Data from Phase 2 Study Presented at the
"HPP is a devastating disease that affects people of all ages, and patients can experience debilitating systemic complications that can be life-threatening," said study author
About HPP and Asfotase Alfa
HPP is an ultra-rare, inherited, life-threatening metabolic disease affecting patients of all ages for which there are currently no approved or effective treatment options. Patients with HPP have an inborn error of metabolism resulting from a genetic, life-long deficiency of the enzyme known as TNSALP. This lack of TNSALP leads to accumulation of substrates, causing abnormalities in calcium and phosphate regulation, which can result in progressive damage to multiple vital organs, destruction and deformity of bones, profound muscle weakness, impaired renal function and respiratory failure.1,2,3,4 In addition, infants with HPP may experience seizures, and approximately 50 percent of infants with severe disease do not survive past one year of age.1,5
Asfotase alfa is an investigational, highly innovative, first-in-class targeted enzyme replacement therapy designed to address the underlying cause of HPP by targeting replacement of the missing enzyme to the necessary body tissues. Asfotase alfa is designed to normalize the genetically defective metabolic process and prevent or reverse the severe and life-threatening complications of life-long uncontrolled mineral metabolism in patients with HPP.
About the Study
The open-label, multicenter, randomized, controlled, Phase 2 study enrolled 19 adolescent and adult patients with HPP. Patients in the study were between the ages of 14 and 68 years old, with an average age of 42 years. Thirteen patients in the study received daily asfotase alfa subcutaneous injections in one of two dose cohorts (2.1 mg/kg/week (N=7) or 3.5 mg/kg/week (N=6)), while six patients received no treatment. The primary objective of the study was to evaluate the effect of asfotase alfa on TNSALP substrate levels and secondary objectives included assessments of changes in 6MWT following 24 weeks of treatment.
The study achieved its primary endpoint, as treatment with asfotase alfa was associated with statistically and clinically significant reductions in the two measured TNSALP substrates, PPi (inorganic pyrophosphate) and PLP (pyridoxal 5' phosphate). PPi has several functions, including the inhibition of mineralization. Asfotase alfa treatment was associated with a significant reduction in PPi at 24 weeks in the combined treatment groups compared to the untreated cohort (p=0.002). Asfotase alfa treatment was associated with a decrease in PPi from 5.5 μM (± 1.51) at baseline to 3.5 μM (± 0.49) at Week 24 in the lower dose cohort and from 5.0 μM (± 1.84) at baseline to 2.8 μM (± 1.44) in the higher dose cohort. Asfotase alfa treatment was also associated with significant reductions in PLP at 24 weeks in the combined treatment groups compared to the untreated cohort (p=0.009). Asfotase alfa treatment was associated with a decrease in PLP from 324 ng/mL (±254) at baseline to 69 ng/mL (± 80) at 24 weeks in the lower dose cohort group and from 603 ng/mL (± 660) to 38 ng/mL (± 45) in the higher dose cohort.
Functional capacity, as measured by the 6MWT, improved in patients treated with asfotase alfa. At baseline, patients had an average distance walked of 349 meters (range of 6-620 meters), with 10 of the 19 patients requiring assistive devices to complete the test. Patients treated with asfotase alfa had an average improvement of 26 meters walked, while the untreated patients had an average decrease from baseline of 14 meters walked at 24 weeks. In treated patients who had a baseline 6MWT between 25% and 75% of normal for their age (9 out of 13 patients), mean improvement in 6MWT at 24 weeks was 35 meters in the lower dose cohort (n=5) and 44 meters in the higher dose cohort (n=4).
The most common treatment-related adverse events observed in the study were injection site erythema, pain in extremities and arthralgia (joint pain). There were three serious adverse events in two of the 13 patients treated with asfotase alfa; all three were deemed to be unrelated to asfotase alfa. In addition, there were four serious adverse events in two of six patients in the no treatment cohort.
"Following the recent publication of strong data from our study of asfotase alfa treatment of infants with HPP, this study now indicates the positive impact that asfotase alfa may have on adult and adolescent patients suffering with HPP," said
About Alexion
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Safe Harbor Statement
This news release contains forward-looking statements, including statements related to potential medical benefits of 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, decisions of regulatory authorities regarding marketing approval or material limitations on the marketing of asfotase alfa for HPP, delays in arranging satisfactory manufacturing capabilities and establishing commercial infrastructure for asfotase alfa for HPP, the possibility that results of clinical trials are not predictive of safety and efficacy results of asfotase alfa in broader or different patient populations, the risk that third party payors (including governmental agencies) will not reimburse for the use of asfotase alfa (if approved) at acceptable rates or at all, the risk that estimates regarding the number of patients with asfotase alfa and observations regarding the natural history of patients with asfotase alfa are inaccurate, and a variety of other risks set forth from time to time in Alexion's filings with the
References
1. Whyte MP. Hypophosphatasia. In: Glorieux FH, Jueppner H, Pettifor J, eds. Pediatric bone: biology and diseases. 3rd ed.
2. Seshia SS, Derbyshire G, Haworth JC, Hoogstraten J. Myopathy with Hypophosphatasia. Arch Dis Child. 1990. 65(1):130-1.
3. Whyte MP. Hypophosphatasia: Nature's Window on Alkaline Phosphatase Function in Humans, in Principles of Bone Biology, 3rd Ed. Part II: Molecular Mechanisms of Metabolic Bone Disease, Chapter 73: 1573-1598.
4. Silver MM, Vilos GA, Milne KJ. Pulmonary Hypoplasia in Neonatal Hypophosphatasia. Pediatr Pathol. 1998. 8:483-493.
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