[go: up one dir, main page]

WO2012022740A1 - Polythérapie contre la sclérose en plaques - Google Patents

Polythérapie contre la sclérose en plaques Download PDF

Info

Publication number
WO2012022740A1
WO2012022740A1 PCT/EP2011/064080 EP2011064080W WO2012022740A1 WO 2012022740 A1 WO2012022740 A1 WO 2012022740A1 EP 2011064080 W EP2011064080 W EP 2011064080W WO 2012022740 A1 WO2012022740 A1 WO 2012022740A1
Authority
WO
WIPO (PCT)
Prior art keywords
vitamin
treatment
interferon
multiple sclerosis
subjects
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2011/064080
Other languages
English (en)
Inventor
Manolo Beelke
Jérôme Dauvillier
Isabelle Guilleret
Emmanuel Monnet
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Serono SA
Original Assignee
Merck Serono SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Serono SA filed Critical Merck Serono SA
Publication of WO2012022740A1 publication Critical patent/WO2012022740A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • 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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/215—IFN-beta
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to the use of Vitamin D in combination with Interferon-beta for the treatment of multiple sclerosis.
  • MS Multiple sclerosis
  • MS may result in the accumulation of various neurological disabilities.
  • Clinical disability in MS is presumed to be a result of repeated inflammatory injury with subsequent loss of myelin and axons, leading to tissue atrophy.
  • MS is manifested in physical symptoms (relapses and disability progression), Central Nervous System (CNS) inflammatory and neurodegenerative processes (as reported on MRI read outs), brain atrophy and cognitive impairment. Presenting symptoms include focal sensory deficits, focal weakness, visual problems, imbalance and fatigue. Sexual impairment and sphincter dysfunction may occur. Approximately half of the patients with MS may experience cognitive impairment or depression.
  • CNS Central Nervous System
  • MS is now considered to be a multi-phasic disease and periods of clinical quiescence (remissions) occur between exacerbations. Remissions vary in length and may last several years but are infrequently permanent.
  • RR relapsing-remitting
  • SP secondary progressive
  • PP primary progressive
  • PR progressive relapsing
  • MS onset is defined by the occurrence of the first neurological symptoms of CNS dysfunction in addition to at least further signs of dissemination in space and time of CNS lesions (MRI supported or clinically confirmed). Advances in cerebrospinal fluid (CSF) analysis and magnetic resonance imaging (MRI) have simplified the diagnostic process and facilitated early diagnostic.
  • CSF cerebrospinal fluid
  • MRI magnetic resonance imaging
  • the International Panel on the Diagnosis of MS issued revised criteria facilitating the diagnosis of MS and including MRI together with clinical and para-clinical diagnostic methods (Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, Lublin FD, Metz LM, McFarland HF, O 'Connor PW, Sandberg-Wollheim M, Thompson A J, Weinshenker BG, Wolinsky JS. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria”. Ann Neurol. 2005 Dec; 58(6): 840ff).
  • Azathioprine is produced by a number of generic manufacturers and as branded name, it is approved for example in Germany.
  • immunosuppressive agents are used, although not FDA approved.
  • Cladribine a chlorinated purine analogue 2-chloro- 2'deoxyadenosine analogue (2-CdA)
  • 2-CdA chlorinated purine analogue 2-chloro- 2'deoxyadenosine analogue
  • the present invention is directed towards a method of treating a subject suffering from multiple sclerosis wherein Vitamin D or an analogue thereof is administered on top of Interferon-beta.
  • Vitamin D or an analogue thereof is administered during a titration period of 4 weeks in a dose of 7 ⁇ 00 IU/day and thereafter in a dose of 14 ⁇ 00 IU/day.
  • Interferon-beta is Interferon- betala, more preferably Rebif®.
  • Interferon is administered in a dose of 22 or 44 ⁇ g three times a week.
  • Vitamin D or an analogue thereof is administered orally and Interferon is administered intramuscularly or subcutaneously.
  • the subject has a 25-hydroxy- vitamin D plasma level before treatment below 150 nmol/L.
