XENPOZYME 4mg powder for concentrate infusion solution medication leaflet

Xenpozyme 4 mg powder for concentrate for solution for infusion

Xenpozyme 20 mg powder for concentrate for solution for infusion

Xenpozyme 4 mg powder for concentrate for solution for infusion

Each vial contains 4 mg of olipudase alfa*.

Each vial contains 0.60 mg of sodium.

Xenpozyme 20 mg powder for concentrate for solution for infusion

Each vial contains 20 mg of olipudase alfa*.

Each vial contains 3.02 mg of sodium.

After reconstitution, each vial contains 4 mg of olipudase alfa per mL. Each vial must be furtherdiluted before use (see section 6.6).

*Olipudase alfa is a recombinant human acid sphingomyelinase and is produced in a Chinese Hamster

Ovary (CHO) cell line by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion (powder for concentrate).

White to off-white lyophilised powder.

Xenpozyme is indicated as an enzyme replacement therapy for the treatment of non-Central Nervous

System (CNS) manifestations of Acid Sphingomyelinase Deficiency (ASMD) in paediatric and adultpatients with type A/B or type B.

Xenpozyme treatment should be supervised by a healthcare professional experienced in themanagement of ASMD or other inherited metabolic disorders. Xenpozyme infusion should beadministered by a healthcare professional with access to appropriate medical support to managepotential severe reactions such as serious systemic hypersensitivity reactions.

The rapid metabolism of accumulated sphingomyelin (SM) by olipudase alfa generatespro-inflammatory breakdown products, which may induce infusion-associated reactions and/ortransient liver enzyme elevations.

Treatment with Xenpozyme must always be initiated via a dose escalation regimen (see below) tominimise the risk of infusion-associated reactions, including acute phase reactions, and increases inliver transaminases. All instructions for dosage and administration (see below), and for preparationand handling (see section 6.6), should be followed to avoid the risk of overdose (see section 4.9).

Please note that the dose escalation for paediatric patients differs from the one for adults. In addition tothe dose escalation regimen, each dose must be administered using a staggered infusion rate (see

Tables 3 and 4).

For missed doses see also below. Home infusion for patients should only be considered after the doseescalation phase.

Xenpozyme dose is based on the actual body weight for patient with a body mass index (BMI) ≤ 30 oran optimal body weight for patient with a BMI > 30 (see section for patients with a BMI > 30).

Dose escalation phase

The recommended starting dose of Xenpozyme is 0.1 mg/kg* for adults (also see missed dosessubsection for additional guidance) and subsequently, the dose should be increased according to thedose escalation regimen presented in Table 1:

Table 1: Dose escalation regimen in adults

Adult patients (≥18 years old)

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) 3 mg/kg* (recommendedmaintenance dose)

*Actual body weight will be used for patients with a BMI ≤ 30. For patients with a BMI > 30, anoptimal body weight will be used as described below.

Maintenance phase

The recommended maintenance dose of Xenpozyme is 3 mg/kg* every 2 weeks.

*Actual body weight will be used for patients with a BMI ≤ 30. For patients with a BMI > 30, anoptimal body weight will be used as described below.

Dose escalation phase

The recommended starting dose of Xenpozyme is 0.03 mg/kg* for paediatric patients, and the doseshould be subsequently increased according to the dose escalation regimen presented in Table 2:

Table 2A: Dose escalation regimen in paediatric patients

Paediatric patients (0 to <18 years old)

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) 3 mg/kg* (recommendedmaintenance dose)

*Actual body weight will be used for patients with a BMI ≤ 30. For patients with a BMI > 30, anoptimal body weight will be used as described below.

Maintenance phase

The recommended maintenance dose of Xenpozyme is 3 mg/kg* every 2 weeks.

*Actual body weight will be used for patients with a BMI ≤ 30. For patients with a BMI > 30, anoptimal body weight will be used as described below.

Patients with BMI> 30

In adult and paediatric patients with a body mass index (BMI) > 30, the body weight that is used tocalculate the dose of Xenpozyme is estimated via the following method (for dose escalation andmaintenance phases).

Body weight (kg) to be used for dose calculation = 30 × (actual height in m)2

Example:

For a patient with:

BMI of 38body weight of 110 kgheight of 1.7 m.

The dose to be administered will be calculated using a body weight of 30 × 1.72 = 86.7 kg.

A dose is considered missed when not administered within 3 days of the scheduled date. When a doseof Xenpozyme is missed, the next dose should be administered as described below as soon as possible.

Thereafter, administrations should be scheduled every 2 weeks from the date of the last administration.

The dose escalation regimen for administration of Xenpozyme prevents a rapid release of catabolites,which can result in serious toxicity such as hepatic inflammation/transaminase elevations, serious andlife-threatening infusion associated reactions or even death (see section 4.4, pct. 4.8 and 4.9). A patientwho has not been largely debulked or has suspected re-accumulation, due to missed doses, shouldresume treatment at a lower dose.

Table 2B: Xenpozyme dosing recommendations for adult and paediatric patients after one orseveral missed dose(s).

Consecutive Dose escalation phase Maintenance phasemissed doses

If 1 infusion is The last tolerated dose should be The maintenance dose should bemissed*: administered, before resuming dose administered and the treatmentescalation according to the regimen in schedule adjusted accordingly.

adults (Table 1) or in paediatric patients(Table 2A).

If 2 consecutive 1 dose level lower than the last tolerated 1 dose below the maintenance doseinfusions are dose (using a minimal dose of 0.3 mg/kg) (i.e. 2 mg/kg) should be administered.

missed*: should be administered, before resuming Then for subsequent infusions, thedose escalation according to Table 1 or maintenance dose (3 mg/kg) every 2

Table 2A. weeks should be administered.

