2015年10月23日，美国FDA批准Strensiq（asfotase alfa）作为首款获得批准的治疗药物用于围产期、婴儿及幼儿期发作的低磷酸酯酶症（HPP）。
低磷酸酯酶症是一种罕见的、遗传性、进展性代谢疾病，该病患者的多个人体系统会经历灾难性的影响，导致严重残疾及危及生命的并发症。该疾病的特征是有缺陷的骨骼矿物化，这可导致佝偻病及导致骨骼畸形的骨软化。
低磷酸酯酶症也能引起并发症，如失去运动能力的重度肌无力、癫痫发作、疼痛、呼吸衰竭和过早死亡。严重形式的低磷酸酯酶症影响了大约十万之一的新生儿，但轻微病例，如在儿童或成年期出现的低磷酸酯酶症可能发生的更频繁一些。
低磷酸酯酶症患者人群第一次将可以获得一款被批准的药物用于这种罕见的疾病，FDA药物评价与研究中心药物评价III办公室代理主任、医学博士、公共卫生学硕士Egan称。Strensiq的批准是突破性治疗药物资格项目可以为罕见病患者带来新的及所需治疗药物的一个例证。
Strensiq获得了突破性治疗药物资格，因为它是首款、也是唯一一款用于围产期、婴儿及幼儿期发作的低磷酸酯酶症治疗的药物。突破性治疗药物项目鼓励FDA与申请者一起合作，通过及时建议与互动沟通，帮助快速推进用于严重或危及生命疾病重要新药的开发与审评。除了突破性治疗药物资格，FDA还授予Strensiq孤儿药资格，因为这款药物在美国治疗患者人数不超过20万的疾病。
孤儿药资格可提供经济上的激励，如临床试验税收抵免、免除申请者费用及有资格获得市场专营权，从而促进罕见病药物的开发。Strensiq还被授予优先审评资格，这一条款授予那些在严重疾病治疗中对安全性及有效性有明显改善的药物申请。
此外，Strensiq的生产商被授予一张罕见儿科疾病优先审评券，这一条款旨在鼓励新药及用于罕见儿科疾病预防与治疗的生物药品的开发。这款药物的开发在某种程度上也得到了FDA孤儿药产品授予计划的支持，这一计划授予那些用于罕见病症产品的安全性及/或有效性临床研究。
Strensiq通过注射给药，每周注射三次或六次。Strensiq通过替代在正常骨骼中负责一种主要矿物质形成的酶（称组织非特异性碱性磷酸酶）而发挥作用，这种酶已显示能改善患者的结局。
Strensiq的安全性与有效性在99名围产期（疾病在子宫时发生，出生时比较明显）、婴儿期或幼儿期发作的低磷酸酯酶症患者中得到证实，这些患者在四项前瞻性、开放式研究中接受该药物治疗长达6.5年时间。
研究结果显示，以Strensiq治疗的围产期及婴儿期发作低磷酸酯酶症患者其总生存期及无需呼吸机的生存期（无呼吸机生存期）得到改善。97%的治疗患者在一岁时仍存活，相比之下，从自然历史研究组选取的对照患者一岁时存活率为42%。同样，治疗组患者一岁时的无呼吸机生存率为85%，而自然历史对照患者为50%。
以Strensiq治疗的幼儿期发作低磷酸酯酶症患者与从自然历史数据库选取的对照患者相比，在成长及骨健康方面显示得到改善。所有治疗患者在低体重或身材矮小或保持正常身高与体重方面均有改善。相比之下，对照患者大约有20%的人随时间推移而生长推迟，身高与体重低于同龄儿童正常范围的身高与体重。
幼儿期发病患者还显示骨骼矿物化得到改善，骨骼矿物化是基于X射线影像来评价佝偻病及其它低磷酸酯酶症相关骨骼畸形严重程度的一个指标。基于X射线影像，所有治疗患者证明佝偻病有实质性治愈，而一些自然历史对照患者显示佝偻病随时间推移而日益严重的信号。
在Strensiq治疗患者中最常见的副作用包括注射部位反应、过敏反应（如呼吸困难、恶心、头晕及发烧）、注射部位脂肪代谢障碍（脂肪组织丧失导致皮肤凹陷或脂肪组织变厚导致皮肤下出现肿块）及眼与肾脏出现异位性钙化。Strensiq由康乃迪克州柴郡的亚力兄制药公司生产。

