Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.


Stelara (Janssen-Cilag)
45 mg/0.5 mL solution for injection
Approved indication: psoriasis
Australian Medicines Handbook section 8.2.1

Ustekinumab, a humanised monoclonal antibody, is a new treatment for moderate to severe psoriasis (see 'Treatments for psoriasis' Aust Prescr 2009;32:14-8). It suppresses the immune system by blocking the inflammatory actions of interleukin (IL)-12 and IL-23, which contribute to the symptoms of psoriasis.

In a placebo-controlled study of 320 patients, ustekinumab improved symptoms of moderate to severe psoriasis in a dose-dependent manner.1 Ustekinumab was then investigated in two crossover trials involving 1996 patients (PHOENIX1 and PHOENIX2). In both trials, patients were randomised (1:1:1) to receive ustekinumab 45 mg or 90 mg subcutaneously (at 0, 4 and then every 12 weeks), or placebo (at 0 and 4 weeks). After 4 weeks the patients in the placebo group crossed over to receive ustekinumab 45 mg or 90 mg (at 12 and 16 weeks and then every 12 weeks after that). The primary end point of the trials was the proportion of patients whose symptoms had improved by 75% after 12 weeks of treatment. Overall, significantly more patients in the ustekinumab groups reached this end point than in the placebo groups (67% with 45 mg and 71% (66-76%) with 90 mg vs 3% for placebo). These responses were maintained for up to a year in patients who continued treatment. After patients taking placebo crossed over to receive ustekinumab, a similar pattern of improvement was seen.2,3 A subgroup analysis of the trials indicated that the efficacy of ustekinumab was slightly lower in obese patients and those aged 65 years or over.

In the PHOENIX2 trial, patients who had partially responded after seven months of treatment (50-75% improvement in symptoms) were re-randomised to receive ustekinumab every eight weeks or to continue with the 12-week schedule. After a year, more patients receiving the 90 mg intensified dose responded to treatment than those receiving the original 12-week dosing (69% vs 33%). In contrast, patients did not respond to intensification of the 45 mg dose.3

Ustekinumab has been compared to etanercept, another psoriasis drug, in a trial of 855 patients. After 12 weeks of treatment, both doses of ustekinumab - 45 mg or 90 mg seemed to be more effective than etanercept 50 mg given twice weekly. Of the patients, 72% and 65% receiving ustekinumab had improved symptoms compared to only 57% with etanercept. Adding etanercept to ustekinumab treatment did not improve response rates further. The trial is ongoing and will assess the effect of interrupting and restarting therapy on patients' symptoms.

In the PHOENIX trials, adverse events were similar between treatment and placebo groups with the most common complaints being upper respiratory tract infections, headache and arthralgia. Serious adverse effects with ustekinumab 45 mg included angina, stroke, hypertension, intervertebral disc protrusion, dactylitis, clavicular fracture, sciatica and nephrolithiasis. With the 90 mg dose, there was one sudden cardiac death in a 33-year-old patient. This was thought to be related to dilated cardiomyopathy. Other events included cellulitis, benign meningioma, transient palpitations and ventricular extrasystoles, and coronary artery disease requiring surgery. There were two serious infections with ustekinumab 90 mg (cellulitis and herpes zoster) and one basal cell carcinoma.2,3 Depression was a common adverse event.

After a year of treatment, some patients had developed antibodies to ustekinumab. This was more common in patients who had only partially responded to treatment compared to those who had had a better response (12% vs 2%).3

Because of its immunosuppressant effects, ustekinumab is contraindicated in patients with clinically important active infections, chronic infections or a history of recurrent infections. There is a risk that latent infections may reactivate so patients should be assessed for tuberculosis and given appropriate treatment if necessary before starting ustekinumab. Live vaccines such as BCG (Bacillus Calmette-Gurin) should not be given. As with other immunosuppressants, ustekinumab may increase the risk of malignancy. It should not be given with other systemic treatments for psoriasis, or with phototherapy.

When ustekinumab is given at 0 and 4 weeks and then every 12 weeks, steady-state serum concentrations are achieved by week 28. If a patient has not responded by this time, treatment should be stopped. Ustekinumab has a long half-life (approximately three weeks) and due to the mechanism of action, its effects may last for months.

Ustekinumab appears to be effective for psoriasis, and will probably prove popular with patients since injections are only needed every 12 weeks. However, because of the increased risk of serious adverse effects, ustekinumab is only indicated for patients who have not responded to other systemic treatments or cannot tolerate them.

manufacturer did not respond to request for data

The Transparency Score () is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.

Correction
Ustekinumab T-score (April 2010)
Janssen-Cilag did respond to the request for data, but their response was not received in the Australian Prescriber office. The company declined to provide the clinical evaluation.

manufacturer declined to supply data

References

  1. Krueger GG, Langley RG, Leonardi C, Yeilding N, Guzzo C, Wang Y, et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med 2007;356:580-92.
  2. Leonardi CL, Kimball AB, Papp KA, Yeilding N, Guzzo C, Wang Y, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX1). Lancet 2008;371:1665-74.
  3. Papp KA, Langley RG, Lebwohl M, Krueger GG, Szapary P, Yeilding N, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX2). Lancet 2008;371:1675-84.