Spesolimab-sbzo (Spevigo)

Number: 1013

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 spesolimab-sbzo (Spevigo) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification: 

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

1. Prescriber Specialties

   This medication must be prescribed by or in consultation with a dermatologist.

2. Criteria for Initial Approval

   1. Generalized pustular psoriasis (GPP) flare

      Aetna considers spesolimab-sbzo (Spevigo) medically necessary for treatment of generalized pustular psoriasis (GPP) flares in members 12 years of age or older when all the following criteria are met:

      1. Member has a known documented history of GPP (either relapsing [greater than 1 episode] or persistent [greater than 3 months]); and
      2. Member is presenting with primary, sterile, macroscopically visible pustules (new or worsening) on an erythematous base (excluding cases where pustulation is restricted to psoriatic plaques); and
      3. Member has at least one of the following documented:
         
         
         1. IL36RN, CARD14, or AP1S3 gene mutation; or
         2. Skin biopsy confirming presence of Kogoj’s spongiform pustules; or
         3. Systemic symptoms or laboratory abnormalities commonly associated with GPP flare (e.g., fever, asthenia, myalgia, elevated C-reactive protein [CRP], leukocytosis, neutrophilia [above ULN]); or
         4. GPP flare of moderate-to-severe intensity (e.g., at least 5% body surface area is covered with erythema and the presence of pustules; Generalized Pustular Psoriasis Physician Global Assessment [GPPPGA] total score of greater or equal to 3);

   2. Generalized pustular psoriasis (GPP) when not experiencing a flare

      Aetna considers spesolimab-sbzo (Spevigo) medically necessary for treatment of GPP in members 12 years of age or older when all the following criteria are met:

      1. Member has a known documented history of GPP (either relapsing [greater than 1 episode] or persistent [greater than 3 months]); and
      2. Member meets either of the following:
         
         
         1. Member has had a history of at least two moderate-to-severe GPP flares (e.g., at least 5% body surface area is covered with erythema and the presence of pustules; Generalized Pustular Psoriasis Physician Global Assessment [GPPPGA] total score of greater or equal to 3); or
         2. Member has a history of flaring while on concomitant treatment (e.g., retinoids, methotrexate, cyclosporine); and

      3. Member currently has clear to almost clear skin. 

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

1. Continuation of Therapy

   Aetna considers continuation of spesolimab-sbzo (Spevigo) therapy medically necessary for all members 12 years of age or older (including new members) for treatment of the following indications when criteria are met:

   1. Generalized GPP flare when members meet all initial authorization criteria; or
   2. Generalized GPP when not experiencing a flare and who achieve or maintain a positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition.

2. Other 

   For all indications: Member has had a documented negative tuberculosis (TB) test (which can include a tuberculosis skin test [TST] or an interferon-release assay [IGRA])Footnote1* within 12 months of initiating therapy for persons who are naïve to biologic drugs or targeted synthetic drugs associated with an increased risk of TB. 

   Footnote1* If the screening testing for TB is positive, there must be further testing to confirm there is no active disease (e.g., chest x-ray). Do not administer the requested medication to members with active TB infection. If there is latent disease, TB treatment must be started before initiation of the requested medication.
   
   Member cannot use the requested medication concomitantly with any other biologic drug or targeted synthetic drug for the same indication.

3. Related Policies

   1. CPB 0205 - Phototherapy and Photochemotherapy (PUVA) for Skin Conditions
   2. CPB 0315 - Etanercept
   3. CPB 0341 - Infliximab
   4. CPB 0577 - Laser Treatment for Psoriasis and Other Selected Skin Conditions
   5. CPB 0655 - Adalimumab
   6. CPB 0761 - Certolizumab Pegol (Cimzia)
   7. CPB 0905 - Secukinumab (Cosentyx)
   8. CPB 0912 - Ustekinumab (Stelara)
   9. CPB 1009 - Risankizumab-rzaa (Skyrizi)

Dosage and Administration

Spesolimab-sbzo is available as Spevigo and supplied in the following dosage forms and strengths:

• For subcutaneous (SC) use: 150 mg/mL solution in a single-dose prefilled syringe;
• For intravenous (IV) use: 450 mg/7.5 mL (60 mg/mL) solution in a single-dose vial.

Intravenous Dosage for Treatment of GPP Flare

The recommended dosage of Spevigo for treatment of GPP flare in persons 12 years of age and older and weighing at least 40 kg is a single 900 mg dose administered by IV infusion over 90 minutes. If GPP flare symptoms persist, an additional intravenous 900 mg dose (over 90 minutes) may be administered one week after the initial dose. 

Subcutaneous Dosage for Treatment of GPP When Not Experiencing a Flare

The recommended dosage of Spevigo for treatment of GPP when not experiencing a flare in persons 12 years of age and older and weighing at least 40 kg is a loading dose of 600 mg (four 150 mg injections) followed by 300 mg (two 150 mg injections) administered subcutaneously 4 weeks later and every 4 weeks thereafter.

If required, the 600 mg subcutaneous loading dose of Spevigo is to be administered by a healthcare professional. For subsequent 300 mg doses, if the healthcare professional determines that it is appropriate, a person 12 years of age or older may self-inject or the caregiver may administer Spevigo after proper training. In pediatrics 12 to 17 years of age, Spevigo is administered under the supervision of an adult. If a person experiences a GPP flare while receiving subcutaneous Spevigo, the GPP flare may be treated with intravenous Spevigo.

Subcutaneous use after IV Spevigo for treatment of GPP flare: Four weeks after treatment with intravenous Spevigo, subcutaneous Spevigo is initiated or reinitiated at a dose of 300 mg (two 150 mg injections) administered every 4 weeks. A loading dose is not required following treatment of a GPP flare with intravenous Spevigo.

Source: Boehringer Ingelheim, 2024b

Experimental, Investigational, or Unproven 

Aetna considers concomitant use of spesolimab-sbzo with any other biologic drug (e.g., adalimumab, anakinra, etanercept, infliximab, rilonacept, tocilizumab) or targeted synthetic drug (e.g. tofacitinib) experimental, investigational, or unproven for the same indication because the effectiveness of this approach has not been established.

Aetna considers spesolimab-sbzo (Spevigo) experimental, investigational, or unproven for the following indications (not an all-inclusive list) because its effectiveness for these indications has not been established:

• Atopic dermatitis
• Ulcerative colitis.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
71045 - 71048	Radiologic examination, chest
86480	Tuberculosis test, cell mediated immunity antigen response measurement; gamma interferon
86481	enumeration of gamma interferon - producing T cells in cell suspension
86580	Skin test; tuberculosis, intradermal
96365 - 96368	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug)
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
96413 - 96417	Chemotherapy administration
HCPCS codes covered if selection criteria are met:
J1747	Injection, spesolimab-sbzo, 1 mg
Other HCPCS codes related to the CPB:
J0135	Injection, adalimumab, 20 mg
J1438	Injection, etanercept, 25 mg (code may be used for Medicare when drug administered under the direct supervision of a physician, not for use when drug is self-administered)
J1745	Injection, ferric pyrophosphate citrate solution (Triferic AVNU), 0.1 mg of iron
J3262	Injection, tocilizumab, 1 mg
J7502	Cyclosporine, oral, 100 mg
J7515	Cyclosporine, oral, 25 mg
J7516	Injection, cyclosporine, 250 mg
J8610	Methotrexate; oral, 2.5 mg
J9255	Injection, methotrexate (accord) not therapeutically equivalent to j9250 and j9260, 50 mg
J9260	Injection, methotrexate sodium, 50 mg
Q5103	Injection, infliximab-dyyb, biosimilar, (Inflectra), 10 mg
Q5104	Injection, infliximab-abda, biosimilar, (Renflexis), 10 mg
Q5109	Injection, infliximab-qbtx, biosimilar, (Ixifi), 10 mg
Q5121	Injection, infliximab-axxq, biosimilar, (AVSOLA), 10 mg
Q5133	Injection, tocilizumab-bavi (tofidence), biosimilar, 1 mg
Q5135	Injection, tocilizumab-aazg (tyenne), biosimilar, 1 mg
S0117	Tretinoin, topical, 5 grams
ICD-10 codes covered if selection criteria are met:
L40.1	Generalized pustular psoriasis
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
L20.0 - L20.9	Atopic dermatitis
K51.011 - K51.919	Ulcerative colitis

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Background

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

• Spevigo is indicated for the treatment of generalized pustular psoriasis (GPP) in adults and pediatric patients 12 years of age and older and weighing at least 40 kg

Spesolimab-sbzo is branded as Spevigo (Boehringer Ingelheim Pharmaceuticals, Inc.). Spesolimab-sbzo is a humanized monoclonal immunoglobulin G1 antibody that inhibits interleukin-36 (IL-36) signaling by specifically binding to the interleukin-36 receptor (IL-36R). Binding of spesolimab-sbzo to IL-36R prevents the subsequent activation of IL36R by cognate ligands (IL-36 α, β and γ) and downstream activation of pro-inflammatory and pro-fibrotic pathways. This interleukin-36 receptor antagonist has been evaluated for the treatment of generalized pustular psoriasis (GPP). The precise mechanism linking reduced IL-36R activity and the treatment of GPP is unclear; however, IL-36R has been shown to play a role in the signaling pathway within the immune system involved in the cause of GPP.

Spevigo carries warnings and precautions for increased risk of infections; tuberculosis (TB); and hypersensitivity, including drug reaction with eosinophilia and systemic symptoms (DRESS), and infusion-related reactions. Live vaccines are not to be administered concurrently with Spevigo, and should be avoided for at least 16 weeks after treatment. During the one-week placebo-controlled period in the Effisayil-1 trial, infections were reported in 14% of subjects treated with spesolimab-sbzo compared with 6% of subjects treated with placebo. Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in clinical trials with spesolimab-sbzo in subjects with GPP. Furthermore, Spevigo should not be administered to persons with active TB infection.

The most common adverse reactions (5% or more) in patients treated for GPP flare include asthenia and fatigue, nausea and vomiting, headache, pruritus and prurigo, infusion site hematoma and bruising, and urinary tract infection. 

The most common adverse reactions associated with an increased incidence (9 or more cases per 100 patient-years) in patients receiving treatment for GPP when not experiencing a flare include injection site reaction, urinary tract infection, arthralgia, and pruritus.

Generalized Pustular Psoriasis 

Generalized pustular psoriasis (GPP) is a rare, heterogenous, potentially life-threatening autoinflammatory neutrophilic skin disease characterized by episodes of widespread eruption of aseptic, macroscopically visible pustules, which can occur with or without plaque psoriasis, and may be accompanied by systemic symptoms, such as fever, pain, and fatigue (Choon et al, 2021).

GPP is traditionally classified as a variant of psoriasis; however, evidence suggests that genetic factors distinct from those associated with chronic plaque psoriasis contribute to GPP. In particular, mutations in the IL36RN gene that encodes the interleukin-36 receptor antagonist (IL-36Ra), an anti-inflammatory cytokine in the IL-1 family that inhibits proinflammatory signal pathways by preventing the binding of IL-36 to its receptor, have been detected in some patients with GPP. Pustular psoriasis has also been associated with mutations in caspase recruitment domain family member 14 (CARD14) and the adapter protein family 1 (AP1S3) (Kalb, 2022b).

The clinical course of GPP is usually unstable and prolonged without treatment, with periods of disease dormancy and recurrence over the course of years. Flares may occur upon re-exposure to a precipitating factor or for unknown reasons. Potential complications include sepsis; serious renal, hepatic (neutrophilic cholangitis) or respiratory (neutrophilic pneumonitis, acute respiratory distress syndrome) abnormalities; and death. Patients usually require continued therapy to avoid resurgence of flares (Kalb, 2022a, 2022b).

On September 1, 2022, the U.S. Food and Drug Administration (FDA) approved the first labeled treatment option, Spevigo (spesolimab-sbzo), a monoclonal antibody that inhibits IL-36 signaling, for the treatment of GPP flares in adults. FDA approval was based on positive outcomes from the Phase 2, randomized, double-blind, placebo-controlled Effisayil-1 study (NCT03782792), which found in the 12-week trial, that 54% of patients treated with Spevigo showed no visible pustules after one week compared to those who took a placebo (6%).

The Effisayil-1 study, conducted by Bachelez et al (2021), randomly assigned adult patients (n=53) with a GPP flare in a 2:1 ratio to receive a single 900-mg intravenous dose of spesolimab (n=35) or placebo (n=18). Patients were randomized if their flare was of moderate-to-severe intensity, as defined by: a Generalized Pustular Psoriasis Physician Global Assessment (GPPPGA) total score of at least 3 (moderate) [the total GPPPGA score ranges from 0 (clear) to 4 (severe)], the presence of fresh pustules (new appearance or worsening of pustules), GPPPGA pustulation sub score of at least 2 (mild), and at least 5% of body surface area covered with erythema and the presence of pustules. Patients in both groups could receive an open-label dose of spesolimab on day 8, an open-label dose of spesolimab as a rescue medication after day 8, or both and were followed to week 12. The primary end point was a GPPGA pustulation subscore of 0 at the end of week 1. The key secondary end point was a GPPGA total score of 0 or 1 (clear or almost clear skin) at the end of week 1. At baseline, 46% of the patients in the spesolimab group and 39% of those in the placebo group had a GPPGA pustulation subscore of 3, and 37% and 33%, respectively, had a pustulation subscore of 4. At the end of week 1, a total of 19 of 35 patients (54%) in the spesolimab group had a pustulation subscore of 0, as compared with 1 of 18 patients (6%) in the placebo group (p < 0.001). A total of 15 of 35 patients (43%) had a GPPGA total score of 0 or 1, as compared with 2 of 18 patients (11%) in the placebo group (p = 0.02). Drug reactions were reported in 2 patients who received spesolimab, in 1 of them concurrently with a drug-induced hepatic injury. Among patients assigned to the spesolimab group, infections occurred in 6 of 35 (17%) through the first week; among patients who received spesolimab at any time in the trial, infections had occurred in 24 of 51 (47%) at week 12. Antidrug antibodies were detected in 23 of 50 patients (46%) who received at least one dose of spesolimab. The authors concluded that in a phase 2 randomized trial involving patients with GPP, the interleukin-36 receptor inhibitor spesolimab resulted in a higher incidence of lesion clearance at 1 week than placebo but was associated with infections and systemic drug reactions. The authors state that longer and larger trials are warranted to determine the effect and risks of spesolimab in patients with pustular psoriasis.

Due to the rarity, life-threatening potential, and limited treatment options for GPP flares, Spevigo was granted FDA Breakthrough Therapy Designation and Orphan Drug Designation in the U.S.

On March 19, 2024, the FDA expanded the approval of Spevigo to include the treatment of GPP in adult and pediatric patients 12 years of age or older and weighing at least 40kg. Previously, the treatment was only approved for GPP flares in adults.

FDA approval was based on data from the Effisayil-2 study (NCT04399837), which was a randomized, double-blind, placebo-controlled phase 2 study that evaluated the safety and efficacy of spesolimab for subcutaneous (SC) administration in patients with GPP who were 12 years of age and older and weighing at least 40kg. Patients were required to have a history of at least 2 GPP flares of moderate to severe intensity. Patients must have had a history of flaring while on concomitant treatment for GPP or a history of flaring upon dose reduction or discontinuation of these concomitant medications. Prior to or at study randomization, systemic and topical therapies for GPP were required to be discontinued. Study participants were randomly assigned to receive either spesolimab 600mg SC loading dose followed by 300mg SC every 4 weeks (n=30) or placebo (n=31). The primary endpoint was time to first GPP flare up to week 48, defined as GPPPGA sub score of at least 2 and an increase in GPPPGA total score by at least 2 from baseline. Results showed that treatment with spesolimab reduced the risk of GPP flares by 84% over 48 weeks compared with placebo. Furthermore, 10% of patients (n=3/30) who received spesolimab had at least 1 GPP flare up to week 48 compared with 52% of those (n=16/31) who received placebo (risk difference, -39 [95% CI, -62, -16]). These results were generally consistent across subgroups.

Spevigo is now supplied in 150mg/mL prefilled syringes for subcutaneous (SC) use, which has been approved for the treatment of GPP when patients are not experiencing a flare.

The safety and effectiveness of Spevigo in pediatric patients younger than 12 years of age or in pediatric patients weighing less than 40 kg have not been established.

The National Psoriasis Foundation regarding GPP issued a high consensus statement that strongly advocates for timely access to approved therapies, such as spesolimab, which is critical to reducing morbidity and mortality in patients presenting with GPP (Armstrong et al, 2024).

Other Indications

Atopic Dermatitis

Bissonnette et al (2023) noted that atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease, and there is increasing evidence that the IL-36 pathway may play a role in the pathogenesis of AD.  In a randomized, double-blind, placebo-controlled, multi-center, phase-IIa clinical trial, these researchers examined the safety and effectiveness of spesolimab in adult patients with moderate-to-severe AD.  This study included 51 eligible patients; they were randomized 2:1 to receive IV doses of spesolimab 600 mg or placebo every 4 weeks.  The primary endpoint was percentage change from baseline in Eczema Area and Severity Index (EASI) score at Week 16.  Decrease in EASI score from baseline to Week 16 was - 37.9 % for spesolimab versus - 12.3 % for placebo (adjusted mean difference [MD] of -25.6 %, p = 0.149).  A pre-defined sensitivity analysis, excluding data from patients who used restricted corticosteroids, resulted in an adjusted MD of -48.3 % (nominal p = 0.024).  Spesolimab was well-tolerated, with no clinically relevant safety signals.  The authors concluded that this was the 1st study to examine the IL-36 pathway inhibition in AD.  These researchers stated that although not statistically significant, numerical improvements were observed in the primary endpoint of change from baseline in EASI score.  Spesolimab had an acceptable safety profile, with no unexcepted safety concerns.  These findings need to be validated in phase-III clinical trials.

Ulcerative Colitis

Ferrante et al (2023) stated that IL-36 signaling has been shown to be increased in ulcerative colitis (UC).  In 3 phase-II clinical trials, these researchers examined the safety, immunogenicity, and effectiveness of IV spesolimab in patients with UC.  Study 1: phase-II, randomized, placebo-controlled trial (300 mg, 1 dose; 450 mg every 4 weeks [q4w]; or 1,200 mg q4w, 3 doses).  Study 2: phase IIa, randomized, placebo-controlled trial (1,200 mg q4w).  Study 3: phase IIa, open-label, single-arm trial (1,200 mg q4w).  Studies lasted 12 weeks, with a 12-, 24-, and 16-week safety follow-up, respectively.  Adverse event (AE) rates were similar for spesolimab and placebo in Studies 1 (n = 98; 64.9 %; 65.2 %) and 2 (n = 22; 86.7 %; 71.4 %); all patients in Study 3 (n = 8) experienced AEs.  The most frequent investigator-assessed drug-related (spesolimab; placebo) AEs were skin rash (5.4 %; 0 %) and nasopharyngitis (4.1 %; 0 %) in Study 1; acne (13.3 %; 0 %) in Study 2; 1 patient reported skin rash, nasopharyngitis, headache, and acne in Study 3.  The authors concluded that spesolimab was generally well-tolerated, with no unexpected safety concerns; and the safety data were consistent with studies in other inflammatory diseases.  However, effectiveness endpoints were not met.  

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References