STRENSIQ gets straight to the source of hypophosphatasia (HPP)1
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  • STRENSIQ MOA
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    Dr Steven Petak and Dr Eric Rush share their experiences identifying HPP

    MOD of Hypophosphatasia
    How low alkaline phosphatase (ALP) can be damaging2
    • Alkaline phosphatase dephosphorylates inorganic pyrophosphate (PPi) to release inorganic phosphate (Pi)
      • Pi then combines with calcium to form hydroxyapatite crystal, the foundation of bone formation
    • Alkaline phosphatase also dephosphorylates pyridoxal 5’-phosphate (PLP, the active form of vitamin B6) into pyridoxal, allowing it to cross the blood-brain barrier into the central nervous system (CNS) where it is regenerated into PLP
      • PLP is required for the metabolism of neurotransmitters
    In patients with hypophosphatasia, a loss-of-function mutation on the ALPL gene causes deficient alkaline phosphatase, resulting in low alkaline phosphatase activity.2-8

    When alkaline phosphatase activity is low, PPi, PLP, and calcium accumulate, contributing to complications throughout the body.
    • Excess PPi prevents the formation of hydroxyapatite crystal needed for bone mineralization

    • Excess calcium may cause various renal complications like hypercalcemia, nephrocalcinosis, and pseudogout
    • Excess PLP results in deficient vitamin B6 in the CNS, which can cause some neurologic symptoms (eg, seizures in infants)

    • Phosphoethanolamine (PEA) levels are also elevated in patients with hypophosphatasia. To date, the effects of PEA are not fully understood
    Dr Steven Petak and Dr Eric Rush discuss how STRENSIQ works

    MOA of STRENSIQ
    Only STRENSIQ replaces the deficient alkaline phosphatase enzyme for patients with HPP1

    Replacing alkaline phosphatase enables bone mineralization and reduces levels of substrates1,9
    • STRENSIQ cleaves Pi from PPi so Pi can combine with calcium to form hydroxyapatite crystal, the foundation of strong bones
    • STRENSIQ reduces elevated levels of systemic PPi and PLP (the active form of vitamin B6)
      • Reductions in plasma PPi and PLP did not correlate with clinical outcomes
      • The effect of STRENSIQ on PEA was not measured in clinical trials

    Without STRENSIQ deficient alkaline phosphatase activity and bone mineralization will not improve2,10-13
    Clinical data
    STRENSIQ. Package Insert. Alexion Pharmaceuticals, Inc. Rockman-Greenberg C. Hypophosphatasia. Pediatr Endocrinol Rev. 2013;10(suppl 2):380-388.  Taketani T. Neurological symptoms of hypophosphatasia. In: Fonta C, Negyessy L (eds). Neuronal Tissue-Nonspecific Alkaline Phosphatase (TNAP). Springer; 2015:309-322.  Surtees E, Mills P, Clayton P. Inborn errors affecting vitamin B6 metabolism. Future Neurol. 2006;1(5):615-620.  Bianchi ML, Bishop NJ, Guañabens N, et al; Rare Bone Disease Action Group of the European Calcified Tissue Society. Hypophosphatasia in adolescents and adults: overview of diagnosis and treatment. Osteoporos Int. 2020;31(8):1445-1460.  Conti F, Ciullini L, Pugliese G. Hypophosphatasia: clinical manifestation and burden of disease in adult patients. Clin Cases Miner Bone Metab. 2017;14(2):230-234.  Salles JP. Hypophosphatasia: biological and clinical aspects, avenues for therapy. Clin Biochem Rev. 2020;41(1):13-27.  Colazo JM, Hu JR, Dahir KM, et al. Neurological symptoms in hypophosphatasia. Osteoporos Int. 2019;30(2):469-480.  Orimo H. The mechanism of mineralization and the role of alkaline phosphatase in health and disease. J Nippon Med Sch. 2010;77(1):4-12.  Whyte MP, Leung E, Wilcox WR, et al. Natural history of perinatal and infantile hypophosphatasia: a retrospective study. J Pediatr. 2019;209:116–124.e4.  Szabo SM, Tomazos IC, Petryk A, et al. Frequency and age at occurrence of clinical manifestations of disease in patients with hypophosphatasia: a systematic literature review. Orphanet J Rare Dis. 2019;14(1):85.  Weber TJ, Sawyer EK, Moseley S, Odrljin T, Kishnani PS. Burden of disease in adult patients with hypophosphatasia: results from two patient-reported surveys. Metabolism. 2016;65(10):1522-1530.  Rush ET, Moseley S, Petryk A. Burden of disease in pediatric patients with hypophosphatasia: results from the HPP Impact Patient Survey and the HPP Outcomes Study Telephone interview. Orphanet J Rare Dis. 2019;14(1):201.
    WARNING: HYPERSENSITIVITY REACTIONS INCLUDING ANAPHYLAXIS
    Patients treated with enzyme replacement therapies have experienced life-threatening hypersensitivity reactions, including anaphylaxis. Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy.

    Initiate STRENSIQ under the supervision of a healthcare provider with appropriate medical monitoring and support measures. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue STRENSIQ and immediately initiate appropriate medical treatment, including use of epinephrine. Inform patients of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis and to seek immediate medical care should symptoms occur [see Warnings and Precautions (5.1)].
    • Life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in STRENSIQ-treated patients. Signs and symptoms consistent with anaphylaxis included difficulty breathing, choking sensation, nausea, periorbital edema, and dizziness. These reactions have occurred within minutes after subcutaneous administration of STRENSIQ and have been observed more than 1 year after treatment initiation. Other hypersensitivity reactions have also been reported in STRENSIQ-treated patients, including vomiting, fever, headache, flushing, irritability, chills, erythema, rash, pruritus, and oral hypoesthesia. Consider the risks and benefits of re-administering STRENSIQ following a severe reaction. If the decision is made to re-administer, monitor patients for a reoccurrence of signs and symptoms of a severe hypersensitivity reaction.

    • Lipodystrophy: Localized lipodystrophy, including lipoatrophy and lipohypertrophy has been reported at injection sites after several months in patients treated with STRENSIQ in clinical trials. Advise patients to follow proper injection technique and to rotate injection sites.

    • Ectopic Calcifications: Patients with HPP are at increased risk for developing ectopic calcifications. Events of ectopic calcification, including ophthalmic (conjunctival and corneal) and renal (nephrocalcinosis, nephrolithiasis), have been reported in the clinical trial experience with STRENSIQ. There was insufficient information to determine whether the reported events were consistent with the disease or due to STRENSIQ. No visual changes or changes in renal function were reported resulting from the occurrence of ectopic calcifications.

      Ophthalmology examinations and renal ultrasounds are recommended at baseline and periodically during treatment with STRENSIQ to monitor for signs and symptoms of ophthalmic and renal ectopic calcifications and for changes in vision or renal function.

    • Possible Immune-Mediated Clinical Effects: In clinical trials, most STRENSIQ-treated patients developed anti-asfotase alfa antibodies and neutralizing antibodies which resulted in reduced systemic exposure of asfotase alfa. In postmarketing reports, some STRENSIQ-treated patients with initial therapeutic response subsequently developed recurrence and worsening in disease-associated laboratory and radiographic biomarkers (some in association with neutralizing antibodies) suggesting possible immune-mediated effects on STRENSIQ’s pharmacologic action resulting in disease progression. The effect of anti-asfotase alfa antibody formation on the long-term efficacy of STRENSIQ is unknown. There are no marketed anti-asfotase alfa antibody tests. If patients experience progression of HPP symptoms or worsening of disease-associated laboratory and imaging biomarkers after a period of initial therapeutic response to STRENSIQ, consider obtaining anti-asfotase alfa antibody testing by contacting STRENSIQ Medical Information at Alexion at 1-888-765-4747 or by email at medinfo@alexion.com. Close clinical follow up is recommended.
    In clinical trials, the most common adverse reactions (≥ 10%) reported were injection site reactions (63%), lipodystrophy (28%), ectopic calcifications (14%), and hypersensitivity reactions (12%). Possible immune-mediated clinical effects have been identified during post-approval use of STRENSIQ.
     
    Drug Interference with Laboratory Tests:

    • Laboratory tests utilizing alkaline phosphatase (ALP) as a detection reagent could result in erroneous test results for patients receiving treatment due to the presence of asfotase alfa in clinical laboratory samples. Inform laboratory personnel that the patient is being treated with STRENSIQ and discuss use of an alternative testing platform which does not utilize an ALP-conjugated test system.
    • Elevated serum ALP measurements detected through clinical laboratory testing are expected in patients receiving STRENSIQ due to circulating concentrations of asfotase alfa. Do not rely on serum ALP measurements for clinical decision making in patients treated with STRENSIQ.
    • Pregnancy & Lactation: There are no available data on STRENSIQ use in pregnant women, the presence of STRENSIQ in human milk, or the effects on the breastfed infant or on milk production, to inform a drug associated risk.
    To report SUSPECTED ADVERSE REACTIONS, contact Alexion Pharmaceuticals, Inc. at 1-844-259-6783 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

    STRENSIQ® (asfotase alfa) is indicated for the treatment of patients with perinatal/infantile- and juvenile-onset hypophosphatasia (HPP).

    Please see full Prescribing Information for STRENSIQ (asfotase alfa), including Boxed WARNING regarding hypersensitivity reactions including anaphylaxis.