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use STRENSIQ safely and effectively. See full prescribing information for STRENSIQ.
STRENSIQ™ (asfotase alfa) injection, for subcutaneous use
Initial U.S. Approval: 2015
INDICATIONS AND USAGE
STRENSIQ™ is a tissue nonspecific alkaline phosphatase indicated for the treatment of patients with perinatal/infantile- and juvenile-onset hypophosphatasia (HPP). (1)
DOSAGE AND ADMINISTRATION
Perinatal/Infantile-Onset HPP (2.1)
Recommended dosage regimen is 2 mg/kg administered subcutaneously three times per week, or 1 mg/kg administered six times per week. Injection site reactions may limit the tolerability of the six times per week regimen.
The dose may be increased to 3 mg/kg three times per week for insufficient efficacy.
Juvenile-Onset HPP (2.2)
Recommended dosage regimen is 2 mg/kg administered subcutaneously three times per week, or 1 mg/kg administered six times per week. Injection site reactions may limit the tolerability of the six times per week regimen.
Preparation and Weight-Based Dosing (2.3):
Caution: Do not use the 80 mg/0.8 mL vial in pediatric patients weighing less than 40 kg because the systemic asfotase alfa exposure achieved with the 80 mg/0.8 mL vial (higher concentration) is lower than that achieved with the other strength vials (lower concentration). A lower exposure may not be adequate for this subgroup of patients.
See full prescribing information for tables of weight-based dosing by treatment regimen.
Administration (2.4):
For subcutaneous injection only.
Rotate injection sites. Do not administer to areas that are reddened, inflamed or swollen.
DOSAGE FORMS AND STRENGTHS
Injection: 18 mg/0.45 mL, 28 mg/0.7 mL, 40 mg/mL, or 80 mg/0.8 mL solution in single-use vials. (3)
CONTRAINDICATIONS
None. (4)
WARNINGS AND PRECAUTIONS
Hypersensitivity Reactions: Monitor and if a severe reaction occurs, discontinue treatment and initiate appropriate medical treatment. (5.1)
Lipodystrophy: Localized reactions were reported after several months of treatment; follow proper injection technique and rotate injection sites. (5.2)
Ectopic Calcifications (eye and kidneys): Monitor using ophthalmologic examinations and renal ultrasounds at baseline and periodically during treatment. (5.3)
ADVERSE REACTIONS
Most common adverse reactions (≥ 10%) are injection site reactions, lipodystrophy, ectopic calcifications and hypersensitivity reactions. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Alexion Pharmaceuticals, Inc. at 1-844-259-6783 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 10/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
STRENSIQ™ is indicated for the treatment of patients with perinatal/infantile- and juvenile-onset hypophosphatasia (HPP).
2 DOSAGE AND ADMINISTRATION
2.1 Dosage for Perinatal/Infantile-Onset HPP
The recommended dosage regimen of STRENSIQ for the treatment of perinatal/infantile-onset HPP is 6 mg/kg per week administered subcutaneously as either:
2 mg/kg three times per week, or
1 mg/kg six times per week. Injection site reactions may limit the tolerability of the six times per week regimen [see Adverse Reactions (6.1)].
The dose of STRENSIQ may be increased for lack of efficacy (e.g., no improvement in respiratory status, growth, or radiographic findings) up to 9 mg/kg per week administered subcutaneously as 3 mg/kg three times per week.
2.2 Dosage for Juvenile-Onset HPP
The recommended dosage regimen of STRENSIQ for the treatment of juvenile-onset HPP is 6 mg/kg per week administered subcutaneously as either:
2 mg/kg three times per week, or
1 mg/kg six times per week. Injection site reactions may limit the tolerability of the six times per week regimen [see Adverse Reactions (6.1)].
2.3 Preparation and Weight-Based Dosing Tables
Caution: Do not use the 80 mg/0.8 mL vial of STRENSIQ in pediatric patients weighing less than 40 kg because the systemic exposure of asfotase alfa achieved with the 80 mg/0.8 mL vial (higher concentration) is lower than that achieved with the other strength vials (lower concentration). A lower exposure may not be adequate for this subgroup of patients [see Dosage Forms and Strengths (3), Clinical Pharmacology (12.3)].
1. Determine the volume needed for the prescribed dosage based on the patient's weight and recommended dosage. Follow these steps to determine the patient dose.

Total dose (mg) = patient's weight (kg) × prescribed dose (mg/kg)

Total injection volume (mL) = Total dose (mg) divided by concentration (40 mg/mL or 80 mg/0.8 mL)

Round total injection volume to the nearest hundredth of a mL

Total number of vials = Total injection volume divided by vial volume (mL)

2. Determine frequency of weekly injections.
3. Determine dose. Patient weights should be rounded to the nearest kilogram when determining dose. Use the following tables for guidance, for patients administering 2 mg/kg three times per week (Table 1), 1 mg/kg six times per week (Table 2) and for dose escalations to 3 mg/kg three times per week, recommended only for patients with perinatal/infantile-onset HPP [see Dosage and Administration (2.1)] (Table 3).
4. When preparing a volume for injection greater than 1 mL, split the volume equally between two syringes, and administer two injections. When administering the two injections, use two separate injection sites.
Table 1: Weight-Based Dosing for Administration of 2 mg/kg Three Times per Week 

Body Weight (kg)	Dose to Inject	Volume to Inject	Vial Configuration
3	6 mg	0.15 mL	18 mg/0.45 mL
4	8 mg	0.2 mL	18 mg/0.45 mL
5	10 mg	0.25 mL	18 mg/0.45 mL
6	12 mg	0.3 mL	18 mg/0.45 mL
7	14 mg	0.35 mL	18 mg/0.45 mL
8	16 mg	0.4 mL	18 mg/0.45 mL
9	18 mg	0.45 mL	18 mg/0.45 mL
10	20 mg	0.5 mL	28 mg/0.7 mL
15	30 mg	0.75 mL	40 mg/mL
20	40 mg	1 mL	40 mg/mL
25	50 mg	1.25 mL	Two 28 mg/0.7 mL vials
30	60 mg	1.5 mL	Two 40 mg/mL vials
35	70 mg	1.75 mL	Two 40 mg/mL vials
40	80 mg	0.8 mL	80 mg/0.8 mL
50	100 mg	1 mL	Two 80 mg/0.8 mL vials
60	120 mg	1.2 mL	Two 80 mg/0.8 mL vials
70	140 mg	1.4 mL	Two 80 mg/0.8 mL vials
80	160 mg	1.6 mL	Two 80 mg/0.8 mL vials

