ph-991057
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Multiple Sclerosis Agents Step Therapy with Quantity Limit Program Summary

Policy Number: PH-991057

This program applies to Blue Partner, Commercial, GenPlus, NetResults A series, SourceRx and Health Insurance Marketplace formularies.

Multiple Sclerosis Agents Step Therapy

TARGET AGENT(S)

Preferred generic agent(s)

Dimethyl fumarateb

Glatiramerb

Preferred brand agent(s)

Aubagio® (teriflunomide)

Avonex® (interferon b-1a)

Betaseron® (interferon b-1b)

Gilenya® (fingolimod)

Kesimpta® (ofatumumab)

Mavenclad® (cladribine)

Mayzent® (siponimod)

Plegridy® (peginterferon b-1a)

Rebif® (interferon b-1a)

Nonpreferred agent(s)

Bafiertam™ (monomethyl fumarate)

Copaxone® (glatiramer)a

Extavia® (interferon b-1b)

Glatopa® (glatiramer)a

Tecfidera® (dimethyl fumarate)a

Ponvory™ (ponesimod)

Vumerity™ (diroximel fumarate)

a – generic available

b – these agents are subject to duplicate therapy check only

PRIOR AUTHORIZATION CRITERIA FOR APPROVAL

Target agent(s) will be approved when ALL of the following are met:

  1. ONE of following:
  1. The requested agent is eligible for continuation of therapy AND ONE of the following:
    1. Information has been provided that the patient has been treated with the requested agent within the past 90 days

OR

    1. The prescriber states the patient has been treated with the requested agent within the past 90 days AND is at risk if therapy is changed

Agents Eligible for Continuation of Therapy

All target agents except the following are eligible for continuation of therapy:

Brand Copaxone

Glatopa

Brand Tecfidera

OR

  1. The requested agent is a preferred generic agent

OR

  1. The patient has highly active MS disease activity AND ALL of the following:
  1. The patient has ≥ 2 relapses in the previous year

AND

  1. ONE of the following:
  1. The patient has ≥ 1 gadolinium enhancing lesion on MRI

OR

  1. The patient has significant increase in T2 lesion load compared with a previous MRI

OR

  1. The patient has been treated with at least 3 MS agents from different drug classes

OR

  1. The requested agent is a preferred brand agent AND ONE of the following:
  1. The patient’s medication history includes use of ONE preferred generic agent

OR

  1. The patient has an intolerance (defined as an intolerance to the drug or its excipients, not to the route of administration) or hypersensitivity to ONE preferred generic agent

OR

  1. The patient has an FDA labeled contraindication to ALL preferred generic agents

OR

  1. The prescriber has provided information in support of using the requested agent over ALL preferred generic agents

OR

  1. The requested agent is a nonpreferred agent AND BOTH of the following:
  1. ONE of the following:
        1. The patient’s medication history incudes use of ONE preferred generic agent within the past 365 days

OR

        1. The patient has an intolerance (defined as an intolerance to the drug or its excipients, not to the route of administration) or hypersensitivity to ONE preferred generic agent

OR

  1. The patient has an FDA labeled contraindication to ALL preferred generic agents

AND

  1. ONE of the following:
        1. The patient’s medication history includes the use of ONE preferred brand agent or Zeposia (ozanimod) within the past 365 days 

OR

        1. The patient has an intolerance (defined as an intolerance to the drug or its excipients, not to the route of administration) or Zeposia hypersensitivity to ONE preferred brand agent

OR

        1. The patient has an FDA labeled contraindication to ALL preferred brand agents AND Zeposia

AND

  1. The requested agent is Glatopa or a brand agent with a generic equivalent (listed below) AND ONE of the following:
  1. The patient’s medication history includes use of the corresponding generic equivalent

OR

  1. The patient has an intolerance or hypersensitivity to the corresponding generic equivalent agent that is not expected to occur with the requested agent

OR

  1. The patient has an FDA labeled contraindication to the corresponding generic equivalent agent that is not expected to occur with the requested agent

Non-Preferred products

Corresponding generic equivalent

Copaxone, Glatopa

Glatiramer

Tecfidera

Dimethyl fumarate

AND

  1. The patient will NOT be taking an additional disease modifying agent (DMA) for the requested indication

Length of Approval:  12 months. NOTE: For agents requiring a starter dose for initial use, the starter dose can be approved for the FDA labeled starting dose and the maintenance dose can be approved for the remainder of 12 months.

