Abstract
Subcutaneous asfotase alfa (Strensiq™), a first-in-class bone-targeted human recombinant tissue-nonspecific alkaline phosphatase (TNSALP) replacement therapy, is approved in the USA for the treatment of patients with perinatal/infantile- or juvenile-onset hypophosphatasia (HPP). In clinical trials, asfotase alfa was an effective and generally well tolerated treatment for perinatal/infantile- and juvenile onset-HPP through at least 3 and 5 years’ treatment, respectively. Relative to untreated age-matched, juvenile-onset-HPP historical control cohorts, survival and ventilation-free survival were significantly prolonged in asfotase alfa-treated patients, consequent to preceding improvements in bone mineralization.
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First-in-class bone-targeted human recombinant TNSALP replacement therapy |
Improves skeletal manifestations of HPP |
Improves overall survival and ventilation-free survival, growth, gait and mobility |
The most common adverse reactions are injection-site reactions, lipodystrophy, ectopic calcifications and hypersensitivity reactions |
1 What is the Rationale for Developing Asfotase Alfa?
Hypophosphatasia (HPP) is a rare genetic disease resulting from loss-of-function mutations in the ALPL gene encoding tissue-nonspecific alkaline phosphatase (TNSALP), with at least 300 mutations identified to date (mostly missense mutations) [2, 3]. HPP is associated with significant morbidity and mortality, especially in paediatric patients (onset <18 years of age) in whom mortality rates are as high as 100 % in perinatal-onset HPP and 50 % in infantile-onset HPP [2–7]. There are several forms of HPP, including perinatal severe HPP, infantile HPP (onset <6 months of age), childhood HPP (onset ≥6 months to 18 years of age), adult HPP (onset ≥18 years of age) and odonto-HPP (least severe form; is not associated with bone, articular or muscular problems) [2, 4, 8]. The more severe, life-threatening forms of HPP (severe perinatal and infantile forms) are generally associated with autosomal recessive inheritance (i.e. ≥2 mutations leading to almost complete suppression of TNSALP activity), with milder forms associated with autosomal recessive (i.e. ≥2 mutations) or autosomal dominant (i.e. a single mutation) inheritance (typically involving mutations that reduce TNSALP activity) [2–4]. However, in some cases, autosomal dominant inheritance may result in a near complete loss of enzymatic activity [2–4]. The estimated prevalence of severe HPP in the general population is 1:100,000 [3, 9], but is much higher in some populations (e.g. Canadian Mennonites in whom the estimated prevalence is 1:2500 live births) [3, 10, 11].
The presentation and severity of the disease is highly variable; potential manifestations in paediatric-onset HPP include hypomineralization of bones and teeth (in juvenile-onset HPP, a key manifestation is premature loss of deciduous teeth), HPP-related rickets, fractures, pulmonary insufficiency, failure to thrive, hypotonia, vitamin B6-responsive seizures, non-nutritional nephrocalcinosis, hypercalcaemia/hypercalciuria and craniosynostosis [2, 3, 12]. Mutations in the ALPL gene result in a deficiency of TNSALP activity and consequently an increase in plasma levels of TNSALP substrates, including inorganic pyrophosphate (PPi; involved in hydroxyapatite crystal formation), pyridoxal 5′-phosphate (PLP; main circulating form of vitamin B6) and phosphoethanolamine (PEA). An excess of PPi results in inhibition of hydroxyapatite crystal formation and, as a consequence, causes an accumulation of unmineralized bone matrix, which manifests as bone deformation in infants and children and as osteomalacia once growth plates closes [2, 3, 12].
Given that there are currently no curative options available for the treatment of HPP, management of the disease for the most part has involved symptomatic treatment, orthopaedic surgery and supportive care [3, 4, 12]. Symptomatic treatments for affected patients include lowering calcium intake to improve hypercalciuria, the use of nonsteroidal anti-inflammatory drugs for pain, the use of vitamin B6 in patients who experience seizures or are at risk of seizures (seizures are mainly present in severe perinatal HPP) and craniectomy (for increased intracranial pressure secondary to craniosynostosis) [3, 4, 12]. Hence, there was a need to develop new approaches to therapy for HPP that addressed the fundamental underlying problem of deficient activity of TNSALP, with various strategies investigated in the past without success (e.g. infusions of plasma enriched for alkaline phosphatase, such as that from patients with Paget’s disease) [3, 12]. A new strategy for the treatment of HPP is the human recombinant TNSALP fusion protein asfotase alfa (Strensiq™), a first-in-class enzyme replacement therapy that was recently approved in the USA [13] for the treatment of patients with perinatal/infantile- or juvenile-onset HPP.
2 How Does Asfotase Alfa Work?
Asfotase alfa, a soluble 726 amino acid human recombinant TNSALP fusion protein (homodimer), consists of the catalytic domain of human TNSALP, the human IgG Fc domain and a deca-aspartate bone-targeting peptide domain [13, 14]. In vitro studies showed that the affinity of the human recombinant TNSALP enzyme for hydroxyapatite was enhanced 30-fold and retention of the tagged TNSALP enzyme in bone was fourfold greater than that of untagged TNSALP enzyme after the addition of an acidic oligopeptide of six or eight aspartate residues to human recombinant C-terminal-anchorless TNSALP enzyme [15]. Both the tagged and untagged TNSALP enzymes were bioactive and initiated bone mineralization in cultured bone marrow cells from a patient with HPP [15].
Support for the use of asfotase alfa in the clinical setting comes from several studies using a murine model of infantile HPP [TNSALP knockout mice (Alpl −/−; also known as Akp2 −/−)] [16–19]. In this model, daily subcutaneous asfotase alfa injections from birth prevented enamel defects and/or tooth loss, and improved mineralization in molar and incisor teeth [16–19]. Where evaluated, there was also normalization of growth and prevention of the sequelae of HPP, such as skeletal manifestations [17].
In patients with perinatal/infantile- or juvenile-onset HPP, asfotase alfa treatment resulted in reductions in plasma levels of the TNSALP substrates PPi and PLP within 6–12 weeks of treatment; these reductions did not correlate with clinical outcomes [13]. Plasma PLP levels were significantly reduced from baseline (262 ng/mL; n = 10) at 24 (median change −244 ng/mL; p = 0.004; n = 9) and 48 (median change −182 ng/mL; p = 0.016; n = 8) weeks in infants in the ENB-002-08/ENB-003-08 study [20]. At baseline, plasma PLP levels were 2-fold to 18-fold higher than the upper limit of normal in ten of these patients and one patient was receiving pyridoxine treatment for vitamin B6-responsive seizures. There were also reductions from baseline in median plasma levels of PPi at 24 and 48 weeks (5.2, 1.1 and 1.9 nmoles/L, respectively; n = 5 evaluable), although these differences did not reach statistical significance [20].
As with all therapeutic proteins, there is a potential for immunogenicity with asfotase alfa treatment [13]. Amongst 98 patients with HPP enrolled in clinical trials who had post baseline data, 78 % had anti-drug antibodies at some point during asfotase alfa treatment. Of these 76 patients with anti-drug antibodies, 45 % (34 patients) also showed the presence of neutralizing antibodies. No correlation was observed between anti-drug antibody titre and neutralizing antibody (% inhibition) values. The formation of anti-drug antibodies resulted in reduced systemic exposure to asfotase alfa [13].
3 For Whom is Asfotase Alfa Indicated?
In the USA, subcutaneous asfotase alfa is indicated for the treatment of patients with perinatal/infantile- and juvenile-onset HPP (Table 1) [13].
4 What is the Clinical Efficacy of Asfotase Alfa?
The clinical development programme evaluating the use of subcutaneous asfotase alfa in perinatal/infantile- or juvenile-onset HPP included three ongoing, open-label, phase 2, multinational studies [13]. All participants had diagnosed documented HPP based on specified criteria and symptoms of the disease [13]. Some data are fully published [20, 21], with other data available as abstract, poster and/or oral presentations.
4.1 Perinatal/Infantile-Onset HPP
The efficacy of subcutaneous asfotase alfa in severe perinatal/infantile-onset HPP (onset at <6 months of age) has been evaluated in the 6-month ENB-002-08 study (n = 11) and its ongoing extension ENB-003-08 (n = 10; ENB002-08/ENB-003-08), and in the ongoing ENB-010-10 (n = 59) [13]. The primary endpoint in ENB-002-08 [20] and ENB-010-10 [22, 23] was the change in skeletal manifestations of HPP at week 24, assessed by three independent radiologists using the 7-point Radiographic Global Impression of Change (RGI-C) score [RGI-C scores range from −3 (i.e. severe worsening) to +3 (i.e. near-complete or complete healing)]. A radiographic response was defined as a minimum score of +2 (i.e. substantial healing) on the RGI-C scale. Rickets severity was also assessed using the 10-point Rickets Severity Scale (RSS), with higher scores indicating more severe disease.
In ENB-002-08, infants (age range 3 weeks to 39.5 months) received an initial single intravenous infusion of asfotase alfa 2 mg/kg (one patient withdrew after this dose), followed by subcutaneous asfotase alfa 3 mg/kg/week for the first month, after which the dosage was increased up to 9 mg/kg/week for changes in weight and/or a lack of efficacy [13, 20]. All infants in ENB-002-08/ENB-003-08 received ≥6 mg/kg/week, with nine patients treated for 54 months and four patients for over 60 months [13]. In ENB-010-10, infants (age range 1 day to 78 months) received subcutaneous asfotase alfa 6 mg/kg/week for 4 weeks, after which ten patients received dosage increases to >6 mg/kg/week due to suboptimal efficacy, with 41 patients having received at least 6 months treatment and 15 having received at least 24 months treatment. See Table 1 for the recommended dosages of asfotase alfa in the USA for infants with perinatal/infantile-onset HPP [13].
4.1.1 Survival and Ventilation-Free Survival
The survival rate in an interim analysis of 37 asfotase alfa-treated patients enrolled in the ENB-002-08/ENB-003-08 and ENB-010-10 studies was compared with that of a historical cohort of patients with similar clinical characteristics of perinatal/infantile-onset HPP (n = 48; ENB-011-10, as described by Whyte et al. [24]) [21]. Based on Kaplan–Meier estimates, asfotase alfa treatment significantly (p < 0.0001) prolonged overall survival compared with the historical cohort, with the median survival time inestimable in the asfotase alfa group (as most patients were alive beyond the cutoff date) and 8.9 months (95 % CI 5.1–14.0) in the historical cohort. Survival rates at 1 and 5 years were 95 and 84 % in asfotase alfa recipients, with respective survival rates at these timepoints in the historical cohort of 42 and 27 % [21].
Improvements in ventilation observed in asfotase alfa recipients reflected preceding improvements in bone mineralization and skeletal manifestations (Sect. 4.1.2) [21]. In this interim analysis of the ENB-002-08/ENB-003-08 and ENB-010-10 studies, 53 % of infants (21 of 39 patients) required ventilation support (includes noninvasive and invasive support) at baseline (n = 14) or soon after initiating asfotase alfa treatment (n = 7), with 16 of these infants alive at the time of this interim analysis. Three-quarters (12 of 16 infants) of these infants had been weaned from ventilatory support during asfotase alfa treatment, and all had experienced improvements in respiratory function. In the historical cohort, 42 % of infants (20 of 48 patients) required some form of ventilator support at baseline, one of whom was alive at the time of this analysis [21].
Based on an updated analysis reported in the US prescribing information, at the point of last contact, 91 % of asfotase alfa-treated infants were alive compared with 27 % of infants in the historical untreated cohort (n = 68 and 48 evaluable) [13]. The hazard ratio (HR) for survival after initiating asfotase alfa therapy versus the historical cohort was 0.14 (95 % CI 0.05–0.39). At this timepoint, 85 % of asfotase alfa-treated infants were alive and not on ventilation compared with 25 % of infants in the historical untreated cohort (n = 54 and 48 evaluable). The HR for invasive ventilation-free survival after initiating asfotase alfa therapy versus the historical cohort was 0.21 (95 % CI 0.09–0.51) [13].