Do not use the 80 mg/0.8 mL vial of STRENSIQ in pediatric patients weighing less than 40 kg [see Clinical Pharmacology (12.3)].
When preparing a volume for injection greater than 1 mL, split the volume equally between two syringes, and administer two injections. When administering the two injections, use two separate injection sites.
Table 2: Weight-Based Dosing for Administration of 1 mg/kg Six Times per Week

Body Weight (kg)	Dose to Inject	Volume to Inject	Vial Configuration
3	3 mg	0.08 mL	18 mg/0.45 mL
4	4 mg	0.1 mL	18 mg/0.45 mL
5	5 mg	0.13 mL	18 mg/0.45 mL
6	6 mg	0.15 mL	18 mg/0.45 mL
7	7 mg	0.18 mL	18 mg/0.45 mL
8	8 mg	0.2 mL	18 mg/0.45 mL
9	9 mg	0.23 mL	18 mg/0.45 mL
10	10 mg	0.25 mL	18 mg/0.45 mL
15	15 mg	0.38 mL	18 mg/0.45 mL
20	20 mg	0.5 mL	28 mg/0.7 mL
25	25 mg	0.63 mL	28 mg/0.7 mL
30	30 mg	0.75 mL	40 mg/mL
35	35 mg	0.88 mL	40 mg/mL
40	40 mg	1 mL	40 mg/mL
50	50 mg	0.5 mL	80 mg/0.8 mL
60	60 mg	0.6 mL	80 mg/0.8 mL
70	70 mg	0.7 mL	80 mg/0.8 mL
80	80 mg	0.8 mL	80 mg/0.8 mL
90	90 mg	0.9 mL	Two 80 mg/0.8 mL vials
100	100 mg	1 mL	Two 80 mg/0.8 mL vials

Do not use the 80 mg/0.8 mL vial of STRENSIQ in pediatric patients weighing less than 40 kg [see Clinical Pharmacology (12.3)].
Table 3: Weight-Based Dosing for Administration of 3 mg/kg Three Times per Week – Only for Perinatal/Infantile-Onset HPP*

Body Weight (kg)	Dose to Inject	Volume to Inject	Vial Configuration
3	9 mg	0.23 mL	18 mg/0.45 mL
4	12 mg	0.3 mL	18 mg/0.45 mL
5	15 mg	0.38 mL	18 mg/0.45 mL
6	18 mg	0.45 mL	18 mg/0.45 mL
7	21 mg	0.53 mL	28 mg/0.7 mL
8	24 mg	0.6 mL	28 mg/0.7 mL
9	27 mg	0.68 mL	28 mg/0.7 mL
10	30 mg	0.75 mL	40 mg/mL
15	45 mg	1.13 mL	Two 28 mg/0.7 mL vials
20	60 mg	1.5 mL	Two 40 mg/mL vials
25	75 mg	1.88 mL	Two 40 mg/mL vials

