Asfotase alfa (Strensiq)

Number: 0901

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References


Policy

Scope of Policy

This Clinical Policy Bulletin addresses asfotase alfa (Strensiq) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

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 (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

  1. Criteria for Initial Approval

    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 (ALP) 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 (e.g., serum PLP level, urine PEA level, or urinary or plasma PPi level) as defined by the laboratory performing the test; and
    4. Member’s weekly dose will not exceed the following:

      1. 9 mg/kg weekly in a member with perinatal/infantile-onset HPP; or
      2. 6 mg/kg weekly in a member with juvenile-onset HPP.

    Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections). 

  2. Continuation of Therapy

    Aetna considers continuation of asfotase alfa (Strensiq) therapy medically necessary for members requesting reauthorization for an indication listed in Section I who are currently receiving the requested medication through a previously authorized pharmacy or medical benefit when both of the following are met:

    1. Member is experiencing benefit from therapy as demonstrated by one of the following:

      1. Member has experienced improvement in skeletal manifestations from baseline as assessed by the Radiographic Global Impression of Change (RGI-C) scale; or
      2. Member is less than 18 years of age and has experienced an improvement in height and weight compared to baseline, as measured by z-scores; or
      3. Member has experienced an improvement in step length by at least 1 point in either foot compared to baseline based on the Modified Performance Oriented Mobility Assessment-Gait (MPOMA-G) scale; or
      4. Member has experienced an improvement in 6 Minute Walk Test compared to baseline; or
      5. Member has experienced an improvement in Timed Up & Go (TUG) Test compared to baseline; or
      6. Member has experienced an improvement in Chair Rise Test compared to baseline; or
      7. Member has experienced an improvement in Lower Extremity Function Scale (LEFS) compared to baseline; and
    2. Member’s weekly dose will not exceed the following:

      1. 9 mg/kg weekly in a member with perinatal/infantile-onset HPP; or
      2. 6 mg/kg weekly in a member with juvenile-onset HPP.

Dosage and Administration

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 (up to 9 mg/kg per week) for insufficient efficacy.

Juvenile-Onset HPP

  • Recommended dosage regimen is 2 mg/kg administered subcutaneously three times per week (up to 6 mg/kg 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.

Source: Alexion Pharmaceuticals, 2020


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)
84075 Phosphatase, alkaline [Plasma PPi level]
84207 Pyridoxal phosphate (Vitamin B-6)
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
97750 Physical performance test or measurement (eg, musculoskeletal, functional capacity), with written report, each 15 minutes [Timed Up & Go (TUG) test, Chair Rise Test]
97755 Assistive technology assessment (eg, to restore, augment or compensate for existing function, optimize functional tasks and/or maximize environmental accessibility), direct one-on-one contact, with written report, each 15 minutes [Lower Extremity Function Scale (LEFS)]

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)

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

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

Asfotase alfa for injection is available as Strensiq (Alexion Pharmaceuticals, Inc.). Strensiq is a tissue nonspecific alkaline phosphatase.

The labeled warnings and precautions for Strensiq include hypersensitivity reaction, lipodystrophy, ectopic calcifications (eye and kidneys), and possible immune-mediated clinical effects. The most common adverse reactions (10% or more) include injection site reactions, lipodystrophy, ectopic calcifications and hypersensitivity reactions.

Alkaline Phosphatase (ALP) is used as a detection reagent in many laboratory tests and the presence of asfotase alfa in clinical laboratory samples could result in erroneous test results. Inform laboratory personnel and discuss use of an alternative testing platform for patients on treatment. Serum ALP measurements are expected to be elevated during treatment and may be unreliable for clinical decision making (Alexion, 2020).

Perinatal/Infantile- and Juvenile-Onset Hypophosphatasia (HPP)

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. "HPP is caused by a deficiency in TNSALP enzyme activity, which leads to elevations in several TNSALP substrates, including inorganic pyrophosphate (PPi). TNSALP is a metallo-enzyme that catalyzes the hydrolysis of phosphomonoesters with release of inorganic phosphate and alcohol. Elevated extracellular levels of PPi block hydroxyapatite crystal growth which inhibits bone mineralization and causes an accumulation of unmineralized bone matrix which manifests as rickets and bone deformation in infants and children and as osteomalacia (softening of bones) once growth plates close, along with muscle weakness. Replacement of the TNSALP enzyme upon Strensiq treatment reduces the enzyme substrate levels" (Alexion, 2020).

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.

