WO2017049161A1 - Alpha-glucosidase acide et agoniste β-2 pour le traitement de maladie lysosomale - Google Patents

Alpha-glucosidase acide et agoniste β-2 pour le traitement de maladie lysosomale Download PDF

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WO2017049161A1
WO2017049161A1 PCT/US2016/052254 US2016052254W WO2017049161A1 WO 2017049161 A1 WO2017049161 A1 WO 2017049161A1 US 2016052254 W US2016052254 W US 2016052254W WO 2017049161 A1 WO2017049161 A1 WO 2017049161A1
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disease
lysosomal enzyme
day
therapeutic agent
lysosomal
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Dwight D. Koeberl
Priya Kishnani
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Duke University
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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/465—Hydrolases (3) acting on ester bonds (3.1), e.g. lipases, ribonucleases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y301/00—Hydrolases acting on ester bonds (3.1)
    • C12Y301/04—Phosphoric diester hydrolases (3.1.4)
    • C12Y301/04012—Sphingomyelin phosphodiesterase (3.1.4.12)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y302/00—Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
    • C12Y302/01—Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
    • C12Y302/01021—Beta-glucosidase (3.2.1.21)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y302/00—Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
    • C12Y302/01—Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
    • C12Y302/01022—Alpha-galactosidase (3.2.1.22)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y302/00—Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
    • C12Y302/01—Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
    • C12Y302/01045—Glucosylceramidase (3.2.1.45), i.e. beta-glucocerebrosidase
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y302/00—Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
    • C12Y302/01—Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
    • C12Y302/01049—Alpha-N-acetylgalactosaminidase (3.2.1.49)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y302/00—Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
    • C12Y302/01—Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
    • C12Y302/01076—L-Iduronidase (3.2.1.76)

Definitions

  • Embodiments herein are directed to a method of treating a lysosomal storage disorder in an individual in need thereof, the method comprising administering to the individual a therapeutic agent as an adjunctive therapy to lysosomal enzyme replacement therapy. Some embodiments herein are directed to a method of increasing expression of a receptor for a lysosomal enzyme, the method comprising administering a therapeutic agent as an adjunctive therapy to an individual who is undergoing or has undergone lysosomal enzyme replacement therapy. Some embodiments herein are directed to a method of treating a lysosomal storage disorder in an individual in need thereof, the method comprising administering (1) a lysosomal enzyme; and (2) another therapeutic agent.
  • Some embodiments herein are directed to a method of treating a glycogen storage disease II in an individual in need thereof, the method comprising administering (1) an acid alpha-glucosidase; and (2) a ⁇ 2 agonist. Some embodiments are directed to a method of treating a lysosomal storage disorder comprising administering a composition comprising a lysosomal enzyme and another therapeutic agent. Some embodiments are directed to a composition comprising a lysosomal enzyme and a therapeutic agent.
  • the lysosomal storage disorder may be glycogen storage disease II.
  • the lysosomal enzyme may be acid alpha- glucosidase (acid a-glucosidase or GAA).
  • the other therapeutic agent is a beta-2-adrenergic agonist ( ⁇ 2 agonist).
  • the ⁇ 2 agonist is a selective ⁇ 2 agonist.
  • the ⁇ 2 agonist is clenbuterol, albuterol, formoterol, salmeterol, or a combination thereof.
  • the acid a-glucosidase may be GAA, rhGAA, nco-rhGAA, reveglucosidase alpha, alglucosidase alfa, an rhGAA with higher M6P content than naturally occurring GAA that is administered with a chaperone (e.g. 1- deoxynojirimycin), or a combination thereof.
  • a chaperone e.g. 1- deoxynojirimycin
  • the lysosomal enzyme is acid alpha-glucosidase.
  • the other therapeutic agent is a ⁇ 2 agonist.
  • the lysosomal storage disorder is characterized by reduced or deficient activity of a lysosomal enzyme.
  • the lysosomal storage disorder to be treated is characterized by reduced or deficient activity of the lysosomal enzyme in the brain of the patient.
  • the lysosomal enzyme that is deficient in a patient to be treated is acid a-glucosidase.
  • the lysosomal storage disorder may be Pompe disease (glycogen storage disease II (“GSD II”)), Gaucher disease, Fabry disease, mucopolysaccharidosis type I, mucopolysaccharidosis type II, or Niemann-Pick disease.
  • the lysosomal storage disorder is glycogen storage disease II (Pompe disease).
  • the glycogen storage disease II may be late-onset Pompe disease ("LOPD”), juvenile-onset Pompe disease, or infantile Pompe disease.
  • Fig. 1 illustrates that enzyme replacement therapy (ERT) depends upon receptor- mediated uptake of recombinant lysosomal enzymes.
  • Fig. 1(A) illustrates that in lysosomal storage disorders the CI-MPR is expressed at low levels on the cell membrane, and therefore a drug that increased CI-MPR would enhance biochemical correction from ERT.
  • Fig. 1(B) illustrates that a selective p2-agonist, clenbuterol, increased CI-MPR expression and significantly enhanced biochemical correction in combination with ERT, in comparison with ERT alone, as demonstrated by decreased glycogen storage in mice with a classical lysosomal storage disorder, Pompe disease.
  • FIG. 2 illustrates the use of urinary Glc 4 as a biomarker in mice with Pompe disease.
  • GAA-KO mice were administered four weekly doses of rhGAA (20 mg/kg), and treated with clenbuterol (6 mg/L in drinking water), albuterol (30 mg/L in drinking water), ERT alone, or untreated (Mock).
  • FIG. 3 illustrates a natural history study of LOPD. Sixteen subjects with LOPD were evaluated following enrollment in a research protocol approved by the Duke University IRB. Fig. 3(A) illustrates muscle testing with handheld dynamometry was performed on all subjects. Strength relative to normal controls is shown. Fig. 3(B) illustrates pulmonary function testing was available for 12 subjects. Mean +/- s.d. shown, relative to normal controls.
  • Fig. 4 illustrates the study design and efficacy of a 24-week study of adjunctive albuterol.
  • Fig 4A illustrates the study design, indicating timing for study visits when patients were seen, telephone visits, electrocardiograms (EKG), and pulmonary function tests (PFT).
  • Fig. 4B illustrates the 6 minute walk test ("6MWT") distance at the indicated study visits. Each line connects the datapoints for one research subject. Right (Fig. 4C) and left (Fig. 4D) hand grip strength tested by dynamometry.
  • Fig. 5 illustrates the comparison of urinary Glc 4 biomarker in LOPD at baseline and after 12 weeks.
  • Fig. 6 illustrates the biochemical correction of striated muscle following AAV vector administration and adjunctive small molecule therapy in heart, diaphragm and quadriceps: (A) levels of GAA, and (B) glycogen content. Mean +/- SEM is shown. P ⁇ 0.05 (*),. P ⁇ 0.01 (**), and PO.OOl (***).
  • Fig. 7 illustrates results of Muscle Function Testing, showing (A) Latency change in wirehang testing for each treatment group; and (B) change in body weight. Mean +/- SEM is shown. P ⁇ 0.05 (*),. P ⁇ 0.01 (**), and PO.001 (***).
  • Fig. 8 illustrates the effect of the small molecules alone. To evaluate drug effect in biochemical levels, several different muscles were collected to perform (A) GAA assay and (B) Glycogen content assay for heart, as well as (C) wirehang testing. Mean +/- SEM is shown. P ⁇ 0.05 (*),. P ⁇ 0.01 (**), and PO.OOl (***).
