近日，亚力兄制药其研发的新药Strensiq(asfotase alfa)获上市，用于治疗低磷酸酯酶症（HPP）患者。低磷酸酯酶症是一种极为罕见的危及生命的代谢性疾病。Strensiq作为一种骨靶向酶替代治疗药物，是首次被欧洲批准治疗低磷酸酯酶症的药物。
低磷酸酯酶症是一种极为罕见的，渐进式的遗传性代谢疾病，患者身体多系统受损，导致其身体虚弱甚至威胁其生命。低磷酸酯酶症可使患者骨矿物质化，导致骨畸形及其他骨骼异常性疾病，还可导致多系统并发症，例如严重的肌无力、抽搐、疼痛和可导致婴儿夭折的呼吸困难。据日本处方信息显示，罹患低磷酸酯酶症的婴儿应用Strensiq 168周后，利用Kaplan-Meier法分析，患儿的存活率可达84%。
关于低磷酸酯酶症（HPP）
低磷酸酯酶症是一种极为罕见的慢性遗传性代谢疾病。其主要病症为骨矿物制化能力受损，导致骨破坏与变形、肌无力、哮喘、呼吸困难以致早夭。
低磷酸酯酶症是由于一种编码组织非特异性碱性磷酸酶(TNSALP)的基因发生突变导致的。低磷酸酯酶症的基因缺陷可影响各年龄阶段的患者。根据发病年龄（18岁之前的首发症状表现）可划分为婴儿期和少年期发作的低磷酸酯酶症。
低磷酸酯酶症对各个年龄阶段的患者均具有很大的危害性。一个回顾性研究表明，在出生后6个月内即表现出低磷酸酯酶症首发症状的患儿死亡率很高，患儿5岁时致死率为73%。在这些患者中，致死的首要病因为呼吸障碍。剩余能够存活至青年和成年的患者，则伴有长期临床后遗症，包括复发性和非愈合性骨折、肌无力、疼痛等。此外，患者还需要配备行动辅助设备，例如轮椅、推行器和手杖。
关于Strensiq (asfotase alfa)
Strensiq(asfotase alfa)是第一种针对低磷酸酯酶症的病因，即缺陷的碱性磷酸酶设计的骨靶向酶替代疗法。通过替换缺陷的碱性磷酸酶，Strensiq能够促进提高酶底物水平，提升机体骨矿物质化的能力，进而避免患者出现骨骼及其他器官严重异常和早夭。
Strensiq已经被美国食品药品管理局(FDA)、欧洲药品管理局(EMA)和日本厚生劳动省（MHLW）授予孤儿药资格。亚力兄制药公司已经向美国食品药物管理局提交了Strensiq的生物制品执照申请，并已获得优先处理权。此外，strensiq在欧洲的营销授权申请也正在审查中。

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注：以下产品德国上市包装，采购以咨询为准
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100mg/ml 80mg 12x0.8ml
40mg/ml 28mg 12x0.7ml
40mg/ml 18mg 12x0.45ml
40mg/ml 40mg 12x1ml
Strensiq 40mgml  solution for injection
1. Name of the medicinal product
Strensiq 40 mg/ml solution for injection
Strensiq 100 mg/ml solution for injection
2. Qualitative and quantitative composition
Strensiq 40 mg/ml solution for injection
Each ml of solution contains 40 mg of asfotase alfa*.
Each vial contains 0.3 ml solution and 12 mg of asfotase alfa (40 mg/ml).
Each vial contains 0.45 ml solution and 18 mg of asfotase alfa (40 mg/ml).
Each vial contains 0.7 ml solution and 28 mg of asfotase alfa (40 mg/ml).
Each vial contains 1.0 ml solution and 40 mg of asfotase alfa (40 mg/ml).
Strensiq 100 mg/ml solution for injection
Each ml of solution contains 100 mg of asfotase alfa*.
Each vial contains 0.8 ml solution and 80 mg of asfotase alfa (100 mg/ml).
* produced by recombinant DNA technology using mammalian Chinese Hamster Ovary (CHO) cell culture.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Solution for injection (injection).
Clear, colourless to slightly yellow, aqueous solution; pH 7.4.
4. Clinical particulars
4.1 Therapeutic indications
Strensiq is indicated for long-term enzyme replacement therapy in patients with paediatric-onset hypophosphatasia to treat the bone manifestations of the disease (see section 5.1).
4.2 Posology and method of administration
Treatment should be initiated by a physician experienced in the management of patients with metabolic or bone disorders.
Posology
Recommended dosage regimen of asfotase alfa is 2 mg/kg of body weight administered subcutaneously three times per week, or a dosage regimen of 1 mg/kg of body weight administered subcutaneously six times per week.
Refer to the dosing chart below for more details.

Body Weight (kg)	If injecting 3x per week			If injecting 6 x per week
	Dose to be injected	Volume to be injected	Vial type used for injection	Dose to be injected	Volume to be injected	Vial type used for injection
3	6 mg	0.15 ml	0.3 ml
4	8 mg	0.20 ml	0.3 ml
5	10 mg	0.25 ml	0.3 ml
6	12 mg	0.30 ml	0.3 ml	6 mg	0.15 ml	0.3 ml
7	14 mg	0.35 ml	0.45 ml	7 mg	0.18 ml	0.3 ml
8	16 mg	0.40 ml	0.45 ml	8 mg	0.20 ml	0.3 ml
9	18 mg	0.45 ml	0.45 ml	9 mg	0.23 ml	0.3 ml
10	20 mg	0.50 ml	0.7 ml	10 mg	0.25 ml	0.3 ml
11	22 mg	0.55 ml	0.7 ml	11 mg	0.28 ml	0.3 ml
12	24 mg	0.60 ml	0.7 ml	12 mg	0.30 ml	0.3 ml
13	26 mg	0.65 ml	0.7 ml	13 mg	0.33 ml	0.45 ml
14	28 mg	0.70 ml	0.7 ml	14 mg	0.35 ml	0.45 ml
15	30 mg	0.75 ml	1 ml	15 mg	0.38 ml	0.45 ml
16	32 mg	0.80 ml	1 ml	16 mg	0.40 ml	0.45 ml
17	34 mg	0.85 ml	1 ml	17 mg	0.43 ml	0.45 ml
18	36 mg	0.90 ml	1 ml	18 mg	0.45 ml	0.45 ml
19	38 mg	0.95 ml	1 ml	19 mg	0.48 ml	0.7 ml
20	40 mg	1.00 ml	1 ml	20 mg	0.50 ml	0.7 ml
25	50 mg	0.50 ml	0.8 ml	25 mg	0.63 ml	0.7 ml
30	60 mg	0.60 ml	0.8 ml	30 mg	0.75 ml	1 ml
35	70 mg	0.70 ml	0.8 ml	35 mg	0.88 ml	1 ml
40	80 mg	0.80 ml	0.8 ml	40 mg	1.00 ml	1 ml
50				50 mg	0.50 ml	0.8 ml
60				60 mg	0.60 ml	0.8 ml
70				70 mg	0.70 ml	0.8 ml
80				80 mg	0.80 ml	0.8 ml
90				90 mg	0.90 ml	0.8 ml (x2)
100				100 mg	1.00 ml	0.8 ml (x2)

Renal and hepatic impairment
The safety and efficacy of Strensiq in patients with renal or hepatic impairment have not been evaluated and no specific dose regimen can be recommended for these patients.
Adult patients
Efficacy and safety data in patients with hypophosphatasia >18 years old are limited.
Elderly
There is no evidence for special considerations when Strensiq is administered to elderly patients.
Method of administration
Strensiq is for subcutaneous use only. It is not intended for intravenous or intramuscular injection. The maximum volume of medicinal product per injection should not exceed 1 ml. If more than 1 ml is required, multiple injections may be administered at the same time.
Strensiq should be administered using sterile disposable syringes and injection needles. The syringes should be of small enough volume that the prescribed dose can be withdrawn from the vial with reasonable accuracy.
Injections sites should be rotated and carefully monitored for signs of potential reactions (see section 4.4).