Sugiyama et al (2022) stated that HPP is a rare inherited metabolic disorder caused by mutations in the ALPL gene, which encodes tissue non-specific alkaline phosphatase.  The severity of HPP is widely diverse from the perinatal form to the adult mild form.  The former represents the most severe form and was earlier associated with high mortality due to pneumonia that was caused by severe hypo-mineralization of the bones -- such as chest deformity and fractured ribs -- and muscle weakness.  Enzyme replacement therapy using asfotase alfa (AA) was approved in 2015 in Japan for treating patients with HPP and has improved their pulmonary function and life prognosis.  There are several practical and ethical challenges related to using orphan drugs for a rare disorder in a publicly funded healthcare system.  Sharing experiences regarding their application is essential towards formulating guidelines to help clinicians with decisions regarding their initiation and withdrawal.  These investigators reported the details of AA experience in 10 cases of pediatric-onset HPP in 9 families from January 2015 to November 2019 (median [interquartile range] age of 11.0 [7.6 to 12.5] years; 60 % male).  This was a study of a single-center cohort describing the clinical course of patients with HPP, mainly consisting of the mild childhood form of HPP, treated with AA in Japan.  One case of perinatal form of HPP, 2 cases of benign prenatal form, and 7 cases of childhood form were observed.  The most common symptom at onset was pain.  All patients had low serum alkaline phosphatase levels as compared to the age-matched reference range before the commencement of AA.  All HPP patients appeared to have responded to AA treatment, as evidenced by pain alleviation, increased height standard deviation, improvement in respiratory condition and 6MWT result improvement, disappearance of kidney calcification, alleviation of fatigue, and/or increases in bone mineralization.  There were no serious AEs; however, all patients had an injection site reaction and skin changes at the injection sites.  Genetic analysis showed that 8 out of 10 patients had compound heterozygosity.  The authors concluded that AA may be effective in patients with mild-to-severe pediatric-onset forms of HPP.

Other Indications

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.

Magdaleno and co-workers (2019) reviewed the diagnosis and clinical course of a woman with hypophosphatasia who was treated with asfotase alfa.  This was a report of a woman with debilitating adult-onset hypophosphatasia who was successfully diagnosed with low alkaline phosphatase (ALP) levels and elevated vitamin B6 levels.  Treatment with asfotase alfa resolved her chronic bony pain symptoms and quadrupled her daily pedometer step count.  Furthermore, whole body scans before and after treatment showed less focal uptake overall, suggesting fracture healing after ERT.  The authors concluded that improvement in patient reported symptoms, daily pedometer count, and whole body scans was noted following treatment of adult-onset hypophosphatasia with asfotase alfa ERT; and the significance of increased ALP levels after treatment is currently unknown.

The authors stated that this was a single-case report of 1 patient's experience with the use of this medication.  Furthermore, a limitation of this case report was that the improvement on bone scan imaging could be due to a time-dependent effect of fracture healing, regardless of ERT.  However, this case still highlighted important possible future endeavors with this ERT.

Genest and colleagues (2020) stated that HPP is a rare, inherited, metabolic disease characterized by tissue-nonspecific alkaline phosphatase deficiency resulting in musculoskeletal and systemic clinical manifestations.  In an observational study, these researchers examined the effectiveness of ERT with asfotase alfa on physical function and health-related quality of life (HRQoL) among adults with pediatric-onset HPP who received asfotase alfa for 12 months at a single center.  Primary outcomes evaluated physical function with the 6-minute walk test (6MWT), timed up-and-go (TUG) test, Short Physical Performance Battery (SPPB), and hand-held dynamometry (HHD).  Secondary outcome measures included the Lower Extremity Functional Scale (LEFS), pain prevalence/intensity, and pain medication use; HRQoL was evaluated using the 36-Item Short-Form Health Survey version 2 (SF-36v2).  Safety data were collected throughout the study.  All 14 patients (11 women) had compound heterozygous ALPL gene mutations and greater than or equal to 1 HPP bone manifestation, including history of greater than or equal to 1 fracture.  Mean (min, max) age was 51 (19 to 78) years.  From baseline to 12 months of treatment, median 6MWT distance increased from 267 m to 320 m (n = 13; p = 0.023); median TUG test time improved from 14.4 s to 11.3 s (n = 9; p = 0.008).  Specific components of the SPPB also improved significantly: median 4-m gait speed increased from 0.8 m/s to 1.1 m/s (n = 10; p = 0.007) and median repeated chair-rise time improved from 22 s to 13 s (n = 9; p = 0.008). LEFS score improved from 24 points to 53 points (n = 10; p = 0.002).  Improvements in HHD were not clinically significant.  SF-36v2 Physical Component Score (PCS) improved after 12 months of treatment (n = 9; p = 0.010).  Pain level did not change significantly from baseline to 12 months of treatment.  There were significant improvements on chair-rise time and SF-36v2 PCS by 3 months, and on TUG test time after 6 months.  No new safety signals were identified.  The authors concluded that these findings showed the real-world effectiveness of asfotase alfa in improving physical functioning and HRQoL in adults with pediatric-onset HPP.

