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Multiple Sclerosis
Therapy Recommendations and Treatment Advances
The MS treatment landscape has been centered around disease-modifying therapies (DMTs), with more novel agents, biosimilars, bioequivalents, and generics coming to further saturate the market.
Sue Wilhelm, B.S.Pharm., BCPS Director of Pharmacy Security Health Plan
Multiple sclerosis (MS) is a chronic autoimmune inflammatory demyelinating disease of the central nervous system (CNS) with a largely unknown etiology. 1 The clinical course begins with an immune-mediated attack on the CNS that leads to demyelination via destruction of oligodendrocytes, then degeneration of axons. 1 Activation of both T-lymphocytes and B-lymphocytes are believed to be involved in the inflammation and damage that occurs within the CNS. Research suggests that the risk of developing MS is determined by genetic as well as environmental components, 1 which may include low vitamin D levels, a history of Epstein-Barr virus, ultraviolet light exposure, and cigarette smoking. 1 Currently, an estimated nearly one million people in the U.S. live with MS. Women are three times more likely than men to receive a diagnosis of MS. 2
Patients diagnosed with MS are classified into two core phenotypes: relapsing-remitting and progressive disease. Patients are then further classified into four clinical subtypes:
Clinically isolated syndrome (CIS). A CIS is the first clinical episode suggestive of an MS diagnosis. 3 Patients with a CIS may or may not be diagnosed with MS at a later point in time. 3 Relapsing-remitting MS (RRMS). Accounting for approximately 85% of initial MS diagnoses, RRMS is the most common disease course and is defined by periods of attacks or relapses followed by periods of recovery or remission. 3 Primary progressive MS (PPMS). Approximately 15% of MS patients are diagnosed with PPMS, characterized by progression or worsening of neurologic function from the disease onset without periods of relapse and remission. 3 Secondary progressive MS (SPMS). SPMS is a progressive course with worsening neurologic function that follows an initially relapsing-remitting course. 3 Most patients diagnosed with RRMS will progress to SPMS.
Treatment Guidelines
The following are the MS treatment guidelines set forth by the American Academy of Neurology (AAN) with recommendations for starting, switching, and stopping DMT. 4
Table 1. Therapy Recommendations
Starting DMT Recommendations
Clinicians should counsel patients with newly diagnosed MS about specific treatment options with DMT at a dedicated treatment visit. Clinicians must ascertain and incorporate/review preferences with patients with MS in terms of safety, route of administration, lifestyle, cost, efficacy, common adverse effects (AEs), and tolerability in the choice of DMT.
Clinicians must engage patients with MS in an ongoing dialogue regarding treatment decisions throughout the disease course.
Clinicians should counsel patients with MS that DMTs are prescribed to reduce relapses and new MRI lesion activity. DMTs are not prescribed for symptom improvement in patients with MS.
Clinicians must counsel patients with MS on DMTs to notify the clinicians of new or worsening symptoms.
Clinicians should evaluate readiness or reluctance to initiate DMT and counsel on its importance in patients with MS who are candidates to initiate DMT. Clinicians should counsel patients with MS initiating DMTs about comorbid disease, adverse health behaviors, and potential interactions of the DMT with concomitant medications.
Clinicians should evaluate barriers to adherence to DMT in patients with MS.
Clinicians should counsel patients with MS initiating DMTs on the importance of adherence.
Clinicians should discuss the benefits and risks of DMTs for patients with a single clinical demyelinating event with two or more brain lesions that have imaging characteristics consistent with MS. After discussing the risks and benefits, clinicians should prescribe DMT to patients with a single clinical demyelinating event and two or more brain lesions characteristic of MS who decide they want this therapy. Clinicians may recommend serial imaging at least annually for the first five years and close follow-up rather than initiating DMT in patients with CIS or relapsing forms of MS who are not on DMT, have not had relapses in the preceding two years, and do not have active new MRI lesion activity on recent imaging.
Clinicians should offer DMTs to patients with relapsing forms of MS with recent clinical relapses or MRI activity.
Clinicians should monitor patients with MS on DMTs for medication adherence, AEs, tolerability, safety, and effectiveness of the therapy.
