- Researchers also report improvements in physical function for up to four years as measured by 6-Minute Walk Test and elimination or reduction of use of ambulatory assistance devices in adolescents and adult patients with HPP treated with Strensiq -
Researchers also presented the following data:
- Clinically significant improvements in physical function were observed in children with HPP (ages 11-17 years at analysis) who were treated with Strensiq for up to 5 years (n=12).2
- New interim results indicating a reduction in two key tissue non-specific alkaline phosphatase (TNSALP) substrates that accumulate in HPP, as well as improvements in physical function in adolescent and adult patients with HPP (ages 13-66 years at study entry) treated with Strensiq, as measured by:3
- 6 Minute Walk Test (6MWT) (n=19).
- Reduction or elimination of ambulatory assistive devices during performance of the 6MWT by 2 years of treatment for all patients that required them at baseline (n=5).
"The study results presented at ENDO show clinically significant and sustained improvements across all key measures of pediatric-onset HPP, including bone healing, physical function and pain in patients who were treated with Strensiq," said
Strensiq is approved in
Improvements in Survival and Key Disease Parameters in Patients with Perinatal- or Infantile-Onset HPP Treated with Strensiq for Up to 3.5 Years1
In a poster preview session,
- Clinically significant improvements in skeletal manifestations of HPP at 6 months (p < 0.0001), the primary endpoint, that were sustained through 3.5 years, as measured by a median improvement of +2.3 in Radiographic Global Impression of Change (RGI-C) scores (7-point scale; -3=severe worsening; +3=near/complete healing; p < 0.01).
- A 67 percent reduction in the need for respiratory support among patients who required support during the study (including ventilation and supplemental oxygen).
- An overall survival rate of 90 percent at 3.8 years.
- Improvements in height Z-scores (a measure of patient growth) from baseline to 3.5 years of a median of +0.4 across patients.
"Pediatric patients with HPP face significant challenges related to growth and respiratory function, as well as a high risk of death," said
The most common adverse drug reactions (ADR) were mild-to-moderate injection-site reactions.
Reduction in Pain and Improved Function and Activities of Daily Living in Children with HPP Treated with Strensiq for 5 years2
In an oral session,
- Rapid and sustained improvements in strength and agility, as measured by median changes from baseline in the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition (BOT-2) Strength subscale, and the BOT-2 Running Speed and Agility subscale. Median baseline scaled scores of 4 and 3 improved to median scaled scores of 15 and 13, respectively, at last assessment (p < 0.0001 for both). With these improvements, most patients reached the normal range for healthy peers by 6 months, which was sustained through 5 years.
- Significant and sustained decreases in disability through 5 years, as measured by median changes from baseline in the Pediatric Outcomes Data Collection Instrument (PODCI) Transfer and Basic Mobility subscale, the
PODCI Sports /Physical Functioning subscale, and the Child Health Assessment Questionnaire (CHAQ) Disability Index. Median baseline scores of 37, 20 and 1 improved to median scores of 52, 49 and 0, respectively at last assessment (p < 0.05 for all scores). - Significant decreases in pain, as measured by the PODCI Pain/Comfort subscale, a pain/comfort rating scale with higher scores representing better outcomes or health. The median baseline score of 39 increased to a median score of 56 at 5 years (p < 0.05), and was within normal range for health peers by 6 months and sustained for 5 years. Similar results were observed in the CHAQ scores.
The most common ADRs were injection-site reactions.
Biological Activity of Strensiq and Improved Physical Function in Adolescents and Adults with HPP Treated with Strensiq for up to 4 Years3
In an oral session,
In the initial phase of this study, patients were randomized to receive a control (n=6), 0.3 mg/kg/day of Strensiq (n=7), or 0.5 mg/kg/day of Strensiq (n=6) for 6 months. At 6 months, all 19 patients entered the extension phase of the study and were treated with 0.5 mg/kg/day of Strensiq, then changed to 1 mg/kg/day, 6 times a week, over the next 6 to 12 months. Data from both Strensiq dosage groups were pooled for the analysis.
- Statistically significant reductions in plasma pyridoxal 5' phosphate (PLP) levels from baseline compared to controls were observed at 6 months (p=0.0285), supporting the biological activity of Strensiq. Patients also experienced a decrease in inorganic pyrophosphate (PPi) at 6 months (p=0.0715), compared to controls. Within group decreases in both substrates were statistically significant for the treated patients (p < 0.0001). PLP and PPi are tissue non-specific alkaline phosphatase (TNSALP) substrates that accumulate in HPP and are key indicators of disease activity.
Additional descriptive data collected during the 4 years of the extension phase of the trial demonstrated:
- Sustained decreases in PLP and PPi.
- Physical function, as measured by the Six Minute Walk Test (6MWT), improved from a median of 76 percent of that predicted for healthy peers at baseline (n=15; below normal range) to a median of 85 percent predicted (within the normal range) by 6 months in patients treated with Strensiq (n=16). Results were sustained through four years of treatment.
- All 5 patients who required ambulatory assistive devices in the performance of the 6MWT at study baseline reduced (n=2) or eliminated (n=3) their need by 2 years with ongoing Strensiq treatment.
- Speed and agility, as measured by median change from baseline in the BOT-2 Running Speed and Agility subscale, improved from a median total score of 6.5 at baseline to a median total score of 12 at 6 months (n=13). Improvement was sustained at four years (n=8).
