Rozanolixizumab-noli (Rystiggo)

Number: 1035

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses rozanolixizumab-noli (Rystiggo) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification: 

Precertification of rozanolixizumab-noli (Rystiggo) is required of all Aetna participating providers and members in applicable plan designs. For precertification of rozanolixizumab-noli (Rystiggo), call (866) 752-7021, or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification. 

1. Exclusions 

   The requested medication will not be used in combination with another neonatal Fc receptor blocker (e.g., Vyvgart, Vyvgart Hytrulo) or complement inhibitor (e.g., Soliris, Ultomiris, Zilbrysq).

2. Criteria for Initial Approval

   Aetna considers rozanolixizumab-noli (Rystiggo) medically necessary for treatment of generalized myasthenia gravis (gMG) when all of the following criteria are met:

   1. Anti-acetylcholine receptor (AChR) or anti-muscle-specific tyrosine kinase (MuSK) antibody positive; and
   2. Myasthenia Gravis Foundation of America (MGFA) clinical classification II to IV; and
   3. MG activities of daily living (MG-ADL) total score of greater than or equal to 5; and
   4. Meets one of the following:
      
      
      1. Member has had an inadequate response or intolerable adverse event to at least two immunosuppressive therapies over the course of at least 12 months (e.g., azathioprine, corticosteroids, cyclosporine, methotrexate, mycophenolate, tacrolimus); or
      2. Member has had an inadequate response or intolerable adverse event to at least one immunosuppressive therapy and intravenous immunoglobulin (IVIG) over the course of at least 12 months; or
      3. Member has a documented clinical reason to avoid therapy with immunosuppressive agents and IVIG.

   Aetna considers all other indications as experimental, investigational, or unproven. 

3. Continuation of Therapy

   Aetna considers continuation of rozanolixizumab-noli (Rystiggo) therapy medically necessary for members requesting reauthorization when there is no evidence of unacceptable toxicity or disease progression while on the current regimen and member demonstrates a positive response to therapy (e.g., improvement in MG-ADL score, MG Manual Muscle Test (MMT), MG Composite). 

4. Related Policies 

   1. CPB 0206 - Parenteral Immunoglobulins
   2. CPB 0285 - Plasmapheresis/Plasma Exchange/Therapeutic Apheresis
   3. CPB 0314 - Rituximab
   4. CPB 0807 - Eculizumab (Soliris)
   5. CPB 0946 - Ravulizumab-cwvz (Ultomiris)
   6. CPB 1002 - Efgartigimod Alfa-fcab (Vyvgart) and Efgartigimod Alfa and Hyaluronidase-qvfc (Vyvgart Hytrulo)

Dosage and Administration

Rozanolixizumab-noli is available as Rystiggo and is supplied as 280 mg/2 mL (140 mg/mL) in a single-dose vial. Rystiggo is for subcutaneous administration only using an infusion pump. Rystiggo should only be prepared and infused by a healthcare provider. 

The recommended dosage is based on body weight, as shown in the table below, and administered as a subcutaneous infusion once weekly for 6 weeks.

Table: Recommended Dosage Based on Body Weight

Body Weight of Individual	Dose	Volume to be Infused
Less than 50 kg	420 mg	3 mL
50 kg to less than 100 kg	560 mg	4 mL
100 kg and above	840 mg	6 mL

Per the label, subsequent treatment cycles are administered based on clinical evaluation. The safety of initiating subsequent cycles sooner than 63 days from the start of the previous treatment cycle has not been established.

If a scheduled dose is missed, Rystiggo may be administered up to 4 days after the scheduled time point. Thereafter, the original dosing schedule can be resumed until the treatment cycle is completed.

Source: UCB, 2023a

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to CPB: :
96369	Subcutaneous infusion for therapy or prophylaxis (specify substance or drug); initial, up to 1 hour, including pump set-up and establishment of subcutaneous infusion site(s)
96371	additional pump set-up with establishment of new subcutaneous infusion site(s) (List separately in addition to code for primary procedure)
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular.
96401	Chemotherapy administration, subcutaneous or intramuscular; non-hormonal anti-neoplastic.
HCPCS codes covered for indications listed in the CPB:
J9333	Injection, rozanolixizumab-noli, 1 mg
Other HCPCS codes related to the CPB:
Zilbrysq - no specific code
J0702	Injection, betamethasone acetate 3mg and betamethasone sodium phosphate 3mg
J1020	Injection, methylprednisolone acetate, 20 mg
J1030	Injection, methylprednisolone acetate, 40 mg
J1040	Injection, methylprednisolone acetate, 80 mg
J1094	Injection, dexamethasone acetate, 1 mg
J1100	Injection, dexamethasone sodium phosphate, 1mg
J1300	Injection, eculizumab, 10 mg
J1303	Injection, ravulizumab-cwvz, 10 mg
J1720	Injection, hydrocortisone sodium succinate, up to 100 mg
J2650	Injection, prednisolone acetate, up to 1 ml
J2920	Injection, methylprednisolone sodium succinate, up to 40 mg
J2930	Injection, methylprednisolone sodium succinate, up to 125 mg
J7500	Azathioprine, oral, 50 mg
J7501	Azathioprine, parenteral, 100 mg
J7507	Tacrolimus, immediate release, oral, 1 mg
J7508	Tacrolimus, extended release, (astagraf xl), oral, 0.1 mg
J7509	Methylprednisolone oral, per 4 mg
J7510	Prednisolone oral, per 5 mg
J7512	Prednisone, immediate release or delayed release, oral, 1 mg
J7515	Cyclosporine, oral, 25 mg
J7516	Injection, cyclosporine, 250 mg
J7518	Mycophenolic acid, oral, 180 mg
J7519	Injection, mycophenolate mofetil, 10 mg
J8540	Dexamethasone, oral, 0.25 mg
J9260	Injection, methotrexate sodium, 50 mg
J9332	Injection, efgartigimod alfa-fcab, 2mg
ICD-10 codes covered if selection criteria are met:
G70.00 - G70.01	Myasthenia gravis [Generalized]

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications 

• Rystiggo is indicated for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) or anti-muscle-specific tyrosine kinase (MuSK) antibody positive.

Rozanolixizumab-noli is branded as Rystiggo (UCB, Inc.). Rozanolixizumab-noli is a humanized IgG4 monoclonal antibody that binds to the neonatal Fc receptor (FcRn), resulting in the reduction of circulating IgG.  

Rystiggo carries labeled warnings and precautions for infections, aseptic meningitis, and hypersensitivity reactions. Rystiggo may increase the risk for infection. Immunization with vaccines during Rystiggo treatment has not been studied. Serious adverse reactions of aseptic meningitis (also called drug-induced aseptic meningitis) have been reported in patients treated with Rystiggo. Hypersensitivity reactions, including angioedema and rash, were observed in patients treated with Rystiggo. 

The most common adverse reactions (10% or more) in patients with generalized myasthenia gravis (gMG) are headache, infections, diarrhea, pyrexia, hypersensitivity reactions, and nausea.

Generalized Myasthenia Gravis (gMG)

Myasthenia gravis is a chronic autoimmune, neuromuscular disease that is characterized by weakness and fatigue of skeletal (voluntary) muscles that worsens after periods of activity and improves after periods of rest. The voluntary muscles affected can include those that are responsible for controlling the eyes, face, mouth, throat, limbs and respiratory muscles. In some affected individuals, the condition may be limited to certain eye muscles, which is often described as “ocular myasthenia". When myasthenia gravis affects multiple muscle groups throughout the body, it is called generalized myasthenia gravis (gMG). 

In myasthenia gravis, the immune system produces anti-acetylcholine receptor (AChR) antibodies that interfere with communication between nerves and muscles, resulting in muscle weakness and fatigue. Severe attacks of weakness, such as in myasthenia gravis crisis, can cause breathing and swallowing problems that can be life-threatening.

