Kanuma

3.      How KANUMA is given - [editorial update]

Children and adults

The recommended dose is 1 mg per kg body weight once every other week through a drip into a vein. Dose adjustments may be considered based on how well you or your child responds to treatment. 

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4.      Possible side effects - [Adverse events reporting to Alexion Pharma has been removed]

6.      Contents of the pack and other information

Marketing Authorisation Holder and Manufacturer - [section has been updated to include details of local representative of MA Holder]

Change in recommended infusion volumes and mode of administration:

4.2    Posology and method of administration

Method of administration

KANUMA is for intravenous (IV) use only. 

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

4.8 Reporting of suspected adverse reactions

[Adverse events reporting to Alexion Pharma has been removed]

6.6    Special precautions for disposal and other handling

(...) Table 5: Recommended infusion volumes [are updated for the lower body weight range]

10 Date of revision of the text - 22 June 2023

Manufacturer name change from 'Alexion Pharma International Operations Unlimited Company' to 'Alexion Pharma International Operations Limited'.

Document format update

Product Information has been updated to reflect new posology regimen (higher starting dose of 3mg/kg once weekly for patients with Rapidly Progressive LAL deficiency presenting within the first six months of life) based on cumulative data from clinical studies and real-world clinical practice. Update includes:

3. How KANUMA is given

(...) 

Infants (< 6 months of age)

For patients who have signs and symptoms of the disease when they are infants, the recommended starting dose is 1 mg/kg or 3 mg/kg once weekly. Dose adjustments may be considered based on how well your child responds to treatment.

Children and adults

The recommended dose is 1 mg per kg body weight once every other week through a drip into a vein. Dose adjustments may be considered based on how well the patient responds to treatment.

Each infusion will take approximately 1 to 2 hours. You or your child may be monitored by your doctor or nurse for an additional hour after the infusion. KANUMA should be started at as young an age as possible and is intended for long-term use. (...)

4. Possible side effects

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Very Common (may affect 1 in 10 people or more) side effects reported in children and adolescents (4 to 18 years old) and adults are:

Hypersensitivity (chills, eczema, laryngeal oedema, nausea, pruritus and urticaria)

Dizziness

Stomach ache, diarrhoea

Tiredness, fever

Common (may affect up to 1 in 10 people) side effects reported in children and adolescents (4 to 18 years old) and adults are:

Hypersensitivity (chills, eczema, laryngeal oedema, nausea, pruritus and urticaria)

Severe allergic reaction (anaphylactic reaction)

Fast heartbeat

Skin redness, low blood pressure

Shortness in breath

Stomach bloating

Rash, red swollen skin

Chest discomfort, reaction at the infusion site

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Reporting of side effects

(...)

Ireland

HPRA Pharmacovigilance

Website: www.hpra.ie

United Kingdom (Northern Ireland)

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Adverse events should also be reported to Alexion Pharma UK Ltd on uk.adverseevents@alexion.com, Freephone (Ireland): 1 800 936 544, (UK Northern Ireland): 0800321 3902.

6.       Contents of the pack and other information

(...) This leaflet was last revised in December 2021.

Information is intended for healthcare professionals only.

Tables have been updated for recommended infusion volumes.

Product Information has been updated to reflect new posology regimen (higher starting dose of 3mg/kg once weekly for patients with Rapidly Progressive LAL deficiency presenting within the first six months of life) based on cumulative data from clinical studies and real-world clinical practice. Update includes:

3. How KANUMA is given

(...) 

Infants (< 6 months of age)

For patients who have signs and symptoms of the disease when they are infants, the recommended starting dose is 1 mg/kg or 3 mg/kg once weekly. Dose adjustments may be considered based on how well your child responds to treatment.

Children and adults

The recommended dose is 1 mg per kg body weight once every other week through a drip into a vein. Dose adjustments may be considered based on how well the patient responds to treatment.

Each infusion will take approximately 1 to 2 hours. You or your child may be monitored by your doctor or nurse for an additional hour after the infusion. KANUMA should be started at as young an age as possible and is intended for long-term use. (...)

4. Possible side effects

(...)

Very Common (may affect 1 in 10 people or more) side effects reported in children and adolescents (4 to 18 years old) and adults are:

Hypersensitivity (chills, eczema, laryngeal oedema, nausea, pruritus and urticaria)

Dizziness

Stomach ache, diarrhoea

Tiredness, fever

Common (may affect up to 1 in 10 people) side effects reported in children and adolescents (4 to 18 years old) and adults are:

Hypersensitivity (chills, eczema, laryngeal oedema, nausea, pruritus and urticaria)

Severe allergic reaction (anaphylactic reaction)

Fast heartbeat

Skin redness, low blood pressure

Shortness in breath

Stomach bloating

Rash, red swollen skin

Chest discomfort, reaction at the infusion site

(...)

Reporting of side effects

(...)

