Multiple Sclerosis
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Development of a Central Nervous System Axonal Myelination Assay for High Throughput Screening Karen D
Lariosa‑Willingham et al. BMC Neurosci (2016) 17:16 DOI 10.1186/s12868-016-0250-2 BMC Neuroscience METHODOLOGY ARTICLE Open Access Development of a central nervous system axonal myelination assay for high throughput screening Karen D. Lariosa‑Willingham1,2, Elen S. Rosler1,3, Jay S. Tung1, Jason C. Dugas1,4, Tassie L. Collins1,5 and Dmitri Leonoudakis1,2* Abstract Background: Regeneration of new myelin is impaired in persistent multiple sclerosis (MS) lesions, leaving neurons unable to function properly and subject to further degeneration. Current MS therapies attempt to ameliorate auto‑ immune-mediated demyelination, but none directly promote the regeneration of lost and damaged myelin of the central nervous system (CNS). Development of new drugs that stimulate remyelination has been hampered by the inability to evaluate axonal myelination in a rapid CNS culture system. Results: We established a high throughput cell-based assay to identify compounds that promote myelination. Culture methods were developed for initiating myelination in vitro using primary embryonic rat cortical cells. We developed an immunofluorescent phenotypic image analysis method to quantify the morphological alignment of myelin characteristic of the initiation of myelination. Using γ-secretase inhibitors as promoters of myelination, the optimal growth, time course and compound treatment conditions were established in a 96 well plate format. We have characterized the cortical myelination assay by evaluating the cellular composition of the cultures and expres‑ sion of markers of differentiation over the time course of the assay. We have validated the assay scalability and consist‑ ency by screening the NIH clinical collection library of 727 compounds and identified ten compounds that promote myelination. -
211855Orig1s000
&(17(5)25'58*(9$/8$7,21$1' 5(6($5&+ APPLICATION NUMBER: 2ULJV 6800$5<5(9,(: Summary Memorandum for Regulato1y Action Summary Memorandum for Regulatory Action Date October 11, 2019 Paul Lee, MD, PhD From Nick Kozauer, MD Subject Summary Memorandum for Regulatory Action NDA/BLA # and Supplement# NDA 211855 under 505(b)(2)1 Applicant Alkermes Date of Submission December 13, 2018 PDUFA Goal Date October 13, 2019 Proprietary Name Vun1erity Established or Proper Name Diroximel fumarate Dosage Form(s) 231 mg delayed release capsules Applicant Proposed VUMERITY is indicated for the treatment of adult patients Indication(s)/Population(s) with relapsing forms of multiple sclerosis The starting dose for VUMERITY is 231 mg twice a day Applicant Proposed Dosing orally. After 7 days, the dose should be increased to 462 Regimen(s) mg (two 231 mg capsules) twice daily orally. Recommendation on Tentative Approval Regulatory Action VUMERITY is indicated for the treatment of adult patients Recommended with relapsing forms of multiple sclerosis (MS), to include Indication(s)/Population(s) (if clinically isolated syndrome, relapsing-remitting disease, applicable) and active secondary progressive d isease, in adults Recommended Dosing Same as proposed Recimen(s) (if applicable) 1The referenced dmg for this 505(b)(2) application is Tecfidera (NDA 204063) Reference ID: 4504909 Summary Memorandum for Regulatory Action 1. Benefit-Risk Assessment The application provides an adequate bridge to Tecfidera, the referenced product for this 505(b)(2) application. Therefore, the previous findings of safety and effectiveness for Tecfidera also apply to Vumerity. 2. Background The applicant seeks approval of Vumerity (diroximel fumarate) using the 505(b)(2) regulatory pathway for monomethyl fumarate (MMF), relying on the previous findings of safety and effectiveness for Tecfidera (dimethyl fumarate [DMF]). -
Oral MS Disease-Modifying Therapies C21142-A
