Risankizumab-rzaa (Skyrizi)

Number: 1009

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 risankizumab-rzaa (Skyrizi) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

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. 

1. Prescriber Specialties

   This medication in this policy must be prescribed by or in consultation with one of the following:

   1. Plaque psoriasis: dermatologist;
   2. Psoriatic arthritis: rheumatologist or dermatologist;
   3. Crohn's disease and ulcerative colitis: gastroenterologist.

2. Criteria for Initial Approval

   Aetna considers risankizumab-rzaa (Skyrizi) medically necessary for the following indications when criteria are met: 

   1. Plaque psoriasis (PsO)

      1. 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
      2. For adult members for treatment of moderate-to-severe plaque psoriasis when any of the following criteria is met:
         
         
         1. Crucial body areas (e.g., hands, feet, face, neck, scalp, genitals/groin, intertriginous areas) are affected; or
         2. At least 10% of the body surface area (BSA) is affected; or
         3. At least 3% of BSA is affected and the member meets either of the following criteria:
            
            
            1. Member has had an inadequate response or intolerance to either phototherapy (e.g., UVB, PUVA) or pharmacologic treatment with methotrexate, cyclosporine, or acitretin; or
            2. Member has a clinical reason to avoid pharmacologic treatment with methotrexate, cyclosporine, and acitretin (see Appendix);

   2. Psoriatic arthritis (PsA)

      1. For adult members who have previously received a biologic or targeted synthetic drug (e.g., Rinvoq, Otezla) indicated for active psoriatic arthritis; or
      2. For adult members for treatment of active psoriatic arthritis when either of the following criteria is met:
         
         

         1. Member has mild to moderate disease and meets one of the following criteria:

            1. 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
            2. Member has an intolerance or contraindication to methotrexate or leflunomide (see Appendix), or another conventional synthetic drug (e.g., sulfasalazine); or
            3. Member has enthesitis; or

         2. Member has severe disease;

   3. Crohn's disease (CD)

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

   4. Ulcerative colitis (UC)

      For treatment of moderately to severely active ulcerative colitis in adult members.

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

3. Continuation of Therapy

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

   1. 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 either of the following is met:

      1. Reduction in body surface area (BSA) affected from baseline; or
      2. Improvement in signs and symptoms from baseline (e.g., itching, redness, flaking, scaling, burning, cracking, pain);

   2. 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: 

      1. Number of swollen joints; or
      2. Number of tender joints; or
      3. Dactylitis; or
      4. Enthesitis; or
      5. Skin and/or nail involvement; or
      6. Functional status; or
      7. C-reactive protein (CRP);

   3. Crohn's disease (CD)

      1. 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
      2. 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:
         
         
         1. Abdominal pain or tenderness; or
         2. Diarrhea; or
         3. Body weight; or
         4. Abdominal mass; or
         5. Hematocrit; or
         6. Appearance of the mucosa on endoscopy, computed tomography enterography (CTE), magnetic resonance enterography (MRE), or intestinal ultrasound; or
         7. Improvement on a disease activity scoring tool (e.g., Crohn’s Disease Activity Index [CDAI] score);

   4. Ulcerative colitis (UC)

      1. For all adult members (including new members) who are using the requested medication for moderately to severely active ulcerative colitis and who achieve or maintain remission; or
      2. For all adult members (including new members) who are using the requested medication for moderately to severely active ulcerative colitis 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:
         
         
         1. Stool frequency; or
         2. Rectal bleeding; or
         3. Urgency of defecation; or
         4. C-reactive protein (CRP); or
         5. Fecal calprotectin (FC); or
         6. Appearance of the mucosa on endoscopy, computed tomography enterography (CTE), magnetic resonance enterography (MRE), or intestinal ultrasound; or
         7. Improvement on a disease activity scoring tool (e.g., Ulcerative Colitis Endoscopic Index of Severity [UCEIS], Mayo score).

4. 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 6 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.

   For all indications: Member cannot use the requested medication concomitantly with any other biologic drug or targeted synthetic drug for the same indication.

5. Related Policies

   1. CPB 0205 - Phototherapy and Photochemotherapy (PUVA) for Skin Conditions
   2. CPB 0314 - Rituximab
   3. CPB 0315 - Etanercept
   4. CPB 0341 - Infliximab
   5. CPB 0577 - Laser Treatment for Psoriasis and Other Selected Skin Conditions
   6. CPB 0655 - Adalimumab
   7. CPB 0720 - Abatacept (Orencia)
   8. CPB 0751 - Natalizumab
   9. CPB 0761 - Certolizumab Pegol (Cimzia)
   10. CPB 0790 - Golimumab (Simponi and Simponi Aria)
   11. CPB 0885 - Vedolizumab (Entyvio)
   12. CPB 0905 - Secukinumab (Cosentyx)
   13. CPB 0912 - Ustekinumab

Dosage and Administration

Note: Approvals may be subject to dosing limits in accordance with FDA-approved labeling, accepted compendia, and/or evidence-based practice guidelines. Below includes dosing recommendations as per the FDA-approved prescribing information.

Risankizumab-rzaa is available as Skyrizi for subcutaneous or intravenous use and is supplied in the following dosage forms and strengths:

• Subcutaneous injection:

  • 150 mg/mL in each single-dose prefilled pen
  • 90 mg/mL in each single-dose prefilled syringe
  • 150 mg/mL in each single-dose prefilled syringe
  • 180 mg/1.2 mL (150 mg/mL) in each single-dose prefilled cartridge
  • 360 mg/2.4 mL (150 mg/mL) in each single-dose prefilled cartridge. 
    
    

• Intravenous infusion:

  • 600 mg/10 mL (60 mg/mL) in each single-dose vial.

Plaque Psoriasis(PsO) and Psoriatic Arthritis (PsA)

The recommended dosage is 150 mg administered by subcutaneous injection at Week 0, Week 4, and every 12 weeks thereafter.

For PsA, Skyrizi can be administered alone or in combination with non-biologic disease-modifying antirheumatic drugs (DMARDs).

Crohn's Disease (CD)

Adult Induction: The recommended induction dosage of Skyrizi is 600 mg administered by intravenous infusion over a period of at least one hour at Week 0, Week 4, and Week 8.

Adult Maintenance: The recommended maintenance dosage of Skyrizi is 180 mg or 360 mg administered by subcutaneous injection at Week 12, and every 8 weeks thereafter. Per the label, use the lowest effective dosage needed to maintain therapeutic response.

Ulcerative Colitis (UC)

Adult Induction: The recommended induction dosage of Skyrizi is 1200 mg administered by intravenous infusion over a period of at least two hours at Week 0, Week 4, and Week 8.

Adult Maintenance: The recommended maintenance dosage of Skyrizi is 180 mg or 360 mg administered by subcutaneous injection at Week 12, and every 8 weeks thereafter. Per the label, use the lowest effective dosage needed to maintain therapeutic response.

Source: AbbVie, 2024

Experimental, Investigational, or Unproven

Aetna considers concomitant use of risankizumab-rzaa 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.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
43233 - 43259	Esophagogastroduodenoscopy
44360 - 44379	Endoscopy, small intestine
44380 - 44408	Endoscopy, stomal
45300 - 45393	Endoscopy [Colon and rectum]
46600 - 46615	Anoscopy
72195	Magnetic resonance (eg, proton) imaging, pelvis; without contrast material(s)
72196	with contrast material(s)
72197	without contrast material(s), followed by contrast material(s) and further sequences
72198	Magnetic resonance angiography, pelvis, with or without contrast material(s)
74261	without contrast material
74262	Computed tomographic (CT) colonography, diagnostic, including image postprocessing; with contrast material(s) including non-contrast images, if performed
74263	Computed tomographic (CT) colonography, screening, including image postprocessing
71045 - 71048	Radiologic examination, chest
86140	C-reactive protein
86141	C-reactive protein; high sensitivity (hsCRP)
86480 - 86481	Tuberculosis test, cell mediated immunity antigen response measurement; [interferon-hyphenrelease assay (IGRA)]
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
96401, 96413-96417	Chemotherapy administration
HCPCS codes covered if selection criteria are met:
J2327	Injection, risankizumab-rzaa, intravenous, 1 mg
Other HCPCS codes related to the CPB:
J0702	Injection, betamethasone acetate 3mg and betamethasone sodium phosphate 3mg
J0717	Injection, certolizumab pegol 1 mg [not covered with Ustekinumab]
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
J1438	Injection, etanercept, 25 mg
J1602	Injection, golimumab, 1mg for intravenous use [not covered with Ustekinumab]
J1700	Injection, hydrocortisone acetate, up to 25 mg
J1710	Injection, hydrocortisone sodium phosphate, up to 50 mg
J1720	Injection, hydrocortisone sodium succinate, up to 100 mg
J1745	Injection, infliximab, 10 mg [not covered with Ustekinumab]
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
J3245	Injection, tildrakizumab, 1 mg
J3380	Injection, vedolizumab, 1 mg
J7500	Azathioprine, oral, 50 mg
J7501	Azathioprine, parenteral, 100 mg
J7506	Prednisone, oral, per 5 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	Cyclosporine, parenteral, 250 mg
J8540	Dexamethasone, oral, 0.25 mg
J8610	Methotrexate; oral, 2.5 mg
J8611	Methotrexate (jylamvo), oral, 2.5 mg
J8612	Methotrexate (xatmep), oral, 2.5 mg
J9250	Methotrexate sodium, 5 mg
J9255	Injection, methotrexate (accord) not therapeutically equivalent to j9250 or j9260, 50 mg
J9260	Methotrexate sodium, 50 mg
Q5109	Injection, infliximab-qbtx, biosimilar, (ixifi), 10 mg
S0108	Mercaptopurine, oral, 50 mg
ICD-10 codes covered if selection criteria are met:
K50.00 - K50.919	Crohn's disease [regional enteritis]
K51.00 – K51.919	Ulcerative colitis
L40.0	Psoriasis vulgaris
L40.50 - L40.59	Arthropathic psoriasis
L40.8	Other psoriasis
L40.9	Psoriasis, unspecified

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Background

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
• Treatment of moderately to severely active ulcerative colitis (UC) in adults

Risankizumab-rzaa is branded 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, 2024).

