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OSE Immunotherapeutics Updates on Anti-IL-7 Receptor Antagonist OSE-127/S95011, a Breakthrough Approach in Chronic Inflammatory Autoimmune Diseases and Hematology

pharmafile | February 22, 2023 | News story | Business Services |

Nantes, France – February 22, 2023, 6:00 p.m. CET – OSE Immunotherapeutics SA (ISIN: FR0012127173; Mnemo: OSE) today announced the online publication in the peer-reviewed ‘The Journal of Immunology’ of positive Phase 1 clinical results with OSE-127/S95011, an anti-IL-7 receptor (IL-7R) antagonist, and provides an overall update on the product, which is being developed in immuno-inflammation through two ongoing Phase 2 clinical trials in Ulcerative Colitis (sponsor OSE) and in primary Sjögren’s Syndrome (sponsor Servier), and in hematology where promising preclinical data in Acute Lymphoblastic Leukemia (ALL) has already been reported.

OSE-127/S95011 is being developed in partnership with Servier* via a collaboration agreement. Two clinical studies evaluating OSE-127/S95011 are ongoing: a Phase 2a study conducted by Servier in primary Sjögren’s syndrome and a Phase 2 study conducted by OSE Immunotherapeutics in ulcerative colitis (UC).

Nicolas Poirier, Chief Executive Officer of OSE Immunotherapeutics, comments: “We are very pleased to have this peer-reviewed data on OSE-127 published in ‘The Journal of Immunology’. It recognizes the value of our Phase 1 data which marked an important step towards understanding the safety and efficacy of OSE-127. It confirms the interest in the novel and differentiated mechanism of action of the only full-antagonist of IL-7R for the treatment of chronic autoimmune diseases. OSE-127 is the only compound targeting IL-7R under clinical development in the primary Sjögren’s syndrome and ulcerative colitis.

Based on this strong scientific rationale, we are confident that the ongoing Phase 2 trials conducted by OSE in ulcerative colitis and Servier in primary Sjögren’s syndrome will start to establish OSE-127 as a potential new best-in-class treatment for these disabling chronic inflammatory diseases.

Patient enrolment is completed in the Phase 2a trial in primary Sjögren’s syndrome, and we are looking forward to the results that are expected in H1 2023.

Besides autoimmune diseases, OSE-127 has also demonstrated great therapeutic potential in Acute Lymphoblastic Leukemia (ALL), a very aggressive tumor arising from B or T cell precursors. Our collaboration with the University of Kiel aims at evaluating the therapeutic potential of OSE-127 in targeting and blocking the high and dysregulated IL-7 receptor-expression observed in more than 80% of B- or T-ALL patients. Relapse remains a clinical challenge in B-ALL in high-risk patients and treatment options for T-ALL remain very limited. Novel targeted immunotherapy approaches are urgently needed to meet these patients’ high medical need.”

*Servier is a global pharmaceutical group

Peer-reviewed data in ‘The Journal of Immunology’ with strong rationale for a potential new breakthrough therapeutic approach

An article, selected as ‘Top Read’ for the March 15^th issue, was published online in ‘The Journal of Immunology’ (online). The publication, entitled “First-in-Human Study in Healthy Subjects with the Non-Cytotoxic 1 Monoclonal Antibody OSE-127, a Strict Antagonist of the IL-7Rα” reports on the Phase 1 positive results. These showed a good safety and tolerability profile for OSE-127/S95011, with no signs of significant lymphopenia, cytokine release syndrome or T-cell compartment alterations. All pharmacokinetic and pharmacodynamic parameters were consistent and demonstrated a dose-proportionality across the several dose-levels up to 10 mg/kg. A decreased IL-7 pathway gene signature in human peripheral blood cells has been demonstrated confirming the efficient blockade of the target.

Enrollment completed in Phase 2a clinical trial in primary Sjögren’s syndrome (Servier)

– Patient enrollment in the Phase 2a clinical trial of OSE-127/S95011 in primary Sjögren’s syndrome conducted by Servier was completed in October 2022.

– This international, randomized, double-blind, placebo-controlled, Phase 2a study is designed to evaluate the efficacy and tolerance of the monoclonal antibody OSE-127/S95011 in primary Sjögren’s syndrome. The multicenter study in the United States, Australia and Europe includes 48 patients. Results are expected in H1 2023.