Drug and Biologic Coverage Criteria Effective Date: 05/01/2019 Last P&T Approval/Version: 07/28/2021 Next Review Due By: 08/2022 Policy Number: C21142-A Oral MS Disease-Modifying Therapies PRODUCTS AFFECTED Mayzent (siponimod), Aubagio (teriflunomide), Gilenya (fingolimod), Mavenclad (cladribine), Tecfidera (dimethyl fumarate), Vumerity (diroximel fumarate), Bafiertam (monomethyl fumarate),dimethyl fumarate, Zeposia (ozanimod), Ponvory (ponesimod) COVERAGE POLICY Coverage for services, procedures, medical devices, and drugs are dependent upon benefit eligibility as outlined in the member's specific benefit plan. This Coverage Guideline must be read in its entirety to determine coverage eligibility, if any. This Coverage Guideline provides information related to coverage determinations only and does not imply that a service or treatment is clinically appropriate or inappropriate. The provider and the member are responsible for all decisions regarding the appropriateness of care. Providers should provide Molina Healthcare complete medical rationale when requesting any exceptions to these guidelines Documentation Requirements: Molina Healthcare reserves the right to require that additional documentation be made available as part of its coverage determination; quality improvement; and fraud; waste and abuse prevention processes. Documentation required may include, but is not limited to, patient records, test results and credentials of the provider ordering or performing a drug or service. Molina Healthcare may deny reimbursement or take additional appropriate action if the documentation provided does not support the initial determination that the drugs or services were medically necessary, not investigational or experimental, and otherwise within the scope of benefits afforded to the member, and/or the documentation demonstrates a pattern of billing or other practice that is inappropriate or excessive DIAGNOSIS: Multiple Sclerosis REQUIRED MEDICAL INFORMATION: A. -
Multiple Sclerosis
bmchp.org | 888-566-0008 wellsense.org | 877-957-1300 Pharmacy Policy Multiple Sclerosis Policy Number: 9.212 Version Number: 2.0 Version Effective Date: 6/1/2021 Product Applicability All Plan+ Products Well Sense Health Plan Boston Medical Center HealthNet Plan New Hampshire Medicaid MassHealth ACO NH Health Protection Program MassHealth MCO Qualified Health Plans/ConnectorCare/Employer Choice Direct Senior Care Options Note: Disclaimer and audit information is located at the end of this document. Prior Authorization Policy Products Affected: Aubagio (teriflunomide) Kesimpta (ofatumumab) Avonex pen (interferon beta-1a) Mayzent (siponimod) Betaseron (interferon beta-1b) Plegridy (peginterferon beta-1a) Dalfampridine ER Rebif (interferon beta-1a) Dimethyl fumarate Tecfidera (dimethyl fumarate) (NF) Gilenya (fingolimod) Vumerity (diroximel fumarate) Glatiramer Zeposia (ozanimod) The Plan may authorize coverage of the above product(s) for members meeting the following criteria: Avonex, Betaseron, glatiramer, Plegridy, Rebif Initial Criteria 1. Member is 18 years of age and older; AND NF = non-formulary + Plan refers to Boston Medical Center Health Plan, Inc. and its affiliates and subsidiaries offering health coverage plans to enrolled members. The Plan operates in Massachusetts under the trade name Boston Medical Center HealthNet Plan and in other states under the trade name Well Sense Health Plan. Multiple Scerlosis 2. Diagnosis of relapsing multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease; AND 3. Prescribed by or in consultation with a neurologist; AND 4. Will not be used in combination with another MS disease modifying agent; AND 5. Will not be given concurrently with live vaccines; AND 6. -
October 2004
Myelin Repair Foundation Research Progress Summary October 2004 This summary outlines progress made by the Myelin Repair Foundation research team since June 2004 and includes findings from on-going research funded by other sources that members of the team found relevant to MRF research plan. Since the success of MRF is dependent on collaboration, rather than reporting on the progress of individual projects, this report describes progress towards MRF’s overall research goals and the contributions of various team members towards completing our understanding of critical aspects of myelination and how it is affected by the multiple sclerosis (MS) disease process. 