KANUMA 2mg / ml concentrate for solution for infusion medication leaflet

KANUMA 2 mg/ml concentrate for solution for infusion

Each ml of concentrate contains 2 mg sebelipase alfa*.

Each vial of 10 ml contains 20 mg sebelipase alfa.

* produced in egg white of transgenic Gallus by recombinant DNA (rDNA) technology.

Each vial contains 33 mg sodium.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

Clear to slightly opalescent, colourless to slightly coloured solution.

KANUMA is indicated for long-term enzyme replacement therapy (ERT) in patients of all ages withlysosomal acid lipase (LAL) deficiency.

KANUMA treatment should be supervised by a healthcare professional experienced in themanagement of patients with LAL deficiency, other metabolic disorders, or chronic liver diseases.

KANUMA should be administered by a trained healthcare professional who can manage medicalemergencies.

It is important to initiate treatment as early as possible after diagnosis of LAL deficiency.

For instructions on the preventive measures and monitoring of hypersensitivity reactions, seesection 4.4. Following the occurrence of a hypersensitivity reaction, appropriate pre-treatment shouldbe considered according to the standard of care (see section 4.4).

Patients with Rapidly Progressive LAL Deficiency Presenting within the First 6 Months of Life

The recommended starting dose in infants (< 6 months of age) presenting with rapidly progressive

LAL deficiency is either 1 mg/kg or 3 mg/kg administered as an intravenous infusion once weekly,depending on the clinical status of the patient. A higher starting dose of 3 mg/kg should be consideredbased on the severity of the disease and rapid disease progression.

Dose escalations should be considered based on suboptimal response to clinical and biochemicalcriteria, including, e.g., poor growth (especially mid-upper arm circumference, MUAC), deterioratingbiochemical markers (e.g. liver transaminases, ferritin, C-reactive Protein, and coagulationparameters), persistent or worsening organomegaly, increased frequency of intercurrent infections,and persistent worsening of other symptoms (e.g. gastrointestinal symptoms):

- a dose escalation to 3 mg/kg should be considered in case of suboptimal clinical response;

- a further dose escalation up to 5 mg/kg should be considered in case of persistent suboptimalclinical response.

Further dose adjustments, as a reduction of the dose or an extension of the dose interval, can be madeon an individual basis based on achievement and maintenance of therapeutic goals. Clinical studiesevaluated doses ranging from 0.35 to 5 mg/kg once weekly, with one patient receiving a higher doseof 7.5 mg/kg once weekly. Doses higher than 7.5 mg/kg have not been studied.

Pediatric and Adult Patients with LAL Deficiency

The recommended dose in children and adults who do not present with rapidly progressive LALdeficiency prior to 6 months of age is 1 mg/kg administered as an intravenous infusion once everyother week. Dose escalation to 3 mg/kg once every other week should be considered based onsuboptimal response to clinical biochemical criteria, including; e.g., poor growth persistent ordeteriorating biochemical markers (e.g., parameters of liver injury (ALT, AST), parameters of lipidmetabolism (TC, LDL-c, HDL-c, TG), persistent or worsening organomegaly, and persistentworsening of other symptoms (e.g., gastrointestinal symptoms).

No dosing adjustment is recommended in patients with renal impairment based on current knowledgeof the pharmacokinetics and pharmacodynamics of sebelipase alfa (see section 5.2).

No dosing adjustment is recommended in patients with hepatic impairment based on currentknowledge of the pharmacokinetics and pharmacodynamics of sebelipase alfa (see section 5.2).

Elderly population ( 65 years old)

The safety and efficacy of sebelipase alfa in patients older than 65 years have not been evaluated andno alternative dose regimens can be recommended for these patients (see section 5.1).

Overweight patients

The safety and efficacy of sebelipase alfa in overweight patients have not been thoroughly evaluatedand therefore no alternative dose regimens can be recommended for these patients at this time.

Administration of sebelipase alfa to infants with confirmed multiple-organ failure should be at thediscretion of the treating physician.

KANUMA is for intravenous (IV) use only.

The total volume of the infusion should be administered over approximately 2 hours. A 1-hourinfusion may be considered for those patients receiving the 1 mg/kg dose after patient tolerability isestablished. (For the recommended infusion volumes, see section 6.6.) The infusion period may beextended in the event of dose escalation.

KANUMA should be administered through a 0.2 μm filter (see section 6.6).

For instructions on dilution of the medicinal product before administration, see section 6.6.

Life-threatening hypersensitivity (anaphylactic reaction) to the active substance when attempts torechallenge are unsuccessful, or to egg or any of the excipients listed 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 product should be clearly recorded.

Hypersensitivity reactions, including anaphylaxis, have been reported in patients treated withsebelipase alfa; see section 4.8. Therefore, appropriate medical support must be readily availablewhen sebelipase alfa is administered. If severe reactions occur, the sebelipase alfa infusion should beimmediately stopped and appropriate medical treatment should be initiated. The risks and benefits ofre-administering sebelipase alfa following a severe reaction should be considered.