The authors concluded that limitations of this study included the small sample size and lack of a comparator arm; however, owing to the rarity of HPP and its debilitating nature, inclusion of a comparator arm (which would involve no treatment) would be unethical and would not be in accordance with the descriptive nature of this study.  Furthermore, 53 % of the patients included in this study had a c.571G>A mutation of the ALPL gene.  Although diligent assessment of familial history did not reveal any kinship among subjects, this could not be ruled out because a haplotyping approach was not applied.  Nevertheless, a similar proportion of individuals (55 %) was found to carry this mutation in a comparable HPP cohort, confirming that this mutation is common among patients with HPP of European ancestry.  Limitations inherent to the use of real‐world data collected in routine clinical practice, and in particular the introduction of bias owing to missing data, were also relevant for this study.  These limitations should be considered when interpreting these results.  In addition, the fact that this study covered a limited number of patients from a single center may restrict the generalizability of these findings.  However, to the best of the authors’ knowledge this was the largest and most consistently monitored cohort of adult patients with HPP receiving long‐term treatment with asfotase alfa.  These investigators stated that these findings established a starting point of how to monitor treatment in these patients, specifically what can be expected regarding treatment effectiveness and clinical improvement and what to focus on to reduce AEs.

Seefried and associates (2021a) noted that there is limited information concerning the appropriate dose of asfotase alfa for adult patients with pediatric-onset HPP.  In a 13-week, phase-IIa, open-label clinical trial, these researchers examined the pharmacodynamics and safety/tolerability of different doses of asfotase alfa in such patients.  This trial enrolled adults (aged greater than or equal to18 years) with pediatric-onset HPP.  Subjects were randomized 1:1:1 to receive a single subcutaneous dose of asfotase alfa (0.5, 2.0, or 3.0 mg/kg) at Week 1, then 3 times per week (i.e., 1.5, 6.0, or 9.0 mg/kg/week) starting at Week 3 for 7 weeks.  Key outcome measures included change from baseline to before the 3rd dose during Week 9 (trough) in plasma PPi (primary outcome measure) and PLP (secondary outcome measure).  A total of 27 adults received asfotase alfa 0.5 (n = 8), 2.0 (n = 10), and 3.0 (n = 9) mg/kg; all completed the study.  Median (range) age was 45 (18 to 77) years; most patients were white (96 %) and female (59 %).  Median plasma PPi and PLP concentrations decreased from baseline to Week 9 in all 3 cohorts.  Least squares mean (LSM) changes in PPi were significant with 2.0 (p = 0.0008) and 3.0 (p < 0.0001) versus 0.5 mg/kg.  LSM differences in PLP changes were significant for 2.0 (p = 0.0239) and 3.0 (p = 0.0128) versus 0.5 mg/kg.  Injection site reactions were the most frequent treatment-emergent AE (78 %), showing increasing frequency with increasing dose.  The authors concluded that adults with pediatric-onset HPP receiving asfotase alfa at 6.0 mg/kg/week (the recommended dose) or 9.0 mg/kg/week had greater reductions in circulating PPi and PLP concentrations compared with a lower dose of 1.5 mg/kg/week.

The authors stated that this study had several drawbacks.  Centralized interpretation of renal and ophthalmologic assessments was not part of the protocol design and may have contributed to uncertainty regarding the findings of treatment-emergent renal ectopic calcifications; detection of ectopic calcifications was limited by the small sample size and short study duration (7 weeks); and the impact of anti-asfotase alfa antibodies and neutralizing antibodies on clinical outcomes was unclear given the short duration of treatment.  Furthermore, patients in the 0.5 mg/kg cohort had a higher median weight and BMI than patients in the other 2 cohorts, which could have influenced study results.  However, since dosing of asfotase alfa was based on body weight, and since baseline weight (greater than or equal to median versus less than median) was included as a co-variate in the analysis model, an impact on study results was unlikely.  Finally, the PPi assay and methodology used in this study may not reflect more recently reported refinements for assessment of PPi concentrations, such as the inclusion of a filtration step to generate platelet-free plasma.

Seefried and colleagues (2021b) stated that there is limited understanding of how asfotase alfa affects mineral metabolism and bone turnover in adults with pediatric-onset HPP.  This study showed that adults with hypophosphatasia treated with asfotase alfa experienced significant changes in biochemical markers of bone and mineral metabolism, possibly reflecting enhanced bone re-modeling of previously osteomalacic bone.  ALP substrates, bone turnover and mineral metabolism markers, and bone mineral density (BMD) data from EmPATHY (a single-center, observational study of adults greater than or equal to 18 years with pediatric-onset HPP treated with asfotase alfa), were collected during routine clinical care and analyzed from baseline through 24 months of treatment.  Data from 21 patients showed significantly increased ALP activity and reduced urine phosphoethanolamine (PEA)/creatinine (Cr) ratios after baseline through 24 months of asfotase alfa treatment.  There were significant transient increases in parathyroid hormone 1-84 (PTH), osteocalcin, and procollagen type 1 N-propeptide (P1NP) levels at 3 and 6 months and in tartrate-resistant acid phosphatase 5b (TRAP5b) levels at 3 months, with a significant decrease in N-terminal telopeptide of type 1 collagen (NTX) levels at 24 months.  Lumbar spine BMD T-scores continuously increased during treatment.  The authors concluded that findings of this study indicated that treatment with asfotase alfa was associated with significant changes in biochemical markers of bone and mineral metabolism in adult patients with pediatric-onset HPP.  These changes suggested that treatment-mediated mineralization may enable bone re-modeling and bone turnover on previously unmineralized and thus inaccessible bone surfaces.  Furthermore, these findings suggested that the urine PEA/Cr ratio should be further examined as a potential biochemical marker for monitoring asfotase alfa treatment.  Moreover, these researchers stated that the main drawbacks of this study were its observational nature and the limited sample size (n = 21), which limited generalizability of these findings.

Dahir et al (2022) noted that the clinical signs and symptoms of HPP can manifest during any stage of life.  The age at which a patient's symptoms were reported could impact access to targeted treatment with ERT (asfotase alfa), as this treatment is indicated for patients with pediatric-onset HPP in most countries.  As such, many patients reported to have adult-onset HPP typically do not receive treatment.  Comparison of the disease in treated and untreated adult patients is confounded by the approved indication.  To avoid this confounding factor, a comparison between baseline disease manifestations prominent among treated versus untreated adult patients was limited to those with pediatric-onset HPP using data collected from the Global HPP Registry.  The hypothesis was that treated adults will have a greater disease burden at baseline than untreated adults.  The analysis of disease manifestations in adults with adult-onset HPP was conducted separately.  A total of 398 adults with HPP were included; 213 with pediatric-onset (114 treated, 99 untreated) and 141 with adult-onset HPP (2 treated and 139 untreated).  The treated, pediatric-onset patients were more likely to have a history of pain (prevalence ratio [PR]: 1.3, 95 % confidence interval [CI]: 1.1 to 1.4), skeletal (PR: 1.3, 95 % CI: 1.1 to 1.6), constitutional/metabolic (PR: 1.7, 95 % CI: 1.3 to 2.0), muscular (PR: 1.8, 95 % CI: 1.4 to 2.1) and neurological (PR: 1.7, 95 % CI: 1.1 to 2.3) manifestations of HPP, and also had poorer measures for HRQoL, pain, and disability compared with untreated pediatric-onset patients.  In patients with adult-onset HPP, the most frequent signs and symptoms were chronic bone pain (52.5 %), dental manifestations (42.6 %), fatigue (23.4 %), recurrent fractures or pseudo-fractures (22.0 %), and generalized body pain (22.0 %).  The authors concluded that along with the more classical skeletal signs and symptoms, pain, muscular, and constitutional/metabolic manifestations are common in adults with HPP, regardless of age of disease onset, highlighting a full spectrum of HPP manifestations.

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 et al, 2021) 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 or metaphyseal fractures
  • Osteomalacia with lateral pseudofractures
  • Osteopenia, osteoporosis, or low bone mineral content for age (as detected by dual-energy x-ray absorptiometry [DEXA])
  • Prenatal long bone bowing with osteochondral spurs.

