Idorsia initiates OPUS a Phase 3 program to investigate cenerimod for the
treatment of patients with systemic lupus erythematosus Idorsia to host an
investor webcast to discuss the Phase 3 program today at 15:00hrs CET
Allschwil, Switzerland – Dec ember 15 , 202 2
Idorsia Ltd (SIX: IDIA) today announced that the first patient has entered
screening to participate in OPUS, a Phase 3 program to investigate the efficacy
and safety of cenerimod, Idorsia’s novel, highly selective S1P 1 receptor
modulator, as an oral treatment for adult patients with moderate to severe
systemic lupus erythematosus.
Systemic lupus erythematosus (SLE), the most common form of lupus, is an
autoimmune disease. While the cause of SLE is not fully known, T and B
lymphocytes are considered the key immune cells that play a role in the
development of SLE. In individuals with SLE, both T and B cells become
overactive, infiltrate different tissues and produce autoantibodies, leading to
inflammation and organ damage.
Anca Askanase , MD, MPH, Director of the Columbia Lupus Center, and Professor
of Medicine, Columbia University and an investigator in both the CARE study and
OPUS program commented :
“The extraordinary heterogeneity in the pathogenesis and clinical
manifestations of SLE highlight the need for medications with broad coverage of
abnormal immune responses. The hope for cenerimod, as an S1P 1 receptor
modulator, is that, with an oral therapy, it can correct several aspects of
these immune dysregulations that cause the symptoms of lupus. There is solid
scientific rationale, and consistent clinical and laboratory evidence, to
suggest that cenerimod has great potential in the treatment of lupus.
Accordingly, I’m eager to enroll my patients in the cenerimod Phase 3 program.”
Alberto Gimona, MD and Head of Global Clinical Development of Idorsia,
commented:
“In Phase 2 studies, cenerimod 4 mg consistently showed clinically meaningful
and sustained improvement from baseline on multiple measures of SLE disease
activity compared to placebo. The effect of the 4 mg dose appears to be higher
in patients with severe and immunologically active disease. Across all doses
including the 4 mg dose, cenerimod was well tolerated with an adverse event
profile consistent with the mechanism of action, allowing us to move forward
with the dose that has demonstrated optimal efficacy. I am very excited to
announce that the Phase 3 program is now enrolling patients.”
About the O PUS program
The OPUS program ( O ral S1 P 1 Receptor Mod U lation in S LE) consists of two
Phase 3 multicenter, randomized, double-blind, placebo-controlled,
parallel-group studies to evaluate the efficacy, safety, and tolerability of
cenerimod in adult patients with moderate to severe SLE on top of background
therapy.
The main objectives of the program are to evaluate the effectiveness of
cenerimod 4 mg at reducing disease activity, as well as controlling the
disease, compared to placebo. The primary endpoint is change from baseline to
Month 12 in the modified Systemic Lupus Erythematosus Disease Activity Index
2000 (mSLEDAI-2K)* score. Secondary endpoints include the SLE Responder Index
(SRI-4) at Month 12 and, for the first time in a lupus registration study,
measures of ‘sustained disease control': Time to first confirmed 4-month
sustained mSLEDAI 2K response; Time to first confirmed 4-month sustained
response in mucocutaneous manifestations (i.e., rash, alopecia, mucosal
ulcers).
The program is expected to enroll 840 patients with SLE from around 25
countries, including Japan. Following a Phase 2a study with cenerimod showing a
dose-dependent reduction in plasma interferon-alpha, feedback from the lupus
community, and data from the CARE Phase 2b study that suggests that the
treatment effect of cenerimod was greater in patients with higher disease
activity and persistent inflammation, the Phase 3 study includes revised
eligibility criteria, as well as a screening period of up to 60 days to ensure
that only patients with true moderate to severe SLE are enrolled. Those who
complete the 12-month double-blind treatment period will have the option to
enroll into an open-label extension (OLE) study, where all patients will
receive cenerimod for at least one year.
The investigation of cenerimod for the treatment of SLE has been designated as
a “fast-track” development program by the FDA. This designation is intended to
promote communication and collaboration between the FDA and pharmaceutical
companies for drugs that treat serious conditions and fill an unmet medical
need. The Phase 3 program has been discussed with health authorities.
Alberto Gimona co ntinued :
“With OPUS investigating an oral treatment option for lupus, we are offering a
potential alternative to currently available biologic treatments that are
either self-injected or received via infusion in hospital on top of standard
care. By adding a new key secondary endpoint of ‘sustained disease control’,
Idorsia has designed a program that not only fulfills regulatory requirements,
but also has the potential to provide a more holistic view on how patients
respond to treatment. Since the course of the disease can vary widely for
patients during the study, taking a measurement at a fixed timepoint gives only
a snapshot on how the investigational treatment is performing. Instead, by
measuring the ability to sustain control of the disease for at least 4 months,
this endpoint becomes the most meaningful measure of disease activity for
patients and their physicians.”
About the efficacy of cenerimod in the CARE Phase 2b study
The decision to move into Phase 3 was based on the results of the CARE study
which were recently shared as an oral presentation by A. Askanase, MD, MPH at
the American College of Rheumatology (ACR) Convergence 2022: Abstract number
1656 “ Efficacy and Safety of Cenerimod in Patients with Moderate to Severe
Systemic Lupus Erythematosus (SLE): A Multicenter, Randomized, Parallel-Group,
Double-Blind, Placebo-Controlled, Dose-Finding Phase 2b Trial .”
The double-blind study equally randomized 427 adult patients with moderate to
severe SLE on stable background therapy, to cenerimod (0.5, 1, 2, 4 mg) or
placebo. The study duration was 18 months, two 6-month treatment periods and a
6-month follow-up. After the first 6 months, patients on 0.5, 1, 2 mg cenerimod
and on placebo continued the same blinded treatment, whereas patients taking
cenerimod 4 mg were re-randomized to blinded cenerimod 2 mg or placebo allowing
to assess reversibility of lymphocyte reduction.
The primary endpoint was change from baseline to Month 6 in the mSLEDAI-2K.
Secondary endpoints were SRI-4 and BILAG-2004 improvement. Safety endpoints
included adverse events (AEs) and AEs of special interest (AESI). Of 427
randomized patients, 339 completed 12 months of treatment. Baseline
characteristics were balanced across groups. The study did not meet its primary
endpoint after type I error control. However, the reduction in mSLEDAI-2K from
baseline to Month 6 with cenerimod 4 mg versus placebo was nominally
statistically significant: least squares [LS] mean difference (95% CI)
-1.19(-2.25, -0.12), p=0.0291. This effect was greater in patients with greater
disease severity (BILAG-2004 Grade B in ≥2 organ systems and/or Grade A in ≥1
organ system at BL; LS mean difference [95%CI] -1.39 [-2.59, -0.19]) and
patients with high Interferon Type 1 (IFN-1) gene expression signature status
(LS mean difference [95%CI] -2.79[-4.50, -1.08]). The definition of high versus
low IFN-1 gene expression signature status was recently shared as a poster
presentation at ACR Convergence 2022: Abstract number 1002 “ Investigation of
Pharmacodynamic Biomarkers in a Phase 2b Study in Patients with Moderate to
Severe SLE Treated with the S1P 1 Receptor Modulator Cenerimod .”
At Month 6, the proportion of SRI-4 responders was higher in patients
randomized to cenerimod 4 mg versus placebo. This difference was also greater
in IFN-1 high patients (difference +24%). Sustained mSLEDAI-2K response started
earlier in patients on cenerimod 4 mg versus placebo; this difference was
greater in the IFN-1 high subgroup. Lymphocyte count decreased in all cenerimod
groups; greater decreases were seen with the 2 and 4 mg doses.
At baseline, patients with SLE were identified as either IFN-1 high or IFN-1
low. The distribution was well balanced in the placebo (n=86) and cenerimod 4
mg group (n=85) with approximately 50% IFN-1 high in both treatment arms. At 6
months, cenerimod 4 mg treatment modulated gene expression signatures and
proteins linked to several of those molecular pathways associated with SLE
pathogenesis.
