Strensiq (asfotase alfa) / AstraZeneca - LARVOL DELTA

Burden of fatigue in Hypophosphatasia: findings from an observational study in a Tertiary Care Hospital in the United Kingdom (EULAR 2025) - "The patients were divided into two groups for, those receiving Enzyme replacement therapy (ERT, n=12) with Asfotase Alfa and those not receiving ERT (n=40)... In this predominantly female cohort of adults with HPP, fatigue assessed by FAS was very common, affecting eighty percentage of the patients overall. A one hundred percent of ERT group and seventy five percent from the non-ERT experience fatigue. The self-reported fatigue percentages align with these findings."

Clinical • Observational data • Fatigue • Musculoskeletal Diseases • Orthopedics • Pain • Pediatrics • ALPL

Adult Hypophosphatasia Presenting with Soft Tissue Heterotopic Calcific Mass Lesions. (ENDO 2025) - "The patient was started on asfotase alfa therapy with significant improvement in nonspecific myalgia, asthenia, fatigue and mobility within the intervening 1.5 months of therapy...Attention to the presence of persistently low ALP serum levels is often the first clue to the correct diagnosis. Our patient adds heterotopic soft tissue mass calcifications to the growing profile of possible clinical presentations of adult HPP."

Clinical • Chronic Kidney Disease • CNS Disorders • Fatigue • Genetic Disorders • Mood Disorders • Musculoskeletal Pain • Nephrology • Orthopedics • Osteoporosis • Pain • Psychiatry • Renal Calculi • Rheumatology • ALPL

Recurrent metatarsal, scapular and acromial fractures during Denosumab therapy in Adult-onset Hypophosphatasia with a pathogenic variant of the ALPL gene and a variant of uncertain significance of the ATRIP Gene (ENDO 2025) - "She was initially started on risedronate at age 61y but due to continued non-traumatic metatarsal fractures teriparatide was recommended...She has been offered treatment with Asfotase alfa (AA). Adult-onset HPP was recognized in a 66-yo female who presented with acromial, scapular and recurrent metatarsal fractures while on denosumab therapy for 4 y for osteoporosis...AA, a human recombinant enzyme replacement therapy was approved for HPP in 2015. Treatment with anabolic agents such as teriparatide and romosozumab has been reported while anti-resorptives such as bisphosphonates and denosumab are contraindicated."

Clinical • Addiction (Opioid and Alcohol) • Endocrine Disorders • Fibromyalgia • Growth Hormone Deficiency (Adult) • Musculoskeletal Diseases • Musculoskeletal Pain • Orthopedics • Osteoporosis • Pain • Rheumatology • ALPL • ATRIP

Adult-Onset Hypophosphatasia with Atypical Femoral Fractures: A Diagnostic and Management Challenge (ENDO 2025) - "It is often misdiagnosed as osteoporosis, and treatment with bisphosphonates or denosumab can worsen the disease, increasing the risk of atypical femoral fractures. AHPP poses a significant diagnostic challenge, particularly in patients with long-term antiresorptive therapy. Persistently low ALP, atypical fractures, and genetic confirmation are key diagnostic markers. This case underscores the need for clinical awareness and early intervention, as asfotase alfa may play a crucial role in improving skeletal outcomes in adults with progressive disease."

Clinical • Musculoskeletal Diseases • Orthopedics • Osteoporosis • Rheumatology • ALPL

Treatment Efficacy and Complications Associated with Asfotase alfa Therapy in Hypophosphatasia (ENDO 2025) - "Asfotase alfa enzyme replacement therapy not only improves the clinical symptoms and quality of life but also may be beneficial in reducing the future risk of bone and teeth complications."

Clinical • Endocrine Disorders • Lipodystrophy • Metabolic Disorders • Musculoskeletal Diseases • Musculoskeletal Pain • Orthopedics • Pain • ALPL

Bone Mineral Density in Adults With Hypophosphatasia With or Without History of Fractures (ENDO 2025) - " Fractures occurring before asfotase alfa treatment (or at any time in untreated patients) were analyzed in younger (aged 18-≤50 y) and older (aged >50 y) adults from the Global HPP Registry (data cut: June 2023)... Median BMD T-scores were within a normal range in adults regardless of fracture history. Some patients may have concomitant osteoporosis in addition to the underlying HPP-related osteomalacia. Further analysis to distinguish fractures due to osteoporosis vs compromised mineralization is warranted."

Clinical • Musculoskeletal Diseases • Orthopedics • Osteoporosis • Rheumatology

Delayed Diagnosis of Hypophosphatasia in a 91-year-old: An Opportunity to Improve Screening (ENDO 2025) - "His low BMD had been treated with six 5-mg doses of zoledronate (ZOL) from 2010 to 2023 and alendronate prior to 2010...Additional ZOL was held and he was evaluated for asfotase alfa... HPP may be overlooked particularly in older adults with low BMD and low ALP on long-term bisphosphonate therapy as illustrated in this case. Our patient's low ALP level was presumed secondary to longstanding suppression of bone turnover from many years of bisphosphonate exposure. Although bisphosphonates can increase risk of atypical femur fractures in HPP, our patient had no such complications."

CNS Disorders • Depression • Musculoskeletal Diseases • Orthopedics • Otorhinolaryngology • Psychiatry • Rheumatology • ALPL

Applying the Hypophosphatasia Diagnostic Criteria in a Patient Cohort at the Penn Bone Center (ENDO 2025) - "Six patients within the cohort had previous or current treatment with asfotase alfa, and FDA-approved enzyme replacement therapy used in adult patients if one of the presenting symptoms was before age 18 years...1 Khan AA, et al. Hypophosphatasia diagnosis: current state of the art and proposed diagnostic criteria for children and adults."

Clinical • Genetic Disorders • Hematological Disorders • Metabolic Disorders • Musculoskeletal Diseases • Musculoskeletal Pain • Nephrology • Orthopedics • Pain • Rheumatology

Mobility and Quality of Life in Children with Paediatric-Onset Hypophosphatasia Treated with Asfotase Alfa: Results from UK Managed Access Agreement. (PubMed, Adv Ther) - "This analysis confirmed the clinical benefit of asfotase alfa in children with HPP. Asfotase alfa was well tolerated, with no new safety signals identified."

HEOR • Journal • Orthopedics • Pain • Pediatrics

Phenotypic and Genotypic Spectrum of Indian Patients with Hypophosphatasia. (PubMed, Indian J Endocrinol Metab) - "Case 1 received asfotase alfa with remarkable improvement in growth...In the largest case series of hypophosphatasia from India, we report five cases of hypophosphatasia with two novel variants. Our study emphasizes the need to increase awareness regarding the disease to improve its early diagnosis and also, the need to form strategies to reduce the challenges in obtaining enzyme replacement therapy for hypophosphatasia in India."

Journal • Endocrine Disorders • Metabolic Disorders • Musculoskeletal Diseases • Musculoskeletal Pain • Orthopedics • Pain • Rare Diseases • ALPL

Markedly discordant hypophosphatasia in a young girl. (PubMed, Bone) - "Hypercalcemia, unresponsive to bone antiresorptive drugs, corrected promptly with asfotase alfa TNSALP supplementation therapy. Her markedly discordant findings highlight genotype/phenotype plasticity for pediatric HPP, and her clinical course importance for early diagnosis."

Journal • Chronic Kidney Disease • CNS Disorders • Endocrine Disorders • Metabolic Disorders • Nephrology • Oncology • Ophthalmology • Orthopedics • Pediatrics • Renal Disease • Transplantation • ALPL

Hypophosphatasia (HPP) Patient & Caregiver Disease Burden, Quality of Life & Treatment Experience: A Mixed Methods Study Concept (ISPOR 2025) - "A mix of caregivers of patients from different age, severity levels, asfotase alfa treatment status and country income levels (and correspondingly healthcare systems) will be targeted... To the best of our knowledge, this is the first study measuring HPP caregiver quality of life. It is expected to contribute to better understanding of the wider disease impact beyond patients and to help decision making with regards to resource allocation for treatments that reduce the burden of HPP patients and, correspondingly, their caregivers."

Clinical • HEOR • Genetic Disorders • Musculoskeletal Diseases

A Novel Non-Viral DNA Gene Therapy Ameliorates Disease in a Mouse Model of Hypophosphatasia (ASGCT 2025) - "Currently, the standard-of-care is enzyme replacement therapy with asfotase alfa (STRENSIQ®)...These data provide proof-of-concept for HALO as a viable and durable non-viral DNA platform for the next generation treatment for HPP. Disease Focus of Abstract:Inborn Errors in Metabolism"

Gene therapy • Preclinical • CNS Disorders • Epilepsy • Gene Therapies • Immunology • Musculoskeletal Diseases • Musculoskeletal Pain • Pain • Respiratory Diseases

Lentivirus-based Hematopoietic Stem/Progenitor Cell Therapy Provides Safe and Long-term Treatment in Hypophosphatasia Mouse Model (ASGCT 2025) - "Currently, enzyme replacement therapy with asfotase alfa (STRENSIQ®) is the only FDA-approved treatment for HPP, though it is only approved for individuals with severe forms of the condition...Our study provides critical insights into treating metabolic bone disorders with an autologous HSPC-based gene therapy and demonstrates that this approach is a potential safe and one-time treatment for HPP. Disease Focus of Abstract:Musculo-Skeletal Disorders"

