Anifrolumab-fnia (Saphnelo)

Number: 0997

Policy

Note: Requires Precertification:

Precertification of anifrolumab-fnia (Saphnelo) is required of all Aetna participating providers and members in applicable plan designs. For precertification of anifrolumab-fnia (Saphnelo), call (866) 752-7021 (commercial), (866) 503-0857 (Medicare), or fax (888) 267-3277. 

Note: Site of Care Utilization Management Policy applies.  For information on site of service for anifrolumab-fnia (Saphnelo), see Utilization Management Policy on Site of Care for Specialty Drug Infusions. 

1. Criteria for Initial Approval

   Aetna considers anifrolumab-fnia (Saphnelo) medically necessary for the treatment of active systemic lupus erythematosus (SLE) when all of the following criteria are met:

   1. Prior to initiating therapy, the member is positive for autoantibodies relevant to SLE (e.g., ANA, anti-ds DNA, anti-Sm, antiphospholipid antibodies, complement proteins); and
   2. The member is receiving a stable standard treatment for SLE with any of the following (alone or in combination):
      
      
      1. Glucocorticoids (e.g., prednisone, methylprednisolone, dexamethasone); or
      2. Antimalarials (e.g., hydroxychloroquine); or
      3. Immunosuppressants (e.g., azathioprine, methotrexate, mycophenolate, cyclosporine, cyclophosphamide).

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections) 

2. Continuation of Therapy

   Aetna considers continuation of anifrolumab-fnia (Saphnelo) therapy medically necessary for members requesting reauthorization for an indication listed in Section I who achieve or maintain a positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition.
   
   

See also: CPB 0818 - Belimumab (Benlysta).

Dosage and Administration

Saphnelo is supplied as 300 mg/2 mL (150 mg/mL) in a single-dose vial. Saphnelo should be administered by healthcare providers prepared to manage hypersensitivity reactions, including anaphylaxis, and infusion-related reactions.

The recommended dosage for moderate to severe systemic lupus erythematosus (SLE) is 300 mg as an intravenous infusion over a 30-minute period every 4 weeks. If a planned infusion is missed, it is recommended to administer Saphnelo as soon as possible. Maintain a minimum interval of 14 days between infusions.

Source: AstraZeneca, 2021b

Experimental and Investigational 

Aetna considers the use of anifrolumab-fnia in combination with other biologics, including B-cell-targeted therapies, experimental and investigational because the safety and efficacy for combination use has not been established. 

Aetna considers anifrolumab-fnia therapy experimental and investigational for the following indications (not an all-inclusive list) because its effectiveness for these indications has not been established: 

• Severe active central nervous system (CNS) lupus (including seizures that are attributed to CNS lupus, psychosis, organic brain syndrome, cerebrovascular accident, cerebritis, or CNS vasculitis requiring therapeutic intervention within 60 days before initiation of anifrolumab-fnia);
• Severe active lupus nephritis.

Background

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

• Saphnelo is indicated for the treatment of adult patients with moderate to severe systemic lupus erythematosus (SLE), who are receiving standard therapy.

  Limitations of Use: 

  The efficacy of Saphnelo has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus. Use of Saphnelo is not recommended in these situations.

Anifrolumab-fnia is available as Saphnelo (AstraZeneca Pharmaceuticals LP), a type I interferon (IFN) receptor antagonist. Type I IFNs play a role in the pathogenesis of systemic lupus erythematosus (SLE). Type I IFNs such as IFN-alpha, IFN-beta and IFN-kappa are cytokines involved in regulating the inflammatory pathways implicated in SLE. Anifrolumab is a human monoclonal antibody that binds to subunit 1 of the type I IFN receptor, blocking the activity of type I IFNs. The majority of adults with SLE have increased type I IFN signaling, which is associated with increased disease activity and severity (AstraZeneca, 2021a, 2021b).

The label for Saphnelo carries warnings and precautions for serious infections, hypersensitivity reactions including anaphylaxis, and malignancy.  Serious and sometimes fatal infections have occurred in patients receiving Saphnelo. Saphnelo increases the risk of respiratory infections and herpes zoster. It is recommended to avoid initiating treatment during an active infection, and consider the individual benefit-risk if using in patients with severe or chronic infections. Consider interrupting therapy with Saphnelo if patients develop a new infection during treatment. Serious hypersensitivity reactions (including anaphylaxis) have been reported following Saphnelo administration. Events of angioedema have also been reported. Consider pre-medication before infusion for patients with a history of these reactions. Saphnelo should be administered by healthcare providers prepared to manage hypersensitivity reactions, including anaphylaxis, and infusion-related reactions. There is an increased risk of malignancies with the use of immunosuppressants; however, the impact of Saphnelo treatment on the potential development of malignancies is not known (AstraZeneca, 2021b).

