Asfotase alfa (Strensiq)

Number: 0901

Policy

Note: REQUIRES PRECERTIFICATION. Precertification of asfotase alfa (Strensiq) is required of all Aetna participating providers and members in applicable plan designs. For precertification of asfotase alfa (Strensiq) call (866) 752-7021, or fax (866) 267-3277.

Aetna considers asfotase alfa (Strensiq) medically necessary for the treatment of perinatal/infantile-onset and juvenile-onset hypophosphatasia (HPP) when all of the following criteria are met:

1. The member has clinical signs and/or symptoms of hypophosphatasia (See Appendix A); and

2. The onset of the disease was perinatal/infantile or juvenile. If the member is 18 years of age or older at the time of the request, documentation of the presence of the condition before the age of 18 must be provided (e.g., member began experiencing symptoms at age 10); and

3. The diagnosis was confirmed by one of the following (1 or 2):

   1. The presence of a known pathological mutation in the ALPL gene as detected by ALPL molecular genetic testing; or
   2. The diagnosis is supported by ALL of the following:
      
      
      1. Radiographic imaging demonstrating skeletal abnormalities (See Appendix B); and
      2. A serum alkaline phosphatase level below the gender- and age-specific reference range of the laboratory performing the test; and 
      3. Elevated tissue-nonspecific alkaline phosphatase (TNSALP) substrate level (i.e., serum PLP level, serum or urine PEA level, urinary PPi level)

Aetna considers continuation of asfotase alfa (Strensiq) medically necessary for members with perinatal/infantile-onset and juvenile-onset HPP who meet initial selection criteria and are currently receiving the requested medication through a paid pharmacy or medical benefit and are experiencing benefit from therapy (e.g., improvement in skeletal manifestations, growth, gait/mobility, muscle strength).

Aetna considers asfotase alfa experimental and investigational for all other indications (e.g., adult (greater than 18 years of age) hypophosphatasia, and neurofibromatosis; not an all-inclusive list).

Dosing Recommendations

Asfotase alfa is available as Strensiq for subcutaneous injection supplied as 18 mg/0.45 mL, 28 mg/0.7 mL, 40 mg/mL, or 80 mg/0.8 mL solution in single-use vials. For subcutaneous injection only.

Perinatal/Infantile-Onset HPP

• Recommended dosage regimen is 2 mg/kg administered subcutaneously three times per week, or 1 mg/kg administered six times per week. Injection site reactions may limit the tolerability of the six times per week regimen.
• The dose may be increased to 3 mg/kg three times per week for insufficient efficacy.

Juvenile-Onset HPP

Recommended dosage regimen is 2 mg/kg administered subcutaneously three times per week, or 1 mg/kg administered six times per week. Injection site reactions may limit the tolerability of the six times per week regimen.

Preparation and Weight-Based Dosing

• Caution: Do not use the 80 mg/0.8 mL vial in pediatrics weighing less than 40 kg because the systemic asfotase alfa exposure achieved with the 80 mg/0.8 mL vial (higher concentration) is lower than that achieved with the other strength vials (lower concentration). A lower exposure may not be adequate for this subgroup of individuals.
• See full prescribing information for tables of weight-based dosing by treatment regimen.

Weight-based dosing tables can be found in the Full Prescribing Information. See Strensiq Prescribing Information (Alexion Pharmaceuticals, Inc..

Source: Alexion Pharmaceuticals, 2018

Background

Hypophosphatasia (HPP) is a rare, genetic, progressive, metabolic disease characterized by defective bone mineralization that can lead to rickets and softening of the bones that result in skeletal abnormalities (FDA, 2015). It can also cause complications such as profound muscle weakness with loss of mobility, seizures, pain, respiratory failure and premature death. Severe forms of HPP affect an estimated one in 100,000 newborns, but milder cases, such as those that appear in childhood or adulthood, may occur more frequently.

The U.S. Food and Drug Administration (FDA) approved Strensiq (asfotase alfa) for the treatment for perinatal (disease occurs in utero and is evident at birth), infantile and juvenile-onset hypophosphatasia (HPP).  Strensiq received a breakthrough therapy designation by the FDA as the first treatment for perinatal, infantile and juvenile-onset HPP. In addition to designation as a breakthrough therapy, the FDA granted Strensiq orphan drug designation because it treats a disease affecting fewer than 200,000 patients in the United States.

Strensiq replaces the enzyme tissue-nonspecific alkaline phosphatase, which is responsible for formation of an essential mineral in normal bone, which has been shown to improve patient outcomes.

The safety and efficacy of Strensiq were established in 99 patients with perinatal (disease occurs in utero and is evident at birth), infantile- or juvenile-onset HPP who received treatment for up to 6.5 years during four prospective, open-label studies. Study results showed that patients with perinatal- and infantile-onset HPP treated with Strensiq had improved overall survival and survival without the need for a ventilator (ventilator-free survival). Ninety-seven percent of treated patients were alive at one year of age compared to 42 percent of control patients selected from a natural history study group. Similarly, the ventilator-free survival rate at one year of age was 85 percent for treated patients compared to less than 50 percent for the natural history control patients.  

The approval of Strensiq in the U.S. was based on data from 99 patients in four prospective open-label studies and supporting extension trials comprising patients with perinatal-, infantile- and juvenile-onset HPP who received treatment with Strensiq for up to 6.5 years. In patients (ages 1 day to 6.5 years) with perinatal/infantile-onset HPP, treatment with Strensiq resulted in a significant survival benefit compared to control patients with similar clinical characteristics selected from a natural history study group. At week 48, the Kaplan-Meier estimate of overall survival was 97 percent for treated patients (n=68) compared to 42 percent for historical control patients (n=48). In addition, estimated invasive ventilator-free survival was 96 percent for treated patients (n=54) compared to 31 percent for historical control patients (n=48). Study results also demonstrated substantial improvements in the skeletal manifestations of HPP, as assessed by the Radiographic Global Impression of Change (RGI-C) scale, and improvements in height and weight, as measured by z-scores, in patients treated with Strensiq.

In patients (ages 6 to 12 years) with juvenile-onset HPP, treatment with Strensiq resulted in significant improvements in the skeletal manifestations of HPP at 24 weeks, as measured by RGI-C, compared to historical controls. By month 54, 100 percent of Strensiq-treated juvenile-onset patients were responders to treatment (n=8), as measured by substantial bone healing, compared to 6 percent of patients in the historial control group (n=32) at last assessment. In addition, patients treated with Strensiq had improvements in height and weight, as measured by z-scores, compared with untreated historical controls. Patients with juvenile-onset HPP treated with Strensiq showed improvements in growth and bone health compared to control patients selected from a natural history database. All treated patients had improvement in low weight or short stature or maintained normal height and weight. In comparison, approximately 20 percent of control patients had growth delays over time, with shifts in height or weight from the normal range for children their age to heights and weights well below normal for age. 

Patients treated with Strensiq had improvements in gait and mobility. By 4 years of treatment, 100 percent of patients assessed (n=6) achieved the 6 Minute Walk Test within the normal range for age-, sex- and height-matched peers, whereas no patients were in the normal range at baseline.

The most commonly reported adverse events (AEs) observed in clinical trials were injection site reactions. Other common adverse reactions included lipodystrophy, ectopic calcifications, and hypersensitivity reactions.

Hypersensitivity reactions have been reported in Strensiq-treated patients. In clinical trials, 1 out of 99 treated patients (1%) experienced signs and symptoms consistent with anaphylaxis. Localized lipodystrophy, including lipoatrophy and lipohypertrophy, has been reported at injection sites after several months in patients treated with Strensiq.

Patients with HPP are at increased risk for developing ectopic calcifications. In clinical trials, 14 cases (14%) of ectopic calcification of the eye including the cornea and conjunctiva, and the kidneys (nephrocalcinosis) were reported. 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. The product labeling recommends that patients be monitored for ectopic calcifications with ophthalmologic examinations and renal ultrasounds at baseline and during treatment.

Adults Hypophosphatasia

Hofmann and colleagues (2016) noted that HPP is a rare disease caused by loss-of-function mutations in the tissue-nonspecific alkaline phosphatase (TNAP, TNSALP) gene; HPP causes a multi-systemic syndrome with a predominant bone phenotype. The clinical spectrum ranges from high lethality in early onset (less than 6 months) HPP to mild late-onset syndromes, and the management of HPP so far has been only supportive.  Subcutaneous asfotase alfa, a first-in-class bone-targeted human TNAP enzyme replacement therapy (ERT), is the first compound to be approved for long-term treatment of bone manifestations in pediatric-onset HPP.  In non-comparative clinical trials (treatment up to 7 years), this treatment was associated with skeletal, respiratory and functional improvement in perinatal, infantile and childhood-onset HPP.  Compared with age-matched historical controls, patients with life-threatening perinatal and infantile HPP treated with asfotase alfa had substantially improved bone mineralization, survival and ventilation-free survival.  In childhood HPP, asfotase alfa improved growth, gross motor function, strength and agility and decreased pain.  The compound was well-tolerated and most AEs were of mild-to-moderate intensity.  To-date, data and experience concerning its safety and effectiveness in long-term treatment are not yet available.  The authors concluded that further studies to evaluate risks and benefits of ERT with asfotase alfa in adults are in progress and are also strongly needed.

Neurofibromatosis

de la Croix Ndong and associates (2014) stated that individuals with neurofibromatosis type-1 (NF1) can manifest focal skeletal dysplasias that remain extremely difficult to treat. Neurofibromatosis type-1 is caused by mutations in the NF1 gene, which encodes the RAS GTPase-activating protein neurofibromin.  These investigators reported that ablation of Nf1 in bone-forming cells led to supra-physiologic accumulation of pyrophosphate (PPi), a strong inhibitor of hydroxyapatite formation, and that a chronic extracellular signal-regulated kinase (ERK)-dependent increase in expression of genes promoting PPi synthesis and extracellular transport, namely Enpp1 and Ank, causes this phenotype.  Nf1 ablation also prevents bone morphogenic protein-2-induced osteoprogenitor differentiation and, consequently, expression of alkaline phosphatase and PPi breakdown, further contributing to PPi accumulation.  The short stature and impaired bone mineralization and strength in mice lacking Nf1 in osteochondro-progenitors or osteoblasts can be corrected by asfotase alfa ERT aimed at reducing PPi concentration.  The authors concluded that these findings established neurofibromin as an essential regulator of bone mineralization; and they also suggested that altered PPi homeostasis contributed to the skeletal dysplasias associated with NF1 and that some of the NF1 skeletal conditions could be prevented pharmacologically.

Furthermore, an UpToDate review on “Neurofibromatosis type 1 (NF1): Management and prognosis” (Korf, 2016) does not list asfotase alfa as a therapeutic option.

Appendix

Appendix A: Examples of Signs and Symptoms of HPP

• Perinatal/infantile-onset HPP:

  • Generalized hypomineralization with rachitic features, chest deformities and rib fractures
  • Skeletal abnormalities (e.g., short limbs, abnormally shaped chest, soft skull bone)
  • Respiratory problems (e.g., pneumonia)
  • Hypercalcemia
  • Failure to thrive
  • Severe muscular hypotonia and weakness
  • Nephrocalcinosis secondary to hypercalciuria
  • Swallowing problems
  • Seizures.
    
    

• Juvenile-onset HPP:

  • Premature loss of deciduous teeth
  • Failure to thrive with anorexia, nausea, and gastrointestinal problems
  • Short stature with bowed legs or knock knees
  • Skeletal deformities (e.g., enlarged wrist and ankle joints, abnormal skull shape)
  • Bone and joint pain
  • Rickets
  • Fractures
  • Delayed walking
  • Waddling gait.

Appendix B: Examples of Radiographic Findings that Support HPP Diagnosis 

• Infantile rickets
• Alveolar bone loss
• Focal bony defects of the metaphyses
• Metatarsal stress fractures
• Osteomalacia with lateral pseudofractures
• Osteopenia, osteoporosis, or low bone mineral content for age (as detected by dual-energy x-ray absorptiometry [DEXA]).

Table: CPT Codes / HCPCS Codes / ICD-9 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
76770 - 76775	Ultrasound, retroperitoneal (eg, renal, aorta, nodes), real time with image documentation; complete; limited
76811	Ultrasound, pregnant uterus, real time with image documentation, fetal and maternal evaluation plus detailed fetal anatomic examination, transabdominal approach; single or first gestation
+76812	each additional gestation (List separately in addition to code for primary procedure)
77075	Radiologic examination, osseous survey; complete (axial and appendicular skeleton)
84207	Pyridoxal phosphate (Vitamin B-6)
84075	Phosphatase, alkaline
92012 - 92014	Ophthalmological services: medical examination and evaluation, with initiation or continuation of diagnostic and treatment program; intermediate, established patient; 1 or more visits
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
HCPCS codes covered if selection criteria are met :
Asfotase alfa (Strensiq) - no specific code :
ICD-10 codes covered if selection criteria are met:
E83.31	Familial hypophosphatemia [perinatal/infantile- and juvenile-onset hypophosphatasia (HPP)]
E83.39	Other disorders of phosphorus metabolism [perinatal/infantile- and juvenile-onset hypophosphatasia (HPP)]
ICD-10 codes not covered for indications listed in the CPB (not all inclusive):
Q85.00 - Q85.09	Neurofibromatosis (nonmalignant)

The above policy is based on the following references: