Data from Phase 2 Extension Studies Presented at ESPE Meeting
DUBLIN, Ireland I September 19, 2014 I Alexion Pharmaceuticals today announced that researchers presented data from the open-label extension phases of two Phase 2 studies of asfotase alfa, an investigational enzyme replacement therapy, in paediatric patients with hypophosphatasia (HPP).1,2 In the ongoing studies, researchers observed sustained improvements in growth, strength, physical function, and other key measures in paediatric patients with HPP who were treated with asfotase alfa for up to three years. HPP is a genetic, chronic and progressive ultra-rare metabolic disease that can lead to ongoing damage to multiple vital organs, destruction and deformity of bones, and premature death.3-7 Data were presented today at the 53rd Annual European Society for Paediatric Endocrinology (ESPE) Meeting in Dublin, Ireland, following a presentation of similar data earlier this month at the American Society for Bone and Mineral Research (ASBMR) 2014 Annual Meeting.8,9
“We also observed important improvements in gross motor, fine motor, and cognitive skills throughout the treatment period. These findings are meaningful given the developmental challenges and failure to thrive often associated with severe HPP.”
“Paediatric patients with severe HPP face significant challenges related to growth, development and physical function,” said Martin Mackay, Ph.D., Executive Vice President and Global Head of R&D at Alexion. “Researchers reported substantial improvements in developmental milestones such as height, strength, agility and motor function over the course of three years of treatment with asfotase alfa.”
Asfotase Alfa in Infants and Young Children with HPP: Extension Study Results (Abstract FC2.1)
In an oral presentation today, researchers reported that severely affected infants and young children with HPP (aged ≤3 years at study entry, N=11) treated with asfotase alfa for up to three years experienced sustained improvements in growth and physical function.1 Findings were from the extension phase of a multinational, open-label Phase 2 study of asfotase alfa treatment in severely affected infants with HPP.
In the data presented today at ESPE, investigators observed that patients treated with asfotase alfa had improvement in weight as measured by Z-score. Median weight Z-score was -3.8 at baseline; over the course of treatment, median change from baseline in Z-score steadily increased from +0.6 at one year to +2.6 at three years. Additionally, as reported at ASBMR, improvement in growth as measured by height/length Z-score was also observed in treated patients. Median height/length Z-score was -3.7 at baseline, indicating marked delay relative to peers; over the course of treatment, median change from baseline in Z-score steadily increased from +1.2 at one year to +2.3 at three years. Patients treated with asfotase alfa also had gains in gross motor function, fine motor function and cognitive function.
“We are pleased to report steady improvements in growth and weight for infants and young children with life-threatening HPP who were treated with asfotase alfa for up to three years,” said lead author Professor Nick Bishop, Professor of Paediatric Bone Disease, the Mellanby Centre for Bone Research, University of Sheffield. “We also observed important improvements in gross motor, fine motor, and cognitive skills throughout the treatment period. These findings are meaningful given the developmental challenges and failure to thrive often associated with severe HPP.”
Asfotase alfa was generally well-tolerated in the extension study. The most common adverse events (AEs) were pyrexia (7/10), mild or moderate injection-site reactions (6/10) and upper respiratory tract infection (6/10). Three serious AEs were reported as possibly related to treatment: craniosynostosis, conductive deafness and mild chronic hepatitis. Both craniosynostosis and conductive deafness were reported in the same patient, and are findings previously described as associated with HPP. The report of hepatitis was in a patient taking a medication for asthma, which was discontinued; liver function tests were within normal limits at last assessment. Four patients tested positive for neutralizing antibodies, without apparent impact on treatment efficacy or safety.
Asfotase Alfa in Children with HPP: Extension Study Results (Abstract FC2.1)
In a separate oral presentation today, researchers reported that children with HPP (aged 5-12 at study entry, N=13) who were treated with asfotase alfa experienced significant gains in height and rapid and sustained improvements in strength, agility, and physical function.2 The data were from the extension phase of a multinational, open-label Phase 2 study of asfotase alfa treatment in HPP patients.
In the data presented at ESPE, researchers reported improvements in right hip abductor muscle strength over the course of treatment, from 48% predicted at baseline to 83% predicted at last assessment (p=0.001). Additionally, and as reported at ASBMR, improvement in growth, as measured by height Z-score, was observed in treated patients, from a median of -1.26 at baseline to a median of -0.72 at last assessment (p=0.0027). Improvements in strength and agility were also observed for treated patients as measured by the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition (BOT-2). BOT-2 composite standardized score improved from a median of 28 at baseline to a median of 50 at last assessment (p<0.0008), which is the mean score for normal, healthy peers.
“In the data presented at ESPE, we reported that children with HPP who received treatment with asfotase alfa had encouraging gains in height as well as rapid and sustained improvement in muscle strength and agility,” said lead author Katherine L. Madson, M.D., Ph.D., from the Center for Metabolic Bone Disease and Molecular Research at Shriners Hospitals for Children, St. Louis. “These children previously had difficulty walking and muscle weakness that limited their physical function, so the improvements seen in the study were meaningful for these patients and their families.”
Asfotase alfa was generally well-tolerated in the study. The most common AEs were mild or moderate injection site reactions. There were no deaths, serious AEs or withdrawals due to AEs over the three years of treatment in this study. Twelve patients tested positive for anti-asfotase antibodies, two of whom had neutralizing antibodies with no apparent effect on efficacy or safety.
About Hypophosphatasia (HPP)
HPP is a genetic, chronic and progressive ultra-rare metabolic disease characterized by defective bone mineralization that can lead to destruction and deformity of bones, profound muscle weakness, seizures, respiratory failure and premature death.3-7
HPP is caused by mutations in the gene encoding an enzyme known as tissue non-specific alkaline phosphatase (TNSALP).3,4 The genetic deficiency in HPP can affect people of all ages.5 HPP is classified by the age of the patient at the onset of symptoms of the disease, and paediatric-onset HPP is defined as manifestation of the first symptom prior to 18 years of age.
HPP can have devastating consequences for patients at any stage of life.3 Paediatric patients with HPP have a high mortality rate, with 73% mortality reported in a natural history study at 5 years.10 In these patients, mortality is primarily due to respiratory failure.3,7,11 In patients surviving to adolescence and adulthood, long-term clinical sequelae include recurrent and non-healing fractures, debilitating weakness, severe pain and the requirement for ambulatory assistive devices such as wheelchairs, wheeled walkers and canes.3,10
About Asfotase Alfa
Asfotase alfa is an investigational, first-in-class targeted enzyme replacement therapy. Asfotase alfa is designed to address the underlying cause of HPP by aiming to restore the genetically defective metabolic process, thereby preventing or reversing the severe and potentially life-threatening complications of life-long dysregulated mineral metabolism.
In 2013, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation for asfotase alfa. According to the FDA, a Breakthrough Therapy designation is designed to expedite the development of a drug to treat a serious or life-threatening disease when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.
Asfotase alfa is not approved in any country. In April 2014, Alexion initiated the rolling submission of a Biologics License Application (BLA) for asfotase alfa as a treatment for patients with HPP with the FDA. In July 2014, the Marketing Authorization Application (MAA) for asfotase alfa was validated and granted accelerated assessment by the European Medicines Agency (EMA).
About Alexion
Alexion is a biopharmaceutical company focused on serving patients with severe and rare disorders through the innovation, development and commercialization of life-transforming therapeutic products. Further information about Alexion can be found at: www.alexionpharma.eu.
References
1. Bishop N, Simmons J, Lutz R, et al. Hypophosphatasia: Gross Motor Function and Height Improvement in Infants and Young Children Treated with Asfotase Alfa for up to 3 Years. Poster presented at the 53rd Annual European Society for Paediatric Endocrinology (ESPE) Meeting, Dublin, Ireland, September 19, 2014. Abstract FC2.1.
2. Madson KL, Rockman-Greenberg C, Melian A, et al. Asfotase Alfa: Sustained Improved Growth and Function with Extended Treatment in Children with Hypophosphatasia. Poster presented at the 53rd Annual European Society for Paediatric Endocrinology (ESPE) Meeting, Dublin, Ireland, September 19, 2014. Abstract FC2.2.
3. Rockman-Greenberg C. Hypophosphatasia. Pediatr Endocrinol Rev. 2013;10(suppl 2):380-388.
4. 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. San Diego, CA: Academic Press; 2008:1573-1598.
5. Whyte MP, Greenberg CR, Salman N, et al. Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med. 2012;366(10):904-913.
6. Seshia SS, Derbyshire G, Haworth JC, Hoogstraten J. Myopathy with hypophosphatasia. Arch Dis Child. 1990; 65(1):130-131.
7. Baumgartner-Sigl S, Haberlandt E, Mumm S, et al. Pyridoxine-responsive seizures as the first symptom of infantile hypophosphatasia caused by two novel missense mutations (c.677T>C, p.M226T; c.1112C>T, p.T371I) of the tissue-nonspecific alkaline phosphatase gene. Bone. 2007; 40(6):1655-1661.
8. Whyte MP, Simmons JH, Lutz RE. Enzyme-replacement therapy in life-threatening hypophosphatasia: The 3-year experience with asfotase alfa. Poster presented at the American Society for Bone and Mineral Research (ASBMR) 2014 Annual Meeting, Houston, September 12, 2014. Abstract FR0435.
9. Madson KL, Rockman-Greenberg C, Whyte MP. Asfotase alfa: Sustained improvements in hypophosphatasia-related rickets, physical function, and pain during 3 years of treatment for severely affected children. Presented at the American Society for Bone and Mineral Research (ASBMR) 2014 Annual Meeting, Houston, September 14, 2014. Abstract 1081.
10. 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 Pediatric Academic Societies and Asian Society for Pediatric Research Joint Meeting, Vancouver, B.C., Canada, May 5, 2014. Abstract 752416.
11. Whyte MP, Rockman-Greenberg C, Hofmann C, et al. Improved survival with asfotase alfa treatment in pediatric patients with hypophosphatasia at high risk of death. Presented at the American Society for Bone and Mineral Research (ASBMR) 2014 Annual Meeting, Houston, September 14, 2014. Abstract 1097.
SOURCE: Alexion Pharmaceuticals
Post Views: 45
Data from Phase 2 Extension Studies Presented at ESPE Meeting
DUBLIN, Ireland I September 19, 2014 I Alexion Pharmaceuticals today announced that researchers presented data from the open-label extension phases of two Phase 2 studies of asfotase alfa, an investigational enzyme replacement therapy, in paediatric patients with hypophosphatasia (HPP).1,2 In the ongoing studies, researchers observed sustained improvements in growth, strength, physical function, and other key measures in paediatric patients with HPP who were treated with asfotase alfa for up to three years. HPP is a genetic, chronic and progressive ultra-rare metabolic disease that can lead to ongoing damage to multiple vital organs, destruction and deformity of bones, and premature death.3-7 Data were presented today at the 53rd Annual European Society for Paediatric Endocrinology (ESPE) Meeting in Dublin, Ireland, following a presentation of similar data earlier this month at the American Society for Bone and Mineral Research (ASBMR) 2014 Annual Meeting.8,9
“We also observed important improvements in gross motor, fine motor, and cognitive skills throughout the treatment period. These findings are meaningful given the developmental challenges and failure to thrive often associated with severe HPP.”
“Paediatric patients with severe HPP face significant challenges related to growth, development and physical function,” said Martin Mackay, Ph.D., Executive Vice President and Global Head of R&D at Alexion. “Researchers reported substantial improvements in developmental milestones such as height, strength, agility and motor function over the course of three years of treatment with asfotase alfa.”
Asfotase Alfa in Infants and Young Children with HPP: Extension Study Results (Abstract FC2.1)
In an oral presentation today, researchers reported that severely affected infants and young children with HPP (aged ≤3 years at study entry, N=11) treated with asfotase alfa for up to three years experienced sustained improvements in growth and physical function.1 Findings were from the extension phase of a multinational, open-label Phase 2 study of asfotase alfa treatment in severely affected infants with HPP.
In the data presented today at ESPE, investigators observed that patients treated with asfotase alfa had improvement in weight as measured by Z-score. Median weight Z-score was -3.8 at baseline; over the course of treatment, median change from baseline in Z-score steadily increased from +0.6 at one year to +2.6 at three years. Additionally, as reported at ASBMR, improvement in growth as measured by height/length Z-score was also observed in treated patients. Median height/length Z-score was -3.7 at baseline, indicating marked delay relative to peers; over the course of treatment, median change from baseline in Z-score steadily increased from +1.2 at one year to +2.3 at three years. Patients treated with asfotase alfa also had gains in gross motor function, fine motor function and cognitive function.
“We are pleased to report steady improvements in growth and weight for infants and young children with life-threatening HPP who were treated with asfotase alfa for up to three years,” said lead author Professor Nick Bishop, Professor of Paediatric Bone Disease, the Mellanby Centre for Bone Research, University of Sheffield. “We also observed important improvements in gross motor, fine motor, and cognitive skills throughout the treatment period. These findings are meaningful given the developmental challenges and failure to thrive often associated with severe HPP.”
Asfotase alfa was generally well-tolerated in the extension study. The most common adverse events (AEs) were pyrexia (7/10), mild or moderate injection-site reactions (6/10) and upper respiratory tract infection (6/10). Three serious AEs were reported as possibly related to treatment: craniosynostosis, conductive deafness and mild chronic hepatitis. Both craniosynostosis and conductive deafness were reported in the same patient, and are findings previously described as associated with HPP. The report of hepatitis was in a patient taking a medication for asthma, which was discontinued; liver function tests were within normal limits at last assessment. Four patients tested positive for neutralizing antibodies, without apparent impact on treatment efficacy or safety.
Asfotase Alfa in Children with HPP: Extension Study Results (Abstract FC2.1)
In a separate oral presentation today, researchers reported that children with HPP (aged 5-12 at study entry, N=13) who were treated with asfotase alfa experienced significant gains in height and rapid and sustained improvements in strength, agility, and physical function.2 The data were from the extension phase of a multinational, open-label Phase 2 study of asfotase alfa treatment in HPP patients.
In the data presented at ESPE, researchers reported improvements in right hip abductor muscle strength over the course of treatment, from 48% predicted at baseline to 83% predicted at last assessment (p=0.001). Additionally, and as reported at ASBMR, improvement in growth, as measured by height Z-score, was observed in treated patients, from a median of -1.26 at baseline to a median of -0.72 at last assessment (p=0.0027). Improvements in strength and agility were also observed for treated patients as measured by the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition (BOT-2). BOT-2 composite standardized score improved from a median of 28 at baseline to a median of 50 at last assessment (p<0.0008), which is the mean score for normal, healthy peers.
“In the data presented at ESPE, we reported that children with HPP who received treatment with asfotase alfa had encouraging gains in height as well as rapid and sustained improvement in muscle strength and agility,” said lead author Katherine L. Madson, M.D., Ph.D., from the Center for Metabolic Bone Disease and Molecular Research at Shriners Hospitals for Children, St. Louis. “These children previously had difficulty walking and muscle weakness that limited their physical function, so the improvements seen in the study were meaningful for these patients and their families.”
Asfotase alfa was generally well-tolerated in the study. The most common AEs were mild or moderate injection site reactions. There were no deaths, serious AEs or withdrawals due to AEs over the three years of treatment in this study. Twelve patients tested positive for anti-asfotase antibodies, two of whom had neutralizing antibodies with no apparent effect on efficacy or safety.
About Hypophosphatasia (HPP)
HPP is a genetic, chronic and progressive ultra-rare metabolic disease characterized by defective bone mineralization that can lead to destruction and deformity of bones, profound muscle weakness, seizures, respiratory failure and premature death.3-7
HPP is caused by mutations in the gene encoding an enzyme known as tissue non-specific alkaline phosphatase (TNSALP).3,4 The genetic deficiency in HPP can affect people of all ages.5 HPP is classified by the age of the patient at the onset of symptoms of the disease, and paediatric-onset HPP is defined as manifestation of the first symptom prior to 18 years of age.
HPP can have devastating consequences for patients at any stage of life.3 Paediatric patients with HPP have a high mortality rate, with 73% mortality reported in a natural history study at 5 years.10 In these patients, mortality is primarily due to respiratory failure.3,7,11 In patients surviving to adolescence and adulthood, long-term clinical sequelae include recurrent and non-healing fractures, debilitating weakness, severe pain and the requirement for ambulatory assistive devices such as wheelchairs, wheeled walkers and canes.3,10
About Asfotase Alfa
Asfotase alfa is an investigational, first-in-class targeted enzyme replacement therapy. Asfotase alfa is designed to address the underlying cause of HPP by aiming to restore the genetically defective metabolic process, thereby preventing or reversing the severe and potentially life-threatening complications of life-long dysregulated mineral metabolism.
In 2013, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation for asfotase alfa. According to the FDA, a Breakthrough Therapy designation is designed to expedite the development of a drug to treat a serious or life-threatening disease when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.
Asfotase alfa is not approved in any country. In April 2014, Alexion initiated the rolling submission of a Biologics License Application (BLA) for asfotase alfa as a treatment for patients with HPP with the FDA. In July 2014, the Marketing Authorization Application (MAA) for asfotase alfa was validated and granted accelerated assessment by the European Medicines Agency (EMA).
About Alexion
Alexion is a biopharmaceutical company focused on serving patients with severe and rare disorders through the innovation, development and commercialization of life-transforming therapeutic products. Further information about Alexion can be found at: www.alexionpharma.eu.
References
1. Bishop N, Simmons J, Lutz R, et al. Hypophosphatasia: Gross Motor Function and Height Improvement in Infants and Young Children Treated with Asfotase Alfa for up to 3 Years. Poster presented at the 53rd Annual European Society for Paediatric Endocrinology (ESPE) Meeting, Dublin, Ireland, September 19, 2014. Abstract FC2.1.
2. Madson KL, Rockman-Greenberg C, Melian A, et al. Asfotase Alfa: Sustained Improved Growth and Function with Extended Treatment in Children with Hypophosphatasia. Poster presented at the 53rd Annual European Society for Paediatric Endocrinology (ESPE) Meeting, Dublin, Ireland, September 19, 2014. Abstract FC2.2.
3. Rockman-Greenberg C. Hypophosphatasia. Pediatr Endocrinol Rev. 2013;10(suppl 2):380-388.
4. 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. San Diego, CA: Academic Press; 2008:1573-1598.
5. Whyte MP, Greenberg CR, Salman N, et al. Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med. 2012;366(10):904-913.
6. Seshia SS, Derbyshire G, Haworth JC, Hoogstraten J. Myopathy with hypophosphatasia. Arch Dis Child. 1990; 65(1):130-131.
7. Baumgartner-Sigl S, Haberlandt E, Mumm S, et al. Pyridoxine-responsive seizures as the first symptom of infantile hypophosphatasia caused by two novel missense mutations (c.677T>C, p.M226T; c.1112C>T, p.T371I) of the tissue-nonspecific alkaline phosphatase gene. Bone. 2007; 40(6):1655-1661.
8. Whyte MP, Simmons JH, Lutz RE. Enzyme-replacement therapy in life-threatening hypophosphatasia: The 3-year experience with asfotase alfa. Poster presented at the American Society for Bone and Mineral Research (ASBMR) 2014 Annual Meeting, Houston, September 12, 2014. Abstract FR0435.
9. Madson KL, Rockman-Greenberg C, Whyte MP. Asfotase alfa: Sustained improvements in hypophosphatasia-related rickets, physical function, and pain during 3 years of treatment for severely affected children. Presented at the American Society for Bone and Mineral Research (ASBMR) 2014 Annual Meeting, Houston, September 14, 2014. Abstract 1081.
10. 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 Pediatric Academic Societies and Asian Society for Pediatric Research Joint Meeting, Vancouver, B.C., Canada, May 5, 2014. Abstract 752416.
11. Whyte MP, Rockman-Greenberg C, Hofmann C, et al. Improved survival with asfotase alfa treatment in pediatric patients with hypophosphatasia at high risk of death. Presented at the American Society for Bone and Mineral Research (ASBMR) 2014 Annual Meeting, Houston, September 14, 2014. Abstract 1097.
SOURCE: Alexion Pharmaceuticals
Post Views: 45
