- Email: [email protected]
Virtual collaborations for developing Sanfilippo syndrome treatments on a shoestring
Abstracts / Molecular Genetics and Metabolism 117 (2016) S14–S124
88 Outcomes of enzyme replacement therapy in a 14-year-old female with Hurler syndrome Julie B. Eisengarta, Elsa Shapiroa,b, Kate Delaneyb, Igor Nestrasila, Alia Ahmeda, Lyla Hamptonc, Chester B. Whitleya, aUniversity of Minnesota, Minneapolis, MN, United States, bShapiro & Delaney LLC, Minneapolis, MN, United States, cChildren's Hospital of Philadelphia, Philadelphia, PA, United States Mucopolysaccharidosis type I (MPS I) is a rare lysosomal disorder associated with deficiency in alpha-L-iduronidase, which leads to accumulation of glycosaminoglycans and progressive multi-organ compromise. Standard of care for the attenuated types of MPS I is intravenous enzyme replacement therapy (ERT). However, the severe form of MPS I (MPS IH, Hurler syndrome) involves the central nervous system including cognitive decline, which presents a challenge for ERT due to the impermeable blood-brain-barrier. Hematopoietic cell transplantation (HCT) is the standard method to reach the brain in MPS IH. We present a 14-year-old female with Hurler syndrome who has had an unusual treatment course consisting of exclusively ERT, and examine whether her clinical outcomes differ from the untreated natural history of MPS IH or HCT. She has received weekly intravenous ERT from age 27 months. Her medical history, school records, and research data, including annual neuropsychological evaluations, were reviewed longitudinally. She was neurologically stable until she developed cervical compression at age 8 and hydrocephalus at age 11. Scores on IQ testing were average throughout her life until a decline at age 12, thought to be associated with hydrocephalus. Current reading comprehension is at a 5th grade level. The somatic disease course is significant throughout her life for first degree AV block, restrictive lung disease, short stature, bilateral hearing loss, corneal clouding, joint pain/ limitations requiring mobility assistance, and short stature. Urine glycosaminoglycan levels were elevated 3-fold the upper limit of normal at age 12. This patient has displayed outcomes distinct from the untreated natural history of MPS IH as demonstrated by extended survival as well as prolonged intact cognitive functioning. Neurologic and somatic symptoms that are typically controlled by HCT did emerge and have important implications for quality of life. Future studies should compare findings to a broader sample. (NIH U54NS065768, UL1TR000114, CMRR and CNBD at University of Minnesota.) doi:10.1016/j.ymgme.2015.12.246
89 Virtual collaborations for developing Sanfilippo syndrome treatments on a shoestring Sean Ekins, Derek R. Moen, Jill Wood, Phoenix Nest, Brooklyn, NY, United States Phoenix Nest (http://www.phoenixnestbiotech.com/) was cofounded with a rare disease parent and is working on treatments for Sanfilippo syndrome (MPS III), a devastating neurodegenerative lysosomal disorder of childhood. In the space of 4 years, we have built up collaborations with leading academics and industry and submitted multiple NIH grant proposals. We have now completed our first phase I NIH NINDS STTR grant to fund development of an enzyme replacement therapy with our academic collaborator (LA BioMed) for MPS IIID. This has enabled us to submit a Phase II grant to further evaluate this product, which is currently pending. Challenges we foresee and have started to address include identifying patients for clinical studies with this disease and demonstrating to investors that we can have a return on investment (ROI). We will describe the importance of the rare pediatric disease
S43
priority review voucher as a means to demonstrate ROI. In addition, we have recently obtained a second Phase I grant to develop a treatment for MPS IIIB. We will highlight our evolving, lean company strategy, which enables a small virtual team to coordinate and leverage the academic research resources that have been accumulated. We will summarize our collaborative strategy and efforts to partner with global groups to pursue additional treatments for MPS III. At a bare minimum, we propose that other rare diseases could leverage our approach. To do this, they require at least one scientist with whom you can submit grants and papers, and ultimately, licensing what comes out of the work will be just as important to aid in funding of further development. We would encourage other scientists to meet with rare disease parents, patients, or advocates and to work with them to further the research on their diseases. doi:10.1016/j.ymgme.2015.12.247
90 Twenty-six week or longer intracerebroventricular (ICV) infusion study of BMN 250 administered once every 2 weeks in a canine model of mucopolysaccharidosis type IIIB (MPS IIIB) N. Matthew Ellinwooda, Bethann N. Johnsona, Jackie K. Jensa, Elizabeth M. Snellaa, Wendy A. Warea, Shannon Hostettera, Gil Ben-Shlomoa, Nicholas Jefferya, Sina Safayia, Suzanne Millmana, Rebecca Parsonsa, Brian R. Vuillemenotb, Mark T. Buttc, Jonathan Cooperd, Igor Nestrasile, Daniel Wendtb, Derek Kennedyb, Anita Groverb, Andrew Meltonb, Anu Cherukurib, Jill C.M. Waitb, Jason K. Pinkstaffb, aIowa State University, Ames, IA, United States, bBioMarin Pharmaceutical Inc, San Rafael, CA, United States, cTox Path Specialists, LLC, Frederick, MD, United States, d King's College London, London, United Kingdom, eUniversity of MN, Minneapolis, MN, United States MPS IIIB is a fatal neurodegenerative lysosomal disorder disease caused by genetic deficiency of the enzyme N-acetyl-alpha-Dglucosaminidase (Naglu). Deficiency of Naglu leads to accumulation of the glycosaminoglycan (GAG) heparan sulfate (HS) in the central nervous system (CNS) and other tissues. In humans, the resulting progressive neurodegeneration is typically fatal during the second decade of life. Naglu-null dogs are a relevant large animal model of MPS IIIB. These animals display HS accumulation in blood, liver, kidney, cerebrospinal fluid, urine, and CNS tissues. Gross clinical signs are present at approximately 18-24 months of age. Progressive neurological decline follows leading to mortality at 3-5 years of age. End-stage CNS histopathology includes severe cerebellar atrophy, Purkinje cell loss, and cytoplasmic vacuolation. BMN 250 is a fusion protein of recombinant human Naglu with an insulin-like growth factor 2 (IGF2), in development as a potential enzyme replacement therapy for MPS IIIB. The IGF2 moiety or GILT (glycosylation independent lysosomal targeting) tag allows for enhanced lysosomal uptake via the IGF-2 receptor (Maga et al., 2013). Direct delivery to the CNS via intracerebroventricular (ICV) infusion is the planned clinical route of administration for BMN 250. The objectives of this study are 1) to characterize the safety of BMN 250 in Naglu-null dogs and normal littermate controls; 2) to determine the pharmacodynamic effects of BMN 250 on lysosomal storage accumulation, brain morphology, and functional assessment of gait and cognition in this relevant dog disease model; and 3) to describe the pharmacokinetics, CNS distribution, and immunogenicity of ICV-administered BMN 250. This ongoing blinded study is fully enrolled with 24 dogs; 12 normal and 12 Naglu-null, MPS IIIB affected dogs, distributed to 3 groups of 4 dogs each designed to be treated with vehicle, 12 mg, or 48 mg of BMN 250 administered every two weeks via ICV catheters. doi:10.1016/j.ymgme.2015.12.248
88 Outcomes of enzyme replacement therapy in a 14-year-old female with Hurler syndrome Julie B. Eisengarta, Elsa Shapiroa,b, Kate Delaneyb, Igor Nestrasila, Alia Ahmeda, Lyla Hamptonc, Chester B. Whitleya, aUniversity of Minnesota, Minneapolis, MN, United States, bShapiro & Delaney LLC, Minneapolis, MN, United States, cChildren's Hospital of Philadelphia, Philadelphia, PA, United States Mucopolysaccharidosis type I (MPS I) is a rare lysosomal disorder associated with deficiency in alpha-L-iduronidase, which leads to accumulation of glycosaminoglycans and progressive multi-organ compromise. Standard of care for the attenuated types of MPS I is intravenous enzyme replacement therapy (ERT). However, the severe form of MPS I (MPS IH, Hurler syndrome) involves the central nervous system including cognitive decline, which presents a challenge for ERT due to the impermeable blood-brain-barrier. Hematopoietic cell transplantation (HCT) is the standard method to reach the brain in MPS IH. We present a 14-year-old female with Hurler syndrome who has had an unusual treatment course consisting of exclusively ERT, and examine whether her clinical outcomes differ from the untreated natural history of MPS IH or HCT. She has received weekly intravenous ERT from age 27 months. Her medical history, school records, and research data, including annual neuropsychological evaluations, were reviewed longitudinally. She was neurologically stable until she developed cervical compression at age 8 and hydrocephalus at age 11. Scores on IQ testing were average throughout her life until a decline at age 12, thought to be associated with hydrocephalus. Current reading comprehension is at a 5th grade level. The somatic disease course is significant throughout her life for first degree AV block, restrictive lung disease, short stature, bilateral hearing loss, corneal clouding, joint pain/ limitations requiring mobility assistance, and short stature. Urine glycosaminoglycan levels were elevated 3-fold the upper limit of normal at age 12. This patient has displayed outcomes distinct from the untreated natural history of MPS IH as demonstrated by extended survival as well as prolonged intact cognitive functioning. Neurologic and somatic symptoms that are typically controlled by HCT did emerge and have important implications for quality of life. Future studies should compare findings to a broader sample. (NIH U54NS065768, UL1TR000114, CMRR and CNBD at University of Minnesota.) doi:10.1016/j.ymgme.2015.12.246
89 Virtual collaborations for developing Sanfilippo syndrome treatments on a shoestring Sean Ekins, Derek R. Moen, Jill Wood, Phoenix Nest, Brooklyn, NY, United States Phoenix Nest (http://www.phoenixnestbiotech.com/) was cofounded with a rare disease parent and is working on treatments for Sanfilippo syndrome (MPS III), a devastating neurodegenerative lysosomal disorder of childhood. In the space of 4 years, we have built up collaborations with leading academics and industry and submitted multiple NIH grant proposals. We have now completed our first phase I NIH NINDS STTR grant to fund development of an enzyme replacement therapy with our academic collaborator (LA BioMed) for MPS IIID. This has enabled us to submit a Phase II grant to further evaluate this product, which is currently pending. Challenges we foresee and have started to address include identifying patients for clinical studies with this disease and demonstrating to investors that we can have a return on investment (ROI). We will describe the importance of the rare pediatric disease
S43
priority review voucher as a means to demonstrate ROI. In addition, we have recently obtained a second Phase I grant to develop a treatment for MPS IIIB. We will highlight our evolving, lean company strategy, which enables a small virtual team to coordinate and leverage the academic research resources that have been accumulated. We will summarize our collaborative strategy and efforts to partner with global groups to pursue additional treatments for MPS III. At a bare minimum, we propose that other rare diseases could leverage our approach. To do this, they require at least one scientist with whom you can submit grants and papers, and ultimately, licensing what comes out of the work will be just as important to aid in funding of further development. We would encourage other scientists to meet with rare disease parents, patients, or advocates and to work with them to further the research on their diseases. doi:10.1016/j.ymgme.2015.12.247
90 Twenty-six week or longer intracerebroventricular (ICV) infusion study of BMN 250 administered once every 2 weeks in a canine model of mucopolysaccharidosis type IIIB (MPS IIIB) N. Matthew Ellinwooda, Bethann N. Johnsona, Jackie K. Jensa, Elizabeth M. Snellaa, Wendy A. Warea, Shannon Hostettera, Gil Ben-Shlomoa, Nicholas Jefferya, Sina Safayia, Suzanne Millmana, Rebecca Parsonsa, Brian R. Vuillemenotb, Mark T. Buttc, Jonathan Cooperd, Igor Nestrasile, Daniel Wendtb, Derek Kennedyb, Anita Groverb, Andrew Meltonb, Anu Cherukurib, Jill C.M. Waitb, Jason K. Pinkstaffb, aIowa State University, Ames, IA, United States, bBioMarin Pharmaceutical Inc, San Rafael, CA, United States, cTox Path Specialists, LLC, Frederick, MD, United States, d King's College London, London, United Kingdom, eUniversity of MN, Minneapolis, MN, United States MPS IIIB is a fatal neurodegenerative lysosomal disorder disease caused by genetic deficiency of the enzyme N-acetyl-alpha-Dglucosaminidase (Naglu). Deficiency of Naglu leads to accumulation of the glycosaminoglycan (GAG) heparan sulfate (HS) in the central nervous system (CNS) and other tissues. In humans, the resulting progressive neurodegeneration is typically fatal during the second decade of life. Naglu-null dogs are a relevant large animal model of MPS IIIB. These animals display HS accumulation in blood, liver, kidney, cerebrospinal fluid, urine, and CNS tissues. Gross clinical signs are present at approximately 18-24 months of age. Progressive neurological decline follows leading to mortality at 3-5 years of age. End-stage CNS histopathology includes severe cerebellar atrophy, Purkinje cell loss, and cytoplasmic vacuolation. BMN 250 is a fusion protein of recombinant human Naglu with an insulin-like growth factor 2 (IGF2), in development as a potential enzyme replacement therapy for MPS IIIB. The IGF2 moiety or GILT (glycosylation independent lysosomal targeting) tag allows for enhanced lysosomal uptake via the IGF-2 receptor (Maga et al., 2013). Direct delivery to the CNS via intracerebroventricular (ICV) infusion is the planned clinical route of administration for BMN 250. The objectives of this study are 1) to characterize the safety of BMN 250 in Naglu-null dogs and normal littermate controls; 2) to determine the pharmacodynamic effects of BMN 250 on lysosomal storage accumulation, brain morphology, and functional assessment of gait and cognition in this relevant dog disease model; and 3) to describe the pharmacokinetics, CNS distribution, and immunogenicity of ICV-administered BMN 250. This ongoing blinded study is fully enrolled with 24 dogs; 12 normal and 12 Naglu-null, MPS IIIB affected dogs, distributed to 3 groups of 4 dogs each designed to be treated with vehicle, 12 mg, or 48 mg of BMN 250 administered every two weeks via ICV catheters. doi:10.1016/j.ymgme.2015.12.248