Multiple Sclerosis

Multiple sclerosis (MS) is a disorder of the central nervous system (CNS) characterized by demyelization, inflammation, and degenerative changes. Most people with MS experience relapses and remissions of neurological symptoms, particularly early in the disease, and clinical events are usually associated with areas of CNS inflammation. Gradual worsening or progression, with or without subsequent acute attacks of inflammation or radiological activity, may take place early, but usually becomes more prominent over time. While traditionally viewed as a disease solely of CNS white matter, more advanced imaging techniques have demonstrated significant early and ongoing CNS gray matter damage as well.(4)

Those diagnosed with MS may have many fluctuating and disabling symptoms (including, but not limited to, fatigue, pain, bladder and bowel issues, sexual dysfunction, movement and coordination problems, visual disturbances, and cognition and emotional changes).(17) There are currently four major types of MS: clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS).(11)

Relapsing remitting multiple sclerosis (RRMS)

RRMS is characterized by clearly defined attacks (relapses) of new or increasing neurologic symptoms. These relapses are followed by periods of partial or complete recovery. There is no or minimal disease progression during the periods between disease relapses, though individual relapses may result in severe residual disability. The course of MS varies, however, about 85-90% of individuals with MS demonstrate a relapsing pattern at onset, which transitions over time in the majority of untreated patients to a pattern of progressive worsening with few or no relapses or MRI activity.(11)

Secondary progressive multiple sclerosis (SPMS)

SPMS begins as RRMS, but over time the disease enters a stage of steady deterioration in function, unrelated to acute attacks. Most people with RRMS will transition to SPMS. In SPMS there is progressive worsening of symptoms over time with no definite periods of remission.(11)

Primary progressive multiple sclerosis (PPMS)

PPMS is characterized by worsening symptoms and disability from the start, rather than sudden attacks or relapses followed by recovery.(11) Currently ocrelizumab is the only DMA FDA approved for PPMS. A 2017 Institute for Clinical and Economic Review (ICER) report included rituximab as treatment for both relapsing forms and progressive forms of MS based on feedback from practicing clinicians, specialty societies, manufacturers, and payors. The results of the ICER evaluation on the use of rituximab for MS showed that the evidence is promising and recommend rituximab as an option for treating multiple forms of MS.(5)

2017 McDonald Criteria for the diagnosis of Multiple Sclerosis:

Diagnostic criteria for multiple sclerosis (MS) combining clinical, imaging, and laboratory evidence have evolved over time. The increasing incorporation of paraclinical assessments, especially imaging, to supplement clinical findings has allowed earlier, more sensitive, and more specific diagnosis.(9,10)

The diagnosis of MS requires elimination of more likely diagnoses and demonstration of dissemination of lesions in the CNS in space and time.(9)

Misdiagnosis of MS remains an issue in clinical practice, and several factors that potentially increase this risk have been identified. MS has heterogeneous clinical and imaging manifestations, which differ between patients over time. There is no single pathognomonic clinical feature or diagnostic test; diagnosis of MS relies on the integration of clinical, imaging, and laboratory findings. MRI abnormalities associated with other diseases and non-specific MRI findings, which are common in the general population, can be mistaken for MS. The increasingly strong focus on timely diagnosis to alleviate uncertainty for patients and allow initiation of disease-modifying therapies might also increase the risk of misdiagnosis.(9)

With increasing availability and use of MRI, incidental T2 hyperintensities on brain imaging are common, the subset of individuals with MRI findings that are strongly suggestive of MS lesions but with no neurological manifestations or other clear-cut explanation are said to have radiologically isolated syndrome. There is no consensus on whether patients with radiologically isolated syndrome will develop MS. Some practitioners argue that these patients have a high likelihood of developing MS while others argue that up to two-thirds of these patients will not receive a diagnosis of MS in 5 years. A consensus panel decided to require clinical manifestations to make the diagnosis of MS (2017 McDonald Criteria for the diagnosis of MS).(9)

The 2017 McDonald criteria to diagnose MS is shown in the chart below.(9,10)

* - Dissemination in space is defined as one or more T2-hyperintense lesions that are characteristic of MS in 2 or more of four areas of the CNS (periventricular, cortical or juxtacortical, and infratentorial brain regions, and the spinal cord) demonstrated by an additional clinical attack implicating a different CNS site or by MRI.(9)

** - Dissemination in time is defined as simultaneous presence of gadolinium-enhancing and non-enhancing lesions at any time or by a new T2-hyperintense or gadolinium-enhancing lesion on follow-up MRI, with reference to a baseline scan, irrespective of the timing of the baseline MRI. The presence of CSF-specific oligoclonal bands does not demonstrate dissemination in time per se but can substitute for the requirement for demonstration of this measure.(9)

Treatment of MS

Both the Multiple Sclerosis Coalition and the American Academy of Neurology recommend initiating treatment with a DMA FDA approved for the patient’s phenotype as soon as possible following the diagnosis of multiple sclerosis. There are several DMAs with at least 10 mechanisms of action available to people with MS. The factors affecting choice of therapy at any point in the disease course are complex and most appropriately analyzed and addressed through a shared decision-making process between the individual and the treating clinician.(4,7)

The Multiple Sclerosis Coalition recommends that clinicians should consider prescribing a high efficacy medication such as alemtuzumab, cladribine, fingolimod, natalizumab or ocrelizumab for newly diagnosed individuals with highly active MS. Clinicians should also consider prescribing a high efficacy medication for individuals who have breakthrough activity on another DMA regardless of the number of previously used agents.(4) The American Academy of Neurology has recommended alemtuzumab, fingolimod, and natalizumab as options for patients with MS with highly active MS. There lacks a consensus for what constitutes as highly active MS, however.(7) The National Institute for Health and Care Excellence (NICE) defines rapidly evolving severe RRMS as two or more disabling relapses in 1 year, and one or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load compared with a previous MRI.(18)

Lack of response to DMAs is hard to define, as most patients with MS are not free of all disease activity. Relapses or new MRI detected lesions may develop after initiation of a DMA and before the treatment becomes effective for patients.  When determining efficacy, sufficient time for the DMA therapy to take full effect and patient adherence are important considerations. Evidence of one or more relapses, 2 or more unequivocally new MRI-detected lesions, or increased disability on examination while being treated with a DMA for a 1 year period suggests a sub-optimal response, an alternative regimen (e.g., different mechanism of action) should be considered to optimize therapeutic benefit.(6) A National MS Society consensus statement recommends changing from one disease modifying therapy to another only for medically appropriate reasons (e.g., lack of efficacy, adverse effects, or if better treatments options become available).(4)

Existing MS therapies are partly effective in halting ongoing inflammatory tissue damage and clinical progression. MS pathogenesis is complex and probably heterogeneous among patient, suggesting that combination therapy strategies that target a range of disease mechanisms might be more effective than medications used as monotherapy. Although preliminary studies have provided favorable results, several subsequent large, randomized, controlled trials have had negative of conflicting results. There also may be more adverse reactions associated with combination therapies due to the additive effect.(13)

In 2020 a Canadian MS working group published recommendations on optimal therapy in relapsing forms of MS. This group notes that there are few studies that have directly compared injectable and oral DMTs. A recent network meta-analysis suggested that pegylated interferon-β-1a and dimethyl fumarate have superior efficacy to other base therapies, there are insufficient data to demonstrate that one base injectable or oral DMT is superior to another. As a result, the choice of initial treatment will need to be individualized according to disease activity, severity, and comorbidities.(14)

In addition to base therapies, the working group considers 5 DMTs to be of higher efficacy which although can be used as initial therapy, they are generally reserved for patients with a poor response or tolerability with a base therapy. Patients presenting with high disease activity or aggressive/rapidly evolving MS at onset could be considered to initiate therapy with one of these more effective therapies, but the most common treatment initiation is to start on a base therapy with the view of switching within 6 -12 months. The 5 agents considered to be of higher efficacy are:(14)

·         Oral agents

o    Fingolimod

o    Cladribine

·         Monoclonal antibodies

o    Natalizumab

o    Ocrelizumab

o    Alemtuzumab

The MS working group discussed the criteria for switching therapies in RRMS and recommends a change in DMT is indicated for patients who meet any of the Major criteria below:(14)