A regimen of 3 mg/kg three times per week is recommended only for patients with perinatal/infantile-onset HPP [see Dosage and Administration (2.1)]
Do not use the 80 mg/0.8 mL vial of STRENSIQ in pediatric patients weighing less than 40 kg [see Clinical Pharmacology (12.3)].
When preparing a volume for injection greater than 1 mL, split the volume equally between two syringes, and administer two injections. When administering the two injections, use two separate injection sites.
5. Inspect the solution in the vial(s) for particulate matter and discoloration. STRENSIQ is supplied as a clear, slightly opalescent or opalescent, colorless to slightly yellow aqueous solution; few small translucent or white particles may be present. Discard any vial(s) not consistent with this appearance.
6. Assemble injection supplies. Administer STRENSIQ using sterile disposable 1 mL syringes and ½ inch injection needles, between 25 to 29 gauge are recommended. For doses greater than 1 mL, the injection volume should be split equally between two 1 mL syringes. Always use a new syringe and needle.
7. Remove vial cap, aseptically prepare the vial and insert the syringe into the vial to withdraw the prescribed dose for administration.
8. Remove any air bubbles in the syringe and verify the correct dose.
2.4 Administration
STRENSIQ is for subcutaneous injection only.
1. Administer STRENSIQ within 1 hour upon removal of the vial(s) from refrigeration.
2. Rotate the injection from among the following sites to reduce the risk of lipodystrophy: abdominal area, thigh, or deltoid [see Warnings and Precautions (5.2), Adverse Reactions (6.1)].
3. Do NOT administer injections in areas that are reddened, inflamed, or swollen.
4. Inject STRENSIQ subcutaneously into the determined site and properly dispose of the needle.
5. STRENSIQ vials are single use only. Discard any unused product. 
3 DOSAGE FORMS AND STRENGTHS
STRENSIQ is supplied as a sterile, preservative-free, nonpyrogenic, clear, slightly opalescent or opalescent, colorless to slightly yellow aqueous solution; few small translucent or white particles may be present. The product is available as:
Injection: 18 mg/0.45 mL, 28 mg/0.7 mL, 40 mg/mL, or 80 mg/0.8 mL solution in single-use vials
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Reactions
Hypersensitivity reactions have been reported in STRENSIQ-treated patients. In clinical trials, 1 out of 99 patients (1%) treated with STRENSIQ experienced signs and symptoms consistent with anaphylaxis, including difficulty breathing, nausea, periorbital edema, and dizziness. In this patient, the reaction occurred approximately 1 minute after STRENSIQ injection in the setting of 3.5 years of ongoing STRENSIQ treatment and resolved without medical treatment. The patient resumed STRENSIQ treatment and received pre-medication with diphenhydramine for an unspecified period and then subsequently continued treatment with STRENSIQ without pre-medication. Other hypersensitivity reactions have also been reported in STRENSIQ-treated patients, including vomiting, fever, headache, flushing, irritability, chills, skin erythema, rash, pruritus and oral hypoesthesia [see Adverse Reactions (6.1)].
If a severe hypersensitivity reaction occurs, discontinue STRENSIQ treatment and initiate appropriate medical treatment. Consider the risks and benefits of re-administering STRENSIQ to individual patients following a severe reaction. If the decision is made to re-administer the product, monitor patients for a reoccurrence of signs and symptoms of a severe hypersensitivity reaction.
5.2 Lipodystrophy
Localized lipodystrophy, including lipoatrophy and lipohypertrophy, has been reported at injection sites after several months in patients treated with STRENSIQ in clinical trials [see Adverse Reactions (6.1)]. Advise patients to follow proper injection technique and to rotate injection sites [see Dosage and Administration (2.4)].
5.3 Ectopic Calcifications
Patients with HPP are at increased risk for developing ectopic calcifications. In clinical trials with STRENSIQ, 14 cases (14%) of ectopic calcification of the eye including the cornea and conjunctiva, and the kidneys (nephrocalcinosis) were reported. There was insufficient information to determine whether or not the reported events were consistent with the disease or due to STRENSIQ. No visual changes or changes in renal function were reported resulting from the occurrence of ectopic calcifications.
Ophthalmology examinations and renal ultrasounds are recommended at baseline and periodically during treatment with STRENSIQ to monitor for signs and symptoms of ophthalmic and renal ectopic calcifications and for changes in vision or renal function.
6 ADVERSE REACTIONS
The following adverse reactions are described below and elsewhere in the labeling:
Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
Lipodystrophy [see Warnings and Precautions (5.2)]
Ectopic Calcifications [see Warnings and Precautions (5.3)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described below reflect exposure to STRENSIQ in 99 patients with perinatal/infantile- or juvenile-onset HPP (age 1 day to 58 years) treated with STRENSIQ, most for more than 2 years (range 1 day to 312 weeks [78 months]): 51 patients received at least 96 weeks (24 months) of treatment and 39 patients received 168 weeks (42 months) or more of treatment.
Common Adverse Reactions
Overall, the most common adverse reactions reported were injection site reactions (63%). Other common adverse reactions included lipodystrophy (28%), ectopic calcifications (14%), and hypersensitivity reactions (12%).
Table 4 summarizes the adverse reactions that occurred at a rate of at least 10% in clinical trials following subcutaneous injection of STRENSIQ, by patient population and STRENSIQ dosage regimen.
The frequency of injection site reactions, lipodystrophy and ectopic calcification were higher in patients with juvenile-onset HPP as compared to perinatal/infantile-onset HPP patients.
The majority of injection site reactions resolved within a week. Two patients experienced injection site reactions that led to reductions of their STRENSIQ dose. One patient switched from six times per week dosing to 3 times per week dosing as a result of injection site reactions. One other patient experienced a severe injection site reaction of injection site discoloration and withdrew from the trial.
Table 4: Adverse Reactions Reported in at Least 10% of Patients with Perinatal/Infantile- or Juvenile-onset HPP Enrolled in STRENSIQ Clinical Trials 

Perinatal/Infantile-onset HPP			Juvenile-onset HPP
Adverse Reaction Category or Term	STRENSIQ less than or equal to 6 mg/kg per week (N=66) n (%)	STRENSIQ more than 6 mg/kg/week (N=13) n (%)	Total (N=79) n (%)	(N=20) n (%)
Injection site reactions	38 (58)	6 (46)	44 (56)	18 (90)
Erythema	29 (44)	3 (23)	32 (41)	15 (75)
Discoloration/ Hypopigmentation	11 (17)	1 (8)	12 (15)	8 (40)
Pain/ Tenderness	10 (15)	1 (8)	11 (14)	8 (40)
Pruritus/ Itching	10 (15)	0 (0)	10 (13)	7 (35)
Swelling	8 (12)	0 (0)	8 (10)	6 (30)
Induration	9 (14)	1 (8)	10 (13)	3 (15)
Macule	4 (6)	0 (0)	4 (5)	7 (35)
Reaction, not otherwise specified	6 (9)	1 (8)	7 (9)	4 (20)
Bruising	6 (9)	0 (0)	6 (8)	4 (20)
Nodule	2 (3)	0 (0)	2 (3)	2 (10)
Other injection site reactions	10 (15)	3 (23)	13 (17)	4 (20)
Ectopic calcifications	3 (5)	0 (0)	3 (4)	11 (55)
Lipodystrophy	12 (18)	2 (15)	14 (18)	14 (70)
Injection site atrophy	4 (6)	2 (15)	6 (8)	8 (40)
Injection site hypertrophy	5 (8)	0 (0)	5 (6)	6 (30)
Other lipodystrophy	4 (6)	0 (0)	4 (5)	1 (5)
Hypersensitivity reactions	7 (11)	3 (23)	10 (13)	2 (10)
Vomiting/emesis	2 (3)	2 (15)	4 (5)	2 (10)
Other hypersensitivity reactions	6 (9)	2 (15)	8 (10)	2 (10)