NOTE: If Quantity Limit program also applies, please refer to Quantity Limit documents.

 
Dosing table for agents requiring a starter dose

Agent

Starting Dose

Maintenance dose

Avonex (interferon b-1a)

Initial 7.5 mcg, then dose may be increased by 7.5 mcg each week for the next 3 weeks until the recommended dose of 30 mcg is achieved

30 mcg intramuscularly once a week

Bafiertam (monomethyl fumarate)

95 mg twice daily for 7 days

190 mg (two 95 mg capsules) twice daily

Betaseron/

Extavia (interferon b-1b)

Starting dose is 0.0625 mg (0.25 mL) subcutaneously every other day with dose increase over a 6-week period to the recommended dose of 0.25 mg (1 mL) every other day.

Week 1-2: 0.625 mg

Week 3-4: 0.125 mg

Week 5-6: 0.1875 mg

Week 7 and thereafter: 0.25 mg

0.25 mg subcutaneously every other day

Kesimpta (ofatumumab)

Initial dose is 20 mg subcutaneously at Weeks, 0, 1, and 2

20 mg subcutaneously once monthly starting at week 4

Mayzent (siponimod)

Patients with CYP2C9 genotypes *1/*1, *1/*2, or *2/*2:

Days 1 and 2 :0.25 mg orally daily

Day 3: 0.5 mg orally daily

Day 4: 0.75 mg orally daily

Day 5: 1.25 mg orally daily

Day 6 and thereafter: 2 mg orally once daily

Patients with CYP2C9 genotypes *1/*3 or *2/*3:

Days 1 and 2: 0.25 mg orally daily

Day 3: 0.5 mg orally daily

Day 4: 0.75 mg orally daily

Day 5 and thereafter: 1 mg orally once daily

If a titration dose is missed, reinstate from Day 1 of dose titration

Patients with CYP2C9 genotypes *1/*1, *1/*2, or *2/*2:

2 mg orally once daily

Patients with CYP2C9 genotypes *1/*3 or *2/*3:

1 mg orally once daily

If 4 or more maintenance doses are missed, reinstate from Day 1 of Dose titration

Plegridy (peginterferon b-1a)

Start 63 mcg on day 1, 94 mcg on day 15, and 125 mcg on day 29. (Requires 1 starter pen or syringe)

125 mcg every 14 days following the starting dose

Ponvory

(ponesimod)

Days 1 and 2: 2 mg

Days 3 and 4: 3 mg

Days 5 and 6: 4 mg

Day 7: 5 mg

Day 8: 6 mg

Day 9: 7 mg

Day 10: 8 mg

Day 11: 9 mg

Days 12, 13, and 14: 10 mg

20 mg once daily starting on day 15

Rebif (peginterferon b-1a)

Patients should be started at 20% of the prescribed dose three times a week and increased over a 4-week period to the targeted dose, either 22 mcg or 44 mcg three times a week. See recommended titration table:

Recommended Titration

Titration Dose for 22 mcg

Titration Dose for 44 mcg

Weeks 1-2

20%

4.4 mcg

8.8 mcg

Weeks 3-4

50%

11 mcg

22 mcg

Weeks 5+

100%

22 mcg

44 mcg

22 mcg to 44 mcg three times per week

Tecfidera (dimethyl fumarate)

Starting dose is 120 mg twice a day orally for 7 days (requires 1 starter kit). After 7 days, the dose should be increased to maintenance dose.

240 mg orally twice daily

Vumerity (dimethyl fumarate)

Starting dose is 231 mg twice a day orally for 7 days (requires starting bottle). After 7 days, the dose should be increased to maintenance dose.

462 mg orally twice daily

Class Ia antiarrhythmics

Class III antiarrhythmics

Norpace (disopyramide)

Cordarone, Pacerone (amiodarone)

Pronestyl (procainamide)

Betapace (sotalol)

quinidine

Tikosyn (dofetilide)

Multaq (dronedarone)

Corvert (ibutilide)

Examples of Contraindicated Concomitant Disease Modifying Agents (DMAs)

Aubagio (teriflunomide)

Avonex (interferon β-1a)

Bafiertam (monomethyl fumarate)

Betaseron (interferon β-1b)

Copaxone (glatiramer)

Extavia (interferon β-1b)

Gilenya (fingolimod)

Glatopa (glatiramer)

Kesimpta (ofatumumab)

Lemtrada (alemtuzumab)

Mavenclad (cladribine)

Mayzent (siponimod)

Ocrevus (ocrelizumab)

Plegridy (peginterferon β-1a)

Ponvory (ponesimod)

Rebif (interferon β-1a)

Tecfidera (dimethyl fumarate)

Tysabri (natalizumab)

Vumerity (diroximel fumarate)

Zeposia (ozanimod)

MS Disease Modifying Agents drug classes

Drug Class

Agents

CD20 monoclonal antibody

Kesimpta, Ocrevus

CD 52 monoclonal antibody

Lemtrada

Fumarates

Bafiertam, Tecfidera, Vumerity

Glatiramer

Copaxone, Glatopa

IgG4k monoclonal antibody

Tysabri

Interferons

Avonex, Betaseron, Extavia, Plegridy, Rebif

Purine antimetabolite

Mavenclad

Pyrimidine synthesis inhibitor

Aubagio

Sphingosine 1-phosphate (SIP) receptor modulator

Gilenya, Mayzent, Ponvory, Zeposia

FDA APPROVED INDICATIONS AND DOSAGE1-15,28

Agent(s)

Indication(s)

Dosage

Aubagio®

(teriflunomide)

Tablet

Treatment of patients with relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults

7 mg or 14 mg orally once daily, with or without food

Avonex®

(interferon b-1a)

Injection for intramuscular use

Treatment of relapsing forms of MS, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults

May be titrated: starting with 7.5 mcg for first week, to reduce flu-like symptoms. Increase dose by 7.5 mcg each week for next 3 weeks until recommended dose of 30 mcg once weekly

Maintenance dose: 30 mcg once a week

Bafiertam™

(monomethyl fumarate)

Delayed-release capsule

Treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults

The starting dose is 95 mg twice daily orally for 7 days. After 7 days, the dosage should be increased to the maintenance dose of 190 mg (administered as two 95 mg capsules) twice a day orally

Betaseron®

(interferon b-1b)

Injection for subcutaneous use

Treatment of relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults

Initial titration: 0.0625 mg (0.25 mL) every other day, and increase over a six-week period to 0.25 mg (1 mL) every other day

Maintenance dose: 0.25 mg every other day

Copaxone®

(glatiramer acetate)a

Injection for subcutaneous use 

Treatment of relapsing forms of MS, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults

20 mg administered once per day or

40 mg administered three times per week at least 48 hours apart

(Copaxone 20 mg per mL and Copaxone 40 mg per mL are not interchangeable)

Extavia®

(interferon b-1b)

Injection for subcutaneous use

Treatment of relapsing forms of Multiple Sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults

Initial titration: 0.0625 mg (0.25 mL) every other day, and increase over a six-week period to 0.25 mg (1 mL) every other day

Maintenance dose: 0.25 mg every other day

Gilenya®

(fingolimod)

Capsule

Treatment of relapsing forms of Multiple Sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in patients 10 years of age and older

10 years of age and above, weighing less than or equal to 40 kg: 0.25 mg orally once daily with or without food

Adults and pediatric patients 10 years of age and older and weighing more than 40 kg: 0.5 mg orally once daily with or without food

Glatopa®

(glatiramer acetate)

Injection for subcutaneous use

Treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults

20 mg administered once daily or

40 mg administered three times per week and at least 48 hours apart

(Glatopa 20mg/mL and Glatopa 40/mL are not interchangeable)

Kesimpta®

(ofatumumab)

Injection for subcutaneous injection

Treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults

Initial dosing:

20 mg by subcutaneous injection at Weeks, 0, 1, and 2

Subsequent dosing:

20 mg by subcutaneous injection once monthly starting at week 4

Mavenclad®

(cladribine)

Tablet

● Treatment of relapsing forms of multiple sclerosis (MS), to include relapsing-remitting disease and active secondary progressive disease in adults

Limitation of use:

Mavenclad is not recommended for use in patients with clinically isolated syndrome (CIS) because of its safety profile

Cumulative dosage of 3.5 mg/kg orally and divided into 2 treatment courses (1.75 mg/kg per treatment course). Each treatment course is divided into 2 treatment cycles

Administration of cycles:

First course/first cycle: start anytime

First course/second cycle: start 23-27 days after last dose of first course/first cycle

Second course/first cycle: start at least 43 weeks after the last dose of first course/second cycle

Second course/second cycle: start 23-27 days after last dose of second course/first cycle

If a dose is missed do not double doses, extend cycle by 1 day. If 2 doses are missed, extend cycle by 2 days.