If 3 or more For adult patients who have not completedconsecutive the dose escalation regimen, re-initiate the For adult patients who have missedinfusions are dose escalation regimen starting at first maintenance dosing for 3 or moremissed: escalation dose described in Table 1. consecutive doses during whichsphingomyelin could have

For paediatric patients who have not reaccumulated, the treating physiciancompleted the dose escalation regimen, re- is advised to re-initiate the doseinitiate the dose escalation regimen escalation regimen starting at the firststarting at at the first escalation dose escalation dose described in Table 1.

described in Table 2A.

For paediatric patients who havemissed maintenance dosing for 3 ormore consecutive doses during whichsphingomyelin could havereaccumulated, the treating physicianis advised to re-initiate the doseescalation regimen starting at the firstescalation dose described in Table 2A.

* In case the next scheduled infusion after a missed dose is a dose of 0.3 or 0.6 mg/kg, that doseshould be administered twice as per Table 1 and Table 2A.

Monitoring of transaminase level

Transaminase (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) levels shouldbe obtained prior to treatment initiation and monitored during any dose escalation phases (see section4.4). If the pre-infusion transaminase levels are elevated above baseline and >2 times the upper limitof normal (ULN), the Xenpozyme dose can be adjusted (prior dose repeated or reduced) or treatmentcan be temporarily withheld in accordance with the degree of transaminase elevation. If a patientrequires a dose adjustment or treatment interruption, treatment re-initiation should follow the doseescalation regimen described in Table 1 and Table 2A for adult and paediatric patients, respectively,and recommendations in case of missed doses (see missed doses section).

No dose adjustment is recommended for patients over the age of 65 (see section 5.2).

No dose adjustment is recommended in patients with hepatic impairment (see section 5.2).

No dose adjustment is recommended in patients with renal impairment (see section 5.2).

Xenpozyme is for intravenous use only. Infusions should be administered in a stepwise mannerpreferably using an infusion pump.

For instructions on reconstitution and dilution of the medicinal product before administration, seesection 6.6.

After reconstitution and dilution, the solution is administered as an intravenous infusion. The infusionrates must be incrementally increased during the infusion only in the absence of infusion-associatedreactions (in case of infusion-associated reactions, see section 4.4.). The infusion rate and duration ofinfusion (+/- 5 min) for each step of infusion are detailed in Table 3 and Table 4.

When determining the infusion rate in Tables 3 and 4, use the dose level from the dose escalationregimen, found in either Table 1 (adult) or Table 2A (paediatric patients).

Table 3: Infusion rates and duration of infusion in adult patients

Approximate

Dose* Infusion rateduration of(mg/kg) Duration of infusioninfusionstep 1 step 2 step 3 step 420 mL/hr 60 mL/hr0.1 NA NA 35 minfor 20 min for 15 min3.33 mL/hr 10 mL/hr 20 mL/hr 33.33 mL/hr0.3 to 3 220 minfor 20 min for 20 min for 20 min for 160 minhr: hour; min: minute; NA: Not applicable

*Dose level from the dose escalation regimen in Table 1

Table 4: Infusion rates and duration of infusion in paediatric patients

Infusion rate Approximate

Dose* Duration of infusion duration of(mg/kg)step 1 step 2 step 3 step 4 infusion0.1 mg/kg/hrfor the full0.03 NA NA NA 18 minlength of theinfusion0.1 mg/kg/hr 0.3 mg/kg/hr0.1 NA NA 35 minfor 20 min onwards0.1 mg/kg/hr 0.3 mg/kg/hr 0.6 mg/kg/hr0.3 NA 60 minfor 20 min for 20 min onwards0.6 80 min1 0.1 mg/kg/hr 0.3 mg/kg/hr 0.6 mg/kg/hr 1 mg/kg/hr 100 min2 for 20 min for 20 min for 20 min onwards 160 min3 220 minhr: hour; min: minute; NA: Not applicable

*Dose level from the dose escalation regimen in Table 2A

Signs and symptoms of infusion-associated reactions (IARs), such as headache, urticaria, pyrexia,nausea and vomiting, and other signs or symptoms of hypersensitivity should be monitored during theinfusion. Depending on the symptom severity, the infusion may be slowed, paused or discontinued andappropriate medical treatment initiated as needed.

In case of severe hypersensitivity and/or anaphylactic reaction, treatment with Xenpozyme should bediscontinued immediately (see section 4.4).

At the end of infusion (once the syringe or infusion bag is empty), the infusion line should be flushedwith sodium chloride 9 mg/mL (0.9%) solution for injection using the same infusion rate as the oneused for the last part of the infusion.

Home infusion during maintenance phase

Home infusion under the supervision of a healthcare professional may be considered for patients onmaintenance dose and who are tolerating their infusions well. The decision to have patients moved tohome infusion should be made after evaluation and recommendation by the prescribing physician.

Appropriate medical support, including personnel trained in emergency measures, should be readilyavailable when Xenpozyme is administered. If anaphylactic or other acute reactions occur,immediately discontinue the Xenpozyme infusion, initiate appropriate medical treatment and seek theattention of a physician. If severe hypersensitivity reactions occur, subsequent infusions should onlyoccur in a setting where resuscitation measures are available. The dose and infusion rate used in thehome settings should remain the same as were used in the supervised clinical settings, and should notbe changed without supervision of the prescribing physician. In case of missed doses or delayedinfusion, the prescribing physician should be contacted as subsequent infusions may occur in asupervised clinical setting.

Life-threatening hypersensitivity (anaphylactic reaction) to olipudase alfa or to any of the excipientslisted in section 6.1 (see section 4.4).

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered medicinal product should be clearly recorded.

Absence of blood-brain barrier transfer

Xenpozyme is not expected to cross the blood-brain barrier or modulate the CNS manifestations of thedisease.