The FDA-approved label recommends that patients update immunizations, according to current immunization guidelines, prior to initiating Saphnelo therapy. Per the label, avoid concurrent use of live or live-attenuated vaccines in patients treated with Saphnelo.

Saphnelo has not been studied in combination with other biologic therapies, including B-cell-targeted therapies. Therefore, use of Saphnelo is not recommended for use in combination with biologic therapies.

The most common adverse drug reactions (incidence 5% or more) include nasopharyngitis, upper respiratory tract infections, bronchitis, infusion related reactions, herpes zoster and cough (AstraZeneca, 2021b).

Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a complex, chronic, potentially life-threatening, autoimmune disease that is characterized by immunologic abnormalities resulting in systemic inflammation affecting multiple organs such as the skin, joints, kidney, lungs and central nervous system.

The prevalence of SLE has been reported in the United States to be 20 to 150 cases per 100,000 (Schur and Hahn, 2021). SLE is more common in women than men by nearly 10 to 1. It may occur at any age. However, it appears most often in young women between the ages of 15 and 44 (NIH/NLM, 2021).

The etiology of SLE is unknown and is clearly multifactorial, but are thought to be related to genetic, immunologic, environmental, and hormonal factors (NIH/NLM, 2021; Schur and Hahn, 2021). SLE involves aberrations in multiple components of the immune system, which includes T-cells, B-cells, cytokines and production of antibodies, especially antinuclear antibodies (ANA) that are positive in the majority of individuals with active SLE. Antibodies to native double-stranded DNA (dsDNA) are relatively specific for the diagnosis of SLE (Bartels and Muller, 2021). 

SLE is hard to diagnose because the symptoms are often mistaken for those of other diseases. The 2019 European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) include classification criteria for SLE which requires the presence of a positive antinuclear antibodies (ANA) as an entry criterion. Additive criteria consist of seven clinical (ie, constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and three immunologic (ie, antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, each of which are weighted from 2 to 10. Patients accumulating 10 or more points are classified as having SLE (Aringer et al., 2019). There is no cure for SLE, but symptoms can be managed (CDC, 2021).

On August 2, 2021, the U.S. FDA approved anifrolumab, brand name Saphnelo (AstraZeneca Pharmaceuticals LP), for the treatment of adult patients with moderate to severe systemic lupus erythematosus (SLE) who are receiving standard therapy. FDA approval was based on the efficacy and safety data from TULIP-1 (NCT02446912), TULIP-2 (NCT02446899) Phase III trials and the MUSE (NCT01438489) Phase II trial. All three trials were randomized, double-blinded, and placebo-controlled in patients (18 years of age and older) with moderate to severe SLE, with a SLE Disease Activity Index 2000 (SLEDAI-2K) score 6 or more points, organ level involvement based on BILAG assessment, and a Physician’s Global Assessment [PGA] score of 1 or more who were receiving standard therapy, which included at least one of the following: oral corticosteroids (OCS), antimalarials and immunosuppressants (methotrexate, azathioprine or mycophenolate mofetil). Patients continued to receive their existing SLE therapy at stable doses during the clinical trials, with the exception of OCS (prednisone or equivalent) where tapering was a component of the protocol. Patients who had severe active lupus nephritis and patients who had severe active central nervous system lupus were excluded. The use of other biologic agents and cyclophosphamide were not permitted during the trials; patients receiving other biologic therapies were required to complete a wash-out period prior to enrollment. In all three trials, patients received anifrolumab-fnia or placebo, administered by intravenous infusion, every 4 weeks for 52 weeks. The outcomes for these trials found that more patients treated with anifrolumab-fnia experienced a reduction in overall disease activity across organ systems, including skin and joints, and achieved sustained reduction in OCS use compared to placebo, with both groups receiving standard therapy (AstraZeneca, 2021a, 2021b).

