.6 Preparation Instructions Use aseptic technique during preparation. Reconstitute and dilute XENPOZYME in the following manner: Reconstitution and Dilution Instru

WARNINGS AND PRECAUTIONS 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. In animal reproduction studies, exencephaly, a neural tube defect occurring in the first trimester of pregnancy

ADVERSE REACTIONS 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) ] .