Infusion associated reactions (IARs)

IARs occurred in approximately 60% of patients treated with Xenpozyme in clinical studies. These

IARs included hypersensitivity reactions and acute phase reactions (see section 4.8). The mostfrequent IARs were headache, urticaria, pyrexia, nausea and vomiting (see section 4.8). IARs typicallyoccurred between the time of infusion and up to 24 hours after infusion completion.

Serious adverse reactions, including death, have occurred following overdose during the doseescalation phase (see sections 4.2 and 4.9).

Hypersensitivity/anaphylaxis

Hypersensitivity reactions, including anaphylaxis, have been reported in Xenpozyme-treated patients(see section 4.8). In clinical studies, hypersensitivity reactions occurred in 9 (22.5%) adult and9 (45%) paediatric patients including one paediatric patient who experienced anaphylaxis.

Patients should be observed closely during and for an appropriate period of time after the infusion,based on clinical judgement. Patients must be informed of the potential symptoms ofhypersensitivity/anaphylaxis and instructed to seek immediate medical care should symptoms occur.

IARs management should be based on the severity of signs and symptoms and may includetemporarily interrupting the Xenpozyme infusion, lowering the infusion rate, and/or appropriatemedical treatment.

If severe hypersensitivity or anaphylaxis occurs, Xenpozyme should be discontinued immediately, andappropriate medical treatment should be initiated. The prescriber should evaluate the risks and benefitsof Xenpozyme re-administration following anaphylaxis or severe hypersensitivity reaction. Ifconsidering re-administration of Xenpozyme following anaphylaxis, the prescribing physician shouldcontact the local Sanofi representative for advice on re-administration. In patients with severehypersensitivity, desensitisation procedure to Xenpozyme may be considered (see section 4.8). In suchpatients, extreme caution should be exercised, with appropriate resuscitation measures available, when

Xenpozyme is readministered.

If mild or moderate IARs occur, the infusion rate may be slowed or temporarily stopped, the durationof each step for an individual infusion increased, and/or the Xenpozyme dose reduced. If a patientrequires a dose reduction, re-escalation should follow dose escalation described in Table 1 and Table2A for adult and paediatric patients, respectively (see section 4.2).

Patients may be pre-treated with antihistamines, antipyretics, and/or glucocorticoids to prevent orreduce allergic reactions.

Treatment-emergent antidrug antibodies (ADA) were reported in adult and paediatric patients duringthe clinical trials (see section 4.8). IARs and hypersensitivity reactions may occur independent of thedevelopment of ADA. The majority of IARs and hypersensitivity reactions were mild or moderate andwere managed with standard clinical practices.

IgE ADA testing may be considered for patients who experienced a severe hypersensitivity reaction toolipudase alfa.

While in clinical studies, no loss of efficacy was reported, IgG ADA testing may be considered in caseof loss of response to therapy.

Transient transaminases elevation

Transient transaminase elevations (ALT or AST) within 24 to 48 hours after infusions were reportedduring the dose escalation phase with Xenpozyme in clinical studies (see section 4.8). At the time ofthe next scheduled infusion, these elevated transaminase levels generally returned to the levelsobserved prior to the Xenpozyme infusion.

Transaminases (ALT and AST) levels should be obtained within 1 month prior to Xenpozymetreatment initiation (see section 4.2). During dose escalation or upon resuming treatment followingmissed doses, transaminases levels should be obtained within 72 hours prior to the next scheduled

Xenpozyme infusion. If either the baseline or a pre-infusion transaminase level is > 2 times the ULNduring dose escalation, then additional transaminase levels should be obtained within 72 hours afterthe end of the infusion. If the pre-infusion transaminase levels are elevated above baseline and> 2 times the ULN, the Xenpozyme dose can be adjusted (prior dose repeated or reduced) or treatmentcan be temporarily withheld in accordance with the degree of transaminase elevation (see section 4.2).

Upon reaching the recommended maintenance dose, transaminase testing can be performed as part ofroutine clinical management of ASMD.

This medicinal product contains 0.60 mg sodium per 4 mg vial or 3.02 mg sodium per 20 mg vial,equivalent to 0.03 and 0.15%, respectively, of the WHO recommended maximum daily intake of 2 gsodium for an adult or an adolescent, and ≤0.08% and ≤0.38%, respectively, of the maximumacceptable daily intake of sodium for children below 16 years of age.

No drug interaction studies have been performed. Because olipudase alfa is a recombinant humanprotein, no cytochrome P450 mediated drug-drug interactions are expected.

Women of childbearing potential are advised to use effective contraception during treatment and for14 days after the last dose if Xenpozyme is discontinued.

There are limited data from the use of olipudase alfa in pregnant women. Studies in animals haveshown reproductive toxicity (see section 5.3). Xenpozyme is not recommended during pregnancy andin women of childbearing potential not using effective contraception, unless the potential benefits tothe mother outweigh the potential risks, including those to the foetus.

It is unknown whether olipudase alfa is excreted in human milk. Olipudase alfa was detected in themilk of lactating mice (see section 5.3). A risk to the newborns/infants cannot be excluded. A decisionmust be made whether to discontinue breast-feeding or to discontinue Xenpozyme therapy taking intoaccount the benefit of breast feeding for the child and the benefit of therapy for the woman.

No human data are available on the effects of olipudase alfa on male and female fertility. Animal datado not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).

Because hypotension has been reported in clinical studies, Xenpozyme may have minor influence onthe ability to drive and use machines (see section 4.8).

Serious adverse reactions reported in patients treated with Xenpozyme were an event of extrasystolesin the context of a history of cardiomyopathy in 1 (2.5%) adult patient, and anaphylactic reaction,urticaria, rash, hypersensitivity, and alanine aminotransferase level increase, each in 1 (5%) paediatricpatient. The incidence of serious hypersensitivity-related IARs were higher in paediatric patientscompared to adults. One adult patient discontinued due to recurrent adverse events of rash.

