Pediatric

In pediatric patients, ongoing treatment with STRENSIQ may help improve hypophosphatasia (HPP)-related rickets1,2

See the results from one pediatric patient’s 6-minute walk test (6MWT) after taking STRENSIQ.

WATCH WALK TEST
All patient images are hypothetical.
Child holding soccer ball
Bone mineralization Growth 6-minute walk test Pain and disability Strength and agility
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

Bone mineralization (primary endpoint)

Ongoing treatment with STRENSIQ showed improvements in bone mineralization as early as 6 months, which were sustained over 7 years1-3

  • After 6 months, 69% (9/13) of patients experienced complete or substantial healing of HPP-related rickets as measured by the Radiographic Global Impression of Change (RGI-C) scale2
  • After 7 years, 100% (12/12)* of patients experienced complete or substantial healing of HPP-related rickets as measured by the RGI-C scale3

*During the 6-month initial phase involving 13 participants, 1 child withdrew for elective surgery after 1 month of treatment. The remaining 12 then entered the long-term extension phase of the trial.2

Patient 1: Hand4

Substantial healing of HPP-related rickets4
6 YEARS OF AGE (AT BASELINE)
6 years hand
11 YEARS OF AGE (AT 5 YEARS)
11 years hand
In just 5 years, patient 1 saw substantial healing with an RGI-C score of +2.67.

Patient 1: Knee4

Patient 2: Hand4

Patient 2: Knee4

Natural history of HPP

Among 16 historical control patients with pediatric-onset HPP, the median RGI-C score was 0 at both the 6-month and 2-year timepoints, indicating no improvement in bone mineralization occurred during this period.2

Radiographic global impression of change (RGI-C) scale
Radiographic global impression of change (RGI-C) scale

Ongoing treatment with STRENSIQ may help patients reduce, reverse, or avoid burden associated with reduced bone mineralization.1,2

Growth (secondary endpoint)

STRENSIQ promotes statistically significant catch-up growth in pediatric patients with HPP1,2

STRENSIQ provided early (6 months) and sustained improvements in growth in patients 6 to 12 years of age as measured by change in height z scores.1,2
Catch-up growth in pediatric patients with HPP treated with Strensiq®
Catch-up growth in pediatric patients with HPP treated with Strensiq®
Natural history of HPP

In a retrospective chart review study that characterized the natural history of HPP in 32 untreated patients with juvenile-onset HPP and with similar clinical characteristics, there was no improvement in height z scores from baseline to last assessment. The mean time interval between baseline and last assessment was 61 months.6

  • Mean (min, max) height z score at baseline: -1.1 (-4.9, 2.6)6
  • Mean (min, max) height z score at last assessment: -1.1 (-4.9, 1.8)6

6-minute walk test (secondary endpoint)

With STRENSIQ, pediatric patients achieved clinically significant normalized 6MWT results.1,2

Significant improvements in the 6MWT were seen as early as 6 months and were sustained in the normal range through 7 years.1,2

WATCH 6-MINUTE WALK VIDEO
6-minute walk test with pediatric patients
6-minute walk test with pediatric patients
  • At 6 months, there was a 29% median change from baseline in distance walked (482 meters vs 350 meters) (P=0.001)3
  • At 7 years, there was a 68% median change from baseline in distance walked (588 meters vs 350 meters) (588 meters vs 350 meters) (P=0.001)3
    • For pediatric patients with HPP, the minimal clinically important difference (MCID) is estimated at 21 meters and 31 meters based on 2 distribution-based methods7

Pain and disability (secondary endpoint)

Pain and disability as measured by the patient-/caregiver-reported Childhood Health Assessment Questionnaire (CHAQ) through 7 years1,2,8,9

Median discomfort index score of pain
  • The CHAQ discomfort index measured HPP-related pain (eg, bone, joint, and muscle pain)10
  • The CHAQ discomfort index is determined by visual analog scale of pain (0=no pain, 100=very severe pain)8
Median disability index score
  • The CHAQ disability index measures hygiene, activities, eating, walking, grip, arising, reach, dressing, and grooming11
  • CHAQ disability index scores range from 0 to 3, with lower scores indicating less disability. The disability index score is calculated by averaging the highest scores of each of the 8 domains8