Martine Clozel, MD and Chief Scientific Officer of Idorsia, co ncluded :
'Cenerimod acts on both T cells and B cells and at a fundamental stage in the
autoimmune response, meaning it has the potential to alter the course of lupus.
Cenerimod showed the potential to modify several inflammatory pathways
demonstrating its broad immune-modulatory pharmacodynamics. In our Phase 2b
study, patients with a high interferon-1 gene expression signature showed
greater levels of improvement, this gives us even more confidence in the
potential of cenerimod because this pathway is already validated in the
treatment of lupus.”
About the safety of cenerimod in the CARE Phase 2b study
Cenerimod was well tolerated with similar rates of AEs reported across all
treatment groups, 0.5 mg: 49.4%; 1 mg: 64.7%; 2 mg: 59.3%; 4 mg: 58.3%;
placebo: 54.7%, during six months of treatment. The most frequent treatment
emergent AEs reported over 5% incidence in any group and higher than placebo
during six months of treatment were: abdominal pain, headache, and lymphopenia.
A reversible decrease in lymphocyte count is linked to the mechanism of action
of cenerimod and as expected lymphopenia was more often seen in patients
treated with the higher 2 mg and 4 mg doses. Importantly, there was no
increased rate of infections compared to placebo: 0.5 mg: 23.5%; 1 mg: 11.8%; 2
mg: 19.8%; 4 mg: 20.2%; placebo: 18.6%.
At Month 12, the incidence of AEs reported were between 60% and 80% across all
treatment groups with no dose relationship: 0.5 mg: 63.1%; 1 mg: 81.2%; 2 mg:
77.0%; placebo: 70.9%. For the 4 mg group which was re-randomized to either
placebo or 2 mg cenerimod, the AE incidences were 77.1% (switch from 4 mg to 2
mg) and 65.7% (switch from 4 mg to placebo). Compared to placebo, as seen
during the first 6 months, treatment with cenerimod was not associated with an
increased risk of infections.
* Since cenerimod induces a reduction in lymphocyte count as part of its
mechanism of action, the SLEDAI-2K, a recognized index used to assess disease
activity in patients with lupus, was modified (mSLEDAI-2K) to exclude
leukopenia - a reduction of
1 point from 105 possible total points.
Notes to the editor
About s ystemic lupus erythematosus
Systemic lupus erythematosus (SLE), the most common form of lupus, is an
autoimmune disease, which means that the body’s immune system malfunctions and
attacks the body’s own tissues. While some autoimmune diseases affect just one
organ, in the case of lupus, many parts of the body can be affected, such as
the skin, joints, kidneys, blood cells, lungs, and other organs. As a result,
symptoms vary widely and are often similar to other conditions, which need to
be ruled out before a diagnosis can be made. Lupus therefore often goes
undetected or misdiagnosed for long periods. Yet early diagnosis is important
to manage the symptoms of lupus, initiate treatment to reduce the risk of
long-term complications, and enable access to wider support (e.g. local patient
groups).
It is estimated that 1.5 million Americans, and at least 5 million people
worldwide, have a form of lupus, and that 90% of people living with lupus are
women, with most developing the disease between the ages of 15 and 44. There is
a higher prevalence of lupus among people of Asian and Afro-Caribbean origin
than in Caucasians.
There is no cure for SLE and a significant need exists for safe and effective
therapies. Most people with SLE are prescribed a combination of different
medications to manage their symptoms, improve their quality of life and reduce
the risk of more serious complications. The choice of treatment depends on how
the patient with SLE presents, which part of their body is affected and the
severity of the condition at the time.
The only FDA-approved treatments for SLE are acetylsalicylic acid (aspirin),
hydroxychloroquine (an antimalarial), corticosteroids, belimumab, and
anifrolumab. Some other immunosuppressive therapies are used off-label.
About S1P 1 receptor modulation
While the cause of SLE is not fully known, T and B lymphocytes are considered
the key immune cells that play a role in the development of SLE. In individuals
with SLE, both T and B cells become overactive. The main consequence of this
increased activity is the infiltration of immune cells into different tissues
and the production of autoantibodies (antibodies that recognize and destroy the
body’s own cells), leading to inflammation and organ damage.