The most frequently reported adverse drug reactions (ADRs) were headache (31.7%), urticaria(26.7%), pyrexia (25%), nausea (20%), abdominal pain (16.7%), vomiting (16.7%), pruritus (13.3%),myalgia (13.3%), rash (11.7%), abdominal pain upper (10%), erythema (10%), and C-reactive proteinincreased (11.7%).

The pooled safety analysis from 4 clinical studies (a tolerability study in adult patients, ASCEND,

ASCEND-Peds, and an extension study in adult and paediatric patients) included a total of 60 patients(40 adult and 20 paediatric patients) treated with Xenpozyme at doses up to 3 mg/kg every 2 weeks.

Adverse reactions reported in the pooled safety analysis of clinical studies are listed in Table 5 per

System Organ Class, presented by frequency categories: very common (≥1/10), common (≥1/100to<1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000) andnot known (cannot be estimated from the available data).

Table 5: Adverse drug reactions in patients treated with Xenpozyme in pooled analysis ofclinical studies

System Organ Class Frequency

Very common Common

Immune system disorders Anaphylaxis and hypersensitivity

Nervous system disorders Headache

Ocular hyperaemia, ocular

Eye disordersdiscomfort, eye pruritus

Cardiac disorders Palpitations, tachycardia

Vascular disorders Hypotension, hot flush, flushing

Pharyngeal oedema, pharyngeal

Respiratory, thoracic, and swelling, throat tightness,mediastinal disorders wheezing, larynx irritation,dyspnoea, throat irritation

Nausea, abdominal pain,

Diarrhoea, abdominal discomfort,

Gastrointestinal disorders vomiting, abdominal paingastrointestinal painupper

Hepatobiliary disorders Hepatic painangioedema, fixed eruption, rashpapular, rash macular, rash

Skin and subcutaneous tissue Urticaria, pruritus, rash,maculopapular, rash erythematous,disorders erythemarash pruritic, rash morbilliform,papule, macule

Musculoskeletal and

Myalgia Bone pain, arthralgia, back painconnective tissue disorders

Pain, chills, catheter site pain,

General disorders and catheter site related reaction,

Pyrexiaadministration site conditions catheter site pruritus, catheter siteswelling, fatigue, asthenia

C-reactive protein Alanine aminotransferaseincreased increased, aspartateaminotransferase increased, serum

Investigationsferritin increased, C-reactiveprotein abnormal, bodytemperature increased

Infusion-associated reactions (IARs), including hypersensitivity/anaphylactic reactions

IARs were reported in 57.5% of adult and 65% of paediatric patients. IAR symptoms reported mostfrequently in adult patients were headache (25%), nausea (17.5%), urticaria (17.5%), myalgia (12.5%),arthralgia (10%), pyrexia (10%), pruritus (10%), vomiting (7.5%), abdominal pain (7.5%), erythema(7.5%) and fatigue (7.5%). IAR symptoms reported most frequently in paediatric patients were pyrexia(40%), urticaria (40%), vomiting (30%), C-reactive protein increased (20%), headache (20%), nausea(20%), erythema (15%), rash (15%), serum ferritin increased (15%), abdominal pain (10%), andpruritus (10%). IARs typically occurred between the time of infusion and 24 hours after infusion end.

Hypersensitivity-related IARs, including anaphylaxis, occurred in 30% patients, 22.5% adult and 45%paediatric patients in clinical studies. The most frequently reported hypersensitivity-related IARsymptoms were urticaria (25%), pruritus (10%), erythema (10%), and rash (8.3%).

Anaphylactic reactions were reported in paediatric patients in the clinical studies and in the post-marketing setting. Anti-olipudase alfa IgE antibodies were detected in some of those patients.

Although a tailored desensitisation regimen enabled certain patients to resume long term treatment atthe recommended maintenance dose, there are also cases where desensitisation was unsuccessful, andtreatment had to be stopped due to anaphylactic reactions before reaching the maintenance dose.

In 2 adults and 3 paediatric patients, IAR symptoms were associated with changes in laboratoryparameters (e.g C-reactive protein, ferritin value) indicative of acute phase reaction.

Transient transaminase (ALT or AST) elevations within 24 to 48 hours after an infusion occurred insome patients treated with Xenpozyme during the dose escalation phase in the clinical studies. Theseelevations generally returned to the previous pre-infusion transaminase levels by the next scheduledinfusion.

Overall, after 52 weeks of treatment with Xenpozyme, mean ALT decreased 46.9% and mean ASTdecreased 40.2%, compared to baseline. In adult patients, all 16 patients with an elevated baseline

ALT had an ALT within the normal range and 10 of 12 patients with an elevated baseline AST had an

AST within the normal range.

Overall, 19 out of 40 (47.5%) adult patients and 15 out of 20 (75%) paediatric patients treated with

Xenpozyme developed treatment-emergent anti-drug antibodies (ADA). The median time toseroconversion from first Xenpozyme infusion was approximately 52 weeks in adults and 12 weeks inpaediatric patients. The majority of ADA-positive patients ( 16 out of 19 adult and 10 out of15 paediatric patients) had a low ADA response (peak titer ≤ 400) or reverted to ADA-negative. Threeadult ADA-positive patients and 4 paediatric ADA-positive patients developed intermediate ADAresponses (peak titer ranged 800-6400). Eight out of the 19 adult ADA-positive patients and 9 out ofthe 15 paediatric ADA-positive patients had Neutralizing Antibodies (NAb) that inhibited theolipudase alfa activity. Only 2 adult patients and 3 paediatric patients had NAb at more than onetimepoint. One paediatric patient experienced an anaphylactic reaction and developed IgE ADA, and

IgG ADA with a peak titer of 1600.

