Ustekinumab trials

Introduction

Ustekinumab (STELARA™; Centocor Inc., Horsham, PA, USA) is a human interleukin-12 and -23 antagonist. It is indicated for the treatment of adult patients (18 years or older) with moderate to severe psoriasis that are candidates for phototherapy or systemic therapy. Ustekinumab was approved in the United States (September 2009) for the treatment of moderate-to-severe plaque psoriasis, and has already been marketed in Canada (December 2008) and Europe (January 2009). In April 2010, Medsafe’s Medicines Classification Committee recommended that ustekinumab should be added to the New Zealand Schedule as a prescription medicine for the treatment of plaque psoriasis in adult patients. To date (August 2018), it is not funded by PHARMAC.

Psoriasis imposes a heavy burden on the lifestyle of those affected. Recent research has focused on the genetic and immunologic features of psoriasis to create more targeted, effective, and safe treatment. In recent years, biologics have increased the options for the treatment of severe psoriasis. These drugs are potentially less toxic to the liver, kidneys, and bone marrow, and do not cause birth deformities unlike traditional systemic therapies for psoriasis (acitretin, methotrexate, and ciclosporin).

Ustekinumab has been shown in small studies to be useful in other forms of psoriasis, including nail psoriasis, erythrodermic psoriasis and palmoplantar pustulosis.

Mechanism of action of ustekinumab

T-cell mediated inflammatory conditions are influenced by cytokines, the chemical messengers produced by cells. The cytokines interleukin (IL)-12 and IL-23 result in skin disease such as psoriasis due to dysregulation of the immune system. Ustekinumab is a monoclonal antibody belonging to a class of biological, anti-cytokine medications that notably targets the p40 subunit of both interleukins (IL)-12 and -23.

Psoriasis is caused by an increase in the production of T-cells (lymphocytes) in response to the attachment of a stimulant, such as IL, to the lymphocyte. Stimulated T-cells cause skin cells to grow rapidly, producing plaques of psoriasis. Ustekinumab reduces psoriasis by attaching to IL-12 and IL-23 and preventing them from binding and activating T-lymphocytes.

Pharmacokinetics of ustekinumab

In psoriasis subjects, the median time to reach the maximum serum concentration (Tmax) was 13.5 days and 7 days, respectively, after a single subcutaneous administration of 45 mg (N=22) and 90 mg (N=24) of ustekinumab. In healthy subjects (N=30), the median Tmax value (8.5 days) following a single subcutaneous administration of 90 mg of ustekinumab was comparable to that observed in psoriasis subjects. Following multiple subcutaneous doses of ustekinumab, the steady-state serum concentrations were achieved by week 28. The mean (±SD) steady-state trough serum concentration ranged from 0.31 ± 0.33 mcg/mL (45 mg) to 0.64 ± 0.64 mcg/mL (90 mg). There was no apparent accumulation in serum ustekinumab concentration over time when given subcutaneously every 12 weeks.

The mean (± SD) systemic clearance (CL) following a single intravenous administration of ustekinumab to psoriasis subjects ranged from 1.90 ± 0.28 to 2.22 ± 0.63 mL/day/kg. The mean (±SD) half-life ranged from 14.9 ± 4.6 to 45.6 ± 80.2 days across all psoriasis studies following intravenous and subcutaneous administration.

Clinical trials in psoriasis

Ustekinumab's safety and efficacy has been evaluated for the treatment of moderate-to-severe plaque psoriasis in 3 phase III clinical trials, 2 placebo-controlled (PHOENIX 1 and 2), and 1 comparator-controlled (ACCEPT) study. Ustekinumab was effective in patients who had not received previous treatment, who had previously failed other immunosuppressive medications including ciclosporin or methotrexate, who were unresponsive to phototherapy, or who were unable to use or tolerate other therapies.

PHOENIX 1 and 2

PHOENIX 1 enrolled 766 subjects and PHOENIX 2 enrolled 1230 subjects with chronic plaque psoriasis. The studies had the same design through Week 28. In both studies, subjects were randomised in equal proportion to placebo, 45 mg, or 90 mg of ustekinumab. Subjects randomised to ustekinumab received 45 mg or 90 mg doses, regardless of weight, at Weeks 0, 4, and 16. Subjects randomised to receive placebo at Weeks 0 and 4, crossed over to receive ustekinumab (either 45 mg or 90 mg) at Weeks 12 and 16. The endpoints were the proportion of subjects who achieved at least a 75% reduction in Psoriasis Area Severity Index score (PASI 75) from baseline to Week 12 and treatment success (cleared or minimal) on the Physician's Global Assessment (PGA). The PGA is a 6-category scale ranging from 0 (cleared) to 5 (severe) that indicates the physician's overall assessment of psoriasis focusing on plaque thickness/induration, erythema (redness) and scaling.