Myasthenia gravis is chronic but treatable disease, with many individuals achieving remission of symptoms. Initial symptomatic therapy consists of an acetylcholinesterase inhibitor such as oral pyridostigmine. Glucocorticoids and/or other immunosuppressive therapies are indicated for patients who remain significantly symptomatic on pyridostigmine (Bird, 2023).

In June 2023, the FDA approved Rystiggo for the treatment of gMG in adult patients who are anti-acetylcholine receptor (AChR) or anti-muscle-specific tyrosine kinase (MuSK) antibody positive. FDA approval was based on the pivotal Phase 3 MycarinG study that demonstrated that treatment with rozanolixizumab-noli resulted in statistically significant improvements in gMG-specific outcomes, including everyday activities such as breathing, talking, swallowing, and being able to rise from a chair (UCB, 2023b).

Bril et al (2023) conducted a randomized, double-blind, placebo-controlled, multicenter, adaptive phase 3 (MycarinG) study to evaluate the safety and efficacy of rozanolixizumab in patients with AChR or MuSK autoantibody-positive gMG. Selection criteria included patients (aged 18 years or older) with AChR or MuSK autoantibody-positive gMG (Myasthenia Gravis Foundation of America class II-IVa), a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 3 (non-ocular symptoms), and a quantitative myasthenia gravis (QMG) score of at least 11. Patients were required to be on a stable dose of myasthenia gravis (MG) therapy prior to screening that included acetylcholinesterase (AChE) inhibitors, steroids, or non-steroidal immunosuppressive therapies (NSISTs), either in combination or alone. A total of 200 adult patients were then randomized 1:1:1 to receive weight-tiered doses of rozanolixizumab 7 mg/kg (n=66; 33%), rozanolixizumab 10 mg/kg (n=67; 34%), or placebo (n=67; 34%). The study included a 4-week screening period and a 6-week treatment period followed by 8 weeks of observation. During the treatment period, rozanolixizumab or placebo were administered by subcutaneous infusion once a week for 6 weeks. The efficacy was measured using the MG-ADL scale, which assesses the impact of gMG on daily functions of 8 signs or symptoms that are typically affected in gMG. A total MG-ADL score ranges from zero to 24, with higher scores indicating more impairment. The primary efficacy endpoint was change from baseline to day 43 in MG-ADL score, assessed in the intention-to-treat population. The secondary endpoint was the change between treatment groups from baseline to day 43 in the QMG score. The QMG is a 13-item categorical grading system that assesses muscle weakness. Treatment-emergent adverse events (TEAEs) were assessed in all randomly assigned patients who received at least one dose of study drug. The authors observed a statistically significant difference favoring rozanolixizumab in the MG-ADL total score change from baseline [-3.4 points in rozanolixizumab-treated group at either dose vs -0.8 points in the placebo-treated group (p<0.001)]. Furthermore, a statistically significant difference favoring rozanolixizumab was observed in the QMG total score change from baseline [-5.4 points and -6.7 points in rozanolixizumab-treated group at ≈7 mg/kg and ≈10 mg/kg dose level, respectively, vs -1.9 points in the placebo-treated group (p<0.001)]. TEAEs were experienced by 52 (81%) of 64 patients treated with rozanolixizumab 7 mg/kg, 57 (83%) of 69 treated with rozanolixizumab 10 mg/kg, and 45 (67%) of 67 treated with placebo. The most frequent TEAEs were headache (29 [45%] patients in the rozanolixizumab 7 mg/kg group, 26 [38%] in the rozanolixizumab 10 mg/kg group, and 13 [19%] in the placebo group), diarrhea (16 [25%], 11 [16%], and nine [13%]), and pyrexia (eight [13%], 14 [20%], and one [1%]). Five (8%) patients in the rozanolixizumab 7 mg/kg group, seven (10%) in the rozanolixizumab 10 mg/kg group, and six (9%) in the placebo group had a serious TEAE. No deaths occurred. The authors' interpretation of the results were that rozanolixizumab showed clinically meaningful improvements in patient-reported and investigator-assessed outcomes in patients with gMG, for both 7 mg/kg and 10 mg/kg doses. Both doses were generally well tolerated, and that these findings support the mechanism of action of neonatal Fc receptor inhibition in this patient population. The authors concluded that rozanolixizumab represents a potential additional treatment option for patients with gMG.