No effect of ADA was observed on pharmacokinetics and efficacy of Xenpozyme in adult and paediatricpopulations. There was a higher percentage of patients with treatment-emergent IARs (includinghypersensitivity reactions) in patients who developed treatment-emergent ADA versus those who didnot (70.6% versus 46.2%).

Except for a higher incidence of hypersensitivity-related IARs in paediatric patients compared toadults, the safety profile of Xenpozyme in paediatric and adult patients was similar.

Long-term use

The median exposure duration was 4.95 years (range: 0.4 to 9.6 years) in adult patients and 6.15 years(range: 4.3 to 8.2 years) in paediatric patients. Overall, the pattern of adverse events observed in adultand paediatric patients in longer term use was consistent with that observed during the first year oftreatment.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Cases of overdose of Xenpozyme have been reported in paediatric patients during dose escalation.

Some of these patients experienced serious adverse reactions within 24 hours of treatment initiation,including death. The main clinical findings included respiratory failure, hypotension, markedelevations in liver function tests, and gastrointestinal bleeding.

There is no known specific antidote for Xenpozyme overdose. In the event of overdose, the infusionshould be stopped immediately, and the patient should be monitored closely in a hospital setting forthe development of IARs including acute phase reactions. For the management of adverse reactions,see sections 4.4 and 4.8.

Pharmacotherapeutic group: Other alimentary tract and metabolism products, Enzymes, ATC code:

A16AB25

Olipudase alfa is a recombinant human acid sphingomyelinase that reduces sphingomyelin (SM)accumulation in organs of patients with Acid Sphingomyelinase Deficiency (ASMD).

The efficacy of olipudase alfa has been evaluated in 3 clinical studies (ASCEND study in adultpatients, ASCEND-Peds study in paediatric patients and an extension study in adult and paediatricpatients) involving a total of 61 patients with ASMD.

Clinical study in adult patients

The ASCEND study is a multicenter, randomised, double-blinded, placebo-controlled, repeat-dosephase II/III study in adult patients with ASMD type A/B and B. A total of 36 patients wererandomised in a 1:1 ratio to receive either Xenpozyme or placebo. Treatment was administered in bothgroups as an intravenous infusion once every 2 weeks. Patients receiving olipudase alfa were uptitrated from 0.1 mg/kg to a target dose of 3 mg/kg. The study was divided into 2 consecutive periods:

a randomised placebo-controlled, double-blinded primary analysis period (PAP) which lasted toweek 52, followed by an extension treatment period (ETP) for up to 4 years.

Patients randomised to the placebo arm in the PAP crossed over to active treatment in the ETP toreach the targeted dose of 3 mg/kg, while patients in the original Xenpozyme arm continued treatment.

Patients enrolled in the study had a diffusion capacity of the lungs for carbon monoxide (DLco) ≤ 70%of the predicted normal value, a spleen volume ≥ 6 multiples of normal (MN) measured by magneticresonance imaging (MRI) and scores ≥ 5 in splenomegaly related score (SRS). Overall, demographicand disease characteristics at baseline were similar between the two treatment groups. The medianpatient age was 30 years (range: 18-66 years). The mean (standard deviation, SD) age at ASMDdiagnosis was 18 (18.4) years. At baseline, neurologic manifestations were seen in 9 out of 36 adultpatients (25%) consistent with a clinical diagnosis of ASMD Type A/B. The remaining 27 patients hada clinical diagnosis consistent with ASMD Type B.

This study included 2 separate primary efficacy endpoints: the percentage change in DLco (in %predicted of normal) and spleen volume (in MN), as measured by MRI, from baseline to week 52.

Secondary efficacy endpoints included the percentage change in liver volume (in MN) and plateletcount from baseline to week 52. Pharmacodynamic parameters (ceramide and lyso-sphingomyelin [adeacylated form of SM] levels) were also assessed.

Improvements in mean percent change in % predicted DLco (p= 0.0004) and spleen volume(p< .0001) as well as in mean liver volume (p< .0001) and platelet count (p= 0.0185) were observed inthe Xenpozyme group as compared to the placebo group during the 52-week primary analysis period.

A significant improvement in mean percent change in % predicted DLco, spleen volume, liver volumeand platelet count was noted at week 26 of treatment, the first post-dose endpoint assessment.

The results from the PAP at week 52 are detailed in Table 6.

Table 6: Mean (SD) values for efficacy endpoints at baseline and least squares (LS) meanpercentage change (SE) from baseline to week 52

Placebo Xenpozyme Difference p value*(n=18) (n=18) [95% CI]

Primary endpoints

Mean % predicted DLco at 48.5 (10.8) 49.4 (11.0) NA NAbaseline

Percent change in % predicted 3 (3.4) 22 (3.3) 19 (4.8) 0.0004

DLco from baseline to week 52 [9.3, 28.7]

Mean spleen volume (MN) at 11.2 (3.8) 11.7 (4.9) NA NAbaseline

Percent change in spleen volume 0.5 (2.5) -39.4 (2.4) -39.9 (3.5) <0.0001from baseline to week 52 [-47.1, -32.8]

Secondary endpoints

Mean liver volume (MN) at 1.6 (0.5) 1.4 (0.3) NA NAbaseline

Percent change in liver volume -1.5 (2.5) -28.1 (2.5) -26.6 (3.6) <0.0001from baseline to week 52 [-33.9, -19.3]

Mean platelet count (109/L) at 115.6 (36.3) 107.2 (26.9) NA NAbaseline

Percent change in platelet count 2.5 (4.2) 16.8 (4.0) +14.3 (5.8) 0.0185from baseline to week 52 [2.6, 26.1]

*Statistically significant after multiplicity adjustment

In addition, lyso-sphingomyelin, which is substantially elevated in plasma of ASMD patients, declinedsignificantly, reflecting reduction of sphingomyelin content in tissue. The LS mean percentage changefrom baseline to week 52 (SE) in pre-infusion plasma lyso-sphingomyelin level was 77.7 % (3.9) inthe Xenpozyme treatment group compared to 5.0% (4.2) in the placebo group. The liversphingomyelin content, as assessed by histopathology, decreased by 92.0% (SE: 8.1) from baseline toweek 52 in the Xenpozyme treatment group (compared to +10.3% (SE: 7.8) in the placebo group).

Seventeen of 18 patients previously receiving placebo and 18 of 18 patients previously treated witholipudase alfa for 52 weeks (PAP) started or continued treatment with olipudase alfa, respectively, forup to 4 years. Sustained effects of olipudase alfa on efficacy endpoints up to week 104 are presented in

Figures 1 and 2 and Table 7.

Figure 1: Plot of the LS means (95%CI) of the percentage change in DLco (% predicted) frombaseline to week 104 - mITT population

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 dataup to week 104.

Patients in placebo/Xenpozyme group received placebo up to week 52 and switched to olipudase alfathereafter.

Figure 2: Plot of the LS means (95%CI) of the percentage change in spleen volume (MN) frombaseline to week 104 - mITT population

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 dataup to week 104.

Patients in placebo/Xenpozyme group received placebo up to week 52 and switched to olipudase alfathereafter.

Table 7: LS mean percentage change (SE) from baseline to week 104 for liver volume (MN) andplatelet count (109/L) in patients treated with olipudase alfa for 104 weeks

Previous olipudase alfa groupweek 52 (ETP start) week 104

N 17 14

Percent change in liver volume (SD) -27.8 (2.5) -33.4 (2.2)

N 18 13

Percent change in platelet count (SD) 16.6 (4.0) 24.9 (6.9)

N: number of patients

Extension study in adult patients

Five adult patients who participated in an open-label ascending dose study in ASMD patientscontinued treatment in an open-label extension study and received olipudase alfa for up to > 9 years.

Sustained improvements in % predicted DLco, spleen and liver volumes and platelet count, comparedto baseline, were noted in adult over the course of the study (see Table 8).

Table 8: Mean percentage change (SD) from baseline to month 78 of efficacy parameters

Month 78(N=5)

Percent change in % predicted DLco (SD) 55.3% (48.1)

Percent change in spleen volume (SD) -59.5% (4.7)

Percent change in liver volume (SD) -43.7% (16.7)

Percent change in platelet count (SD) 38.5% (14.7)

N: number of patients

The ASCEND-Peds study (Phase 1/2 clinical study) is a multi-center, open-label, repeated-dose studyto evaluate the safety and tolerability of olipudase alfa administered for 64 weeks in paediatric patientsaged <18 years with ASMD (type A/B and B). In addition, exploratory efficacy endpoints related toorganomegaly, pulmonary and liver functions, and linear growth were evaluated at week 52.

A total of 20 patients (4 adolescents from 12 to < 18 years old, 9 children from 6 to < 12 years old, and7 infants/ children < 6 years old) were up-titrated with olipudase alfa via a dose escalation regimenfrom 0.03 mg/kg to a target dose of 3 mg/kg. Treatment was administered as an intravenous infusiononce every 2 weeks for up to 64 weeks. Patients enrolled in the study had a spleen volume ≥ 5 MNmeasured by MRI. Patients were distributed across all ages from 1.5 to 17.5 years old, with both sexesequally represented. The mean (SD) age at ASMD diagnosis was 2.5 (2.5) years. At baseline,neurologic manifestations were seen in 8 out of 20 paediatric patients (40%) consistent with a clinicaldiagnosis of ASMD Type A/B. The remaining 12 patients had a clinical diagnosis consistent with

ASMD Type B.

Treatment with olipudase alfa 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 (see Table 9).

Table 9: LS Mean percentage change (SE) or change (SD) from baseline to week 52 (all agecohort) of efficacy parameters

Baseline value Week 52(n=20) (n=20)

Mean % predicted DLco (SD) 54.8 (14.2) 71.7 (14.8)

Percent change in % predicted DLco* 32.9 (8.3)95% CI 13.4, 52.5

Mean spleen volume (MN) (SD) 19.0 (8.8) 9.3 (3.9)

Percent change in spleen volume (in MN) -49.2 (2.0)95% CI -53.4, -45.0

Mean liver volume (MN) (SD) 2.7 (0.7) 1.5 (0.3)

Percent change in liver volume (in MN) -40.6 (1.7)95% CI -44.1, -37.1

Mean platelet count (109/L) (SD) 137.7 (62.3) 173.6 (60.5)

Percent change in platelet count 34.0 (7.6)95% CI 17.9, 50.1

Mean height Z-scores (SD) -2.1 (0.8) -1.6 (0.8)

Change in height Z-scores* 0.6 (0.4)95% CI (0.38,0.73)

*DLco was evaluated in 9 paediatric patients aged ≥ 5 years who were able to perform the test, changein height Z-score was evaluated in 19 paediatric patients.

In addition, LS mean pre-infusion plasma ceramide and lyso-sphingomyelin levels were reduced by57% (SE: 5.1) and 87.2% (SE: 1.3), respectively, compared to baseline following 52 weeks oftreatment.

The effects of olipudase alfa on spleen and liver volumes, platelets and height z-scores were seenacross all paediatric age cohorts included in the study.

Extension study paediatric patients

Twenty paediatric patients who participated in ASCEND-Peds study continued treatment in an open-label extension study and received olipudase alfa for up to > 8 years.

Sustained improvements in efficacy parameters (% predicted DLco, spleen and liver volumes, plateletcounts, height Z-scores and bone age) were noted in paediatric patients over the course of the study upto month 48 (see Table 10).

Table 10: Mean percentage change or change (SD) from baseline to month 48 (all age cohort) ofefficacy parameters

Month 48

N 5

Percent change in % predicted DLco (SD) 60.3 (58.5)

N 7

Percent change in spleen volume (SD) -69.1 (4.1)

N 7

Percent change in liver volume (SD) -55.4 (11.0)

N 5

Percent change in platelet count (SD) 35.8 (42.4)

N 5

Change in height Z-scores (SD) 2.3 (0.8)

N 7

Change in bone age (months) (SD) 18.5 (19.0)

N: number of patients

The pharmacokinetics (PK) of olipudase alfa were assessed in 49 adult ASMD patients from allclinical studies, receiving single or multiple administrations. At the dose of 3 mg/kg administered onceevery 2 weeks, the mean (percent coefficient of variation, CV%) maximum concentration (Cmax) andarea under the concentration-time curve over a dosing interval (AUC0-τ) at steady state were30.2 µg/mL (17%) and 607 µg.h/mL (20%), respectively.

There is no absorption since Xenpozyme is administered intravenously.

The estimated mean (CV%) volume of distribution of olipudase alfa is 13.1 L (18%).

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

The mean (CV%) clearance of olipudase alfa is 0.331 L/h (22%). The mean terminal half-life (t1/2)ranged from 31.9 to 37.6 hours.

Olipudase alfa exhibited linear pharmacokinetics over the dose range of 0.03 to 3 mg/kg. Following adose escalation regimen from 0.1 to the maintenance dose of 3 mg/kg administered once every2 weeks, there was minimal accumulation in plasma levels of olipudase alfa.

There were no clinically relevant differences in olipudase alfa pharmacokinetics based on gender.

Population pharmacokinetic analysis indicated that the exposure in Asian (n=2) and other race patients(n=2) were within the exposure ranges observed for Caucasian patients.

Elderly (≥ 65 years old)

Population pharmacokinetic analysis did not indicate a difference in exposure in elderly (only2 patients between 65 and 75 years of age were included in clinical studies with Xenpozyme).

Paediatric

The PK of olipudase alfa were assessed in 20 paediatric patients including 4 adolescent patients,9 child patients and 7 child/infant patients (Table 11). Olipudase alfa exposures were lower inpaediatric patients compared to those in adult patients. However, these differences were notconsidered to be clinically relevant.

Table 11: Mean (CV%) of olipudase alfa PK parameters following administration of 3 mg/kgevery 2 weeks in adolescent, child and child/infant patients with ASMD

Age Group Age (year) Cmax (µg/mL) AUC0-τ (µg.h/mL)

Adolescent (n=4) 12, < 18 27.5 (8) 529 (7)

Child (n=9) 6, < 12 24.0 (10) 450 (15)

Child/Infant (n=7) < 6 22.8 (8) 403 (11)

Descriptive statistics represent the post hoc estimates of steady-state exposures usingpopulation PK analysis.

AUC0-τ: area under the plasma concentration versus time curve over a dosing interval;

Cmax: maximum plasma concentration; n: total number of patients.

Olipudase alfa is a recombinant protein and is expected to be eliminated by proteolytic degradation.

Therefore, impaired liver function is not expected to affect the pharmacokinetics of olipudase alfa.

Four patients (11.1%) with mild renal impairment (60 mL/min ≤ creatinine clearance < 90 mL/min)were included in the ASCEND study. There were no clinically relevant differences in olipudase alfapharmacokinetics in patients with mild renal impairment. The impact of moderate to severe renalimpairment on the pharmacokinetics of olipudase alfa is not known. Olipudase alfa is not expected tobe eliminated through renal excretion. Therefore, renal impairment is not expected to affect thepharmacokinetics of olipudase alfa.

Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, singledose toxicity and repeated dose toxicity conducted in wild type animals (mice, rats, rabbits, dogs andmonkeys) at dose levels 10 times above the Maximum recommended human dose (MRHD). Studies toevaluate the mutagenic and carcinogenic potential of olipudase alfa have not been performed.

In acid sphingomyelinase knockout (ASMKO) mice (a disease model for ASMD), mortality wasobserved following an administration of single doses of olipudase alfa ≥ 3.3 times higher than MRHDas an intravenous bolus injection. However, repeat dose studies show that administration of olipudasealfa via a dose escalation regimen did not result in compound-related mortality and reduced theseverity of other toxicity findings up to the highest tested dose of 10 times the MRHD.

An increased incidence of exencephaly was observed when pregnant mice were treated daily witholipudase alfa at exposure levels less than the human exposure at the recommended maintenancetherapeutic dose and frequency. This incidence was slightly higher than historical control data. Therelevance of this observation for humans is unknown. The daily intravenous administration ofolipudase alfa to pregnant rabbits did not result in foetal malformations or variations at exposuressignificantly exceeding the human exposure at the recommended maintenance therapeutic dose andfrequency.

In mice administered 3 mg/kg olipudase alfa on postpartum day 7, olipudase alfa was detected in milk2 days after administration.

L-methionine

Sodium phosphate dibasic heptahydrate

Sodium phosphate monobasic monohydrate

Sucrose

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

Unopened vials60 months.

After reconstitution with sterile water for injection, chemical, physical and microbiological in-usestability has been demonstrated for up to 24 hours at 2-8°C or 6 hours at room temperature (up to25°C).

From a microbiological point of view, the reconstituted medicinal product should be usedimmediately. If not used for dilution immediately, in-use storage times and conditions prior to dilutionare the responsibility of the user and would normally not be longer than 24 hours at 2°C - 8°C.

After dilution with sodium chloride 9 mg/mL (0.9%) solution for injection, chemical, physical andmicrobiological in-use stability has been demonstrated between 0.1 mg/mL and 3.5 mg/mL for24 hours at 2-8°C, and up to 12 hours (including infusion time) when stored at room temperature (upto 25°C).

