Study design and safety

A legacy in the making:
7 years of long-term data1-7

All patient images are hypothetical.
Woman and child on bicycles
Study design Safety

Study design

Clinical development program for STRENSIQ

INFANT/YOUNG CHILD INFANT/YOUNG CHILD PEDIATRICADOLESCENT ADOLESCENTADULT
Study 11-3ENB-002-08/
ENB-003-08		 Study 21,5ENB-010-10 Study 31,5,6ENB-006-09/
ENB-008-10		 Study 47ENB-009-10
Design Prospective, single-arm trial and extension in patients with severe perinatal/infantile-onset HPP Prospective, open-label trial in patients with perinatal/infantile-onset HPP Prospective, open-label trial and extension in patients with juvenile- or perinatal/infantile-onset HPP Multicenter, randomized, open-label concurrent control trial including adolescents and adults with pediatric-onset HPP
Duration 7 years 6 years 7 years 5 years
Primary treatment phase 6 months 1-6 years 6 months 6 months
Extension 6.5 years 1-6 years 6.5 years 4.5 years
Number of patients 11 69 13(9 reached adolescencea
during the study8)		 19(13 adults,b
6 adolescents)a
Age at inclusion ≤3 years ≤5 years 6 to 12 years 13 to 65 years

Study 11-3ENB-002-08/ENB-003-08

INFANT/YOUNG CHILD
DESIGN

Prospective, single-arm trial and extension in patients with severe perinatal/infantile-onset HPP

DURATION

7 years

PRIMARY Tx PHASE

6 months

EXTENSION

6.5 years

# OF PATIENTS

11

AGE AT INCLUSION

≤3 years

Study 21,5ENB-010-10

INFANT/YOUNG CHILD
DESIGN

Prospective, open-label trial in patients with perinatal/infantile-onset HPP

DURATION

6 years

PRIMARY Tx PHASE

1-6 years

EXTENSION

—

# OF PATIENTS

69

AGE AT INCLUSION

≤5 years

Study 31,5,61,2,61,4,6ENB-006-09/ENB-008-10

PEDIATRICADOLESCENT
DESIGN

Prospective, open-label trial and extension in patients with juvenile- or perinatal/infantile-onset HPPa

DURATION

7 years

PRIMARY Tx PHASE

6 months

EXTENSION

6.5 years

# OF PATIENTS

13

(9 reached adolescenceab
during the study382)
AGE AT INCLUSION

6 to 12 years

Study 417ENB-009-10

ADOLESCENTADULT
DESIGN

Multicenter, randomized, open-label concurrent control trial including adolescents and adults with pediatric-onset HPPa

DURATION

5 years

PRIMARY Tx PHASE

6 months

EXTENSION

4.5 years

# OF PATIENTS

19

(13 adults,b
6 adolescents)a
AGE AT INCLUSION

13 to 65 years

Abbreviation: HPP, hypophosphatasia.

aAdolescents in the study were aged 13 to 17 years.6-8

bAdults in the study were aged ≥18 years and 12/13 had pediatric-onset HPP.7

aAdolescents in the study were aged 13 to 17 years.2,3

aThe data represented are from subgroup analysis.2

bAdolescents in the study were aged 13 to 17 years.1,2,81,2

aData represent subgroup analysis of adults with pediatric-onset HPP.

bAdults in the study were aged ≥18 years and 12/13 had pediatric-onset HPP.1

STRENSIQ was studied using skeletal, survival, functional, biochemical, and quality of life measures in patients across age groups

INFANT1-4

INFANT/YOUNG CHILD, 0-5 YEARS: STUDIES 1 AND 21-4

SKELETAL

  • Change in HPP-related rickets at 6 months
  • Growth

SURVIVAL/FUNCTIONAL

  • Survival and invasive ventilation–free survival vs untreated historical controls
 = Primary endpoint = Secondary endpoint

PEDIATRIC6

PEDIATRIC, 6-12 YEARS: STUDY 3

SKELETAL

  • HPP-related rickets vs historical controls
  • Growth

 