Preclinical • CNS Disorders • Epilepsy • Gene Therapies • Metabolic Disorders • Musculoskeletal Diseases • Orthopedics • ALPL • ITGAX • PTPRC

Four patients with hypercalcemia and low parathyroid hormone due to different underlying genetic diseases (ESPE-ESE 2025) - "Unique, Diagnosis and Specific Age (months) informative Genetic results pathophysiology treatment parameter idiopathic infantile TmP/GFR#: WES*: two hypercalcaemia compound 2.7 mg/dL type 2 heterozygous pathogenic (OMIM 616963) Case 1 (N 4-8) transient variants in 1 impaired renal phosphate (male) 1,25- SLC34A1 gene, proximal substitution dihydroxyvitamin c.1223T>A, p. D3 275 ng/mL (Val408Glu) and tubular sodium- c.1425_1426del, p. (N 25-154) phosphate (Cys476Serfs*128) cotransporter Unique, Diagnosis and Specific Age (months) informative Genetic results pathophysiology treatment parameter idiopathic infantile 25- hypercalcaemia hydroxyvitamin D3 84.5 ng/mL WES*: type 1 homozygous Case 2 (N 6.3-46.4) (OMIM 143880) pathogenic variant avoiding vitamin 6 (male) 1,25- in CYP24A1 gene, reduced D intake dihydroxyvitamin c.1186C>T p. degradation of D3 186 ng/mL (Arg396Trp) 1,25- dihydroxyvitamin (N 25-154) D3 25- FISH analysis: Williams-Beuren hydroxyvitamin syndrome..."

Clinical • Late-breaking abstract • Cardiovascular • Endocrine Disorders • Genetic Disorders • Hypoparathyroidism • Metabolic Disorders • Nephrology • Pulmonary Arterial Hypertension • CYP24A1

Suspected growth hormone deficiency as a mask of hypophosphatasia in a male patient with verified compound heterozygous variant in ALPL gene (ESPE-ESE 2025) - "The patient’s sister age 14 (height 146cm (SDS: -2.2), weight 41 kg) was diagnosed with primary hypothyroidism at the age of 6, since then she has taken Levothyroxine. this clinical case emphasizes a compound heterozygous variant in the ALPL gene as a plausible cause of short-statue. It is not clear if treatment with asfotase alfa would have improved this patient’s height if it were given at a younger age."

Clinical • Endocrine Disorders • Genetic Disorders • Growth Hormone Deficiency • Metabolic Disorders • Musculoskeletal Diseases • Nephrology • Orthopedics • Pain • ALPL

Design of 3 Multicenter, Phase 3, Randomized Trials to Evaluate Efficacy and Safety of the Enzyme Replacement Therapy Efzimfotase Alfa in Patients With Hypophosphatasia (HICKORY, MULBERRY, CHESTNUT) (ESPE-ESE 2025) - P3 | "Introduction: Hypophosphatasia (HPP) is a rare inherited, metabolic disease caused by deficient tissue- nonspecific alkaline phosphatase (ALP) activity and characterized by skeletal and nonskeletal manifestations, including rickets/osteomalacia, fractures/pseudofractures, muscle weakness, and pain, which significantly impact quality of life. Treatment-naive patients have no prior exposure to asfotase alfa. BOT-2, Bruininks Oseretsky Test of Motor Proficiency, Second Edition; LEFS, Lower Extremity Functional Scale; PDMS-3, Peabody Developmental Motor Scales, Third Edition; RGI-C, Radiographic Global Impression of Change; RSS, Rickets Severity Scale; TEAE, treatment-emergent adverse event; TUG, Timed Up-and-Go."

Clinical • P3 data • Metabolic Disorders • Musculoskeletal Diseases • Orthopedics • Pain

Clinical Features of Pediatric Hypophosphatasia and Eight-year Outcomes of Enzyme Replacement Therapy in Korea (ESPE-ESE 2025) - "Enzyme replacement therapy (ERT) with human recombinant tissue-nonspecific ALP (asfotase alfa) became available in Korea since 2016...In particular, patients with perinatal lethal and infantile HPP should receive prompt treatment to avoid premature mortality and improve long-term prognosis. Keywords: alkaline phosphatase, ALPL, bone, enzyme replacement therapy, hypophosphatasia"

Clinical • Genetic Disorders • Pain • Pediatrics

Patient-Reported Outcomes and Quality of Life in Children and Adults With HPP Treated With Asfotase Alfa (ESPE-ESE 2025) - "Pain in adults and QoL in children with HPP significantly improved following asfotase alfa treatment. ** Table. Outcome Baseline 6 Months 12 Months 24 Months BPI-SF pain 61 49 41 28 severity, n Mean (SD) 5.2 (1.9) 4.5* (2.2) 4.0* (2.1) 3.9* (1.7) Change from -0.8 -1.1 -0.9 baseline, mean (95% CI) (-1.2, -0.3) (-1.6, -0.6) (-1.5, -0.3) BPI-SF pain 61 50 40 28 interference, n Mean (SD) 5.5 (2.6) 4.6* (2.8) 4.3* (2.9) 3.7* (2.4) Outcome Baseline 6 Months 12 Months 24 Months Change from -0.9 -1.3 -1.1 baseline, mean (95% CI) (-1.5, -0.3) (-2.0, -0.6) (-1.9, -0.2) SF-36v2 Physical 56 47 36 21 Component Summary, n Mean (SD) 34.7 (10.2) 36.8 (9.7) 36.9* (8.6) 40.6 (10.6) Change from 2.2 4.6 3.4 baseline, mean (95% CI) (-1.2, 5.5) (1.8, 7.4) (-4.1, 10.9) SF-36v2 Mental 56 47 36 21 Component Summary, n Mean (SD) 39.4 (12.5) 41.9 (12.9) 45.7* (10.4) 47.5 (9.3) Change from 2.1 6.1 4.3 baseline, mean (95% CI) (-1.6, 5.8) (2.2, 9.9) (-1.9, 10.5) PedsQL Total, 26 22 18 13 n Mean (SD)..."

Clinical • HEOR • Patient reported outcomes • Pain • Pediatrics • Rare Diseases

Recent advances in the diagnosis and management of Hypophosphatasia (ESPE-ESE 2025) - "Asfotase alfa as first-in-class enzyme replacement therapy (ERT) for HPP was shown to improve survival, rickets, and functional outcomes in severely affected children. However, we need to know more the effects of the enzyme replacement therapy on emerging manifestations of the disease. The understanding of the pathophysiology behind the diverse clinical manifestations of HPP is instrumental for improving the diagnostic process, working on novel means to substitute enzyme activity, and developing an integrative care of the HPP patient."

Fatigue • Gastrointestinal Disorder • Metabolic Disorders • Musculoskeletal Diseases • Musculoskeletal Pain • Pain • Psychiatry • ALPL

Severe Hypercalcemia Associated With Perinatal Hypophosphatasia While Receiving Enzyme Replacement Therapy. (PubMed, JCEM Case Rep) - "Hypercalcemia is more common in the perinatal and infantile forms and may be mitigated or prevented with enzyme replacement therapy asfotase alfa (AA)...This case underscores the significance of vigilant monitoring of calcium levels and dietary intake in infants diagnosed with HPP. While calcitonin is typically not considered as a sustained treatment for hypercalcemia, the present case illustrates the efficacy of adjunct calcitonin therapy, in conjunction with restricted calcium intake and maximum AA dosing, in managing severe hypercalcemia in an infant with perinatal HPP."

Journal • Endocrine Disorders • Metabolic Disorders • ALPL

HICKORY: Phase 3 Study of ALXN1850 Versus Placebo in Adolescent and Adult Participants With HPP Who Have Not Previously Been Treated With Asfotase Alfa (clinicaltrials.gov) - P3 | N=124 | Active, not recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Trial completion date: Mar 2028 ➔ May 2029

Trial completion date • ALPL

Effects of asfotase alfa on fracture healing of adult patient with hypophosphatasia and literature review. (PubMed, Orphanet J Rare Dis) - "Adult HPP patients mainly present with recurrent or poorly healing fractures, bone pain, and early loss of teeth. AA replacement therapy can effectively promote fracture healing, relieve bone pain, and enhance mobility."

Journal • Review • Genetic Disorders • Musculoskeletal Diseases • Musculoskeletal Pain • Orthopedics • Pain • ALPL

Mobility and Quality of Life in Adults with Paediatric-Onset Hypophosphatasia Treated with Asfotase Alfa: Results from UK Managed Access Agreement. (PubMed, Adv Ther) - "Asfotase alfa treatment improved mobility, physical function, pain, and HRQoL and was well tolerated. These data show the benefit of asfotase alfa in adults with paediatric-onset HPP."

HEOR • Journal • Musculoskeletal Diseases • Orthopedics • Pain • Pediatrics • Rare Diseases

Safety and efficacy of long term asfotase alfa treatment in childhood hypophosphatasia. (PubMed, Ital J Pediatr) - "Pediatricians should consider HPP in children presenting with a suggestive clinical phenotype. Calcium-phosphorus metabolism, ALP, and vitamin B6 should always be investigated in suspected cases. Moreover, asfotase alfa represents a safe, well-tolerated, and effective drug in children with HPP."

Journal • Genetic Disorders • Pediatrics • ALPL