If lymphocyte count is < 800 cells/μL delay second course for up to 6 months. If recovery takes longer than 6 months the patient should not receive further treatment with Mavenclad

Mayzent®

(siponimod)

Tablet

Treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults

Patients with CYP2C9 genotypes *1/*1, *1/*2, or *2/*2:

0.25 mg orally daily for 2 days, then 0.5 mg orally daily for 1 day, then 0.75 mg orally daily for 1 day, then 1.25 mg orally daily for 1 day. After treatment titration, the recommended maintenance dose is 2 mg orally once daily

Patients with CYP2C9 genotypes *1/*3 or *2/*3:

0.25 mg orally daily for 2 days, then 0.5 mg orally daily for 1 day, then 0.75 mg orally daily for 1 day. After treatment titration, the recommended maintenance dosage is 1 mg orally once daily

If a titration dose is missed or if 4 or more consecutive daily doses are missed during maintenance treatment, reinstate Day 1 of the dose titration

Plegridy®

(peginterferon b-1a)

Injection for subcutaneous use

Injection for intramuscular use

Treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults

Dose titration: 63 mcg on day 1, 94 mcg on day 15, and 125 mcg (full dose) on day 29

Maintenance dose:125 mcg subcutaneously every 14 days 

Ponvory™

(ponesimod)

Tablet

Treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults

Dose titration:

Days 1 and 2: 2 mg

Days 3 and 4: 3 mg

Days 5 and 6: 4 mg

Day 7: 5 mg

Day 8: 6 mg

Day 9: 7 mg

Day 10: 8 mg

Day 11: 9 mg

Days 12, 13, and 14: 10 mg

Maintenance dose: 20 mg once daily starting on day 15

Rebif®

(interferon b-1a)

Injection for subcutaneous use 

Treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults

Titration: Generally, the starting dose should be 20% of the prescribed dose three times per week, and increased over a 4 week period to the targeted recommended dose of either 22 mcg or 44 mcg injected subcutaneously three times per week

Maintenance dose: 22 mcg or 44 mcg injected subcutaneously three times per week

Tecfidera®

(dimethyl fumarate)a

Capsule

Treatment of relapsing forms of MS, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults

Starting dose:  120 mg orally twice daily for 7 days

Maintenance dose:  240 mg twice daily

Vumerity®

(diroximel fumarate)

Delayed-release capsule

Treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults

Starting dose: 231 mg twice daily for 7 days

Maintenance dose: 462 mg twice daily

  1. Generic available

CLINICAL RATIONALE

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.16

Those diagnosed with MS may have many fluctuating and disabling symptoms (including, but not limited to, fatigue, impaired mobility, mood and cognitive changes, pain and other sensory problems, visual disturbances, and elimination dysfunction), resulting in a significant impact on quality of life for patients and their families. Diagnosis of MS is primarily based on clinical presentation. The core requirement for the diagnosis is demonstration of CNS lesion dissemination and presence of symptoms such as visual loss, motor function loss, difficulty with balancing, and vertigo. 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).23

Clinically isolated syndrome

CIS is a first episode of neurologic symptoms caused by inflammation and demyelination in the central nervous system. The episode, which by definition must last for at least 24 hours, is characteristic of multiple sclerosis but does not yet meet the criteria for a diagnosis of MS because people who experience a CIS may or may not go on to develop MS. When CIS is accompanied by lesions on a brain MRI that are similar to those seen in MS, the person has a high likelihood of a second episode of neurologic symptoms and diagnosis of relapsing-remitting MS. When CIS is not accompanied by MS-like lesions on brain MRI, the person has a much lower likelihood of developing MS.23

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 (SPMS).23

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. Typically, when SPMS stage is reached, the relapse rate is also reduced. Prior to the era of disease-modifying agents (DMAs), approximately half of patients diagnosed with relapsing MS would progress to SPMS by 10 years, and 80-90% would do so by 25 years.23

2017 McDonald Criteria for the diagnosis of Multiple Sclerosis:

Diagnostic criteria for multiple sclerosis 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.21-22

The diagnosis of MS requires elimination of more likely diagnoses and demonstration of dissemination of lesions in the CNS in space and time.22

 

