Strensiq (asfotase alfa) / AstraZeneca - LARVOL DELTA

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: Jul 2028 ➔ Mar 2028

Trial completion date • ALPL

Assessing the Value of the Enzyme Replacement Therapy for Hypophosphatasia (HPP): A Spanish Subanalysis of a Pan-European Multidisciplinary Multicriteria Decision Analysis (MCDA) (ISPOR-EU 2025) - "In the Spanish context, experts concluded that asfotase alfa offers superior value compared to the BSC for all patient subgroups (0.74). This value contribution is even much higher than the reported in other recently financed drugs for rare diseases, ranging from 0.44 to 0.63. This reinforces its status as a potentially transformative therapy for HPP, and will inform future decisions regarding access, reimbursement and policy in Spain."

Rare Diseases

Neonatal Multiple Bone Fractures: A Case Report of Hypophosphatasia. (PubMed, Case Rep Endocrinol) - "Consequently, she was treated with enzyme replacement therapy (ERT) using asfotase alfa. Our case emphasized the need for proper diagnosis of severe perinatal HPP to initiate life-saving ERT after delivery. Cooperation between obstetricians and clinical genetics teams is essential to avoid delayed or misdiagnosis."

Journal • CNS Disorders • Critical care • Endocrine Disorders • Epilepsy • Metabolic Disorders • Musculoskeletal Diseases • Obstetrics • Orthopedics • Pediatrics

Late diagnosis of childhood-onset hypophosphatasia in an adult with recurrent fractures: the impact of enzyme replacement therapy (SSIEM 2023) - "Enzyme replacement therapy with asfotase-alfa was started to enhance bone healing and to reduce the risk of bone fracturing in future... Rapid improvement of bone healing with consolidation of fractures as well as significant improvement of patient-reported QoL were observed in this patient soon after starting ERT, suggesting that ERT is effective even in late-diagnosed patients with clearly symptomatic childhood-onset HPP. Therefore, awareness of HPP in patients with suggestive clinical findings is important."

Clinical • Genetic Disorders • Musculoskeletal Diseases • Orthopedics

CRISPR/Cas9-based precision B cell gene engineering produces active tissue nonspecific alkaline phosphatase for the potential treatment of hypophosphatasia (ESGCT 2024) - "Currently, the only treatment for HPP is enzyme replacement therapy (ERT), asfotase alfa, requiring subcutaneous injections 3 to 6 times per week which is accompanied by injection site reactions including lipodystrophy...In summary, we demonstrated successful production of active ALP from our novel BCM platform. The potential therapeutic application of this unique biologic delivery system could afford a new treatment modality for HPP."

Genetic Disorders • Lipodystrophy • Metabolic Disorders

Targeted Alkaline Phosphatase Therapy Enhances Alveolar Bone Healing in X-Linked Hypophosphatemia in Mice. (PubMed, J Periodontal Res) - "TNAP enhanced socket healing in Hyp mice, overcoming inherent bone healing defects in XLH. These results provide new insights into bone healing with implications beyond alveolar bone in XLH."

Journal • Preclinical • Endocrine Disorders • Renal Disease • SPP1

Hypophosphatasia - Pathophysiological understanding, preclinical data looking beyond the skeleton, and upcoming treatments. (PubMed, J Bone Miner Res) - "Enzyme replacement therapy based on recombinant mineral-targeted alkaline phosphatase (asfotase alfa) has been approved multinationally since 2015 for the treatment of pediatric-onset HPP, remarkably increasing the lifespan, their skeletal condition and the quality of life of patients affected by the severe forms of HPP...A better understanding of the cells expressing TNAP physiologically, the metabolic pathways involved and the natural substrates of TNAP in each tissue will help design improved and/or alternative therapies to prevent/correct known or yet to be discovered non-skeletal manifestations of HPP. Figure 1 graphically lays out the topics discussed in this invited perspective article that follows the contents of the Louis V Avioli Memorial lecture delivered during the ASBMR 2025 annual meeting."

Journal • Preclinical • Gene Therapies • Genetic Disorders • Metabolic Disorders • Orthopedics • Pediatrics • ALPL

ENPP1 inhibition as a therapeutic approach for later-onset hypophosphatasia. (PubMed, J Bone Miner Res) - "Enzyme replacement with mineral-targeted TNAP (asfotase alfa) improves skeletal mineralization but the almost daily injections of this biologic can lead to injection site reactions and discontinuation of treatment...We tested if pharmacologically inhibiting ENPP1, the enzyme that generates PPi, could lower PPi concentrations and ameliorate soft bone disease in a mouse model of later-onset HPP. The results were efficacious and point to the potential usefulness of this strategy to treat HPP."

Journal • Orthopedics • ALPL • ENPP1

Adult Hypophosphatasia in a Middle-Aged Patient With Recurrent Fractures: Prevention of New Fractures With Asfotase Alfa. (PubMed, JCEM Case Rep) - "He therefore started enzyme replacement therapy with asfotase alfa. After 12 months of treatment with asfotase alfa, his motor function showed marked improvement and he experienced fewer falls and no new fragility fractures, although his chronic pain remained."