  • the subject is carrier of a variant of the CYP24A1 gene.
  • MS MS is a chronic disease without any cure currently available
  • the above-mentioned drugs are the only therapeutic agents able to slow down the disease progression of MS.
  • long-term treatment is required, as well as high treatment adherence.
  • the currently marketed formulation of Rebif® (recombinant human interferon beta- la) has been evaluated in a series of well-controlled MS studies that have demonstrated that Rebif® significantly reduces clinical attack rate, MRI lesion activity, accumulation of new lesion burden, and disability progression.
  • Vitamin D or an analogue thereof is administered according to the invention during a titration period in a dose of 7 ⁇ 00 IU/day and thereafter in a dose of 14 ⁇ 00 IU/day.
  • the titration period has a duration of about 4 weeks. This dosing leads to particularly good results.
  • Interferon-beta is administered in the methods of the invention according to approved standard treatment regimes, in particular in a dose of 22 or 44 ⁇ g three times a week.
  • interferon-beta IFN- ⁇
  • IFN- ⁇ interferon-beta
  • fibroblast interferon in particular of human origin, as obtained by isolation from biological fluids or as obtained by DNA recombinant techniques from prokaryotic or eukaryotic host cells, as well as its salts, functional derivatives, variants, analogs and active fragments.
  • IFN- ⁇ suitable in accordance with the present invention is commercially available e.g. as Rebif® (Serono), Avonex® (Biogen) or Betaferon® (Schering).
  • the use of interferons of human origin is also preferred in accordance with the present invention.
  • the term interferon, as used herein, is intended to encompass salts, functional derivatives, variants, analogs and active fragments thereof.
  • Rebif® (recombinant human interferon- ⁇ ) is the latest development in interferon therapy for multiple sclerosis (MS) and represents a significant advance in treatment.
  • Rebif® is interferon (IFN)-beta la, produced from mammalian cell lines.
  • Interferon beta- la can have a positive effect on the long-term course of MS by reducing number and severity of relapses and reducing the burden of the disease and disease activity as measured by MRI.
  • the dosing of IFN- ⁇ in the treatment of relapsing-remitting MS according to the invention depends on the type of IFN- ⁇ used.
  • IFN is recombinant IFN- ib produced in E. Coli, commercially available under the trademark Betaseron®
  • it may be administered sub-cutaneously every second day at a dosage of about of 250 to 300 ⁇ g or 8 MIU to 9.6 MIU per person.
  • IFN is recombinant IFN- ia, produced in Chinese Hamster Ovary cells (CHO cells), commercially available under the trademark Avonex®, it may be administered intra-muscularly once a week at a dosage of about of 30 ⁇ g to 33 ⁇ g or 6 MIU to 6.6 MIU per person.
  • IFN when IFN is recombinant IFN- ia, produced in Chinese Hamster Ovary cells (CHO cells), commercially available under the trademark Rebif®, it may be administered sub-cutaneously three times a week (TIW) at a dosage of 22 to 44 ⁇ g or 6 MIU to 12 MIU per person.
  • TIW sub-cutaneously three times a week
  • Vitamin D according to the invention is preferably Vitamin D3 (cholecalciferol). Vitamin D according to the invention may also be Vitamin D2 (ergocalciferol). According to the invention it is most preferred to use the cholecalciferol product Vigantol® oil.
  • "Analogues of Vitamin D” according to the invention are structurally modified Vitamin D derivatives which are approximately equal to Vitamin D in lessening a patient's multiple sclerosis symptoms when used in combination with Interferon-beta, while preferably producing fewer side effects.
  • analogues of Vitamin D encompasses for example the following compounds: 22- Oxacalcitriol, Paricalcitol, Doxercalciferol, Alfacalcidol, Dihydrotachysterol 2 and Falecalcitriol.
  • 22-oxacalcitriol (OCT) differs from l,25(OH) 2 D 3 by virtue of an oxygen atom replacing carbon-22 on the side chain.
  • Paricalcitol is a vitamin D 2 derived sterol lacking the carbon- 19 methylene group found in all natural vitamin D metabolites.
  • Doxercalciferol (lo:-hydroxy vitamin D 2 ), like alfacalcidol (lis-hydroxy vitamin D 3 ), is a pro-drug which is hydroxylated in the liver to 1 « ,25(OH) 2 D 2 .
