MADRID–(BUSINESS WIRE)–The Janssen Pharmaceutical Companies of Johnson & Johnson presented this
week results of two analyses from a Phase 2 study of Stelara®* (ustekinumab)
in systemic lupus erythematosus (SLE). The studies highlight not only
the sustained clinical benefit of ustekinumab – an anti-interleukin (IL)
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.1,2
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).1 Patients were
randomized (3:2) to receive intravenous (IV) 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.1
Results reported previously at week 24 showed the considerable efficacy
of ustekinumab vs placebo on both global and organ-specific disease
measures.1 The new long-term results (48 weeks) confirmed the
sustained clinical efficacy of ustekinumab, with all measures maintained
over a one-year period.1 Importantly, ustekinumab reduced the
occurrence of severe British Isles Lupus Assessment Group (BILAG) flares.1,3
Results showed a 4-fold decrease in the rate of severe flares with
ustekinumab vs placebo in weeks 0–24.1 The flare rate was
also lower in week 24-48 compared to placebo or ustekinumab rates in
weeks 0-24.1 In addition, the safety profile of ustekinumab
through one year in SLE was consistent with that observed in other
immune-mediated conditions.1
Commenting on the results, van Vollenhoven, who is also Professor and
Chief of Rheumatology at the Amsterdam University Medical Center
explained, “SLE flares are very unpredictable and have a major impact
on patients’ quality of life. As such, these results present an
impactful and clinically relevant finding, and suggest ustekinumab could
in the future offer patients a valuable new treatment option.”
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.1 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.1
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.2 The analysis specifically showed an association of
clinical response with novel biomarker responses that were independent
of IFN-I.2 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.2
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.2
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.11
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.4 Helping to put
these observations into context, study investigator, Dr George Tsokos,
commented, “This is an important finding because SLE drivers have,
until recently, been considered to be led by IFN-I. These results
suggest that the classical model suspected to be functioning in SLE may
be supported by an alternative mechanism of disease via
IL-12/-23-dependent T-helper-1 cell differentiation and IFN-γ. It might
be this pathway helping to improve clinical disease activity and reduce
severe flares, which are currently challenging to manage with lupus.”
“Lupus is a complex disease, it can produce many symptoms and in some
cases, can take years to be diagnosed. If left untreated, this disease
can be fatal,” commented Dr Jaime Oliver, Therapeutic Area Lead,
Immunology and CVT, Europe Middle East & Africa, Janssen Cilag GmbH
International. “We are committed to advancing our understanding of
lupus in order to develop therapies that have the potential to change
the lives of people in need.”
SLE most often affects women and disproportionately affects women of
African American, Hispanic, Asian and Native American descent compared
to Caucasian women.5 Incidence rates vary across European
countries, ranging from 2.2 cases/100,000 in Spain to 5 cases/100,000 in
France.6
The findings from both analyses will be confirmed in the ongoing Phase 3
LOTUS study (NCT no. NCT03517722 / EudraCT no. 2017-001489-53).
END
About the Phase 2 ustekinumab SLE Trial
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).1 Patients
were randomised (3:2) to receive intravenous (IV) ustekinumab 6 mg/kg or
placebo (PBO) at week 0, followed by subcutaneous (SC) 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.1
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.1 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 (PGA) of disease activity and no worsening of moderate/severe
organ disease on the BILAG disease activity index.1 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.1 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%).1
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.
About systemic lupus erythematosus (SLE)
Lupus is a chronic, inflammatory autoimmune disease that can affect many
different body systems, including joints, skin, heart, lungs, kidneys
and brain. Most people with lupus have mild disease characterised by
episodes of disease worsening called flares. When a flare occurs, many
people will either notice a return of symptoms, an increase in symptom
severity or may develop new symptoms. Common symptoms that indicate a
flare include ongoing fever not due to an infection or other cause,
painful or swollen joints, fatigue, rashes or sores or ulcers in the
mouth or nose.7 During a flare signs and symptoms get worse
for a while, then improve or even disappear completely for a time.8
SLE can range from mild to severe and is characterised by inflammation
of any organ system including the kidneys, nervous system and brain.9
Lupus is estimated to affect at least 5 million people worldwide.10
About ustekinumab11
In the European Union, ustekinumab is approved for the treatment of
moderate to severe plaque psoriasis in adults who failed to respond to,
or who have a contraindication to, or are intolerant to other systemic
therapies including ciclosporin, methotrexate (MTX) or psoralen plus
ultraviolet A (PUVA), and is also indicated for the treatment of
moderate to severe plaque psoriasis in adolescent patients from the age
of 12 years and older who are inadequately controlled by or are
intolerant to other systemic therapies or phototherapies. In addition,
ustekinumab is approved alone or in combination with MTX for the
treatment of active psoriatic arthritis in adult patients when the
response to previous non-biological disease-modifying antirheumatic drug
(DMARD) therapy has been inadequate. Ustekinumab is approved by the
European Commission for the treatment of adult patients with moderately
to severely active Crohn’s disease who have had an inadequate response
with, lost response to, or were intolerant to either conventional
therapy or a TNF-alpha antagonist or have medical contraindications to
such therapies.
*Ustekinumab is currently under investigation and is not approved for
SLE. A Phase 3 programme evaluating ustekinumab in the treatment of
adults with active SLE is ongoing.
