Positive Phase II Trial Results Assessing Ustekinumab for the Treatment of Systemic Lupus Erythematosus (SLE)
Discussion Points with the Janssen Pharmaceutical Companies of Johnson & Johnson
Disclosure: This is a non-commercial feature.
Lupus is a condition for which the creation of new treatment options is of paramount importance. There is as yet no cure for the disease, which is estimated to affect around 6 million people worldwide.1 Lupus can have a major impact on quality of life and sometimes even be life threatening, capable of affecting different areas of the body including joints, skin, and kidneys. During this year’s American College of Rheumatology and Association of Rheumatology Health Professionals (ACR/ARHP) Annual Meeting, held from 19th–24th October, new data were presented by Janssen Pharmaceutical Companies of Johnson & Johnson from a Phase II trial investigating the use of ustekinumab (STELARA®, Janssen Pharmaceutica, Beerse, Belgium) to treat the condition, and displayed positive results. To find out more about the study and its potential future impact, we spoke to two key members of the Janssen team involved in the study. These are Dr Jaime Oliver Vigueras, EMEA Immunology Therapeutic Area Lead and Dr Wim Noel, EMEA Director Medical Affairs Rheumatology. In addition to discussing this particular study, which forms part of Janssen’s extensive work in the field of immunology, we also explored the importance of the collaborations they have with non-profit and patient advocacy organisations; this is something that is a major aspect of the Phase III trial they have now initiated following the Phase II results.
Dr Oliver Vigueras firstly explained why the findings have the potential to have an important impact for lupus patients. “Lupus is a really devastating disease which is highly immunogenetic and very complex, with no cure currently available. Therefore, any treatment at this point that we can develop that can provide a benefit for the patient is very welcome. For example, only one biologic treatment has been approved for this indication in the last 60 years whereas other conditions have got 3, 4, 5, or 6 different treatments,” he commented. Ustekinumab is a human monoclonal antibody that has been approved to treat a number of immunologic conditions, notably psoriasis, psoriatic arthritis, and Crohn’s disease.
Phase II Findings
In this study, sustained improvements across global and organ-specific disease activity measures in patients receiving ustekinumab continuously through 1 year in addition to improvements in patients who were switched from placebo to ustekinumab at Week 24 through to 1 year were observed.2 The new 1 year results built on initial findings from the Phase II trial showing that a significantly higher proportion of patients had improvements in lupus disease activity compared with placebo, measured by SLE Responder Index (SLI)-4 response (62% vs. 33%, respectively, p=0.0057).
Following the end of the 24-week placebo-controlled period of the study, positive results continued to be displayed in both patients who crossed over from placebo to receive ustekinumab at a dose of 90 mg SC every 8 weeks and those who remained on that dosage of the drug from the beginning. Of those initially randomised to ustekinumab and who continued to receive it after 24 weeks, 63% met the SRI-4 response criteria at 1 year. In addition, from Week 24 through to 1 year, sustainment in the rates of changes from baseline in SLE Disease Acitvity-2K (SLEDAI-2K) and in rates of Physician Global Assessment (PGA) and active joint responses were observed, while there was an increase in the response rate of Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) in that same period (53% and 69%, respectively). In the patients who switched to ustekinumab from placebo at 24 weeks, an SRI-4 response was achieved at 1 year in 55%.
Measured through Week 56, 15% of patients who had either continued on ustekinumab or crossed over from placebo to ustekinumab had serious adverse events, while 7.5% had serious infections. These safety events were consistent with the known ustekinumab safety profile and no deaths, malignancies, opportunistic infections, or tuberculosis cases occurred.
Phase III Lotus Trial
Dr Noel spoke about these findings further: “On the SRI (SLE Responder Index)-4 score, which is the standard endpoint that is measured in trials for SLE, ustekinumab showed a very significant response rate of 62% versus 33%, which was statistically significant and really reinforced our belief in this drug for the treatment of SLE and our commitment to rheumatology by engaging in the Phase III LOTUS trial, which has just started. We saw the incredible sustainment of response after 1 year with this drug which really indicated that ustekinumab may be an effective therapy and we’re looking forward to bringing that further to market.”
These findings, if replicated in the aforementioned Phase III LOTUS study, should have an important impact for lupus patients. “We expect that the Phase III study will confirm this study and the drug will become available (for lupus patients),” said Dr Oliver Vigueras. “The rheumatologists are eager to get new alternative treatments because they currently have very few effective tools to treat their patients.”
The enthusiastic reaction of rheumatologists to this study at the ACR/ARPH Annual Meeting demonstrated the extent of its possible impact, with a great deal of questions about when the Phase III results are published; Dr Noel informed us that the study primary completion date is expected to be in January 2021. “We got a very positive response from participants at ACR and a lot of questions at the research and development booth that we had. And I think that shows the high unmet need from a physician`s as well as a patient’s perspective in regard to this disease.”