SURVIVAL/FUNCTIONAL

  • Mobility
  • Strength and agility

QUALITY OF LIFE

  • Activities of daily living and pain
= Primary endpoint = Secondary endpoint

ADOLESCENT6

ADOLESCENT, 13-17 YEARS: STUDY 3 SUBANALYSIS

SKELETAL

  • HPP-related rickets vs historical controls

SURVIVAL/FUNCTIONAL

  • Mobility
= Primary endpoint = Secondary endpoint

ADULT7

ADULT, 18+ YEARS: STUDY 4 SUBANALYSIS

BIOCHEMICAL

  • Changes in tissue-nonspecific alkaline phosphatase (TNSALP) substrate levels: inorganic pyrophosphate (PPi) and pyridoxal 5′-phosphate (PLP)

 

SKELETAL

  • Bone mineralization

SURVIVAL/FUNCTIONAL

  • Mobility
= Primary endpoint = Secondary endpoint

STRENSIQ has been studied in 112 patients up to 7 years.9

Safety

A well-established safety profile, evidenced by 7 years of data1,10

In a pooled analysis of patients treated with STRENSIQ for up to 7 years, the most commonly reported adverse reactions were injection-site reactions (ISRs) (82/112, 73%).9

  • These events were most frequent within the first 3 months of treatment9
  • Other complications include lipodystrophies, hypersensitivity reactions, ectopic calcifications, craniosynostosis, elevated transaminases, and chronic hepatitis9

aAdverse reactions are from the combined period of 6 mg/kg and above (ie, total drug exposure regardless of starting dose and intermediary doses as long as the patient reached doses >6 mg/kg).

bOther injection-site reactions include injection-site rash, inflammation, papule, hemorrhage, hematoma, urticaria, warmth, calcification, mass, scar, and cellulitis.

cOther lipodystrophy includes lipohypertrophy.

dOther hypersensitivity reactions include erythema/redness, pyrexia/fever, irritability, nausea, pain, rigor/chills, hypoesthesia oral, headache, flushing, and anaphylaxis.

Infant

Infant/Young Child

CLINICAL DATA
Pediatric

Pediatric

CLINICAL DATA

Adolescent

CLINICAL DATA
Adult

Adult

CLINICAL DATA

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Important Safety Information and Indication for STRENSIQ® (asfotase alfa) 40mg/mL vial
Important Safety Information
WARNINGS AND PRECAUTIONS
  • Hypersensitivity Reactions, including anaphylaxis, have been reported in STRENSIQ-treated patients. 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, skin erythema, rash, pruritus and oral hypoesthesia.
    Inform patients and/or caregivers of the signs and symptoms of hypersensitivity reactions and have them seek immediate medical care should signs and symptoms occur. 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.
  • Lipodystrophy: Localized lipodystrophy, including lipoatrophy (depression in the skin) and lipohypertrophy (enlargement or thickening of tissue), has been reported at injection sites after several months in patients treated with STRENSIQ in clinical trials. Advise patients to follow proper injection technique and to rotate injection sites.
  • 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.
  • 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. 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. 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.
ADVERSE REACTIONS
  • Overall, the most common adverse reactions (≥ 10%) reported were injection site reactions (63%). Other common adverse reactions included lipodystrophy (28%), ectopic calcifications (14%), and hypersensitivity reactions (12%). Possible immune-mediated clinical effects have been identified during post-approval use of STRENSIQ.
DRUG INTERACTIONS
    Drug Interference with Laboratory Tests:
  • Laboratory tests utilizing alkaline phosphatase (ALP) as a detection reagent could result in erroneous test results for patients receiving treatment due to the presence of asfotase alfa in clinical laboratory samples. Inform laboratory personnel that the patient is being treated with STRENSIQ and discuss use of an alternative testing platform which does not utilize an ALP-conjugated test system.
  • Elevated serum ALP measurements detected through clinical laboratory testing are expected in patients receiving STRENSIQ due to circulating concentrations of asfotase alfa and may be unreliable for clinical decision making.
SPECIAL POPULATIONS
  • Pregnancy & Lactation: There are no available data on STRENSIQ use in pregnant women, the presence of STRENSIQ in human milk, or the effects on the breastfed infant or on milk production, to inform a drug associated risk.
Indication

STRENSIQ® is indicated for the treatment of patients with perinatal/infantile- and juvenile-onset hypophosphatasia (HPP).