Following the first sebelipase alfa infusion, including the first infusion after a dose escalation, patientsshould be observed for 1 hour in order to monitor for any signs or symptoms of anaphylaxis or asevere hypersensitivity reaction.

The management of hypersensitivity reactions may include temporarily interrupting the infusion,lowering the infusion rate, and/or treatment with antihistamines, antipyretics, and/or corticosteroids.

For patients who have experienced allergic reactions during infusion, caution should be exercisedupon re-administration. If interrupted, the infusion may be resumed at a slower rate with increases astolerated. Pre-treatment with antipyretics and/or antihistamines may prevent subsequent reactions inthose cases where symptomatic treatment was required.

In cases of severe infusion reactions and in cases of lack or loss of effect, patients should be tested forthe presence of antibodies.

This medicinal product may contain traces of egg proteins. Patients with known egg allergies wereexcluded from clinical studies (see section 4.3).

As with all therapeutic proteins, there is potential for immunogenicity. In the sebelipase alfa clinicalprogram, patients were routinely tested for anti-sebelipase alfa anti-drug antibodies (ADAs) todetermine the immunogenicity potential of sebelipase alfa. Patients who tested positive for ADAswere also tested for inhibitory antibody activity. The presence of inhibitory activity has been detectedat some postbaseline timepoints in clinical studies (see section 4.8). Overall, no conclusion on therelationship between development of ADAs/NAbs and associated hypersensitivity reactions orsuboptimal clinical response can be made.

In clinical studies, 3 patients homozygous for a deletion affecting both alleles of genes Lipase A,lysosomal acid [LIPA] and Cholesterol 25-Hydroxylase developed inhibitory antibody activityassociated with a suboptimal clinical response. These patients underwent either immunomodulatorytherapy alone or in combination with haematopoietic stem cell transplant (HSCT) or bone marrowtransplant (BMT), resulting in improved clinical response to sebelipase alfa.

This medicinal product contains 33 mg sodium per vial equivalent to 1.7% of the WHO recommendedmaximum daily intake of 2 g sodium for an adult. It is administered in sodium chloride 9 mg/ml(0.9%) solution for infusion (see section 6.6). This should be taken into consideration by patients on acontrolled sodium diet.

No interaction studies have been performed.

Because it is a recombinant human protein, sebelipase alfa is an unlikely candidate for cytochrome

P450 mediated or other drug-drug interactions.

There are no or limited data from the use of sebelipase alfa in pregnant women. Animal studies do notindicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As aprecautionary measure, it is preferable to avoid use of sebelipase alfa during pregnancy.

There are no data from studies in breast-feeding women. It is not known whether sebelipase alfa isexcreted in human milk. A decision must be made whether to discontinue breast-feeding or todiscontinue/abstain from sebelipase alfa therapy taking into account the benefit of breast-feeding forthe child and the benefit of therapy for the woman.

There are no clinical data on the effects of sebelipase alfa on fertility. Animal studies show noevidence of impaired fertility (see section 5.3).

KANUMA may have a minor influence on the ability to drive and use machines. Adverse events ofdizziness have been reported with the use of sebelipase alfa, which could affect the ability to drive oruse machines (see section 4.8).

The data described below reflect the exposure to sebelipase alfa in 125 patients at doses ranging from0.35 mg/kg once every other week to 7.5 mg/kg once weekly in clinical studies (see section 5.1), witha treatment duration range from 1 day to 60.5 months (5 years).

Of the 106 children and adults enrolled in clinical studies, 102 (96.2%) have received sebelipase alfaat a dosage regimen of 1 mg/kg once every other week, with a median duration of exposure of 33months (6, 59 months). The median duration of exposure for the 19 infants enrolled in clinical studieswas 35.5 months (1 day to 60 months).

The most serious adverse reactions experienced by 4% of patients in clinical studies were signs andsymptoms consistent with anaphylaxis. Signs and symptoms included chest discomfort, conjunctivalhyperaemia, dyspnoea, hyperaemia, eyelid oedema, rhinorrhoea, severe respiratory distress,tachycardia, tachypnoea, irritability, flushing, pruritus, urticaria, stridor, hypoxia, pallor anddiarrhoea.

The data in Table 1 describe adverse reactions reported in infants who received sebelipase alfa inclinical studies. The data in Table 2 describe adverse reactions reported in children and adults whoreceived sebelipase alfa in clinical studies.

Adverse reactions are listed by system organ class (SOC) and frequency. Frequencies are definedaccording to the following convention: very common ( 1/10); common ( 1/100 to < 1/10),uncommon ( 1/1,000 to < 1/100), rare ( 1/10,000 to < 1/1,000), very rare (< 1/10,000) and notknown (cannot be estimated from the available data).

Table 1: Adverse reactions reported in infants receiving sebelipase alfa (N = 19 patients)

MedDRA System organ class MedDRA Preferred Term Frequencya

Immune system disorders Hypersensitivity Very common

Anaphylactic reactionb

Eye Disorders Eyelid oedema Very common

Cardiac disorders Tachycardia Very common

Respiratory, thoracic and mediastinal Respiratory distress Very commondisorders

Gastrointestinal disorders Vomiting Very common

Skin and subcutaneous tissue disorders Rash Very common

Rash maculo-papular

General disorders and administration Pyrexia Very commonsite conditions Hyperthermia

Drug specific antibody present Very common

Body temperature increased

Investigations Oxygen saturation decreased

Blood pressure increased

Heart rate increased

Respiratory rate increaseda May include: irritability, agitation, vomiting, urticaria, eczema, pruritus, pallor, and drughypersensitivityb Occurred in 3 infant patients treated in clinical studies. Based on Preferred Term ‘anaphylacticreaction’ and application of Sampson criteria to identify signs/symptoms consistent with anaphylaxis.

Table 2: Adverse reactions reported in children and adults receiving sebelipase alfa (N = 106patients)

MedDRA System organ class MedDRA preferred term Frequency

Hypersensitivityb Very Common

Anaphylactic reactiona Common

Nervous system disorders Dizziness Very common

Cardiac disorders Tachycardia Common

Vascular disorders Hyperaemia

Hypotension Common

Respiratory, thoracic and mediastinaldisorders Dyspnoea Common

Abdominal pain

Gastrointestinal disorders Diarrhoea Very common

Abdominal distension Common

Skin and subcutaneous tissue disorders Rash Common

Rash papular

General disorders and administration Pyrexia Very commonsite conditions Chest discomfort

Infusion site reactionc Common

Investigations Body temperature increased Commona Occurred in 2 patients treated in clinical studies. Based on Preferred Term ‘anaphylactic reaction’and application of Sampson criteria to identify signs/symptoms consistent with anaphylaxis.b May include: chills, eczema, laryngeal oedema, nausea, pruritus, urticaria.c Includes: infusion site extravasation, infusion site pain and infusion site urticaria

Five of 125 (4%) patients treated with sebelipase alfa, including 3 of 19 (16%) infants and 2 of 106(2%) children and adults, in clinical studies experienced serious signs and symptoms consistent withanaphylaxis to sebelipase alfa. Anaphylaxis occurred during the infusion as late as 1 year aftertreatment initiation.

In clinical studies, 59 of 125 (47%) sebelipase alfa-treated patients, including 13 of 19 (68%) infantsand 46 of 106 (43%) children and adults, experienced at least 1 hypersensitivity reaction (selectedusing a validated, pre-determined set of terms grouped together to identify potential hypersensitivityreactions). Signs and symptoms either consistent with or that may be related to a hypersensitivityreaction occurring in two or more patients included but were not limited to abdominal pain, agitation,bronchospasm, chills, diarrhoea, eyelid oedema, eczema, face oedema, hypertension, irritability,laryngeal oedema, lip swelling, nausea, oedema, pallor, pruritus, pyrexia/body temperature increased,rash, tachycardia, urticaria, and vomiting. The majority of reactions occurred during or within 4 hoursof the completion of the infusion.

Transient hyperlipidaemia

Consistent with its known mechanism of action, asymptomatic increases in circulating cholesterol andtriglycerides have been observed following initiation of treatment. These increases have generallyoccurred within the first 2 to 4 weeks and improved within a further 8 weeks of treatment. Seesection 5.1.

There is potential for immunogenicity (see section 4.4). Patients have developed anti-drug antibodies(ADA) to sebelipase alfa. Compared to children and adults, an increased occurrence of ADApositivity was observed within the infant population (10/19 patients).

Among 125 patients with LAL Deficiency enrolled in the clinical studies, 19/125 (15.0%) patientstested positive for anti-drug antibodies (ADAs) at some timepoint after starting treatment withsebelipase alfa (9 children and adult patients and 10 infants). For children and adult patients with LAL

Deficiency, ADA positivity was transient with generally low titers of ADAs reported. Persistence of

ADA positivity was observed for all 10 infants and persistence of high titer ADAs was observed for 3of the 10 infants. Among those 19 patients, 11 (58%) also showed the presence of inhibitory antibodyactivity (NAbs) at some postbaseline timepoint.

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.

In clinical studies, doses of sebelipase alfa were explored up to 7.5 mg/kg once weekly and nospecific signs or symptoms were identified following the higher doses. For management of adversereactions, see sections 4.4 and 4.8.

