17 June 2019 - - US-based healthcare company Johnson and Johnson's (NYSE: JNJ) The Janssen Pharmaceutical Companies business has presented results of two analyses from a Phase 2 study of Stelara (ustekinumab) in systemic lupus erythematosus, the company said.
The studies highlight not only the sustained clinical benefit of ustekinumab - an anti-interleukin IL-12/23 p40 neutralising monoclonal antibody - on SLE disease activity at one-year, but also show a reduction in the rate of severe flares.
They also provide new insights into the possible pathway through which ustekinumab is acting in SLE patients who respond to IL-12/23 p40 blockade.
The Phase 2 study, presented by lead study investigator Ronald van Vollenhoven MD PhD and colleagues, is a global randomized, placebo-controlled trial in 102 adults with seropositive SLE by Systemic Lupus International Collaborating Clinics (SLICC) criteria and active disease despite ongoing standard of care therapy (steroid, antimalarial and/or immunosuppressive therapies).
Patients were randomised to receive intravenous ustekinumab or placebo, both in addition to standard of care therapy for 24 weeks.
At week 24, patients in the placebo arm crossed over to active study agent.
Results reported previously at week 24 showed the considerable efficacy of ustekinumab vs placebo on both global and organ-specific disease measures.
The new long-term results (48 weeks) confirmed the sustained clinical efficacy of ustekinumab, with all measures maintained over a one-year period.
Importantly, ustekinumab reduced the occurrence of severe British Isles Lupus Assessment Group (BILAG) flares.
Results showed a four-fold decrease in the rate of severe flares with ustekinumab vs placebo in weeks 0–24. The flare rate was also lower in week 24-48 compared to placebo or ustekinumab rates in weeks 0-24.
In addition, the safety profile of ustekinumab through one year in SLE was consistent with that observed in other immune-mediated conditions.
The ustekinumab group had a severe BILAG flares rate of 2.1/10,000 patient-days in weeks 0–24, compared to 8.4/10,000 patient-days in the placebo group. 
In weeks 24–48, the rate of severe BILAG flares for patients in the ustekinumab group was 1.1/10,000 patient-days.
Patients in the placebo group who crossed over to ustekinumab at week 24 had severe BILAG flare rate of 4.6/10,000 patient-days.
The second study, presented by Dr George Tsokos, the study steering committee lead and Chief of the Division of Rheumatology and Clinical Immunology, Beth Israel Deaconess Medical Center, Boston, was an additional analysis of the ustekinumab Phase 2 study using biomarker data that could help to explain the mechanism through which ustekinumab may be effective in SLE.
Biomarker data was collected over 24 weeks from ustekinumab responders, ustekinumab non-responders and patients on placebo.
The analysis specifically showed an association of clinical response with novel biomarker responses that were independent of IFN-I.
The analysis measured the cytokines interferon gamma (IFN-γ), IL-17 A/F and IL-22 which are downstream mediators of the IL-12/IL-23 pathways, as well as type I interferons (IFN-I), believed to be a major contributor to SLE pathogenesis.
The results showed that people who responded to ustekinumab had durable reductions in IFN-γ protein levels relative to baseline a finding which was not observed in patients who did not respond to ustekinumab or who received placebo.
Other biomarkers measured including IFN-I, IL-17 A/F and IL-22 remained largely unchanged.
These findings implicate the involvement of the IL-12 pathway linked to IFN-γ production and not the IFN-I pathway in SLE responders to ustekinumab, but this will require confirmation in an ongoing Phase 3 study.
The common (≥1/100) adverse reactions reported in controlled periods of the adult psoriasis, psoriatic arthritis and Crohn's disease clinical studies with ustekinumab as well as post-marketing experience were: upper respiratory tract infection, arthralgia, back pain, diarrhoea, dizziness, fatigue, headache, infection site pain, injection site erythema, myalgia, nasopharyngitis, nausea, oropharyngeal pain, pruritus and vomiting.
The IL-12 pathway is important in T-helper-1 and T-follicular-helper cell differentiation in autoimmune diseases, production of IFN-γ, and activation and function of cytotoxic cells.
SLE most often affects women and disproportionately affects women of African American, Hispanic, Asian and Native American descent compared to Caucasian women.
Incidence rates vary across European countries, ranging from 2.2 cases/100,000 in Spain to 5 cases/100,000 in France.
The findings from both analyses will be confirmed in the ongoing Phase 3 LOTUS study (NCT no. NCT03517722 / EudraCT no. 2017-001489-53).
The efficacy and safety of ustekinumab was evaluated in a global Phase 2, randomised, placebo-controlled trial in 102 adults with seropositive SLE by Systemic Lupus International Collaborating Clinics (SLICC) criteria and active disease despite ongoing standard of care therapy (steroid, antimalarial and/or immunosuppressive therapies) (NCT no. NCT02349061 / EudraCT no. 2014-005000-19).
Patients were randomised to receive intravenous ustekinumab 6 mg/kg or placebo at week 0, followed by subcutaneous injections of ustekinumab 90 mg or placebo every eight weeks, both in addition to standard of care therapy for 24 weeks.
At week 24, patients in the placebo arm crossed over to active study agent.
The primary endpoint was the proportion of patients achieving SLE Responder Index-4 (SRI-4) response at week 24. The SRI combines scores from three different validated lupus disease indexes to define responders versus non-responders, and has previously been accepted by health authorities in SLE registration trials.
To achieve SRI-4 response, an individual with lupus must have at least a four-point improvement on the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score, less than 10% increase in Physician's Global Assessment of disease activity and no worsening of moderate/severe organ disease on the BILAG disease activity index.
Major secondary endpoints included change from baseline in SLEDAI-2K score, change from baseline in PGA of disease activity, and proportion of patients with BILAG-based Combined Lupus Assessment (BICLA) response, all at week 24.
Joint and cutaneous disease activity were also assessed with joint counts and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), respectively.
Ustekinumab response rates were sustained through one year in organ-specific disease measures (≥50% improvement in active joint counts: week 24: 87% vs week 48: 87%; ≥50% improvement in CLASI activity score: week 24: 53% vs week 48: 69%).
Endpoint analyses included all patients who received at least one dose of study agent, had at least one measurement prior to administration, and had at least one post-baseline measurement.
Patients with missing data and treatment failures were imputed as non-responders. Long-term safety and efficacy data are currently being collected through 104 weeks.