Ireland

HPRA Pharmacovigilance

Website: www.hpra.ie

United Kingdom (Northern Ireland)

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Adverse events should also be reported to Alexion Pharma UK Ltd on uk.adverseevents@alexion.com, Freephone (Ireland): 1 800 936 544, (UK Northern Ireland): 0800321 3902.

6.       Contents of the pack and other information

(...) This leaflet was last revised in December 2021.

Information is intended for healthcare professionals only.

Tables have been updated for recommended infusion volumes.

Product Information has been updated to reflect new posology regimen (higher starting dose of 3mg/kg once weekly for patients with Rapidly Progressive LAL deficiency presenting within the first six months of life) based on cumulative data from clinical studies and real-world clinical practice. Update includes:

4. CLINICAL PARTICULARS 

4.2 Posology and method of administration

(...) Posology

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, see section 4.4. Following the occurrence of a hypersensitivity reaction, appropriate pre-treatment should be 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 considered based on the severity of the disease and rapid disease progression.

Dose escalations should be considered based on suboptimal response to clinical and biochemical criteria, including, e.g., poor growth (especially mid-upper arm circumference, MUAC), deteriorating biochemical markers (e.g. liver transaminases, ferritin, C-reactive Protein, and coagulation parameters), 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 suboptimal clinical response.

Further dose adjustments, as a reduction of the dose or an extension of the dose interval, can be made on an individual basis based on achievement and maintenance of therapeutic goals. Clinical studies evaluated doses ranging from 0.35 to 5 mg/kg once weekly, with one patient receiving a higher dose of 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 LAL deficiency prior to 6 months of age is 1 mg/kg administered as an intravenous infusion once every other week. Dose escalation to 3 mg/kg once every other week should be considered based on  suboptimal response to clinical biochemical criteria, including; e.g., poor growth persistent or deteriorating biochemical markers (e.g., parameters of liver injury (ALT, AST), parameters of lipid metabolism (TC, LDL-c, HDL-c, TG), persistent or worsening organomegaly, and persistent worsening of other symptoms (e.g., gastrointestinal symptoms).

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 4.8 Undesirable effects

(...)

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

Reporting of suspected adverse reactions

(...)

Ireland

HPRA Pharmacovigilance

Website: www.hpra.ie

United Kingdom (Northern Ireland)

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

5.  PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

(...) Study LAL-CL03

LAL‑CL03 was a multicentre, open-label, single-arm study of sebelipase alfa in 9 patients under 24 months of age with a confirmed diagnosis of LAL deficiency and growth failure with onset before 6 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 60 months). Patients received sebelipase alfa at 0.35 mg/kg once weekly (qw) for the first 2 weeks and then 1 mg/kg once weekly. Based on clinical response, dose escalation to 3 mg/kg once weekly occurred 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 the study protocol. (...)

10. DATE OF REVISION OF THE TEXT - 13 Dec 2021

aRMM update following approval of variation related to the completion of safety and efficacy studies (Studies LAL-CL04, LAL-CL03, LAL-CL06, LAL-CL08 and LAL-CL02).

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4.2     Posology and method of administration

(...)

Posology

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Infants (< 6 months of age)

The recommended starting dose in infants (< 6 months of age) presenting with rapidly progressive LAL deficiency is 1 mg/kg administered as an intravenous infusion once weekly. Dose escalations should be considered based on response to clinical and biochemical criteria, including, e.g., poor growth (especially mid-upper arm circumference, MUAC), deteriorating biochemical markers (e.g. liver transaminases, ferritin, C-reactive Protein, and coagulation parameters), 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 after a minimum of 4 infusions;

- a further dose escalation up to 5 mg/kg should be considered in case of suboptimal clinical response after a minimum of additional 4 infusions.

Further dose adjustments, as a reduction of the dose or an extension of the dose interval, can be made on an individual basis based on achievement and maintenance of therapeutic goals. Clinical studies evaluated doses ranging from 1 to 5 mg/kg once weekly, with one patient receiving a higher dose of 7.5 mg/kg once weekly. Doses higher than 7.5 mg/kg have not been studied.

Children and adults

The recommended dose in children and adults who do not present with rapidly progressive LAL deficiency prior to 6 months of age is 1 mg/kg administered as an intravenous infusion once every other week. Dose escalation to 3 mg/kg once every other week should be considered based on clinical response.

(...)

Method of administration

KANUMA is for intravenous (IV) use only.

(...)

4.4     Special warnings and precautions for use

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Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. In the sebelipase alfa clinical program, patients were routinely tested for anti-sebelipase alfa anti-drug antibodies (ADAs) to determine the immunogenicity potential of sebelipase alfa. Patients who tested positive for ADAs were also tested for inhibitory antibody activity. The presence of inhibitory activity has been detected at some postbaseline timepoints in clinical studies (see section 4.8). Overall, no conclusion on the relationship between development of ADAs/NAbs and associated hypersensitivity reactions or suboptimal 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 activity associated with a suboptimal clinical response. These patients underwent either immunomodulatory therapy alone or in combination with haematopoietic stem cell transplant (HSCT) or bone marrow transplant (BMT), resulting in improved clinical response to sebelipase alfa.

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4.6     Fertility, pregnancy and lactation

Pregnancy

There are no or limited data from the use of sebelipase alfa in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid use of sebelipase alfa during pregnancy.
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4.7     Effects on ability to drive and use machines

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

4.8     Undesirable effects

 Summary of safety profile

The data described below reflect the exposure to sebelipase alfa in 125 patients at doses ranging from 0.35 mg/kg once every other week to 7.5 mg/kg once weekly in clinical studies (see section 5.1), with a 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 alfa with a median duration of exposure of 33 months (6, 59 months). The median duration of exposure for the 19 infants enrolled in clinical studies was 35.5 months (1 day to 60 months).
The most serious adverse reactions experienced by 4% of patients in clinical studies were signs and symptoms consistent with anaphylaxis. Signs and symptoms included chest discomfort, conjunctival hyperaemia, dyspnoea, hyperaemia, eyelid oedema, rhinorrhoea, severe respiratory distress, tachycardia, tachypnoea, irritability, flushing, pruritus, urticaria, stridor, hypoxia, pallor and diarrhoea. 

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  ^a May include: irritability, agitation, vomiting, urticaria, eczema, pruritus, pallor, and drug hypersensitivity

^b Occurred in 3 infant patients treated in clinical studies. Based on Preferred Term ‘anaphylactic reaction’ and application of Sampson criteria to identify signs/symptoms consistent with anaphylaxis.

a 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

​

Description of selected adverse reactions

Hypersensitivity
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 with anaphylaxis to sebelipase alfa. Anaphylaxis occurred during the infusion as late as 1 year after treatment initiation.

In clinical studies, 59 of 125 (47%) sebelipase alfa-treated patients, including 13 of 19 (68%) infants and 46 of 106 (43%) children and adults, experienced at least 1 hypersensitivity reaction (selected using a validated, pre-determined set of terms grouped together to identify potential hypersensitivity reactions). Signs and symptoms either consistent with or that may be related to a hypersensitivity reaction 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 hours of the completion of the infusion.

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Immunogenicity 
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 ADA positivity was observed within the infant population (10/19 patients).

Among 125 patients with LAL Deficiency enrolled in the clinical studies, 19/125 (15.0%) patients tested positive for anti-drug antibodies (ADAs) at some timepoint after starting treatment with sebelipase 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 3 of the 10 infants. Among those 19 patients, 11 (58%) also showed the presence of inhibitory antibody activity (NAbs) at some postbaseline timepoint.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system 
detailed below:
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Ireland
HPRA Pharmacovigilance
Website: www.hpra.ie

Adverse events should also be reported to Alexion Pharma UK Ltd on uk.adverseevents@alexion.com, Freephone (UK): 0800321 3902, (Ireland): 1 800 936 544.

(...)

            4.9     Overdose

In clinical studies, doses of sebelipase alfa were explored up to 7.5 mg/kg once weekly and no specific signs or symptoms were identified following the higher doses. For management of adverse reactions, see sections 4.4 and 4.8.

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5.1     Pharmacodynamic properties

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 affects individuals from infancy through adulthood. LAL deficiency presenting in infants is a medical emergency with rapid disease progression over a period of weeks that is typically fatal within the first 6 months of life. LAL deficiency is an autosomal recessive lysosomal storage disorder characterised by 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 and triglycerides in a variety of cell populations, organs and organ systems, among them hepatocytes and macrophages. In the liver, this accumulation leads to hepatomegaly, increased hepatic fat content, transaminase elevation signaling chronic liver injury, and progression to fibrosis, cirrhosis, and complications 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 and growth 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 liver fat content and transaminase elevations. In addition to liver disease, patients with LAL deficiency experience increased risk for cardiovascular disease and accelerated atherosclerosis. 

Mechanism of action 

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

Sebelipase alfa binds to cell surface receptors via glycans expressed on the protein and is subsequently internalised into lysosomes. Sebelipase alfa catalyses the lysosomal hydrolysis of cholesteryl 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 enables metabolism of cholesteryl esters and triglycerides in the lysosome, leading to reductions in LDL-C and non- HDL-C, triglycerides, and increases in HDL-C. Improvement in growth occurs as a result of substrate 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 24 months of age with a confirmed diagnosis of LAL deficiency and growth failure with onset before 6 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 55.5 months per patient (range = 1 day to 60 months). Patients received sebelipase alfa at 0.35 mg/kg once weekly (qw) for the first 2 weeks and then 1 mg/kg once weekly. Based on clinical response, dose escalation to 3 mg/kg once weekly occurred 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 the study protocol. 