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

A16AB14

Lysosomal acid lipase (LAL) deficiency

LAL deficiency is a rare disease associated with significant morbidity and mortality, which affectsindividuals from infancy through adulthood. LAL deficiency presenting in infants is a medicalemergency with rapid disease progression over a period of weeks that is typically fatal within the first6 months of life. LAL deficiency is an autosomal recessive lysosomal storage disorder characterisedby a genetic defect resulting in a marked decrease or loss in activity of the lysosomal acid lipase(LAL) enzyme.

Deficient LAL enzyme activity results in the lysosomal accumulation of cholesteryl esters andtriglycerides in a variety of cell populations, organs and organ systems, among them hepatocytes andmacrophages. In the liver, this accumulation leads to hepatomegaly, increased hepatic fat content,transaminase elevation signaling chronic liver injury, and progression to fibrosis, cirrhosis, andcomplications of end-stage liver disease. In the spleen, LAL deficiency results in splenomegaly,anaemia, and thrombocytopenia. Lipid accumulation in the intestinal wall leads to malabsorption andgrowth failure. Dyslipidaemia is common, with elevated low-density lipoprotein cholesterol (LDL-C)and triglycerides and low high-density lipoprotein cholesterol (HDL-C), associated with increase liverfat content and transaminase elevations. In addition to liver disease, patients with LAL deficiencyexperience increased risk for cardiovascular disease and accelerated atherosclerosis.

Sebelipase alfa is a recombinant human lysosomal acid lipase (rhLAL).

Sebelipase alfa binds to cell surface receptors via glycans expressed on the protein and issubsequently internalised into lysosomes. Sebelipase alfa catalyses the lysosomal hydrolysis ofcholesteryl esters and triglycerides to free cholesterol, glycerol and free fatty acids. Replacement of

LAL enzyme activity leads to reductions in liver fat content and transaminases, and enablesmetabolism of cholesteryl esters and triglycerides in the lysosome, leading to reductions in LDL-Cand non- HDL-C, triglycerides, and increases in HDL-C. Improvement in growth occurs as a result ofsubstrate reduction in the intestine.

Clinical studies

Infants presenting with LAL deficiency

Study LAL-CL03

LAL-CL03 was a multicentre, open-label, single-arm study of sebelipase alfa in 9 patients under 24months of age with a confirmed diagnosis of LAL deficiency and growth failure with onset before6 months of age. Patients also had rapidly progressive liver disease and severe hepatosplenomegaly.

The median age of patients at the time of initiation of dosing was 3 months (range = 1 to 6 months).

The median duration of exposure to sebelipase alfa was 55.6 months per patient (range = 1 day to 60months). Patients received sebelipase alfa at 0.35 mg/kg once weekly (qw) for the first 2 weeks andthen 1 mg/kg once weekly. Based on clinical response, dose escalation to 3 mg/kg once weeklyoccurred as early as 1 month and up to 20 months after starting treatment at 1 mg/kg qw for 6 patients.

Two of these 6 patients were subsequently dose escalated to 5 mg/kg once weekly, as allowed by thestudy protocol.

Efficacy was assessed by comparing the survival experience of sebelipase alfa-treated patients whosurvived past 12 months of age in Study LAL-CL03 with a historical cohort of untreated infantspresenting with LAL deficiency with similar clinical characteristics. In LAL-CL03, 6 of 9 sebelipasealfa-treated infants survived beyond 12 months (67% 12-month survival, 95% CI: 30% to 93%). Withcontinued treatment until 48 months of age, 1 additional patient died at age 15 months. In thehistorical cohort, 0 of 21 patients survived beyond 8 months of age (0% 12-month survival, 95% CI:0% to 16%).

Sebelipase alfa resulted in improvements in alanine aminotransferase (ALT)/aspartateaminotransferase (AST) levels (indicating a decrease in liver injury) and in weight gain;improvements were noted within the first several weeks of treatment and were maintained through theend of the study. From baseline to Week 240 (Month 60), the mean reductions for ALT and ASTwere -43.5 U/l and -45.25 U/l, respectively. From baseline to Week 240, mean weight-for-agepercentile improved from 12.74% to 43.17% and mean serum albumin levels increased from 26.9 g/lto 31.98 g/l. Dose escalation to 3 mg/kg once weekly was associated with additional improvements inweight gain, lymphadenopathy and serum albumin.

Study LAL-CL08

Study LAL-CL08 was a multicentre, open-label study of sebelipase alfa in 10 infants ≤ 8 months ofage with confirmed diagnosis of rapidly progressive LAL deficiency requiring urgent intervention,including but not restricted to marked abdominal distension and hepatomegaly, failure to thrive,disturbance of coagulation, severe anaemia, and/or a sibling with a rapidly progressive course of LALdeficiency.