  • doxercalciferol is also 24-hydroxylated to produce le3 ⁇ 4,24(S)- (OH) 2 D 2 , a metabolite with potent pro-differentiation actions and low calcaemic potency.
  • Dihydrotachysterol 2 (DHT 2 ) hydroxylated in vivo to 25(OH)DHT 2 and l,25(OH) 2 DHT 2 is also of interest.
  • the fluorinated calcitriol analogue 26,27-hexafluorocalcitriol may also be used.
  • Vitamin D is biologically inactive and is a precursor for hormone-like active substances that influence the regulation of the calcium and phosphate balance.
  • the most important, though most probably not the only, metabolically active metabolite is 1, 25-dihydroxycholecalciferol (1, 25- (OH) 2 D 3 ) or calcitriol.
  • the cellular effect of calcitriol is mediated, like the mechanism of action of other steroid hormones, via binding to a nuclear receptor protein, the vitamin D receptor. Calcitriol regulates the transcription of specific genes.
  • the primary sites of activity for the vitamin D hormones are the bone intestine, kidney, and parathyroid.
  • Calcitriol plays not only a pivotal role in systemic calcium homeostasis but also in the intracellular calcium homeostasis of various tissues.
  • Vitamin D receptors are present in more than 30 different tissues and calcitriol can be locally produced in tissues that possess vitamin D receptors. The number of genes known to be regulated by the vitamin D hormone is still growing. Effects on other cell systems include modulation of the immune system and inhibition of proliferation of cancer cells.
  • Epidemiological data indicate that a low vitamin D status is correlated with disturbed muscle function, tuberculosis, rheumatoid arthritis, type 1 diabetes, multiple sclerosis (MS), inflammatory bowel diseases, hypertension and specific types of cancer (Barthel et al. Dtsch Med Klischr 2003, 128:440-46; Bikle DD, Current Opinion in Rheumatology 2007, 19, 4:383-8; Zittermann A., British Journal of Nutrition 2003, 89:552-572).
  • Vitamin D 3 decreases the proliferation of pro-inflammatory T lymphocytes and influences the production of cytokines, both of which contribute to the pathogenesis of MS (Cantorna et al. J Immunol 1998, 160 :5314-5319 ; Kimball et al, Am J Clin Nutr 2007, 86:645- 651; Takeuchi et al, J Immunol 1998, 160:209-218 )
  • 25(OH) D 25-hydroxyvitamin D
  • Vitamin D there are no clinical studies available on the benefit of administering Vitamin D on top of established therapies for multiple sclerosis.
  • the present invention provides evidence that daily administration of 14 '000 IU Vitamin D in conjunction with standard treatment with Interferon-beta results in particularly good clinical efficacy in multiple sclerosis treatment.
  • This new add-on therapy is particularly beneficial to subjects with a low Vitamin D status.
  • Vitamin D status is defined as serum levels of 25 -hydroxy vitamin D (25(OH)D).
  • a low endogenous Vitamin D status according to this invention is defined as a 25 -hydroxy- vitamin D plasma level before treatment below 100 nmol/L.
  • vitamin D status is determined not only by the dietary intake of vitamin D, and exposure of the skin to sun, but also by genetic constitution.
  • Orton et al. showed that a genetic factor contributes to the 25(OH)D levels which were measured in the sera of their participants (Orton et al. Am J Clin Nutr 2008;88:441-7). A heritability estimate of 0.77 was calculated.
  • polymorphisms within several vitamin D metabolism-related genes have been assessed, including S Ps in the vitamin D receptor (VDR), vitamin D binding protein (VDBP), CYP27B1, and CYP24A1.
  • Subjects which are carriers of a variant of the CYP24A1 gene may have low Vitamin D status and thus the methods according to this invention would be particularly beneficial to them (Fu et al, Clin. Biochem. 2009 Jul : 42 (10-11): 1174-7. Epub 2009 May 18).
  • Table 1 List of CYP24A1 genetic variants found associated with the absence of relapses.
  • Figure 1 shows the distribution of genotype of SNP rs 2762934 in gene CYP24A1 and of the absence of relapses.
  • the total number of subj ects is indicated at the bottom of each patch.
  • the number of responders is indicated at the top of each patch.
  • the dotted line represents the mean response for the total population.
  • P-value is based on Fisher' s test.