- Strength, as measured by median change from baseline in the BOT-2 Strength subscale, increased by 2 points at 6 months (n=14) and by 1 after 4 years of treatment.
The most common ADRs were mild to moderate injection-site reactions.
In a separate presentation at ENDO today, researchers will report preclinical findings on the effect of Strensiq on muscle strength in Akp2-/-mice, a model of HPP which mimics the muscle weakness observed in patients.4
About Hypophosphatasia (HPP)
HPP is a genetic, chronic, progressive, and life-threatening ultra-rare metabolic disease characterized by low alkaline phosphatase (ALP) activity and defective bone mineralization that can lead to destruction and deformity of bones and other skeletal abnormalities, as well as systemic complications such as profound muscle weakness, seizures, pain, and respiratory failure leading to premature death in infants.5-9
HPP is caused by mutations in the gene encoding an enzyme known as tissue non-specific alkaline phosphatase (TNSALP).5,6 The genetic deficiency in HPP can affect people of all ages.5 HPP is traditionally classified by the age of the patient at the onset of symptoms of the disease, with perinatal-, infantile- and juvenile-onset HPP defined by the onset of the first symptom prior to 18 years of age.
HPP can have devastating consequences for patients at any stage of life.5 In a natural history study, infants who had their first symptom of HPP within the first 6 months of life had high mortality, with an overall mortality rate of 73 percent at 5 years.11 In these patients, mortality is primarily due to respiratory failure.5,9,12 In patients surviving and those with juvenile-onset HPP, long-term clinical sequelae include recurrent and non-healing fractures, profound muscle weakness, debilitating pain and the requirement for ambulatory assistive devices such as wheelchairs, wheeled walkers and canes.5,8
About Strensiq® (asfotase alfa)
Strensiq® (asfotase alfa) is a highly innovative bone-targeted enzyme replacement therapy that treats the underlying cause of HPP by replacing the missing TNSALP enzyme. In clinical studies of patients with HPP who had their first symptom prior to the age of 18, treatment with Strensiq improved overall survival in infants, enhanced bone mineralization and improved height, weight and mobility.
Strensiq is approved in
IMPORTANT SAFETY INFORMATION
Hypersensitivity reactions have been reported in STRENSIQ-treated patients. In clinical trials, 1 out of 99 treated patients (1%) experienced signs and symptoms consistent with anaphylaxis.
Localized lipodystrophy, including lipoatrophy and lipohypertrophy, has been reported at injection sites after several months in patients treated with STRENSIQ.
Patients with HPP are at increased risk for developing ectopic calcifications. In clinical trials, 14 cases (14%) of ectopic calcification of the eye including the cornea and conjunctiva, and the kidneys (nephrocalcinosis) were reported. There was insufficient information to determine whether or not the reported events were consistent with the disease or due to STRENSIQ. No visual changes or changes in renal function were reported.
ADVERSE REACTIONS
The most common adverse reactions reported were injection site reactions, lipodystrophy, ectopic calcifications, and hypersensitivity reactions.
Please click here for the full Prescribing Information.
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Forward-Looking Statements
This news release contains forward-looking statements, including statements related to potential medical benefits of Strensiq® (asfotase alfa) for hypophosphatasia (HPP). Forward-looking statements are subject to factors that may cause Alexion's results and plans to differ from those expected, including, for example, risks and uncertainties of drug development, decisions of regulatory authorities regarding marketing approval or material limitations on the marketing of Strensiq for HPP, delays in arranging satisfactory manufacturing capabilities and establishing commercial infrastructure for Strensiq for HPP, the possibility that results of clinical trials are not predictive of safety and efficacy results of Strensiq in broader or different patient populations, the risk that estimates regarding the number of patients with Strensiq and observations regarding the natural history of patients with Strensiq are inaccurate, and a variety of other risks set forth from time to time in
References
1. Liese J, Hofmann C, Harmatz P, et al. Efficacy and Safety of Asfotase Alfa in Patients with Infantile Hypophosphatasia Treated for up to 3.5 Years: Results from a Phase II, Open-Label, Uncontrolled Study. Poster preview presented at the
2. Phillips D, Madson KL,
3. Kishnani P, Madson K, Whyte M, et. al. Biochemical and Physical Function Outcomes in Adolescents and Adults with Hypophosphatasia Treated with Asfotase Alfa for up to 4 Years: Interim Results from a Phase II Study. Oral presented at the
4. Marozsan A. Muscular Function in Akp2-/- Mice and Evaluation of the Effect of Asfotase Alfa on the Akp2-/- Phenotype. Oral presented at the
5.
6. Whyte MP. Hypophosphatasia: nature's window on alkaline phosphatase function in humans. In: Bilezikian JP, Raisz LG, Martin TJ, eds. Principles of Bone Biology. Vol 1. 3rd ed.
7. Whyte MP, Greenberg CR, Salman N, et al. Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med. 2012; 366(10):904-913.
8. Seshia SS, Derbyshire G, Haworth JC, Hoogstraten J. Myopathy with hypophosphatasia.
9.
10. REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of
11. Whyte MP, Leung E, Wilcox W, et al. Hypophosphatasia: a retrospective natural history study of the severe perinatal and infantile forms. Poster presented at the 2014
12. Whyte MP,
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