4.1.2 Skeletal Manifestations
In ENB-002-08/ENB-003-08, there were significant (p = 0.004) improvements in skeletal manifestations from baseline to week 24 and 48, based on RGI-C scores at week 24 (median score +2.0 points) and 48 (median score +2.3) [20]. These data were supported by improvements from baseline (median score 9.5) in RSS score at 24 (median reduction 3.5 points; p = 0.004; n = 9) and 48 weeks (median reduction 8.8; p = 0.008; n = 9). After 6 months, asfotase alfa-treated patients showed no deterioration in skeletal manifestations of HPP, whereas the patient who withdrew from treatment after a single intravenous dose showed a marked deterioration in skeletal manifestations of HPP at 14 months. At 6 months, skeletal improvements in asfotase alfa recipients included diffusely increased bone mineralization, corrected or improved endochondral and membranous bone formation, fracture healing, reduced deformity, resolution of redundancies and sclerosis, and extensive modelling and remodelling of bone [20].
Radiographically-assessed improvements from baseline in bone mineralization were observed through 3 years of asfotase alfa therapy in infants and children with severe HPP (n = 9 ongoing; ENB-003-08), with these improvements generally evident from 3 months (as assessed by RGI-C and RSS scores) [25]. Median RGI-C scores in evaluable patients (n = 9 and 8) at 2 and 3 years were +2 and +1.7 (both p ≤ 0.008), with RGI-C responder rates at these respective timepoints of 100 and 75 %. Improvements in median RSS total scores over the 3-year period were consistent with those for RGI-C scores, with the median RSS total score reduced from 8.25 (severe rickets) at baseline to −6.50 at 2 years (p = 0.008) and −6.25 at 3 years (p = 0.016); scores at 2 and 3 years indicate a near absence of rickets [25].
Results from the ongoing ENB-010-10 study in infants and children ≤5 years of age (HPP onset at <6 months of age) support evidence from the ENB-002-08/ENB-003-08 study; one patient withdrew from treatment because of encephalopathy (considered unrelated to treatment) [22]. In an interim analysis, there were significant improvements in skeletal manifestations of HPP at 24 weeks (median RGI-C score +1.7; p < 0.0001; n = 28 evaluable), 48 weeks (median RGI-C score +2.0; p < 0.0001; n = 19) and 120 weeks (median RGI-C score +2.5; p < 0.0001; n = 10) [22].
4.1.3 Growth
In a pooled analysis of ENB-002-08/ENB-003-08 and ENB-010-10 (n = 68), mean height Z-scores improved from −3.3 at baseline to −2.9 at last assessment, with mean weight Z-scores improving from −3.2 at baseline to −2.4 [13]. The mean time interval between baseline and last assessment was 21 months (range 1–72 months). These data are supported by results from four infants with perinatal/infantile-onset HPP enrolled in ENB-006-09/ENB-008-10 [13].
4.2 Juvenile-Onset HPP
In the 6-month ENB-006-09 study, children (aged 6–12 years at study entry) with HPP onset at <6 (n = 5; perinatal/infantile-onset HPP) or ≥6 (n = 8; juvenile-onset) months of age received subcutaneous asfotase alfa 6 mg/kg/week (n = 6) or 9 mg/kg/week (n = 7) [13, 26]. At the end of the study, all eight patients with juvenile-onset HPP entered the ongoing ENB-008-10 extension study, during which they initially received asfotase alfa 3 mg/kg/week; upon analysis of interim data, the dosage was increased to 6 mg/kg/week (recommended dosage for patients with juvenile-onset HPP) [13]. The primary efficacy endpoint was the change in rickets severity at 6 months, as assessed using RGI-C scores [26]. Comparisons were with an age-matched historical control cohort (as described by Whyte et al. [27]); based on dates of available radiographs, the historical cohort comparator interval was 16 months for the primary endpoint [26].