Clinicians should follow up with patients with MS on DMTs either annually or according to medication-specific REMS.
Clinicians should monitor the reproductive plans and counsel regarding reproductive risks and use of birth control during DMT use in women of childbearing potential who have MS. Clinicians should counsel men with MS on their reproductive plans regarding treatment implications before initiating treatment with teriflunomide or cyclophosphamide. Because of the high frequency of severe AEs, clinicians should not prescribe mitoxantrone to patients with MS unless the potential therapeutic benefits greatly outweigh the risks.
Clinicians should prescribe alemtuzumab, fingolimod, or natalizumab for patients with highly active MS.
Clinicians may direct patients with MS who are candidates for DMTs to support programs.
Clinicians may recommend azathioprine or cladribine for patients with relapsing forms of MS who do not have access to approved DMTs. Clinicians may initiate natalizumab treatment in patients with MS with positive anti-JCV antibody indexes above 0.9 only when there is a reasonable chance of benefit compared with the low but serious risk of progressive multifocal leukoencephalopathy (PML). Clinicians should offer ocrelizumab to patients with PPMS who are likely to benefit from this therapy unless there are risks of treatment that outweigh the benefits.
Evidence Level
Level B
Level A
Level A
Level B
Level A
Level B
Level B
Level B
Level B
Level B
Level B
Level C
Level B
Level B
Level B
Level B
Level B
Level B
Level B
Level C
Level C
Level C
Level B
Table 1. Therapy Recommendations (cont.)
Switching DMT Recommendations
Clinicians should monitor MRI disease activity in patients with MS using DMT from the clinical onset of disease to detect the accumulation of new lesions in order to inform treatment decisions.
Clinicians should recognize that relapses or new MRI-detected lesions may develop in patients with MS after initiation of a DMT and before the treatment becomes effective.
Clinicians should discuss switching patients with MS from one DMT to another if they have been using one long enough for the treatment to take full effect and are adherent to their therapy but experience one or more relapses, two or more unequivocally new MRI-detected lesions, or increased disability on examination over a one-year period.
Clinicians should evaluate the degree of disease activity, adherence, AE profiles, and mechanism of action of DMTs when switching patients with MS with breakthrough disease activity during DMT use to another DMT.
Clinicians should discuss a change to noninjectable or less-frequently injectable DMTs with patients with MS on injectable DMTs who report intolerable discomfort with the injections or injection fatigue.
Clinicians should ask patients with MS who are using a DMT about medication AEs and attempt to manage these AEs as appropriate.
Clinicians should monitor laboratory abnormalities found on requisite laboratory surveillance (as outlined in the medication’s package insert) in patients with MS who are using a DMT.
Clinicians should discuss switching DMT or reducing dosage or frequency (where there are data on different doses — e.g., interferons, teriflunomide, azathioprine) when patients with MS exhibit persistent laboratory abnormalities.
Clinicians should counsel patients with MS considering natalizumab, fingolimod, rituximab, ocrelizumab, and dimethyl fumarate about the PML risk associated with these agents.
Clinicians should discuss switching to a DMT with a lower PML risk with patients with MS taking natalizumab who are or become JCV antibody-positive, especially those with anti-JCV antibody indexes above 0.9 while on therapy.
Clinicians should counsel patients with MS starting or using new DMTs without long-term safety data that they have an undefined risk of malignancy and infection.
If a patient with MS develops a malignancy while using a DMT — especially azathioprine, methotrexate, mycophenolate, cyclophosphamide, fingolimod, teriflunomide, alemtuzumab, or dimethyl fumarate — clinicians should promptly discuss switching to an alternate DMT.
Patients with MS with serious infections potentially linked to their DMT should switch DMTs (does not pertain to PML management in patients with MS using DMT).
Clinicians should check for natalizumab antibodies in patients with MS who have infusion reactions before subsequent infusions or experience breakthrough disease activity with natalizumab use.
Clinicians should switch patients with MS who have persistent natalizumab antibodies to a different DMT.