Efficacy was assessed by comparing the survival experience of sebelipase alfa-treated patients who survived past 12 months of age in Study LAL CL03 with a historical cohort of untreated infants presenting with LAL deficiency with similar clinical characteristics. In LAL CL03, 6 of 9 sebelipase alfa-treated infants survived beyond 12 months (67% 12 month survival, 95% CI: 30% to 93%). With continued treatment until 48 months of age, 1 additional patient died at age 15 months. In the historical 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) / aspartate aminotransferase (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 the end of the study. From baseline to Week 240 (Month 60), the mean reductions for ALT and AST were 43.5 U/l and 45.25 U/l, respectively. From baseline to Week 240, mean weight-for-age percentile improved from 12.74% to 43.17% and mean serum albumin levels increased from 26.9 g/l to 31.98 g/l. Dose escalation to 3 mg/kg once weekly was associated with additional improvements in weight 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 of age 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 LAL deficiency. 

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 exposure was 34 months (range: 1 to 37 months). Two (20%) patients were considered early terminated due to death. 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 subsequent dose escalation to 5 mg/kg qw, as allowed per study protocol. One patient received a further dose escalation to 7.5 mg/kg qw. Two patients had a subsequent dose reduction, which occurred after successful 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 months of 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 were excluded 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 study population, with median changes from baseline to last assessment of -34.5 U/L, -66.67 IU/L, -63.64 μmol/L, and 33.33 g/L, respectively.

Height and weight increased gradually. Median changes from baseline in Z-scores for weight for height (WFH) were decreases through Week 4. Starting from Week 24, there were consistent improvements. 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 adults with 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 and 71% were < 18 years old). For study entry, patients were required to have ALT levels of ³1.5 X upper limit of normal (ULN). The majority of patients (58%) had LDL-cholesterol > 190 mg/dl at study entry, and 24% of patients with LDL-cholesterol > 190 mg/dl were on lipid lowering medicinal products. Of the 32 patients who had a liver biopsy at study entry, 100% had fibrosis and 31% had cirrhosis. The age range of patients with biopsy evidence of cirrhosis was 4 21 years.

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Open-label period
Patients who participated in Study LAL-CL02 were eligible to continue treatment in an open-label periods of the study. 66 patients entered the first open-label period (up to 130 weeks) at a sebelipase alfa dose of 1 mg/kg once every other week. In patients who had received sebelipase alfa during the double-blind period, reductions in ALT levels during the first 20 weeks of treatment were maintained and 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 3 mg/kg once every other week based on clinical response.

Placebo patients had persistently elevated serum transaminase and abnormal serum lipid levels during the double blind period. Consistent with what was observed in sebelipase alfa-treated patients during the double-blind period, initiation of treatment with sebelipase alfa during the open-label period produced 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), with overall 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 treatment period. Eight of nine patients transitioned from Study LAL-CL01 after 4 weeks of treatment (0.35 mg/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 5 patients receiving a dose of 1 mg/kg qow and 3 patients receiving a dose of 3 mg/kg qow. Increases in serum transaminases and LDL-cholesterol and decreases in HDL-cholesterol were observed during the 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 and was designed to include patients who may have been ineligible for previous clinical studies due to age, disease progression, previous treatment by haematopoietic stem cell or liver transplantation, less common 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. The study consisted of a screening period of up to 45 days, a treatment period of up to 96 weeks and an expanded treatment period of up to 48 weeks (for a total of up to 144 weeks of treatment). The median 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 discontinued treatment at week 61 due to withdrawal of consent, 1 patient at week 64 due to pregnancy and 1 patient at week 76 due to transition to commercial therapy). Twenty-five of the 28 patients who completed the 96-week treatment period continued to receive treatment with sebelipase alfa during the extended 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 these 13 patients had an initial dose escalation from 1 mg/kg qow to 3 mg/kg qow, and 4 of these patients had a further dose escalation to 3 mg/kg qw.

Serum transaminases (ALT/AST) were elevated at baseline in approximately 75% of patients, and approximately half of the patients had levels > 1.5 x ULN. Reductions in ALT and AST were evident by week 4 and were sustained during long-term treatment with sebelipase alfa, with mean changes from 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 initiation of 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 affected tissues and has been observed in previous clinical studies of sebelipase alfa. Continued long-term therapy with sebelipase alfa produced an improvement in the serum lipid profile, with mean changes from 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 week 144 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, and subjective scoring.

Liver biopsies from 59 patients enrolled in Studies LAL-CL02 and LAL CL06 were assessed by an independent pathologist at a central facility, who was blinded to assessment timepoint and treatment assignment. All biopsies were evaluated semi-quantitatively for histologic features such as Ishak Fibrosis Score, portal inflammation, lobular inflammation, macrovesicular steatosis, and microvesicular 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 Ishak scores of 6, indicating established or advanced cirrhosis. Ishak scores improved by Month 12, when 9 of 38 patients (24%) had Ishak scores of 0 and 7 patients (18%) had Ishak scores of 6. Overall, 31 of 36 patients (86.1%) had Ishak scores that had improved or did not progress at Month 12. There were 10 patients (28%) with a ≥ 2 point reduction in Ishak scores from baseline to Month 12, including changes from stage 2 to stage 0, from stage 3 to stages 1 and 0, from stage 5 to stage 0 (> 3-point reduction), and from stage 6 to stages 4 and 3. Globally, these 10 patients with a ≥ 2-point reduction in Ishak stage scores had also substantial improvements in other study-related assessments, such as reduction 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 more cirrhosis and intractable disease than patients in Study LAL CL02, due to more advanced liver disease at baseline. The liver biopsy findings in Studies LAL-CL02 and LAL CL06 were consistent with each other. 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 and equivalent 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 17 of 38 patients (45%) having > 66% hepatocyte involvement/replacement (score 4).