New Insights into Lupus
Another important, if secondary aspect of the study, is the new insights made regarding the pathophysiology of lupus disease, which will be greatly welcomed by the research community and potentially be used to assist with other treatments in the future. “Every study in my opinion gives us a lot of knowledge, whether it’s positive or negative,” explained Dr Oliver Vigueras. “In that sense what has been shown is that lupus is an autoimmune disease and that the main cells that are implicated in the inflammatory production are also involved in lupus. We have many different drugs targeting many different cells, but again this particular drug is shown to be working. It is still a Phase II and we should be cautious until the Phase III data confirm these findings showing that the same cytokines such as the IL-12, IL-23, TH1, and TH17 pathways play a key role; this is good learning for scientists to potentially develop further treatments in the future.”
Collaboration with Non-Profit Organisations
Another notable aspect of this study is the close collaboration Janssen had with the Lupus Research Alliance (LRA), a voluntary organisation which supports research into lupus. This body in fact triggered the Phase II study by approaching Janssen with the idea of exploring the use of ustekinumab to treat lupus patients after conducting their own research into the matter. The study is a prime example of how the pharmaceutical industry and non-profit healthcare organisations can use their combined expertise to provide better outcomes for patients. Dr Oliver Vigueras outlined the importance of this kind of collaboration for Janssen in their product development. “For Janssen it is critical, and I’m really proud to work for a company that understands the need to work closely with non-profit and patient organisations, because they really know the disease and can give new insights, and the voice of the patient is always critical to modify and create new tools to evaluate the impact of treatment,” he stated.
In keeping with this theme, a new disease-monitoring tool will be incorporated into the Phase III study. This is the Lupus Foundation of America – Rapid Evaluation of Activity in Lupus (LFA-REAL™) instrument, which aims to determine the impact of a treatment on the patient’s health and daily life. One set of questions and observations is designed for clinicians, referred to as a Clinician Reported Outcome measure (ClinRO) while the other, which is aimed at patients, is known as a Patient Reported Outcome measure (PRO).3
“It’s quite unique, it tries to integrate both a clinician’s perspective as well as a patient’s perspective to determine the treatment’s impact on the health and daily quality of life of those patients,” explained Dr Noel. “It’s basically a composite of a clinician-reported outcome and a patient-reported outcome in one. It’s been implemented and will be validated within the framework of our Phase III study and hopefully it will properly reflect the impact of the drug on the patient outcome. And I think it’s a good example of how essential it is to incorporate the patient’s vision in the outcome of clinical trials, especially given the complexity and heterogeneity of this disease.”
Another important aspect of the LOTUS study is the careful consideration made regarding the patients selected for the study, designed to ensure the results are as valid as possible. The condition not only disproportionately affects women, but especially those of African American, Hispanic, Asian, and Native American origin compared to Caucasian women. Great care is therefore being taken by Janssen to ensure that the demographic make-up of the study participants reflects this fact. “As we know, different ethnicities can influence the degree of sensitivity of that population towards SLE. The Phase II study was, as is usual with a Phase II study, a relatively more limited study in terms of patient numbers, and included about 44 centres. For the Phase III study we’re looking at 500 patients from 244 study locations across the globe,” said Dr Noel. “And we have really taken care to ensure that those specific ethnicities that display a higher sensitivity to the disease are well represented in the study. In the Phase III study we have deliberately put all those ethnicities in with a specific cap on each one of them so that when the results come out we are able to interpret them with respect to the different ethnicities represented. So in the end we want to have a true readout and then evaluation of the efficacy of our drug across all those ethnicities and the general population.”
EMJ Rheumatology 5.1
It was fascinating to gain further insights from Dr Oliver Vigueras and Dr Noel regarding this Phase II study assessing the use ustekinumab to treat lupus. It is clear there is much anticipation on the part of rheumatologists regarding its potential to provide an effective new treatment option for lupus patients, and we look forward to hearing more about the progression of the ongoing Phase III LOTUS study in the future. Lupus was one of the many rheumatological conditions to be covered in depth in the latest edition of the EMJ Rheumatology eJournal, which was published in July. This journal included a review of this year’s European League Against Rheumatism (EULAR) Annual Meeting, abstract reviews from the same event, interviews with members of our distinguished Editorial Board, and a range of peer-reviewed papers. This open-access edition can be accessed by clicking here.
- Lupus UK. World Lupus Day 2018 Awareness Survey Findings. 2018. Available at: https://www.lupusuk.org.uk/wld-survey-2018/. Last accessed: 7 November 2018.
- Janssen. New Phase 2 Data Show Stelara® (Ustekinumab) Sustained Improvement In Disease Activity In Adults With Systemic Lupus Erythematosus Through One Year. 2018. Available at: https://www.janssen.com/new-phase-2-data-show-stelarar-ustekinumab-sustained-improvement-disease-activity-adults-systemic-0. Last accessed: 7 November 2018.
- Lupus Foundation of America (LFA). LFA-REAL System to Improve Health and Quality of Life. Available at: https://www.lupus.org/research/lfa-real. Last accessed: 7 November 2018.