The median age of the study patients on the date of their first infusion of sebelipase alfa was 3 months(range: 0.5 to 4 months). Eight (80%) patients completed the study. The median duration of exposurewas 34 months (range: 1 to 37 months). Two (20%) patients were considered early terminated due todeath. All 10 patients received a starting dose of 1 mg/kg qw. The 9 patients who survived beyond

Week 4 each received a dose escalation to 3 mg/kg qw, and 7 of these patients received a subsequentdose escalation to 5 mg/kg qw, as allowed per study protocol. One patient received a further doseescalation to 7.5 mg/kg qw. Two patients had a subsequent dose reduction, which occurred aftersuccessful transplant procedures; one patient received a BMT and the other patient received a HSCT.

The percentages (95% confidence intervals [CIs]) of patients surviving to 12, 18, 24, and 36 monthsof age were 90% (55.5%, 99.7%), 80% (44.4%, 97.5%), 80% (44.4%, 97.5%), and 75% (34.9%,96.8%), respectively. Two patients were < 36 months of age at the time of study completion and wereexcluded from the analysis for survival to 36 months. Reductions in AST, gamma glutamyltransferase(GGT), and total bilirubin and increases in serum albumin were observed in the overall studypopulation, with median changes from baseline to last assessment of -34.5 U/L, -66.67 IU/L, -63.64μmol/L, and 33.33 g/L, respectively.

Height and weight increased gradually. Median changes from baseline in Z-scores for weight forheight (WFH) were decreases through Week 4. Starting from Week 24, there were consistentimprovements. At Week 144, the median change (range) in Z-scores for WFH was 3.07 (-1.0, 5.3)from baseline.

Children and adults with LAL deficiency

Study LAL-CL02

Study LAL-CL02 was a multicentre, double-blind, placebo-controlled study in 66 children and adultswith LAL deficiency. Patients were randomised to receive sebelipase alfa at a dose of 1 mg/kg(n = 36) or placebo (n = 30) once every other week (qow) for 20 weeks in the double-blind period.

The mean age range at randomisation was 16.5 years, range 4-58 years (36% were < 12 years old and71% were < 18 years old). For study entry, patients were required to have ALT levels of 1.5 X upperlimit of normal (ULN). The majority of patients (58%) had LDL-cholesterol > 190 mg/dl at studyentry, and 24% of patients with LDL-cholesterol > 190 mg/dl were on lipid lowering medicinalproducts. Of the 32 patients who had a liver biopsy at study entry, 100% had fibrosis and 31% hadcirrhosis. The age range of patients with biopsy evidence of cirrhosis was 4-21 years.

The following endpoints were assessed: normalisation of ALT, decrease in LDL-cholesterol, decreasein non-HDL-cholesterol, normalisation of AST, decrease in triglycerides, increase in HDL-cholesterol, decrease in liver fat content assessed by multi-echo gradient echo magnetic resonanceimaging (MEGE-MRI), and improvement in hepatic steatosis measured by morphometry.

A statistically significant improvement in multiple endpoints was observed in the sebelipase alfa-treated group as compared to the placebo group at the completion of the 20-week double-blind periodof the study, as shown in Table 3. The absolute reduction in mean ALT level was -57.9 U/l (-53%) inthe sebelipase alfa-treated group and -6.7 U/l (-6%) in the placebo group.

Table 3: Primary and secondary efficacy endpoints in LAL-CL02

Sebelipase

Endpoint alfa Placebo P-valued(n = 36) (n = 30)

Primary Endpoint

Normalisation of ALTa 31% 7% 0.0271

Secondary Endpoints

LDL-cholesterol, mean % change from baseline -28% -6% < 0.0001

Non-HDL-cholesterol, mean % change from baseline -28% -7% < 0.0001

Normalisation of ASTb 42% 3% 0.0003

Triglycerides, mean % change from baseline -25% -11% 0.0375

HDL-cholesterol, mean % change from baseline 20% -0.3% < 0.0001

Liver fat content c, mean % change from baseline -32% -4% < 0.0001a Proportion of patients who achieved normalisation defined as 34 or 43 U/l, depending on age andgender.

b Proportion of patients who achieved normalisation defined as 34-59 U/l, depending on age andgender. Evaluated in patients with abnormal baseline values (n = 36 for sebelipase alfa; n = 29 forplacebo).

c Evaluated in patients with MEGE-MRI assessments performed (n = 32 for sebelipase alfa; n = 25for placebo).

d P-values are from Fisher’s exact test for normalisation endpoints and Wilcoxon rank-sum test forall other endpoints.

Paired liver biopsies at baseline and week 20 were available in a subset of patients (n = 26). Ofpatients with paired liver biopsies, 63% (10/16) of sebelipase alfa-treated patients had improvement inhepatic steatosis (at least  5% reduction) as measured by morphometry compared to 40% (4/10) ofplacebo patients. This difference was not statistically significant.