  • FIG. 9 illustrates the effect of small molecules upon CI-MPR and LC3.
  • Western blotting and quantification for CI-MPR and LC3-II in (A) heart and (B) quadriceps (n 5 in each group).
  • the signals for CI-MPR and for LC3-II were normalized to tubulin (heart) or glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Mean +/- SEM is shown. P ⁇ 0.05 (*),. P ⁇ 0.01 (**), and PO.OOl (***).
  • LSDs The lysosomal storage disorders
  • lysosomal storage disorders are characterized by deficiencies in lysosomal enzymes resulting from mutations in genes that encode the enzyme proteins and related cofactors. Lysosomal enzymes degrade most biomolecules, the products of which are then recycled in a process that is essential for cell health and growth. LSDs result in accumulation of undegraded products in lysosomes and concomitant cell enlargement, dysfunction, and death.
  • the clinical manifestations of LSDs include neuronal lipidosis, leukodystrophy, mucopolysaccharidosis, and storage histiocytosis.
  • Pompe disease Glycogen storage disease type II; acid maltase deficiency; MTM 232300
  • GAA acid a-glucosidase
  • ERT enzyme replacement therapy
  • rhGAA recombinant human GAA
  • Infantile-onset Pompe disease affects the heart and skeletal muscle primarily, and causes death early in childhood from cardiorespiratory failure related to an underlying hypertrophic cardiomyopathy, if initiation of ERT is delayed or the patient fails to respond sustainably due to high, sustained anti-GAA antibodies.
  • GAA normally functions as an acid hydrolase that metabolizes lysosomal glycogen, and GAA deficiency causes lysosomal glycogen accumulation in virtually all tissues.
  • the availability of ERT with rhGAA has prolonged survival and ameliorated the cardiomyopathy of infantile Pompe disease.
  • ERT has largely resulted in stabilization of the disease process from a pulmonary and motor perspective.
  • Documented limitations of ERT in Pompe disease include the requirement for frequent intravenous infusions of high levels of GAA to achieve efficacy, degree of pre-ERT muscle damage, and the possibility of humoral immunity.
  • the rhGAA doses are markedly higher than doses required for ERT in other lysosomal storage disorders, reflecting the high threshold for correction of GAA deficiency in the skeletal muscle of Pompe disease patients.
  • lysosomal storage disorders such as Pompe disease.
  • the present disclosure is directed to the premise that Pompe disease can be more effectively treated by increasing the cation- independent mannose 6- phosphate receptor (CI-MPR) mediated uptake of rhGAA with simultaneous ⁇ 2 agonist administration.
  • CI-MPR mannose 6- phosphate receptor
  • methods of treating lysosomal storage disorders comprising an adjuvant therapy comprising a ⁇ 2 agonist to enhance efficacy of ERT.
  • administering when used in conjunction with a therapeutic, means to administer a therapeutic directly into or onto a target tissue or to administer a therapeutic to a subject, whereby the therapeutic positively impacts the tissue to which it is targeted.
  • administering when used in conjunction with a therapeutic, can include, but is not limited to, providing a therapeutic to a subject systemically by, for example, intravenous injection, whereby the therapeutic reaches the target tissue.
  • Administering a composition or therapeutic may be accomplished by, for example, injection, oral administration, topical administration, or by these methods in combination with other known techniques.
  • Administering may be self-administration, wherein the therapeutic or composition is administered by the subject themselves. Alternatively, administering may be administration to the subject by a health care provider.
  • Providing when used in conjunction with a therapeutic, means to administer a therapeutic directly into or onto a target tissue, or to administer a therapeutic to a subject whereby the therapeutic positively impacts the tissue to which it is targeted.
  • treat and “treatment,” as used herein, refer to amelioration of one or more symptoms associated with the disease, prevention or delay of the onset of one or more symptoms of the disease, and/or lessening of the severity or frequency of one or more symptoms of the disease.
  • treatment can refer to improvement in mortality, improvement of cardiac status (e.g., increase of end-diastolic and/or end-systolic volumes, or reduction, amelioration or prevention of the progressive cardiomyopathy that is typically found in GSD-II) or of pulmonary function (e.g., increase in crying vital capacity over baseline capacity, and/or normalization of oxygen desaturation during crying, reduction in need for invasive or non-invasive ventilator support); improvement in neurodevelopment and/or motor skills (e.g., increase in AIMS score or 6MWT); reduction of glycogen levels in tissues of the individual affected by the disease; or any combination of these effects.
  • treatment includes improvement of cardiac status, particularly in reduction or prevention of GSD-II-associated cardiomyopathy.
  • the term "therapeutic” means an agent utilized to treat, combat, ameliorate, prevent or improve an unwanted condition or disease of a subject.
  • embodiments described herein may be directed to the treatment of various lysosomal storage disorders, including, but not limited to, Pompe disease (GSD II), Gaucher disease, Fabry disease, mucopolysaccharidosis type I, mucopolysaccharidosis type II, or Niemann- Pick disease.
  • the lysosomal storage disorder is glycogen storage disease II (Pompe disease).
  • the glycogen storage disease II may be LOPD, juvenile-onset Pompe disease, or infantile Pompe disease.
  • the terms, "improve,” “increase” or “reduce,” as used herein, indicate values that are relative to a baseline measurement, such as a measurement in the same individual prior to initiation of the treatment described herein, or a measurement in a control individual (or multiple control individuals) in the absence of the treatment described herein.
  • a control individual is an individual afflicted with the same form of GSD-II (either infantile, juvenile or adult-onset) as the individual being treated, who is about the same age as the individual being treated (to ensure that the stages of the disease in the treated individual and the control individual(s) are comparable).
  • a therapeutically effective amount of a composition is an amount of the composition, and particularly the active ingredient, such as a beta-2 agonist and/or GAA, that generally achieves the desired effect.
  • the desired effect can be an improvement, prevention, or reduction of a particular disease state.
  • a "therapeutically effective amount” or “effective amount” of a composition is an amount necessary or sufficient to achieve the desired result or clinical outcome.
  • the desired result or clinical outcome can be an improvement, prevention, or reduction of a particular disease state.
  • the therapeutic effect contemplated by the embodiments herein includes medically therapeutic, cosmetically therapeutic and/or prophylactic treatment, as appropriate.
  • the specific dose of a compound administered according to embodiments of the present invention to obtain therapeutic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, and the condition being treated.
  • the effective amount administered may be determined by the practitioner or manufacturer or patient in light of the relevant circumstances including the condition to be treated, the choice of compound to be administered, and the chosen route of administration, and therefore, the above dosage ranges are not intended to limit the scope of the invention in any way.
  • a therapeutically effective amount of the compound of embodiments herein is typically an amount such that when it is administered in a physiologically tolerable excipient composition, it is sufficient to achieve an effective systemic concentration or local concentration in or on the tissue to achieve the desired therapeutic or clinical outcome.
  • the term "consists of or “consisting of means that the composition or method includes only the elements, steps, or ingredients specifically recited in the particular claimed embodiment or claim.
  • composition or method includes only the specified materials or steps and those that do not materially affect the basic and novel characteristics of the claimed invention.
  • tissue refers to any aggregation of similarly specialized cells which are united in the performance of a particular function.
  • animal as used herein includes, but is not limited to, humans and non-human vertebrates such as wild, domestic and farm animals.
  • patient or "subject” as used herein is an animal, particularly a human, suffering from an unwanted disease or condition that may be treated by the therapeutic and/or compositions described herein.
  • inhibiting generally refers to prevention of the onset of the symptoms, alleviating the symptoms, or eliminating the disease, condition or disorder.
  • room temperature means an indoor temperature of from about 20°C to about 25°C (68 to 77°F).
  • compositions, carriers, diluents, and reagents or other ingredients of the formulation can be used interchangeably and represent that the materials are capable of being administered without the production of undesirable physiological effects such as rash, burning, irritation or other deleterious effects to such a degree as to be intolerable to the recipient thereof
  • Embodiments herein describe a novel therapeutic approach comprising administering a therapeutic agent as an adjunctive therapy for enzyme replacement therapy to treat a lysosomal storage disorder. It is believed that increasing CI-MPR expression could reduce the dosage requirements for ERT or a future gene therapy. Overall, it is believed that the availability of treatments that can improve efficacy of ERT for Pompe disease and other lysosomal storage disorders will reduce the costs of therapies for these diseases. ⁇ 2 agonists are generally affordable and well-tolerated. This therapeutic strategy may also be applicable to other lysosomal storage disorders for which ERT is available, where therapy is complicated by inefficient receptor-mediated uptake of the therapeutic enzyme. Such lysosomal storage disorders include Gaucher disease, Fabry disease, mucopolysaccharidosis type I, mucopolysaccharidosis type II, or Niemann-Pick disease.
  • a method of treating a lysosomal storage disorder in an individual comprises administering a lysosomal enzyme and another therapeutic agent. Certain embodiments are directed to the use of a lysosomal enzyme and another therapeutic agent in the manufacture of a medicament for the treatment of a lysosomal storage disorder.
  • the lysosomal storage disorder to be treated may be Pompe disease (GSD II), Gaucher disease, Fabry disease, mucopolysaccharidosis type I, mucopolysaccharidosis type II, or Niemann-Pick disease.
  • the lysosomal storage disorder is glycogen storage disease II.
  • the glycogen storage disease II may be late-onset Pompe disease (LOPD), juvenile-onset Pompe disease, or infantile Pompe disease.
  • the lysosomal enzyme and the other therapeutic agent are in a single composition.
  • the lysosomal enzyme and the other therapeutic agent may be in separate compositions.
  • the other therapeutic agent may be administered prior to, concurrently with, or after the lysosomal enzyme.
  • the lysosomal enzyme is acid a- glucosidase (GAA).
  • the therapeutic agent is a ⁇ 2 agonist.
  • the individual, patient, or subject being treated may be a human (fetus, child, adolescent, or adult human) having a lysosomal storage disorder, such as, for example, GSD-II (i.e., infantile GSD-II, juvenile GSD-II, or adult- onset GSD-II).
  • GSD-II i.e., infantile GSD-II, juvenile GSD-II, or adult- onset GSD-II
  • the individual may have residual GAA activity, or no measurable activity.
  • the individual having GSD-II may have GAA activity that is less than about 1% of normal GAA activity (infantile GSD-II), GAA activity that is about 1-10% of normal GAA activity (juvenile GSD-II), or GAA activity that is about 10-40% of normal GAA activity (adult GSD-II).
  • the individual may be CRIM-negative for endogenous GAA.
  • the individual is CRIM-positive for endogenous GAA.
  • the individual has been recently diagnosed with the disease. Early treatment (treatment commencing as soon as possible after diagnosis) may be important to minimize the effects of the disease and to maximize the benefits of treatment.
  • adjunctive therapy as described in the various embodiments herein, with a ⁇ 2 agonist will enhance the response to ERT in Pompe disease by increasing the expression of CI-MPR.
  • CI-MPR in type II myofibers, which were glycogen-laden despite ERT, of mice with Pompe disease.
  • Applicants have demonstrated that treatment with a selective ⁇ 2 agonist increased expression of CI-MPR in skeletal muscle, resulting in a marked improvement in the response to ERT in mice with Pompe disease.
  • increasing expression of receptors for a lysosomal enzyme may be used in combination with enzyme replacement therapy, for example, administration and expression of a vector encoding the lysosomal enzyme in the individual.
  • useful vectors include viral vectors, such as an adeno-associated virus (AAV) vector.
  • the individual may receive enzyme replacement therapy prior to, concurrently with, or subsequent to, increasing expression of receptors for the lysosomal enzyme in the individual.
  • the efficacy of the enzyme replacement therapy may be enhanced, including efficacy of the enzyme replacement in brain.
  • the activity of the lysosomal enzyme in the individual may be increased to a level greater than that observed in a patient receiving enzyme replacement therapy alone or in a patient prior to increasing expression of receptors for the lysosomal enzyme.
  • increasing expression of receptors for the lysosomal enzyme is performed by administering a ⁇ 2 agonist
  • the activity of the lysosomal enzyme in the individual is increased to a level greater than that observed in a patient receiving enzyme replacement therapy alone or receiving the ⁇ 2 agonist alone.
  • Some embodiments herein are directed to a method for treating a lysosomal storage disorder (e.g. Pompe disease) by increasing a lysosomal enzyme receptor (e.g. CI-MPR) expression in target tissues.
  • a lysosomal storage disorder e.g. Pompe disease
  • CI-MPR lysosomal enzyme receptor
  • some embodiments of the present disclosure contemplate methods of treating a lysosomal storage disorder in an individual by administering, as an adjunctive therapy, a therapeutic agent to the individual, wherein the individual is undergoing or has undergone enzyme replacement therapy.
  • increasing CI-MPR expression will enhance the uptake and lysosomal targeting of GAA and enhance biochemical correction in skeletal muscle, including in Pompe disease.
  • Some embodiments are directed to methods of increasing CI-MPR expression comprising administering GAA and a ⁇ 2 agonist.
  • a method of increasing CI-MPR expression in an individual having a lysosomal storage disorder comprises administering a ⁇ 2 agonist as an adjuvant therapy, wherein the individual is undergoing or has undergone enzyme replacement therapy with acid alpha- glucosidase, a recombinant form thereof, or a functional equivalent thereof.
  • the lysosomal storage disorder is Pompe disease.
  • Some embodiments herein describe a method of increasing receptor mediated uptake of a lysosomal enzyme, a recombinant form thereof, or a functional equivalent thereof in an individual having a lysosomal storage disorder, the method comprising administering a therapeutic agent as an adjuvant therapy to lysosomal enzyme replacement therapy.
  • the lysosomal enzyme may be in a form that, when administered, targets tissues such as the tissues affected by the disease (e.g., heart, muscle).
  • the lysosomal enzymes may include a human enzyme, recombinant enzyme, wild-type enzyme, synthetic enzyme, or a combination thereof.
  • lysosomal enzymes may be selected from glucocerebrosidase (for the treatment of Gaucher disease; U.S. Pat. No. 5,879,680 and U.S. Pat. No.
  • alpha-glucosidase e.g., acid alpha-glucosidase
  • alpha-galactosidase e.g., alpha-gal, alpha-galactosidase or alpha-gal
  • alpha-n-acetylgalactosaminidase for the treatment of Schindler Disease; U.S. Pat. No. 5,382,524
  • acid sphingomyelinase for the treatment of Niemann- Pick disease; U.S. Pat. No.
  • the lysosomal enzyme is selected from glucocerebrosidase, acid alpha- glucosidase, alpha-galactosidase, alpha-n-acetylgalactosaminidase, acid sphingomyelinase, alpha-iduronidase, or a combination thereof.