1. Fundamental control of myelination: There are several MRF investigations focused on understanding the processes that control both myelination in development and remyelination after myelin loss due to inflammation and cell death: • Dr. Ben Barres’ lab has screened thousands of genes and identified 46 genes, specific to the myelination process, that show significantly higher or lower activity levels during developmental myelination than before or after the myelination process. In addition, Dr. Barres’ lab has demonstrated the timing of these changes during the developmental myelination process. The next step is to analyze the function of each of these 46 genes by artificially controlling its level of activity (expression) and observing the effect it has on myelin formation. Finding ways to artificially manipulate the expression of each gene is a formidable task. Although the functional analysis of each gene in this group is a significant project that may take several years to complete because of the large number of genes to be analyzed, the initial identification of these active genes is providing clues to other MRF researchers that will help prioritize which genes to evaluate first and which to ignore. -
Prior Authorization Multiple Sclerosis – Ponvory™ (Ponesimod Tablets)
Cigna National Formulary Coverage Policy Prior Authorization Multiple Sclerosis – Ponvory™ (ponesimod tablets) Table of Contents Product Identifier(s) National Formulary Medical Necessity ................ 1 79750 Conditions Not Covered....................................... 2 Background .......................................................... 2 References .......................................................... 2 Revision History ................................................... 2 INSTRUCTIONS FOR USE The following Coverage Policy applies to health benefit plans administered by Cigna Companies. Certain Cigna Companies and/or lines of business only provide utilization review services to clients and do not make coverage determinations. References to standard benefit plan language and coverage determinations do not apply to those clients. Coverage Policies are intended to provide guidance in interpreting certain standard benefit plans administered by Cigna Companies. Please note, the terms of a customer’s particular benefit plan document [Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Policies are based. For example, a customer’s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer’s benefit plan document always supersedes the information in the Coverage Policies. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular situation. -
5948 6 March 2020 Freedom of Information Request I Am Writing In
Trust Headquarters East Surrey Hospital Canada Avenue Redhill RH1 5RH Tel: 01737 768511 www.surreyandsussex.nhs.uk Our ref: 5948 6 March 2020 Freedom of information request I am writing in response to your request for information which has been handled under the Freedom of Information Act 2000 (FOIA). Could you please provide us with the numbers of patients in relation to the questions mentioned below, for a period of last 12 months: We do not record the number of patients who have attended the trust who have a diagnosis on MS 1. In your trust how many patients have a diagnosis of Multiple Sclerosis (MS), regardless of whether they are currently on treatment? We only record the number of patients who have attended the trust who have a diagnosis but we are unable to tell if they were diagnosed for the first time within this admission. 2. Of these MS patients, how many have been diagnosed with relapsing (RRMS), primary progressive (PPMS) or secondary progressive (SPMS) MS; See above If you do not code your MS patients in this way, do you have plans to do this? RRMS PPMS SPMS Not known 3. How many patients with Multiple Sclerosis have been treated with disease modifying drugs in the past 6 months. Please include all patients whose treatment is ongoing, even those with infrequent dosing schedules (e.g. Lemtrada, Mavenclad, Ocrevus). Please provide the total number of patients by treatment for the following disease modifying drugs: See question 5 below. Aubagio (teriflunomide) Avonex (interferon beta-1a) Betaferon (interferon beta-1b) Brabio (glatiramer acetate) Copaxone (glatiramer acetate) Extavia (beta interferon-1b) Gilenya (fingolimod) Lemtrada (alemtuzumab) Mavenclad (cladribine) Mayzent (siponimod) Ocrevus (ocrelizumab) Plegridy (peginterferon beta-1a) Rebif (beta interferon-1a) Tecfidera (dimethyl fumarate) Tysabri (natalizumab) Vumerity (diroximel fumarate) Zinbryta (daclizumab) Ampyra (fampyra) Ozanimod 4. -
Timeline of Progress in MS Research
