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

Treatment of moderate-to-severe plaque psoriasis (PsO) in adults who are candidates for systemic therapy or phototherapy

Treatment of active psoriatic arthritis (PsA) in adults

Treatment of moderately to severely active Crohn’s disease (CD) in adults

Risankizumab-rzaa is available as Skyrizi (AbbVie Inc.). Risankizumab-rzaa is a humanized IgG1 monoclonal antibody that selectively binds to the p19 subunit of human IL-23 cytokine and inhibits its interaction with the IL-23 receptor. IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses. Risankizumab-rzaa inhibits the release of pro-inflammatory cytokines and chemokines (AbbVie, 2023).

Skyrizi labeling carries the following warnings and precautions:

Hypersensitivity reactions: Serious hypersensitivity reactions, including anaphylaxis, have been reported with use of Skyrizi.

Infections: Skyrizi may increase the risk of infection.

Tuberculosis (TB): Evaluate for TB prior to initiating treatment with Skyrizi

Across the Phase 3 psoriasis clinical studies, of the 72 subjects with latent TB who were concurrently treated with Skyrizi and appropriate TB prophylaxis during the studies, none developed active TB during the mean follow-up of 61 weeks on Skyrizi. Two subjects taking isoniazid for treatment of latent TB discontinued treatment due to liver injury. Of the 31 subjects from the PsO-3 study with latent TB who did not receive prophylaxis during the study, none developed active TB during the mean follow-up of 55 weeks on Skyrizi. Per the prescribing information, consider anti-TB therapy prior to initiating Skyrizi in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Monitor patients for signs and symptoms of active TB during and after Skyrizi treatment. Do not administer Skyrizi to patients with active TB.

Hepatotoxicity in treatment of Crohn’s disease:

A serious adverse reaction of drug-induced liver injury was reported in a patient with Crohn’s disease (ALT 54x ULN, AST 30x ULN, and total bilirubin 2.2x ULN) following two intravenous doses of Skyrizi 600 mg in conjunction with a rash that required hospitalization. The liver test abnormalities resolved following administration of steroids. Skyrizi was subsequently discontinued. Per the label, for the treatment of Crohn’s disease, evaluate liver enzymes and bilirubin at baseline, and during induction at least up to 12 weeks of treatment. Monitor thereafter according to routine patient management. Consider other treatment options in patients with evidence of liver cirrhosis.

Administration of Vaccines: Avoid use of live vaccines.

The most common adverse reactions in patients with plaque psoriasis and psoriatic arthritis (1% or more) are upper respiratory infections, headache, fatigue, injection site reactions, and tinea infections. The most common adverse reactions in patients with Crohn's disease (greater than 3%) for induction dosing are upper respiratory infections, headache, and arthralgia; and for maintenance dosing, arthralgia, injection site reactions, abdominal pain, anemia, pyrexia, back pain, arthropathy, and urinary tract infection (AbbVie, 2023).

Active Psoriatic Arthritis and Plaque Psoriasis

On April 23, 2019, AbbVie Inc (Chicago, IL) announced the FDA approval of Skyrizi (risankizumab-rzaa), an interleukin-23 (IL-23) inhibitor, for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy.

FDA approval was based on four multicenter, randomized, double-blind, placebo and/or active-controlled pivotal studies: ULTIMMA-1, ULTIMMA-2, IMMHANCE and IMMVENT (NCT02684370, NCT02684357, NCT02672852, NCT02694523).