  • Figure 2 shows the distribution of genotype of SNP rs2296241 in gene CYP24A1 and of the absence of relapses.
  • the total number of subjects is indicated at the bottom of each patch.
  • the number of responders is indicated at the top of each patch.
  • the dotted line represents the mean response for the total population.
  • P-value is based on Fisher' s test.
  • Figure 3 shows the distribution of genotype of SNP rs2762942 in gene CYP24A1 and of the absence of relapses.
  • Total number of subjects is indicated at the bottom of each patch.
  • the number of responders is indicated at the top of each patch.
  • the dotted line represents the mean response for the total population.
  • P-value is based on Fisher's test.
  • GG 100% For each of these markers, the proportion of subjects responding to treatment was higher for carriers of the G allele. Based on the observed association, it was concluded that genetic variants involved in vitamin D metabolism could affect the disease course. Therefore supplementing current treatments by adapting vitamin D concentrations based on the genetic background of the patients could enhance the effectiveness of the treatments. For example, carriers of AA genotype might receive a high dose, carriers of AG a lower dose, and carriers of GG an even smaller dose.
  • a week refers to a period of time of about 7 days.
  • treat or “treating” as used herein is meant to ameliorate, alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.
  • treatment as used herein also encompasses the term “prevention of the disorder”, which is, e.g., manifested by delaying the onset of the symptoms of the disorder to a medically significant extent. Treatment of the disorder is, e.g., manifested by a decrease in the symptoms associated with the disorder or an amelioration of the reoccurrence of the symptoms of the disorder.
  • a typical MS relapse involves a period of worsening, with development of neurological deficits, then a plateau, in which the patient is not getting any better but also not getting any worse followed by a recovery period. Recovery usually begins within a few weeks.
  • Effectiveacy of a treatment according to the invention can be measured based on changes in the course of disease in response to a use according to the invention.
  • treatment of MS efficacy can be measured by the frequency of relapses in RRMS and the presence or absence of new lesions in the CNS as detected using methods such as MRI technique ⁇ Miller et al, 1996, Neurology, 47(Suppl 4): S217; Evans et al, 1997, Ann. Neurology, 41: 125-132).
  • Secondary efficacy variables include MRI Ti enhanced brain lesion volume, MRI Ti enhanced lesion number, MRI T 2 lesion volume (thought to represent total disease burden, i.e. demyelination, gliosis, inflammation and axon loss), MRI Ti enhanced hypointense lesion volume (thought to represent primarily demyelination and axon loss), time-to-progression of MS, frequency and severity of exacerbations and time-to-exacerbation, Expanded Disability Status Scale score and Scripps Neurologic Rating Scale (SNRS) score (Sipe et al, 1984, Neurology, 34, 1368-1372). Methods of early and accurate diagnosis of multiple sclerosis and of following the disease progression are described mMattson, 2002, Expert Rev. Neurotherapeutics, 319-328.
  • Degree of disability of MS patients can be for example measured by Kurtzke Expanded Disability Status Scale (EDSS) score (Kurtzke, 1983, Neurology, 33, 1444-1452).
  • EDSS Kurtzke Expanded Disability Status Scale
  • a decrease in EDSS score corresponds to an improvement in the disease and conversely, an increase in EDSS score corresponds to a worsening of the disease.
  • compositions of this invention may further comprise one or more pharmaceutically acceptable additional ingredient(s).
  • Compositions of this invention may be liquid formulations including, but not limited to, aqueous or oily suspensions, solutions, emulsions, syrups, and elixirs.
  • the compositions may also be formulated as a dry product for constitution with water or other suitable vehicle before use.
  • Patients according to the invention are patients suffering from multiple sclerosis, preferably RRMS or early SPMS with superimposed relapses.
  • patients are selected from human males or females between 18 and 65 years age.
  • patients had at least one relapse within the prior 12 months of the treatment.
  • Example 1 Vigantol® oil as add-on to Rebif® in the treatment of RRMS
  • a maximum of 358 eligible subjects are enrolled in this trial: 348 subjects with 25-hydroxy-vitamin D plasma levels below 150 nmol/L and around 10 subjects with 25-hydroxy-vitamin D plasma levels equal or higher than 150 nmol/L.
  • Patients are selected from Male or Female, between 18 and 65 years of age with a history of one recent MS attack or an MRI-based proven disease activity within the last 12 months before screening.
  • Female subjects must be neither pregnant nor breastfeeding and must lack child-bearing potential, as defined by either being post-menopausal or surgically sterile or using a highly effective method of contraception for the entire duration of the trial.
  • the subjects with 25 -hydroxy- vitamin D plasma levels below 150 nmol/L are randomized to Treatment Group 1 or 2.
  • the subjects with 25 -hydroxy- vitamin D plasma levels equal or higher than 150 nmol/L are automatically assigned to Treatment Group 3.
  • Treatment Group 1 Vigantol oil® 14.000 IU/d (350 ⁇ g/d) as add-on to Rebif® 22 or 44 ⁇ g three times a week in subjects with 25-hydroxy -vitamin D plasma levels below 150 nmol/L (174 subjects)
  • Treatment Group 2 Matching placebo daily as add-on to Rebif® 22 or 44 ⁇ g three times a week in subjects with 25-hydroxy-vitamin D plasma levels below 150 nmol/L (174 subjects)
  • Treatment Group 3 Matching placebo daily as add-on to Rebif® 22 or 44 ⁇ g three times a week in subjects with 25-hydroxy-vitamin D plasma levels equal or higher than 150 nmol/L (around 10 subjects)
  • IVRS interactive voice-response system
  • Randomization is done only for subjects with 25-hydroxy-vitamin D plasma levels lower than 150 nmol/L by means of IVRS. These subjects are randomly assigned to Vigantol oil® (Treatment Group 1) and placebo treatment (Treatment Group 2) in a 1 : 1 ratio on top of the preexisting treatment with Rebif®. Subjects with 25-hydroxy-vitamin D plasma levels equal or higher than 150 nmol/L are assigned automatically to Treatment Group 3. All three treatment groups are double- blinded for all assessments.
  • pre-dosing baseline assessments are performed for safety (blood sample), MRI and Neurological evaluation.
  • one single blood sample is taken for exploratory PGx analysis at Study Day 1.
  • MRI scans are performed after 48 and 96 weeks from Study Day 1.
  • Blood samples are collected for routine analysis at Weeks 4 and 12, and every 12 weeks thereafter.
  • Neurological assessments are performed at Study Day 1 and every 12 weeks.
  • double-blinding is ensured for the whole duration of the 96 weeks of the treatment period for all subjects' assessments of all three treatment groups. Double blinding is ensured by means of the Two-Physician concept for the clinical assessments and by means of centralized lab procedures for MRI, PGx, heamatology and blood chemistry analysis.
  • the Two-Physician concept consists of a "Treating Physician” and an "Evaluating Physician".
  • the treating Physician is responsible for all aspects of treatment and clinical management of the subject, including the management of clinical attacks. He has the same blinding as the subject.
  • the Evaluating Physician performs all the standardized neurological examinations needed. He is completely blinded to all aspects related to the subj ect' s treatment, including the assessment of side effects and drug administration problems.
  • the primary endpoint is a composite endpoint, based on predefined MRI and clinical efficacy outcomes:
  • the primary MRI endpoint is the change from baseline in the mean number of T2-lesions at Week 48;
  • the primary clinical endpoint is the proportion of relapse-free patients at Week 96. Patients in Group 1 have a statistically significant decrease in total volume of T2 brain lesions and relapse rate with respect to Group 2.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne l'utilisation de vitamine D associée à de l'interféron bêta dans le traitement de la sclérose en plaques.
PCT/EP2011/064080 2010-08-18 2011-08-16 Polythérapie contre la sclérose en plaques Ceased WO2012022740A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP10173251 2010-08-18
EP10173251.9 2010-08-18

Publications (1)

Publication Number Publication Date
WO2012022740A1 true WO2012022740A1 (fr) 2012-02-23

Family

ID=43133465

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2011/064080 Ceased WO2012022740A1 (fr) 2010-08-18 2011-08-16 Polythérapie contre la sclérose en plaques

Country Status (1)

Country Link
WO (1) WO2012022740A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014052807A1 (fr) * 2012-09-27 2014-04-03 Quincy Bioscience, Llc Procédés d'atténuation des symptômes de la sclérose en plaques basés sur des compositions contenant de l'apoaequorine

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5506214A (en) 1986-02-03 1996-04-09 The Scripps Research Institute Use of substituted adenine derivatives for treating multiple sclerosis
US20030017135A1 (en) * 2001-07-17 2003-01-23 Cruz Tony F. Pharmaceutical compositions comprising vitamin B12 and interferon for treating multiple sclerosis
US20050220764A1 (en) * 2004-04-01 2005-10-06 Schering Aktiengesellschaft Higher-doses of interferon-beta for treatment of multiple sclerosis

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5506214A (en) 1986-02-03 1996-04-09 The Scripps Research Institute Use of substituted adenine derivatives for treating multiple sclerosis
EP0626853B1 (fr) 1992-02-19 2000-04-26 The Scripps Research Institute Utilisation de derives d'adenine substituee pour le traitement de la sclerose en plaques
US20030017135A1 (en) * 2001-07-17 2003-01-23 Cruz Tony F. Pharmaceutical compositions comprising vitamin B12 and interferon for treating multiple sclerosis
US20050220764A1 (en) * 2004-04-01 2005-10-06 Schering Aktiengesellschaft Higher-doses of interferon-beta for treatment of multiple sclerosis

