Rare metabolic diseases: the miglustat experience Fran Platt Fran Platt Department of Pharmacology Department of Pharmacology University of Oxford University of Oxford
The lysosome lysosome is an organelle involved in The is an organelle involved in degrading and recycling macromolecules degrading and recycling macromolecules Christian de Duve Christian de Duve The Nobel Prize in Physiology or The Nobel Prize in Physiology or Medicine 1974 Medicine 1974 “I have been privileged to contemplate many marvelous I have been privileged to contemplate many marvelous “ aspects of the structural and functional organization of aspects of the structural and functional organization of living cells. In addition, we have the deep satisfaction of living cells. In addition, we have the deep satisfaction of seeing that our findings do not simply enrich knowledge, seeing that our findings do not simply enrich knowledge, but may also help to conquer disease” ”. . but may also help to conquer disease
Functional roles of Lysosomes Functional roles of Lysosomes Macromolecule degradation, sorting and recycling • Endocytosis and vesicular trafficking • • Exocytosis and membrane repair • Cell death (release of cathepsins) • Clearance of phagocytosed material • Ion compartmentalization and signaling (calcium - NAADP receptor, iron, zinc, copper etc.) Over 50 diseases known that result from defective lysosomal function
Lysosomal Storage Diseases Lysosomal Storage Diseases • The majority have a neurodegenerative clinical course The majority have a neurodegenerative clinical course • • Majority present in infancy/early childhood Majority present in infancy/early childhood • • CNS inflammation (microglial/macrophage) CNS inflammation (microglial/macrophage) • • Visceral organs often involved (spleen/liver) Visceral organs often involved (spleen/liver) • • Clinical course is highly variable Clinical course is highly variable • • Genotype:phenotype correlations limited Genotype:phenotype correlations limited • • Small increase in residual enzyme major clinical impact Small increase in residual enzyme major clinical impact •
Lysosomal Storage Diseases Lysosomal Storage Diseases Lysosomal storage diseases 1:5000 Lysosomal storage diseases 1:5000 50% are glycolipid lysosomal storage diseases 1:10000 50% are glycolipid lysosomal storage diseases 1:10000 Gaucher disease (Ashkenazi Jews) 1:450- - 1:1000 1:1000 Gaucher disease (Ashkenazi Jews) 1:450 Gaucher (general population) 1:200,000 Gaucher (general population) 1:200,000 Fabry disease 1:40,000 Fabry disease 1:40,000 Tay- Tay -Sachs (Ashkenazi Jews) Sachs (Ashkenazi Jews) 1:4,000 1:4,000 (non- -Jewish) Jewish) 1:300,000 (non 1:300,000 Sandhoff (Jewish) 1:1,000,000 Sandhoff (Jewish) 1:1,000,000 (non- -Jewish) Jewish) 1:309,000 (non 1:309,000 Niemann- -Pick type C Pick type C 1:150,000 Niemann 1:150,000
Glycosphingolipid Storage Disorders Glycosphingolipid Storage Disorders Impaired Impaired catabolism catabolism Lysosome Lysosome Storage Diseases Storage Diseases Golgi Golgi Gaucher Gaucher Tay- -Sachs Sachs Tay Sandhoff Sandhoff Fabry Fabry GM1 Gangliosidosis GM1 Gangliosidosis
Problem Therapeutic approach Problem Therapeutic approach Gene therapy, stop codon read Gene therapy, stop codon read • Genetic defect Genetic defect • through through Enzyme replacement, BMT, , Enzyme replacement, BMT • Enzyme defect • Enzyme defect chaperones, stem cells chaperones, stem cells • Storage of substrate Storage of substrate Substrate reduction therapy (SRT) • Substrate reduction therapy (SRT) ++ modulators • Secondary consequences Secondary consequences NSAIDS, Ca ++ modulators • NSAIDS, Ca
Imino Sugar NB- -DNJ DNJ Imino Sugar NB CH OH CH OH CH OH CH OH 2 2 2 2 HO HO HO HO O O N N CH CH 3 3 HO HO HO HO OH OH OH OH OH OH -Glucose Glucose NB- -DNJ DNJ α - NB α • Derived from natural products (plants/fungi) Derived from natural products (plants/fungi) • • Water soluble, orally available, not metabolised Water soluble, orally available, not metabolised • • Developed (Monsanto) as anti Developed (Monsanto) as anti- -viral in 1980s (HIV) viral in 1980s (HIV) • • alpha alpha- -glucosidase inhibitor glucosidase inhibitor •
Serendipity: novel discovery in 1993 Serendipity: novel discovery in 1993 Platt et al, 1994, JBC, 269, 8362- -8365 8365 Platt et al, 1994, JBC, 269, 8362
Inhibition of glycosphingolipid biosynthesis Inhibition of glycosphingolipid biosynthesis L- -Serine, Palmitoyl Serine, Palmitoyl- -Coenzyme A Coenzyme A L O C Ceramide Ceramide CH 3 H HN HO CH 3 C C C H OH UDP- UDP -Glucose Glucose N B B- -DNJ DNJ N UDP- -Glucose: N Glucose: N- -acylsphingosine acylsphingosine UDP glucosyltransferase glucosyltransferase miglustat miglustat UDP UDP O Glucosylceramide Glucosylceramide OH C CH 3 H HN O O HO C CH 3 C C HO OH H OH Lactosylceramide Lactosylceramide Ganglio- - series series Lacto(neo)- - series series Globo- - series series Ganglio Lacto(neo) Globo
Imino Sugar N N B B- -DNJ (miglustat) DNJ (miglustat) Imino Sugar CH 2 OH HO N CH 3 HO OH N B B- -DNJ (miglustat) DNJ (miglustat) N • Proof of principle in an Proof of principle in an in vitro in vitro model of model of Gaucher Gaucher disease disease • • GSL depletion well tolerated long GSL depletion well tolerated long- -term in mice term in mice • • Proof of principle in mouse models with CNS disease Proof of principle in mouse models with CNS disease • (Tay- -Sachs, Sachs, Sandhoff Sandhoff & GM1 gangliosidosis gangliosidosis) ) (Tay & GM1
In our favor… …. . In our favor • Pre existing toxicology and DMPK data in multiple species Pre existing toxicology and DMPK data in multiple species • • Pre existing clinical safety data at high dosage (HIV studies) Pre existing clinical safety data at high dosage (HIV studies) • • A metric ton synthesized A metric ton synthesized • • 1 drug to treat multiple diseases 1 drug to treat multiple diseases • • A small company wanting to develop it (Oxford A small company wanting to develop it (Oxford GlycoSciences GlycoSciences) ) • • Key opinion leaders who believed in the concept/data/approach Key opinion leaders who believed in the concept/data/approach • (Prof. Tim Cox & Prof. Bryan Winchester Prof. Tim Cox & Prof. Bryan Winchester (
Clinical trial Clinical trial • Disease with no CNS involvement Disease with no CNS involvement • • Clinically relevant end points (consensus) Clinically relevant end points (consensus) • • Surrogate disease markers/biochemical markers Surrogate disease markers/biochemical markers • • An effective therapy to compare SRT with An effective therapy to compare SRT with • • Expectation that clinical changes will be manifest within 1 yea Expectation that clinical changes will be manifest within 1 year r • Type 1 Gaucher disease (glucocerebrosidase deficiency) Type 1 Gaucher disease (glucocerebrosidase deficiency) • Standard of care: Intravenous enzyme replacement therapy (ERT) Standard of care: Intravenous enzyme replacement therapy (ERT) • • Increase choice for Gaucher disease clinical management with an Increase choice for Gaucher disease clinical management with an oral drug? oral drug? •
Cathepsins Cathepsins Chitotriosidase Chitotriosidase Cytokines Cytokines Gaucher cell Gaucher cell Spleen Liver Bone marrow Spleen Liver Bone marrow
• Trial based on 28 patients Trial based on 28 patients • • 1 year open label trial 1 year open label trial • • Trial data positive (Cox et al, Lancet 2000) • Trial data positive (Cox et al, Lancet 2000) • EMEA approved 2002 EMEA approved 2002 • • FDA approved 2003 FDA approved 2003 • • Requirement for post Requirement for post- -marketing surveillance marketing surveillance • • Drug transferred to Actelion, Basel Drug transferred to Actelion, Basel • • 10 Years from first data to EMEA approval 10 Years from first data to EMEA approval •
Niemann-Pick type C disease • Neurodegenerative lysosomal lysosomal disorder • Neurodegenerative disorder • 1:120,000 live births, carrier frequency • 1:120,000 live births, carrier frequency 1:100 1:100 • Ataxia, dementia, speech and swallowing • Ataxia, dementia, speech and swallowing defects, premature death defects, premature death • In NPC disease there is secondary GSL • In NPC disease there is secondary GSL storage, candidate for miglustat miglustat therapy storage, candidate for therapy
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