Adverse reactions are from the combined period of 6 mg/kg and above (i.e. total drug exposure regardless of starting dose and intermediary doses as long as the patient reached doses > 6 mg/kg).
Other injection site reactions include injection site rash, inflammation, papule, hemorrhage, hematoma, urticaria, warmth, calcification, mass, scar and cellulitis.
Other lipodystrophy includes lipohypertrophy.
Other hypersensitivity reactions include erythema/redness, pyrexia/fever, irritability, nausea, pain, rigor/chills, hypoesthesia oral, headache, flushing, and anaphylaxis.
Less Common Adverse Reactions
Adverse reactions that occurred at rates less than 1% included:
Hypocalcemia
Renal stones
Chronic hepatitis
Decreased vitamin B6
6.2 Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. During clinical trials, anti-drug antibodies have been detected in patients receiving treatment with STRENSIQ using an electrochemiluminescent (ECL) immunoassay. Antibody positive samples were tested to determine the presence of neutralizing antibodies based on in vitro inhibition of the catalytic activity of STRENSIQ. Among 98 patients with hypophosphatasia (HPP) enrolled in the clinical trials and who had post-baseline antibody data, 76 (78%) tested positive for anti-drug antibodies at some time point after receiving STRENSIQ treatment. Among those 76 patients, 34 (45%) also showed the presence of neutralizing antibodies. No correlation was observed between the anti-drug antibody titer and neutralizing antibody (% inhibition) values. Formation of anti-drug antibody resulted in a reduced systemic exposure of asfotase alfa. [see Clinical Pharmacology (12.3)].
The detection of antibody formation is dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of the antibodies to STRENSIQ with the incidence of antibodies to other products may be misleading.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
There are no available human data on STRENSIQ use in pregnant women to inform a drug associated risk. In animal reproduction studies, asfotase alfa administered intravenously to pregnant rats and rabbits during the period of organogenesis showed no evidence of fetotoxicity, embryolethality or teratogenicity at doses causing plasma exposures up to 21 and 24 times, respectively, the exposure at the recommended human dose [see Data].
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Data
Animal Data
Asfotase alfa administered during the period of organogenesis to rats (from gestation Day 6 to Day 19 post-partum) and rabbits (on gestation days 7 to 19) at intravenous doses up to 50 mg/kg/day, approximately 21 and 24 times the human AUC of 65486 ng.h/mL at 2 mg/kg dose administered three times weekly for a 50 kg individual, respectively did not cause any adverse effects on embryofetal development. A pre- and post-natal development study in pregnant rats showed no evidence of adverse effects on pre- and post-natal development at intravenous doses (from Day 6 of gestation to Day 19 postpartum) of asfotase alfa up to 50 mg/kg/day approximately 21 times the human AUC of 65486 ng.h/mL at 2 mg/kg dose administered three times weekly for a 50 kg individual.
8.2 Lactation
Risk Summary
There are no data on the presence of asfotase alfa in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for STRENSIQ and any potential adverse effects on the breastfed infant from asfotase alfa or from the underlying maternal condition.
8.4 Pediatric Use
The safety and effectiveness of STRENSIQ have been established in pediatric patients. Use of STRENSIQ is based on 4 prospective, open-label clinical trials conducted in 99 adult and pediatric patients with perinatal/infantile-onset or juvenile-onset HPP. The majority of patients were pediatric patients 1 day to 16 years of age (89/99 [90%]) [see Clinical Studies (14)].
8.5 Geriatric Use
No patients with perinatal/infantile- or juvenile-onset HPP aged 65 years were enrolled in clinical trials of STRENSIQ. Therefore, there is no information available to determine whether patients aged 65 years and over respond differently from younger patients.
11 DESCRIPTION
STRENSIQ is a formulation of asfotase alfa, which is a soluble glycoprotein composed of two identical polypeptide chains. Each chain contains 726 amino acids with a theoretical mass of 161 kDa. Each chain consists of the catalytic domain of human tissue non-specific alkaline phosphatase (TNSALP), the human immunoglobulin G1 Fc domain and a deca-aspartate peptide used as a bone targeting domain. The two polypeptide chains are covalently linked by two disulfide bonds.
STRENSIQ is a tissue nonspecific alkaline phosphatase produced by recombinant DNA technology in a Chinese hamster ovary cell line. TNSALP is a metallo-enzyme that catalyzes the hydrolysis of phosphomonoesters with release of inorganic phosphate and alcohol. Asfotase alfa has a specific activity of 620 to 1250 units/mg. One activity unit is defined as the amount of asfotase alfa required to form 1 µmol of p-nitrophenol from pNPP per minute at 37°C.
STRENSIQ (asfotase alfa) is a sterile, preservative-free, nonpyrogenic, clear, slightly opalescent or opalescent, colorless to slightly yellow, with few small translucent or white particles, aqueous solution for subcutaneous administration. STRENSIQ is supplied in glass single-use vials containing asfotase alfa; dibasic sodium phosphate, heptahydrate; monobasic sodium phosphate, monohydrate; and sodium chloride at a pH between 7.2 and 7.6. Table 5 describes the content of STRENSIQ vial presentations.
Table 5: Content of STRENSIQ Vial Presentations

Ingredient	Quantity per Vial
Asfotase Alfa	18 mg/0.45 mL	28 mg/0.7 mL	40 mg/mL	80 mg/0.8 mL
Dibasic sodium phosphate, heptahydrate	2.48 mg	3.85 mg	5.5 mg	4.4 mg
Monobasic sodium phosphate, monohydrate	0.28 mg	0.43 mg	0.62 mg	0.5 mg
Sodium chloride	3.94 mg	6.13 mg	8.76 mg	7.01 mg

12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
HPP is caused by a deficiency in TNSALP enzyme activity, which leads to elevations in several TNSALP substrates, including inorganic pyrophosphate (PPi). Elevated extracellular levels of PPi block hydroxyapatite crystal growth which inhibits bone mineralization and causes an accumulation of unmineralized bone matrix which manifests as rickets and bone deformation in infants and children and as osteomalacia (softening of bones) once growth plates close, along with muscle weakness. Replacement of the TNSALP enzyme upon STRENSIQ treatment reduces the enzyme substrate levels.
12.2 Pharmacodynamics
Perinatal/infantile- and juvenile-onset HPP patients treated with STRENSIQ had reductions in plasma TNSALP substrates, PPi and pyridoxal 5'-phosphate (PLP) within 6 to 12 weeks of treatment. Reductions in plasma PPi and PLP levels did not correlate with clinical outcomes.
Bone biopsy data from perinatal/infantile-onset and juvenile-onset HPP patients treated with STRENSIQ demonstrated decreases in osteoid volume and thickness indicating improved bone mineralization.
12.3 Pharmacokinetics
Based on data in 38 HPP patients, the pharmacokinetics of asfotase alfa exhibit dose proportionality across the dose range of 0.3 mg/kg to 3 mg/kg and appear to be time-independent. Steady state exposure was achieved as early as three weeks after the administration of the first dose. The elimination half-life following subcutaneous administration was approximately 5 days.
Table 6 summarizes the pharmacokinetic parameters following multiple doses in 20 HPP patients after subcutaneous administration of STRENSIQ at 2 mg/kg three times per week in Study 2 (age of less than or equal to 5 years) and Study 3 (age of greater than 5 to 12 years), indicating the pharmacokinetics were similar between patients in the two age groups.
Table 6: Summary of Pharmacokinetic Parameters Following Multiple Subcutaneous Administration of STRENSIQ 2 mg/kg Three Times per Week

Study 2	Study 3
N	14	6
Age (year)	3.4 ± 2.1 (0.2, 6.2)	8.6 ± 2.2 (6.1, 12.6)
Weight at baseline (kg)	11.2 ± 5.0 (2.9, 17.1)	21.2 ± 7.9 (11.4, 35.4)
tlast (h)	48.1 ± 0.1 (47.9, 48.3)	48.0 ± 0.1 (48.0, 48.1)
tmax (h)	14.9 ± 10.4 (0, 32.2)	20.8 ± 10.0 (11.9, 32.2)
Cmax (ng/mL)	1794 ± 690 (856, 3510)	2108 ± 788 (905, 3390)
AUCt (h*ng/mL)	66042 ± 25758 (27770, 119122)	89877 ± 33248 (37364, 142265)
Accumulation Ratio	1.5	3.9

Data are presented as mean ± standard deviation (range). Study 3 includes patients with perinatal/infantile- or juvenile-onset of disease. tlast, time of last concentration; tmax, time of maximal concentration; Cmax, maximal concentration; AUCt, area under the concentration-time curves over a dosing interval of 48 hours
Ratio values reflect the fold increase of AUC t from Week 1 based on mean AUC t, values. 
Population PK analysis of asfotase alfa concentrations supports weight-based dosing because body weight is a major covariate of asfotase alfa clearance. The formulation concentration had an impact on the systemic exposure of asfotase alfa in HPP patients. The higher concentration formulation (80 mg/0.8 mL vial) achieved an approximately 25% lower systemic asfotase alfa exposure (i.e., concentrations and AUC) compared to the lower concentration formulations (18 mg/0.45 mL, 28 mg/0.7 mL or 40 mg/mL vials) at the same dose of STRENSIQ [see Dosage and Administration (2.1)].
Formation of anti-drug antibodies resulted in reduced systemic exposure of asfotase alfa.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with asfotase alfa. Asfotase alfa at intravenous doses up to 50 mg/kg/day administered daily in pregnant rats (approximately 21 times the human AUC of 65486 ng.h/mL at 2 mg/kg dose administered three times weekly for a 50 kg individual) was found to have no adverse effect on fertility and reproductive performance of male and female rats.
14 CLINICAL STUDIES
14.1 Perinatal/Infantile-Onset HPP
Study 1 was a 24-week prospective single-arm trial in 11 patients, 7/11 (64%) were female and 10/11 (91%) were white, aged 3 weeks to 39.5 months with severe perinatal/infantile-onset HPP. Severe perinatal/infantile-onset HPP was defined as biochemical, medical history and radiographic evidence of HPP as well as the presence of any of the following: rachitic chest deformity, vitamin B6-dependent seizures, or failure to thrive. Ten of 11 patients completed the 24-week trial and continued treatment in the extension phase. Nine patients have been treated for at least 216 weeks (54 months) and 4 patients have been treated for over 240 weeks (60 months). Patients received STRENSIQ at 3 mg/kg per week for the first month; subsequently, dose increases up to 9 mg/kg per week were allowed for changes in weight and/or for lack of efficacy. All 10 patients required dose increases of up to 6 mg/kg per week or higher; 9 patients increased between 4 and 24 weeks after starting treatment and 1 patient increased after 70 weeks due to suboptimal clinical response. One patient's dose was decreased from 9 mg/kg per week to 6 mg/kg per week based on PK data.
Study 2 was a prospective open-label study in 59 patients, 32/59 (54%) were female and 46/59 (78%) were white, aged 1 day to 78 months with perinatal/ infantile-onset HPP. Patients received STRENSIQ at 6 mg/kg per week for the first 4 weeks. Ten patients received dose increases higher than 6 mg/kg per week due to suboptimal clinical response, with dose increases occurring between 8 and 24 weeks after starting treatment. The recommended dosage regimen of STRENSIQ for the treatment of perinatal/infantile-onset HPP is up to 9 mg/kg per week administered subcutaneously as 3 mg/kg three times per week [see Dosage and Administration (2.1)].
Forty-one patients have been treated for at least 24 weeks (6 months) and 15 patients have been treated for at least 96 weeks (24 months).
Survival and Ventilation-Free Survival
Survival and invasive ventilation-free survival were compared in STRENSIQ-treated patients (Studies 1 and 2) with a historical cohort of untreated patients with similar clinical characteristics (Table 7 and Figure 1).
Table 7: Survival and Invasive Ventilation-Free Survival in STRENSIQ-Treated versus Historical Control Patients with Perinatal/ Infantile-Onset HPP 

STRENSIQ-Treated	Historical Controls
Survival	n = 68	n = 48
Alive at Point of Last Contact (%)	91	27
Hazard Ratio (STRENSIQ/Historical Control), 95% Confidence Interval*	0.14 (0.05, 0.39)
Kaplan-Meier Estimate and Alive at Age 1 Year (Week 48) (%)	97	42
Invasive Ventilation-Free Survival†	n = 54	n = 48
Alive and Not on Ventilation at Point of Last Contact (%)	85	25
Hazard Ratio (STRENSIQ/Historical Control), 95% Confidence Interval*	0.21 (0.09, 0.51)
Kaplan-Meier Estimate of Alive and Not on Ventilation at Age 1 Year (Week 48) (%)	96	31

Adjusted for year of diagnosis.
Alive and not initiating invasive ventilation after start of STRENSIQ treatment. STRENSIQ-treated patients on invasive ventilation at baseline were excluded from this analysis.
Figure 1: Overall Survival in STRENSIQ-Treated versus Historical Control Patients with Perinatal/ Infantile-Onset HPP

Skeletal Manifestations
Radiographs from 68 STRENSIQ-treated perinatal/infantile-onset HPP patients, including 64 patients in Studies 1 and 2, and 4 patients in Study 3 [see Clinical Studies (14.2)], were examined to assess HPP-related rickets using the 7-point Radiographic Global Impression of Change (RGI-C) scale. Patients with a minimum RGI-C score of +2 were defined as "responders". Radiologic improvements could be seen by Month 24; at last assessment, 50/68 [74%] treated patients were rated as RGI-C responders. No comparative data were available from historical controls. The mean time interval between the baseline and last RGI-C assessment was 24 months (range was 1 month to 67 months).
Eighteen perinatal/infantile-onset HPP patients experienced fractures during the course of treatment. There were insufficient data to determine the effect of STRENSIQ on fractures.
Growth
Height and weight measurements (as measured by z-scores) were available post-treatment for 72 perinatal/infantile-onset HPP patients, including 68 patients enrolled in Studies 1 and 2, and 4 patients enrolled in Study 3 (Table 8).
Table 8: Perinatal/Infantile-Onset Height and Weight Measurements as Measured by Z-Score 

Height Z-score				Weight Z-score
Baseline		Last Assessment		Baseline		Last Assessment
Mean	Min, Max	Mean	Min, Max	Mean	Min, Max	Mean	Min, Max
Studies 1 and 2 (N=68)	-3.3	-10.1, 0.9	-2.9	-10.6, 0.4	-3.2	-23.8, 0	-2.4	-20.9, 1.1
Study 3 (N=4)	-2.6	-6.6, -0.7	-1.5	-5.8, 0.4	-2.5	-8.2, -1.0	-1.5	-

The mean time interval between baseline and last assessment was 21 months (range was 1 month to 72 months).
The mean time between baseline and last assessment was 56 months (range was 53 months to 60 months).
14.2 Juvenile-Onset HPP
Study 3 was a prospective open-label 24-week trial that included 8 juvenile-onset HPP patients and 5 perinatal/ infantile-onset HPP patients, 11/13 (85%) were male and 12/13 (92%) were white [see Clinical Studies (14.1)]; on entry, patients were 6 to 12 years of age. All 8 juvenile-onset patients entered the extension study and were treated for at least 48 months. At trial entry, patients were randomized to receive STRENSIQ at 6 mg/kg per week or 9 mg/kg per week. Two patients received dose reductions during the primary treatment period, including one patient who experienced a decrease in vitamin B6 levels and one patient who experienced recurrent injection site reactions. During the extension phase, the dosing regimen for all patients was initially changed to 3 mg/kg per week. Dosing was subsequently increased to 6 mg/kg per week, with no patients requiring doses higher than 6 mg/kg per week. The recommended dosage regimen of STRENSIQ for the treatment of juvenile-onset HPP is 6 mg/kg per week [see Dosage and Administration (2.1)].
Growth
Height and weight measurements (as measured by z-scores) in 8 STRENSIQ-treated patients were compared with a historical cohort of 32 untreated patients with similar clinical characteristics (Table 9). Height and weight data for historical patients were collected from medical records.
Table 9: Juvenile-Onset Height and Weight Measurements as Measured by Z-Score 