    CHAQ is not validated specifically for HPP, so inferences of clinical benefit should not be made. It was developed to assess health status for children with arthritis. Interpretation of these findings is limited due to the lack of control group and the potential bias introduced by use of parent-reported data for some patients. MCID has not been established for the HPP population.1,10

    Strength and agility (secondary endpoint)

    Strength and agility as measured by the Bruininks-Oseretsky Test of Motor Proficiency Second Edition (BOT-2) through 7 years1,2

    At baseline, patients showed lower strength and agility scores than healthy age-matched peers.2

    • Improvement was observed as early as 6 months, and patients showed normalized scores by 1 year and through 7 years1,2
    • The BOT-2 measures hand and arm coordination, balance, mobility, and strength relative to healthy same-aged peers12,13

    BOT-2 is not validated specifically for HPP. It has been validated in pediatric populations (aged 4 to 21 years) with mild to moderate motor impairment12,13

    Median BOT-2 strength and agility composite standard score
    Median BOT-2 strength and agility composite standard score

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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. Whyte MP, Rockman-Greenberg C, Moseley S, Denker AE, McAlister WH. Sustained radiographic and functional improvements with asfotase alfa treatment for up to 7 years in children with hypophosphatasia. Slides presented at: 8th Biennial International Conference on Children's Bone Health (ICCBH); June 13, 2017; Wurzburg, Germany.

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

    3. Data on file. Alexion Pharmaceuticals.

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

    5. Whyte MP, Fujita KP, Moseley S, Thompson D, McAlister W. Validation of a novel scoring system for changes in skeletal manifestations of hypophosphatasia in newborns, infants, and children: the Radiographic Global Impression of Change Scale. J Bone Miner Res. 2018;33(5):868-874.

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

    7. Phillips D, Tomazos IC, Moseley S, L’Italien G, Gomes da Silva H, Lerma Lara S. Reliability and validity of the 6-minute walk test in hypophosphatasia. JBMR Plus. 2019;3(6):e10131.

    8. Dempster H, Porepa M, Young N, Feldman BM. The clinical meaning of functional outcome scores in children with juvenile arthritis. Arthritis Rheum. 2001;44(8):1768-1774.

    9. Phillips D, Madson KL, Rockman-Greenberg C, et al. Reduction in pain and improved function and activities of daily living in children with hypophosphatasia treated with asfotase alfa for 5 years. Endocrine Society Annual Meeting website. Accessed February 6, 2020. https://endo.confex.com/endo/2016endo/webprogram/Paper24241.html.

    10. Klepper SE. Measures of pediatric function: the Child Health Assessment Questionnaire (CHAQ), Juvenile Arthritis Functional Assessment Report (JAFAR), Juvenile Arthritis Functional Assessment Scale (JAFAS), Juvenile Arthritis Functional Status Index (JASI), and Pediatric Orthopedic Surgeons of North America (POSNA) Pediatric Musculoskeletal Functional Health Questionnaire. Arthritis Care Res. 2003;49(suppl 5):S5-S14.

    11. Klepper SE. Measures of pediatric function. Arthritis Care Res. 2011;63(suppl 11):S371-S382.

    12. Bruininks RH, Bruininks BD. Bruininks-Oseretsky Test of Motor Proficiency, Second Edition. Pearson website. Updated October 22, 2013. Accessed January 24, 2020. http://images.pearsonclinical.com/images/Assets/BOT-2/BOT-2_Complete_Form_Sample_Report.pdf.

    13. Bruininks RH, Bruininks BD. Bruininks-Oseretsky Test of Motor Proficiency, Second Edition. Pearson website. Accessed January 24, 2020. https://www.pearsonassessments.com/store/usassessments/en/Store/Professional-Assessments/Motor-Sensory/Bruininks-Oseretsky-Test-of-Motor-Proficiency-%7C-Second-Edition/p/100000648.html. 

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