Median baseline PASI scores in PHOENIX 1 and 2 ranged from approximately 17 to 18. Baseline PGA scores were marked or severe in 44% of subjects in PHOENIX 1 and 40% of subjects in PHOENIX 2. Approximately two-thirds of all subjects in PHOENIX 1 and 2 had received prior phototherapy and 69% had received either prior conventional systemic or biologic therapy for the treatment of psoriasis. A total of 28% of the study subjects had a history of psoriatic arthritis.

Results of PHOENIX 1 and 2 are summarised in the tables below.

Examination of age, sex, and race subgroups did not identify differences in response to ustekinumab among these subgroups. In subjects who weighed < 100 kg, response rates were similar with both the 45 mg and 90 mg doses; however, in subjects who weighed > 100 kg, higher response rates were seen with 90 mg dosing compared with 45 mg dosing.

Subjects in PHOENIX 1 were evaluated through Week 52. At Week 40, those who were PASI 75 responders at both Weeks 28 and 40 were re-randomized to either continued dosing (ustekinumab at Week 40) or to the withdrawal of therapy (placebo at Week 40). At Week 52, 89% (144/162) of subjects re-randomised to ustekinumab were PASI 75 responders compared with 63% (100/159) of subjects re-randomised to placebo (treatment withdrawal after Week 28 dose).

Adverse events were similar for patients treated with placebo or either of the ustekinumab doses. Upper respiratory tract infection, nasopharyngitis headache, and arthralgias were the most common adverse events reported.

ACCEPT — Comparison of ustekinumab with etanercept

Ustekinumab was also studied in phase III multicenter, randomised, head-to-head study comparing ustekinumab and etanercept for the treatment of moderate-to-severe plaque psoriasis. Findings from this landmark study showed that ustekinumab was more effective than etanercept in both primary (PASI 75 at week 12) and secondary (PGscore of cleared (0) or minimal (1) at week 12 and PASI 90 at week 12) efficacy endpoints. The ACCEPT trial included 903 patients (3:5:5 ratio; etanercept = 347, ustekinumab 45 mg = 209, ustekinumab 90 mg = 347) with chronic plaque psoriasis. Patients were randomised to receive either ustekinumab 45 mg or 90 mg subcutaneously at weeks 0 and 4 or etanercept 50 mg subcutaneously two times per week for 12 weeks.

• There was at least 75% improvement in the PASI at week 12 in 67.5% of patients who received 45 mg of ustekinumab and 73.8% of patients who received 90 mg, as compared with 56.8% of those who received etanercept (P = 0.01 and P < 0.001, respectively).
• Similarly, 65.1% of patients who received 45 mg of ustekinumab and 70.6% of patients who received 90 mg of ustekinumab had cleared or minimal disease according to the physician's global assessment, as compared with 49.0% of those who received etanercept (P < 0.001 for both comparisons).
• Among patients who did not have a response to etanercept, 48.9% had at least 75% improvement in the PASI within 12 weeks after crossover to ustekinumab.
• It was concluded that the efficacy of ustekinumab at a dose of 45 or 90 mg was superior to that of high-dose etanercept over a 12-week period in patients with psoriasis.

One or more adverse events occurred through week 12 in 66.0% of patients who received 45 mg of ustekinumab and 69.2% of patients who received 90 mg of ustekinumab and in 70.0% who received etanercept; 1.9%, 1.2%, and 1.2%, respectively, had serious adverse events. Safety patterns were similar before and after crossover from etanercept to ustekinumab.

Ustekinumab compared with secukinumab

Secukinumab was superior to ustekinumab in clearing skin of subjects with moderate to severe psoriasis and improving health-related quality of life with a comparable safety profile over 16 weeks.