The workgroup does note that on-treatment relapses should only be performed once the drug has achieved a full clinical effect (typically 2-6 months after drug initiation). Relapses that occur before the maximal efficacy of the drug has been reached should be given less weight, but major criteria should take precedence regardless of timing.(14)

For patients with SPMS the workgroup states that is generally advised to continue with the current DMT after onset of SPMS since many patients will have ongoing inflammatory disease and subclinical disease activity may worsen if treatment is withdrawn. A change in treatment may be warranted in patients with active SPMS who continue to have relapses or new MRI lesions, with the caveat that there is insufficient evidence to identify criteria for a suboptimal response in patients with SPMS.(14)

For patients with primary progressive MS clinicians should offer ocrelizumab to patients with active disease provided the benefits outweigh the risks. Caution is recommended when considering treatment for PPMS subgroups that are less likely to benefit from treatment, such as older patients, those with long-standing stable disease, and/or significant neurological deficits, since the limited benefits may not justify the risk associated with treatment. Rituximab may be considered as an alternative therapy for PPMS in regions that permit off-label use in MS due to cost or other considerations.(14)

The ICER evaluated a new IV treatment, ublituximab against current FDA and accepted use DMT for adults with RRMS. Only in the case of ublituximab vs placebo/no DMT is ublituximab superior rated. The ratings are noted below.(20)

Adults with RRMS

A: Superior - High certainty of a substantial (moderate-large) net health benefit
B: Incremental -  High certainty of a small net health benefit
C++: Comparable or better - Moderate certainty of a comparable, small, or substantial net health benefit, with which certainty of at least a comparable net health benefit
I: Insufficient - Any situation where the level of certainty in the evidence is low

ICER does note that payors should consider the following:(20)

• Payors should remove barriers to access to rituximab for RMS patients who are appropriate candidates for this therapy. This includes coverage of biosimilar rituximab with little or no prior authorization given the lack of concern regarding use in appropriate patients and how inexpensive it is compared with other monoclonal antibodies of equal effectiveness
• Payors should not unilaterally implement policies to switch RMS patients who are stable on their chosen DMT over to lower-cost biosimilar rituximab

Crohn's Disease

Crohn’s Disease (CD) is an inflammatory condition that can affect any portion of the gastrointestinal tract from the mouth to the perianal area. Choice of therapy is dependent on the anatomic location of disease, the severity of disease, and whether the treatment goal is to induce remission or maintain remission.(12,16) The American Gastroenterological Association (AGA) 2021 guideline recommends the following:(12)

• Biologic therapy:
  • The AGA suggest early introduction with a biologic, with or without an immunomodulator, rather than delaying their use until after failure of 5-aminosalicylates and/or corticosteroids
  • Anti-TNF (i.e., infliximab or adalimumab) and ustekinumab are recommended over no treatment for the induction and maintenance of remission
  • Vedolizumab is suggested over no treatment for the induction and maintenance of remission
  • AGA suggests against the use of natalizumab over no treatment for the induction and maintenance of remission
  • Patients naïve to biologic therapy, the AGA recommends infliximab, adalimumab, or ustekinumab over certolizumab pegol and suggests the use of vedolizumab over certolizumab pegol for the induction of remission
  • Patients with primary non-response to anti-TNF, the AGA recommends ustekinumab and suggests vedolizumab for induction of remission
  • Patients with secondary non-response to infliximab, the AGA recommends use of adalimumab or ustekinumab and suggests the use of vedolizumab for the induction of remission (if adalimumab was the first-line drug, there is indirect evidence to suggest using infliximab as a second-line agent)
• DMARD therapy:
  • Corticosteroids are suggested over no treatment for the induction of remission, and are recommended against for maintenance of remission
  • Patients in corticosteroid induced remission or with quiescent moderate to severe CD, the AGA suggests thiopurines for maintenance of remission
  • Subcutaneous or intramuscular methotrexate are suggested over no treatment for the induction and maintenance of remission
  • The AGA recommends against the use of 5-aminosalicylates or sulfasalazine over no treatment for the induction or maintenance of remission
  • The AGA suggests against the use of thiopurines over no treatment for achieving remission and recommends biologic drug monotherapy over thiopurine monotherapy for induction of remission
  • The AGA suggests against the use of oral methotrexate monotherapy over no treatment for the induction and maintenance of remission
• Combination therapy:
  • Patients that are naïve to biologics and immunomodulators, the AGA suggest use of infliximab in combination with thiopurines over infliximab monotherapy for the induction and maintenance of remission (combination infliximab with methotrexate may be more effective over infliximab monotherapy)
  • Patients that are naïve to biologics and immunomodulators, the AGA suggest use of adalimumab in combination with thiopurines over adalimumab monotherapy for the induction and maintenance of remission (combination adalimumab with methotrexate may be more effective over adalimumab monotherapy)
  • No recommendations are being made regarding the use of ustekinumab or vedolizumab in combination with thiopurines or methotrexate over biologic monotherapy for induction or maintenance or remission

The 2018 American College of Gastroenterology (ACG) guideline recommends the following:(12)

• Mild to moderately severe disease/low risk disease:
  • Sulfasalazine (in doses of 3-6 grams daily) is effective in colonic and/or ileocolonic CD, but not those with isolated small bowel disease
  • 5-aminosalicylic (ASA) suppositories and enema preparations are effective for induction and maintenance of remission in rectal and sigmoid disease
  • Conventional corticosteroids are primarily used for the treatment of flares, and are often used as a bridge until immunomodulators and/or biologic agents become effective
  • Controlled ileal release budesonide is effective for induction of remission in ileocecal disease
• Moderate to severe disease/moderate to high risk disease
  • Corticosteroids are effective for short-term use in alleviating signs and symptoms of moderate to severely active CD, but do not induce mucosal healing and should be used sparingly
  • Azathioprine, 6-mercaptopurine, or MTX (15 mg once weekly) may be used in treatment of active disease and as adjunctive therapy for reducing immunogenicity against biologic therapy
  • TNF inhibitors should be used to treat CD that is resistant to treatment with corticosteroids and that is refractory to thiopurines or MTX
  • Natalizumab should be considered to be used for induction of symptomatic response and remission in patients with active Crohn’s disease
  • Vedolizumab with or without an immunomodulator should be considered for induction of symptomatic remission for patients with moderate to severely active CD and objective evidence of active disease
  • Ustekinumab should be used in patients that have failed previous treatment with corticosteroids, thiopurines, MTX, or TNF inhibitors, or in patients with no prior TNF inhibitor exposure
• Maintenance therapy:
  • Thiopurines or methotrexate should be considered once remission is induced with corticosteroids
  • TNF inhibitors, specifically infliximab, adalimumab, and certolizumab pegol, should be used in combination with azathioprine, MTX, or 6-mercaptopurine to maintain remission of TNF induced remission
  • Natalizumab should be used for maintenance of natalizumab-induced remission of Crohn’s disease only if serum antibody to John Cunningham virus (JCV) is negative. Testing for anti-JCV antibody should be repeated every 6 months and treatment stopped if the result is positive
  • Vedolizumab should be used for maintenance of remission of vedolizumab induced remission
  • Ustekinumab should be used for maintenance of remission of ustekinumab induced remission

Safety

• Briumvi (ublituximab) is contraindicated in:(19)
  • Active hepatitis B virus infection
  • History of life-threatening infusion reaction to Briumvi
• Lemtrada (alemtuzumab) has boxed warnings for:(1)
  • Serious (including fatal) autoimmune conditions
  • Serious and life-threatening infusion site reactions
  • Serious or life-threatening stroke
  • Increased risk of malignancies
• Lemtrada is contraindicated in:(1)
  • Known hypersensitivity or anaphylactic reactions to alemtuzumab or any of the excipients in Lemtrada
  • HIV infection
  • Active infection
• Lemtrada is available only through a restricted program under a REMS (LEMTRADA REMS Program)(1)
• Ocrevus (ocrelizumab) is contraindicated in:(2)
  • Active hepatitis B virus infection
  • Patients who have history of life-threatening infusion reaction to Ocrevus 
• Tysabri (natalizumab) has a boxed warning for:(3) 
  • Increased risk of progressive multifocal leukoencephalopathy (PML)  
• Tysabri is contraindicated in:(3)
  • Patients who have had or who have PML
  • Patients who have had a hypersensitivity reaction to Tysabri
• Tysabri is available only through a restricted program under a REMS (TOUCH® prescribing program)(3)

