Idorsia to advance cenerimod into Phase 3 development for treatment
of patients with systemic lupus erythematosus
Ad hoc announcement pursuant to Art. 53 LR
- Cenerimod 4 mg showed clinically meaningful improvement in the
mSLEDAI-2K* primary efficacy endpoint and other measures of
efficacy, consistent with the effect seen on biological
activity
- Effect of cenerimod 4 mg is particularly observable in patients
with high disease activity and increases over time
- Good safety profile – consistent with the mechanism of action –
across all doses
- Phase 3 program to be discussed with health authorities and
advanced as rapidly as possible
Allschwil, Switzerland –
November
01, 2021Idorsia
Ltd (SIX: IDIA) today announced that on the basis of the results
seen in CARE, the Phase 2b study which investigated the effect of
cenerimod, a novel S1P1 receptor modulator, as an oral treatment of
adult patients with moderate to severe systemic lupus erythematosus
(SLE), the company has decided to advance into Phase 3.
The CARE study equally randomized 427 adult patients with SLE on
background therapy, to cenerimod (0.5, 1, 2, 4 mg) or placebo.
Patients randomized to cenerimod 4 mg showed an improvement in the
modified-Systemic Lupus Erythematosus Disease Activity Index-2000
(mSLEDAI-2K) score compared to placebo from baseline to Month 6
(p=0.029). However, this result did not reach statistical
significance in the formal testing strategy when adjusting for
multiplicity of tests for the four doses against placebo.
The increasing improvement compared to placebo in mSLEDAI-2K
with cenerimod 4 mg over time was further supported by a consistent
improvement across several patient sub-populations, particularly in
patients with more severe disease activity; on Systemic Lupus
Erythematosus Responder Index 4 (SRI-4); and was associated with an
effect on several biological markers of disease activity.
Cenerimod was well tolerated in all treatment groups such that
similar rates of AEs were 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 adverse events 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%.
While S1P1 receptor modulators are known to transiently affect
heart rate (HR) at initiation of therapy, to potentially decrease
pulmonary function and increase blood pressure, cenerimod showed a
transient, asymptomatic, dose-dependent decrease in HR at first
dose; over the 6 months of treatment, effects on pulmonary function
could not be discerned from placebo, and there was minimal to no
effect on blood pressure.
Guy Braunstein, MD and Head of Global Clinical
Development of Idorsia, commented:“I’m very pleased to see
that the results with 4 milligrams of cenerimod, particularly the
safety profile, have confirmed the data generated in the proof of
concept study. We have seen a large effect on biomarkers of disease
activity, and this has translated into improvement on multiple
clinical measures. The six months of treatment results have
provided us with the information we need to design our Phase 3
program in SLE and to discuss with health authorities, including
the patient population, the optimal dose and endpoints. I also look
forward to seeing the results of the next treatment period of CARE,
where patients will continue to receive blinded treatment for a
further six months. A lot can be learned from the long-term
treatment data, further characterizing the efficacy, safety and
tolerability of cenerimod.”
Martine Clozel, MD and Chief Scientific Officer of
Idorsia, commented: “Cenerimod is an oral drug that offers
a completely novel approach to the treatment of SLE. It is a highly
selective S1P1 receptor modulator, with biased S1P1 receptor
signaling, which can control lymphocyte trafficking out of the
lymph nodes into the circulation. The presence of autoreactive T
cells and B cells and the subsequent production of autoantibodies
is key to the inflammation and organ damage seen in lupus. By
acting on both of these cell types and at a fundamental stage in
the autoimmune response, cenerimod has the potential to alter the
course of the disease. Furthermore, I believe that the good safety
profile we have observed, can be explained in part by the mechanism
of action and by observations we made in preclinical studies, where
cenerimod did not induce any bronchoconstriction or
vasoconstriction.”
The company will now fully analyze the data, including patient
reported outcomes showing the effect of cenerimod on quality of
life measures, and will discuss the Phase 3 program with health
authorities as soon as possible. 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.
Detailed results of CARE will be made available to the
scientific community through scientific disclosure at upcoming
congresses and in peer-reviewed publications.
Jean-Paul Clozel, MD and Chief Executive Officer of
Idorsia, concluded:“I am
very pleased to observe an oral drug given once a day with an
evolving safety profile coming up to the standards set by
biologics. As with many of our projects, Idorsia is benefiting from
our rich drug discovery and development experience, especially in
the field of S1P1 receptor modulators. Idorsia must advance the
clinical development program as fast as possible and, if the Phase
3 confirms the results with cenerimod, get this new therapeutic
option to patients with SLE.”
About CARECARE is a multiple-dose, efficacy,
safety, and tolerability study investigating cenerimod for the
treatment of adult patients with moderately to severely active,
autoantibody-positive SLE. The study assesses the efficacy and
safety of cenerimod treatment to determine the appropriate dose and
endpoints for further development in SLE. In addition, the study
evaluates the effects on quality of life and fatigue, using
patient-reported outcome instruments, as well as the effects on SLE
biomarkers. 427 patients were randomized in a 1:1:1:1:1 ratio to
either cenerimod 0.5, 1, 2, 4 mg, or placebo. After 6 months of
treatment, patients receiving cenerimod 4 mg were re-randomized in
a 1:1 ratio to either cenerimod 2 mg or placebo, while the other
treatment arms continued with the study treatment for a further
treatment period of 6 months, which is currently ongoing.* 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 total points.
Notes to the editor
About systemic 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. Some autoimmune diseases affect just one organ, but 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 S1P1
receptor modulationWhile the
cause of SLE is not fully known, T and B lymphocytes are considered
the key immune cells playing 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 (S1P1). 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 S1P1 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, it is
hypothesized that a reduction in autoantibodies and immune
cytokines – markers of the underlying disease processes – would
also be seen, ultimately further reducing inflammation and tissue
damage, key contributors to the disease.
Cenerimod in systemic lupus
erythematosusCenerimod, the result of 20 years of research
in Idorsia’s labs, is a highly selective S1P1 receptor modulator,
given 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.
In a mouse model of SLE, mice typically develop an aggressive
version of a lupus-like disease, with increased inflammation,
autoantibodies and immune cytokines, resulting in damage to the
kidney and death. When treated with cenerimod, an increase in
survival was observed. This was underpinned by improved kidney
structure and function, as well as marked decreases in important
key markers of disease.
The effect of cenerimod on lymphocyte trafficking was confirmed
in humans when administration of cenerimod induced a
dose-dependent, sustained, and reversible reduction in circulating
lymphocyte count.
In a Phase 2 proof-of-concept study investigating the effect of
cenerimod on circulating lymphocytes, disease activity, safety, and
pharmacokinetics in patients with SLE, cenerimod dose dependently
reduced total lymphocyte count from baseline to end of treatment
(p<0.001). In addition, the antibody-producing B cells, which
are elevated in patients with SLE and critical to disease
progression, were markedly reduced by cenerimod. Cenerimod was well
tolerated at all dose levels. The occurrence of adverse events was
similar in all five treatment groups.
Key Literature
- Hermann V, et al. First use of cenerimod, a selective S1P1
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 S1P1 receptor modulator, in systemic lupus
erythematosus. RMD Open. 2020;6:e001261.
- Piali L, et al. Cenerimod, a novel selective S1P1 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.
About IdorsiaIdorsia 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 contactAndrew
C. WeissSenior Vice President, Head of Investor Relations &
Corporate CommunicationsIdorsia Pharmaceuticals Ltd,
Hegenheimermattweg 91, CH-4123 Allschwil+41 58 844 10
10investor.relations@idorsia.commedia.relations@idorsia.com
www.idorsia.com
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