Timeline of Progress in MS Research This timeline highlights a selection of major landmarks in research into multiple sclerosis and the launch of programs to propel this research forward. These are only a few of thousands of advances in basic and clinical research that have laid the foundation for the rapid progress we’re seeing today. 1421 First documented case of MS; St. Lidwina of Schiedam 1860-70 First studies of myelin and glial cells in brain tissue 1868 First correlation of MS clinical symptoms with central nervous system pathology; disease named "Sclerose en plaques" by Jean Martin Charcot 1869 First attempts to treat MS with gold chloride, zinc, sulfate, silver nitrate, strychnine and electrical stimulation (by Charcot) 1928 Discovery that myelin is produced by oligodendrocyte glial cells 1933 Acute experimental allergic encephalomyelitis (EAE) developed as model for MS 1936 Discovery that lymphocytes are involved in immune function 1943 First detailed description of the composition of myelin 1946 National MS Society USA Launched 1947 First research grant to Elvin A. Kabat, MD 1950 National Institute of Neurological Diseases founded at National Institutes of Health through the work of the Society 1950 Society funds first major survey of MS in the U.S. and Canada 1954 First Fellowship programs to train MS Scientists offered 1965 Society-convened panel of experts develops precise criteria for diagnosing MS 1969 Society co-funds research of steroid ACTH, which becomes the first drug shown to speed recovery from MS relapses 1974 -
Ponesimod (Ponvory) Reference Number: ERX.SPA.437 Effective Date: 06.01.21 Last Review Date: 05.21 Line of Business: Commercial, Medicaid Revision Log
Clinical Policy: Ponesimod (Ponvory) Reference Number: ERX.SPA.437 Effective Date: 06.01.21 Last Review Date: 05.21 Line of Business: Commercial, Medicaid Revision Log See Important Reminder at the end of this policy for important regulatory and legal information. Description Ponesimod (Ponvory™) is a sphingosine 1-phosphate receptor modulator. FDA Approved Indication(s) Ponvory is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria. Health plan approved formularies should be reviewed for all coverage determinations. Requirements to use preferred alternative agents apply only when such requirements align with the health plan approved formulary. It is the policy of health plans affiliated with Envolve Pharmacy Solutions™ that Ponvory is medically necessary when the following criteria are met: I. Initial Approval Criteria A. Multiple Sclerosis (must meet all): 1. Diagnosis of one of the following (a, b, or c): a. Clinically isolated syndrome, and member is contraindicated to all, or has experienced clinically significant adverse effects to two, of the following: Aubagio®, glatiramer (Copaxone®, Glatopa®), an interferon-beta agent (Betaseron® or Rebif®); b. Relapsing-remitting MS, and failure of two of the following, unless clinically significant adverse effects are experienced or all are contraindicated: Aubagio®, dimethyl fumarate, Gilenya®, glatiramer (Copaxone®, Glatopa®), an interferon-beta agent (Betaseron® or Rebif®), Kesimpta®, Mayzent®, Ocrevus®, Tysabri®, Vumerity®, Zeposia®;* *Prior authorization is required for all disease modifying therapies for MS. -
MRF Archive Compiled Research Summaries
Myelin Repair Foundation Archived Research Summaries Summaries – 2008 Bailey, S. L., B. Schreiner, and S. D. Miller. 2008. CNS dendritic cells in inflammation and disease. In: Central Nervous System Diseases and Inflammation. (T. E. Lane, M. Carson, C. Bergmann and T. Wyss-Coray, eds.). Springer, New York, NY. Pp 263-275. http://www.springerlink.com/content/l17910144487u803/ Scientific Summary: CD11c+ DCs play a major role in both the initiation and progression of autoimmune inflammatory disease in the CNS. Since the CNS serves as the primary site where activation of pathogenic Th1/Th17 cells specific for endogenous myelin epitopes (i.e., epitope spreading), which play a critical role in driving progressive autoimmune disease, the current data suggests that the inflamed CNS can function as a neo-lymphoid organ. In support of this our recent unpublished data indicates that expression of genes encoding multiple receptor:ligand pairs involved in lymphoid organogenesis (including LTα1β2/LTβR, CXCL12/CXCR4, CSCL13/CXCR5, CCL21/CCR7, and CCL19/CCR7) are highly upregulated in the CNS. Further, mDCs are the main drivers of epitope spreading displaying the unique ability to acquire and present endogenous myelin peptides, to cluster specifically with naïve CD4+ T cells in the inflamed CNS and to polarize towards a Th17 phenotype when presenting endogenous myelin peptides. In conclusion, understanding the cues that determine DC signals to T cells will be crucial to understanding the fate of pathological (auto)immune inflammation in different tissues and diseases. Moreover, strategies targeting inhibition of the migration of myeloid DCs to the CNS may be an effective therapy for chronic immune-mediated CNS demyelinating diseases including MS. -