Final Module

Wildcard

HCPC Codes

Target Brand Agent Name(s)

Target Generic Agent Name(s)

Strength

Targeted MSC

Targeted NDCs When Exclusions Exist

Final Age Limit

Preferred Status

Effective Date

62405085052030

J2329

Briumvi

ublituximab-xiiy soln for iv infusion

150 MG/6ML

M ; N ; O ; Y

02-16-2023

62405010002020

J0202

Lemtrada

alemtuzumab iv inj

12 MG/1.2ML

M ; N ; O ; Y

62405060002020

J2350

Ocrevus

ocrelizumab soln for iv infusion

300 MG/10ML

M ; N ; O ; Y

62405050001320

J2323

Tysabri

natalizumab for iv inj conc

300 MG/15ML

M ; N ; O ; Y

Final Module

Targeted Agent(s) GPI

Targeted Brand Agent(s) Name

Targeted Generic Agent(s) Name

Multi-Source

Targeted NDCs When Exclusions Exist

Prerequisite Grouping Description

Auto-Continuation Grouping Description

Contraindicated Grouping Description

6240407000

Aubagio

teriflunomide tab

M ; N ; O

58468021001 ; 58468021004 ; 58468021102 ; 58468021104

6240306045

Avonex ; Avonex pen

Interferon Beta- ; interferon beta-

M ; N ; O ; Y

59627022205 ; 59627033304

6240555000

Bafiertam

monomethyl fumarate capsule delayed release

M ; N ; O ; Y

6240306050

Betaseron

Interferon Beta- ; interferon beta-

M ; N ; O ; Y

50419052401 ; 50419052435

6240003010

Copaxone

glatiramer acetate soln prefilled syringe

M ; N ; O

68546031730 ; 68546032506 ; 68546032512

6240306050

Extavia

Interferon Beta- ; interferon beta-

M ; N ; O ; Y

00078056912 ; 00078056961 ; 00078056999

62407025100110

Gilenya

Fingolimod HCl Cap 0.25 MG (Base Equiv)

M ; N ; O

62407025100120

Gilenya

Fingolimod HCl Cap 0.5 MG (Base Equiv)

M ; N ; O

6240506500

Kesimpta

ofatumumab soln auto-injector

M ; N ; O ; Y

6240101500

Mavenclad

cladribine tab therapy pack

M ; N ; O ; Y

6240707020

Mayzent ; Mayzent starter pack

siponimod fumarate tab

M ; N ; O ; Y

6240307530

Plegridy ; Plegridy starter pack

peginterferon beta-

M ; N ; O ; Y

6240706000

Ponvory ; Ponvory 14-day starter pa

ponesimod tab  ; ponesimod tab starter pack

M ; N ; O ; Y

6240306045

Rebif ; Rebif rebidose ; Rebif rebidose titration ; Rebif titration pack

Interferon Beta- ; interferon beta-

M ; N ; O ; Y

44087002203 ; 44087002209 ; 44087004403 ; 44087004409 ; 44087018801 ; 44087332201 ; 44087332209 ; 44087334401 ; 44087334409 ; 44087882201

62407025207230

Tascenso odt

Fingolimod Lauryl Sulfate Tablet Disintegrating

M ; N ; O ; Y

62407025207220

Tascenso odt

Fingolimod Lauryl Sulfate Tablet Disintegrating

M ; N ; O ; Y

6240552500

Tecfidera ; Tecfidera starter pack

dimethyl fumarate capsule delayed release  ; dimethyl fumarate capsule dr starter pack

M ; N ; O

64406000501 ; 64406000602 ; 64406000703

6240553000

Vumerity

diroximel fumarate capsule delayed release

M ; N ; O ; Y