In order to maintain the integrity of the ADBL, and having regard to the financial and social implications of covering asfotase alfa for the treatment of perinatal/infantile or juvenile-onset hypophosphatasia (HPP), the following special authorization criteria must be satisfied.

In order to be eligible for asfotase alfa coverage for the treatment of HPP, a patient must have submitted a completed Application and have satisfied all of the following requirements:

The patient must:
1) Be diagnosed with HPP in accordance with the requirements specified in the Clinical Criteria for asfotase alfa;
2) Have Alberta government-sponsored drug coverage;
3) Meet the Registration Requirements;
4) Satisfy the Clinical Criteria for asfotase alfa (initial or continued coverage, as appropriate); AND
5) Meet the criteria specified in Discontinuance of Coverage.

There is no guarantee that any application, whether for initial or continued coverage, will be approved. Depending on the circumstances of each case, the Minister or the Minister's delegate may:
- approve an Application;
- approve an Application with conditions;
- deny an Application;
- discontinue an approved Application; OR
- defer an Application pending the provision of further supporting information.

The process for review and approval is explained in further detail below.

If the patient is a citizen or permanent resident of Canada, the patient must be continuously registered in the Alberta Health Care Insurance Plan for a minimum of one (1) year prior to an application for coverage unless:
- the patient is less than one (1) year of age at the date of the application, then the patient's parent/guardian/legal representative must be registered continuously in the Alberta Health Care Insurance Plan for a minimum of one (1) year; OR
- the patient has moved to Alberta from another province or territory in Canada (the "province of origin"), and immediately prior to moving to Alberta, was covered for asfotase alfa in the province of origin by a provincial or territorial government sponsored drug plan, (or the province of origin provided equivalent coverage for asfotase alfa as does Alberta) and the patient has been registered in the Alberta Health Care Insurance Plan (the patient must provide supporting documentation from the province of origin to prove prior coverage).

If the patient is not a citizen or permanent resident of Canada, the patient must be continuously registered in the Alberta Health Care Insurance Plan for a minimum of five (5) years prior to an application for coverage unless:
- the patient is less than five years of age at the date of the application, then the patients parent/guardian/legal representative must be registered continuously in the Alberta Health Care Insurance Plan for a minimum of five years; OR
- the patient has moved to Alberta from another province or territory in Canada (the "province of origin"), and immediately prior to moving to Alberta, was covered for asfotase alfa in the province of origin by a provincial or territorial government sponsored drug plan, (or the province of origin provided equivalent coverage for asfotase alfa as does Alberta) and the patient has been registered in the Alberta Health Care Insurance Plan (the patient must provide supporting documentation from the province of origin to prove prior coverage).

The Minister reserves the right to modify or waive the Registration Requirements applicable to a given patient if the patient or the patient's parent/guardian/legal representative can establish to the satisfaction of the Minister that the patient has not moved to Alberta for the sole/primary purpose of obtaining coverage of asfotase alfa.

"For enzyme replacement therapy (ERT) in patients with a confirmed diagnosis of perinatal/infantile or juvenile -onset hypophosphatasia (HPP). These patients must have been diagnosed prior to 12 years of age and have documented onset of signs/symptoms of HPP prior to 12 years of age.

Initiation Criteria:

1. Confirmed diagnosis of perinatal/infantile or juvenile-onset hypophosphatasia (HPP) as defined below:
- Confirmed diagnosis via genetic testing (documented tissue-nonspecific alkaline phosphatase (TNSALP) gene mutations(s) AND
- Serum alkaline phosphatase (ALP) level below the age-adjusted normal range (these are age and gender adjusted norms developed through CALIPER which are used as reference https://apps.sbgh.mb.ca/labmanual/test/view?seedId=3662) AND
NOTE: Below upper limit of normal refers to 2 or lower standard deviations above the mean
- Plasma pyridoxal-5-phosphate (PLP) above the upper limit of normal established and validated in testing laboratory AND
- Documented history of HPP-related skeletal abnormalities confirmed radiologically:
For Infantile HPP: Full skeletal survey done at baseline - examine chest, wrist, knees, and skull.
Changes to monitor include: abnormalities of skeletal mineralization including severely undermineralized and even "absence" of some or all bones; undermineralized skull; functional craniosynostosis; gracile bones; thin ribs; chest deformities; evidence of recent/ healed fractures; non-traumatic fractures, recurrent or poorly healing fractures; at the ends of long bones evaluate widening of the growth plate (physis) with irregularity of the provisional zone of calcification; metaphyseal radiolucencies, flaring and fraying at ends of metaphyses and metadiaphyseal patchy focal sclerosis

