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Key clinical-trial evidence for risankizumab

Author: Anoma Ranaweera, Medical Writer, Auckland, New Zealand. DermNet NZ Editor in Chief: Adjunct A/Prof Dr Amanda Oakley, Dermatologist, Hamilton, New Zealand. Copy edited by Gus Mitchell. August 2019.


Introduction

In March 2019, risankizumab (trade name SKYRIZI™) received US Food and Drug Administration (FDA) for the treatment of moderate-to-severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy [1].

Risankizumab is not currently available in New Zealand. It has been approved for the treatment of psoriasis in both Japan and the European Union in March 2019.

Risankizumab received FDA approval in the USA was based on data from a phase 3 psoriasis clinical trial program, which evaluated the safety and efficacy of risankizumab in adults with moderate-to-severe plaque psoriasis across 4 studies: UltIMMa-1, UltIMMa-2, IMMhance, and IMMvent [1,2].

Chronic plaque psoriasis

ULTIMMA-1 and ULTIMMA-2

Study design

UltIMMa-1 patients were randomly assigned to receive [3]:

In UltIMMa-2 patients were randomly assigned to receive [3]:

  • 150 mg risankizumab (n=294)
  • 45 mg or 90 mg ustekinumab (n=99)
  • Placebo (n=98).

Following the 16-week double-blind treatment period (part A), patients initially assigned to placebo switched to 150 mg risankizumab at week 16; other patients continued their originally randomised treatment (part B, double-blind, weeks 16–52). Study drug was administered subcutaneously at weeks 0 and 4 during part A and at weeks 16, 28, and 40 during part B.

Co-primary endpoints were proportions of patients achieving a 90% improvement in the Psoriasis Area Severity Index (PASI 90) and a static Physician's Global Assessment (sPGA) score of 0 or 1 at week 16. All efficacy analyses were done in the intention-to-treat patient population.

Results

UltIMMa-1 (16 weeks)

At week 16, PASI 90 was achieved by 229 (75.3%) patients receiving risankizumab versus five (4.9%) receiving placebo and 42 (42.0%) receiving ustekinumab (p<0.0001 vs placebo and ustekinumab) [3].

sPGA 0 or 1 at week 16 was achieved by 267 (87.8%) patients receiving risankizumab versus eight (7.8%) receiving placebo and 63 (63.0%) receiving ustekinumab (p<0.0001 vs placebo and ustekinumab) [3].

UltIMMa-2 (16 weeks)

At week 16, PASI 90 was achieved by 220 (74.8%) patients receiving risankizumab versus two (2.0%) receiving placebo and 47 (47.5%) receiving ustekinumab (p<0.0001 vs placebo and ustekinumab) [3].

At week 16, 246 (83.7%) patients receiving risankizumab versus five (5.1%) receiving placebo and 61 (61.6%) receiving ustekinumab achieved sPGA 0 or 1 (p<0.0001 vs placebo and ustekinumab).

Examination of age, gender, race, body weight, baseline PASI score and previous treatment with systemic or biologic agents did not identify differences in response to risankizumab among these subgroups at Week 16 [3].

UltIMMa-1 and -2 (one year results)

At 1 year in UltIMMa-1 and UltIMMa-2, 82% and 81% of patients treated with risankizumab achieved PASI 90, respectively, and 56% and 60% achieved PASI 100, respectively (p<0.0001 vs placebo).

In ultIMMa-1 and ultIMMa-2, most patients treated with risankizumab who achieved PASI 90 and PASI 100 at week 16 maintained this response at 1 year (88% and 80%, respectively).

Adverse reactions - UltIMMa-1 & UltIMMa-2

Part A — 16 weeks

Overall, the most common adverse events associated with risankizumab treatment were [3]:

  • Upper respiratory infections (13%)
  • Headache (3.5%)
  • Fatigue (2.5%)
  • Injection site reactions (1.5%)
  • Tinea infections (1.1%).

In part A of UltIMMa-1, adverse events occurred in 49.7% of the patients on risankizumab, 50.0% on ustekinumab, and 51.0% on placebo.

In part A of UltIMMa-2, adverse events occurred in 45.6% of the patients on risankizumab, 53.5% on ustekinumab, and 45.9% on placebo.

Serious infections occurred in 0.3% in the risankizumab group and 3.0% in the ustekinumab group in UltIMMa-1, and in 1.0% in both risankizumab and ustekinumab groups in UltIMMa-2. Serious infections in the risankizumab group included cellulitis, osteomyelitis, sepsis, and herpes zoster.

