Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Other alimentary tract and metabolism products, enzymes, ATC code: A16AB13

Asfotase alfa is a human recombinant tissue-nonspecific alkaline phosphatase-Fc-deca-aspartate fusion protein that is expressed in an engineered Chinese hamster ovary cell line. Asfotase alfa is a soluble glycoprotein comprised of two identical polypeptide chains, each with a length of 726 amino acids made from (i) the catalytic domain of human tissue-nonspecific alkaline phosphatase, (ii) the human immunoglobulin G1 Fc domain and (iii) a deca-aspartate peptide domain.

Hypophosphatasia
Hypophosphatasia is a rare, severe, and potentially fatal, genetic disorder caused by loss-of-function mutation(s) in the gene encoding tissue non-specific alkaline phosphatase. Hypophosphatasia is associated with multiple bone manifestations including rickets / osteomalacia, altered calcium and phosphate metabolism, impaired growth and mobility, respiratory compromise that may require ventilation, and vitamin B6-responsive seizures.

Mechanism of action
Asfotase alfa, a human recombinant tissue-nonspecific alkaline phosphatase-Fc-deca-aspartate fusion protein with enzymatic activity, promotes mineralisation of the skeleton in patients with hypophosphatasia.

Clinical efficacy and safety

Study ENB-006-09/ENB-008-10
Study ENB-006-09/ENB-008-10 was an open-label, randomised study. Thirteen patients were enrolled, 12 completed, and 1 discontinued (discontinuation early in the study due to a previously planned elective scoliosis surgery). At study completion patients had received a median of over 76 months (6.3 years) of treatment (1 to 79 months). Five patients presented with symptoms of hypophosphatasia before 6 months age and 8 patients presented after 6 months age. Age at inclusion in the study was between 6 and 12 years old and was between 10 and 18 years old at completion, with 9 patients who became between 13 and 17 years old during the study.
The study employed historical controls from the same centres as patients who received asfotase alfa and who had been subject to a similar protocol of clinical management.

The effects of asfotase alfa on x-ray appearance
Trained radiologists evaluated pre- and post-baseline x-rays of wrists and knees of patients for the following signs: apparent physeal widening, metaphyseal flaring, irregularity of provisional zone of calcification, metaphyseal radiolucencies, metadiaphyseal sclerosis, osteopenia, ‘popcorn’ calcification in metadiaphysis, demineralization of distal metaphysis, transverse subphyseal band of lucency and tongues of radiolucency. X-ray changes from baseline were then rated using the Radiographic Global Impression of Change rating scale as follows: -3=severe worsening, -2=moderate worsening, -1=minimal worsening, 0=no change, +1=minimal healing, +2=substantial healing, +3= near-complete or complete healing. The majority of the patients who received asfotase alfa moved to scores of +2 and +3 over the first 6 months of exposure and this was sustained with on-going treatment. Historical controls did not show change over time.

Bone biopsy
Tetracycline for bone-labelling was administered in two 3-day courses (separated by a 14-day interval) prior to acquisition of the bone biopsy. Trans-iliac crest bone biopsies were obtained by standard procedure. Histological analysis of biopsies used Osteomeasure software (Osteometrics, USA).
Nomenclature, symbols and units followed recommendations of the American Society for Bone and Mineral Research. For 10 patients in the per-protocol set (excludes those patients who received oral vitamin D between baseline and week 24) who underwent biopsy of the trans-iliac bone crest before and after receiving asfotase alfa:
- Mean (SD) osteoid thickness was 12.8 (3.5) µm at baseline and 9.5 (5.1) µm at week 24 - Mean (SD) osteoid volume / bone volume was 11.8 (5.9)% at baseline and 8.6 (7.2)% at week 24
- Mean (SD) mineralisation lag-time was 93 (70) days at baseline and 119 (225) days at week 24

Growth
Height, weight and head circumference were plotted on growth charts (series of percentile curves that illustrate distribution) available from the Centers for Disease Control and Prevention, USA. These reference data were drawn from a representative sample of healthy children and are not specific for 

children with special health care needs: they have been used in the absence of growth charts for children with hypophosphatasia.
For those patients who received asfotase alfa: 11/13 patients displayed persistent apparent catch-up height-gain as shown by movement over time to a higher percentile on CDC growth charts.
1/13 patients did not display apparent catch-up height-gain and 1 patient did not have enough data to permit judgement. Progress through Tanner stages appeared appropriate.
For the time period of observation of historical controls: 1/16 patients displayed apparent catch-up height-gain, 12/16 patients did not display apparent catch-up height-gain and data were inconclusive in 3/16 patients.

Some patients required oral vitamin D supplements during the study (see sections 4.4 and 4.8).

Study ENB-002-08/ENB-003-08
Study ENB-002-08/ENB-003-08 was an open-label, non-randomised, non-controlled study.
11 patients were enrolled in the initial study and 10 patients entered the extension study, with 9 patients completing the extension study. At study completion, patients had received a median of over 79 months (6.6 years) of treatment (1 to >84 months). Onset of hypophosphatasia was under 6 months in all patients. Age at treatment initiation in the study was between 0.5 to 35 months.
7/11 patients in the full analysis set achieved Radiographic Global Impression of Change scores of +2 at Week 24 compared to baseline radiographs. The improvement in rickets severity was maintained for at least 72 months of follow-up treatment (including at least 84 months in 4 patients), as measured by the RGI C.
5/11 subjects displayed apparent catch-up height-gain. At last assessment (n = 10, 9 of whom had at least 72 months of treatment), median Z-score improvements from baseline were 1.93 for length/height and 2.43 for weight. Fluctuation in height-gain was apparent and may reflect the more severe disease and higher rate of morbidity in these younger patients.

Study ENB-010-10
Study ENB-010-10 was a controlled open-label study in 69 patients, aged 1 day to 72 months, with perinatal/infantile-onset HPP. The mean age at sign/symptom onset was 1.49 months. Patients received STRENSIQ at 6 mg/kg per week for the first 4 weeks. All patients began the study on a dose of asfotase alfa 6 mg/kg per week. The dose of asfotase alfa was increased for 11 patients during the study. Of these 11 patients, 9 patients had their doses increased specifically to improve clinical response. Thirty-eight patients were treated for at least 2 years (24 months) and 6 patients have been treated for at least 5 years (60 months).
At Week 48, 50/69 patients (72.5%) in the full analysis set achieved Radiographic Global Impression of Change scores ≥ 2, and were considered responders. Improvements in median RGI-C were maintained over the course of treatment, which ranged from 0.9 to 302.3 weeks, even if fewer patients were followed after Week 96 (a total of 29 patients were followed after Week 96 and ≤8 patients after Week 192).
Height, weight and head circumference were plotted on growth charts (series of percentile curves that illustrate distribution) available from the Centers for Disease Control and Prevention (CDC), USA. A total of 24/69 (35%) patients displayed apparent catch-up height-gain and 32/69 (46%) patients displayed apparent catch-up weight-gain, as shown by movement over time to a higher percentile on CDC growth charts. 40/69 patients and 32/69 patients did not show apparent catch-up gain in height and in weight, respectively. 4 patients did not have enough data to permit judgement and 1 patient could not be determined with certainty.

Study ENB-009-10
Study ENB-009-10 was an open-label, randomised study. The patients were randomly assigned to treatment group for the primary treatment period. Nineteen patients were enrolled, 14 completed, and 5 discontinued. At study completion patients had received a median of over 60 months of treatment (24 to 68 months). The onset of hypophosphatasia was under 6 months in 4 patients, between 6 months and 17 years in 14 patients, and over 18 years in one patient. Age at inclusion was from 13 to 66 years and was between 17 and 72 years at study completion.

The adolescent (and adult) patients in this study did not display apparent height-gain.

Patients underwent biopsy of the trans-iliac bone crest either as part of a control group or before and after exposure to asfotase alfa:
- Control group, standard of care (5 evaluable patients): mean (SD) mineralisation lag-time was 226 (248) days at baseline and 304 (211) days at week 24
- 0.3 mg/kg/day asfotase alfa group (4 evaluable patients): mean (SD) mineralisation lag-time was 1236 (1468) days at baseline and 328 (200) days at week 48
- 0.5 mg/kg/day asfotase alfa group (5 evaluable patients): mean (SD) mineralisation lag-time was 257 (146) days at baseline and 130 (142) days at week 48
After approximately 48 weeks all patients were adjusted to the recommended dose 1.0 mg/kg/day.

Ventilation support
In studies ENB-002-08/ENB-003-08 (11 patients) and ENB-010-10 (69 patients), both open-label, non-randomised, non-controlled studies of patients aged 0.1 to 312 weeks at baseline. 69 patients completed the studies, and 11 discontinued. Patients received a median duration of treatment of 27.6 month (range from 1 day to 90 months). 29 of 80 patients required ventilation support at baseline:
∙ 16 patients required invasive ventilation support (intubation or tracheostomy) at baseline (one had a brief period of non-invasive ventilation at baseline before transfer).
- 7 patients were weaned off invasive ventilation (time on ventilation from 12 to 168 weeks), 4 patients were off any ventilation support, and 3 patients were on non- invasive ventilation support. Five out of 7 patients achieved an RGI-C score ≥2 -5 patients continued with invasive ventilation support, 4 of them with RGI-C score <2
- 3 patients died whilst on ventilation support
- 1 patient withdrew consent
∙ 13 patients required non-invasive ventilation support at baseline.
- 10 patients were weaned off any ventilation support (time on ventilation from 3 to 216 weeks). 9 out of 10 patients achieved a RGI-C score ≥2, only 1 with RGI-C <2.
- 2 patients required invasive ventilation support and 1 patient continued with non- invasive ventilation support, all 3 patients died and with RGI-C score <2 The natural history of untreated infantile-onset hypophosphatasia patients suggests high mortality if ventilation is required.

Due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product, in case new information become available, this SmPC will be updated as necessary.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Pharmacokinetics of asfotase alfa were evaluated in a 1-month, multicenter, open-label, dose- escalating, study in adults with hypophosphatasia. Cohort 1 (n=3) of the study received asfotase alfa 3 mg/kg intravenously the first week followed by 3 doses at 1 mg/kg subcutaneous at weekly intervals from weeks 2 to 4. Cohort 2 (n=3) received asfotase alfa 3 mg/kg intravenously the first week followed by 3 doses at 2 mg/kg subcutaneous at weekly intervals from weeks 2 to 4. After the 3 mg/kg for 1.08 hours intravenous infusion, the median time (Tmax) ranged between 1.25 to 1.50 hours, and the mean (SD) Cmax ranged between 42694 (8443) and 46890 (6635) U/L over the studied cohorts. The absolute bioavailability after the first and third subcutaneous administration ranged from 45.8 to 98.4%, with median Tmax ranging between 24.2 to 48.1 hours. After the 1 mg/kg weekly subcutaneous administration in Cohort 1 the mean (SD) AUC over the dosing interval (AUC) was 66034 (19241) and 40444 (N=1) U*h/L following the first and the third dose, respectively. After the 2 mg/kg weekly subcutaneous administration in Cohort 2 the mean (SD) AUC was 138595 (6958) and 136109 (41875) following the first and the third dose, respectively.

Pharmacokinetic data from all asfotase alfa clinical trials were analysed using population pharmacokinetic methods. The pharmacokinetic variables characterized by population pharmacokinetic analysis represent the overall hypophosphatasia patient population with age range 
from 1 day to 66 years, subcutaneous doses of up to 28 mg/kg/week and a range of disease onset cohorts. Twenty five percent (15 out of 60) of the overall patient population was adult (>18 years) at baseline. The absolute bioavailability and absorption rate following subcutaneous administration were estimated to be 0.602 (95% CI: 0.567, 0.638) or 60.2% and 0.572 (95%CI: 0.338, 0.967)/day or 57.2%, respectively. The central and peripheral volumes of distribution estimates for a patient with body weight of 70 kg (and 95% CI) were 5.66 (2.76, 11.6) L and 44.8 (33.2, 60.5) L, respectively. The central and peripheral clearance estimates for a patient with body weight of 70 kg (and 95% CI) were 15.8 (13.2, 18.9) L/day and 51.9 (44.0, 61.2) L/day, respectively. The extrinsic factors affecting asfotase alfa pharmacokinetic exposures were formulation specific activity and total sialic acid content. The average ± SD elimination half-life following subcutaneous administration was 2.28 ± 0.58 days.
In adult patients with pediatric-onset HPP, the pharmacokinetics of asfotase alfa at doses of 0.5, 2 and 3 mg/kg administered three times per week was consistent with those observed in pediatric patients with pediatric-onset HPP, and thus supported the approved dose of 6 mg/kg per week in treating adult patients with pediatric-onset HPP.

Linearity/non-linearity
Based on the results of population pharmacokinetic analysis it was concluded that asfotase alfa exhibits linear pharmacokinetic up to subcutaneous doses of 28 mg/kg/week. The model identified body weight to affect asfotase alfa clearance and volume of distribution parameters. It is expected that pharmacokinetic exposures will increase with body weight. The impact of immunogenicity on asfotase alfa pharmacokinetic varied over time due to the time varying nature of immunogenicity and overall was estimated to decrease pharmacokinetic exposures by less than 20%.