For Juvenile HPP: Similar to above however generally milder

AND

2. Assessed by a metabolic specialist who determines that the criteria noted above has been met as well as documented signs/symptoms that includes:

a. For Infantile HPP: Failure to thrive AND poor growth AND gross motor delay with substantial skeletal disease. May also have hypercalcemia, B6-responsive seizures and/or respiratory failure, respiratory compromise, including decreased thoracic volume and/or pulmonary hypoplasia; need for respiratory support;

b. For Juvenile HPP: Poor weight gain; unusual gait or running; delayed walking (>15 months); impaired mobility, need for ambulatory assistance; knock-knees; or rickets/bowed legs; muscle weakness/hypotonia; joint pain; muscle pain; bone pain sufficient to limit activity and require medication

c. Childhood HPP (after 6 months of age): gait disturbance, fractures, rickets and RGIC score(NOTE: RGIC score is a 7-point score of Radiographic Global Impressive of Change ie RGIC score assesses changes from baseline and is obtained on paired sequential radiographs with a score of +2 indicating substantial healing/improvement in HPP-related skeletal abnormalities), Thacher score (NOTE: Thacher score is a 10-point Rickets Severity Scale validated for Vitamin D deficiency rickets (and also valid for HPP); score of 10 = severe rickets and 0 = no rickets based on quantified growth plate abnormalities at wrists and knees), bowing of legs, short stature unexplained by other reasons and/or pain score. RGIC and Thacher scores are ideal as they are validated in HPP but a comparable radiologic assessment by an expert bone pediatric radiologist could also be considered

3. Patient is not an adult (ie > 18 years of age) at the time treatment is initiated AND

4. Patient does not have odontoHPP, IE premature loss of deciduous teeth alone or pseudoHPP and vitamin D deficiency to be ruled out. Patients with craniosynostosis alone who do not have other criteria noted above for the diagnosis of HPP need to be followed closely as initiation of treatment with ERT may be indicated if other systemic signs and symptoms develop including muscle weakness, fractures, rickets, pain or nephrocalcinosis and/or if bony disease develops clinically and radiologically AND

5. Patients should be initiated on treatment and followed in a specialized clinic with expertise in the diagnosis and management of HPP. Goals of therapy should be developed on a case-by-case basis prior to the initiation of therapy depending on age and signs and symptoms at presentation.

Signs and symptoms to be monitored depend on age at diagnosis and may include:

a) For perinatal/infantile would expect in addition to above parameters to be followed goals of therapy should include discontinuation or reduction of ventilatory support, increased mobility (improvement in gait vs. baseline), attainment of age-appropriate gross motor milestones. Clinical, radiological and biochemical criteria should be surveilled and these pre-specified goals met at Coverage should be reassessed following a trial of 24 weeks of therapy or more frequently depending on clinical status of patient at initiation of therapy.

b) For juvenile Healing of rickets, improvement of bone mineralization and/bony deformities, fewer fractures, less pain, need for less pain medication, improved growth, increased mobility.

If Initiation Criteria met, 24 week trial to be followed by reassessment by a metabolic specialist

Of Note: Treatment with ERT may not be recommended for newborns who are unable to be successfully ventilated and who have respiratory failure, irreversible pulmonary hypoplasia (underdeveloped lungs with reduced number of alveoli for air exchange) as assessed postnatally by established clinical and radiologic criteria (narrow chest circumference and apparent low lung volumes, evidence for increased pulmonary resistance, MRI changes consistent with lung hypoplasia), very small chest walls, very thin or absent ribs radiologically as assessed by pediatric respirologist, radiologist and treating metabolic specialist. A 6 month trial of ERT may however be recommended for such infants by the treating metabolic specialist and consultants with the consent of the parents. Discontinuation of ERT should be considered at this point and baby moved to palliative care.

Continuation Criteria:
- Assessed by a metabolic specialist who determines that the pre-specified goals have been met and includes documented signs/symptoms noted above.
- Documented compliance by patient and family with respect to follow up visits and reevaluation of laboratory and radiological parameters.
- Additional 24 week trials to be followed by reassessment by a metabolic specialist.

If Continuation Criteria are not met, the treatment should not be continued. In addition, ERT should be discontinued for lack of compliance or if patient does not come for follow up appointments, in spite of all efforts to assist patient and family in this regard, development of craniosynostosis or premature loss of deciduous teeth alone would not signify failure of treatment and ERT should be continued provided other continuation criteria are met.

Stopping Criteria:
- Consider discontinuation after growth is completed based on objective measurement of height and closure of growth plates (closure to be confirmed by Xray criteria and report from a Radiologist).
- Criteria for tapering and discontinuing treatment should be developed by expert committee and evaluated on a case-by-case basis at all age groups.
- Babies with perinatal/infantile HPP who fail treatment trials of 6 months as described above may be discontinued from ERT and moved to palliative care.

*Reference will be made re: dosing and approved vial use to minimize wastage"

For both initial and continued coverage the following documents (the Application) must be completed and submitted:

- An Asfotase alfa Special Authorization Request Form completed by the patient's Metabolic Specialist;
- An Asfotase alfa Consent Form completed by the patient, or a patient's parent/guardian/legal representative, and the patients Metabolic Specialist (for any initial coverage application); AND
- Any other documentation that may be required by the Minister or the Minister's delegate.

a. Expert Review

Once the Minister or the Minister's delegate has confirmed that the patient meets the Registration Requirement or granted a waiver of the Registration Requirement, the Application will be given to one or more Expert Advisors for review.

The Application, together with the recommendation or recommendations of the Expert Advisor(s), is then forwarded to the Minister or the Minister's delegate for a decision regarding coverage.

After the Minister or Minister's delegate has rendered a decision, the patient's Metabolic Specialist and the patient or patient's parent/guardian/legal representative will be notified by letter of the Minister's decision.

The Minister or the Minister's delegate's decision in respect of an Application will specify the effective date of asfotase alfa coverage, if coverage is approved.

Initial coverage may be approved for a period of up to 26 weeks as follows: One dose of 2 mg/kg of asfotase alfa administered three times a week or one dose of 1 mg/kg of asfotase alfa administered six times a week (total of 78 doses for the 2mg/kg dosage regimen and a total of 156 doses for the 1 mg/kg dosage regimen).

Continued coverage may be approved for up to one dose of 2 mg/kg of asfotase alfa administered three times a week or one dose of 1 mg/kg of asfotase alfa administered six times a week for a period of six (6) months (total of 78 doses for the 2mg/kg dose and a total of 156 doses for the 1 mg/kg dose).

If a patient is approved for coverage, prescriptions for asfotase alfa must be written by a Metabolic Specialist. To avoid wastage, prescription quantities are limited to a two week supply. Extended quantity and vacation supplies are not permitted. The Government is not responsible and will not pay for costs associated with wastage or improper storage of asfotase alfa.

Approval of coverage is granted for a specific period, to a maximum of 26 weeks. If continued treatment is necessary, it is the responsibility of the patient or patient's parent/guardian/legal representative and the Metabolic Specialist to submit a new Application to re-apply for asfotase alfa coverage, and receive a decision thereon, prior to the expiry date of the authorization period.

Therapy may be withdrawn at the request of the patient or the patient's parent/guardian/legal representative at any time. Notification of withdrawal from therapy must be made by the Metabolic Specialist or patient in writing.

Applications, withdrawal requests, and any other information to be provided must be sent to Clinical Drug Services, Alberta Blue Cross.