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 include the following:

• Plaque psoriasis and psoriatic arthritis (1% or more): upper respiratory infections, headache, fatigue, injection site reactions, and tinea infections;
• Crohn's disease (greater than 3%) for induction dosing: upper respiratory infections, headache, and arthralgia; and maintenance dosing: arthralgia, injection site reactions, abdominal pain, anemia, pyrexia, back pain, arthropathy, and urinary tract infection; 
• Ulcerative colitis (3% or more) for induction dosing: arthralgia; and maintenance dosing: arthralgia, pyrexia, injection site reactions, and rash.

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 analyzed 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).

Ulcerative Colitis

In June 2024, the FDA approved Skyrizi for the treatment of adults with moderately to severely active ulcerative colitis (UC). FDA approval was based on results from two phase 3 clinical trials: a 12-week induction study (INSPIRE), and a 52-week maintenance study (COMMAND), for which both met its primary endpoint of clinical remission, along with secondary endpoint, endoscopic improvement.

The INSPIRE 12-week induction study was a randomized, double-blind, placebo-controlled, multicenter trial that evaluated risankizumab in 966 adult patients with moderately to severely active UC. Patients were randomized to receive either risankizumab 1,200 mg (n=646) or placebo (n=320) via intravenous (IV) infusion at Week 0, 4, and 8. Enrolled patients were permitted to use a stable dose of oral corticosteroids (up to 20 mg/day prednisone or equivalent), immunomodulators, and aminosalicylates. The primary endpoint was clinical remission (per Adapted Mayo Score, defined as stool frequency (SFS) 1 or less and not greater than baseline, rectal bleeding (RBS) of 0 and endoscopic subscore (ES) less than or equal to 1 without friability) at Week 12. Secondary endpoints included clinical response (decrease from baseline in the Adapted Mayo Score greater than or equal to 2 points and greater than or equal to 30% from baseline, plus a decrease in RBS greater than or equal to 1 or an absolute RBS less than or equal to 1), endoscopic improvement (ES less than or equal to 1 without friability), and histologic and endoscopic mucosal improvement (HEMI) (ES of 0 or 1 without friability and Geboes score less than or equal to 3.1) at Week 12. In the risankizumab arm, 24% achieved clinical remission compared to 8% in the placebo group, 36% achieved endoscopic improvement compared to 12% (placebo group), and 24% achieved HEMI compared to 7% (placebo group) at 12 weeks.

The COMMAND 52-week maintenance study was a randomized, double-blind, controlled, phase 3, multicenter trial that evaluated the safety and efficacy of risankizumab 180 mg or 360 mg subcutaneously (SC) administered in 547 adult patients with moderately to severely active UC. This study followed a re-randomized withdrawal design in which all patients received risankizumab IV induction and those who responded to risankizumab were re-randomized to receive risankizumab 180 mg or 360 mg SC or withdrawal from risankizumab treatment (induction-only control group). The objective of the phase 3 study was to evaluate the efficacy and safety of risankizumab 180 mg or 360 mg as maintenance therapy versus withdrawal from risankizumab treatment (control) in patients with moderately to severely active ulcerative colitis who responded to risankizumab IV induction in the INSPIRE study. The primary endpoint was clinical remission (per Adapted Mayo Score) at week 52. Secondary endpoints included endoscopic improvement, HEMI, and steroid-free clinical remission (defined as clinical remission per Adapted Mayo Score at week 52 and corticosteroid free for greater than or equal to 90 days prior to week 52) at week 52. Clinical remission was achieved in 45% (n=179) taking 180 mg and 41% (n=186) taking 360 mg versus 26% (n=182) in the control group at 52 weeks. Endoscopic improvement was achieved in 51% taking 180 mg, 48% taking 360 mg compared to 31% in control group. HEMI was achieved in 43% taking 180 mg, 42% taking 360 mg compared to 24% in control group.

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Appendix

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

1. Clinical diagnosis of alcohol use disorder, alcoholic liver disease or other chronic liver disease
2. Drug interaction
3. Risk of treatment-related toxicity
4. Pregnancy or currently planning pregnancy
5. BreastfeedingSignificant comorbidity prohibits use of systemic agents (examples include liver or kidney disease, blood dyscrasias, uncontrolled hypertension)
6. Hypersensitivity
7. History of intolerance or adverse event.

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References