Asfotase Alfa

STRENSIQ ® is indicated for the treatment of patients with perinatal/infantile- and juvenile-onset hypophosphatasia (HPP). STRENSIQ is a tissue nonspecific alkaline phosphatase indicated for the treatment of patients with perinatal/infantile- and juvenile-onset hypophosphatasia (HPP). ( 1 )

STRENSIQ is a 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-dose vials Injection: 18 mg/0.45 mL, 28 mg/0.7 mL, 40 mg/mL, or 80 mg/0.8 mL solution in single-dose vials. ( 3 )

None. None. ( 4 )

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 ) Possible Immune-Mediated Clinical Effects: Evaluate patients for antibody formation if clinically indicated. ( 5.4 )

5.1 Hypersensitivity Reactions Including Anaphylaxis Life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in patients treated with enzyme replacement therapies, including STRENSIQ. Signs and symptoms consistent with anaphylaxis included difficulty breathing, choking sensation, nausea, periorbital edema, and dizziness. These reactions have occurred within minutes after subcutaneous administration of STRENSIQ and have been observed more than 1 year after treatment initiation. Other hypersensitivity reactions have also been reported in STRENSIQ-treated patients, including vomiting, fever, headache, flushing, irritability, chills, erythema, rash, pruritus and oral hypoesthesia [see Adverse Reactions (6.1) ] . Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy. Initiate STRENSIQ under the supervision of a healthcare provider with appropriate medical monitoring and support measures. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue STRENSIQ and immediately initiate appropriate medical treatment, including use of epinephrine. 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. Inform patients of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis and to seek immediate medical care should symptoms occur.

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 (2.5) ] .

5.3 Ectopic Calcifications Patients with HPP are at increased risk for developing ectopic calcifications. Events of ectopic calcification, including ophthalmic (conjunctival and corneal) and renal (nephrocalcinosis, nephrolithiasis), have been reported in the clinical trial experience with STRENSIQ. 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.

5.4 Possible Immune-Mediated Clinical Effects In clinical trials, most STRENSIQ-treated patients developed anti-asfotase alfa antibodies and neutralizing antibodies which resulted in reduced systemic exposure of asfotase alfa [see Immunogenicity (6.2) ]. In postmarketing reports, some STRENSIQ-treated patients with initial therapeutic response subsequently developed recurrence and worsening in disease-associated laboratory and radiographic biomarkers (some in association with neutralizing antibodies) suggesting possible immune-mediated effects on STRENSIQ's pharmacologic action resulting in disease progression [see Adverse Reactions (6.3) ] . The effect of anti-asfotase alfa antibody formation on the long-term efficacy of STRENSIQ is unknown. There are no marketed anti-asfotase alfa antibody tests. If patients experience progression of HPP symptoms or worsening of disease-associated laboratory and imaging biomarkers after a period of initial therapeutic response to STRENSIQ, consider obtaining anti-asfotase alfa antibody testing by contacting STRENSIQ Medical Information at Alexion at 1-888-765-4747 or by email at medinfo@alexion.com. Close clinical follow up is recommended.

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) ] Possible Immune-Mediated Clinical Effects [see Warnings and Precautions (5.4) ] 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.

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 [see Clinical Studies (14) ] . 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 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) (N=13) n (%) Total (N=79) n (%) STRENSIQ (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 Other injection site reactions include injection site rash, inflammation, papule, hemorrhage, hematoma, urticaria, warmth, calcification, mass, scar and cellulitis. 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 Other lipodystrophy includes lipohypertrophy. 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 Other hypersensitivity reactions include erythema/redness, pyrexia/fever, irritability, nausea, pain, rigor/chills, hypoesthesia oral, headache, flushing, and anaphylaxis. 6 (9) 2 (15) 8 (10) 2 (10) Less Common Adverse Reactions Adverse reactions that occurred at rates less than 1% included: Hypocalcemia Renal Stones Chronic hepatitis Decreased vitamin B6 Long-Term Safety In long-term extension trials reflecting a median exposure to STRENSIQ of 142 weeks (range 0.1 weeks to 392 weeks) in 112 patients with perinatal/infantile- (n = 89), juvenile- (n = 22), and adult-onset (n = 1) HPP (age at enrollment = 1 day to 66.5 years), the most common adverse reactions were similar to those reported in Table 4.

6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly 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 in the studies described below with the incidence of antibodies in other studies or to other asfotase alfa products may be misleading. During clinical trials, anti-asfotase alfa 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 STRENSIQ-treated patients with hypophosphatasia (HPP) in clinical studies who had post-baseline antibody data available, 97/109 (89%) tested positive for anti-asfotase alfa antibodies at some time point during STRENSIQ treatment. Among those 97 patients, 55 (57%) also tested positive for neutralizing antibodies at some time point during STRENSIQ treatment. No correlation was observed between the anti-asfotase alfa antibody titers and the neutralizing antibody (% inhibition) values. Formation of anti-asfotase alfa antibody resulted in a reduced systemic exposure of asfotase alfa [see Clinical Pharmacology (12.3) ] .

6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of STRENSIQ. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Some STRENSIQ-treated patients with initial therapeutic response to STRENSIQ subsequently developed worsening in disease-associated laboratory and radiographic biomarkers (some in association with neutralizing antibodies) suggesting possible immune-mediated effects on STRENSIQ's pharmacologic action resulting in disease progression [see Warnings and Precautions (5.4) ].

Drug Interference with Laboratory Tests: Alkaline Phosphatase (ALP) is used as a detection reagent in many laboratory tests and the presence of asfotase alfa in clinical laboratory samples could result in erroneous test results. Inform laboratory personnel and discuss use of an alternative testing platform for patients on treatment. ( 7.1 ) Serum Alkaline Phosphatase : Serum ALP measurements are expected to be elevated during treatment and may be unreliable for clinical decision making. ( 7.1 )

7.1 Drug Interference with Laboratory Tests Laboratory Tests Utilizing Alkaline Phosphatase as a Detection Reagent Studies have shown that there is analytical interference between asfotase alfa and laboratory tests that utilize an alkaline phosphatase (ALP)-conjugated test system, rendering erroneous test results in patients treated with STRENSIQ. ALP-conjugated test systems are utilized to measure substances such as hormones, bacterial antigens and antibodies. Therefore, it is recommended that laboratory assays which do not have ALP-conjugate technology be used when testing samples from patients who are receiving STRENSIQ. To avoid erroneous test results for patients treated with STRENSIQ, inform laboratory personnel that the patient is being treated with STRENSIQ and discuss the use of a testing platform which does not utilize an ALP-conjugated test system. Serum Alkaline Phosphatase High serum ALP measurements detected through clinical laboratory testing are expected in patients receiving STRENSIQ and reflect circulating concentrations of asfotase alfa . Do not rely on serum ALP measurements for clinical decision making in patients treated with STRENSIQ.

8.1 Pregnancy Risk Summary There are no available 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 for the treatment of perinatal/infantile- and juvenile-onset HPP have been established in pediatric patients. Use of STRENSIQ for this indication is based on 4 prospective, open-label clinical trials conducted in 89 pediatric patients with perinatal/infantile-onset or juvenile-onset HPP [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.

HPP is caused by a deficiency in TNSALP enzyme activity, which leads to elevations in several TNSALP substrates, including inorganic pyrophosphate (PPi). TNSALP is a metallo-enzyme that catalyzes the hydrolysis of phosphomonoesters with release of inorganic phosphate and alcohol. 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.