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Appendix

Myasthenia Gravis Foundation of America (MGFA) Clinical Classification

1. Class I: Any ocular muscle weakness; may have weakness of eye closure. All other muscle strength is normal.

2. Class II: Mild weakness affecting muscles other than ocular muscles; may also have ocular muscle weakness of any severity.

   1. IIa. Predominantly affecting limb, axial muscles, or both. May also have lesser involvement of oropharyngeal muscles.
   2. IIb. Predominantly affecting oropharyngeal, respiratory muscles, or both. May also have lesser or equal involvement of limb, axial muscles, or both.

3. Class III: Moderate weakness affecting muscles other than ocular muscles; may also have ocular muscle weakness of any severity.

   1. IIIa. Predominantly affecting limb, axial muscles, or both. May also have lesser involvement of oropharyngeal muscles.
   2. IIIb. Predominantly affecting oropharyngeal, respiratory muscles, or both. May also have lesser or equal involvement of limb, axial muscles, or both.

4. Class IV: Severe weakness affecting muscles other than ocular muscles; may also have ocular muscle weakness of any severity.

   1. IVa. Predominantly affecting limb, axial muscles, or both. May also have lesser involvement of oropharyngeal muscles.
   2. IVb. Predominantly affecting oropharyngeal, respiratory muscles, or both. May also have lesser or equal involvement of limb, axial muscles, or both.

5. Class V: Defined as intubation, with or without mechanical ventilation, except when employed during routine postoperative management. The use of a feeding tube without intubation places the patient in class IVb.

Source: Myasthenia Gravis Foundation of America (MGFA)

Myasthenia Gravis Activities of Daily Living Scale

The Myasthenia Gravis Activities of Daily Living Scale (MG-ADL) is an 8-item patient-reported outcome measure assessing myasthenia gravis (MG) symptoms and functional activities related to activities of daily living and producing a total score ranging from 0 to 24, where higher scores indicate greater severity of symptoms. The MG-ADL is composed of items related to patients’ assessment of functional disability secondary to ocular (2 items), bulbar (3 items), respiratory (1 item), and gross motor or limb impairment (2 items).

Source: Canadian Agency for Drugs and Technologies in Health (2020)

The Myasthenia Gravis Composite

The Myasthenia Gravis Composite (MG Composite) is a 10-item tool that measures the signs and symptoms of myasthenia gravis (MG) based on physician examination and patient history. Scored items include ptosis, double vision, eye closure, talking, chewing, swallowing, breathing, neck flexion, shoulder abduction, and hip flexion. Each item is scored on an ordinal scale with four possible categories and weighted. The total score ranges from 0 to 50, with higher scores indicating more severe impairments. The MG Composite is composed of items originating from other scales (i.e., Quantitative Myasthenia Gravis [QMG], Manual Muscle Test [MMT], Myasthenia Gravis Activities of Daily Living [MG-ADL] scale).

Source: Canadian Agency for Drugs and Technologies in Health (2020)

The Manual Muscle Test

The MMT is a tool that evaluates the strength in 12 bilateral muscle groups and 6 ocular or axial (eg, neck flexors) muscles, that are usually affected in MG. Each muscle is scored from 0 (normal strength) to 4 (paralysis), and the total score is the sum of each muscle, where higher scores indicate more strength (less disease severity).

Source: Barnett et al (2018)

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References