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 Janssen Pharmaceutical Companies of Johnson & Johnson maintain
exclusive worldwide marketing rights to ustekinumab, which is currently
approved for the treatment of moderate to severe plaque psoriasis in 89
countries, paediatric psoriasis in 44 countries, psoriatic arthritis in
83 countries and Crohn’s disease in 70 countries.
Stelara® (ustekinumab) is a registered trademark of Johnson &
Johnson.
Important Safety Information
For complete European Union (EU) prescribing information, please visit: www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000958/WC500058513.pdf.
About the Janssen Pharmaceutical Companies of Johnson & Johnson
At Janssen, we’re creating a future where disease is a thing of the
past. We’re the Pharmaceutical Companies of Johnson & Johnson, working
tirelessly to make that future a reality for patients everywhere by
fighting sickness with science, improving access with ingenuity, and
healing hopelessness with heart. We focus on areas of medicine where we
can make the biggest difference: Cardiovascular & Metabolism,
Immunology, Infectious Diseases & Vaccines, Neuroscience, Oncology, and
Pulmonary Hypertension.
Learn more at www.janssen.com/EMEA.
Follow us at www.twitter.com/JanssenEMEA.
Janssen-Cilag International NV and Cilag GmbH International are part of
the Janssen Pharmaceutical Companies of Johnson & Johnson.
Cautions Concerning Forward-Looking Statements
This press release contains “forward-looking statements” as defined in
the Private Securities Litigation Reform Act of 1995 regarding
development of ustekinumab in systemic lupus erythematosus. The reader
is cautioned not to rely on these forward-looking statements. These
statements are based on current expectations of future events. If
underlying assumptions prove inaccurate or known or unknown risks or
uncertainties materialize, actual results could vary materially from the
expectations and projections of any of the other Janssen Pharmaceutical
Companies and/or Johnson & Johnson. Risks and uncertainties include, but
are not limited to: challenges and uncertainties inherent in product
research and development, including the uncertainty of clinical success
and of obtaining regulatory approvals; uncertainty of commercial
success; manufacturing difficulties and delays; competition, including
technological advances, new products and patents attained by
competitors; challenges to patents; product efficacy or safety concerns
resulting in product recalls or regulatory action; changes in behavior
and spending patterns of purchasers of health care products and
services; changes to applicable laws and regulations, including global
health care reforms; and trends toward health care cost containment. A
further list and descriptions of these risks, uncertainties and other
factors can be found in Johnson & Johnson’s Annual Report on Form 10-K
for the fiscal year ended December 30, 2018, including in the sections
captioned “Cautionary Note Regarding Forward-Looking Statements” and
“Item 1A. Risk Factors,” and in the company’s most recently filed
Quarterly Report on Form 10-Q, and the company’s subsequent filings with
the Securities and Exchange Commission. Copies of these filings are
available online at www.sec.gov,
www.jnj.com
or on request from Johnson & Johnson. None of the Janssen Pharmaceutical
Companies nor Johnson & Johnson undertakes to update any forward-looking
statement as a result of new information or future events or
developments.
References
1 Vollenhoven R et al (2019) Maintenance of Efficacy
and Safety and Reduction of BILAG Flares with Ustekinumab, an
Interleukin-12/23 Inhibitor, in Patients with Active Systemic Lupus
Erythematosus (SLE): 1-Year Results of a Phase 2, Randomized
Placebo-Controlled, Crossover Study. Abstract at Annual European
Congress of Rheumatology (EULAR 2019), Madrid, Spain.
2
Cesaroni M et al. (2019) Biomarker Profiling Reveals Novel
Mechanistic Insights into Ustekinumab Therapeutic Responses in Systemic
Lupus Erythematosus. Abstract at Annual European Congress of
Rheumatology (EULAR 2019), Madrid, Spain.
3 Gordon C et
al. (2003) Definition and treatment of lupus flares measured by the
BILAG index. Rheum;42(11):1372-1379.
4 Bettelli E et
al (2005). IL-12– and IL-23–induced T helper cell subsets: birds of
the same feather flock together. J Exp Med;201(2):169-171.
5
Lupus Research Alliance. About Lupus. Available at: www.lupusresearch.org/understanding-lupus/what-is-lupus/about-lupus/.
Last accessed June 2019.
6 Danchenko N, et al (2006)
Epidemiology of systemic lupus erythematosus: a comparison of worldwide
disease burden. Lupus;15(5):308–318.
7 Lupus
Foundation of America. When Flares Happen. Available at: www.lupus.org/blog/when-flares-happen.
Last accessed June 2019.
8 Mayo Clinic. Lupus. Available
at: www.mayoclinic.org/diseases-conditions/lupus/symptoms-causes/syc-20365789.
Last accessed June 2018.
9 Arthritis Research UK. Lupus
(SLE). Available at: www.arthritisresearchuk.org/arthritis-information/conditions/lupus.aspx.
Last accessed June 2019.
10 Lupus UK. World Lupus Day
2018 Survey Findings. Available at: www.lupusuk.org.uk/wld-survey-2018/.
Last accessed June 2019.
11 European Medicines Agency.
Stelara Summary of Product Characteristics. Available at: www.ema.europa.eu/en/documents/product-information/stelara-epar-product-information_en.pdf.
Last accessed June 2019.
CP-96134
June 2019
Contacts
Media contacts:
Emily Bone
+44
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ebone1@its.jnj.com
Investor contacts:
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DelOrefice
Johnson & Johnson
+1 732 524 2955
Lesley Fishman
Johnson & Johnson
+1 732 524 3922