– The estimated prevalence of Sjögren’s varies from 2.5 million to 4 million patients (Sjögren’s Syndrome Foundation) in the US alone, with a worldwide estimate of up to 7.7 million in the key markets (US, France, Germany, Italy, Spain, UK and Japan) by the year 2024 (Global Data Research).

– To date there is no treatment approved in altering the course of the disease for primary Sjögren’s syndrome, a disease with significant unmet medical need, and only a few molecules are being evaluated in Phase 2/3 clinical development.

Phase 2 clinical trial in ulcerative colitis (UC) with interim analysis (OSE Immunotherapeutics)

– The randomized, double-blind Phase 2 clinical trial aims to assess the efficacy and safety of
OSE-127/S95011 versus placebo in patients with moderate to severe active UC who have previously failed or lost response or are intolerant to previous treatment(s).

– An interim futility analysis was conducted on the prespecified first 50 patients (i.e., 33% of the total patient enrollment in the study) having completed the Induction Phase. After completion of the planned safety and efficacy assessment for futility, the trial’s Independent Data Monitoring Committee (IDMC) recommended the continuation of the study.

– UC is a debilitating and chronic inflammatory bowel disease which affects 3.3 million patients in US, Europe and Japan⁽¹⁾ representing 12.2 per 100,000 people by year ⁽²⁾. Despite broad options, remission rates are only 25-30% ⁽³⁾leaving most patients without satisfactory treatments.

– UC is characterized by a heavy burden on patients’ lives with a strong medical need for new therapeutic options.

Positive preclinical efficacy data in B- and T-Cell Acute Lymphoblastic Leukemia (B- and T-ALL)

– The research program of IL-7R antagonist OSE-127 in Acute Lymphoblastic Leukemia (ALL) is being conducted through a collaborative research program between OSE Immunotherapeutics and the University Medical Center Schleswig-Holstein in Kiel (Germany). This collaboration is using patient-derived samples and in-vivo xenograft models to evaluate the therapeutic potential of OSE-127 in targeting and blocking the high and dysregulated IL-7R-expression observed in 84% of B- or T-ALL patients.

– The latest preclinical data on the use of OSE-127 for the treatment of B- and T-Cell ALL (B- and T-ALL) were presented at the American Society of Hematology (ASH) annual meeting in December 11, 2022. This oral presentation has received the merit-based “Abstract Achievement Award” from the peer-review committee. The presentation, entitled “The IL7R-Antagonist OSE-127 Blocks Acute Lymphoblastic Leukemia Development Via a Dual Mode of Action”, reported on the preclinical efficacy of OSE-127 in ALL and on the mechanism of action underlying its anti-leukemic efficacy:

. In a large prospective ALL patient cohort, IL-7R cell positivity was detected in more than 84% of cases.
. OSE-127 demonstrated preclinical in vivo efficacy as monotherapy in 96% of tested B- and T‑ALL Patient Derived Xenografts (PDXs), including samples from relapse and refractory patients.

– The American Cancer Society estimated that almost 6,660 new cases of ALL will have been diagnosed in the United States in 2022⁽⁴⁾. In Europe, 7,000 cases of ALL are diagnosed each year⁽⁵⁾.The number of patients in Japan was reported to be about 5,000 in a survey by the Japanese MHLW (Ministry of Health, Labour and Welfare) in 2017. The number of diagnosed incident cases of ALL in Europe, US, Japan and China is estimated to achieve 26,482 cases in 2029⁽⁶⁾.

A global patent protection

Given the potential of OSE-127, OSE Immunotherapeutics has strengthened its global intellectual property until 2037. This has been achieved through the grant of a large number of patents worldwide, notably in major territories including Europe, the US, China and Japan.

These patents protect anti-IL-7R antagonist OSE-127 and its therapeutic applications, in particular in autoimmune and inflammatory diseases.

(1) EvaluatePharma

(2) Updated Incidence and Prevalence of Crohn’s Disease and Ulcerative Colitis in Olmsted County, Minnesota (1970-2011). Loftus EV et al. October 2014.

(3) Drugs Context. 2019; 8: 212572 –doi: 10.7573/dic.212572

(4) American Cancer Society. Key 2022 Statistics for Acute Lymphocytic Leukemia (ALL). Available at: https://www.cancer.org/cancer/acute-lymphocytic-leukemia/about/key-statistics.html#references., accessed Oct. 2022

(5) Gatta G, van der Zwan JM, Casali P, et al. Rare cancers are not so rare: The rare cancer burden in Europe. Eur. J. Cancer. 2011; 47: 2493-2511.

(6) Global Data