  • the lysosomal enzyme may be GAA. In some embodiments, the GAA may be human.
  • the human GAA is administered in its precursor form, as the precursor contains motifs which allow efficient receptor-mediated uptake of GAA.
  • the precursor contains motifs which allow efficient receptor-mediated uptake of GAA.
  • a mature form of human GAA that has been modified to contain motifs to allow efficient uptake of GAA can be administered.
  • the GAA may be GAA, rhGAA, neo-rhGAA (modified recombinant human GAA with synthetic oligosaccharide ligands which is sold by Genzyme Corp.), reveglucosidase alpha (a fusion of IGF-2 and GAA sold by Biomarin Pharmaceuticals, Inc.), ATB200 (an rhGAA with a higher bis-M6P content) that may optionally be administered in combination with AT221 (an oral chaperone molecule -1- deoxynojirimycin) (sold by Amicus Therapeutics, Inc.; described in U.S. Pat. App. No. 12/616,670), or a combination thereof.
  • the rhGAA may be alglucosidase alfa (sold by Genzyme Corp. under the tradename Myozyme® (for infantile onset Pompe disease) and Lumizyme®).
  • the GAA may have a specific enzyme activity in the range of about 1.0-3.5 ⁇ /min/mg protein, preferably in the range of about 2-3.5 ⁇ /min/mg protein. In some embodiments, the GAA has a specific enzyme activity of at least about 1.0 ⁇ /min/mg protein; more preferably, a specific enzyme activity of at least about 2.0 ⁇ /min/mg protein; even more preferably, a specific enzyme activity of at least about 2.5 ⁇ /min/mg protein; and still more preferably, a specific enzyme activity of at least about 2.75 ⁇ /min/mg protein.
  • a method of treating a lysosomal storage disease may be by increasing expression of receptors for the lysosomal enzyme, or otherwise increasing cell surface density of such receptors, in an individual in need thereof.
  • the therapeutic agent may be selected from a growth hormone (e.g., human growth hormone), an autocrine glycoprotein (e.g., Follistatin), and a ⁇ 2 agonist.
  • a growth hormone e.g., human growth hormone
  • an autocrine glycoprotein e.g., Follistatin
  • ⁇ 2 agonist e.g., a growth hormone
  • Such therapeutic agents may selectively modulate expression of receptors for particular lysosomal enzymes. Expression of receptors for a lysosomal enzyme may also be increased by behaviors, such as exercise.
  • a ⁇ 2 agonist may be administered to an individual suffering from adult-onset or late-onset glycogen storage disease II, or a patient who presents with only partial enzyme deficiency, wherein administering the ⁇ 2 agonist results in biochemical correction of the enzyme deficiency in target tissues and improved motor function.
  • ⁇ 2 agonists are molecules that stimulate the receptor. Numerous ⁇ 2 agonists are known in the art and may be used in the therapeutic methods of the invention. In some embodiments, the ⁇ 2 agonist used in embodiments herein may be selected from albuterol, arbutamine, bambuterol, befunolol, bitolterol, bromoacetylalprenololmenthane, broxaterol, carbuterol, cimaterol, cirazoline, clenbuterol, clorprenaline, denopamine, dioxethedrine, dopexamine, ephedrine, epinephrine, etafedrine, ethylnorepinephrine, etilefrine, fenoterol, formotorol, hexoprenaline, higenamine, ibopamine, isoetharine, isoproterenol, isoxs
  • ⁇ 2 agonists used in the disclosed methods do not interact, or show substantially reduced interaction, with ⁇ - adrenergic receptors.
  • the ⁇ 2 agonist is a selective ⁇ 2 agonist.
  • the ⁇ 2 agonist is clenbuterol, albuterol, formoterol, salmeterol, or a combination thereof.
  • the ⁇ 2 agonist is clenbuterol.
  • the ⁇ 2 agonist is albuterol.
  • lysosomal storage disease therapy e.g., substrate deprivations and small molecule therapies
  • lysosomal enzyme replacement therapy including gene therapy (e.g., transfection of cells in a patient with a vector encoding a deficient lysosomal enzyme), or any other form of therapy where the levels of the deficient lysosomal enzyme in a patient are supplemented.
  • these therapies may comprise increasing expression of receptors for a lysosomal enzyme, for example, by administering a therapeutically effective amount of a therapeutic agent (e.g. a ⁇ 2 agonist).
  • a therapeutic agent e.g. a ⁇ 2 agonist
  • the other therapeutic agent may be administered in combination with a second therapeutic agent or treatment.
  • the therapeutic agents or treatments may be administered concurrently or consecutively in either order.
  • the therapeutic agents may be formulated as a single composition or as separate compositions. The optimal method and order of administration of the therapeutic agents capable of increasing expression of a receptor for a lysosomal enzyme and a second therapeutic agent or treatment may be ascertained by those skilled in the art using conventional techniques and in view of the information set out herein.
  • the disclosed combination therapies may elicit a synergistic therapeutic effect, i.e., an effect greater than the sum of their individual effects or therapeutic outcomes.
  • a synergistic therapeutic effect may be an effect of at least about two-fold greater than the therapeutic effect elicited by a single agent, or the sum of the therapeutic effects elicited by the single agents of a given combination, or at least about five-fold greater, or at least about ten-fold greater, or at least about twenty-fold greater, or at least about fifty-fold greater, or at least about one hundred-fold greater.
  • a synergistic therapeutic effect may also be observed as an increase in therapeutic effect of at least 10% compared to the therapeutic effect elicited by a single agent, or the sum of the therapeutic effects elicited by the single agents of a given combination, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 100%, or more.
  • a synergistic effect may also be an effect that permits reduced dosing of therapeutic agents when they are used in combination.
  • a therapeutic agent of embodiments described herein may be administered to a patient in combination with a lysosomal enzyme.
  • the other therapeutic agent and lysosomal enzyme may be components of a single pharmaceutical composition.
  • the other therapeutic agent and lysosomal enzyme may be components of separate pharmaceutical compositions that are mixed together before administration.
  • the other therapeutic agent and lysosomal enzyme may be components of separate pharmaceutical compositions that are administered separately.
  • the other therapeutic agent and the lysosomal enzyme may be administered simultaneously, without mixing (e.g., by delivery of the ⁇ 2 agonist on an intravenous line by which the lysosomal enzyme is also administered).
  • the other therapeutic agent may be administered separately (e.g., not admixed), but within a short time frame (e.g., within 24 hours) prior to or subsequent to administration of the lysosomal enzyme.
  • a synergistic effect may support reduced dosing of ERT when used with the other therapeutic agent and a reduced dosing of the other therapeutic agent.
  • a lysosomal enzyme such as GAA
  • GAA may be administered in a form that targets tissues such as the tissues affected by the disease (e.g., heart, muscle, brain).
  • the lysosomal enzyme may be optionally administered in conjunction with other agents, such as antihistamines or immunosuppressants or other immunotherapeutic agents that counteract anti-lysosomal enzyme antibodies.
  • agents such as antihistamines or immunosuppressants or other immunotherapeutic agents that counteract anti-lysosomal enzyme antibodies.
  • genes encoding the aforesaid lysosomal enzymes are described in the preceding patent publications as well.
  • the patents and published patent applications mentioned in this paragraph are specifically incorporated herein by reference in their entirety, and in particular, the disclosures contained therein with respect to the indicated enzymes, and sequences encoding such enzymes, are also incorporated by reference.
  • administration of a lysosomal enzyme may also encompass administration of a functional equivalent of a lysosomal enzyme.
