Medical Policy



Subject: Asfotase Alfa (Strensiq™)
Document #: DRUG.00087 Current Effective Date:    09/27/2017
Status: Reviewed Last Review Date:    08/03/2017

Description/Scope

This document addresses asfotase alfa (Strensiq, Alexion Pharmaceuticals, New Haven, CT), a tissue nonspecific alkaline phosphatase (TNSAP) recombinant isozyme developed to target underlying genetic causes of hypophosphatasia (HPP). HPP is a rare inherited error of metabolism caused by mutations of the alkaline phosphatase (ALPL) gene that results in deficient activity of alkaline phosphatase and low levels of the enzyme in serum and bone. This condition disrupts mineralization, in which minerals such as calcium and phosphorus are deposited in developing bones and teeth.

Position Statement

Medically Necessary:

Asfotase alfa is considered medically necessary for the treatment of hypophosphatasia when the following criteria are met:

  1. Onset of symptoms occurred prior to 6 months of age; and
  2. Total serum alkaline phosphatase is below the lower limit of normal for the individual's age and gender at diagnosis; and
  3. Plasma pyridoxal 5'-phosphate levels are greater than the upper limit of normal at the time of diagnosis; and
  4. One or more of the following:
    1. Radiographic evidence of poor bone mineralization such as flared and frayed metaphyses, severe/generalized osteopenia or widened growth plates; or
    2. Genetic test results that confirm infantile HPP; or
    3. One or more of the following:
      1. History or presence of nontraumatic postnatal fracture healing; or
      2. History of elevated serum calcium; or
      3. Functional craniosynostosis with decreased head circumference growth; or
      4. Nephrocalcinosis; or
      5. Rachitic chest deformity; or
      6. Respiratory compromise; or
      7. Vitamin B6-responsive seizures; or
      8. Failure to thrive.

Continuation of treatment with asfotase alfa is considered medically necessary when the following criteria have been met:

  1. The above criteria are met at the time of initiation; and
  2. The individual has demonstrated clinical improvement in symptoms following asfotase alfa therapy.

Investigational and Not Medically Necessary:

Asfotase alfa is considered investigational and not medically necessary when criteria above are not met.

Rationale

Strensiq was approved by the U.S. Food and Drug Administration (FDA) on October 23, 2015 as an orphan drug. Prior to the development of Strensiq, there was no specific treatment for HPP. The mortality rate for infants and children is 50-100%. Approval was based on four ongoing prospective, open-label studies of treatment with Strensiq using historical controls. The ongoing studies are focused on disease development in two areas: perinatal in utero/infantile (less than 6 months of age) and childhood (greater than or equal to 6 months of age). Perinatal diagnosis was likely found on ultrasound, showing unmineralized or hypomineralized bone in the fetus. In the perinatal/infantile stage, affected infants develop clinical signs and symptoms of rickets, including growth failure, hypotonia, bowing of long bones, and rachitic changes of the ribs. Other clinical hallmarks are wide fontanels (due to hypomineralized skull bone) and craniosynostosis. In the childhood stage, premature loss of the primary teeth (prior to age 5 years) is a major clinical indicator of disease. Radiographic evidence of dental hypoplasia may precede radiographic evidence of skeletal disease. The individuals who develop rickets may have delayed walking, gait abnormalities and short stature. Other complications include pathologic fractures, most commonly involving the metaphysis, and static myopathy. The FDA approval also requires the manufacturer to conduct a prospective, long-term, observational study in Strensiq (asfotase alfa) treated individuals with perinatal/infantile-onset and juvenile-onset HPP from ages birth and older. The purpose of the study is to assess the long-term safety of treatment with Strensiq (asfotase alfa) with respect to incidence rates of severe hypersensitivity reactions (including anaphylaxis), systemic immune complex-mediated reactions and ectopic calcification events. The study must include an adequate number of participants, including those with infantile and juvenile-HPP, and followed for a minimum of 5 years from the time of enrollment.