Height Z-score				Weight Z-score
Baseline		Last Assessment		Baseline		Last Assessment
Mean	Min, Max	Mean	Min, Max	Mean	Min, Max	Mean	Min, Max
STRENSIQ (N=8)	-1.5	-3.8, 0	-0.9	-2, 0	-1.1	-3.5, 2.3	0	-1.3, 2.2
Control (N=32)	-1.1	-4.9, 2.6	-1.1	-4.9, 1.8	-1.2	-5, 2.1	-1	-

The mean time interval between baseline and last assessment was 55 months (range was 53 months to 60 months).
The mean time interval between baseline and last assessment was 61 months (range was 19 months to 109 months)
Skeletal Manifestations
Radiographs from 8 STRENSIQ-treated patients and 32 historical controls were compared to assess HPP-related rickets using the 7-point RGI-C (Radiographic Global Impression of Change) scale. Patients who achieved a RGI-C score of 2 or higher (corresponding to substantial healing of rickets) were classified as being responders to treatment. All 8 treated patients were rated as responders by Month 54 of treatment. The mean duration between the baseline and last RGI-C assessments for control patients was 56 months (range was 8 to 95 months). At last assessment, 2/32 (6%) of control patients were rated as responders.
Eight of 20 (40%) patients with juvenile-onset HPP experienced new fractures during the course of treatment. There were insufficient data to assess the effect of STRENSIQ on fractures.
Gait/Mobility
Gait was assessed using a modified Performance Oriented Mobility Assessment-Gait (MPOMA-G) scale in 8 STRENSIQ-treated patients at 6 month intervals out to 36 months. Mobility was also assessed using the 6 Minute Walk Test (6MWT) in 7 of the 8 patients. Step length improved by at least 1 point in either foot in 6/8 patients compared to 1/6 (17%) control patients. The proportion of patients who had 6MWT percent predicted values within the normal range for age, sex, and height-matched peers increased from 0/8 patients at baseline to 6/6 patients (100%) by Month 48 and all 6 were also able to walk longer distances at this time point compared to baseline.
16 HOW SUPPLIED/STORAGE AND HANDLING
STRENSIQ is supplied as a sterile, nonpyrogenic, preservative free, clear, slightly opalescent or opalescent, colorless to slightly yellow aqueous solution; a few small translucent or white particles may be present. The product is available as single-use vials in a carton of one (1) or twelve (12) vials at the following strengths:
Table 10: STRENSIQ Vial Presentations 

Strength	National Drug Code (NDC)	Quantity of 2 mL Vials in Carton
18 mg/0.45 mL	NDC 25682-010-01	1
	NDC 25682-010-12	12
28 mg/0.7 mL	NDC 25682-013-01	1
	NDC 25682-013-12	12
40 mg/mL	NDC-25682-016-01	1
	NDC-25682-016-12	12
For pediatric patients 40 kg and greater
80 mg/0.8 mL	NDC 25682-019-01	1
	NDC 25682-019-12	12

STRENSIQ vials must be stored in the original carton until the time of use under refrigerated conditions at 2°C to 8°C (36°F to 46°F) and protected from light.
Once removed from refrigeration, STRENSIQ should be administered within 1 hour.
Do not use beyond the expiration date stamped on the carton.
DO NOT FREEZE OR SHAKE.
Vials are single-use only. Discard any unused product.
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Labeling and Instructions for Use).
Advise patients or caregivers of the following:
Preparation
When preparing a volume for injection greater than 1 mL, split the volume equally between two syringes, and administer two injections. When administering the two injections, use two separate injection sites.
Inspect the solution in the vial(s) for particulate matter and discoloration.
Assemble injection supplies. Administer STRENSIQ 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. Always use a new syringe and needle.
Remove vial cap, aseptically prepare the vial and insert the syringe into the vial to withdraw the prescribed dose for administration.
Remove any air bubbles in the syringe and verify the correct dose.
Administration
Administer STRENSIQ within 1 hour upon removal of the vial(s) from refrigeration.
Rotate the injection site to reduce the risk of lipohypertrophy and injection site atrophy.
Do NOT administer injections in areas that are reddened, inflamed, or swollen.
Inject STRENSIQ subcutaneously into the determined site and properly dispose of the needle.
STRENSIQ vials are single use only. Discard any unused product.
Hypersensitivity Reactions
Reactions related to administration and injection may occur during and after STRENSIQ treatment. Inform patients of the signs and symptoms of hypersensitivity reactions, and have them seek immediate medical care should signs and symptoms occur.
Lipodystrophy
Lipohypertrophy (enlargement or thickening of tissue) and localized atrophy (depression in the skin) have been reported at injection sites after several months. Follow proper injection technique and rotate injection sites.
Hypophosphatasia (HPP) Registry
A registry has been established in order to better understand HPP in the population, and to monitor and evaluate long-term treatment effects of STRENSIQ. Patients and their caregivers should be encouraged to participate and advised that their participation is voluntary and may involve long-term follow-up. For more information, visit www.hppregistry.com
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3387574f-5eaa-4501-a71d-4cbfbd563031