Physicians must counsel patients with MS discontinuing natalizumab that there is an increased risk of MS relapse or MRI-detected disease activity within six months of discontinuation.
Patients with MS choosing to switch from natalizumab to fingolimod should initiate treatment within eight to 12 weeks after discontinuing natalizumab (for reasons other than pregnancy or pregnancy planning) to diminish the return of disease activity.
Clinicians should counsel women to stop their DMT before conception for planned pregnancies unless the risk of MS activity during pregnancy outweighs the risk associated with the specific DMT during pregnancy.
Clinicians should discontinue DMTs during pregnancy if accidental exposure occurs, unless the risk of MS activity during pregnancy outweighs the risk associated with the specific DMT during pregnancy.
Clinicians should not initiate DMTs during pregnancy unless the risk of MS activity during pregnancy outweighs the risk associated with the specific DMT during pregnancy.
Evidence Level
Level B
Level B
Level B
Level B
Level B
Level B
Level B
Level B
Level B
Level B
Level B
Level B
Level B
Level B
Level B
Level A
Level B
Level B
Level B
Level B
Table 1. Therapy Recommendations (cont.)
Stopping DMT Recommendations Evidence Level
Clinicians should counsel patients with RRMS who are stable on DMT and want to discontinue DMT on the need for ongoing followup and periodic reevaluation of the decision.
Clinicians should advocate that patients with MS who are stable on DMT (that is, no relapses, no disability progression, stable imaging) should continue their current DMT unless the patient and physician decide a trial off therapy is warranted. Level B
Level B
Clinicians should assess the likelihood of future relapse in patients with SPMS by assessing patient age, disease duration, relapse history, and MRI-detected activity (e.g., frequency, severity, time since most recent relapse or gadolinium-enhanced lesion). Level B
Clinicians may advise discontinuation of DMT in patients with SPMS who do not have ongoing relapses (or gadolinium-enhanced lesions on MRI activity) and have not been ambulatory (EDSS 7 or greater) for at least two years. Level C
*Definitions for evidence levels can be found within the American Academy of Neurology Guidelines for Disease-Modifying Therapies for Adults with Multiple Sclerosis.
Treatment Advances
The number of DMTs for MS has increased rapidly over the past several years, with a total of 15 medications currently available. New agents released within the past few years include ocrelizumab (Ocrevus ® ), siponimod (Mayzent ® ), and diroximel fumarate (Vumerity™).
Ocrelizumab
Ocrelizumab was approved in 2017 based on the results from the OPERA I and II trials for patients with relapsing forms of MS. 8 These identically designed trials were randomized, double-blind, doubledummy, active comparator-controlled clinical trials. 8 Included patients had experienced at least one relapse within the prior year, or two relapses within the prior two years, and had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5. 8 Patients with PPMS were excluded. 8 Patients were randomized 1:1 to receive either ocrelizumab 600 mg every 24 weeks or interferon beta-1a 44 mcg three times weekly. 8
OPERA I and II Results:
» The annualized relapse rate (ARR) was 46% lower with ocrelizumab compared to interferon beta-1a (0.16 versus 0.29; p<0.001), and
47% lower in OPERA II 2 (0.16 versus 0.29; p<0.001). 8 » In prespecified pooled analyses, the proportion of patients with confirmed disability progression was significantly lower with ocrelizumab than with interferon beta-1a — 9.1% versus 13.6% respectively (p<0.001) at 12 weeks and 6.9% versus 10.5% respectively (p=0.003) at 24 weeks. 8 » The mean number of gadolinium-enhancing lesions was 94% lower in OPERA I with ocrelizumab (p<0.001) and 95% lower in
OPERA II (p<0.001) than with interferon beta-1a. 8 » The percentage of patients with serious infections was 1.3% of those treated with ocrelizumab and 2.9% of patients treated with interferon beta-1a. » In the ocrelizumab treatment group, 0.5% of the patients developed a neoplasm, compared with 0.2% of patients in the interferon beta-1a group. 8
The safety and efficacy of ocrelizumab as the first DMT indicated for the treatment of PPMS were established in the ORATORIO trial. 9
ORATORIO Results:
» At 12 weeks, 32.9% of patients on ocrelizumab (p=0.03) had confirmed disability progression, compared with 39.3% of placebo patients. » At 24 weeks, 29.6% of patients on ocrelizumab had confirmed disability progression, compared with 35.7% of placebo patients (p=0.04). » At 120 weeks, performance on the timed 25-foot walk worsened 38.9% in patients on ocrelizumab and 55.1% in placebo patients (p=0.04). » Patients on ocrelizumab had a 3.4% decrease in total brain lesion volume on T2-weighted MRI, while placebo patients had a 7.4% increase (p<0.001). » Patients on ocrelizumab had a brain-volume loss of 0.9%, compared with 1.09% in placebo patients (p=0.02).
» Infusion-related reactions, upper respiratory tract infections, and oral herpes infections occurred more frequently in patients on ocrelizumab than in placebo patients. » Neoplasms occurred in 2.3% of patients on ocrelizumab and 0.8% of placebo patients. » The difference in the rates of serious adverse events and serious infections between groups was not clinically significant.
Siponimod
Siponimod (Mayzent ® ) was approved in March 2019, joining fingolimod (Gilenya ® ) in the class of sphingosine-1-phosphate receptor (S1P) modulators. Siponimod was designed to be more selective than fingolimod and may have fewer risks. 10 Siponimod is also proven to be effective in patients with active SPMS. 10 Compared to fingolimod, which requires first-dose monitoring for all patients, siponimod requires first-dose monitoring only in patients with pre-existing heart conditions. 10
The safety and efficacy of siponimod were established in patients with SPMS in the EXPAND trial. 11 This trial was a randomized, double-blind, parallel-group, placebocontrolled, time-to-event study in patients with SPMS. 11 Included patients were 18 to 60 years old, had evidence of disability progression in the previous two years, no relapse in the three months prior to study entry, and an EDSS score of 3.0 to 6.5 at the time of study entry. 11 Patients were randomized 2:1 to receive siponimod 2 mg once daily following an initial dose titration or placebo for up to 3 years or until the occurrence of a predetermined number of confirmed disability progression events. 11 The primary endpoint was the time to 3-month continued disability progression (CDP), which was defined as a ≥1-point increase in EDSS, or a ≥0.5-point increase for baseline EDSS ≥5.5, sustained for three months. 11
EXPAND Results:
» 26% of patients on siponimod had confirmed disease progression, compared with 32% of placebo patients (p=0.013). » The ARR with siponimod was 0.071 versus 0.16 with placebo (relative reduction of 55%; p<0.01). » While a significant difference in disability progression was found in patients with active SPMS, or those with a relapse in the prior two years, the effect on patients with nonactive
SPMS was not statistically significant. » 82% of patients on siponimod and 78% of placebo patients completed the study. » AEs occurred in 89% of patients on siponimod and 82% of placebo patients.
» Serious AEs occurred in 18% of patients on siponimod and 15% of placebo patients. » Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular edema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently in the siponimod treatment group. » Cardiac first-dose effects were managed by the initial dose titration.
Diroximel fumarate
Diroximel fumarate was approved in November 2019 via the 505(b)(2) pathway, meaning that at least a portion of the data supporting its approval was derived from a reference product (dimethyl fumarate). 12 Diroximel fumarate shares the same active metabolite as Tecfidera ® (dimethyl fumarate), with potentially fewer side effects. 13 Bioavailability studies comparing dimethyl fumarate to diroximel fumarate in patients with relapsing forms of MS and healthy subjects were used to establish the efficacy of diroximel fumarate. 12
The safety of diroximel fumarate is currently being evaluated in the EVOLVE-MS-1 trial, which is an ongoing open-label, phase three, long-term safety study. 14 The ongoing EVOLVE-MS-2 trial is assessing the GI tolerability of diroximel fumarate versus dimethyl fumarate. 15
Multiple Sclerosis Pipeline
Monomethyl Fumarate
Monomethyl fumarate (Bafiertam™) is an immunomodulator and the active metabolite of dimethyl fumarate. 16 Monomethyl fumarate received tentative approval via the 505(b)(2) pathway as a bioequivalent of dimethyl fumarate (Tecfidera ® ). 16 A portion of the data supporting its approval was derived from the
prodrug, dimethyl fumarate. 16 A trial is currently ongoing to assess the GI tolerability of monomethyl fumarate compared to dimethyl fumarate. 17 Market entry is expected in June 2020, pending the patent expiration of Tecfidera ® . 16
Ozanimod
Ozanimod, a selective S1P modulator, acts by blocking lymphocytes from exiting the lymph nodes, decreasing the number of lymphocytes in the peripheral blood. 18 Ozanimod is highly selective for the S1P 1 and 5 subtypes. 18
The safety and efficacy were established in the phase three SUNBEAM and RADIANCE trials. 18, 19 The SUNBEAM trial and the RADIANCE trial studied the efficacy of ozanimod versus interferon beta-1a over 12 months and 24 months respectively. 18, 19
SUNBEAM and RADIANCE Results:
» In the SUNBEAM trial, adjusted ARR were 0.35 with interferon beta-1a, 0.18 with ozanimod 1 mg, and 0.24 with ozanimod 0.5 mg. There were no clinically significant reports of bradycardia or second-degree or third-degree atrioventricular block related to the first dose of ozanimod. 19 » In the RADIANCE trial, adjusted ARR were 0.28 with interferon beta-1a, 0.17 with ozanimod 1 mg, and 0.22 with ozanimod 0.5 mg. 18 » In both trials, fewer patients treated with ozanimod discontinued treatment due to adverse events than did those treated with interferon beta-1a. 18, 19 » There were no reports of bradycardia or second-degree or third-degree atrioventricular block related to ozanimod in either trial. 18, 19 » Approval is currently pending, and market entry is expected
March 25, 2020. 20
Ponesimod
Ponesimod is another S1P modulator. 21 It was studied in patients with relapsing forms of MS in the Oral Ponesimod Versus Teriflunomide In Relapsing Multiple Sclerosis (OPTIMUM) trial, a phase three multicenter, randomized, double-blind, parallel-group, active-controlled, superiority study. 22
The study was completed May 16, 2019, and early data showed statistically significant reduction of the ARR by 30.5% at week 108 with ponesimod versus teriflunomide (ARR=0.202 for ponesimod 20 mg versus 0.290 for teriflunomide 14 mg, p=0.0003). 21, 22 Nasopharyngitis, headache, upper respiratory tract infections, and an increase in alanine amino transferase (ALT) were the most com
mon adverse events. 21 Market entry is expected in late 2020. 23
Ofatumumab
Ofatumumab, an anti-CD20 antibody, is currently marketed under the trade name Arzerra ® for the treatment of chronic lymphocytic leukemia (CLL). 24 Ofatumumab acts by binding to the CD20 antigen on B-cells leading to B-cell lysis. 24
The safety and efficacy of ofatumumab is currently being evaluated in the phase three ASCLEPIOS I and II studies, which are identically designed, flexible duration (up to 30 months), double-blind, randomized, multicenter studies evaluating ofatumumab 20 mg monthly versus teriflunomide 14 mg once daily in adults with relapsing MS. 24
ASCLEPIOS I and II Results:
The ARR was 0.11 for patients on ofatumumab, compared with 0.22 for patients on teriflunomide (relative reduction 50.5%, p<0.001). The ARR was 0.10 for patients on ofatumumab, compared with 0.25 for patients on teriflunomide (relative reduction 58.5%, p<0.001.) Significant suppression of new inflammatory activity with ofatumumab compared to teriflunomide was demonstrated by a suppression of gadolinium (Gd)-enhancing T1 lesions. In prespecified pooled analyses, ofatumumab demonstrated relative risk reductions of 34.4% (p=0.002) and 32.5% (p=0.012) in 3- and 6-month confirmed disease progression, respectively, compared with teriflunomide. 24 Market entry is expected in late 2020. 23
Ublituximab
Ublituximab is an anti-CD20 antibody. Phase two trials showed annualized relapse rate of 0.07, with 93% of patients relapse-free at week 48. 25 T1 Gd-enhancing lesions were eliminated by ublituximab at week 24 and complete elimination was maintained at week 48. 25 Ublituximab was well-tolerated overall, and rapid infusion as low as one hour was also well-tolerated. 25 The ULTIMATE 1 and 2 trials are currently two ongoing phase three, randomized, multicenter, double-blinded, active-controlled trials comparing ublituximab to teriflunomide in patients with relapsing MS. 25 Market entry is expected in 2021. 23
Natalizumab (Tysabri ® )
Polpharma is currently recruiting participants for a phase three trial to establish efficacy and similarity of safety with biosimilar
PB006 compared to Tysabri ® in patients with relapsing-remitting MS. 26, 27 The estimated study completion date is August 2021. 27 Market entry is to be determined.
Dimethyl fumarate
Several generic manufacturers have submitted ANDAs for generic dimethyl fumarate. 28 Market entry is expected in June 2020 pending the patient expiration of Tecfidera ® . 29
Effectiveness and Value of Disease Modifying Therapies
The Institute for Clinical and Economic Review (ICER) published a final evidence report in 2017, “Disease-Modifying Therapies for Relapsing-Remitting and Primary-Progressive Multiple Sclerosis: Effectiveness and Value,” as well as “Siponimod for the Treatment of Secondary Progressive Multiple Sclerosis: Effectiveness and Value” in 2019. 30, 31 These reports outline the clinical effectiveness of each therapy as well as the cost effectiveness and value. 30, 31
The 2017 report determined that the most effective DMTs for reduction of relapses were alemtuzumab, natalizumab, and ocrelizumab. 30 The next-most effective therapies were fingolimod, rituximab, and dimethyl fumarate. The least effective therapies were interferons, glatiramer acetate, and teriflunomide. 30 The report also determined that for treating RRMS, there was moderate certainty of small to substantial net health benefit for alemtuzumab, natalizumab, and ocrelizumab, and moderate certainty of comparable or better net health benefit for fingolimod and dimethyl fumarate, compared with the interferons and glatiramer acetate. For the treatment of PPMS, the report concluded that, compared with best supportive care, there is moderate certainty of small to substantial net health benefit for ocrelizumab. 30 Although the newer therapies are more effective, they also have greater risks of life-threatening infections and serious AEs compared with interferons and glatiramer acetate. 30 ICER calculated the incremental cost-effectiveness ratio using the cost per additional qualityadjusted life year (QALY) for each DMT compared with best supportive care and determined that alemtuzumab had good value with a cost per QALY of $38,000. 30 The other DMTs were above the range of reasonable value, $100,000-$150,000, meaning that these therapies have poor long-term value for money. 30 The report recommended that launch prices of new DMTs be better aligned with the value they provide to the patients. 30
The 2019 report concluded with high certainty that siponimod provides at least a small net benefit in patients with active SPMS, compared to placebo. However, economic analyses concluded that siponimod exceeds the commonly cited thresholds of costeffectiveness. 31 The report recommended that the manufacturer lower the current price of siponimod in order to better align with the value that this therapy provides to patients. 31
Managed Care Implications
The MS treatment guidelines recommend initiation of DMT early in the disease course of MS patients to delay the progression. As a result, the treatment landscape is becoming increasingly centered around these DMTs. As many novel agents, biosimilars, bioequivalents, and generics come to the market, and the therapeutic class becomes more saturated, formulary management and selection of preferred agents are likely to become the focus for payers.
References
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Hauser, Stephen L. et al. “Ocrelizumab versus Interferon Beta1a in Relapsing Multiple Sclerosis.” New England Journal of Medicine, Jan. 19, 2017, https://www.nejm.org/doi/full/10.1056/ NEJMoa1601277. Montalban, Xavier et al. “Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis.” New England Journal of Medicine, Jan. 19, 2017, https://www.nejm.org/doi/full/10.1056/ NEJMoa1606468.
References (cont.)
“FDA Approves Siponimod - Brand named Mayzent ® - for Relapsing Forms of MS Including Active Secondary Progressive MS UPDATE.” National Multiple Sclerosis Society, March 27, 2019, https://www. nationalmssociety.org/About-the-Society/News/FDA-ApprovesSiponimod-Brand-named-Mayzent%C2%AE-for-Re.
Kappos, L et al. “Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study.” The Lancet, March 31, 2018, https://www.thelancet.com/journals/lancet/article/PIIS0140- 6736(18)30475-6/fulltext.
Vumerity™ [package insert]. Cambridge, MA; Biogen; October 2019.
“FDA Approves Oral Vumerity™ (Diroximel Fumarate), Similar to Tecfidera ® , for Relapsing MS.” National Multiple Sclerosis Society, Oct. 30, 2019, https://www.nationalmssociety.org/Aboutthe-Society/News/FDA-Approves-Oral-Vumerity™-(DiroximelFumarate),.
“A Study of ALKS 8700 in Adults With Relapsing Remitting Multiple Sclerosis (MS) EVOLVE-MS-1.” Clinical Trial NCT02634307, https:// clinicaltrials.gov/ct2/show/NCT02634307.
“A Tolerability Study of ALKS 8700 in Subjects With Relapsing Remitting Multiple Sclerosis (RRMS) EVOLVE-MS-2.” Clinical Trial NCT03093324, https://clinicaltrials.gov/ct2/show/ NCT03093324?term=ALKS+8700&draw=1&rank=2.
“Banner Receives FDA Tentative Approval for BAFIERTAM for the Treatment of Relapsing Forms of Multiple Sclerosis.” Banner Life Sciences. Business Wire, Jan. 2, 2019, https://www.businesswire. com/news/home/20190102005088/en/Banner-Receives-FDATentative-Approval-BAFIERTAM-Treatment.
“Study to Compare GI Tolerability Following Oral Administration of Bafiertam™ or Tecfidera to Healthy Volunteers.” Clinical Trial NCT04022473, https://clinicaltrials.gov/ct2/show/NCT04022473.
Cohen, Jeffrey A. et al. “Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial.” The Lancet Neurology, November 2019, https://www.thelancet.com/article/ S1474-4422(19)30238-8/fulltext.
Comi, Giancarlo et al. “Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial.” The Lancet Neurology, November 2019, https://www.thelancet.com/ journals/laneur/article/PIIS1474-4422(19)30239-X/fulltext.
Payesko, Jenna. “FDA Accepts Ozanimod NDA for Treatment of Relapsing Forms of Multiple Sclerosis.” Neurology Live, June 6, 2019, https://www.neurologylive.com/clinical-focus/fda-acceptsozanimod-nda-for-treatment-of-relapsing-forms-of-multiplesclerosis.
“New Head-to-Head Phase 3 Study Data Show Ponesimod Superiority Versus Aubagio ® (teriflunomide) 14 mg in Adults with Relapsing Multiple Sclerosis (MS).” Johnson & Johnson, Sept. 11, 2019, https://www.jnj.com/new-head-to-head-phase-3-study-datashow-ponesimod-superiority-versus-aubagio-teriflunomide-14-mgin-adults-with-relapsing-multiple-sclerosis-ms. 22.
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Kish, Troy. “Promising Multiple Sclerosis Agents In Late-Stage Development.” P&T Community, December 2018, https://www. ptcommunity.com/journal/article/full/2018/12/750/promisingmultiple-sclerosis-agents-late-stage-development.
“Novartis Phase III ASCLEPIOS trials demonstrate robust efficacy of ofatumumab in patients with relapsing multiple sclerosis.” Novartis, Sept. 13, 2019, https://www.novartis.com/news/media-releases/ novartis-phase-iii-asclepios-trials-demonstrate-robust-efficacyofatumumab-patients-relapsing-multiple-sclerosis.
“TG Therapeutics, Inc. Announces Final Phase 2 Multiple Sclerosis Data Presentation at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Annual Meeting.” TG Therapeutics, March 1, 2019, http://ir.tgtherapeutics.com/newsreleases/news-release-details/tg-therapeutics-inc-announces-finalphase-2-multiple-sclerosis-1.
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