Non-Patent Citations (37)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "The effects of Interferon Beta combined with Vitamin D on relapsing remitting multiple sclerosis patients", 29 October 2009 (2009-10-29), XP002612130, Retrieved from the Internet <URL:http://www.clinicaltrials.gov/ct2/show/NCT01005095?term=vitamin+d3+multiple+sclerosis&rank=5> [retrieved on 20101130] *
BARTHEL ET AL., DTSCH MED WOCHENSCHR, vol. 128, 2003, pages 440 - 46
BIKLE DD, CURRENT OPINION IN RHEUMATOLOGY, vol. 19, no. 4, 2007, pages 383 - 8
BURTON ET AL., MULTIPLE SCLEROSIS, vol. 14, no. 1, 2008, pages 34
BURTON, J.M. ET AL.: "A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis", NEUROLOGY, vol. 74, 8 June 2010 (2010-06-08), pages 1852 - 1859, XP002612127 *
CANTORNA ET AL., J IMMUNOL, vol. 160, 1998, pages 5314 - 5319
CANTORNA, M.T.: "Vitamin D and multiple sclerosis: an update", NUTRITION REVIEWS, vol. 66, no. s2, 2008, pages S135 - S138, XP002612128 *
CORREALE, J. ET AL.: "Immunomodulatory effects of Vitamin D in multiple sclerosis", BRAIN, vol. 132, 2009, pages 1146 - 1160, XP002612129 *
EVANS ET AL., ANN. NEUROLOGY, vol. 41, 1997, pages 125 - 132
FU ET AL., CLIN. BIOCHEM., vol. 42, no. 10-11, 18 May 2009 (2009-05-18), pages 1174 - 7
HATHCOCK ET AL., AM J CLIN NUTR, vol. 85, 2007, pages 6 - 18
HIREMATH ET AL., MULTIPLE SCLEROSIS, vol. 15, 2009, pages 735 - 740
JG PHADKE ET AL., J EPIDEMIOL COMMUNITY HEALTH, vol. 41, 1987, pages 5 - 13
JG PHADKE ET AL., J. EPIDEMIOL COMMUNITY HEALTH, vol. 41, 1987, pages 5 - 13
KIMBALL ET AL., AM J CLIN NUTR, vol. 86, 2007, pages 645 - 651
KURTZKE, NEUROLOGY, vol. 33, 1983, pages 1444 - 1452
LASSMANN ET AL., TRENDS MOL. MED, vol. 7, 2001, pages 115 - 121
LASSMANN ET AL., TRENDS MOL. MED., vol. 7, 2001, pages 115 - 121
LUBLIN, REINGOLD, NEUROLOGY, vol. 46, 1996, pages 907 - 911
LUCCHINETTI ET AL., CURR. OPIN. NEUROL., vol. 14, 2001, pages 259 - 269
MATTSON, EXPERT REV. NEUROTHERAPEUTICS, 2002, pages 319 - 328
MILLER ET AL., NEUROLOGY, vol. 47, no. 4, 1996, pages 217
MUNGER ET AL., NEUROLOGY, vol. 62, 2004, pages 60 - 65
ORTON ET AL., AM J CLIN NUTR, vol. 88, 2008, pages 441 - 7
PANITCH H. ET AL., JOURNAL OF THE NEUROLOGICAL SCIENCES, vol. 239, 2005, pages 67 - 74
PANITCH H. ET AL., JOURNAL OF THE NEUROLOGICAL SCIENCES, vol. 239, no. 1, 2005, pages 67 - 74
POLMAN CH, REINGOLD SC, EDAN G, FILIPPI M, HARTUNG HP, KAPPOS L, LUBLIN FD, METZ LM, MCFARLAND HF, O'CONNOR PW: "Diagnostic criteria for multiple sclerosis: 2005 revisions to the ''McDonald Criteria", ANN NEUROL., vol. 58, no. 6, December 2005 (2005-12-01), pages 840FF
S. STEDDON ET AL., NEPHROL DIAL TRANSPLANT, vol. 16, 2001, pages 1965 - 1967
SIPE ET AL., NEUROLOGY, vol. 34, 1984, pages 1368 - 1372
TAKEUCHI ET AL., J IMMUNOL, vol. 160, 1998, pages 209 - 218
TAKEUCHI ET AL., J LMMUNOL, vol. 160, 1998, pages 209 - 218
VAN ETTEN, E ET AL.: "Immunomodulatory properties of a 1,25(OH)2 Vitamin D3 analog combined with INF-beta in animal model of syngenic islet transplantation", TRANSPLANTATION PROCEEDINGS, vol. 33, 2001, pages 2319, XP009141883 *
VAN ETTEN, E. ET AL.: "Novel insights in the immune function of the vitamin D system: synergism with interferon-beta", JOURNAL OF STEROID BIOCHEMISTRY & MOLECULAR BIOLOGY, vol. 103, 2007, pages 546 - 551, XP009141882 *
VIETH R., AM J CLIN NUTR, vol. 69, 1999, pages 842 - 856
VIETH R., ANN EPIDEMIOL, 2009
ZITTERMANN A., BRITISH JOURNAL OF NUTRITION, vol. 89, 2003, pages 552 - 5 72
ZITTERMANN A., BRITISH JOURNAL OF NUTRITION, vol. 89, 2003, pages 552 - 572