• The study was not placebo-controlled and was of short-term duration.
• In this 52-week, double-blind study (NCT02074982), 676 subjects were randomized 1:1 to subcutaneous injection of secukinumab 300 mg or ustekinumab per label.
• Secukinumab (79.0%) was superior to ustekinumab (57.6%) as assessed by PASI 90 (primary endpoint) response at week 16 (P < .0001).
• Percentage of subjects with the Dermatology Life Quality Index score 0/1 (week 16) was significantly higher with secukinumab (71.9%) than ustekinumab (57.4%) (P < 0.0001).
• The safety profile of secukinumab was comparable with ustekinumab and consistent with pivotal phase III secukinumab studies.

Ustekinumab compared with brodalumab

Results of two phase 3 studies comparing ustekinumab with brodalumab in psoriasis have shown brodalumab to have superior 75% PASI response rates and sPGA scores at week 12.

• In two phase 3 studies (AMAGINE-2 and AMAGINE-3), patients with moderate-to-severe psoriasis were randomly assigned to receive brodalumab (210 mg or 140 mg every 2 weeks), ustekinumab (45 mg for patients with body weight ≤ 100 kg and 90 mg for patients > 100 kg), or placebo.
• At week 12, patients receiving brodalumab were randomly assigned again to receive a brodalumab maintenance dose of 210 mg every 2 weeks or 140 mg every 2 weeks, every 4 weeks, or every 8 weeks; patients receiving ustekinumab continued to receive ustekinumab every 12 weeks, and patients receiving placebo received 210 mg of brodalumab every 2 weeks.
• At week 12, the PASI 75 response rates were higher with brodalumab at the 210-mg and 140-mg doses than with placebo (86% and 67%, respectively, vs. 8% [AMAGINE-2] and 85% and 69%, respectively, vs. 6% [AMAGINE-3]; P < 0.001).
• The rates of sPGA scores of 0 or 1 were also higher with brodalumab (P < 0.001). The week 12 PASI 100 response rates were significantly higher with 210 mg of brodalumab than with ustekinumab (44% vs. 22% [AMAGINE-2] and 37% vs. 19% [AMAGINE-3], P < 0.001).
• Rates of neutropenia were higher with brodalumab and with ustekinumab than with placebo. Mild or moderate candida infections were more frequent with brodalumab than with ustekinumab or placebo.

Psoriatic arthritis

Ustekinumab was shown to result in modest clinical improvement in a phase II study in patients with psoriatic arthritis. This study was a double-blind, randomised, placebo-controlled, crossover study at 24 sites in North America and Europe. Patients with active psoriatic arthritis were randomly assigned to either: ustekinumab (90 mg or 63 mg) subcutaneous every week for 4 weeks (weeks 0–3) followed by placebo at weeks 12 and 16 (group 1); or placebo subcutaneous every week for 4 weeks (weeks 0–3) followed by ustekinumab (63 mg) at weeks 12 and 16 (group 2). The primary endpoint was a 20% improvement in the American College of Rheumatology core set of measures (ACR20) at week 12. ACR20, ACR50, and ACR70 were determined in both groups at week 12. Groups 1 and 2 demonstrated: 42% versus 14%, 25% versus 7%, and 11% versus 0% for the respective ACR scores. ACR20 was maintained by 36% of patients treated only with ustekinumab throughout the trial for up to 32 weeks. Ustekinumab significantly reduced signs and symptoms of psoriatic arthritis, diminished skin lesions compared with placebo, and was well tolerated. Larger and longer-term phase III studies are needed to definitively establish safety and efficacy in this population of patients. Nonetheless, results from this study are promising and suggest that treatment with ustekinumab can remain safe and effective for a long duration as well as maintain improvements in physical function and quality of life.

Results of a separate phase III study (PSummit 1) also confirmed ustekinumab’s efficacy in the treatment of psoriatic arthritis and might offer an alternative therapeutic mechanism of action to approved biological treatments.
In this phase III, multicentre, double-blind, placebo-controlled trial at 104 sites in Europe, North America, and Asia-Pacific, adults with active psoriatic arthritis (≥ 5 tender and ≥ 5 swollen joints, C-reactive protein ≥ 3.0 mg/L) were randomly assigned to 45 mg ustekinumab (n = 205), 90 mg ustekinumab (n = 204), or placebo (n= 206) at week 0, week 4, and every 12 weeks thereafter.
At week 16, patients with less than 5% improvement in both tender and swollen joint counts entered masked early-escape and were given 45 mg ustekinumab (if in the placebo group) or 90 mg ustekinumab (if in the ustekinumab 45 mg group).
At week 24, all remaining patients in the placebo group received ustekinumab 45 mg, which they continued till week 28 and every 12 weeks thereafter.
The primary endpoint was 20% or greater improvement in American College of Rheumatology (ACR20) criteria at week 24.
Significantly more ustekinumab-treated patients compared with placebo achieved ACR20 at week 24:

• 87 of 205 (42·4%) in the 45 mg group (p<0·0001 vs placebo)
• 101 of 204 (49·5%) in the 90 mg group (p<0·0001 vs placebo)
• 47 of 206 (22·8%) in the placebo group.

Adverse events due to ustekinumab

To date, adverse events associated with ustekinumab are consistent with that seen with other biologics.

• Infections – ustekinumab may increase the risk of infections and reactivation of latent infections. Serious bacterial, fungal, and viral infections have been observed in subjects receiving the drug.
• Malignancies – ustekinumab is an immunosuppressant and may increase the risk of malignancy (cancer). In the clinical development programme, 0.4% of patients treated with ustekinumab reported malignancies. Serious malignancies included breast, colon, head and neck, kidney, prostate, and thyroid cancers. The safety of ustekinumab has not been evaluated in patients who have a history of malignancy or who have a known malignancy.
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS) – RPLS is a neurological disorder, which is not caused by demyelination or a known infectious agent. RPLS can present with headache, seizures, confusion and visual disturbances. One case of reversible posterior leukoencephalopathy syndrome (RPLS) was observed during the clinical development program which included 3523 subjects treated with ustekinumab. The affected patient had received 12 doses of ustekinumab over approximately two years and presented with headache, seizures and confusion. No additional injections were administered and the subject fully recovered with appropriate symptomatic treatment. If RPLS is suspected, ustekinumab should be discontinued and the appropriate treatment administered.
• Post-marketing Experience – Immune system disorders have been reported during post-approval use with ustekinumab. These have included serious allergic reactions (including angioedema, breathlessness and low blood pressure) and hypersensitivity (allergy) reactions (including rash and urticaria). It is not always possible to reliably estimate their frequency or to establish a causal relationship to ustekinumab exposure because these events are reported voluntarily from a population of uncertain size.
• Overall, in placebo-controlled trials, the most common adverse reactions occurring at an incidence of > 3% were nasopharyngitis, upper respiratory infections, headache and fatigue. Adverse drug reactions that occurred at rates less than 1% included: cellulitis and certain injection site reactions including pain, swelling, pruritus, induration, haemorrhage, bruising, and irritation.

Long term safety of ustekinumab

Safety data were pooled from four randomised studies of ustekinumab for psoriasis including Accept, Phoenix 1 and 2.

• Analyses included 3117 patients who received one or more doses of ustekinumab, with 1482 patients treated for ≥ 4 years and 838 patients ≥ 5 years).
• At year 5, event rates for ustekinumab 45 mg and 90 mg were comparable between dose groups for serious infections, non-melanoma skin cancers, other malignancies and major cardiovascular events. Year-to-year variability was observed, but no increasing trend was evident.
• No dose‐related or cumulative toxicity was observed with increasing duration of ustekinumab exposure for up to 5 years. Rates of AEs reported in ustekinumab psoriasis trials are generally comparable with those reported for other biologics approved for the treatment of moderate‐to‐severe psoriasis.

Dosage and administration of ustekinumab

• Ustekinumab is administered by subcutaneous injection.
• For patients weighing < 100 kg (220 lbs), the recommended dose is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks.
• For patients weighing > 100 kg (220 lbs), the recommended dose is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks.
• It is recommended that each injection be administered at a different location (such as upper arms, gluteal regions, thighs, or any part of the abdomen) than the previous injection, and not into areas where the skin is tender, bruised, red, or indurated (thickened).
• Before use, ustekinumab should be visually inspected for particulate matter and discolouration. The product is colourless to light yellow, does not contain preservatives and may contain a few small translucent or white particles. It should not be used if it is discoloured or cloudy, or if another particulate matter is present.
• The needle cover on the prefilled syringe contains dry natural rubber (a derivative of latex). The needle cover should not be handled by persons sensitive to latex.
• Ustekinumab should only be administered by a healthcare provider and patients should be closely monitored and have regular follow-up visits with a physician.