In the MUSE trial, Furie et al (2017) assessed the efficacy and safety of anifrolumab, a type I interferon (IFN) receptor antagonist, in a phase IIb, randomized, double-blind, placebo-controlled study of adults with moderate-to-severe systemic lupus erythematosus (SLE). Patients (n = 305) were randomized to receive intravenous anifrolumab (300 mg or 1,000 mg) or placebo, in addition to standard therapy, every 4 weeks for 48 weeks. Randomization was stratified by SLE Disease Activity Index 2000 score (<10 or ≥10), oral corticosteroid dosage (<10 or ≥10 mg/day), and type I IFN gene signature test status (high or low) based on a 4-gene expression assay. The primary end point was the percentage of patients achieving an SLE Responder Index (SRI[4]) response at week 24 with sustained reduction of oral corticosteroids (<10 mg/day and less than or equal to the dose at week 1 from week 12 through 24). Other end points (including SRI[4], British Isles Lupus Assessment Group [BILAG]-based Composite Lupus Assessment [BICLA], modified SRI[6], and major clinical response) were assessed at week 52. The primary end point was analyzed in the modified intent-to-treat (ITT) population and type I IFN-high subpopulation. The study result was considered positive if the primary end point was met in either of the 2 study populations. The Type I error rate was controlled at 0.10 (2-sided), within each of the 2 study populations for the primary end point analysis.The primary end point was met by more patients treated with anifrolumab than placebo (p = 0.014 for 300 mg and p = 0.063 for 1,000 mg, versus placebo), with greater effect size in patients with a high IFN signature at baseline (13.2% in placebo-treated patients versus 36.0% [p = 0.004] and 28.2% [p = 0.029]) in patients treated with anifrolumab 300 mg and 1,000 mg, respectively. At week 52, patients treated with anifrolumab achieved greater responses in SRI(4) (40.2% versus 62.6% [p < 0.001] and 53.8% [p = 0.043] with placebo, anifrolumab 300 mg, and anifrolumab 1,000 mg, respectively), BICLA (25.7% versus 53.5% [p < 0.001] and 41.2% [p = 0.018], respectively), modified SRI(6) (28.4% versus 49.5% [p = 0.002] and 44.7% [p = 0.015], respectively), major clinical response (BILAG 2004 C or better in all organ domains from week 24 through week 52) (6.9% versus 19.2% [p = 0.012] and 17.3% [p = 0.025], respectively), and several other global and organ-specific end points. Herpes zoster was more frequent in the anifrolumab-treated patients (2.0% with placebo treatment versus 5.1% and 9.5% with anifrolumab 300 mg and 1,000 mg, respectively), as were cases reported as influenza (2.0% versus 6.1% and 7.6%, respectively), in the anifrolumab treatment groups. Incidence of serious adverse events was similar between groups (18.8% versus 16.2% and 17.1%, respectively). The authors concluded that anifrolumab substantially reduced disease activity compared with placebo across multiple clinical end points in the patients with moderate-to-severe SLE.

The TULIP-1 trial randomised 457 eligible patients (1:2:2) to receive a fixed-dose intravenous infusion of 150mg anifrolumab, 300mg anifrolumab, or placebo every four weeks, in addition to standard therapy. TULIP-1 assessed the effect of anifrolumab in reducing disease activity as measured by the SRI4. The trial did not meet its primary endpoint based on the SLE Responder Index 4 (SRI4) composite measure (AstraZeneca, 2021a).

In the TULIP-2 trial, Morand et al (2020) state that anifrolumab for the treatment of SLE did not have a significant effect on the primary end point in a previous phase 3 trial (TULIP-1). Thus, the authors randomly assigned 362 patients in a 1:1 ratio to receive intravenous anifrolumab (n=180; 300 mg) or placebo (n=182) every 4 weeks for 48 weeks. The primary end point of this trial was a response at week 52 defined with the use of the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA). A BICLA response requires reduction in any moderate-to-severe baseline disease activity and no worsening in any of nine organ systems in the BILAG index, no worsening on the Systemic Lupus Erythematosus Disease Activity Index, no increase of 0.3 points or more in the score on the Physician Global Assessment of disease activity (on a scale from 0 [no disease activity] to 3 [severe disease]), no discontinuation of the trial intervention, and no use of medications restricted by the protocol. Secondary end points included a BICLA response in patients with a high interferon gene signature at baseline; reductions in the glucocorticoid dose, in the severity of skin disease, and in counts of swollen and tender joints; and the annualized flare rate. The percentage of patients who had a BICLA response was 47.8% in the anifrolumab group and 31.5% in the placebo group (p = 0.001). Among patients with a high interferon gene signature, the percentage with a response was 48.0% in the anifrolumab group and 30.7% in the placebo group; among patients with a low interferon gene signature, the percentage was 46.7% and 35.5%, respectively. Secondary end points with respect to the glucocorticoid dose and the severity of skin disease, but not counts of swollen and tender joints and the annualized flare rate, also showed a significant benefit with anifrolumab. Herpes zoster and bronchitis occurred in 7.2% and 12.2% of the patients, respectively, who received anifrolumab. There was one death from pneumonia in the anifrolumab group. The authors concluded that monthly administration of anifrolumab resulted in a higher percentage of patients with a response (as defined by a composite end point) at week 52 than did placebo, in contrast to the findings of a similar TULIP-1 trial involving patients with SLE that had a different primary end point. The frequency of herpes zoster was higher with anifrolumab than with placebo. 

Furie et al (2021) state that the objective to managing SLE includes preventing disease flares while minimizing glucocorticoids. Thus, pooled data from the phase 3 TULIP-1 and TULIP-2 trials in patients with moderate to severe SLE were analyzed to determine anifrolumab's effect on flares, including those arising with glucocorticoid taper. Compared with placebo (n = 366), anifrolumab (n = 360) was associated with lower annualized flare rates, prolonged time to first flare, and fewer patients with 1 or more flare, as well as flares in organ domains commonly active at baseline (musculoskeletal, mucocutaneous). Fewer BILAG-based Composite Lupus Assessment responders had 1 or more flare with anifrolumab (21.1%, 36/171) versus placebo (30.4%, 34/112). Of patients who achieved sustained glucocorticoid reductions from 10 or more mg/day at baseline, more remained flare free with anifrolumab (40.0%, 76/190) versus placebo (17.3%, 32/185). The authors concluded that analyses of pooled TULIP-1 and TULIP-2 data support that anifrolumab reduces flares while permitting glucocorticoid taper in patients with SLE.

Casey et al (2021) evaluated the ability of anifrolumab, a type I IFN receptor-blocking antibody, to reduce neutrophil extracellular trap (NET) formation and modulate cardiometabolic disease markers in comparison to placebo. Study subjects comprised patients with moderate-to-severe SLE who were enrolled in phase IIb of the MUSE trial (A Phase II, Randomized Study to Evaluate the Efficacy and Safety of MEDI-546 in Subjects with Systemic Lupus Erythematosus), with healthy individuals as controls. Blood samples were collected from SLE patients (n = 305) and healthy controls (n = 10-20) before the initiation of treatment (baseline) and from SLE patients after they had been treated with 300 mg of anifrolumab (n = 99) or placebo (n = 102). Baseline IFN gene signature test status was determined, and the IFN gene signature (21-gene panel) was monitored over time. Serum proteins were measured by multiplex immunoassay or ultrasensitive Simoa assay. NET complexes, cholesterol efflux capacity (CEC), and glycoprotein acetylation (GlycA) and other lipid parameters were assessed in plasma. Formation of NET complexes and levels of tumor necrosis factor (TNF) and interleukin-10 (IL-10) were correlated with extent of type I IFN pathway activity. NET complexes and IL-10 levels were up-regulated in SLE patients compared to healthy controls (p < 0.008). The cardiometabolic disease markers CEC and GlycA were also found to be dysregulated in patients with SLE (p < 0.001 versus healthy controls). Type I IFN receptor inhibition with anifrolumab significantly reduced NET complexes and GlycA and improved CEC compared to baseline (p < 0.05) whereas no improvements were seen with placebo. Levels of TNF and IL-10 were reduced with anifrolumab compared to placebo (p < 0.05). The authors concluded that these data support a key role for type I IFNs in modulating factors contributing to SLE vasculopathy and suggest that inhibition of this pathway could decrease cardiovascular risk in individuals with SLE.

According to AstraZeneca (2021a), Saphnelo is under regulatory review for SLE in the EU and Japan. The Phase III trial in SLE using subcutaneous delivery has been initiated and additional Phase III trials are planned for lupus nephritis, cutaneous lupus erythematosus and myositis.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
96365 – 96368	Intravenous infusion administration
96413 - 96417	Chemotherapy administration
HCPCS codes covered if selection criteria are met:
J0491	Injection, anifrolumab-fnia, 1 mg
Other HCPCS codes related to the CPB:
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
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
J7502	Cyclosporine, oral, 100 mg
J7509	Methylprednisolone oral, per 4 mg
J7512	Prednisone, immediate release or delayed release, oral, 1 mg
J7515	Cyclosporine, oral, 25 mg
J7516	Cyclosporin, parenteral, 250 mg
J7517	Mycophenolate mofetil, oral, 250 mg
J8530	Cyclophosphamide; oral, 25 mg
J8540	Dexamethasone, oral, 0.25 mg
J8610	Methotrexate; oral, 2.5 mg
J9070	Cyclophosphamide, 100 mg
J9250	Methotrexate sodium, 5 mg
J9260	Methotrexate sodium, 50 mg
ICD-10 codes covered if selection criteria are met:
M32.0 – M32.9	Systemic lupus erythematosus (SLE) [not covered for severe active central nervous system (CNS) lupus and severe active lupus nephritis]

The above policy is based on the following references: