From September 2017, ustekinumab (Stelara) is available on the Pharmaceutical Benefits Scheme for the treatment of severe Crohn’s disease in adults.1,2
Ustekinumab is a human monoclonal antibody that binds to and inhibits the biological activity of proinflammatory cytokines interleukin (IL)-12 and IL-23, which are involved in the pathophysiology of Crohn’s disease.3-5
Ustekinumab was already PBS-listed for the treatment of severe chronic plaque psoriasis and severe psoriatic arthritis.1
The Pharmaceutical Benefits Advisory Committee recommended listing in the General Schedule and in the S100 Highly Specialised Drugs Program as an Authority Required (in writing) benefit with the same conditions for severe Crohn’s disease in adults as other biological disease-modifying anti-rheumatic drugs (bDMARDs).5
When used in the treatment of Crohn’s disease, ustekinumab is administered as a single, intravenous, induction tiered dose (260–520 mg) based on body weight, followed by subcutaneous injections of 90 mg every 8–12 weeks as maintenance therapy.4
Eligible patients must be in the care of a consultant physician with specialist qualifications in gastroenterology, and the clinical criteria for use are extensive.
Only patients who demonstrate a clinical response after a minimum of 12 weeks of treatment are eligible for continuing treatment.1
PBAC summary of findings
The new PBS listing follows a decision by the Therapeutic Goods Administration in February 2017 to approve use of ustekinumab for the treatment of adults with moderate to severe Crohn’s disease who have had an inadequate or lost response to, or were intolerant of, either conventional therapy or a tumour necrosis factor alpha (TNFα) antagonist, or have medical contraindications to such therapies.4-6
The PBS listing requires patients to have had an inadequate or lost response to, or be intolerant of, conventional therapy.
The PBAC recommended PBS listing of ustekinumab for severe Crohn’s disease on the basis of cost minimisation, compared with infliximab.5
In making its decision, the PBAC noted that ustekinumab would provide patients with an alternative treatment option for severe Crohn’s disease, with a different mechanism of action to other PBS-listed bDMARDs (infliximab, adalimumab and vedolizumab).5
An accompanying application for PBS listing of ustekinumab for the treatment of complex refractory fistulising Crohn’s disease was rejected, the PBAC concluding that non-inferiority of ustekinumab was not supported by the submission.5
Place of ustekinumab in the treatment of Crohn’s disease
Crohn’s disease is a chronic inflammatory disease that can affect any part of the gastrointestinal tract.7,8 Symptoms are heterogeneous but commonly include abdominal pain, weight loss and chronic diarrhoea.7,8
The aims of pharmacological therapy in Crohn’s disease are to induce remission in active disease, maintain corticosteroid-free remission and prevent relapse, and achieve mucosal healing, when possible.7
Choice of therapy is influenced by:8,9
- the location, extent and severity of disease
- medication efficacy and potential side effects
- previous response to treatment
- the presence of complications.
Despite the availability of many treatments for Crohn’s disease, there remains a subset of patients who are unresponsive to and/or intolerant of already registered agents.3 Ustekinumab will offer another treatment option for this patient group.5
Evidence for ustekinumab in Crohn’s disease
For severe Crohn’s disease, the PBAC submission was based on three head-to-head trials comparing ustekinumab to placebo – UNITI-1 and UNITI-2 (induction trials), and IM-UNITI (maintenance trial) – as well as indirect comparisons with placebo-controlled trials of adalimumab, infliximab and vedolizumab. The results of all comparator trials had been previously considered by the PBAC.5
The design and results of the UNITI-1, UNITI-2 and IM-UNITI trials were summarised by Feagen et al in 2016.10
The two 8-week induction trials, UNITI-1 and UNITI-2, enrolled patients 18 years or older who had Crohn’s disease for at least 3 months and a score on the Crohn’s Disease Activity Index (CDAI) of 220–450 (ie, moderately active disease; see box below for explanation).10
The Crohn’s Disease Activity Index
The CDAI (range zero to 600) is widely accepted as a standard index for assessment of disease activity in Crohn's disease clinical trials. Mildly active disease is defined as a CDAI score 150–219, moderately active disease as 220–450 points, and severe disease as a CDAI score > 450 points.11,12 Eight variables, based in part on a symptom diary recorded by the patient for 7 days before evaluation, determine the CDAI score:12
- number of liquid stools
- extent of abdominal pain
- general wellbeing
- complications (eg, arthralgia, uveitis, anal fissure, fever, etc)
- need for antidiarrhoeal drugs
- presence of abdominal masses
- body weight.
Clinical remission is generally defined as CDAI score < 150, consistent with the continuation criteria for PBS treatment.1,5 A CDAI assessment form is available to download from the Department of Human Services website.
Patients were required to have no history of treatment with IL-12 or IL-23 antagonists. Participants were randomly assigned to receive a single intravenous dose of ustekinumab (either 130 mg or weight-range-based dose that approximated 6 mg/kg of body weight) or placebo.10
UNITI-1 enrolled patients who met the criteria for non-response to TNF antagonists or had unacceptable side effects. UNITI-2 enrolled patients who were intolerant of conventional therapy (immunosuppressants or glucocorticoids) or for whom conventional therapy had failed, as well as having objective evidence of active disease.10
Patients who completed these trials then participated in the 44-week maintenance trial IM-UNITI, in which ustekinumab responders were randomly assigned to receive 90 mg of ustekinumab subcutaneously (either every 8 weeks or every 12 weeks) or placebo.10
The primary endpoint for the induction trials was a clinical response at week 6 (decrease from baseline CDAI score of ≥ 100 points or a CDAI score < 150).
Major secondary end points were clinical remission (CDAI score < 150) at week 8, clinical response at week 8, and a decrease from baseline CDAI score of at least 70 points at weeks 3 and 6.
The primary endpoint for the maintenance trial was remission (CDAI score < 150) at week 44.
Secondary endpoints also included changes in, and normalisation of, C-reactive protein (CRP) and faecal calprotectin levels in the induction trials and changes in these inflammatory markers in the maintenance trial. Efficacy analyses were conducted in accordance with intention-to-treat principles.10
Results for the primary endpoint are summarised in Table 1. Patients receiving intravenous ustekinumab had a significantly higher rate of clinical response than did those receiving placebo, with remission maintained with subcutaneous ustekinumab in patients who had a clinical response to induction therapy.
Greater reductions in, and normalisation of, CRP and faecal calprotectin levels were also observed in the groups receiving ustekinumab, compared with the placebo group.10
Table 1: Placebo-controlled trials with ustekinumab in Crohn's disease10
|Trial||Duration||Patient population||Primary outcome measures||Resultsa|
|UNITI-1||8 weeks||TNFα refractory/intolerant (n = 741)||Clinical response: reduction of ≥ 100 points from baseline CDAI (or CDAI < 150) at week 6||
130 mg: 34.3%
6 mg/kg: 33.7%
130 mg vs placebo: 12.8%
(95% CI 5.0 to 20.7, p = 0.002)
6 mg/kg vs placebo: 12.3%
(95% CI 4.5 to 20.1, p = 0.003)
TNF naïve and TNF experienced (but non- refractory)
(n = 628)
|Clinical response: reduction of ≥ 100 points from baseline CDAI (or CDAI < 150) at week 6||
130 mg: 51.7%
6 mg/kg: 55.5%
130 mg vs placebo: 23.0%
(95% CI 13.8 to 32.1)
6 mg/ kg vs placebo 26.8%
(95% CI 17.7 to 35.9)
(p < 0.001 for both comparisons)
|IM-UNITI||44 weeks||Patients with clinical response to ustekinumab induction (see next column) at week 8 of UNITI-1 or UNITI-2 (n = 397)||Remission (CDAI < 150)||
90 mg 8-weekly: 53.1%
90 mg 12-weekly: 48.8%
8-weekly vs placebo: 17.2%
(95% CI 5.3 to 29.2, p = 0.005)
12-weekly vs placebo: 13.0%
(95% CI 1.1 to 24.9, p = 0.04)
a Percentage of patients who met criteria for clinical response, and absolute difference between groups
CDAI: Crohn’s Disease Activity Index; CI: confidence interval; CR: clinical response
Safety of ustekinumab in Crohn’s disease
Rates of adverse events, serious adverse events or events occurring 1 hour after an ustekinumab infusion were similar across the groups in both induction trials.10 No events of anaphylaxis or other serious infusion reactions were reported.4
At week 44 in the IM-UNITI trial the rates of serious adverse events were 9.9% for 8-weekly ustekinumab, 12.1% for 12-weekly ustekinumab and 15.0% for placebo.10
Adverse events associated with immunosuppression, such as serious infections, malignancy (excluding non-melanoma skin cancer) and non-melanoma skin cancers, were no more common in the ustekinumab-treated groups.4,10
The adverse event profile observed was consistent with that reported after long-term treatment with ustekinumab for psoriasis and psoriatic arthritis.10
After induction therapy with ustekinumab 130 mg, two patients developed neutralising antidrug antibodies. However, at week 44 in the IM-UNITI trial, the overall incidence of antidrug antibodies was too low (2.3%) for definite conclusions to be drawn about their effect.10
Refer to the prescribing information for dosing information and the full list of contraindications, precautions and adverse events with ustekinumab.4
- Pharmaceutical Benefits Scheme. Ustekinumab. Canberra: Australian Government Department of Health, 2017 (accessed 12 September 2017).
- Pharmaceutical Benefits Scheme. Schedule of Pharmaceutical Benefits: Summary of changes effective 1 September 2017. Canberra: Australian Government Department of Health 2017 (accessed 28 September 2017).
- Committee for Medicinal Products for Human Use (CHMP). Assessment report : Stelara (ustekinumab). London: European Medicines Agency 2016 (accessed 9 June 2017).
- Janssen-Cilag Pty Ltd. Stelara: Approved Product Information Sydney: Janssen-Cilag Pty Ltd, 2017 (accessed 21 July 2017).
- Pharmaceutical Benefits Advisory Committee. Public Summary Document: Ustekinumab March 2017 PBAC Meeting. Canberra: PBS, 2017 (accessed 21 July 2017).
- Therapeutic Goods Administration. Prescription medicines: new or extended uses, or new combinations of registered medicines. Canberra: Australian Government Department of Health 2017 (accessed 27 July 2017).
- Gastrointestinal Expert Group. Therapeutic Guidelines: Gastrointestinal. West Melbourne, Victoria: Therapeutic Guidelines Ltd, 2016 (accessed 27 July 2017).
- Gomollon F, Dignass A, Annese V, et al. 3rd European evidence-based consensus on the diagnosis and management of Crohn's disease 2016: Part 1: Diagnosis and medical management. J Crohns Colitis 2017;11:3-25.
- Australian Medicines Handbook. Crohn\u2019s disease. Adelaide: Australian Medicines Handbook Pty Ltd, 2017 (accessed 27 July 2017).
- Feagan BG, Sandborn WJ, Gasink C, et al. Ustekinumab as induction and maintenance therapy for Crohn's disease. N Engl J Med 2016;375:1946-60.
- Best WR, Becktel JM, Singleton JW, et al. Development of a Crohn's disease activity index. National Cooperative Crohn's Disease Study. Gastroenterology 1976;70:439-44.
- Sandborn WJ, Feagan BG, Hanauer SB, et al. A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn's disease. Gastroenterology 2002;122:512-30.