Open-label period

Patients who participated in Study LAL-CL02 were eligible to continue treatment in an open-labelperiods of the study. 66 patients entered the first open-label period (up to 130 weeks) at a sebelipasealfa dose of 1 mg/kg once every other week. In patients who had received sebelipase alfa during thedouble-blind period, reductions in ALT levels during the first 20 weeks of treatment were maintainedand further improvements were seen in lipid parameters including LDL-cholesterol and

HDL-cholesterol levels. Twelve (12) of 66 patients in the open label period were dose escalated to 3mg/kg once every other week based on clinical response.

Placebo patients had persistently elevated serum transaminase and abnormal serum lipid levels duringthe double-blind period. Consistent with what was observed in sebelipase alfa-treated patients duringthe double-blind period, initiation of treatment with sebelipase alfa during the open-label periodproduced rapid improvements in ALT levels and in lipid parameters including LDL-cholesterol and

HDL-cholesterol levels.

Improvements in ALT levels and in lipid parameters (LDL-cholesterol and HDL-cholesterol levels)were maintained during the open-label expanded treatment period for up to 256 weeks (5 years), withoverall mean treatment duration of 42.5 months.

Study LAL-CL01/LAL-CL04

In a separate open-label study (LAL-CL01/LAL-CL04) in adult patients with LAL deficiency,improvements in serum transaminase and lipid levels were sustained through the 260-week treatmentperiod. Eight of nine patients transitioned from Study LAL-CL01 after 4 weeks of treatment (0.35mg/kg qw, 1 mg/kg qw, or 3 mg/kg qw) to Study LAL-CL04 (1 mg/kg qow or 3 mg/kg qow), with 5patients receiving a dose of 1 mg/kg qow and 3 patients receiving a dose of 3 mg/kg qow. Increases inserum transaminases and LDL-cholesterol and decreases in HDL-cholesterol were observed duringthe period in which patients were off treatment with sebelipase alfa.

Study LAL-CL06

LAL-CL06 was a multicenter, open-label study in 31 children and adults with LAL deficiency andwas designed to include patients who may have been ineligible for previous clinical studies due toage, disease progression, previous treatment by haematopoietic stem cell or liver transplantation, lesscommon disease manifestations, or disease characteristics that precluded participation in a placebo-controlled study. At least 4 patients in the study were to be between the age of 2 and 4 years. Thestudy consisted of a screening period of up to 45 days, a treatment period of up to 96 weeks and anexpanded treatment period of up to 48 weeks (for a total of up to 144 weeks of treatment). Themedian duration of exposure to sebelipase alfa was 33 months (range: 14 to 33.5 months).

Twenty-eight of the 31 patients completed the 96-week treatment period (1 patient discontinuedtreatment at week 61 due to withdrawal of consent, 1 patient at week 64 due to pregnancy and 1patient at week 76 due to transition to commercial therapy). Twenty-five of the 28 patients whocompleted the 96-week treatment period continued to receive treatment with sebelipase alfa during theextended treatment period. All 31 patients received sebelipase alfa at a starting dose of 1 mg/kg qow.

Thirteen of the 31 patients received dose escalations as allowed by the study protocol. Eleven of these13 patients had an initial dose escalation from 1 mg/kg qow to 3 mg/kg qow, and 4 of these patientshad a further dose escalation to 3 mg/kg qw.

Serum transaminases (ALT/AST) were elevated at baseline in approximately 75% of patients, andapproximately half of the patients had levels > 1.5 x ULN. Reductions in ALT and AST were evidentby week 4 and were sustained during long-term treatment with sebelipase alfa, with mean changesfrom baseline to week 144 of -40.3 U/L (-32.0%) and -42.2 U/L (34.2%), respectively.

Transient increases in total cholesterol, non-HDL-C, and LDL-C were observed shortly after initiationof treatment (week 4), and then levels dropped to below baseline by the next assessment at week 8.

This observation is consistent with mobilization of accumulated lipid substrates from the affectedtissues and has been observed in previous clinical studies of sebelipase alfa. Continued long-termtherapy with sebelipase alfa produced an improvement in the serum lipid profile, with mean changesfrom baseline to week 144 in LDL-C, triglycerides, and non-HDL-C of -54.2 mg/dL, -47.5 mg/dL,and -63.7 mg/dL, respectively, and mean percent changes of -31.2%, -19.1%, and -30.3%,respectively. An increase in HDL-C levels was observed, with a mean increase from baseline to week144 of 10.2 mg/dL and a mean percent increase of 39.7%.

Liver biopsy data in children and adult population

Liver biopsy is the accepted standard for histologic assessment of liver disease activity and fibrosis,despite such limitations as sampling variability, potential complications of an invasive technique, andsubjective scoring.