Whyte and colleagues (2012) conducted a preliminary open-label study of HPP treatment with Strensiq in 9 children who were treated for 1 year.  Eligibility criteria were an age of 3 years or less, symptoms of hypophosphatasia occurring before the age of 6 months, hypophosphatasemia, an elevated plasma pyridoxal 5′-phosphate (PLP) level, hypophosphatasia related skeletal disease as assessed radiographically, failure to thrive, rachitic chest deformity or pyridoxine-responsive seizures, nontraumatic or poorly healing fractures, hypercalcemia, craniosynostosis, nephrocalcinosis, or respiratory compromise from hypophosphatasia. Children were excluded if they had a major coexisting disease, a treatable form of rickets, previous exposure to bisphosphonates, hypocalcemia, hypophosphatemia, serum 25-hydroxyvitamin D level of less than 20 ng per milliliter, or if they had received another experimental treatment for hypophosphatasia (for example, bone marrow transplantation).  Results showed healing of rickets at 6 months, accompanied by improvement in developmental milestones and pulmonary function. Elevated plasma levels of the TNSAP substrates inorganic pyrophosphate and pyridoxal 5′-phosphate diminished. Increases in serum parathyroid hormone accompanied skeletal healing, often necessitating dietary calcium supplementation. There was no evidence of hypocalcemia, ectopic calcification, or definite drug-related serious adverse events. Low titers of anti-ENB-0040 (Strensiq) antibodies developed in 4 subjects with no evident clinical, biochemical, or autoimmune abnormalities at 48 weeks of treatment. Radiographic improvements in the treatment group were evident in Radiographic Global Impression of Change (RGI-C) scores from baseline to week 24 and from baseline to week 48, with 9 of 10 subjects (90%; 95% confidence interval [CI], 55 to 100) and 8 of 9 subjects (89%; 95% CI, 52 to 100), respectively meeting the criterion for a treatment response.

In an ongoing open-label study, Whyte and colleagues (2015) further assessed the safety, tolerability, and efficacy of asfotase alfa treatment for HPP using historical controls. Individuals in the treatment group (n=37) were 5 years of age or younger at enrollment with symptoms of HPP before 6 months of age. Those in the historical control group (n=48) were of similar chronological age and HPP characteristics. Strensiq was administered in subcutaneous injections either 1 mg/kg 6 times per week or 2 mg/kg 3 times weekly. The median treatment duration was 2.7 years. Treatment efficacy evaluated in both subgroups included growth, radiological assessments of HPP-related skeletal abnormalities, bone biopsy, bone mineral density, and age-appropriate measurements of gross motor function. Thus far, the studies are showing that the treated group had improved survival as opposed to the historical control group: 95% versus 42% at age 1 year and 84% versus 27% at age 5 years, respectively (p<0.0001, Kaplan-Meier log-rank test). Additionally, 5% (1/20) of the historical control group who required ventilator assistance survived. Of those in the treatment group who required ventilator assistance, 76% (16/21) survived, among whom 75% (12/16) were weaned from ventilator support.

Kitaoka and colleagues (2017) conducted an open-label study assessing the safety and efficacy of asfotase alfa treatment in individuals with HPP. The study included 13 individuals with the ALPL gene mutation; 11 of which were diagnosed with perinatal or infantile forms fo HPP (age of onset: range 0 to 2 months). The study reported 6 serious adverse events in 2 individuals. Of these 6 events, 2 (convulsion and hypocalcaemia) were possibly related to the treatment. The other 4 adverse events were considered unrelated to the treatment.

Currently, two clinical trials addressing juvenile onset HPP have been completed; however, the results have not been published in the peer reviewed literature.

Background/Overview

The ALPL gene provides instructions for making an enzyme called alkaline phosphatase. This enzyme plays an important role in the growth and development of bones and teeth. It is also active in many other tissues, particularly in the liver and kidneys. Mutations in the ALPL gene lead to the production of an abnormal version of alkaline phosphatase that is not effective in the mineralization of developing bones and teeth. Additionally, the removal of phosphate from PLP by alkaline phosphatase is key to the movement of pyridoxal across cell membranes in the brain; PLP is a key neurotransmitter substrate (Bishop, 2015). A shortage of alkaline phosphatase allows substances that are normally processed by the enzyme to build up abnormally in other parts of the body.

According to the National Institutes of Health (NIH):

Hypophosphatasia is an inherited disorder that affects the development of bones and teeth. This condition disrupts a process called mineralization, in which minerals such as calcium and phosphorus are deposited in developing bones and teeth. Mineralization is critical for the formation of bones that are strong and rigid and teeth that can withstand chewing and grinding.

The signs and symptoms of hypophosphatasia vary widely and can appear anywhere from before birth to adulthood. The most severe forms of the disorder tend to occur before birth and in early infancy. Hypophosphatasia weakens and softens the bones, causing skeletal abnormalities similar to another childhood bone disorder called rickets. Affected infants are born with short limbs, an abnormally shaped chest, and soft skull bones. Additional complications in infancy include poor feeding and a failure to gain weight, respiratory problems, and high levels of calcium in the blood (hypercalcemia), which can lead to recurrent vomiting and kidney problems. These complications are life-threatening in some cases.