Journal • Musculoskeletal Diseases • Orthopedics • Pain • ALPL

Registry of Patients With Hypophosphatasia (clinicaltrials.gov) - P=N/A | N=1571 | Enrolling by invitation | Sponsor: Alexion Pharmaceuticals, Inc. | N=900 ➔ 1571

Enrollment change • ALPL

RESTORE: Mitigate Immune-Mediated Loss of Therapeutic Response to Asfotase Alfa (STRENSIQ®) for Hypophosphatasia (clinicaltrials.gov) - P4 | N=8 | Not yet recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Trial completion date: Feb 2029 ➔ Jul 2029 | Trial primary completion date: Feb 2029 ➔ Jul 2029

Trial completion date • Trial primary completion date

RESTORE: Mitigate Immune-Mediated Loss of Therapeutic Response to Asfotase Alfa (STRENSIQ®) for Hypophosphatasia (clinicaltrials.gov) - P4 | N=8 | Not yet recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Trial completion date: Jul 2029 ➔ Mar 2030 | Trial primary completion date: Jul 2029 ➔ Mar 2030

Trial completion date • Trial primary completion date

A Prospective Sub-Study of the Global Hypophosphatasia Registry (clinicaltrials.gov) - P=N/A | N=30 | Recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Trial completion date: Aug 2029 ➔ Jul 2028 | Trial primary completion date: Aug 2029 ➔ Jul 2028

Trial completion date • Trial primary completion date • ALPL

MULBERRY: Phase 3 Study of ALXN1850 in Treatment-Naïve Pediatric Participants With HPP (clinicaltrials.gov) - P3 | N=30 | Active, not recruiting | Sponsor: Alexion Pharmaceuticals, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Pediatrics • ALPL

Successful Treatment Of Delayed Stress Fracture Healing In A Child With Hypophosphatasia Using Asfotase Alfa (ASBMR 2025) - No abstract available

Clinical • Late-breaking abstract • Musculoskeletal Diseases • Orthopedics

Asfotase alfa treatment in a mouse model of later-onset HPP with comorbid chronic kidney disease (ASBMR 2025) - No abstract available

Preclinical • Chronic Kidney Disease • Nephrology • Renal Disease

Asfotase alfa treatment in a mouse model of later-onset HPP with comorbid chronic kidney disease (ASBMR 2025) - No abstract available

Preclinical • Chronic Kidney Disease • Nephrology • Renal Disease

Hypophosphatasia: A case report. (PubMed, World J Clin Cases) - "Recognizing HPP is crucial, as early diagnosis and treatment can significantly improve patient outcomes and prevent complications."

Journal • Endocrine Disorders • Metabolic Disorders • Musculoskeletal Diseases • Musculoskeletal Pain • Orthopedics • Osteoporosis • Pain • Rheumatology • ALPL

Key Learnings from Clinical Research and Real-World Evidence on Asfotase Alfa Effectiveness in Hypophosphatasia: 10 Years Post-Approval. (PubMed, Adv Ther) - "Further, asfotase alfa treatment has improved survival and respiratory outcomes, skeletal outcomes, physical and motor function, pain, disability, and quality of life in patients with HPP. This evidence-based review aims to generate a foundation for improving the understanding of disease pathophysiology, hence enhancing the effectiveness of ERT in patients with HPP."

HEOR • Journal • Real-world evidence • Review • Musculoskeletal Diseases • Musculoskeletal Pain • Orthopedics • Pain • Pediatrics

Improvements in Bone Disorganization and Pseudo-Fracture Healing in Hypophosphatasia Following Asfotase Alfa Therapy May Be Detectable by the ALIGNOGRAM Before Changes in Bone Radiography or Scintigraphy. (PubMed, Case Rep Endocrinol) - "We show that improvements in bone disorganization were detectable as early as 3 months after treatment initiation-before changes on X-ray or bone scintigraphy were detected. As such, assessment of the degree of bone disorganization could serve as an early indicator of treatment efficacy in HPP."

Journal • Genetic Disorders • Musculoskeletal Diseases • Orthopedics

Hypophosphatasia in childhood: Diagnosis to management. (PubMed, Osteoporos Sarcopenia) - "However, the introduction of asfotase alfa, a bone-targeted recombinant TNSALP, has improved the prognosis. Early diagnosis of HPP is essential for timely initiation of enzyme replacement therapy (ERT). This review aims to provide an updated current knowledge on the genetic basis, pathophysiology, epidemiology, clinical classification, diagnosis, and management of HPP, with particular emphasis on ERT and emerging diagnostic approaches."

Journal • Review • Orthopedics • Renal Disease • ALPL

Unspoken Signs: A Rare Case Of Hypophosphatasia In An Adult With Down Syndrome (ENDO 2025) - "She was started on asfotase alfa (Strensiq) at 2 mg/kg three times weekly with positive tolerance... This case exemplifies the importance of maintaining a high index of suspicion for HPP in adults with nonspecific musculoskeletal symptoms and cognitive challenges. Recognizing biochemical red flags and utilizing confirmatory genetic testing is vital to initiating timely enzyme replacement therapy. Increased awareness is essential to improve outcomes in this underdiagnosed population."

Clinical • Late-breaking abstract • Alzheimer's Disease • Cardiovascular • Chronic Kidney Disease • CNS Disorders • Cognitive Disorders • Developmental Disorders • Endocrine Disorders • Fatigue • Fibromyalgia • Genetic Disorders • Hypotension • Movement Disorders • Musculoskeletal Diseases • Musculoskeletal Pain • Nephrology • Orthopedics • Osteoporosis • Pain • Renal Disease • Rheumatology • 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

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