Liver biopsies from 59 patients enrolled in Studies LAL-CL02 and LAL-CL06 were assessed by anindependent pathologist at a central facility, who was blinded to assessment timepoint and treatmentassignment. All biopsies were evaluated semi-quantitatively for histologic features such as Ishak

Fibrosis Score, portal inflammation, lobular inflammation, macrovesicular steatosis, andmicrovesicular steatosis. Computer-assisted morphometry was used to quantify percent steatosis,fibrogenic cells, collagen, and macrophages.

Liver biopsies were evaluable for Ishak Fibrosis Scores for 59 patients at baseline and 38 patients at

Month 12 (meaning after 12 months of exposure to sebelipase alfa). There were 36 patients who had

Ishak scores at both baseline and Month 12.

At baseline, 3 of 59 patients (5%) had Ishak scores of 0 (no fibrosis) and 15 (25%) patients had Ishakscores of 6, indicating established or advanced cirrhosis. Ishak scores improved by Month 12, when 9of 38 patients (24%) had Ishak scores of 0 and 7 patients (18%) had Ishak scores of 6. Overall, 31 of36 patients (86.1%) had Ishak scores that had improved or did not progress at Month 12. There were10 patients (28%) with a ≥ 2 point reduction in Ishak scores from baseline to Month 12, includingchanges from stage 2 to stage 0, from stage 3 to stages 1 and 0, from stage 5 to stage 0 (> 3-pointreduction), and from stage 6 to stages 4 and 3. Globally, these 10 patients with a ≥ 2-point reductionin Ishak stage scores had also substantial improvements in other study-related assessments, such asreduction in ALT, LDL-C, HDL-C, and non-HDL-C over the same time period.

Based on eligibility criteria, patients in Study LAL-CL06 generally were expected to have morecirrhosis and intractable disease than patients in Study LAL-CL02, due to more advanced liver diseaseat baseline. The liver biopsy findings in Studies LAL-CL02 and LAL-CL06 were consistent with eachother. At baseline, in both studies, the majority of patients had microvesicular steatosis (57 of 59,97%), including 45 of 59 patients (76%) with a score 4 (scale of 0-4, with severe is defined as 4 andequivalent to > 66% hepatocyte involvement/replacement), as expected with the underlying disease.

At month 12, the percentage of patients with severe microvesicular steatosis were decreased, with 17of 38 patients (45%) having > 66% hepatocyte involvement/replacement (score 4).

Eighty-eight of 125 patients (70%) who received sebelipase alfa during clinical studies were in thepaediatric and adolescent age range (1 month up to 18 years) at the time of first dose. Currentlyavailable data are described sections 4.8 and 5.1.

LAL deficiency registry

Medical or healthcare professionals are encouraged to participate and enrol all patients diagnosed with

LAL deficiency in the LAL deficiency registry..

The pharmacokinetics of sebelipase alfa in children and adults were determined using a populationpharmacokinetic analysis of 102 patients with LAL deficiency who received intravenous infusions ofsebelipase alfa across 4 clinical studies LAL-CL02, LAL-CL03, LAL-CL04 and LAL-CL06(Table 4).

Predicted pharmacokinetic and exposure parameters of sebelipase alfa from clinical trials arepresented by age group in Table 4.

Table 4: Mean (SD) Predicted Pharmacokinetic and Exposure Parameters following

Repeated Administration of 1 mg/kg Sebelipase Alfa in Patients With LAL

Deficiency by Age Group

Parameter Age < 4 years Age 4 to < 12 years Age 12 to < 18 ≥ 18 years(N = 5) (N = 32) years (N=34) (N = 31)

CL (L/h) 17.2 (7.07) 22.8 (11.2) 32.7 (10.8) 37.6 (13.8)

Q (L/h) 1.96 (0.963) 1.41 (0.633) 1.61 (0.551) 1.54 (0.594)

Vc (L) 2.06 (1.22) 2.72 (1.43) 4.06 (2.01) 6.01 (5.43)

Vss (L) 6.13 (1.22) 6.79 (1.43) 8.13 (2.01) 10.1 (5.43)t½β (h) 1.88 (0.69) 2.71 (1.63) 2.18 (1.28) 2.24 (1.05)

AUCss(ng × h/mL) 521 (174) 1410 (774) 1610 (658) 2060 (793)

Cmax,ss(ng/mL) 247 (80.6) 679 (370) 786 (315) 997 (367)

Note: Estimates are derived from data from Studies LAL-CL02, LAL-CL03, LAL-CL04, and LAL-CL06.

AUCss = area under the serum concentration-time curve at steady state; CL = clearance; Cmax,ss = maximumobserved serum concentration under steady state conditions; PK = pharmacokinetic(s); Q = peripheral clearance;t½β = terminal elimination half-life; Vc = central volume of distribution; Vss = Volume of distribution at steadystate

No conclusion on the linearity of sebelipase alfa pharmacokinetics can be made due to limited data athigher exposures. No drug accumulation is observed following 1 mg/kg or 3 mg/kg once every otherweek dosing, although observations for the drug accumulation at 3mg/kg every other week are basedon a limited number of patients. Accumulation following once weekly dosing is not expected basedon relatively rapid drug clearance.