Source: Bianchi, 2015; Nunes, 2022; Whyte, 2017


References

The above policy is based on the following references:

  1. Alexion Pharmaceuticals, Inc. FDA approves Strensiq (asfotase alfa) for treatment of patients with perinatal-, infantile- and juvenile-onset hypophosphatasia (HPP). Press Release. Cheshire, CT: Alexion; October 23, 2015.
  2. Alexion Pharmaceuticals, Inc. Strensiq (asfotase alfa) injection, for subcutaneous use. Prescribing Information. Cheshire, CT: Alexion; revised October 2015. 
  3. Alexion Pharmaceuticals, Inc. Strensiq (asfotase alfa) injection, for subcutaneous use. Prescribing Information. Boston, MA: Alexion; revised June 2020.
  4. Bianchi ML. Hypophosphatasia: an overview of the disease and its treatment. Osteoporos Int. 2015; 26(12):2743-57.
  5. Canadian Agency for Drugs and Technologies in Health (CADTH). Asfotase alfa (Strensiq)  CADTH Common Drug Reviews [Internet]. Ottawa, ON: CADTH; April 2017.
  6. Dahir KM, Seefried L, Kishnani PS, et al. Clinical profiles of treated and untreated adults with hypophosphatasia in the global HPP registry. Orphanet J Rare Dis. 2022;17(1):277.
  7. de la Croix Ndong J, Makowski AJ, Uppuganti S, et al. Asfotase-α improves bone growth, mineralization and strength in mouse models of neurofibromatosis type-1. Nat Med. 2014;20(8):904-910.
  8. Genest F, Rak D, Petryk A, Seefried L. Physical function and health-related quality of life in adults treated with asfotase alfa for pediatric-onset hypophosphatasia. JBMR Plus. 2020;4(9):e10395.
  9. Hofmann C, Seefried L, Jakob F. Asfotase alfa: Enzyme replacement for the treatment of bone disease in hypophosphatasia. Drugs Today (Barc). 2016;52(5):271-285.
  10. Jelin AC, O'Hare E, Blakemore K, et al. Skeletal dysplasias: Growing therapy for growing bones. Front Pharmacol. 2017;8:79.
  11. Kishnani PS, Rush ET, Arundel P, et al. Monitoring guidance for patients with hypophosphatasia treated with asfotase alfa. Mol Genet Metab. 2017;122(1-2):4-17.
  12. 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.
  13. Korf BR, Lobbous M, Metrock LK. Neurofibromatosis type 1 (NF1): Management and prognosis. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed June 2021.
  14. Magdaleno AL, Singh S, Venkataraman S, et al. Adult-onset hypophosphatasia: Before and after treatment with asfotase alfa. AACE Clin Case Rep. 2019;5(6):e344-e348.
  15. Nunes ME. Hypophosphatasia. In: GeneReviews [internet]. Adam MP, Everman DB, Mirzaa GM, et al., eds. Seattle, WA: University of Washington, Seattle; updated March 30, 2023.
  16. Roumpou A, Yavropoulou MP, Chronopoulos E, Kassi E. Novel therapeutic agents for rare diseases of calcium and phosphate metabolism. Horm Metab Res. 2022 Sep 1 [Online ahead of print].
  17. Scott LJ. Asfotase alfa in perinatal/infantile-onset and juvenile-onset hypophosphatasia: A guide to its use in the USA. BioDrugs. 2016;30(1):41-48.
  18. Seefried L, Kishnani PS, Moseley S, et al. Pharmacodynamics of asfotase alfa in adults with pediatric-onset hypophosphatasia. Bone. 2021a;142:115664.
  19. Seefried L, Rak D, Petryk A, Genest F. Bone turnover and mineral metabolism in adult patients with hypophosphatasia treated with asfotase alfa. Osteoporos Int. 2021b;32(12):2505-2513.
  20. Sugiyama Y, Watanabe T, Tajika M, et al. A Japanese single-center experience of the efficacy and safety of asfotase alfa in pediatric-onset hypophosphatasia. Orphanet J Rare Dis. 2022;17(1):78.
  21. Ucakturk SA, Elmaogullari S, Uuml Nal S, et al. Enzyme replacement therapy in hypophosphatasia. J Coll Physicians Surg Pak. 2018;28(9):S198-S200. 
  22. U.S. Food and Drug Administration (FDA). FDA approves new treatment for rare metabolic disorder. FDA News Release. Silver Spring, MD: FDA; October 23, 2015.
  23. Whyte MP, Greenberg CR, Salman NJ, et al. Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med. 2012;366(10):904-913.
  24. Whyte MP. Hypophosphatasia: An overview for 2017. Bone. 2017;102:15-25.