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014052807A1 (fr) * 2012-09-27 2014-04-03 Quincy Bioscience, Llc Procédés d'atténuation des symptômes de la sclérose en plaques basés sur des compositions contenant de l'apoaequorine
JP2015532288A (ja) * 2012-09-27 2015-11-09 クインシー バイオサイエンス，リミティド ライアビリティ カンパニー アポイクオリンを含有する組成物に基づく多発性硬化症の症状を軽減する方法

Similar Documents

Publication Publication Date Title
Christakos et al. Vitamin D and the intestine: Review and update
Tella et al. Prevention and treatment of postmenopausal osteoporosis
Smolders et al. Efficacy of vitamin D3 as add-on therapy in patients with relapsing–remitting multiple sclerosis receiving subcutaneous interferon beta-1a: A Phase II, multicenter, double-blind, randomized, placebo-controlled trial
El-Etr et al. Steroid hormones in multiple sclerosis
Wright et al. Hypovitaminosis D is associated with greater body mass index and disease activity in pediatric systemic lupus erythematosus
US20210137943A1 (en) Estrogen combination for treatment of multiple sclerosis
US9617596B2 (en) Biomarkers predictive for clinical response for glatiramer acetate
Arafa et al. Diosmin mitigates dexamethasone-induced osteoporosis in vivo: Role of Runx2, RANKL/OPG, and oxidative stress
IL225118A (en) Cytokines as biomarkers predicting clinical response to glutiramer acetate
Weiss et al. Prenatal vitamin D supplementation to prevent childhood asthma: 15-year results from the Vitamin D Antenatal Asthma Reduction Trial (VDAART)
Alroughani et al. Risk of relapses during pregnancy among multiple sclerosis patients
Steffensen et al. Can vitamin D3 supplementation prevent bone loss in persons with MS? A placebo-controlled trial
Yeon et al. Gomisin G improves muscle strength by enhancing mitochondrial biogenesis and function in disuse muscle atrophic mice
Khan et al. Risk factors for hematopoietic stem cell transplantation-associated bone loss
Tanaka et al. Analysis of bone metabolism during early stage and clinical benefits of early intervention with alendronate in patients with systemic rheumatic diseases treated with high-dose glucocorticoid: Early DIagnosis and Treatment of OsteopoRosis in Japan (EDITOR-J) study
El-Husseini et al. A Prospective Randomized Study for the Treatment of Bone Loss with Vitamin D During Kidney Transplantion in Children and Adolescents
EP3137088B1 (fr) Conditionnement pharmaceutique pour thérapie à l&#39;estriol pour le traitement de la sclérose en plaques
WO2012022740A1 (fr) Polythérapie contre la sclérose en plaques
van der Eerden et al. A human vitamin D receptor mutation causes rickets and impaired Th1/Th17 responses
WO2016064997A1 (fr) Compositions et méthodes pour le traitement de la fatigue et de la dépression
Wang et al. Treatment of membranous nephropathy with mizoribine: a control trial
Varoglu et al. The effect of interferon beta 1B on bone mineral density in multiple sclerosis patients
WO2009115398A1 (fr) Composés de vitamine d pour le traitement de maladies biliaires
Lei et al. Efficacy of L-carnitine in the treatment of osteoporosis in men
Zotarelli-Filho et al. Major meta-analysis, randomized clinical studies, and international consensus on serum levels and importance of supplementing vitamin D: State of the art

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11745963

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11745963

Country of ref document: EP

Kind code of ref document: A1