Asfotase Alfa for Subcutaneous Administration

Name: Asfotase Alfa for Subcutaneous Administration

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

Side effects

The following adverse reactions are described below and elsewhere in the labeling:

  • Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
  • Lipodystrophy [see WARNINGS AND PRECAUTIONS]
  • Ectopic Calcifications [see WARNINGS AND PRECAUTIONS]

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

Adverse Reaction Category or Term Perinatal/ Infantile-onset HPP Juvenile-onset HPP
(N=20) n (%)
STRENSIQ less than or equal to 6 mg/kg per week
(N=66) n (%)
STRENSIQ more than 6 mg/kg/weeka
(N=13) n (%)
Total
(N=79) 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 reactionsb 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 lipodystrophyc 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 reactionsd 6 (9) 2 (15) 8 (10) 2 (10)
a 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).
b Other injection site reactions include injection site rash, inflammation, papule, hemorrhage, hematoma, urticaria, warmth, calcification, mass, scar and cellulitis.
c Other lipodystrophy includes lipohypertrophy.
d 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

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].

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.

Warnings

Included as part of the PRECAUTIONS section.

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