The forms of hypophosphatasia that appear in childhood or adulthood are typically less severe than those that appear in infancy. Early loss of primary (baby) teeth is one of the first signs of the condition in children. Affected children may have short stature with bowed legs or knock knees, enlarged wrist and ankle joints, and an abnormal skull shape. Adult forms of hypophosphatasia are characterized by a softening of the bones known as osteomalacia. In adults, recurrent fractures in the foot and thigh bones can lead to chronic pain. Affected adults may lose their secondary (adult) teeth prematurely and are at increased risk for joint pain and inflammation.

The mildest form of this condition, called odontohypophosphatasia, only affects the teeth. People with this disorder typically experience abnormal tooth development and premature tooth loss, but do not have the skeletal abnormalities seen in other forms of hypophosphatasia.

Definitions

Bone density: A measurement of strength and quantity of bone.

Craniosynostosis: Premature closure of the cranial sutures, resulting in skull deformities.

Hypotonia: Decreased muscle tone and strength.

Isozyme: An enzyme that differs in amino acid sequence but catalyzes the same chemical reaction.

Nephrocalcinosis: A condition where calcium deposits form in the kidney tissue itself secondary to high blood levels of calcium. Most of the time, both kidneys are affected. Nephrocalcinosis is related to, but not the same as, kidney stones (nephrolithiasis).

Orphan drug: A pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease.

Osteopenia: Mild thinning of the bone mass.

Recombinant: Produced by combining genetic material from different sources.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met: 

HCPCS    
J3490 Unclassified drugs [when specified as asfotase alfa (Strensiq)]  
     
ICD-10 Diagnosis  
E83.31 Familial hypophosphatemia
E83.39 Other disorders of phosphorus metabolism

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications:

  1. Bishop N, Munns CF, Ozono K. Transformative therapy in hypophosphatasia. Arch Dis Child. 2016; 101(6):514-515.
  2. Kitaoka T, Tajima T, Nagasaki K, et al. Safety and efficacy of treatment with asfotase alfa in patients with hypophosphatasia: results from a Japanese clinical trial. Clin Endocrinol (Oxf). 2017; 87(1):10-19.
  3. Mornet E, Nunes ME. Hypophosphatasia. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1150/. Accessed on June 21, 2017.
  4. Whyte MP, Greenberg CR, Salman NJ, et al. Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med. 2012; 366(10):904-913.
  5. Whyte MP, Rockman-Greenberg C, Ozono K, et al. Asfotase alfa treatment improves survival for perinatal and infantile hypophosphatasia. J Clin Endocrinol Metab. 2016; 101(1):334-342.
  6. Whyte MP, Zhang F, Wenkert D, et al. Hypophosphatasia: validation and expansion of the clinical nosology for children from 25 years experience with 173 pediatric patients. Bone. 2015; 75:229-239.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Agency for Healthcare Research and Quality. AHRQ Healthcare Horizon Scanning System – Potential High-Impact Interventions Report. Priority Area 08: Functional Limitations and Disability. Asfotase Alfa (Strensiq™) for Treatment of Hypophosphatasia in Infants and Children. 2015 December. Available at: https://www.effectivehealthcare.ahrq.gov/ehc/assets/File/Functional-Limitations-Horizon-Scan-High-Impact-1512.pdf . Accessed on June 21, 2017.
  2. National Institutes of Health. Hypophosphatasia. April 2016. Available at: https://ghr.nlm.nih.gov/condition/hypophosphatasia . Accessed on June 21, 2017.
  3. U.S. Food and Drug Administration (FDA). Asfotase alfa (Strensiq™) Original BLA 125513. October 2015. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125513Orig1s000Approv.pdf. Accessed on June 21, 2017.
  4. U.S. National Institutes of Health. ClinicalTrials.gov. Hypophosphatasia. Available at: https://clinicaltrials.gov/ct2/results?term=Hypophosphatasia&Search=Search . Accessed on June 21, 2017.
Websites for Additional Information
  1. National Organization for Diseases (NORD). Hypophosphatasia. Available at: https://rarediseases.org/rare-diseases/hypophosphatasia/ . Accessed on June 21, 2017.
Index

Alkaline phosphatase
Hypophosphatasia
Tissue nonspecific alkaline phosphatase

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History
Status Date Action
Reviewed 08/03/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Deleted semi-colon after "greater than" in criteria C. Updated Background, Rationale, References, and Website sections.
New 08/04/2016 MPTAC review. Initial document development.