From a microbiological point of view, the diluted medicinal product should be used immediately. Ifnot used immediately after dilution, in-use storage times and conditions are the responsibility of theuser and should normally not be longer than 24 hours at 2°C to 8°C followed by 12 hours (includinginfusion time) at room temperature (up to 25°C).

Store in a refrigerator (2°C - 8°C).

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

Xenpozyme 4 mg powder for concentrate for solution for infusion4 mg of powder for concentrate for solution for infusion in a 5 mL vial (Type I glass) with asiliconized chlorobutyl-elastomer lyophilization stopper, and an aluminum seal with a plastic flip-offcap.

Each pack contains 1, 5 or 10 vials. Not all pack sizes may be marketed.

Xenpozyme 20 mg powder for concentrate for solution for infusion20 mg of powder for concentrate for solution for infusion in a 20 mL vial (Type I glass) with asiliconized chlorobutyl-elastomer lyophilization stopper, and an aluminum seal with a plastic flip-offcap.

Each pack contains 1, 5, 10 or 25 vials. Not all pack sizes may be marketed.

Vials are for single use only.

Infusions should be administered in a stepwise manner preferably using an infusion pump.

Preparation of the dosing solution

The powder for concentrate for solution for infusion must be reconstituted with sterile water forinjection, diluted with sodium chloride 9 mg/mL (0.9%) solution for injection and then administeredby intravenous infusion.

The reconstitution and dilution steps must be completed under aseptic conditions. Filtering devicesshould not be used at any time during the preparation of the infusion solution. Avoid foaming duringreconstitution and dilution steps.

1) Determine the number of vials to be reconstituted based on the individual patient’s weight andthe prescribed dose.

Patient weight (kg) × dose (mg/kg) = patient dose (in mg). For example, when using 20 mgvials, patient dose (in mg) divided by 20 mg/vial = number of vials to reconstitute. If thenumber of vials includes a fraction, round up to the next whole number.

2) Remove the required number of vials from refrigeration and set aside for approximately 20 to30 minutes to allow them to reach room temperature.

3) Reconstitute each vial by injecting:

1.1 mL of sterile water for injection into the 4 mg vial5.1 mL of sterile water for injection into the 20 mg vialusing a slow drop-wise addition technique to the inside wall of the vial.

4) Tilt and roll each vial gently. Each vial will yield a 4 mg/mL clear, colorless solution.

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

Xenpozyme solution should be clear and colorless. Any vials exhibiting opaque particles ordiscoloration should not be used.

6) Withdraw the volume of reconstituted solution, corresponding to the prescribed dose, from theappropriate number of vials and dilute with sodium chloride 9 mg/mL (0.9%) solution forinjection, in a syringe or infusion bag depending on the volume of infusion (see Table 12 for therecommended total infusion volume based on patients age and/or weight).

Table 12: Recommended infusion volumes

Body weight Body weight Body weight Adult patients≥3 kg to <10 kg ≥10 kg to <20 kg ≥20 kg (paediatric (≥18 years)patients <18 years)

Dose Total infusion Total infusion Total infusion Total infusion(mg/kg) volume (mL) volume (mL) volume (mL) volume (mL)0.03 Variable volume will Variable volume 5 NAvary based on body will vary based onweight body weight0.1 Variable volume will 5 10 20vary based on bodyweight0.3 5 10 20 1000.6 10 20 50 1001 20 50 100 1002 50 75 200 1003 50 100 250 100

* For variable final volumes of infusion based on body weight in paediatric patients (see Table12):

- Prepare an infusion solution at 0.1 mg/mL by adding 0.25 mL (1 mg) of the reconstitutedsolution prepared in step 3) and 9.75 mL of sodium chloride 9 mg/mL (0.9%) solution forinjection in an empty 10 mL syringe.

- Calculate the volume (mL) required to obtain the patient dose (mg).

Example: 0.3 mg ÷ 0.1 mg/mL = 3 mL

* Dilution instructions for 5 mL ≤ total volume ≤ 20 mL using a syringe:

- Inject the required volume of the reconstituted solution slowly to the inside wall of the emptysyringe.

- Add slowly the sufficient quantity of sodium chloride 9 mg/mL (0.9%) solution for injectionto obtain the required total infusion volume (avoid foaming within the syringe).

* Dilution instructions for a total volume ≥ 50 mL using an infusion bag:

- Empty infusion bag:

o Inject slowly the required volume of the reconstituted solution from step 3) in theappropriate size sterile infusion bag.

o Add slowly the sufficient quantity of sodium chloride 9 mg/mL (0.9%) solutionfor injection to obtain the required total infusion volume (avoid foaming withinthe bag).

- Pre-filled infusion bag:

o Withdraw from the infusion bag pre-filled with sodium chloride 9 mg/mL (0.9%)solution for injection the volume of normal saline to obtain a final volume asspecified in Table 12.

o Add slowly the required volume of the reconstituted solution from step 3) into theinfusion bag (avoid foaming within the bag).

7) Gently invert the syringe or the infusion bag to mix. Do not shake. Because this is a proteinsolution, slight flocculation (described as thin translucent fibers) occurs occasionally afterdilution.

8) The diluted solution must be filtered through an in-line low protein-binding 0.2 μm filter duringadministration.

9) After the infusion is complete, the infusion line should be flushed with sodium chloride9 mg/mL (0.9%) solution for injection using the same infusion rate as the one used for the lastpart of the infusion.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Sanofi B.V.

Paasheuvelweg 251105 BP Amsterdam

The Netherlands

EU/1/22/1659/001

EU/1/22/1659/002

EU/1/22/1659/003

EU/1/22/1659/004

EU/1/22/1659/005

EU/1/22/1659/006

EU/1/22/1659/007

Date of first authorisation: 24 June 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.