Patients can self-inject only if they have properly been trained on administration procedures. For handling of the medicinal product before administration, see section 6.6.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Hypersensitivity
Hypersensitivity, anaphylaxis or anaphylactoid reactions have not been observed with asfotase alfa in any clinical trials. Severe allergic-type hypersensitivity reactions are possible, including urticaria, difficulty breathing and/or cardiovascular collapse. If these reactions occur, immediate discontinuation of treatment is recommended and appropriate medical treatment should be initiated. The current medical standards for emergency treatment should be observed. There have been no adverse reactions related to anti-asfotase alfa antibody status in clinical trials.
Furthermore, patients confirmed positive for anti-drug antibodies have not shown signs of hypersensitivity or tachyphylaxis with asfotase alfa administration.
Injection reaction
Administration of asfotase alfa may result in local injection site reactions (including, but not limited to, erythema, rash, discoloration, pruritus, pain, papule, nodule, atrophy) defined as any related adverse event occurring during the injection or until the end of the injection day (see section 4.8). Rotation of injection sites usually helps to effectively manage these reactions. These have been generally assessed as non-serious, mild to moderate in severity and self-limiting.
Strensiq administration should be interrupted in any patient experiencing severe injection reactions and appropriate medical therapy administered.
Craniosynostosis
In asfotase alfa clinical studies adverse events of craniosynostosis (associated with increased intracranial pressure), including worsening of pre-existing craniosynostosis have been reported in hypophosphatasia patients < 5 years of age. There are insufficient data to establish a causal relationship between exposure to Strensiq and progression of craniosynostosis. Craniosynostosis as a manifestation of hypophosphatasia is documented in published literature and occurred in 61.3% of patients between birth and 5 years of age in a natural history study of untreated infantile-onset hypophosphatasia patients. Craniosynostosis can lead to increased intracranial pressure. Periodic monitoring (including fundoscopy for signs of papilloedema) and prompt intervention for increased intracranial pressure is recommended in hypophosphatasia patients below 5 years of age.
Ectopic calcification
In asfotase alfa clinical studies ophthalmic (conjunctival and corneal) calcification and nephrocalcinosis have been reported in patients with hypophosphatasia. There are insufficient data to establish a causal relationship between exposure to Strensiq and ectopic calcification. Ophthalmic (conjunctival and corneal) calcification and nephrocalcinosis as manifestations of hypophosphatasia are documented in published literature. Nephrocalcinosis occurred in 51.6% of patients between birth and 5 years of age in a natural history study of untreated infantile-onset hypophosphatasia patients. Periodic ophthalmology examination and renal ultrasounds are recommended in hypophosphatasia patients.
Serum Parathyroid Hormone and Calcium
Serum parathyroid hormone concentration may increase in hypophosphatasia patients administered asfotase alfa, most notably during the first 12 weeks of treatment. It is recommended that serum parathyroid hormone and calcium be monitored in patients treated with asfotase alfa. Supplements of calcium and oral vitamin D may be required. See section 5.1.
Disproportionate weight gain
Patients may display disproportionate weight increase. Dietary supervision is recommended.
Excipients
This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. the product is essentially 'sodium-free'.
4.5 Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed with asfotase alfa. Based on its structure and pharmacokinetics, asfotase alfa is unlikely to affect Cytochrome P-450 related metabolism.
Asfotase alfa contains a catalytic domain of tissue non-specific alkaline phosphatase. Administration of asfotase alfa will interfere with routine measurement of serum alkaline phosphatase by hospital laboratories resulting in serum alkaline phosphatase activity measurements of several thousand units per litre. Asfotase alfa activity results must not be interpreted as the same measure as serum alkaline phosphatase activity owing to differences in enzyme characteristics.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no data from the use of asfotase alfa in pregnant women.
Following repeated subcutaneous administration to pregnant mice in the therapeutic dose range (>0.5 mg/kg), asfotase alfa levels were quantifiable in fetuses at all doses tested, suggesting cross- placental transport of asfotase alfa. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Asfotase alfa is not recommended during pregnancy and in women of childbearing potential not using contraception.
Breast-feeding
There is insufficient information on the excretion of asfotase alfa in human milk. A risk to the newborns/infants cannot be excluded.
Breast-feeding should be discontinued during treatment with asfotase alfa.
