Kristen Niedbalski, PharmD, BCGP January 8th, 2020 ▪ Kristen Niedbalski, PharmD, BCGP: Declares no conflicts of interest, real or apparent, and no financial interests in any company, product, or service mentioned in this program, including grants, employment, gifts, stock holding, and honoraria 1. Describe the disease courses/phenotypes of progressive forms of multiple sclerosis (MS) 2. Identify the new drug therapy options that have entered the U.S. drug market, since 2017, for the treatment of progressive MS 3. Describe treatment options for progressive MS 4. Given a patient case, select appropriate drug therapy for treatment of active progressive MS 5. Monitor for the adverse effects and contraindications of drug therapy for progressive MS 6. Discuss clinical studies that led to approval of siponimod and ocrelizumab 1. Describe the disease courses/phenotypes of progressive forms of MS 2. Identify the new drug therapy options that have entered the U.S. drug market, since 2017, for the treatment of progressive MS 3. List the adverse effects and contraindications of drug therapy for progressive MS SR is 42 year old female who was diagnosed with RRMS at age 31. Her relapses have remained consistent with periods of recovery over the years; however, her disability has progressed in the past 12 months, leading her to visit her neurologist’s office to discuss her current symptoms of increased bladder incontinence, numbness and tingling in her left hand and foot, blurred vision in her right eye, decreased cognition and balance, and now walks with a walker. She also complains that spasticity in her legs prevents her from wanting to leave the house because she is afraid of falling. Current Meds: ▪ Rebif 44mcg three times weekly ▪ Lisinopril 10mg qd ▪ Loratadine 10mg qd ▪ Escitalopram 20mg qd ▪ Baclofen 10mg tid ▪ Vitamin D 2000 units qd After SR sees her neurologist, he changes her diagnosis to SPMS and wants to make a change to her drug therapy. She is Genotype *2/*2 for CYP2C9 and she is afraid of needles. Should the neurologist: 1. Switch Rebif to Cladribine 3.5mg/kg over 2-year treatment course 2. Switch Rebif to Ocrelizumab 300mg on day 1 followed by 300mg 2 weeks later then 600mg every 6 months 3. Switch Rebif to Siponimod 0.25mg on days 1 and 2, 0.5mg on day 3, then 0.75mg on day 4, then 1.25mg on day 5, then 2mg daily beginning day 6 4. Stop drug treatment for MS and switch to palliative care and physical therapy to increase her abilities and regain mobility BD is 75 year old male with a 29 year history of RRMS. Early in his diagnosis he had frequent relapses; however, in the past few years he has had progression of disability with decreasing relapses. His last relapse was 5 years ago; however he continues to progress in severity of bowel and bladder incontinence, pain and spasticity in his lower limbs, dysphagia, worsened cognition, diplopia, and vertigo. He now requires a caretaker at home for dressing and personal care and has restricted mobility to a wheelchair. Current Meds ▪ Glatiramer 20mg SQ qd • Amantadine 100mg bid ▪ Baclofen 20mg tid • Oxybutynin 10mg tid ▪ Gabapentin 800mg tid • ▪ Valsartan 80mg qd Sertraline 50mg qd ▪ HCTZ 25mg qd • Vitamin D 5000 units qd ▪ Rosuvastatin 10mg qd • Aspirin 81mg qd After BD sees his neurologist, he changes his diagnosis to SPMS and wants to make a change to his drug therapy. He is Genotype *2/*2 for CYP2C9. Should the neurologist: 1. Switch glatiramer to Cladribine 3.5mg/kg over 2-year treatment course 2. Switch glatiramer to Ocrelizumab 300mg on day 1 followed by 300mg 2 weeks later then 600mg every 6 months 3. Switch glatiramer to Siponimod 0.25mg on days 1 and 2, 0.5mg on day 3, then 0.75mg on day 4, then 1.25mg on day 5, then 2mg daily beginning day 6 4. Stop drug treatment for MS and switch to palliative care and physical therapy to increase his abilities and regain mobility There are effective drug treatment options that are approved for ALL SPMS phenotypes that reduce the frequency and severity of MS relapses and disease progression Cladribine is an approved 1st line therapy option for SPMS Immunosuppressant therapies may diminish the therapeutic effect of vaccines Central Nervous Systen and Demyelination. Digital Image. Medicine Net. https://www.medicinenet.com/multiple_sclerosis_ms/article.htm Central Nervous Systen and Demyelination. Digital Image. Medicine Net. https://www.medicinenet.com/multip le_sclerosis_ms/article.htm Now called Primary Progressive with Central Nervous Systen and active disease Demyelination. Digital Image. Medicine Net. https://www.medicinenet.com/multi ple_sclerosis_ms/article.htm MS Phenotypes. Digital Image, National Multiple Sclerosis Society, https://www.nationalmssociety.org/What-is-MS/Types-of-MS/Secondary-progressive-MS GRAPH OF SPMS CLINICAL COURSE. DIGITAL IMAGE. EASYBIB. APRIL 2018 HTTP://WWW.CLEVELANDCLINICMEDED.COM/MEDICALPUBS/DISEASEMANAGEMENT/NEUROLOGY/MULTIPLE_SCLEROSIS/ MS DISEASE COURSE. DIGITAL IMAGE. BRAIN DIRECT. 