For US healthcare professionals only
APPROVED
THE FIRST AND ONLY DISEASE-SPECIFIC TREATMENT FOR ASMD (NON-CNS MANIFESTATIONS)1
XENPOZYME™ (olipudase alfa-rpcp) is indicated for treatment of non–central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in adult and pediatric patients. Prescribing Information, including Boxed WARNINGASMD=acid sphingomyelinase deficiency; CNS=central nervous system.
ASMD is a progressive, potentially life-threatening genetic disease1-3
- ASMD is historically known as Niemann-Pick disease types A, A/B, and B.
- ASMD is caused by reduced activity of the enzyme acid sphingomyelinase (ASM).
- In unaffected individuals, ASM sufficiently breaks down the phospholipid sphingomyelin.
- In patients with ASMD, deficient ASM activity can result in intra-lysosomal accumulation of sphingomyelin in various tissues.
- Sphingomyelin accumulation can lead to progressive tissue damage and organ impairment throughout a patient's lifetime.
Patients with ASMD types A/B and B can experience multisystemic signs and symptoms2,4,5
XENPOZYME is an enzyme replacement therapy that provides an exogenous source of ASM.
The safety and efficacy of XENPOZYME were evaluated in 3 clinical trials including adult and pediatric patients with ASMD.
XENPOZYME is administered in 2 phases: (1) dose escalation, followed by
(2) maintenance phase,* with an option of home infusion during the maintenance phase.
*3 mg/kg is the target maintenance dose, which can be administered following the dose escalation schedule.1
XENPOZYME replaces the deficient ASM enzyme and breaks down accumulated sphingomyelin
HOW XENPOZYME WORKS
Cell with sphingomyelin accumulation1,2
- In ASMD, sphingomyelin is poorly metabolized, leading to intra-lysosomal accumulation in various tissues.
XENPOZYME acting
within a cell1
- XENPOZYME metabolizes and reduces excess sphingomyelin.
- XENPOZYME is not expected to cross the blood-brain barrier or modulate CNS manifestations of ASMD.
†17 out of 18 patients previously receiving placebo and 13 out of 13 patients previously treated with XENPOZYME in the primary analysis period started or continued treatment with XENPOZYME, respectively, for up to 4 years.
- DLco (% predicted)
- Spleen volume (MN)
- Liver volume (MN)
- Platelet count (109/L)
*Patients received XENPOZYME via a dose escalation regimen over a minimum period of 14 weeks from 0.1 mg/kg to a target dose of 3 mg/kg.1
DLco=diffusing capacity of the lungs for carbon monoxide; IV=intravenous; MN=multiples of normal.
XENPOZYME demonstrated significant multisystemic improvements at Week 52 and sustained improvements at Week 1041
Data are nominally statistically significant
21%
(P =0.0003)*
SIGNIFICANT IMPROVEMENT IN LUNG FUNCTION AS MEASURED BY DLco
- 24% mean increase in % predicted DLco (n=12) vs 3% mean increase with placebo (n=17)
Mean values
- XENPOZYME–
Baseline: 49.1%,
Week 52: 59.4%,
Placebo–
Baseline: 48.5%,
Week 52: 49.9%
39%
(P <0.0001)*
SIGNIFICANT REDUCTION IN SPLEEN VOLUME
- 39% mean reduction in spleen volume (n=13) vs 0.5% mean increase with placebo (n=17)
Mean values
- XENPOZYME–
Baseline: 11.5 MN,
Week 52: 7.2 MN,
Placebo–
Baseline: 11.2 MN,
Week 52: 11.2 MN
25%
(P <0.0001)*
SIGNIFICANT REDUCTION IN LIVER VOLUME
- 27% mean reduction in liver volume (n=12) vs 2% mean reduction with placebo (n=17)
Mean values
- XENPOZYME–
Baseline: 1.4 MN,
Week 52: 1.0 MN,
Placebo–
Baseline: 1.6 MN,
Week 52: 1.6 MN
16%
(P =0.0280)*
SIGNIFICANT INCREASE IN PLATELET COUNT
- 18.3% mean increase in platelet count (n=13) vs 2.7% mean increase with placebo (n=16)
Mean values
- XENPOZYME–
Baseline: 109.3 x 109/L,
Week 52: 126.4 x 109/L,
Placebo–
Baseline: 115.6 x 109/L,
Week 52: 120.2 x 109/L
SUSTAINED IMPROVEMENTS IN MULTIPLE ORGANS AT 104 WEEKS
Patients previously in the XENPOZYME arm continued experiencing sustained improvements in all key endpoints compared to baseline:
- 34% improvement in lung function (n=5)
- 48% reduction in spleen volume (n=9)
- 32% reduction in liver volume (n=9)
- 24% increase in platelet count (n=9)
*P value is nominal (without a prespecified multiplicity adjustment).