Paediatric population

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

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5.2     Pharmacokinetic properties

The pharmacokinetics of sebelipase alfa in children and adults were determined using a population pharmacokinetic analysis of 102 patients with LAL deficiency who received intravenous infusions of sebelipase 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 are presented 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

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

​AUC_ss = area under the serum concentration-time curve at steady state; CL = clearance; C_max,ss = maximum observed serum concentration under steady state conditions; PK = pharmacokinetic(s); Q = peripheral clearance; t_½β = terminal elimination half‑life; Vc = central volume of distribution; volume of distribution at steady state

​

Linearity/non-linearity

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

Special populations

During the covariate analysis of the population pharmacokinetics model for sebelipase alfa, age, sex and 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 significant covariates 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 sebelipase alfa. 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 of data in patients with renal impairment.

Immunogenicity 

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

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6.6    Special precautions for disposal and other handling

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 * The infusion volume should be based on the prescribed dose and should be prepared to a final sebelipase alfa concentration of 0.1 1.5 mg/ml.
** For patients who do not achieve an optimal clinical response with a dose of 1 mg/kg.
*** For patients with LAL Deficiency presenting within the first 6 months of life who do not achieve an optimal clinical response with a dose of 3 mg/kg.

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10.     DATE OF REVISION OF THE TEXT

20 November 2020

2.      What you need to know before KANUMA is given

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Warnings and precautions

• If treated with KANUMA, you or your child may experience a side effect while you or your child is being given the medicine or during the hours following the infusion (see section 4). This is known as an infusion reaction which can sometimes be severe, and may include an allergic reaction that could be lifethreatening and require medical treatment. The first time that you or your child are given KANUMA you should be observed by a healthcare professional for 1 hour to watch for any signs of an infusion reaction. If you or your child experiences a severe infusion reaction like this, seek immediate medical attention. If you or your child has an infusion reaction you or your child may be given additional medicines to treat or help prevent future reactions. These medicines may include antihistamines, feverreducing medicines and/or corticosteroids (a type of anti-inflammatory medicines).

If the infusion reaction is severe, your doctor may stop KANUMA infusion and start giving you or your child appropriate medical treatment.

• The development of blood proteins against KANUMA, also called antidrug antibodies, may occur during the treatment. Talk to your doctor if you experience decreased efficacy with KANUMA

This medicine may contain egg proteins. If you or your child has an egg allergy or a history of allergies to eggs, tell your doctor or nurse (see You must not be given KANUMA)

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Driving and using machines

KANUMA may have a minor influence on the ability to drive and use machines. Adverse effects of sebelipase alfa include dizziness which could affect the ability to drive or use machines.

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4.      Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Side effects were seen while patients were being given the medicine or shortly after (infusion reactions). The most serious side effects may include an allergic reaction (seen very commonly [may affect more than 1 in 10 people] in infants younger than 6 months old, or commonly [may affect up to 1 in 10 people] in children and adults) with symptoms including difficulty breathing,  rapid breathing, fast heartbeat, chest discomfort, mild swelling of eyelids, red eyes, runny nose, flushing, hives, itching, diarrhoea, paleness, wheezing, low blood oxygen, skin redness and irritability. If you or your child experiences symptoms like these, seek immediate medical attention. If you or your child has an infusion reaction you or your child may be given additional medicines to treat or help prevent future reactions. If the infusion reaction is severe, your doctor may stop the infusion of KANUMA in the vein and start giving appropriate medical treatment.

Very Common (may affect more than 1 in 10 people) side effects reported in infants (1 to 6 months old) are:

Hypersensitivity (irritability, agitation, vomiting, urticaria, eczema, pruritus, pallor and drug hypersensitivity), severe allergic reactions (anaphylactic reactions)

Eyelid swelling

Fast heartbeat

Difficulty breathing

Diarrhoea, vomiting

Rash, raised rash

Fever

Decreased oxygen in the blood, blood pressure increased, rapid breathing, development of blood proteins

Very Common (may affect 1 in 10 people or more) side effects reported in children and adolescents (4 to 18 years old) and adults are:

Dizziness

Stomach ache, diarrhoea

Tiredness, fever

Common (may affect up to 1 in 10 people) side effects reported in children and adolescents (4 to 18 years old) and adults are:

Severe allergic reaction (anaphylactic reaction), hypersensitivity (chills, eczema, laryngeal oedema, nausea, pruritus and urticaria)

Fast heartbeat

Skin redness, low blood pressure

Shortness in breath

Stomach bloating

Rash, red swollen skin

Chest discomfort, reaction at the infusion site

Frequency, type and severity of adverse reactions in children are similar to those in adults.