Multiple Sclerosis Disease Modifying Therapy
Neuro-Pharmacology Immuno-modulatory Therapy MULTIPLE SCLEROSIS DISEASE MODIFYING THERAPY Drug Indic Dose Effect Side effects Monitoring Self Injectables IFB 1A Avonex 1996 RRMS 30mic IM weekly Modulates T-cell and B-cell Flu-like symptoms, headaches HGB, WBC, LFTs IFB 1A Rebif 1998 RRMS 44mic SQ MWF function. Down regulates Leukopenia, anemia, depression, suicide TSH/Free T4 IFB 1A Plegridy 2014 RRMS 125mic SQ q2w inflammatory cytokines and T-cells Hepatotoxicity, Thyroid dysfunction Risk for Depression Injection site necrosis with SQ inj IFB 1B Betaseron, RRMS 250mic SQ EOD ↓Relapses = 30% Neutralizing antibodies, Pregnancy Class: C Extavia, 2009 ↓CIS to CDMS = 50% Washout 1 month Glatiramer acetate RRMS 20mg SQ daily or Injection site pain & lipoatrophy Copaxone 1997 40mg SQ MWF Post-injection reactions: (chest/neck tightness Glatopa 2015 tachycardia, diaphoresis, dyspnea, anxiety) No Washout needed Daclizumab RRMS 150mg SC CD25 blocker (IL-2 receptor) Withdrawn from market after patients . Zinbryta, 2016 monthly developed fulminant hepatitis Withdrawn in 2017 Oral Fingolimod RRMS 0.5 mg daily Sphingosine-1-phosphate Bradyarrhythmia, AV block Pre-screen: Gilenya, 2010 receptor modulator. Macular edema - PRES CBC, EKG, LFT, VZV IgG Peripheral T-cell sequestration in Pulmonary function worsening (vaccinate if negative) lymph nodes Lymphopenia & PML - Transaminitis 1st dose monitoring (can be Varicella meningoencephalitis done at home). ↓Relapses = 54% Malignancy risk Then: ↓EDSS = 30% Pregnancy Class: C CBC/LFT’s q6m, fundus at 6m ↓MRI = 74% (T2), 82% (Gd) Washout 2 month (t1/2 is one week) Beware of PML & malignancy Siponimod RRMS 2 mg daily Sphingosine-1-phosphate Bradyarrhythmia, AV block Pre-screen: Mayzent, 2018 SPMS (requires receptor modulator, specific to Macular edema in 1.8% CYP2C9 testing (don’t use in titration) subtype 1&5, sparing subtype 3 Pulmonary function worsening patients with CYP2C9 3/3) (less cardiac side effects). -
Cerebellar Syndrome in a Man Treated with Natalizumab from the National Multiple Sclerosis Society Case Conference Proceedings
DIAGNOSTIC AND TREATMENT CHALLENGES OPEN ACCESS Cerebellar syndrome in a man treated with natalizumab From the National Multiple Sclerosis Society Case Conference Proceedings David A. Lapides, MD, Prem P. Batchala, MD, Joseph H. Donahue, MD, Robert P. Lisak, MD,* Correspondence Ethan I. Meltzer, MD,§* Ram N. Narayan, MD,* Avi Nath, MD, PhD,* Teresa C. Frohman, MPAS, MSCSPA-C,‡* Dr. Goldman [email protected] ‡ † Kathleen Costello, MS, ANP-BC, * Myla D. Goldman, MD, MSc, Scott S. Zamvil, MD, PhD,* and or Dr. Zamvil Elliot M. Frohman, MD, PhD*† [email protected] or Dr. Frohman Neurol Neuroimmunol Neuroinflamm 2019;6:e546. doi:10.1212/NXI.0000000000000546 [email protected] A 57-year-old man with a medical history significant for bipolar disorder, depression, and anxiety presented in 2010 with bilateral lower extremity numbness progressing to perineal numbness and urinary retention. A “working” diagnosis of relapsing-remitting MS (RRMS) was supported by disseminated T2 hyperintensities on MRI investigations of the brain and spinal cord. Furthermore, CSF analysis revealed 4 unique oligoclonal bands not identified in blood. Initial treatment with IM interferon beta-1a exacerbated the patient’s depression, prompting discontinuation after only 6 weeks of injection therapy. He was then transitioned to daily subcutaneous glatiramer acetate, which was well tolerated and resulted in disease stabilization for approximately 12 months. He had a relapse in 2011 with symptoms corresponding to a new enhancing lesion in the thoracic spinal cord. The pronounced MS disease burden in the spinal cord, in conjunction with breakthrough disease activity while on glatiramer acetate, prompted the treating team to recommend in- tensification of disease-modifying therapy with natalizumab, which was administered IV every 4 weeks from 2011 to 2014 for a total of 33 treatments.