Significant improvement in lung function as measured by DLco1
Data are nominally statistically significant
Key endpoint: mean percent change in % predicted DLco
After Week 52, all patients received XENPOZYME. 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 104.1
†P value is nominal (without a prespecified multiplicity adjustment).1
CI=confidence interval; LS=least squares.
Data are nominally statistically significant
Key endpoint: mean percent change in spleen volume
After Week 52, all patients received XENPOZYME. 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 104.1
†P value is nominal (without a prespecified multiplicity adjustment).1
Data are nominally statistically significant
Key endpoint: mean percent change in liver volume
After Week 52, all patients received XENPOZYME. Vertical bars represent the standard errors (SE) for the LS means.1
*P value is nominal (without a prespecified multiplicity adjustment).1
Data are nominally statistically significant
Key endpoint: mean percent change in platelet count
After Week 52, all patients received XENPOZYME. Vertical bars represent the standard errors (SE) for the LS means.1
*P value is nominal (without a prespecified multiplicity adjustment).1
Adverse reactions occurring at >7% in adult patients with ASMD during the 52-week primary analysis period
| 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 |
The trial population included pediatric patients in the following age ranges:
- 7 patients, 2 to <12 years old
- 1 patient, <2 years old
Eight pediatric patients from this trial continued in a long-term, open-label extension trial and were treated for 2.5 to 3.2 years.
- DLco (% predicted)
- Spleen volume (MN)
- Liver volume (MN)
- Platelet count (109/L)
- Height Z-scores
*Patients received XENPOZYME via a dose escalation regimen over a minimum period of 16 weeks from 0.03 mg/kg to a target dose of 3 mg/kg. All but one patient completed the dose escalation up to the maintenance dose of 3 mg/kg within 22 weeks.1
Exploratory efficacy endpoints
The use of XENPOZYME in pediatric patients is supported by evidence from an adequate and well-controlled trial in adults with supportive efficacy, safety, and tolerability data in pediatric patients.
Long-Term Trial: efficacy XENPOZYME was evaluated in pediatric patients in a Long-Term Trial1Trial design:
- 8 pediatric patients from the open-label pediatric trial continued treatment in an open-label, Long-Term Trial.
- Patients ranged from 2 to <12 years of age and were treated for 2.5 to 3.2 years.
- XENPOZYME was administered at 3 mg/kg once every 2 weeks by IV infusion.
Adverse reactions occurring at ≥13% in XENPOZYME-treated pediatric patients with ASMD in the open-label pediatric trial* and a Long-Term Trial for an overall observation period of 2.5 to 3.2 years
| ADVERSE REACTION | XENPOZYME (n=8) |
|---|---|
| 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%) |
*Duration of treatment in the open-label trial was 64 weeks. All patients continued into the Long-Term Trial.
Abdominal pain includes abdominal pain and abdominal pain upper. Fatigue includes fatigue and asthenia. Rash includes rash and erythema.
- Treatment-related serious adverse reactions, hypersensitivity reactions including anaphylaxis, and infusion-associated reactions (IARs) occurred within 24 hours of infusion and were observed in a higher percentage of pediatric patients than in adult patients.
- Serious adverse reactions of anaphylactic reaction were reported in 2 (25%) pediatric patients treated with XENPOZYME.
- XENPOZYME provides an exogenous source of ASM. When infused, it metabolizes accumulated sphingomyelin into ceramide and phosphocholine components.1
- At the start of treatment with XENPOZYME, the rapid metabolism of accumulated sphingomyelin generates pro-inflammatory breakdown products, which may induce IARs and/or transient transaminase elevations.7
An initial dose escalation period is necessary for XENPOZYME
Adult dose escalation and maintenance
- Initial dose escalation should take place in a clinical setting.
- If doses are missed, re-escalation may be necessary.
An initial dose escalation period is necessary for XENPOZYME
Pediatric dose escalation and maintenance
- Initial dose escalation should take place in a clinical setting.
- If doses are missed, re-escalation may be necessary.
- In the clinical trial in pediatric patients, all but one patient completed the dose escalation up to the maintenance dose of 3 mg/kg within 22 weeks.
Re-escalation may be necessary if a patient misses 1 or more doses*
If 1 infusion is missed, administer the last tolerated dose before resuming dose escalation, according to the dose escalation regimens for adult and pediatric patients.
If 2 consecutive infusions are missed, administer 1 dose below the last tolerated dose before resuming dose escalation, according to the dose escalation regimens for adult and pediatric patients.
If 3 or more consecutive infusions are missed, resume dose escalation at 0.3 mg/kg, according to the dose escalation regimens for adult and pediatric patients.
If 1 maintenance infusion is missed, administer the maintenance dose and adjust the treatment schedule accordingly.
If 2 consecutive maintenance infusions are missed, administer 1 dose below the maintenance dose before resuming the maintenance dose.
If 3 or more consecutive maintenance infusions are missed, restart dosing at 0.3 mg/kg, according to the dose escalation regimens for adult and pediatric patients.
*At the next scheduled infusion after a missed dose, if the dose administered is 0.3 mg/kg or 0.6 mg/kg, that dose should be administered twice per Tables 1 and 2 in the XENPOZYME full Prescribing Information.
ALT=alanine aminotransferase; AST=aspartate aminotransferase.
Monitoring transaminase (ALT and AST) levels1
Transaminase testing must occur to manage the risk of elevated transaminase levels prior to and during dose escalation, or upon resuming treatment following a missed doseXENPOZYME may be associated with elevated transaminases within 24 to 48 hours after infusion. In clinical trials, elevated transaminase levels were reported in 4 (13%) adult patients and 1 (13%) pediatric patient during the dose escalation phase with XENPOZYME. Transaminase levels generally returned to pre-infusion levels at the time of the next scheduled infusion.
- Assess baseline ALT and AST levels.
- Assess transaminase levels 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.
- If transaminase levels are elevated above baseline and >2 times the ULN, 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.
- 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 to monitor trends in liver transaminase elevations.
- Transaminase testing is recommended to be continued as part of routine clinical management.
ULN=upper limit of normal.
Monitoring infusion–associated reactions (IARs) and hypersensitivity1
Observe patients closely during and for an appropriate period of time after the infusion, based on clinical judgment
In the event of a severe hypersensitivity reaction (e.g., anaphylaxis) or a severe IAR, immediately discontinue XENPOZYME administration and initiate appropriate medical treatment.
- Consider the risks and benefits of re-administering XENPOZYME following severe hypersensitivity reactions (including anaphylaxis) or IARs.
- 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 rate) may be increased to reach the approved recommended dosage.
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 according to the dose escalation regimens for adult and pediatric patients, as applicable.
- Consider testing for IgE ADA in XENPOZYME-treated patients who experienced severe hypersensitivity reactions including anaphylaxis.
- Consider other clinical laboratory testing such as serum tryptase and complement activation in patients who experience anaphylaxis.
ADA=antidrug antibody; IgE=immunoglobulin E.
Whether a patient is newly diagnosed or trying a systemic therapy, CareConnectPSS has people who can help.
Sometimes insurance information changes. CareConnectPSS seeks to help patients transition without impacting access to treatment.
CareConnectPSS can support patients making the transition from the hospital to home infusions.
CareConnectPSS can help patients and their support system find helpful information and tools.
XENPOZYME HCP Brochure
Overview of key efficacy, safety, and dosing information for XENPOZYME.
