Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

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 55.6 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.

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 ≥1.5 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.

The following endpoints were assessed: normalisation of ALT, decrease in LDL-cholesterol, decrease in 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 resonance imaging (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 period of the study, as shown in Table 3. The absolute reduction in mean ALT level was -57.9 U/l (-53%) in the 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              Placebo
Endpoint                                                                  P-valued alfa (n =              (n = 30)
36)
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 b
Normalisation of AST                                            42%              3%              0.0003 Triglycerides, mean % change from baseline                     -25%             -11%             0.0375 HDL-cholesterol, mean % change from baseline                    20%            -0.3%          < 0.0001 c
Liver fat content , mean % change from baseline                -32%             -4%           < 0.0001 a
Proportion of patients who achieved normalisation defined as 34 or 43 U/l, depending on age and gender.
b
Proportion of patients who achieved normalisation defined as 34-59 U/l, depending on age and gender. Evaluated in patients with abnormal baseline values (n = 36 for sebelipase alfa; n = 29 for placebo).
c
Evaluated in patients with MEGE-MRI assessments performed (n = 32 for sebelipase alfa; n = 25 for placebo).
d
P-values are from Fisher’s exact test for normalisation endpoints and Wilcoxon rank-sum test for all other endpoints.

Paired liver biopsies at baseline and week 20 were available in a subset of patients (n = 26).
Of patients with paired liver biopsies, 63% (10/16) of sebelipase alfa-treated patients had improvement in hepatic steatosis (at least ≥ 5% reduction) as measured by morphometry compared to 40% (4/10) of placebo 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-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.

LAL deficiency registry

Medical or healthcare professionals are encouraged to participate and enrol all patients diagnosed with LAL deficiency in the LAL deficiency registry.

Pharmacokinetic Properties

 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
Age < 4 years       Age 4 to < 12 years        Age 12 to < 18         ≥ 18 years Parameter
(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
521 (174)             1410 (774)              1610 (658)           2060 (793) (ng × h/mL)
Cmax,ss
247 (80.6)             679 (370)               786 (315)            997 (367) (ng/mL)
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 = maximum observed 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 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).