4.2.1 Skeletal Manifestations
In the overall group (n = 13), asfotase alfa significantly (p = 0.007) improved RGI-C and RSS scores at 6 months compared with the untreated age-matched historical controls who had undergone a similar protocol of clinical management without asfotase alfa treatment (median RGI-C score at 6 months +2 vs. 0) [26]. Improvements in skeletal manifestations of HPP were observed in asfotase alfa recipients during ongoing treatment for up to 3 years (i.e. at last assessment; extension study ENB-008-10); at 2 years, the median improvement in RGI-C and RSS scores from baseline in asfotase alfa recipients was +2 (p = 0.001) and −2 (p = 0.003), with similar improvements observed at 3 years [26]. Of the eight patients with juvenile-onset HPP enrolled in this study, all were rated as responders (i.e. had an RGI-C score of ≥2) to asfotase alfa therapy after up to 54 months’ treatment [13]. In the historical control cohort, 2 of 32 patients were rated as responders at the last assessment; the mean duration between baseline and last RGI-C assessment was 56 months [13].
4.2.2 Growth
In eight children treated with asfotase alfa, mean height Z-scores improved from −1.5 at baseline to −0.9 at last assessment, with mean weight Z-scores improving from −1.1 at baseline to 0 at last assessment [13]. Conversely, in the historical control cohort (n = 32), there were minimal changes from baseline to the last assessment point for mean height (−1.1 at both timepoints) and weight (−1.2 vs. −1.0) Z-scores. The mean time interval between baseline and last assessment was 55 months (range 53–60 months) in asfotase alfa-treated children and 61 months (range 19–109 months) in the historical control group [13].
4.2.3 Gait and Mobility
Asfotase alfa-treated children with juvenile-onset HPP experienced an improvement in gait [13, 28, 29], based on the validated modified Performance Orientated Mobility Assessment-Gait (MPOMA-G) test [30]. On the MPOMA-G scale, step length improved by ≥1 point in either foot in 75 % (six of eight children) of asfotase alfa recipients compared with 17 % (one of six children) of children in the control cohort [13]. The rate of change in MPOMA-G score per year was significantly greater in asfotase-alfa treated children (n = 8) than in the untreated historical cohort (n = 6) [median rate of changer per year 0.3 vs. 2.5; p = 0.03], with these improvements in asfotase alfa-treated children considered clinically meaningful [28].
Asfotase alfa-treated children also experienced improvements in mobility, with all six evaluable children having 6 Minute Walk Test (6MWT) percent predicted values within the normal range for age, sex and height-matched peers at 48 months; none of the eight enrolled children had 6MWT values within this range at baseline [13]. In addition, these six children were able to walk further at this timepoint compared with baseline [13]. These data are supported by results in the overall population of asfotase alfa treated children in ENB-006-09 (n = 11 evaluable), with median 6MWT distance walked percent of that predicted for age, sex and height-matched peers improving from 61 % at baseline to 85 % at 6 months (p < 0.0001 vs. baseline) and maintained at this level through to 3 years (87 %; p < 0.0003 vs. baseline) [31].
5 What is the Tolerability and Safety Profile of Asfotase Alfa?
The most common adverse reactions with asfotase alfa treatment were injection-site reactions (68 % of patients), lipodystrophy (28 %), ectopic calcification (14 %) and hypersensitivity reactions (12 %), based on a pooled analysis of 99 patients with perinatal/infantile- or juvenile-onset HPP (aged 1 day to 58 years) [13]. Patients had received asfotase alfa for more than 2 years, with 51 and 39 patients treated for ≥24 or ≥42 months, respectively. Injection-site reactions (90 vs. 56 % of patients), lipodystrophy (70 vs. 18 %) and ectopic calcification (55 vs. 4 %) occurred more frequently in patients with juvenile-onset HPP (n = 20) than patients with in perinatal/infantile-onset HPP (n = 79). The most common (incidence ≥30 % in either group) injection-site reactions in patients with perinatal/infantile- or juvenile-onset HPP were erythema (41 and 75 % of patients, respectively), discolouration/hypopigmentation (15 vs. 40 %), pain/tenderness (14 vs. 40 %), pruritus/itching (13 vs. 35 %), swelling (10 vs. 30 %) and macule (5 vs. 35 %). The majority of these reactions were of mild to moderate intensity and resolved within a week. Two patients experienced serious injection-site reactions that resulted in dosage reductions of asfotase alfa. One patient experienced a severe injection-site reaction involving injection site discolouration and withdrew from the trial [13].
Hypersensitivity reactions have been reported in asfotase-alfa-treated patients, with one patient (1 %) experiencing signs and symptoms consistent with anaphylaxis, including difficulty breathing, nausea, periorbital oedema and dizziness [13]. In this patient, the reaction occurred approximately 1 min after injection of asfotase alfa in the setting of 3.5 years of ongoing asfotase alfa treatment and resolved without medical treatment. The patient resumed asfotase alfa therapy and received pre-medication with diphenhydramine for an unspecified period and then continued asfotase alfa treatment without pre-medication [13].
Localized lipodystrophy, including lipoatrophy (8 and 40 % of patients with perinatal/infantile- or juvenile-onset HPP) and lipohypertrophy (6 vs. 30 %), has been reported at injection sites after several months in asfotase alfa-treated patients [13].
Fourteen cases (14 %) of ophthalmic (conjunctival and corneal) calcification and nephrocalcinosis, both of which are known manifestations of HPP, have been reported in clinical trials of asfotase alfa treatment [13]. No visual changes or changes in renal function were reported as a result of the occurrence of these ectopic calcifications. There was insufficient data to determine whether or not reported ectopic calcification events were consistent with the disease or due to asfotase alfa treatment [13].
6 What is the Current Positioning of Asfotase Alfa?
In clinical trials, asfotase alfa was an effective and generally well tolerated treatment for perinatal/infantile- and juvenile onset-HPP through at least 3 and 5 years’ treatment, respectively. Relative to untreated age-matched, juvenile-onset-HPP historical control cohorts, survival and ventilation-free survival were significantly prolonged in asfotase alfa-treated patients, consequent to preceding improvements in bone mineralization. Most adverse events are of mild to moderate intensity, with relatively few patients discontinuing treatment because of these events. The most common adverse reactions are injection-site reactions, lipodystrophy, ectopic calcifications and hypersensitivity reactions. A long-term registry of patients with HPP has recently been established to enable better characterization and understanding of the epidemiology and clinical course of HPP, and to monitor and evaluate long-term treatment effects of asfotase alfa [32].
HPP is a rare inheritable disease and, especially in those with perinatal/infantile- and juvenile-onset HPP, significantly impacts mortality and morbidity. Globally there has been a lack of treatments available for managing the underlying pathophysiology of the disease (i.e. the underlying TNSALP defect), with the mainstay of treatment to date being management of symptoms and supportive care. Subcutaneous asfotase alfa, a bone-targeted human recombinant TNSALP replacement therapy, was recently approved in the USA for the treatment of patients with perinatal/infantile- and juvenile-onset HPP. Clinical trials of asfotase alfa involved a relatively limited number of patients and were of a noncomparative design, reflecting the rarity of the disease. Albeit data are limited, subcutaneous asfotase alfa is a valuable emerging therapy for the treatment of perinatal/infantile- and juvenile-onset HPP.
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Acknowledgments
The review was adapted and updated from Drugs 2016;76(2);255–262 [1]. During the peer review process, the manufacturer of asfotase alfa was offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.
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Lesley Scott is a salaried employee of Adis/Springer, is responsible for the article content and declares no relevant conflicts of interest.
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The manuscript was reviewed by: M. L. Bianchi, Experimental Laboratory for Children’s Bone Metabolism Research, Bone Metabolism Unit, Istituto Auxologico Italiano IRCCS, Milan, Italy; C. Hofmann, Children’s Hospital University of Wurzburg, Wurzburg, Germany; C. R. Rockman - Greenberg, Department of Paediatrics and Child Health, University of Manitoba, Winnipeg, Canada.
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Scott, L.J. Asfotase Alfa in Perinatal/Infantile-Onset and Juvenile-Onset Hypophosphatasia: A Guide to Its Use in the USA. BioDrugs 30, 41–48 (2016). https://doi.org/10.1007/s40259-016-0161-x
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DOI: https://doi.org/10.1007/s40259-016-0161-x