Reporting of side effects

If you or your child gets any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system detailed below:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Ireland

HPRA Pharmacovigilance

Website: www.hpra.ie

Adverse events should also be reported to Alexion Pharma UK Ltd on uk.adverseevents@alexion.com, Freephone (UK): 0800321 3902, (Ireland): 1 800 936 544.

By reporting side effects you can help provide more information on the safety of this medicine.

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6.       Contents of the pack and other information

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This leaflet was last revised in November 2020.

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Information for healthcare professionals only

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

** For patients who do not achieve an optimal clinical response with a dose of 1 mg/kg.

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

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

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4.2     Posology and method of administration

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Posology

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Infants (< 6 months of age)

The recommended starting dose in infants (< 6 months of age) presenting with rapidly progressive LAL deficiency is 1 mg/kg administered as an intravenous infusion once weekly. Dose escalations should be considered based on response to clinical and biochemical criteria, including, e.g., poor growth (especially mid-upper arm circumference, MUAC), deteriorating biochemical markers (e.g. liver transaminases, ferritin, C-reactive Protein, and coagulation parameters), 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 after a minimum of 4 infusions;

- a further dose escalation up to 5 mg/kg should be considered in case of suboptimal clinical response after a minimum of additional 4 infusions.

Further dose adjustments, as a reduction of the dose or an extension of the dose interval, can be made on an individual basis based on achievement and maintenance of therapeutic goals. Clinical studies evaluated doses ranging from 1 to 5 mg/kg once weekly, with one patient receiving a higher dose of 7.5 mg/kg once weekly. Doses higher than 7.5 mg/kg have not been studied.

Children and adults

The recommended dose in children and adults who do not present with rapidly progressive LAL deficiency prior to 6 months of age is 1 mg/kg administered as an intravenous infusion once every other week. Dose escalation to 3 mg/kg once every other week should be considered based on clinical response.

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Method of administration

KANUMA is for intravenous (IV) use only.

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4.4     Special warnings and precautions for use

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Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. In the sebelipase alfa clinical program, patients were routinely tested for anti-sebelipase alfa anti-drug antibodies (ADAs) to determine the immunogenicity potential of sebelipase alfa. Patients who tested positive for ADAs were also tested for inhibitory antibody activity. The presence of inhibitory activity has been detected at some postbaseline timepoints in clinical studies (see section 4.8). Overall, no conclusion on the relationship between development of ADAs/NAbs and associated hypersensitivity reactions or suboptimal 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 activity associated with a suboptimal clinical response. These patients underwent either immunomodulatory therapy alone or in combination with haematopoietic stem cell transplant (HSCT) or bone marrow transplant (BMT), resulting in improved clinical response to sebelipase alfa.

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4.6     Fertility, pregnancy and lactation

Pregnancy

There are no or limited data from the use of sebelipase alfa in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid use of sebelipase alfa during pregnancy.
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4.7     Effects on ability to drive and use machines

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

4.8     Undesirable effects

 Summary of safety profile

The data described below reflect the exposure to sebelipase alfa in 125 patients at doses ranging from 0.35 mg/kg once every other week to 7.5 mg/kg once weekly in clinical studies (see section 5.1), with a 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 alfa with a median duration of exposure of 33 months (6, 59 months). The median duration of exposure for the 19 infants enrolled in clinical studies was 35.5 months (1 day to 60 months).
The most serious adverse reactions experienced by 4% of patients in clinical studies were signs and symptoms consistent with anaphylaxis. Signs and symptoms included chest discomfort, conjunctival hyperaemia, dyspnoea, hyperaemia, eyelid oedema, rhinorrhoea, severe respiratory distress, tachycardia, tachypnoea, irritability, flushing, pruritus, urticaria, stridor, hypoxia, pallor and diarrhoea. 

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  ^a May include: irritability, agitation, vomiting, urticaria, eczema, pruritus, pallor, and drug hypersensitivity

^b Occurred in 3 infant patients treated in clinical studies. Based on Preferred Term ‘anaphylactic reaction’ and application of Sampson criteria to identify signs/symptoms consistent with anaphylaxis.

a 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

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Description of selected adverse reactions

Hypersensitivity
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 with anaphylaxis to sebelipase alfa. Anaphylaxis occurred during the infusion as late as 1 year after treatment initiation.

In clinical studies, 59 of 125 (47%) sebelipase alfa-treated patients, including 13 of 19 (68%) infants and 46 of 106 (43%) children and adults, experienced at least 1 hypersensitivity reaction (selected using a validated, pre-determined set of terms grouped together to identify potential hypersensitivity reactions). Signs and symptoms either consistent with or that may be related to a hypersensitivity reaction 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 hours of the completion of the infusion.