  • a functional equivalent may include a compound different from the lysosomal enzyme that, when administered to the patient, replaces the function of the lysosomal enzyme to treat the lysosomal storage disorder.
  • Such functional equivalents may include mutants, analogs, and derivatives of lysosomal enzymes.
  • the relevant lysosomal enzyme is an acid alpha-glucosidase.
  • the acid alpha- glucosidase may be a precursor form of human acid alpha-glucosidase, such as recombinant human acid alpha-glucosidase produced in Chinese hamster ovary (CHO) cell cultures.
  • the relevant lysosomal enzyme is glucocerebrosidase, modified glucocerebrosidase or CEREZYME® enzyme.
  • a method of treating a patient having GSD II comprises administering a ⁇ 2 agonist as an adjunctive therapy for enzyme replacement therapy with acid alpha-glucosidase.
  • a method of treating a patient having Pompe disease characterized by reduced or deficient activity of acid a-glucosidase by (a) administering acid a-glucosidase replacement therapy to the patient; and (b) administering a ⁇ 2 agonist to the patient.
  • Cation Independent Mannose-6-Phosphare Receptors are increased in the patient, activity of acid ⁇ -glucosidase is increased in the patient, and/or levels of glycogen are decreased in the patient.
  • the amount of acid alpha-glucosidase required in the ERT may be reduced and the biochemical correction in muscle biopsies may be increased from baseline.
  • a therapeutically effective amount of the other therapeutic agent is administered.
  • the therapeutically effective amount of clenbuterol is about 40 ⁇ g/day to about 160 ⁇ g/day.
  • the therapeutically effective amount is about 20 ⁇ g/day to about 2100 ⁇ g/day, about 20 ⁇ g/day to about 720 ⁇ g/day, about 20 ⁇ g/day to about 500 ⁇ g/day, about 20 ⁇ g/day to about 300 ⁇ g/day, about 20 ⁇ g/day to about 200 ⁇ g/day, about 40 ⁇ g/day to about 2100 ⁇ g/day, about 40 ⁇ g/day to about 720 ⁇ g/day, about 40 ⁇ g/day to about 500 ⁇ g/day, about 40 ⁇ g/day to about 300 ⁇ g/day, about 40 ⁇ g/day to about 200 ⁇ g/day, about 80 ⁇ g/day to about 2100 ⁇ g/day, about 80
  • the therapeutically effective amount of albuterol is about 4 mg/day to about 16 mg/day. In some embodiments, the therapeutically effective amount is about 2 mg/day to about 20 mg/day, about 2 mg/day to about 16 mg/day, about 2 mg/day to about 10 mg/day, about 2 mg/day to about 5 mg/day, about 4 mg/day to about 20 mg/day, about 4 mg/day to about 16 mg/day, about 4 mg/day to about 10 mg/day, about 4 mg/day to about 5 mg/day, about 8 mg/day to about 20 mg/day, about 8 mg/day to about 16 ⁇ g/day, about 8 mg/day to about 10 ⁇ g/day, or a range between any two of these values. In embodiments, the therapeutically effective amount for a particular individual may be varied (e.g., increased or decreased) over time, depending on the needs of the individual.
  • the therapeutic agents may be administered once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 days, or a range between any two of these values. In some embodiments, the therapeutic agents may be administered at least once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 weeks, or a range between any two of these values. In some embodiments, the therapeutic agents may be administered using single or divided doses of every 60, 48, 36, 24, 12, 8, 6, 4, or 2 hours, or a range between any two of these values, or a combination thereof.
  • the methods of the present disclosure contemplate single as well as multiple administrations, given either simultaneously or over an extended period of time.
  • the therapeutic agent may be administered at regular intervals (i.e., periodically) and on an ongoing basis, depending on the nature and extent of effects of the lysosomal storage disease, and also depending on the outcomes of the treatment.
  • the therapeutic agents' periodic administrations may be bimonthly, monthly, biweekly, weekly, twice weekly, daily, twice a day, three times a day, or more often a day. Administrative intervals may also be varied, depending on the needs of the patient.
  • the interval between doses may be decreased.
  • Therapeutic regimens may also take into account half-life of the administered therapeutic agents of embodiments herein.
  • a therapeutically effective amount of a lysosomal enzyme is administered.
  • the lysosomal enzyme is administered as part of a lysosomal enzyme replacement therapy.
  • the therapeutically effective amount of the lysosomal enzyme e.g.
  • GAA is about 1 mg/kg to about 50 mg/kg, about 1 mg/kg to about 40 mg/kg, about 1 mg/kg to about 30 mg/kg, about 1 mg/kg to about 20 mg/kg, about 5 mg/kg to about 50 mg/kg, about 5 mg/kg to about 40 mg/kg, about 5 mg/kg to about 30 mg/kg, about 5 mg/kg to about 20 mg/kg, about 10 mg/kg to about 50 mg/kg, about 10 mg/kg to about 40 mg/kg, about 10 mg/kg to about 30 mg/kg, about 10 mg/kg to about 20 mg/kg, less than about 50 mg/kg, less than about 40 mg/kg, less than about 30 mg/kg, less than about 25 mg/kg, less than about 20 mg/kg, less than about 15 mg/kg, less than about 10 mg/kg, less than about 5 mg/kg, or a range between any two of these values.
  • the effective dose for a particular individual may be varied (e.g., increased or decreased) over time, depending on the needs of the individual. For example, in times of physical illness or stress, or if anti-enzyme antibodies become present or increase, or if disease symptoms worsen, the amount may be increased.
  • the therapeutically effective amount of the lysosomal enzyme may be administered at regular intervals, depending on the nature and extent of the disease's effects, and on an ongoing basis. Administration at a "regular interval,” as used herein, indicates that the therapeutically effective amount is administered periodically (as distinguished from a one-time dose). The interval can be determined by standard clinical techniques.
  • the therapeutic agent's periodic administrations may be bimonthly, monthly, biweekly, weekly, twice weekly, daily, twice a day, three times a day, or more often a day.
  • the administration interval for a single individual need not be a fixed interval, but can be varied over time, depending on the needs of the individual. For example, in times of physical illness or stress, if anti-enzyme antibodies become present or increase, or if disease symptoms worsen, the interval between doses may be decreased.
  • a therapeutically effective amount of 10 mg GAA/kg body weight may be administered weekly. In some embodiments, a therapeutically effective amount of 5 mg GAA/kg body weight may administered twice weekly.
  • the lysosomal enzyme may be administered once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 days, or a range between any two of these values. In some embodiments, the lysosomal enzyme may be administered at least once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 weeks, or a range between any two of these values.
  • the lysosomal enzyme may be administered using single or divided doses of every 60, 48, 36, 24, 12, 8, 6, 4, or 2 hours, or a range between any two of these values, or a combination thereof.
  • the lysosomal enzyme, functional equivalent thereof, or gene may be administered once every about one to about two, about two to about three, about three to about four, or about four to about five weeks.
  • the other therapeutic agent may be administered prior to, or concurrently with, or shortly thereafter, the lysosomal enzyme, functional equivalent thereof or gene encoding such enzyme.
  • the other therapeutic agent may be administered sufficiently prior to administration of the lysosomal enzyme so as to permit modulation (e.g., up-regulation) of the target cell surface receptors to occur, for example, at least about two to about three days, about three to about four days, or about four to about five days before the lysosomal enzyme is administered.
  • a ⁇ 2 agonist in the case of Pompe disease, may be administered to a patient about 0.25, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 hours, or 1, 2, 3, 4, 5, 6, 7, 8 days, prior to administration of acid alpha- glucosidase enzyme, modified acid alpha- glucosidase or a functional equivalent thereof.
  • the optimal dosage of therapeutic agents useful in the invention depend on the age, weight, general health, gender, and severity of the lysosomal storage disease of the individual being treated, as well as route of administration and formulation. A skilled practitioner is able to determine the optimal dose for a particular individual. Additionally, in vitro or in vivo assays may be employed to help to identify optimal dosage ranges, for example, by extrapolation from dose-response curves derived from in vitro or animal model test systems.
  • the therapeutic agents of embodiments herein may be administered by any suitable route, including administration by inhalation or insufflation (either through the mouth or the nose) or oral, sublingual, buccal, parenteral, topical, subcutaneous, intraperitoneal, intravenous, intrapleural, intraocular, intraarterial, rectal administration, or within/on implants, e.g., matrices such as collagen fibers or protein polymers, via cell bombardment, in osmotic pumps, grafts comprising appropriately transformed cells, etc.
  • suitable route including administration by inhalation or insufflation (either through the mouth or the nose) or oral, sublingual, buccal, parenteral, topical, subcutaneous, intraperitoneal, intravenous, intrapleural, intraocular, intraarterial, rectal administration, or within/on implants, e.g., matrices such as collagen fibers or protein polymers, via cell bombardment, in osmotic pumps, grafts comprising appropriately transformed cells, etc.
  • Some embodiments are directed to a pharmaceutical composition comprising the other therapeutic agent and a pharmaceutically acceptable carrier or excipient. Some embodiments are directed to a pharmaceutical composition comprising the lysosomal enzyme and a pharmaceutically acceptable carrier or excipient. Some embodiments are directed to a pharmaceutical composition comprising the other therapeutic agent and a lysosomal enzyme. In some embodiments, a pharmaceutical composition may comprise GAA and a ⁇ 2 agonist. The compositions can be formulated with a physiologically acceptable carrier or excipient to prepare a pharmaceutical composition.
  • the preparation of a pharmacological composition that contains active ingredients dissolved or dispersed therein is well understood in the art.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non- toxic parenterally-acceptable diluent or solvent.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • solid forms suitable for solution, or suspensions, in liquid prior to use can also be prepared. Formulation also varies according to the route of administration selected (e.g., solution, emulsion, capsule).
  • Pharmaceutically acceptable carriers can include inert ingredients which do not interact with the ⁇ 2 agonist, lysosomal enzyme and/or other additional therapeutic agents.
  • These carriers include sterile water, salt solutions (e.g., NaCl), physiological saline, bacteriostatic saline (saline containing about 0.9% benzyl alcohol), phosphate-buffered saline, Hank's solution, Ringer' s-lactate saline, buffered saline, alcohols, glycerol, ethanol, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose, amylose or starch, sugars such as mannitol, sucrose, dextrose, lactose, trehalose, maltose or galactose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid esters, hydroxymethylcellulose and polyvin
  • compositions may be mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, pH buffers, coloring, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compounds.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, pH buffers, coloring, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compounds.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, pH buffers, coloring, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compounds.
  • the compositions of the invention may be lyophilized (and then
  • compositions can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder.
  • the composition can also be formulated as a suppository, with traditional binders and carriers such as triglycerides.
  • Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, polyvinyl pyrollidone, sodium saccharine, cellulose or magnesium carbonate.
  • a composition for intravenous administration typically is a solution in a water- soluble carrier, e.g., sterile isotonic aqueous buffer.
  • the composition may also include a solubilizing agent and a local anesthetic to ease pain at the site of the injection.
  • the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampule or sachette indicating the quantity of active agent.
  • an ampule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
  • the therapeutic agents may be administered as a neutral compound or as a salt or ester.
  • Pharmaceutically acceptable salts may include those formed with free amino groups such as those derived from hydrochloric, phosphoric, acetic, oxalic or tartaric acids, and those formed with free carboxyl groups such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol histidine, and procaine.
  • salts of compounds containing an amine or other basic group can be obtained by reacting with a suitable organic or inorganic acid, such as hydrogen chloride, hydrogen bromide, acetic acid, perchloric acid and the like.
  • a suitable organic or inorganic acid such as hydrogen chloride, hydrogen bromide, acetic acid, perchloric acid and the like.
  • Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like.
  • Salts of compounds containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base such as a hydroxide base. Salts of acidic functional groups contain a countercation such as sodium or potassium.
  • compositions and methods that consist of only the ingredients or steps recited or consist essentially of the ingredients and steps recited, and optionally additional ingredients or steps that do not materially affect the basic and novel properties of the composition or method.
  • EXAMPLE 1 Phase I/II study of oral clenbuterol in adult subjects with Pompe disease
  • the placebo will consist of the same capsules used to disguise clenbuterol tablets, although placebo capsules will contain only dextrose. There will be two phone visits with the subjects to evaluate AEs, one week following the initial administration of clenbuterol at Week 7, and one week after the dose increase at Week 13. Blood sampling for safety testing will be performed at Week 0, 12, 18, and 52 visits.
  • the initial dose of clenbuterol will be 40 meg (one capsule containing two 20 meg tablets) each morning for one week, and the Week 7 phone visit will inquire about any AEs from daily low-dose clenbuterol.
  • the dose of clenbuterol may be reduced for subjects who experience significant side effects to lessen their symptoms as reported for other studies involving ⁇ 2 agonists, and allow those subjects to continue in the study. If the single dose is well tolerated, the clenbuterol dose will be increased to 40 meg (one capsule) BID for the next 5 weeks until the week 12 visit.
  • the dose will be increased to 80 meg (2 capsules) each morning and 40 meg (one capsule) each evening for one week.
  • the Week 13 phone visit will inquire about any AEs, and if the 80 meg morning dose has been well tolerated, the subjects will increase to 80 meg (2 capsules) BID until the week 18 visit.
  • Subjects randomized to placebo will go through the same dose escalations and monitoring, albeit while taking capsules filled with dextrose. This strategy for advancing dosages has been effective in a study with albuterol in LOPD (see Fig. 4).
  • each subject will provide written consent and undergo a screening evaluation to determine eligibility. Screening will consist of taking the medical history, a physical examination, and an electrocardiogram (EKG). Baseline pulmonary function testing will be obtained, and urine will be collected for biomarker analysis. Exclusion criteria will include abnormal EKG, hyperthyroidism, taking incompatible medications, pregnancy, or hypertension. Muscle function and strength testing will be performed on Day 0, and muscle biopsy will be performed on Day 1. The subject will return after 6 weeks for repeat muscle function and strength testing, prior to randomization. The Week 12 visit will assess safety and tolerability, and reassess muscle function testing. The Week 18 visit will evaluate safety and efficacy by performing blood testing, EKG, PFT, and muscle strength and function testing. At Week 52 safety and efficacy will be evaluated prior to a repeat muscle biopsy to determine the effect of clenbuterol on CI-MPR and glycogen content.
  • EKG electrocardiogram
  • the effect of ⁇ 2 agonist therapy upon receptor-mediated uptake of rhGAA in subjects with LOPD will be determined.
  • the effects of ⁇ 2 agonist therapy upon CI-MPR expression will be evaluated in adult subjects with LOPD undergoing ERT with rhGAA during a 12 week study. The dose will be increased after 6 weeks to optimize its effect, if the initial dose is well tolerated.
  • the impact of enhanced CI-MPR-mediated uptake of GAA will be analyzed by comparing muscle function and biochemical correction of glycogen accumulation in muscle at baseline and during clenbuterol administration. The urinary biomarker, Glc 4 , will be monitored. These studies will reveal any correlation between biochemical correction and clinical endpoints.
  • Muscle strength and muscle function will be evaluated with measures of impairment, function, participation, and quality of life at Week 0, 6 12, 18 and 52. Isolated muscle strength will be tested with hand held dynamometry as performed previously (Fig. 3A). Functional strength measures will include classic upper and lower extremity functional grades, GMFM, timed functional tests, and graded functional tests which will be included to allow scoring with the Gait, Stairs, Gowers, Chair (GSCS), and the Quick Motor Function Test, all of which have been used with LOPD, and which offer quantitative assessment of activities of elevation against gravity and gait. Endurance will be assessed with the 6MWT. Pulmonary function will be assessed in both the supine and upright positions to increase sensitivity for abnormalities detected in Pompe disease. Fatigue will be assessed with the Fatigue Severity Scale, level of disability will be assessed with the Rotterdam Handicap Scale, and quality of life will be measured with a SF36 health survey .
  • Pulmonary function testing will include measuring FVC, maximum voluntary ventilation (MVV), and will be measured by electronic spirometer. Pulmonary function will be assessed in both the supine and upright positions to increase sensitivity for abnormalities detected in Pompe disease.
  • Subjects will undergo a muscle biopsy of the quadriceps at the baseline and final visits in this study.
  • the muscle biopsy will be performed in the EMG Clinic at Duke University Medical Center.
  • the needle muscle biopsy is performed under local anesthesia, and subjects have not experienced adverse effects following this procedure beyond transient local pain following the procedure. Other risks associated with the procedure include hematoma, infection and scar formation.
  • the muscle biopsy will be evaluated for biochemical correction as demonstrated by GAA activity and glycogen content, and for CI-MPR expression by Western blot analysis.
  • Oral clenbuterol treatment should increase the performance on muscle strength, muscle functional testing, and pulmonary function testing of subjects with LOPD, based upon published data regarding the outcomes of clinical trials of ERT in subjects with LOPD.
  • the effects of clenbuterol with ERT might be dramatic enough to produce significant improvements in muscle strength and function.
  • increased biochemical correction in the muscle biopsies should be obtained following clenbuterol treatment, in comparison with the baseline muscle biopsy (Fig. IB).
  • mice were treated with four weekly doses of rhGAA (20 mg/kg body weight), with or without concurrent ⁇ 2- agonist treatment.
  • Tolerant GAA mice do not form anti-GAA antibodies or develop hypersensitivity reactions during ERT with rhGAA, similar to the majority of patients with LOPD.
  • clenbuterol treatment in comparison with albuterol treatment, was demonstrated by enhanced efficacy in comparison with ERT alone as follows: 1) Rotarod latency was increased reflecting improved neuromuscular function; 2) glycogen content was significantly decreased in the diaphragm, quadriceps, gastrocnemius, EDL, and soleus muscles; and 3) clenbuterol treatment alone did not achieve efficacy with regard to muscle testing or performance in GAA-KO mice. Subsequently, urinary Glc 4 was analyzed to evaluate it as a biomarker for the evaluation of adjunctive clenbuterol therapy. Urinary Glc 4 was significantly reduced by adjunctive therapy with clenbuterol (Fig. 2), further validating this noninvasive biomarker for monitoring the response to therapy in Pompe disease.
  • CI-MPR detection by Western blot analysis revealed that clenbuterol treatment increased CI-MPR in the EDL muscle and brain. Histopathology was performed to examine brain involvement, and glycogen accumulations were detected in the cerebellum with ERT alone. Both albuterol and clenbuterol reduced the glycogen staining in the cerebellum and hippocampus, in comparison with ERT alone. Increased CI-MPR expression correlated with increased biochemical correction in muscle and brain, and with improved muscle function following p2-agonist treatment. The effect of clenbuterol was further demonstrated to enhance efficacy and reverse neuromuscular involvement from low- dose gene therapy in GAA-KO mice.
  • DKO mice should have a decreased response to the combination of p2-agonist treatment, if CI-MPR modulates the effect of p2-agonists upon ERT.
  • Glycogen content of the heart, diaphragm, and gastrocnemius was only very slightly reduced following high dose clenbuterol and ERT, in comparison with mock treatment.
  • Clenbuterol by itself failed to decrease glycogen content in GAA-KO mice that did express CI-MPR, confirming that biochemical correction depended on ERT, not the P2-agonist drug by itself.
  • a study of albuterol as adjunctive therapy in patients with LOPD on ERT has been initiated.
  • the design is similar to the above example, although without a placebo group (Fig. 4A).
  • subjects undergo a baseline evaluation including blood safety testing, EKG, pulmonary function testing, muscle function and strength testing, and muscle biopsy at Week 0, and subjects return at Week 6 and 12 for follow-up evaluations.
  • the dose of albuterol is increased, barring dose-limiting AEs.
  • EKG, pulmonary function testing, and muscle biopsy are completed at Week 12. Only subjects stably treated with ERT for greater than two years have been enrolled in this study, and inclusion/exclusion criteria are identical to those for the proposed study of clenbuterol.
  • Preliminary data revealed that the 6MWT increased in all 5 subjects at the Week 6 visit following initiation of albuterol at baseline. Two of 7 subjects have completed only the Week 0 visit, having been enrolled ⁇ 6 weeks (data not shown). An increased 6MWT distance from baseline to week 6 in the 6MWT for all 5 subjects was observed. The change in 6MWT on ERT was assessed retrospectively for subjects followed at Duke University. Prior 6MWT data was retrieved for 3 of 5 subjects, which allowed calculation of change in 6MWT between 3-6 months earlier and Week 0 (Pre-albuterol).
  • the 6MWT had decreased (Subject 4), stayed the same (Subject 1 ), or increased slightly (Subject 5) prior to study entry (Prealbuterol); whereas the 6MWT increased for all 3 subjects from baseline to Week 6 (Albuterol).
  • This group of subjects had a negative mean change in 6MWT (-13 +/- 30 meters) in the months prior to stalling albuterol (Prealbuterol), which was reversed after 6 weeks of albuterol (32 +/- 19 meters for those 3 subjects).
  • the mean change in 6MWT for the initial group of 5 subjects over the first 6 weeks was 30 +/- 14 meters, which is equivalent to the increased time in the 6MWT observed after 24 weeks in the initial study of ERT in LOPD.
  • the change in 6MWT after 12 weeks in the study of van der Ploeg et al. was only 14 +/- 3 meters, less than 50% of the observed change after 6 weeks in this pilot study of adjunctive albuterol.
  • an early increase in 6MWT at Week 6 was observed in a stable population of subjects with LOPD on ERT and albuterol, which has exceeded the increase observed at early timepoints in the initial trial of ERT.
  • the albuterol dose was gradually increased to minimize AEs, starting with 4 mg each morning per oral for the first week. If no AEs greater than mild were reported at the Week I phone visit, the dose was increased to 4 mg BID per oral. If the albuterol dose was similarly well-tolerated at the Week 6 visit, the dose was increased to 8 mg in the morning, and remained at 4 mg in the evening for the next week. Finally, if the Week 7 phone visit revealed no more than mild AEs, the evening dose was increased to 8 mg. This dose titration has prevented attrition related to the effects of albuterol, and all 5 subjects who completed the Week 6 visit have tolerated the 8 mg BID dose. Only mild AEs have been reported, including tremor, transient difficulty falling asleep, and mild urinary retention (requiring early morning voiding).
  • This study evaluated 4 new drugs in GAA-KO mice in combination with an adeno-associated virus (AAV) vector encoding human GAA.
  • AAV adeno-associated virus
  • the dosage for each drug was selected to induce muscle hypertrophy with an associated increased expression of CI- MPR, analogous to clenbuterol's effects.
  • Three alternative ⁇ 2 agonists and dehydroepiandrosterone (DHEA) were tested, given that these drugs were expected to upregulate both Igf-1 and downstream Igf-2R/CI-MPR, similar to clenbuterol. See Table 3.
  • Table 3 Small molecule thera ies evaluated in combination with gene therapy
  • mice were injected with AAV2/9-CBhGAApA [lE+11 vector particles (vp)] at a dose previously found to be partially effective at clearing glycogen storage from the heart following the induction of immune tolerance to GAA.
  • Drugs were dosed continuously at dosages determined from the literature (Table 3). After 18 weeks striated muscles were analyzed for GAA and glycogen content. Heart GAA activity was significantly increased by either salmeterol (p ⁇ 0.01) or DHEA (p ⁇ 0.05), in comparison with untreated GAA-KO mice (Fig. 6A).
  • glycogen content was reduced by treatment with DHEA (p ⁇ 0.001), salmeterol (p ⁇ 0.05), formoterol (p ⁇ 0.01), or clenbuterol (p ⁇ 0.01) in combination with the AAV vector, in comparison with untreated mice (Fig. 6A).
  • the reduction of glycogen content in absence of significantly increased GAA activity has been observed following the addition of an adjunctive ⁇ 2 agonist.
  • glycogen content of the heart and skeletal muscle remained highly elevated in comparison with nearly undetectable amounts of glycogen observed in wildtype mice.
  • the GAA activity and glycogen content of the diaphragm and quadriceps were not affected by any of the treatments (Fig. 6B), consistent data showing that heart muscle is more responsive to GAA replacement than skeletal muscle.
  • DHEA dehydroepiandrosterone
  • mice were transgenic for a liver-specific human GAA transgene to induce immune tolerance to introduced GAA and were treated with clenbuterol at a low dose demonstrated to improve the response to ERT as described.
  • Three new ⁇ 2 agonists were chosen to be longer acting than albuterol, because the long-acting ⁇ 2 agonist clenbuterol has been more efficacious than albuterol in rodent experiments.
  • Limitations of the current experiment include a lack of detectable effect upon CI-MPR expression from adjunctive therapy, and a lack of effect of therapy upon the skeletal muscles.
  • One limitation of the current experiment is that CI-MPR was not significantly increased by ⁇ 2 agonist administration, in contrast to prior studies. This may reflect the variability of the individual response to drug therapy over the course of the 18 week experiment, and expect that a larger study with more mice per group might reveal statistically significant increases in CI-MPR.
  • the statistically significant reduction in autophagosomes demonstrated by lower LC3-II indicated that the abnormal accumulation observed in Pompe disease were reduced by the addition of adjunctive ⁇ 2 agonists during ERT.
  • the lack of effect from gene therapy in the skeletal muscles can be attributed to lower efficiency of transduction with an AAV2/9 vector in skeletal muscle, in comparison with the heart.
  • salmeterol has highly effective in comparison with the other drugs evaluated herein. Thus, salmeterol should be further developed as adjunctive therapy in combination with either ERT or gene therapy for Pompe disease.

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Abstract

La présente invention concerne des procédés pour traiter une maladie lysosomale par administration d'un agent thérapeutique comme traitement d'appoint à une thérapie de remplacement d'enzyme lysosomale. D'autres modes de réalisation concernent des procédés pour accroître l'expression d'un récepteur pour une enzyme lysosomale, et des procédés pour traiter une maladie lysosomale. Certains modes de réalisation concernent un procédé pour traiter une maladie de stockage de glycogène II chez un individu par administration, à l'individu, d'un alpha-glucosidase acide et d'un agoniste β2. Certains modes de réalisation de l'invention concernent un procédé pour traiter une maladie de stockage de glycogène II par administration (1) de rhGAA; et (2) de clenbutérol.
PCT/US2016/052254 2015-09-18 2016-09-16 Alpha-glucosidase acide et agoniste β-2 pour le traitement de maladie lysosomale WO2017049161A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018213340A1 (fr) * 2017-05-15 2018-11-22 Amicus Therapeutics, Inc. Alpha-glucosidase d'acide humain recombinant
WO2019051297A1 (fr) * 2017-09-08 2019-03-14 The Nemours Foundation Agent, dispositif et système de circulation sanguine pour traiter des maladies lysosomales, et méthodes de traitement de maladies lysosomales
US11103596B2 (en) 2015-05-11 2021-08-31 Ucl Business Plc Fabry disease gene therapy

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US20120082653A1 (en) * 2010-10-04 2012-04-05 Duke University Methods of lysosomal storage disease therapy
WO2014000058A1 (fr) * 2012-06-29 2014-01-03 Garvan Institute Of Medical Research Méthode de traitement de troubles du métabolisme des sucres
WO2014120900A1 (fr) * 2013-01-31 2014-08-07 Icahn School Of Medicine At Mount Sinai Régimes thérapeutiques améliorés pour le traitement de la maladie de fabry
US20140234288A1 (en) * 2005-09-08 2014-08-21 Children's Hospital Medical Center Lysosomal Acid Lipase Therapy for NAFLD and Related Diseases
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US20140234288A1 (en) * 2005-09-08 2014-08-21 Children's Hospital Medical Center Lysosomal Acid Lipase Therapy for NAFLD and Related Diseases
US8815297B2 (en) * 2009-03-31 2014-08-26 Duke University Modulation of beta 2 adrenergic receptors by inhibitors of EGLN3 or pVHL
US20120082653A1 (en) * 2010-10-04 2012-04-05 Duke University Methods of lysosomal storage disease therapy
WO2014000058A1 (fr) * 2012-06-29 2014-01-03 Garvan Institute Of Medical Research Méthode de traitement de troubles du métabolisme des sucres
WO2014120900A1 (fr) * 2013-01-31 2014-08-07 Icahn School Of Medicine At Mount Sinai Régimes thérapeutiques améliorés pour le traitement de la maladie de fabry

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11103596B2 (en) 2015-05-11 2021-08-31 Ucl Business Plc Fabry disease gene therapy
WO2018213340A1 (fr) * 2017-05-15 2018-11-22 Amicus Therapeutics, Inc. Alpha-glucosidase d'acide humain recombinant
WO2019051297A1 (fr) * 2017-09-08 2019-03-14 The Nemours Foundation Agent, dispositif et système de circulation sanguine pour traiter des maladies lysosomales, et méthodes de traitement de maladies lysosomales
JP2021508312A (ja) * 2017-09-08 2021-03-04 ザ ヌムール ファウンデーション リソソーム蓄積症を治療するための薬剤、デバイス、および血液循環システム、ならびにリソソーム蓄積症を治療するための方法
JP7252211B2 (ja) 2017-09-08 2023-04-04 ザ ヌムール ファウンデーション リソソーム蓄積症を治療するための薬剤、デバイス、および血液循環システム、ならびにリソソーム蓄積症を治療するための方法

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