Strensiq (asfotase alfa) / AstraZeneca - LARVOL DELTA

Asfotase Alfa Hypersensitivity Reaction: Skin Testing and Induction of Tolerance Procedure (AAAAI 2026) - "Asfotase alfa is the only FDA approved pharmacological treatment for hypophosphatasia. This case report discusses skin prick testing (SPT), intradermal testing (IDT), and 5-step outpatient induction of drug tolerance for patients with history of immediate hypersensitivity reactions (I-HSR) to asfotase alfa."

Immunology

Phenotype and genotype of hypophosphatasia cases in Saudi Arabia: multi-center case cohort. (PubMed, Front Genet) - "We identified a high prevalence of consanguinity and family histories of HPP. Treatment with asfotase alfa was generally effective and safe."

Journal • CNS Disorders • Epilepsy • Genetic Disorders • Metabolic Disorders • Musculoskeletal Diseases • Nephrology • Orthopedics • Pediatrics • Respiratory Diseases • ALPL

Genetic Characterization and Clinical Manifestations in Adults with Hypophosphatasia in the United States (ACMG 2026) - "Asfotase alfa (AA), an enzyme replacement therapy, is the only FDA-approved treatment for perinatal/infantile- and juvenile-onset HPP... Clinical manifestations of HPP are remarkably consistent across patients with positive, negative, or VUS genetic results, confirming that disease burden does not depend on the GT category. Importantly, many HPP patients are diagnosed and treated for HPP despite negative or uncertain GT results. While early reports estimated GT sensitivity at 95%, our analysis suggests that this is an overestimate, indicating that a larger proportion of patients with HPP may have negative or VUS results."

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

Prenatal Diagnosis of Hypophosphatasia and Long-Term Outcomes Following Early Neonatal Asfotase Alfa Treatment (ACMG 2026) - "Serum ALP on a standard metabolic panel is a readily available, and affordable, first-line test in patients when evaluating for HPP. Further work is being done to identify the cause of craniosynostosis in this patient's older sibling, as they do not meet a clinical or molecular diagnosis for HPP at this time."

Atopic Dermatitis • CNS Disorders • Dermatology • Endocrine Disorders • Epilepsy • Immunology • Metabolic Disorders • Musculoskeletal Diseases • Ophthalmology • Orthopedics • Otorhinolaryngology • Pulmonary Disease • Respiratory Diseases • ALPL

Survival, Patient-Reported Outcomes, and Quality-of-Life in Children With HPP Treated With Asfotase Alfa Starting Before 2 Years of Age (ACMG 2026) - "High survival rates among infants (largely represented by early-onset HPP) treated with asfotase alfa were confirmed in this real-world study. Some patients had short stature at last assessment. Median QoL scores among children treated with asfotase alfa were below mean parent proxy-reported scores from healthy children (82.3 [Varni JW, et al."

Clinical • HEOR • Patient reported outcomes • CNS Disorders • Immunology • Infectious Disease • Pneumonia • Rare Diseases • Respiratory Diseases • Rheumatology

Efficacy and safety of Asfotase alfa in adults with hypophosphatasia: a systematic review of randomized and non-randomized studies (ACMG 2026) - "Current evidence suggests that asfotase alfa provides meaningful clinical benefits to adults with hypophosphatasia, including improved mobility, reduced pain, better quality of life, and favorable biochemical responses, with an acceptable safety profile. However, existing studies are limited by small sample sizes and predominantly non-randomized designs. Larger, well-controlled trials focused specifically on adult populations are required to confirm long-term efficacy and safety."

Clinical • Review • Musculoskeletal Diseases • Musculoskeletal Pain • Orthopedics • ALPL

Hypophosphatasia in children: From low alkaline phosphatase activity to diagnosis, genetic testing, and treatment options. A narrative review. (PubMed, Adv Clin Exp Med) - "Asfotase alfa, a recombinant human TNSALP enzyme replacement therapy, is now available for the treatment of HPP. The article provides an up-to-date overview of clinical, biochemical and molecular features of HPP. Treatment strategy in HPP was also described."

Journal • Review • Metabolic Disorders • Musculoskeletal Diseases • Orthopedics • ALPL

Change in fracture rate and healthcare resource utilization among patients with hypophosphatasia following initiation of asfotase alfa: a retrospective US claims database analysis. (PubMed, JBMR Plus) - "At baseline, 38.2% of patients were continuously using opioids and 21.8% were using high-dose opioids. Asfotase alfa initiation was associated with a statistically significant reduction in the proportion of patients experiencing fractures and fragility fracture rates, underscoring its potential therapeutic benefits."

HEOR • Journal • Retrospective data • Musculoskeletal Diseases • Orthopedics • Pain

Atypical Fracture From Bisphosphonate Use in Hypophosphatasia With Improved Bone Response to Teriparatide Therapy. (PubMed, JCEM Case Rep) - "We present the case of a middle-aged woman initially misdiagnosed with rickets and later as osteogenesis imperfecta and treated with zoledronate, after which she developed atypical femoral fractures. This case underscores that persistently low alkaline phosphatase with fragility or atypical fractures should prompt evaluation for hypophosphatasia and that antiresorptives (eg, bisphosphonates) may precipitate atypical fractures in this condition and should be avoided. Disease-specific therapy is enzyme replacement with asfotase alfa; anabolic therapy may improve bone mineral density in selected adults when asfotase alfa is unavailable."

Journal • Genetic Disorders • Musculoskeletal Diseases • Orthopedics

RESTORE: Mitigate Immune-Mediated Loss of Therapeutic Response to Asfotase Alfa (STRENSIQ®) for Hypophosphatasia (clinicaltrials.gov) - P4 | N=0 | Withdrawn | Sponsor: Alexion Pharmaceuticals, Inc. | Not yet recruiting ➔ Withdrawn

Trial withdrawal

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