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Immunogenicity 
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 ADA positivity was observed within the infant population (10/19 patients).

Among 125 patients with LAL Deficiency enrolled in the clinical studies, 19/125 (15.0%) patients tested positive for anti-drug antibodies (ADAs) at some timepoint after starting treatment with sebelipase 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 3 of the 10 infants. Among those 19 patients, 11 (58%) also showed the presence of inhibitory antibody activity (NAbs) at some postbaseline timepoint.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system 
detailed below:
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Ireland
HPRA Pharmacovigilance
Website: www.hpra.ie

Adverse events should also be reported to Alexion Pharma UK Ltd on uk.adverseevents@alexion.com, Freephone (UK): 0800321 3902, (Ireland): 1 800 936 544.

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            4.9     Overdose

In clinical studies, doses of sebelipase alfa were explored up to 7.5 mg/kg once weekly and no specific signs or symptoms were identified following the higher doses. For management of adverse reactions, see sections 4.4 and 4.8.

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5.1     Pharmacodynamic properties

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 affects individuals from infancy through adulthood. LAL deficiency presenting in infants is a medical emergency with rapid disease progression over a period of weeks that is typically fatal within the first 6 months of life. LAL deficiency is an autosomal recessive lysosomal storage disorder characterised by 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 and triglycerides in a variety of cell populations, organs and organ systems, among them hepatocytes and macrophages. In the liver, this accumulation leads to hepatomegaly, increased hepatic fat content, transaminase elevation signaling chronic liver injury, and progression to fibrosis, cirrhosis, and complications 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 and growth 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 liver fat content and transaminase elevations. In addition to liver disease, patients with LAL deficiency experience increased risk for cardiovascular disease and accelerated atherosclerosis. 

Mechanism of action 

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

Sebelipase alfa binds to cell surface receptors via glycans expressed on the protein and is subsequently internalised into lysosomes. Sebelipase alfa catalyses the lysosomal hydrolysis of cholesteryl 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 enables metabolism of cholesteryl esters and triglycerides in the lysosome, leading to reductions in LDL-C and non- HDL-C, triglycerides, and increases in HDL-C. Improvement in growth occurs as a result of substrate 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 24 months of age with a confirmed diagnosis of LAL deficiency and growth failure with onset before 6 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 55.5 months per patient (range = 1 day to 60 months). Patients received sebelipase alfa at 0.35 mg/kg once weekly (qw) for the first 2 weeks and then 1 mg/kg once weekly. Based on clinical response, dose escalation to 3 mg/kg once weekly occurred 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 the study protocol. 

Efficacy was assessed by comparing the survival experience of sebelipase alfa-treated patients who survived past 12 months of age in Study LAL CL03 with a historical cohort of untreated infants presenting with LAL deficiency with similar clinical characteristics. In LAL CL03, 6 of 9 sebelipase alfa-treated infants survived beyond 12 months (67% 12 month survival, 95% CI: 30% to 93%). With continued treatment until 48 months of age, 1 additional patient died at age 15 months. In the historical 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) / aspartate aminotransferase (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 the end of the study. From baseline to Week 240 (Month 60), the mean reductions for ALT and AST were 43.5 U/l and 45.25 U/l, respectively. From baseline to Week 240, mean weight-for-age percentile improved from 12.74% to 43.17% and mean serum albumin levels increased from 26.9 g/l to 31.98 g/l. Dose escalation to 3 mg/kg once weekly was associated with additional improvements in weight 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 of age 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 LAL deficiency. 

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 exposure was 34 months (range: 1 to 37 months). Two (20%) patients were considered early terminated due to death. 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 subsequent dose escalation to 5 mg/kg qw, as allowed per study protocol. One patient received a further dose escalation to 7.5 mg/kg qw. Two patients had a subsequent dose reduction, which occurred after successful 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 months of 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 were excluded 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 study population, with median changes from baseline to last assessment of -34.5 U/L, -66.67 IU/L, -63.64 μmol/L, and 33.33 g/L, respectively.

Height and weight increased gradually. Median changes from baseline in Z-scores for weight for height (WFH) were decreases through Week 4. Starting from Week 24, there were consistent improvements. 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 adults with 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 and 71% were < 18 years old). For study entry, patients were required to have ALT levels of ³1.5 X upper limit of normal (ULN). The majority of patients (58%) had LDL-cholesterol > 190 mg/dl at study entry, and 24% of patients with LDL-cholesterol > 190 mg/dl were on lipid lowering medicinal products. Of the 32 patients who had a liver biopsy at study entry, 100% had fibrosis and 31% had cirrhosis. The age range of patients with biopsy evidence of cirrhosis was 4 21 years.

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Open-label period
Patients who participated in Study LAL-CL02 were eligible to continue treatment in an open-label periods of the study. 66 patients entered the first open-label period (up to 130 weeks) at a sebelipase alfa dose of 1 mg/kg once every other week. In patients who had received sebelipase alfa during the double-blind period, reductions in ALT levels during the first 20 weeks of treatment were maintained and 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 3 mg/kg once every other week based on clinical response.

Placebo patients had persistently elevated serum transaminase and abnormal serum lipid levels during the double blind period. Consistent with what was observed in sebelipase alfa-treated patients during the double-blind period, initiation of treatment with sebelipase alfa during the open-label period produced 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), with overall 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 treatment period. Eight of nine patients transitioned from Study LAL-CL01 after 4 weeks of treatment (0.35 mg/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 5 patients receiving a dose of 1 mg/kg qow and 3 patients receiving a dose of 3 mg/kg qow. Increases in serum transaminases and LDL-cholesterol and decreases in HDL-cholesterol were observed during the 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 and was designed to include patients who may have been ineligible for previous clinical studies due to age, disease progression, previous treatment by haematopoietic stem cell or liver transplantation, less common 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. The study consisted of a screening period of up to 45 days, a treatment period of up to 96 weeks and an expanded treatment period of up to 48 weeks (for a total of up to 144 weeks of treatment). The median 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 discontinued treatment at week 61 due to withdrawal of consent, 1 patient at week 64 due to pregnancy and 1 patient at week 76 due to transition to commercial therapy). Twenty-five of the 28 patients who completed the 96-week treatment period continued to receive treatment with sebelipase alfa during the extended 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 these 13 patients had an initial dose escalation from 1 mg/kg qow to 3 mg/kg qow, and 4 of these patients had a further dose escalation to 3 mg/kg qw.

Serum transaminases (ALT/AST) were elevated at baseline in approximately 75% of patients, and approximately half of the patients had levels > 1.5 x ULN. Reductions in ALT and AST were evident by week 4 and were sustained during long-term treatment with sebelipase alfa, with mean changes from 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 initiation of 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 affected tissues and has been observed in previous clinical studies of sebelipase alfa. Continued long-term therapy with sebelipase alfa produced an improvement in the serum lipid profile, with mean changes from 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 week 144 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, and subjective scoring.

Liver biopsies from 59 patients enrolled in Studies LAL-CL02 and LAL CL06 were assessed by an independent pathologist at a central facility, who was blinded to assessment timepoint and treatment assignment. All biopsies were evaluated semi-quantitatively for histologic features such as Ishak Fibrosis Score, portal inflammation, lobular inflammation, macrovesicular steatosis, and microvesicular 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 Ishak scores of 6, indicating established or advanced cirrhosis. Ishak scores improved by Month 12, when 9 of 38 patients (24%) had Ishak scores of 0 and 7 patients (18%) had Ishak scores of 6. Overall, 31 of 36 patients (86.1%) had Ishak scores that had improved or did not progress at Month 12. There were 10 patients (28%) with a ≥ 2 point reduction in Ishak scores from baseline to Month 12, including changes from stage 2 to stage 0, from stage 3 to stages 1 and 0, from stage 5 to stage 0 (> 3-point reduction), and from stage 6 to stages 4 and 3. Globally, these 10 patients with a ≥ 2-point reduction in Ishak stage scores had also substantial improvements in other study-related assessments, such as reduction 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 more cirrhosis and intractable disease than patients in Study LAL CL02, due to more advanced liver disease at baseline. The liver biopsy findings in Studies LAL-CL02 and LAL CL06 were consistent with each other. 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 and equivalent 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 17 of 38 patients (45%) having > 66% hepatocyte involvement/replacement (score 4).

Paediatric population

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

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5.2     Pharmacokinetic properties

The pharmacokinetics of sebelipase alfa in children and adults were determined using a population pharmacokinetic analysis of 102 patients with LAL deficiency who received intravenous infusions of sebelipase 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 are presented 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

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

​AUC_ss = area under the serum concentration-time curve at steady state; CL = clearance; C_max,ss = maximum observed serum concentration under steady state conditions; PK = pharmacokinetic(s); Q = peripheral clearance; t_½β = terminal elimination half‑life; Vc = central volume of distribution; volume of distribution at steady state

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Linearity/non-linearity

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

Special populations

During the covariate analysis of the population pharmacokinetics model for sebelipase alfa, age, sex and 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 significant covariates 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 sebelipase alfa. 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 of data in patients with renal impairment.

Immunogenicity 

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

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6.6    Special precautions for disposal and other handling

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 * The infusion volume should be based on the prescribed dose and should be prepared to a final sebelipase alfa concentration of 0.1 1.5 mg/ml.
** For patients who do not achieve an optimal clinical response with a dose of 1 mg/kg.
*** For patients with LAL Deficiency presenting within the first 6 months of life who do not achieve an optimal clinical response with a dose of 3 mg/kg.

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10.     DATE OF REVISION OF THE TEXT

20 November 2020

changes due to renewal of the marketing authorisation.

This change is purely related to renewal of the marketing authorisation

Update of Med-info details 

Product information was updated to add safety features on marketed packaging.  The date of revision of the text is 14June2018.