During the covariate analysis of the population pharmacokinetics model for sebelipase alfa, age, sexand enzyme maturation were found to not have a significant influence on CL (drug clearance) and Vc(central volume of distribution) of sebelipase alfa. Body weight and body surface area are significantcovariates on CL. Sebelipase alfa has not been investigated in patients aged 65 years or older.

There is limited information on sebelipase alfa pharmacokinetics in non-Caucasian ethnic groups.

Sebelipase alfa is a protein and is expected to be metabolically degraded through peptide hydrolysis.

Consequently, impaired liver function is not expected to affect the pharmacokinetics of sebelipasealfa. There is a lack of data in patients with severe hepatic impairment.

Renal elimination of sebelipase alfa is considered a minor pathway for clearance. There is a lack ofdata in patients with renal impairment.

As with all therapeutic proteins, there is the potential for the development of immunogenicity (seesection 4.8).

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated-dose toxicity in rats and monkeys, or fertility, embryo-foetal and peri- andpostnatal development in rats and rabbits. Chronic toxicity studies in juvenile cynomolgous monkeysshowed no toxicity at doses up to 3 times the recommended dose in infants and 10 times therecommended dose in adults/children. No adverse findings were observed in rat and rabbitembryofoetal development studies at doses up to at least 10 times the adult/children recommendeddose and in rat fertility and peri- postnatal development studies at doses up to 10 times theadult/children recommended dose.

Studies to evaluate the mutagenic and carcinogenic potential of sebelipase alfa have not beenperformed.

Sodium citrate

Citric acid monohydrate

Human serum albumin

Water for injections

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

Unopened vials: 2 years.

After dilution: Chemical and physical in-use stability has been demonstrated for up to 24 hours at 2°Cto 8°C, or up to 12 hours below 25 °C.

From a microbiological point of view, the diluted solution should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 2 °C to 8 °C, or up to 12 hours below 25 °C, unlessdilution has taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2°C to 8°C).

Do not freeze.

Store in the original package in order to protect from light.

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

Clear glass vial (Type I) with a siliconised butyl rubber stopper, and an aluminium seal with a plasticflip-off cap, containing 10 ml of concentrate.

Pack size: 1 vial.

Each vial of KANUMA is intended for single use only. KANUMA has to be diluted with sodiumchloride 9 mg/ml (0.9%) solution for infusion using aseptic technique.

The diluted solution should be administered to patients using a low-protein binding infusion setequipped with an in-line, low-protein binding 0.2 μm filter, with a surface area of greater than 4.5 cm2as available in order to avoid filter occlusion.

Preparation of the sebelipase alfa infusion

KANUMA should be prepared and used according to the following steps. Aseptic technique should beused.

a. The number of vials to be diluted for infusion should be determined based on the patient’sweight and prescribed dose.

b. It is recommended to allow KANUMA vials to reach a temperature between 15 °C and 25 °C

prior to dilution to minimise the potential for the formation of sebelipase alfa protein particlesin solution. The vials should not be left outside the refrigerator longer than 24 hours prior todilution for infusion. The vials should not be frozen, heated or microwaved and should beprotected from light.

c. The vials should not be shaken. Prior to dilution, the concentrate in the vials should beinspected visually; the concentrate should be clear to slightly opalescent, colourless to slightlycoloured (yellow). Due to the proteinaceous nature of the medicinal product, slight flocculation(e.g., thin translucent fibres) may be present in the vial concentrate and is acceptable for use.

d. Do not use if the concentrate is cloudy, or if foreign particulate matter is present.

e. Up to 10 ml of concentrate should be slowly withdrawn from each vial and diluted with sodiumchloride 9 mg/ml (0.9%) solution for infusion. See Table 5 for recommended total infusionvolumes by weight range. The solution should be mixed gently, and not be shaken.

Table 5: Recommended infusion volumes*1 mg/kg dose 3 mg/kg dose 5 mg/kg dose**

Weight range (kg) Total infusion Total Infusion Volume Total Infusion Volumevolume (ml) (mL) (mL)1-2.9 4 8 123-5.9 6 12 206-10.9 10 25 5011-24.9 25 50 15025-49.9 50 100 25050-99.9 100 250 500100-120.9 250 500 600

* The infusion volume should be based on the prescribed dose and should be prepared to a finalsebelipase alfa concentration of 0.1-1.5 mg/ml.

** For patients with LAL Deficiency presenting within the first 6 months of life who do not achievean optimal clinical response with a dose of 3 mg/kg.

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

Alexion Europe SAS103-105 rue Anatole France92300 Levallois-Perret

France

EU/1/15/1033/001

Date of first authorisation: 28 August 2015

Date of latest renewal: 23 April 2020

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

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