Serious adverse events were reported in 2.3% of risankizumab-treated patients, 8.0% of ustekinumab-treated patients, and 2.9% of placebo-treated patients in UltIMMa-1, and in 2.0% of risankizumab-treated patients, 3.0% of ustekinumab-treated patients, and 1.0% of placebo-treated patients in UltIMMa-2.

Malignancy was reported in two patients on risankizumab (squamous cell carcinoma in UltIMMa-1; basal cell carcinoma in UltIMMa-2) and in one patient in the placebo group (squamous cell carcinoma in UltIMMa-1).

Of note, there were no events of tuberculosis, opportunistic infections, major adverse cardiovascular events (MACEs), or serious hypersensitivity across both studies.

Part B — weeks 16–52

In part B, the most frequent adverse events were [3]:

  • Viral upper respiratory tract infection
  • Upper respiratory tract infection
  • Urinary tract infection
  • Influenza
  • Headache.

In UltIMMa-1, adverse events occurred in 61.3% of the patients continuing on risankizumab, 66.7% on ustekinumab, and 67.0% of the patients switching from placebo to risankizumab.

In UltIMMa-2, adverse events occurred in 55.7% of the patients continuing on risankizumab, 74.5% on ustekinumab, and 64.9% of the patients continuing on risankizumab.

During part B, serious infections occurred in 0.7% of the patients on risankizumab in both UltIMMa-1 and UltIMMa-2, and in 1.0% of the patients switching from placebo to risankizumab and ustekinumab in UltIMMa-2.

Serious adverse events in UltIMMa-1 were reported in 5.4% of risankizumab-treated patients, 4.0% of ustekinumab-treated patients, and 3.1% of the patients continuing on risankizumab.

In UltIMMa-2, SAEs were reported in 4.5% of risankizumab-treated patients, 4.3% of ustekinumab-treated patients, and 3.2% of the patients continuing on risankizumab.

Through week 52, two patients on risankizumab had MACEs, including one patient with cardiovascular death and one patient with type 1 myocardial infarction. Malignancy was reported in one patient on continuous risankizumab (basal cell carcinoma in UltIMMa-2), in one patient on ustekinumab (prostate cancer in UltIMMa-2), and in two patients switching from placebo to risankizumab (one patient with both basal cell and squamous cell carcinoma in UltIMMa-1; one patient with breast cancer in UltIMMa-2) [3].

Immunogenicity

By Week 52, approximately 24% (263/1079) of patients treated with risankizumab at the recommended dose had developed antibodies to risankizumab.

Of these patients, approximately 57% (14% of all subjects treated with risankizumab) had antibodies that were classified as neutralizing. Higher antibody titres in approximately 1% of subjects treated with risankizumab were associated with lower risankizumab concentrations and reduced clinical response [1,3].

IMMHANCE study

Study design

IMMhance was a phase 3, multicenter, randomised, double-blind, placebo-controlled study to evaluate the impact of treatment withdrawal and re-treatment with risankizumab compared to placebo in adult patients with moderate to severe plaque psoriasis.

IMMHANCE enrolled 507 patients (407 randomised to risankizumab 150 mg and 100 to placebo). Patients received treatment at Weeks 0, 4, and every 12 weeks thereafter [4].

Results

At Week 16, risankizumab was superior to placebo for the co-primary endpoints of sPGA 0 or 1 (84% risankizumab and 7% placebo) and PASI 90 (73% risankizumab and 2% placebo).

The respective response rates for risankizumab and placebo at Week 16 were [4]:

  • sPGA 0 (46% risankizumab and 1% placebo)
  • PASI 100 (47% risankizumab and 1% placebo)
  • PASI 75 (89% risankizumab and 8% placebo).

Patients who were originally on risankizumab and had sPGA 0 or 1 at Week 28 were re-randomised to continue risankizumab every 12 weeks or withdrawal of therapy.

At Week 52, 87% (97/111) of the patients re-randomised to continue treatment with risankizumab had sPGA 0 or 1 compared to 61% (138/225) who were re-randomised to the withdrawal of risankizumab.

Adverse events

The safety profile was consistent with previously reported phase 3 trials with no new safety signals detected [4].

Through week 16, serious adverse effects occurred in 2% of patients in the risankizumab group and 8% of patients in the placebo group.

In the second part of the study (post-week 28), serious adverse effects occurred in 6% of patients re-randomised to the risankizumab group and 6% of patients re-randomised to the placebo group.