T and B lymphocytes have a cell surface receptor called
sphingosine-1-phosphate receptor 1 (S1P 1 ). These receptors enable T and B
lymphocytes to detect the signaling molecule S1P – sphingosine 1 phosphate –
which is responsible for lymphocyte trafficking from the lymph nodes to the
circulation.
By binding to S1P 1 receptors, a receptor modulator can trigger the
internalization of those receptors. This effectively blinds T and B lymphocytes
to the S1P gradient, thereby holding them in the lymph nodes and reducing
autoreactive T and B cells in the circulation and consequently, also in the
tissues.
Following the reduction of circulating T and B cells, a reduction in
autoantibodies and immune cytokines – markers of the underlying disease
processes – is seen. Idorsia believes that this will ultimately further reduce
inflammation and tissue damage, key contributors to the disease.
Cenerimod in systemic lupus erythematosus
Cenerimod is a highly selective S1P 1 receptor modulator, being investigated
as an oral once-daily tablet. Cenerimod potentially offers a novel approach for
the treatment of SLE, a disease with a significant impact on patients and
limited treatment options.
Cenerimod temporarily stops the body from detecting S1P chemical ‘signposts’
that would otherwise trigger immune cell migration and inflammation. Unlike
other potential treatments for lupus that act on one specific ‘pathway’
involved in the disease, cenerimod is thought to work by targeting multiple
different pathways that researchers believe all contribute to the symptoms of
lupus. Of note, the patients with high level of IFN-1 phenotypes correlated
with other inflammatory pathways, revealing a complex inflammatory pathogenesis
in SLE. Cenerimod showed the potential to modify several of these inflammatory
pathways demonstrating its broad immune-modulatory pharmacodynamics.
Cenerimod is the result of 20 years of research by Idorsia and has been tested
in several clinical studies, including the CARE Phase 2b study ([abstract
1626]. Arthritis Rheumatol. 2022; 74 (suppl 9)) and a Phase 2a proof-of-concept
study (Hermann V, et al. Lupus Sci Med. 2019;6:e000354) in patients with SLE
and a clinical pharmacology program.
About Anca Askanase MD , MPH
Professor of Medicine, Founder and Director of the Columbia University Lupus
Center, Associate Director Division of Rheumatology and Director of
Rheumatology Clinical trials at Columbia University, Clinician, diagnostician,
and researcher specializing in complex Systemic Lupus Erythematosus (SLE)
Prof. Askanase’s research in lupus encompasses multiple areas: lupus
epidemiology including cohort and registry studies to allow for in depth
characterization of disease phenotype and comorbidities; outcomes research to
identify biomarkers and develop objective and novel instruments to more
accurately diagnose lupus, track disease activity, and define treatment
response; clinical trials to increase treatment options.
Much of her research is conducted in collaboration with national and
international lupus researchers. She founded the CUIMC Lupus cohort (n=450),
and is an active participant in the SLICC and LuCIN SLE registries. Ongoing
projects include the use of optical tomography to evaluate lupus arthritis,
development of virtual lupus disease activity measures for use in clinical
research, and lupus outreach to disparate populations in NYC. Dr Askanase
serves as a consultant to Idorsia.
Key Literature Askanase A, et al. Efficacy and Safety of Cenerimod in Patients
with Moderate to Severe Systemic Lupus Erythematosus (SLE): A Multicenter,
Randomized, Parallel-Group, Double-Blind, Placebo-Controlled, Dose-Finding
Phase 2b Trial [abstract 1626]. Arthritis Rheumatol. 2022; 74 (suppl 9).
Strasser D, et al. Investigation of Pharmacodynamic Biomarkers in a Phase 2b
Study in Patients with Moderate to Severe SLE Treated with the S1P 1 Receptor
Modulator Cenerimod [abstract 1002]. Arthritis Rheumatol. 2022; 74 (suppl 9).
Hermann V, et al. First use of cenerimod, a selective S1P 1 receptor modulator,
for the treatment of SLE: a double-blind, randomised, placebo-controlled,
proof-of-concept study. Lupus Sci Med. 2019;6:e000354. Juif P, et al.
Pharmacokinetics and Pharmacodynamics of Cenerimod, A Selective S1P 1 R
Modulator, Are Not Affected by Ethnicity in Healthy Asian and White Subjects.
Clin Transl Sci. 2021;14:143–7. Strasser DS, et al. Preclinical to clinical
translation of cenerimod, a novel S1P 1 receptor modulator, in systemic lupus
erythematosus. RMD Open. 2020;6:e001261. Piali L, et al. Cenerimod, a novel
selective S1P 1 receptor modulator with unique signaling properties. Pharmacol
Res Perspect. 2017;5:e00370. McGinley MP, et al. Sphingosine 1-phosphate
receptor modulators in multiple sclerosis and other conditions. Lancet.
2021;398:1184-1194. Lasa JS, et al. Safety of S1P Modulators in Patients with
Immune-Mediated Diseases: A Systematic Review and Meta-Analysis. Drug Saf.
2021;44:645-660. Stepanovska B, et al. Targeting the S1P receptor signaling
pathways as a promising approach for treatment of autoimmune and inflammatory
diseases. Pharmacol Res. 2020;154:104170. Barber MRW, et al. Global
epidemiology of systemic lupus erythematosus. Nat Rev Rheumatol.
2021;17:515-532. Kaul A, Gordon, et al. Systemic lupus erythematosus. Nat Rev
Dis Primers. 2016;2:16039. Davis LS, et al. Research and
therapeutics—traditional and emerging therapies in systemic lupus
erythematosus. Rheumatol. 2017;56:i100-i113. Birt JA, et al. Patient
Experiences, Satisfaction, and Expectations with Current Systemic Lupus
Erythematosus Treatment: Results of the SLE-UPDATE Survey. Rheumatol Ther.
2021;8:1189-1205. Tse K, et al. The ALPHA Project: Establishing consensus and
prioritisation of global community recommendations to address major challenges
in lupus diagnosis, care, treatment and research. Lupus Sci Med.
2021;8:e000433.
Investor webcast
An investor conference call and webcast will be held to discuss the initiation
of the Phase 3 study with cenerimod for patients with systemic lupus
erythematosus, followed by a Q&A session.
Date : T hursday , Dec ember 15 , 2022
Time: 1 5 :00 CET | 1 4 :00 GMT | 0 9 :00 EST
Dial-in procedure: Participants are required to register in advance of the
conference (link already open for registration) using the link provided below.
Upon registration, each participant will be provided with participant dial in
numbers, and a unique personal PIN. In the 10 minutes prior to the call start
time, participants will need to use the conference access information provided
in the e-mail received at the point of registering. Participants may also use
the Call Me feature instead of dialing the nearest dial in number.
Online Registration: LINK
Webcast participants should visit Idorsia's website www.idorsia.com 10-15
minutes before the webcast is due to start.
About Idorsia
Idorsia Ltd is reaching out for more – We have more ideas, we see more
opportunities and we want to help more patients. In order to achieve this, we
will develop Idorsia into a leading biopharmaceutical company, with a strong
scientific core.
Headquartered near Basel, Switzerland – a European biotech-hub – Idorsia is
specialized in the discovery, development, and commercialization of small
molecules to transform the horizon of therapeutic options. Idorsia has a broad
portfolio of innovative drugs in the pipeline, an experienced team of
professionals covering all disciplines from bench to bedside, state-of-the-art
facilities, and a strong balance sheet – the ideal constellation to translate
R&D efforts into business success.
Idorsia was listed on the SIX Swiss Exchange (ticker symbol: IDIA) in June
2017 and has over 1000 highly qualified specialists dedicated to realizing our
ambitious targets.
For further information, please contact
Andrew C. Weiss
Senior Vice President, Head of Investor Relations & Corporate Communications
Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, CH-4123 Allschwil
+41 58 844 10 10
investor.relations@idorsia.com – media.relations@idorsia.com – www.idorsia.com
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Anhang Medienmitteilung PDF