Fertility
Preclinical fertility studies were conducted and showed no evidence of effect on fertility and embryo- fetal development.
4.7 Effects on ability to drive and use machines
Strensiq has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
Summary of the safety profile
The most common adverse reactions observed were injection site reactions and injection-associated adverse reactions. Most of these reactions were non-serious, mild to moderate in intensity. Serious injection-associated reactions were reported in 2 patients with no discontinuation of asfotase alfa treatment: 1 patient with infantile-onset hypophosphatasia recorded fever and chills, and in 1 patient with juvenile-onset hypophosphatasia recorded hypoaesthesia oral, pain in extremity, chills, and headache.
Tabulated list of adverse reactions
Table 1 gives the adverse reactions observed from clinical trials in 71 patients (age 1 day to 66 years). Adverse reactions with asfotase alfa are listed by system organ class and preferred term using MedDRA frequency convention very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1: Adverse Reactions Reported in clinical trials in hypophosphatasia patients (age 1 day to 66 years)

System Organ Class	Frequency category	Adverse reaction
Infections and infestations	common	Injection site cellulitis
Blood and lymphatic system disorders	common	Increased tendency to bruise
Nervous system disorders	very common	Headache
Vascular disorders	common	Hot flush
Gastrointestinal disorders	common	Hypoaesthesia oral Nausea
Skin and subcutaneous tissue disorders	very common	Erythema
	common	Lipohypertrophy Cutis Laxa Skin discolouration including hypopigmentation Skin disorder (stretched skin)
Musculoskeletal and connective tissue disorders	very common	Pain in extremity
	common	Myalgia
General disorders and administration site conditions	very common	Injection site reactions1 Pyrexia Irritability
	common	Chills
Injury, poisoning and procedural complications	very common	Contusion
	common	Scar

1- Preferred terms considered as injection site reactions are presented in section below
Description of selected adverse reactions
Injection site reactions
Injection site reactions (including injection site erythema, discolouration, pain, pruritus, macule, swelling, bruising, hypertrophy, induration, reaction, atrophy, nodule, rash, papule, haematoma, inflammation, urticarial, warmth, haemorrhage, cellulitis and mass) are the most common adverse reactions observed in about 73% of the patients in clinical studies. The frequency of injection site reactions was higher in patients with juvenile-onset hypophosphatasia and in patients who received injections 6 times/week (compared to 3 times/week).Most injection site reactions were mild and self- limiting, and none was reported as a serious adverse event. Two patients experienced injection site reactions that led to reductions of their asfotase alfa dose.
One patient out of 71 patients treated in clinical trials experienced a severe injection site reaction of injection site discolouration which led to the discontinuation of treatment.
Immunogenicity
There is potential for immunogenicity. Among 69 hypophosphatasia patients enrolled in the clinical trials and who have post baseline data, 56 (81.2%) tested positive for anti-drug antibodies at some time point after receiving Strensiq treatment. Among those 56 patients, 25 (44.6%) also showed the presence of neutralizing antibodies. The antibody response (with or without presence of neutralizing antibodies) was time variant in nature. The development of antibodies has not been shown to affect clinical efficacy or safety (see section 5.2).
No trends in adverse events based on antibody status were observed in clinical trials. Furthermore, patients confirmed positive for antibodies have not shown signs of hypersensitivity or tachyphylaxis following subcutaneous administration of asfotase alfa.
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. Reporting forms can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Alexion Pharma UK Ltd on uk.adverseevents@alxn.com, Freephone: 0800 321 3902, Ireland Freephone: 1 800 936 544
4.9 Overdose
There is no experience with overdose of asfotase alfa. For management of adverse reactions, see sections 4.4 and 4.8.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: <not yet assigned>, ATC code: <not yet assigned>
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, non-randomised study. 13 patients were enrolled. 5 patients presented with 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. 12 patients are on-going in the study. The study employed historical controls from the same centre 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. 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: 9/13 patients displayed persistent apparent catch-up height-gain as shown by movement over time to a higher percentile on CDC growth charts.
3/13 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 and 9 patients are on-going in the study. Onset of hypophosphatasia was under 6 months in all patients. Age at inclusion 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.
5/11 subjects displayed apparent catch-up height-gain. Fluctuation in height-gain was apparent and may reflect the more severe disease and higher rate of morbidity in these younger patients.
Study ENB-009-10
Study ENB-009-10 was an open-label, non-randomised study. 19 patients were enrolled and 18 patients are on-going in the study. Onset of hypophosphatasia was under 6 months in 4 patients, between 6 months and 18 years in 12 patients and over 18 years in 2 patients. Age of onset was not known for 1 patient. Age at inclusion was from 13 to 66 years.
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 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 (26 patients), both open-label, non-randomised, non-controlled studies of patients aged 0.1 to 310 weeks at baseline, 21 of 37 patients required ventilation support:
· 14 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 ventilation (time on ventilation from 24 to 168 weeks), all had achieved an RGI-C score ≥2
- 3 patients continued with ventilation support, RGI-C score ≤2
- 3 patients died whilst on ventilation support
- 1 patient withdrew consent
· 7 patients started non-invasive ventilation (BiPAP or CPAP) after baseline (2 patients required brief support with invasive ventilation).
- 5 patients were weaned off ventilation (time on ventilation from 4 weeks to 48 weeks)
- 2 patients died
The natural history of untreated infant hypophosphatasia patients suggests high mortality if ventilation is required.
Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with Strensiq in one or more subsets of the paediatric population in hypophosphatasia (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under 'exceptional circumstances'.
This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product.
The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.
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.
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%.
5.3 Preclinical safety data
In nonclinical safety testing in rats, no body system-specific adverse effects were noted at any dose or route of administration.
Dose - and time-dependent acute injection reactions that were transient and self-limiting were noted in rats at intravenous use doses of 1 to 180 mg/kg.
Ectopic calcifications and injection site reactions were observed in monkeys when asfotase alfa was administered subcutaneously at daily doses up to 10 mg/kg through 26 weeks. These effects were restricted to injection sites and were partially or completely reversible.
There was no evidence of ectopic calcification observed in any other tissues examined.
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity or toxicity to reproduction and development. However, in pregnant rabbits administered intravenous doses of up to 50 mg/kg/day asfotase alfa, anti-drug antibodies were detected in up to 75% of animals which could affect the detection of reproductive toxicity.
No animal studies have been conducted to evaluate the genotoxic and carcinogenic potential of asfotase alfa.
6. Pharmaceutical particulars
6.1 List of excipients
Sodium chloride
Sodium phosphate dibasic heptahydrate
Sodium phosphate monobasic monohydrate
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
15 months
Chemical and physical in-use stability has been demonstrated for up to 1 hour at a temperature between 23°C to 27°C.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C).
Do not freeze.
Store in the original package in order to protect from light.
For storage conditions before administration of the medicinal product, see section 6.3.
6.5 Nature and contents of container
2 ml vial (Type I glass) with a stopper (butyl rubber) and a seal (aluminium) with a flip-off cap (polypropylene).
Strensiq 40 mg/ml solution for injection
Filled volumes of the vials are: 0.3 ml, 0.45 ml, 0.7 ml and 1.0 ml
Strensiq 100 mg/ml solution for injection
Filled volumes of the vials are: 0.8 ml
Pack sizes: cartons of 1 or 12 vials
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Each vial is intended for single use only and should only be punctured once. Any unused solution in the vial should be discarded.
Strensiq should be administered using sterile disposable syringes and injection needles. The syringes should be of small enough volume that the prescribed dose can be withdrawn from the vial with reasonable accuracy. An aseptic technique should be used.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
Alexion Europe SAS
1-15, Avenue Edouard Belin
92500 Rueil-Malmaison
France
8. Marketing authorisation number(s)
Strensiq 40 mg/ml solution for injection
EU/1/15/1015/001
EU/1/15/1015/002
EU/1/15/1015/005
EU/1/15/1015/006
EU/1/15/1015/007
EU/1/15/1015/008
EU/1/15/1015/009
EU/1/15/1015/010
Strensiq 100 mg/ml solution for injection
EU/1/15/1015/003
EU/1/15/1015/004
9. Date of first authorisation/renewal of the authorisation
28 August 2015
10. Date of revision of the text
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
U/UNB-HPP/15/0001