Misdiagnosis of multiple sclerosis remains an issue in clinical practice, and several factors that potentially increase this risk have been identified. Multiple sclerosis has heterogeneous clinical and imaging manifestations, which differ between patients over time. There is no single pathognomonic clinical feature or diagnostic test; diagnosis of multiple sclerosis 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 multiple sclerosis. 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.21

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 multiple sclerosis 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 Multiple Sclerosis).21

The 2017 McDonald criteria to diagnose MS is shown in the chart below.21-22

Clinical Presentation

Additional Data needed to make MS diagnosis

In a person with a typical attack/CIS at onset

≥ 2 attacks and objective clinical evidence of ≥ 2 lesions

OR

≥ 2 attacks and objective clinical evidence of 1 lesion with historical evidence of prior attack involving lesion in different location

None. Dissemination in spacea and dissemination in timeb have been met

≥ 2 attacks and objective clinical evidence of 1 lesion

ONE of these criteria:

Additional clinical attack implicating different CNS site

OR

≥ 1 symptomatic or asymptomatic MS-typical T2 lesions in ≥ 2 areas of CNS: periventricular, juxtacortical/cortical, infratentorial, or spinal cord

1 attack and objective clinical evidence of ≥ 2 lesions

ONE of these criteria:

Additional clinical attack

OR

Simultaneous presence of both enhancing and non-enhancing symptomatic or asymptomatic MS-typical MRI lesions

OR

New T2 or enhancing MRI lesion compared to baseline scan (without regard to timing of baseline scan)

OR

CSF specific (i.e., not in serum) oligoclonal bands

1 attack and objective clinical evidence of 1 lesion

ONE of these criteria:

Additional attack implicating different CNS site

OR

≥ 1 MS-Typical symptomatic or asymptomatic T2 lesions in ≥ 2 areas of CNS: periventricular, juxtacortical/cortical, infratentorial, or spinal cord

AND

ONE of these criteria:

Additional clinical attack

OR

Simultaneous presence of both enhancing and non-enhancing symptomatic or asymptomatic MS-typical MRI lesions

OR

New T2 enhancing MRI lesion compared to baseline scan (without regard to timing of baseline scan)

OR

CSF-specific (i.e., not in serum) oligoclonal bands

a - Dissemination in space is defined as one or more T2-hyperintense lesions that are characteristic of multiple sclerosis 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.21

b - 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.21

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.16,19

There is a subgroup of RRMS patients who have a more aggressive disease course marked by a rapid accumulation of physical and cognitive deficit, despite treatment with 1 or more DMTs. In the past, this disease phenotype was called aggressive MS; it is now called highly active MS. It is generally agreed that the severe nature of this phenotype requires different treatment decisions. There is no consensus on the definition of highly active MS or the treatment algorithm.2  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.20

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.17 The American Academy of Neurology has recommended alemtuzumab, fingolimod, and natalizumab as options for patients with MS with highly active MS.19

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.18 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).16

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, however, 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.24

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.25

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:25

  • Oral agents
  • Fingolimod
  • Cladribine
  • Monoclonal antibodies
  • Natalizumab
  • Ocrelizumab
  • 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:25

Minor

Major

Relapse rate

  • One relapse in first 2 years of treatment
  • ≥ 2 relapses in first year of treatment

Severity

  • Mild
  • No functional impairment (school, work, daily activities, etc.)
  • No motor/cerebellar/brain stem /sphincter involvement
  • Moderate to severe
  • Functional impairment
  • Motor/cerebellar/brain stem/sphincter involvement

Recovery

  • Full recovery at 6 months
  • No functional impairment
  • EDSS change from baseline ≤ 1 point at 6 months unless baseline EDSS >5.5
  • Incomplete recovery
  • Functional impairment
  • If EDSS at baseline was 0 then > 1.5 point change from baseline
  • If EDSS > 0 but less than 5.5 at baseline then > 1 point change at 6 months
  • If EDSS > 5.5 any change would be a major concern

MRI

  • One new lesion
  • ≥ 3 new lesions during treatment excluding spinal cord lesions
  • > 1 spinal cord lesion

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.25

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.25

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.25

Safety1-15

  • Aubagio (teriflunomide) has a black box warning with the following:
  • Hepatotoxicity: clinically significant and potentially life-threatening liver injury, including acute liver failure requiring transplant, has been reported in patients treated with Aubagio in the post marketing setting. Concomitant use of Aubagio with other hepatotoxic drugs may increase the risk of severe liver injury. Obtain transaminase and bilirubin levels within 6 months before initiation of Aubagio and monitor ALT levels at least monthly for six months. If drug induced liver injury is suspected, discontinue Aubagio and start accelerated elimination procedure
  • Embryofetal toxicity: teratogenicity and embryolethality occurred in animals administered teriflunomide. Exclude pregnancy prior to initiating Aubagio therapy. Advise use of effective contraception in females of reproductive potential during treatment and during an accelerated drug elimination procedure. Stop Aubagio and use an accelerated drug elimination procedure if the patient becomes pregnant
  • Aubagio (teriflunomide) is contraindicated in:
  • Severe hepatic impairment
  • Pregnancy
  • Hypersensitivity reaction to teriflunomide, leflunomide, or any of the inactive ingredients in Aubagio
  • Current leflunomide treatment
  • Avonex (interferon β-1a) is contraindicated in:
  • History of hypersensitivity to natural or recombinant interferon beta, albumin or any other component of the formulation
  • Bafiertam (monomethyl fumarate) is contraindicated in:
  • Known hypersensitivity to monomethyl fumarate, dimethyl fumarate, diroximel fumarate, or any of the excipients of Bafiertam
  • Co-administration with dimethyl fumarate or diroximel fumarate
  • Betaseron (interferon β-1b) is contraindicated in:
  • History of hypersensitivity to natural or recombinant interferon beta, albumin or mannitol
  • Copaxone (glatiramer) is contraindicated in:
  • Known hypersensitivity to glatiramer acetate or mannitol
  • Extavia (interferon β-1b) is contraindicated in:
  • History of hypersensitivity to natural or recombinant interferon beta, Albumin (Human), USP, or any other component of the formulation
  • Gilenya (fingolimod) is contraindicated in:
  • Recent myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure with hospitalization, or Class III/IV heart failure
  • History of Mobitz Type II 2nd degree or 3rd degree AV block or sick sinus syndrome, unless patient has a pacemaker
  • Baseline QTc interval ≥500 msec
  • Treatment with Class Ia or Class III anti-arrhythmic drugs
  • Hypersensitivity to fingolimod or its excipients
  • Glatopa (glatiramer) is contraindicated in:
  • Known hypersensitivity to glatiramer acetate or mannitol
  • Kesimpta (ofatumumab) is contraindicated in:
  • Active HBV infection
  • Mavenclad (cladribine) contains a black box warning with the following:
  • Malignancies: Mavenclad may increase the risk of malignancy. Mavenclad is contraindicated in patients with current malignancy; evaluate the benefits and risks on an individual basis for patients with prior or increased risk of malignancy
  • Risk of teratogenicity: Mavenclad is contraindicated for use in pregnant women and in women and men of reproductive potential who do not plan to use effective contraception because of the risk of fetal harm
  • Mavenclad (cladribine) is contraindicated in:
  • Patients with current malignancy
  • Pregnant women, and women and men of reproductive potential who do not plan to use effective contraception during Mavenclad dosing and for 6 months after the last dose in each treatment course
  • HIV infection
  • Active chronic infections (e.g., hepatitis or tuberculosis)
  • History of hypersensitivity to cladribine
    • Women intending to breastfeed on a Mavenclad treatment day and for 10 days after the last dose
  • Mayzent (siponimod) is contraindicated in:
  • Patients with a CYP2C9 *3/*3 genotype
  • Patients who in the last 6 months have experienced: myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, or Class III/IV heart failure
    • Presence of Mobitz type II second-degree, third-degree AV block, or sick sinus syndrome, unless patient has a functioning pacemaker
  • Plegridy (peginterferon β-1a) is contraindicated in:
  • History of hypersensitivity to natural or recombinant interferon beta or peginterferon, or any other component of the formulation
  • Ponvory (ponesimod) is contraindicated in:
  • Patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III/IV heart failure
  • Presence of Mobitz type II second-degree, third-degree AV block, or sick sinus syndrome, unless patient has a functioning pacemaker
  • Rebif (interferon β-1a) is contraindicated in:
  • History of hypersensitivity to natural or recombinant interferon beta, human albumin, or any other component of the formulation
  • Tecfidera (dimethyl fumarate) is contraindicated in:
  • Known hypersensitivity to dimethyl fumarate or any of the excipients of Tecfidera
  • Vumerity (diroximel fumarate) is contraindicated in:
  • Known hypersensitivity to diroximel fumarate, dimethyl fumarate, or to any of the excipients of Vumerity
    • Co-administration with dimethyl fumarate

For additional clinical information see Prime Therapeutics Formulary Chapter 9.6C Multiple Sclerosis Agents.