9/2016. HTTPS://WWW.SCIENCEDIRECT.COM/ SCIENCE/ARTICLE/PII/S221103481630102X Treatment options for SPMS based on phenotype Treat with DMT Treat with DMT No approved drug therapy, DMT treatment can continue if necessary but continue only if risk outweighs benefit No approved drug therapy, DMT treatment can continue if necessary but continue only if risk outweighs Olek MJ, Mowry E. Treatment of progressive multiple sclerosis in adults. Post TW, ed. benefit UpToDate Inc. https://www.uptodate.com (accessed on 8/31/2019.) ▪Ocrelizumab (Ocrevus, approved March 2017) Ocrelizumab [package insert]. South San Francisco: Genentech; 2017 ▪ Recommended: ▪ Continuing same disease-modifying therapy (DMT) used during RRMS phase ▪ Switching to a different DMT ▪ Not recommended: ▪ Glucocorticoid monthly pulses, cyclophosphamide, methotrexate Olek MJ, Mowry E. Treatment of progressive multiple sclerosis in adults. Post TW, ed. UpToDate Inc. https://www.uptodate.com (accessed on 8/31/2019.) ▪ MABs: ▪Alemtuzumab (Lemtrada) ▪ Interferons: ▪Natalizumab (Tysabri) ▪Interferon beta-1a (Avonex, Rebif) ▪Ocrelizumab (Ocrevus, 2017) ▪Interferon beta-1b (Betaseron, ▪ Fumaric Acid Derivatives Extavia) ▪ Dimethyl Fumarate (Tecfidera) ▪ Sphingosine 1 phosphate receptor modulators: ▪ Diroximel fumarate (Vumerity, 10/2019) ▪Fingolimod (Gilenya) ▪ Glatiramer Acetate (Copaxone) ▪Siponimod (Mayzent, 3/2019) ▪ Teriflunomide (Aubagio) ▪ Cladribine (Mavenclad, 3/2019) ***Note that although all on this list are approved, Olek MJ, Mowry E. Treatment of progressive multiple sclerosis in adults. Post TW, ed. UpToDate Inc. https://www.uptodate.com the bolded are evidence based treatments ▪The likelihood of future relapse should be assessed by: ▪Patient age ▪Disease duration ▪Relapse history ▪MRI-detected activity ▪Discontinuation of DMT may be advised in patients who do not have ongoing relapses and have not been ambulatory for at least two years Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis A Rae-Grant, GS Day et. Al. Neurology Apr 2018, 90 (17) 777-788; DOI: 10.1212/WNL.0000000000005347 ▪ Class: Sphingosine 1-phosphate receptor modulator ▪ Approved for clinically isolated syndrome (CIS), RRMS, and active SPMS in adults ▪ Requires 5-day dose titration and genotyping for CYP2C9 prior to initiation to determine the optimal dosage ▪ First-dose monitoring recommended for patients with sinus bradycardia, 1st or 2nd degree AV block, or a history of MI or heart failure ▪ Test patients for antibodies to varicella zoster virus before initiation ▪ Baseline labs/tests: CBC, EKG, LFT’s and bilirubin, ophthalmic evaluation of fundus and macula ▪ Use caution in patients with history of anti-neoplastic, immunosuppressive, or immune-modulating therapies (additive effects) Siponimod [package insert]. East Hanover, New Jersey: Novartis; 2019 ▪Siponimod is a sphingosine-1-phosphate (S1P) receptor modulator ▪Binds with high affinity to S1P receptors 1 and 5 ▪Blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood ▪ The mechanism by which siponimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system. Siponimod [package insert]. East Hanover, New Jersey: Novartis; 2019 Fingolimod Siponimod Notes MOA (S1P receptors ) Receptors 1,3,4,5 Receptors 1,5 Cardiac AE are most risky for first 24 hours First dose cardiac All patients Patients w/certain At home or MD office, free to patient monitoring pre-existing cardiac conditions Available generic ***Yes No ***Just announced not available in US yet Pharmacogenomic No (1 strength) Yes (2 strengths) Dosing PML cases reported Yes (low risk) **No **PML has not been reported for siponimod but counsel pts to monitor for symptoms Half life 6 to 9 days; prolonged ~30 hours Important for family planning by ~50% in patients with mod/severe hepatic impairment Complete drug 2 months 7 days Time required to wait after drug d/c before elimination beginning family planning Proven Efficacy in *No- studied in PPMS Yes- studied in *Fingolimod failed to slow disease Progressive MS (INFORMS) SPMS (EXPAND) progression in PPMS Fingolimod. In: Lexicomp Online Database. Hudson (OH): Lexicomp Inc: 2019 Siponimod. In: Lexicomp Online Database. Hudson (OH): Lexicomp Inc: 2019 Fingolimod phosphate binds to S1P receptors 1, 3, 4, and 5 G Comi, Hans-Peter Hartung, Heinz S. Wiendl Published in Drugs 2017 DOI:10.1007/s40265-017-0814-1 Siponimod Binds with high