Precautions when considering ustekinumab

• Exercise caution when considering the use of ustekinumab in patients with a chronic infection or a history of recurrent infection. Serious infections, such as cellulitis, diverticulitis, osteomyelitis, viral infections, gastroenteritis, pneumonia, and urinary tract infections requiring hospitalisation, have been reported in the drug development programme. Ustekinumab should not be administered until the infection resolves or is adequately treated.
• Patients with pharmacologic blockade of IL-12/IL-23 from treatment with ustekinumab may be susceptible to disseminated infections from mycobacteria (including nontuberculous, environmental mycobacteria), salmonella (including nontyphi strains), and Bacillus Calmette-Guerin (BCG) vaccinations based on evidence that individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to the latter infections. Appropriate diagnostic testing should be considered, such as tissue culture, and stool culture, as dictated by clinical circumstances.
• Ustekinumab should not be administered to patients with active tuberculosis (TB). Prior to biologic treatment, testing for latent TB should be performed by chest X-ray, Mantoux and/or Quantiferon gold testing. Consider anti-TB therapy prior to initiation of ustekinumab in patients with a past history of latent or active TB. Patients receiving ustekinumab should be monitored closely for signs and symptoms of active TB during and after treatment.
• BCG vaccines should not be given during treatment with ustekinumab or for one year prior to initiating treatment or one year following discontinuation of treatment. Caution is advised when administering live vaccines to household contacts of patients receiving ustekinumab because of the potential risk for shedding from the household contact and transmission to patient.
• Ustekinumab is an immunosuppressant and may increase the risk of malignancy (cancer). Malignancies have been reported in patients who received ustekinumab in clinical studies, including multiple skin cancers (squamous cell carcinomas) usually in patients with other risk factors such as previous treatment with photochemotherapy (PUVA).
• Serious allergic reactions, including angioedema and possible anaphylaxis, have been reported in post-marketing studies. If an anaphylactic or other serious allergic reaction occurs, ustekinumab should be discontinued and appropriate anti-allergy therapy given.
• Non-live vaccinations received during a course of ustekinumab may not elicit an immune response sufficient to prevent disease. Patients being treated with ustekinumab should not receive live vaccines.

Contraindications to ustekinumab

Ustekinumab is contraindicated in patients with clinically significant hypersensitivity to ustekinumab or to any of the excipients. Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported. If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue ustekinumab.

Drug interactions with ustekinumab

• No formal drug-drug interaction studies have been conducted with ustekinumab.
• A role for IL-12 or IL-23 in the regulation of CYP450 enzymes has not been reported. However, upon initiation of ustekinumab in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, monitoring for therapeutic effect (such as warfarin) or drug concentration (such as ciclosporin) should be considered and the individual dose of the drug adjusted as needed.
• Live vaccines should not be given concurrently with ustekinumab.
• The safety of ustekinumab in combination with immunosuppressive agents or phototherapy has not been evaluated.

Use in specific populations

Pregnancy Category B

There are no studies of ustekinumab in pregnant women. Ustekinumab should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No teratogenic effects were observed in the developmental and reproductive toxicology studies performed in cynomolgus monkeys at doses up to 45 mg/kg ustekinumab.

Nursing mothers

Caution should be exercised when ustekinumab is administered to a nursing woman. The unknown risks to the infant from gastrointestinal or systemic exposure to ustekinumab should be weighed against the known benefits of breastfeeding.

Paediatric use

The safety of ustekinumab was assessed in a study of 110 subjects 12–17 years of age with moderate to severe plaque psoriasis. The safety profile in these subjects through Week 60 was similar to the safety profile from studies in adults with plaque psoriasis.

Geriatric use

No differences in safety or efficacy have been observed between older and younger subjects treated with ustekinumab; however, the number of subjects aged 65 and over participating in clinical trials is not sufficient to determine whether they respond differently from younger subjects. In a population pharmacokinetic analysis study, there were no apparent changes in pharmacokinetic parameters (clearance and volume of distribution) in subjects older than 65 years old.

Hepatic and renal impairment

No pharmacokinetic data are available in patients with liver or kidney disease treated with ustekinumab.

Overdosage of ustekinumab

Single doses of ustekinumab up to 4.5 mg/kg intravenously have been administered in clinical studies without dose-limiting toxicity. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment be instituted immediately.

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