Hearing impairment improved after treatment with asfotase alfa in a case of perinatal hypophosphatasia.
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ABSTRACT:
SUBMITTER: Chida-Naomiya R
PROVIDER: S-EPMC7284058 | biostudies-literature | 2020 Sep
REPOSITORIES: biostudies-literature
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Hearing impairment improved after treatment with asfotase alfa in a case of perinatal hypophosphatasia.
Chida-Naomiya Rie R Shimura Masaru M Nagao Ryuhei R Kumada Atsushi A Kawashima Hisashi H
Molecular genetics and metabolism reports 20200606
Hearing impairment is a neurological symptom of hypophosphatasia (HPP), which leads to a reduced quality of life. However, the pathomechanism of hearing impairment and the effects of asfotase alfa enzyme replacement therapy on hearing function in HPP have not been clarified. Here we report a case and present clinical data of a patient with perinatal HPP whose hearing impairment improved after asfotase alfa treatment. ...[more]
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Project description:Background. Hypophosphatasia (HPP) is caused by loss-of-function mutation(s) of the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Consequently, cell-surface deficiency of TNSALP phosphohydrolase activity leads to extracellular accumulation of inorganic pyrophosphate, a natural substrate of TNSALP and inhibitor of mineralization. Children with HPP can manifest rickets, skeletal pain, deformity, fracture, muscle weakness, and premature deciduous tooth loss. Asfotase alfa is a recombinant, bone-targeted, human TNSALP injected s.c. to treat HPP. In 2012, we detailed the 1-year efficacy of asfotase alfa therapy for the life-threatening perinatal and infantile forms of HPP. Methods. Here, we evaluated the efficacy and safety of asfotase alfa treatment administered to children 6-12 years of age at baseline who were substantially impaired by HPP. Two radiographic scales quantitated HPP skeletal disease, including comparisons to serial radiographs from similarly affected historical control patients. Results. Twelve children receiving treatment were studied for 5 years. The 6-month primary endpoint was met, showing significant radiographic improvement. Additional significant improvements included patient growth, strength, motor function, agility, and quality of life, which for most patients meant achieving normal values for age- and sex-matched peers that were sustained at 5 years of treatment. For most, pain and disability resolved. Mild to moderate injection-site reactions were common and were sometimes associated with lipohypertrophy. Low anti-asfotase alfa antibody titers were noted in all patients. No evidence emerged for clinically important ectopic calcification or treatment resistance. Conclusions. Asfotase alfa enzyme replacement therapy has substantial and sustained efficacy with a good safety profile for children suffering from HPP. Trial Registration. ClinicalTrials.gov NCT00952484 (https://clinicaltrials.gov/ct2/show/NCT00952484) and NCT01203826 (https://clinicaltrials.gov/ct2/show/NCT01203826). Funding. Alexion Pharmaceuticals Inc. and Shriners Hospitals for Children.
| S-EPMC5033855 | biostudies-literature
Project description:Hypophosphatasia (HPP) is a rare inherited metabolic disorder characterized by deficient activity of alkaline phosphatase, causing defective mineralization of bones and teeth. The symptoms vary from no symptoms to stillbirth or skeletal manifestations. Since 2015, asfotase alfa, an enzyme replacement treatment, has been approved for pediatric use in some jurisdictions. We describe the clinical outcome of asfotase alfa therapy in an adolescent patient with childhood HPP. The patient was diagnosed with HPP at 13 months. She had a history of hypertonia and failure to thrive from age 3 months. During childhood the patient experienced chronic skeletal pain, requiring daily use of analgesics and school absences. Her plasma pyridoxal-5-phosphate was elevated at >2500 mmol/L, phosphoethanolamine at 11 μM, and ALP decreased at 25 U/L. On the visual analog scale (VAS), a scale used to determine pain intensity, she stated an average of 7 (maximum 10) at age 13. She had no abnormalities on radiography. At age 13 the patient was started on asfotase alfa 1 mg/kg given subcutaneously 6 times weekly. Three months after treatment the patient had a decreased P-pyridoxal-5-phosphate level of 41 mmol/L, used fewer analgesics, and a lower average VAS-score. At every follow-up, she continued to exhibit improved biochemical values, along with lower VAS-scores. In conclusion, asfotase alfa significantly improved the patient's quality of life. This case suggests an association between children with HPP without radiographic abnormalities, but a debilitating pain phenotype, and a significant pain reduction on enzyme replacement therapy. Thus, this therapy should be considered in such patients.
| S-EPMC8100395 | biostudies-literature
Project description:Hypophosphatasia (HPP) is an inherited systemic bone disease that is characterized by bone hypomineralization. HPP is classified into six forms according to the age of onset and severity as perinatal (lethal), perinatal benign, infantile, childhood, adult, and odontohypophosphatasia. The causative gene of the disease is the ALPL gene that encodes tissue-nonspecific alkaline phosphatase (TNAP). TNAP is expressed ubiquitously, and its physiological role is apparent in bone mineralization. A defect in bone mineralization can manifest in several ways, including rickets or osteomalacia in HPP patients. Patients with severe forms suffer from respiratory failure because of hypoplastic chest, which is the main cause of death. They sometimes present with seizures due to a defect in vitamin B6 metabolism resulting from the lack of alkaline phosphatase activity in neuronal cells, which is also lethal. Patients with a mild form of the disease exhibit rickets or osteomalacia and a functional defect of exercise. Odontohypophosphatasia shows only dental manifestations. To date, 302 mutations in the ALPL gene have been reported, mainly single-nucleotide substitutions, and the relationships between phenotype and genotype have been partially elucidated. An established treatment for HPP was not available until the recent development of enzyme replacement therapy. The first successful enzyme replacement therapy in model mice using a modified human TNAP protein (asfotase alfa) was reported in 2008, and subsequently success in patients with severe form of the disease was reported in 2012. In 2015, asfotase alfa was approved in Japan in July, followed by in the EU and Canada in August, and then by the US Food and Drug Administration in the USA in October. It is expected that therapy with asfotase alfa will drastically change treatments and prognosis of HPP.
| S-EPMC4876073 | biostudies-literature
Project description:Hypophosphatasia is a rare metabolic disease resulting from variant(s) in the gene-encoding tissue-nonspecific isozyme of alkaline phosphatase. In this 13-week, phase 2a, multicenter, randomized, open-label, dose-response study (ClinicalTrials.gov: NCT02797821), the pharmacokinetics of asfotase alfa, an enzyme replacement therapy approved for the treatment of hypophosphatasia, was assessed in adult patients with pediatric-onset hypophosphatasia. In total, 27 adults were randomly assigned 1:1:1 to a single subcutaneous dose of asfotase alfa (0.5, 2.0, or 3.0 mg/kg) during week 1. From week 3 to week 9, patients received 0.5, 2.0, or 3.0 mg/kg subcutaneously 3 times per week (equivalent to 1.5, 6.0, or 9.0 mg/kg/wk, respectively). Noncompartmental analysis revealed exposure (maximum concentration in the dosing interval and area under the concentration-time curve from time 0 to infinity) to asfotase alfa increased between single- and multiple-dose administration and with increasing doses; however, extensive interindividual variability was observed in the concentration-time profiles within each dose cohort. Median terminal elimination half-life was ≈5 days following multiple-dose administration, with steady state achieved by approximately day 29. Dose-normalized exposure data indicated that asfotase alfa activity was approximately dose-proportional within the studied dose range. Additionally, dose-normalized exposure was comparable across body mass index categories of <25, ≥25 to <30, and ≥30 kg/m2 , indicating that asfotase alfa dosing bioavailability was consistent in these patients, including those who were obese. These data, together with previously published pharmacodynamic results in this study population, support the use of asfotase alfa at the recommended dose of 6 mg/kg/wk in adults with pediatric-onset hypophosphatasia.
| S-EPMC8518624 | biostudies-literature
Project description:Hypophosphatasia (HPP) is a multi-systemic metabolic disorder caused by loss-of-function mutations in the ALPL gene that encodes the mineralization-associated enzyme, tissue-nonspecific alkaline phosphatase (TNSALP). HPP is characterized by defective bone and dental mineralization, leading to skeletal abnormalities with complications resulting in significant morbidity and mortality. Management of HPP has been limited to supportive care until the introduction of a recently approved enzyme replacement therapy employing bone-targeted recombinant human TNSALP, asfotase alfa (AA). This new therapy has been transformative as it improves survival in severely affected infants, and overall quality of life in children and adults with HPP. This review provides an overview of HPP, focusing on important steps in the development of AA enzyme replacement therapy, including the drug design, preclinical studies in the HPP mouse model, and outcomes from clinical trials and case report publications to date, with special attention given to response to therapy of skeletal manifestations, biochemical features, and other clinical manifestations. The limitations, adverse effects, and outcomes of AA are outlined and the place in therapy for individuals with HPP is discussed.
| S-EPMC6161731 | biostudies-literature
Project description:There is limited understanding of how asfotase alfa affects mineral metabolism and bone turnover in adults with pediatric-onset hypophosphatasia. 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 remodeling of previously osteomalacic bone.IntroductionHypophosphatasia (HPP), due to a tissue nonspecific alkaline phosphatase (TNSALP) deficiency, can cause impaired bone mineralization and turnover. Although HPP may be treated with asfotase alfa, an enzyme replacement therapy, limited data are available on how treatment with asfotase alfa affects mineral metabolism and bone turnover in adults with HPP.MethodsALP substrates, bone turnover and mineral metabolism markers, and bone mineral density (BMD) data from EmPATHY, a single-center, observational study of adults (≥ 18 years) with pediatric-onset HPP treated with asfotase alfa (NCT03418389), were collected during routine clinical care and analyzed from baseline through 24 months of treatment.ResultsData 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.ConclusionSignificant changes in bone turnover and mineral metabolism markers after asfotase alfa treatment suggest that treatment-mediated mineralization may enable remodeling and bone turnover on previously unmineralized surfaces. Urine PEA/Cr ratios may be a useful parameter in monitoring treatment during routine care.
| S-EPMC8608777 | biostudies-literature
Project description:BackgroundHypophosphatasia (HPP) is a rare inherited metabolic disorder caused by mutations in the ALPL gene, which encodes tissue nonspecific 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 which was caused by severe hypomineralization 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 about their application is essential towards formulating guidelines to assist clinicians with decisions about their initiation and withdrawal. We report the details of AA experience in ten cases of pediatric-onset HPP in nine families from January 2015 to November 2019 (median [interquartile range] age 11.0 [7.6-12.5] years; 60% male). This is 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.ResultsOne case of perinatal form of HPP, two cases of benign prenatal form, and seven 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 seem to have responded to AA treatment, as evidenced by pain alleviation, increased height standard deviation, improvement in respiratory condition and 6-min walk test result improvement, disappearance of kidney calcification, alleviation of fatigue, and/or increases in bone mineralization. There were no serious adverse events, but all patients had an injection site reaction and skin changes at the injection sites. Genetic analysis showed that eight out of ten patients had compound heterozygosity.ConclusionsAA may be effective in patients with mild to severe pediatric-onset forms of HPP.
| S-EPMC8867653 | biostudies-literature
Project description:Hypophosphatasia (HPP) is a rare, inherited, metabolic disease characterized by tissue-nonspecific alkaline phosphatase deficiency resulting in musculoskeletal and systemic clinical manifestations. This observational study evaluated the effectiveness of enzyme replacement therapy 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 (ClinicalTrial.gov no.: NCT03418389). Primary outcomes evaluated physical function with the 6-minute walk test (6MWT), timed up-and-go (TUG) test, Short Physical Performance Battery (SPPB), and handheld 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??1 HPP bone manifestation, including history of ?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. These results show the real-world effectiveness of asfotase alfa in improving physical functioning and HRQoL in adults with pediatric-onset HPP. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
| S-EPMC7507107 | biostudies-literature
Project description:CONTEXT:Long-term data on enzyme replacement treatment of hypophosphatasia (HPP) are limited. OBJECTIVE:To evaluate efficacy and safety of asfotase alfa in patients aged ≤5 years with HPP followed for up to 6 years. DESIGN:Phase 2 open-label study (July 2010 to September 2016). SETTING:Twenty-two sites; 12 countries. PARTICIPANTS:Sixty-nine patients [median (range) age: 16.0 (0.02 to 72) months] with severe HPP and sign/symptom onset before age 6 months. INTERVENTION:Asfotase alfa 2 mg/kg three times/week or 1 mg/kg six times/week subcutaneously. MAIN OUTCOME MEASURES:Primary efficacy measure: Radiographic Global Impression of Change (RGI-C) score [-3 (severe worsening) to +3 (complete/near-complete healing)]. Additional outcome measures: respiratory status, growth, and safety. Post hoc analysis: characteristics of radiographic responders vs nonresponders at Year 1 (RGI-C: ≥+2 vs <+2). RESULTS:During median (minimum, maximum) 2.3 (0.02, 5.8) years of treatment, RGI-C scores improved significantly at Month 6 [+2.0 (-1.7, +3.0)], Year 1 [+2.0 (-2.3, +3.0)], and Last Assessment [+2.3 (-2.7, +3.0); P < 0.0001 all]. Of 24 patients requiring respiratory support at Baseline, 11 (46%) no longer needed support. Height/weight z scores generally increased. Nine patients died (13%). All patients experienced at least one adverse event; pyrexia was most common. Compared with responders [n = 50 (72%)], nonresponders [n = 19 (28%)] had more severe disease at Baseline and a higher rate of neutralizing antibodies (NAbs) at Last Assessment. CONCLUSIONS:Most infants/young children given asfotase alfa showed early radiographic and clinical improvement sustained up to 6 years; radiographic nonresponders had more severe disease and more frequent NAbs at Last Assessment.
| S-EPMC6530655 | biostudies-literature
Project description:Enzyme replacement therapy (ERT) is a newly approved disease-modifying treatment for hypophosphatasia (HPP), a rare metabolic bone disorder. With an orphan drug and ultra-rare disease, sharing information about responders and non-responders is particularly important, as any one centre's familiarity with its use will be limited. Nearly all published data in infants and very young children with life-threatening HPP are from three small clinical trials that have reported generally positive outcomes. We describe in detail a patient with perinatal HPP for whom treatment with ERT was not successful. Lessons learned from this case can inform clinical decision-making and provide topics for the research agenda. We also discuss practical and ethical challenges related to treatment of an ultra-rare disease with an expensive new medication in a publicly funded healthcare system.
| S-EPMC5681336 | biostudies-literature