In the ULTIMMA-1 and ULTIMMA-2 trials, 997 subjects with moderate-to-severe chronic plaque psoriasis, ages 18 years or older, who had a body surface area (BSA) involvement of ≥10%, a static Physician’s Global Assessment (sPGA) score of ≥3 (“moderate”) in the overall assessment (plaque thickness/induration, erythema, and scaling) of psoriasis on a severity scale of 0 to 4, and a Psoriasis Area and Severity Index (PASI) score ≥12 were enrolled. Of the 997 subjects, 598 were randomized to the risankizumab-rzaa 150 mg group, 200 were randomized to the placebo group, and 199 to the biologic (ustekinumab) active control group. Risankizumab-rzaa was administered subcutaneously at Weeks 0, 4, and every 12 weeks thereafter. Both studies assessed the responses at Week 16 compared to placebo for two co-primary endpoints, the proportion of subjects achieving a 90% reduction from baseline in the Psoriasis Area Severity Index (PASI 90), and the proportion of subjects who achieved a sPGA score of 0 (“clear”) or 1 (“almost clear”). Secondary endpoints included the proportion of subjects who achieved PASI 100, sPGA 0, and Psoriasis Symptom Scale (PSS) 0 (“none”) at Week 16 versus placebo. Co-primary endpoints were met for both studies. At Week 16 both ULTIMMA-1 and ULTIMMA-2 found that PASI 90 was achieved in 75 percent of people treated with risankizumab-rzaa (Skyrizi), compared to 5 and 2 percent receiving placebo, respectively (p<0.001). PASI 100 was achieved in 36 and 51 percent of people treated with risankizumab-rzaa, compared to 0 and 2 percent receiving placebo, respectively (p<0.001). At one year (52 weeks), 82 and 81 percent of people treated with risankizumab-rzaa achieved PASI 90, and 56 and 60 percent achieved PASI 100, respectively (p<0.001); in addition, 58 and 60 percent achieved sPGA 0, respectively. An integrated analysis of ULTIMMA-1 and ULTIMMA-2 showed most people treated with risankizumab-rzaa who achieved PASI 90 and PASI 100 at Week 16 maintained this response at one year (88 and 80 percent, respectively) (AbbVie, 2019a; AbbVie, 2019b; Gordon et al., 2018).

In the IMMHANCE trial (NCT02672852), subjects who were originally on risankizumab-rzaa and had sPGA 0 or 1 at Week 28 were re-randomized to continue risankizumab-rzaa every 12 weeks or withdrawal of therapy. At Week 52, 87% (97/111) of the subjects re-randomized to continue treatment with risankizumab-rzaa had sPGA 0 or 1 compared to 61% (138/225) who were re-randomized to withdrawal of risankizumab-rzaa (AbbVie, 2019b).

In January 2022, the U.S. FDA approved Skyrizi for the treatment of adults with active psoriatic arthritis (PsA), a systemic inflammatory disease that affects the skin and joints (AbbVie, 2022). FDA approval was based on data from two pivotal studies, KEEPsAKE-1 and KEEPsAKE-2, which evaluated the efficacy and safety of risankizumab in adults with active PsA, including those who had responded inadequately or were intolerant to biologic therapy and/or non-biologic disease-modifying antirheumatic drugs (DMARDs). In KEEPsAKE-1 and KEEPsAKE-2, 57.3 percent and 51.3 percent of patients receiving risankizumab achieved the primary endpoint of ACR20 response at week 24, respectively, versus 33.5 percent and 26.5 percent receiving placebo. Risankizumab also demonstrated improvements in ACR50 and ACR70 responses compared to placebo at week 24. In addition, risankizumab showed improvements compared to placebo at week 24 in dactylitis and enthesitis for patients with pre-existing dactylitis and enthesitis. Patients with coexistent plaque psoriasis receiving risankizumab saw improvements in the skin lesions of psoriasis, compared to placebo, as measured by the Psoriasis Area Severity Index (PASI 90) at week 24. Furthermore, risankizumab showed a statistically significant improvement in physical function, compared to placebo, as measured by the Health Assessment Questionnaire-Disability Index at week 24, with a mean difference of 0.20 in KEEPsAKE-1 and 0.16 in KEEPsAKE-2 (AbbVie, 2022a, 2022b).

The overall safety profile observed in patients with psoriatic arthritis treated with risankizumab (Skyrizi) is generally consistent with the safety profile in patients with plaque psoriasis.

Crohn's Disease

In June 2022, the FDA approved Skyrizi (risankizumab-rzaa) for the treatment of adults with moderately to severely active Crohn's disease (CD). FDA approval was based on the safety and efficacy data from two induction (ADVANCE and MOTIVATE) and one maintenance (FORTIFY) clinical trials evaluating risankizumab in moderately to severely active Crohn's disease, which demonstrated significant improvements in endoscopic response (defined as a decrease of greater than 50% from the baseline Simple Endoscopic Score in CD [SES-CD] or for patients with isolated ileal disease and SES-CD of 4, at least a 2-point reduction from baseline) and clinical remission (defined as a Crohn's Disease Activity Index [CDAI] of less than 150), compared to placebo, as both an induction and maintenance therapy (AbbVie, 2022b).

D'Haens et al (2022) conducted two randomized, double-masked, placebo-controlled, phase 3 induction studies (ADVANCE and MOTIVATE) to evaluate the safety and efficacy of risankizumab as induction therapy in patients with moderately to severely active Crohn's disease. Eligible patients aged 16-80 years with moderately to severely active Crohn's disease, previously showing intolerance or inadequate response to one or more approved biologics or conventional therapy (ADVANCE) or to biologics (MOTIVATE), were randomly assigned to receive a single dose of intravenous risankizumab (600 mg or 1200 mg) or placebo (2:2:1 in ADVANCE, 1:1:1 in MOTIVATE) at weeks 0, 4, and 8. The authors used interactive response technology for random assignment, with stratification by number of previous failed biologics, corticosteroid use at baseline, and Simple Endoscopic Score for Crohn's disease (SES-CD). All patients and study personnel (excluding pharmacists who prepared intravenous solutions) were masked to treatment allocation throughout the study. Coprimary endpoints were clinical remission (defined by Crohn's disease activity index [CDAI] or patient-reported outcome criteria [average daily stool frequency and abdominal pain score]) and endoscopic response at week 12. The intention-to-treat population (all eligible patients who received at least one dose of study drug in the 12-week induction period) was analysed for efficacy outcomes. Safety was assessed in all patients who received at least one dose of study drug. In ADVANCE, 931 patients were assigned to either risankizumab 600 mg (n=373), risankizumab 1200 mg (n=372), or placebo (n=186). In MOTIVATE, 618 patients were assigned to risankizumab 600 mg (n=206), risankizumab 1200 mg (n=205), or placebo (n=207). The primary analysis population comprised 850 participants in ADVANCE and 569 participants in MOTIVATE. All coprimary endpoints at week 12 were met in both trials with both doses of risankizumab (p values ≤0.0001). In ADVANCE, CDAI clinical remission rate was 45% with risankizumab 600 mg and 42% with risankizumab 1200 mg versus 25% with placebo; stool frequency and abdominal pain score clinical remission rate was 43% with risankizumab 600 mg and 41% with risankizumab 1200 mg versus 22% with placebo; and endoscopic response rate was 40% with risankizumab 600 mg and 32% with risankizumab 1200 mg versus 12% with placebo. In MOTIVATE, CDAI clinical remission rate was 42% with risankizumab 600 mg and 40% with risankizumab 1200 mg versus 20% with placebo; stool frequency and abdominal pain score clinical remission rate was 35% with risankizumab 600 mg and 40% with risankizumab 1200 mg versus 19% with placebo; and endoscopic response rate was 29% with risankizumab 600 mg and 34% with risankizumab 1200 mg versus 11% with placebo. The overall incidence of treatment-emergent adverse events was similar among the treatment groups in both trials. Three deaths occurred during induction (two in the placebo group [ADVANCE] and one in the risankizumab 1200 mg group [MOTIVATE]). The death in the risankizumab-treated patient was deemed unrelated to the study drug. The authors concluded that risankizumab was effective and well tolerated as induction therapy in patients with moderately to severely active Crohn's disease.

The maintenance study (FORTIFY) is a Phase 3, multicenter, randomized, double-blind, control group, 52-week maintenance study designed to evaluate the efficacy and safety of risankizumab 180 mg and 360 mg as maintenance therapy versus withdrawal in 247 patients who responded to risankizumab induction treatment in the ADVANCE and MOTIVATE studies. This study included different sets of primary and secondary endpoints for the OUS analysis plan and U.S. analysis plan due to regulatory requirements in the different regions. The co-primary endpoints were achievement of endoscopic response and clinical remission at week 52. Endoscopic response is defined as a decrease of greater than 50% from the baseline SES-CD or for patients with isolated ileal disease and SES-CD of 4, at least a 2-point reduction from baseline, as scored by a central reviewer. Clinical remission is defined by SF/AP, which was measured by daily stool frequency and abdominal pain score, in the OUS analysis plan and defined by CDAI, which was measured by a CDAI score less than 150, in the U.S. analysis plan. Endoscopic remission was observed at Week 52 in 41% of subjects treated with the risankizumab maintenance regimen and 13% of subjects treated with placebo. This endpoint was not statistically significant under the prespecified multiple testing procedure. An open label extension of FORTIFY will continue to assess the long-term safety of risankizumab in patients who completed participation in the FORTIFY study (AbbVie, 2022a, 2022b).

Appendix

Examples of Clinical Reasons to Avoid Pharmacologic Treatment with Methotrexate, Cyclosporine, Acitretin, or Leflunomide

Clinical diagnosis of alcohol use disorder, alcoholic liver disease or other chronic liver disease

Drug interaction

Risk of treatment-related toxicity

Pregnancy or currently planning pregnancy

Breastfeeding

Significant comorbidity prohibits use of systemic agents (examples include liver or kidney disease, blood dyscrasias, uncontrolled hypertension)

Hypersensitivity

History of intolerance or adverse event

Note

: Requires Precertification:

Commercial plans:

Precertification of intravenous risankizumab-rzaa (Skyrizi) is required of all Aetna participating providers and members in applicable plan designs. For precertification of intravenous

risankizumab-rzaa (Skyrizi)

, call (866) 752-7021, or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see

Specialty Pharmacy Precertification

.

Medicare Part B plans:

Precertification of risankizumab-rzaa (Skyrizi) is required of participating providers and members in applicable Medicare Part B plan designs. For precertification of risankizumab-rzaa (Skyrizi), call (866) 503-0857, or fax (844) 268-7263.

Prescriber Specialties

This medication in this policy must be prescribed by or in consultation with

one

of the following:

Plaque psoriasis: dermatologist;

Psoriatic arthritis: rheumatologist or dermatologist;

Crohn's disease: gastroenterologist.

Criteria for Initial Approval

Aetna considers

risankizumab-rzaa (Skyrizi) medically necessary for the following indications where the member has a documented negati

ve tuberculosis (TB) te

st (which can include a tuberculosis skin test (PPD), an interferon-release assay (IGRA), or a chest x-ray) Footnote1 * within 6 months of initiating therapy for persons who are naïve to biologic drugs or targeted synthetic drugs associated with an increased risk of TB:

Plaque psoriasis (PsO)

For adult members who have previously received a biologic or targeted synthetic drug (e.g., Sotyktu, Otezla) indicated for the treatment of moderate to severe plaque psoriasis;

or

For adult members for treatment of moderate-to-severe plaque psoriasis when

any

of the following criteria is met:

Crucial body areas (e.g., hands, feet, face, neck, scalp, genitals/groin, intertriginous areas) are affected;

or

At least 10% of the body surface area (BSA) is affected;

or

At least 3% of BSA is affected and the member meets

any

of the following criteria:

Member has had an inadequate response or intolerance to either phototherapy (e.g., UVB, PUVA) or pharmacologic treatment with methotrexate, cyclosporine, or acitretin;

or

Member has a clinical reason to avoid pharmacologic treatment with methotrexate, cyclosporine, and acitretin (see

Appendix

);

Psoriatic arthrits (PsA)

For adult members who have previously received a biologic or targeted synthetic drug (e.g., Rinvoq, Otezla) indicated for active psoriatic arthritis; or

For adult members for treatment of active psoriatic arthritis when

either

of the following criteria is met:

Member has mild to moderate disease and meets

one

of the following criteria:

Member has had an inadequate response to methotrexate, leflunomide, or another conventional synthetic drug (e.g., sulfasalazine) administered at an adequate dose and duration;

or

Member has an intolerance or contraindication to methotrexate or leflunomide (see

Appendix

), or another conventional synthetic drug (e.g., sulfasalazine);

or

Member has enthesitis or predominantly axial disease;

or

Member has severe disease;

Crohn's disease (CD)

For treatment of moderately to severely active CD in adult members.

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

Continuation of Therapy

Aetna considers continuation of risankizumab-rzaa (Skyrizi) therapy medically necessary for the following indications:

Plaque psoriasis (PsO)

For all adult members (including new members) who are using the requested medication for moderate to severe plaque psoriasis and who achieve or maintain positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition when any of the following is met:

Reduction in body surface area (BSA) affected from baseline;

or

Improvement in signs and symptoms from baseline (e.g., itching, redness, flaking, scaling, burning, cracking, pain);

Psoriatic arthritis (PsA)

For all adult members (including new members) who are using the requested medication for psoriatic arthritis and who achieve or maintain positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition when there is improvement in

any

of the following from baseline:

Number of swollen joints;

or

Number of tender joints;

or

Dactylitis;

or

Enthesitis;

or

Axial disease;

or

Skin and/or nail involvement;

Crohn's disease

For all adult members (including new members) who are using the requested medication for moderately to severely active Crohn’s disease and who achieve or maintain remission;

or

For all adult members (including new members) who are using the requested medication for moderately to severely active Crohn’s disease and who achieve or maintain a positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition when there is improvement in

any

of the following from baseline:

Abdominal pain or tenderness;

or

Diarrhea;

or

Body weight;

or

Abdominal mass;

or

Hematocrit;

or

Appearance of the mucosa on endoscopy, computed tomography enterography (CTE), magnetic resonance enterography (MRE), or intestinal ultrasound;

or

Improvement on a disease activity scoring tool (e.g., Crohn’s Disease Activity Index [CDAI] score).

Footnote1

* If the screening test for TB is positive, there must be further testing to confirm there is no active disease. 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.