Please see STRENSIQ (asfotase alfa) full Prescribing Information.
Important Safety Information and Indication for STRENSIQ® (asfotase alfa) 40mg/mL vial
Important Safety Information
WARNINGS AND PRECAUTIONS
  • Hypersensitivity Reactions, including anaphylaxis, have been reported in STRENSIQ-treated patients. 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, skin erythema, rash, pruritus and oral hypoesthesia.
    Inform patients and/or caregivers of the signs and symptoms of hypersensitivity reactions and have them seek immediate medical care should signs and symptoms occur. 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.
  • Lipodystrophy: Localized lipodystrophy, including lipoatrophy (depression in the skin) and lipohypertrophy (enlargement or thickening of tissue), has been reported at injection sites after several months in patients treated with STRENSIQ in clinical trials. Advise patients to follow proper injection technique and to rotate injection sites.
  • 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.
  • 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. 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. 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.
ADVERSE REACTIONS
  • Overall, the most common adverse reactions (≥ 10%) reported were injection site reactions (63%). Other common adverse reactions included lipodystrophy (28%), ectopic calcifications (14%), and hypersensitivity reactions (12%). Possible immune-mediated clinical effects have been identified during post-approval use of STRENSIQ.
DRUG INTERACTIONS
    Drug Interference with Laboratory Tests:
  • Laboratory tests utilizing alkaline phosphatase (ALP) as a detection reagent could result in erroneous test results for patients receiving treatment due to the presence of asfotase alfa in clinical laboratory samples. Inform laboratory personnel that the patient is being treated with STRENSIQ and discuss use of an alternative testing platform which does not utilize an ALP-conjugated test system.
  • Elevated serum ALP measurements detected through clinical laboratory testing are expected in patients receiving STRENSIQ due to circulating concentrations of asfotase alfa and may be unreliable for clinical decision making.
SPECIAL POPULATIONS
  • Pregnancy & Lactation: There are no available data on STRENSIQ use in pregnant women, the presence of STRENSIQ in human milk, or the effects on the breastfed infant or on milk production, to inform a drug associated risk.
Indication

STRENSIQ® is indicated for the treatment of patients with perinatal/infantile- and juvenile-onset hypophosphatasia (HPP).

Please see STRENSIQ (asfotase alfa) full Prescribing Information.
; ;

References

1. STRENSIQ [package insert]. Alexion Pharmaceuticals Inc.

2. Whyte MP, Simmons JH, Moseley S, et al. Asfotase alfa for infants and young children with hypophosphatasia: 7 year outcomes of a single-arm, open-label, phase 2 extension trial. Lancet Diabetes Endocrinol. 2019;7(2):93-105.

3. Whyte MP, Greenberg CR, Salman NJ, et al. Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med. 2012;366(10):904-913.

4. Hofmann CE, Harmatz P, Vockley J, et al. Efficacy and safety of asfotase alfa in infants and young children with hypophosphatasia: a phase 2 open-label study. J Clin Endocrinol Metab. 2019;104(7):2735-2747.

5. Whyte MP, Madson KL, Phillips D, et al. Asfotase alfa therapy for children with hypophosphatasia. JCI Insight. 2016;1(9)(suppl):e85971.

6. Whyte MP, Madson KL, Phillips D, et al. Asfotase alfa therapy for children with hypophosphatasia. JCI Insight. 2016;1(9):e85971.

7. Kishnani PS, Rockman-Greenberg C, Rauch F, et al. Five-year efficacy and safety of asfotase alfa therapy for adults and adolescents with hypophosphatasia. Bone. 2019;121:149-162.

8. Data on file. Alexion Pharmaceuticals.

9. Whyte MP, Bishop N, Hasan J, et al. Safety profile of asfotase alfa treatment of patients with hypophosphatasia: a pooled analysis. Paper presented at: 101st Annual Meeting and Expo of the Endocrine Society; March 23-26, 2019; New Orleans, LA.

10. Whyte M, Bishop N, Hasan J, et al. Safety profile of asfotase alfa treatment of patients with hypophosphatasia: a pooled analysis. J Endocr Soc. 2019;15 (3 suppl 1):OR13-4.

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