One patient receiving risankizumab had intestinal adenocarcinoma and metastatic hepatic cancer and died, while a second patient treated with risankizumab died due to an unknown cause that was considered as a major adverse cardiovascular event (MACE).

There were 2 additional adjudicated MACE cases: the first event occurred in the placebo arm in the first phase, while the second occurred in the risankizumab arm in the second phase. All three MACE-case patients had a previous history of cardiovascular risk factors.

IMMVent study

IMMvent was a phase 3, randomised, double-blind, double-dummy, active-controlled study to evaluate the efficacy and safety of risankizumab compared to adalimumab in adult patients with moderate to severe plaque psoriasis over 44 weeks [5].

Study design

Patients were randomised 1:1 to receive 150 mg risankizumab (weeks 0, 4, 16, and 28) or adalimumab (80 mg at week 0, 40 mg every other week from week 1).

Adalimumab-treated patients achieving PASI 50 to < PASI 90 at week 16 were rerandomised 1:1 to either continue adalimumab or switch to risankizumab (weeks 16, 20, and 32).

Results

At week 16, risankizumab-treated patients achieved significantly higher PASI 75 (90.7% vs 71.7%), PASI 90 (72.4% vs 47.4%), PASI 100 (39.9% vs 23.0%), and sPGA 0/1 (83.7% vs 60.2%) response rates compared with adalimumab-treated patients.

Among adalimumab-treated patients with PASI 50 to < PASI 90 responses at week 16, a significantly higher proportion of patients switching to risankizumab achieved PASI 90 (66.0% vs 21.4%) and PASI 100 (39.6% vs 7.1%) responses at week 44 compared with patients continuing on adalimumab.

Among adalimumab-treated patients achieving PASI 50 to < PASI 90 at week 16, PASI 90 and PASI 100 responses were significantly higher in patients switching to risankizumab, starting at week 20, compared with patients continuing on adalimumab.

Adverse reactions

The rates of treatment-emergent adverse events leading to discontinuation were generally low, and comparable between patients continuing on adalimumab and patients switching from adalimumab to risankizumab. A similar safety profile was observed between patients continuing risankizumab and patients switching directly from adalimumab to risankizumab.

What is the future potential for risankizumab?

Risankizumab offers remarkable rates of complete or near-complete clearance of skin disease, along with a good safety profile so far and an excellent dosing regimen. The selective inhibition of the p19 subunit of IL-23 may present several advantages compared to the inhibition of p40 subunit shared by IL-23 and IL-12 and even a downstream inhibition of IL-17 or its receptor.

Overall, risankizumab showed similar safety and tolerability profile compared to ustekinumab and adalimumab but superior efficacy. Future studies with more patients and longer follow-up periods will help establish a more complete safety profile.

More data from clinical trials comparing risankizumab with other IL-23 and IL-17 inhibitors will be essential to establish the value of risankizumab in the treatment of psoriasis.

New Zealand approved datasheets are the official source of information for these prescription medicines, including approved uses and risk information. Check the individual New Zealand datasheet on the Medsafe website.

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References

  1. U.S. Food and Drug Administration. Risankizumab — US FDA prescribing information PDF. Available from: www.accessdata.fda.gov/drugsatfda_docs/label/2019/761105s000lbl.pdf [accessed 30 August, 2019]
  2. Medscape. Risankizumab. Available from: reference.medscape.com/drug/skyrizi-risankizumab-1000307 [accessed 30 August, 2019]
  3. Gordon KB, Strober B, Lebwohl M, et al. Efficacy and safety of risankizumab in moderate-to-severe plaque psoriasis (UltIMMa-1 and UltIMMa-2): results from two double-blind, randomised, placebo-controlled and ustekinumab-controlled phase 3 trials. Lancet 2018; 392: 650–61. PubMed
  4. Blauvelt A, Papp K, Gooderham M, Langley R, Leonardi C, Lacour J, Philipp S, et al. Efficacy and safety of risankizumab, an interleukin-23 inhibitor, in patients with moderate-to-severe chronic plaque psoriasis: 16-week results from the phase III IMMhance trial. BJD 2017; 177: E248–E248.
  5. Reich K, Gooderham M, Thaçi D, Crowley J, et al. Risankizumab compared with adalimumab in patients with moderate-to-severe plaque psoriasis (IMMvent): a randomised, double-blind, active-comparator-controlled phase 3 trial. Lancet 2019. pii: S0140-6736(19)30952-3. doi: 10.1016/S0140-6736(19)30952-3. PubMed

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