REFERENCES

  1. Aubagio prescribing information. Genzyme Corporation. November 2020.
  2. Avonex prescribing information. Biogen, Inc. March 2020.
  3. Bafiertam prescribing information. Banner Life Sciences LLC. August 2020.
  4. Betaseron prescribing information. Bayer HealthCare Pharmaceuticals, Inc. October 2020.
  5. Copaxone prescribing information. Teva Neurosciences, Inc. July 2020.
  6. Extavia prescribing information. Novartis Pharmaceuticals Corporation. October 2020.
  7. Gilenya prescribing information. Novartis Pharmaceuticals Corporation. December 2019.
  8. Glatopa prescribing information. Sandoz. November 2020.
  9. Kesimpta prescribing information. Novartis Pharmaceuticals Corporation. August 2020.
  10. Mavenclad prescribing information. EMD Serono, Inc. March 2019.
  11. Mayzent prescribing information. Novartis Pharmaceuticals Corporation. July 2020.
  12. Plegridy prescribing information. Biogen, Inc. January 2021.
  13. Rebif prescribing information. EMD Serono, Inc. May 2020.
  14. Tecfidera prescribing information.  Biogen, Inc. January 2021.
  15. Vumerity prescribing information. Alkermes Inc. January 2021.
  16. Multiple Sclerosis Coalition. The Use of Disease Modifying Therapies in Multiple Sclerosis: Principals and Current Evidence. Updated June 2019. National Multiple Sclerosis Society. Available at: https://www.nationalmssociety.org/NationalMSSociety/media/MSNationalFiles/Brochures/DMT_Consensus_MS_Coalition.pdf.
  17. Institute for Clinical and Economic Review (ICER). Disease-Modifying Therapies for Relapsing-Remitting and Primary-Progressive Multiple Sclerosis: Effectiveness and Value. March 6, 2017. Available at: https://icer-review.org/wp-content/uploads/2016/08/CTAF_MS_Final_Report_030617.pdf.
  18. Rae-Grant, Alexander, MD, et al. Practice Guideline Recommendations Summary: Disease-Modifying Therapies for Adults with Multiple Sclerosis. Neurology. 2018;90:777-788.
  19. Corboy, John R, MD, et al. Comment on 2018 American Academy of Neurology Guidelines on Disease-Modifying Therapies in MS. Neurology. 2018;90:1106-1112.
  20. National Institute for Health and Care Excellence (NICE). Disease-Modifying Therapies For Multiple Sclerosis. 2018. Available at: https://www.nice.org.uk/guidance/ta127/chapter/2-The-technology.
  21. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis:2017 revisions of the McDonald criteria. Lancet Neurol 2018; 17:162-73.
  22. National Multiple Sclerosis Society 2017 McDonald MS Diagnostic Criteria. Available at: https://www.nationalmssociety.org/For-Professionals/Clinical-Care/Diagnosing-MS/Diagnosing-Criteria.
  23. National MS Society. What is MS/Types of MS. Available at: https://www.nationalmssociety.org/What-is-MS/Types-of-MS.
  24. Conway D, Cohen JA. Combination therapy in multiple sclerosis. Lancet Neurol 2010 Mar;9(3):299-308.
  25. Freedman MS, Devonshire V, Duquette P, et al. Treatment Optimization in Multiple Sclerosis: Canadian MS Working Group Recommendations. The Can J Neurol Sci. 2020;47:437-455.
  26. Díaz C, Zarco LA, Rivera DM. Highly active multiple sclerosis: An update. Multiple sclerosis and Related Disorders 30 (2019) 215-224.
  27. Ponvory Prescribing Information. Janssen Pharmaceuticals, Inc. March 2021.

 

This pharmacy policy is not an authorization, certification, explanation of benefits or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All pharmacy policies are based on (i) information in FDA approved package inserts (and black box warning, alerts, or other information disseminated by the FDA as applicable); (ii) research of current medical and pharmacy literature; and/or (iii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.
 
The purpose of pharmacy policies are to provide a guide to coverage. Pharmacy policies are not intended to dictate to physicians how to practice medicine. Physicians should exercise their medical judgment in providing the care they feel is most appropriate for their patients.
 
Neither this policy, nor the successful adjudication of a pharmacy claim, is guarantee of payment.

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