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Pre/Post Infusion Checklist
A helpful checklist to accurately track the drug administration and monitoring processes.
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Statement of Medical Necessity
A form to use when demonstrating the medical necessity of XENPOZYME for a particular patient.
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Prior Authorization Checklist
A checklist detailing possible required information for obtaining insurer approval.
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Billing and Coding Guide
Reimbursement information for office staff responsible for claims submissions.
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Patients treated with XENPOZYME have experienced hypersensitivity reactions, including anaphylaxis. Appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available during XENPOZYME administration. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, XENPOZYME should be discontinued immediately, and appropriate medical treatment should be initiated. In patients with severe hypersensitivity reaction, a desensitization procedure to XENPOZYME may be considered.
Hypersensitivity Reactions Including Anaphylaxis
Prior to XENPOZYME administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids. Appropriate medical 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 severe hypersensitivity reactions (including anaphylaxis).
- If a mild or moderate hypersensitivity reaction occurs, the infusion rate may be slowed or temporarily withheld, and/or the XENPOZYME dose reduced.
Hypersensitivity reactions, including anaphylaxis, have been reported in olipudase alfa-treated patients.
- 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.
Infusion-Associated Reactions
Antihistamines, antipyretics, and/or corticosteroids may be given prior to XENPOZYME administration to reduce the risk of infusion-associated reactions (IARs). However, IARs may still occur in patients after receiving pretreatment.
- If severe IARs occur, discontinue XENPOZYME immediately and initiate appropriate medical treatment. Consider the risks and benefits of re-administering XENPOZYME following severe IARs.
- If a mild or moderate IAR occurs, the infusion rate may be slowed or temporarily withheld, and/or the XENPOZYME dosage may be reduced.
The most frequent IARs in:
- adult patients were headache, pruritus, vomiting and urticaria;
- pediatric patients were urticaria, erythema, headache, nausea, pyrexia, and vomiting.
An acute phase reaction (APR), an acute inflammatory response accompanied by elevations in inflammatory serum protein concentrations, was observed.
- 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. APRs can be managed as other IARs.
Elevated Transaminases 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 patients during the XENPOZYME 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.
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, or prior to the next scheduled XENPOZYME infusion upon resuming treatment following a missed dose.
- See full Prescribing Information for additional information on assessment and management of elevated transaminases.
Upon reaching the recommended maintenance dose, transaminase testing is recommended to be continued as part of routine clinical management of ASMD.
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. 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.
Verify pregnancy status in females of reproductive potential prior to initiating XENPOZYME treatment. Advise females of reproductive potential to use effective contraception during XENPOZYME treatment and for 14 days after the last dose if XENPOZYME is discontinued.
ADVERSE REACTIONS
- 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.
INDICATIONS AND USAGE XENPOZYME™ (olipudase alfa-rpcp) is indicated for treatment of non–central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in adult and pediatric patients. Please see full Prescribing Information, including Boxed WARNING, for complete details.
References: 1. XENPOZYME. Prescribing Information. Sanofi; 2022. 2. McGovern MM, Avetisyan R, Sanson B-J, Lidove O. Disease manifestations and burden of illness in patients with acid sphingomyelinase deficiency (ASMD). Orphanet J Rare Dis. 2017;12(1):41. 3. Schuchman EH, Desnick RJ. Types A and B Niemann-Pick disease. Mol Genet Metab. 2017;120(1-2):27-33. 4. McGovern MM, Dionisi-Vici C, Giugliani R, et al. Consensus recommendation for a diagnostic guideline for acid sphingomyelinase deficiency. Genet Med. 2017;19(9):967-974. 5. Cox GF, Clarke LA, Giugliani R, et al. Burden of illness in acid sphingomyelinase deficiency: a retrospective chart review of 100 patients. JIMD Rep. 2018;41:119-129. 6. Data on file, Sanofi. 7. Wasserstein MP, Jones SA, Soran H, et al. Successful within-patient dose escalation of olipudase alfa in sphingomyelinase deficiency. Mol Genet Metab. 2015;116(1-2):88-97.
