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EP-4423126-B1 - METHODS OF TREATING CROHN'S DISEASE WITH ANTI-IL23 SPECIFIC ANTIBODY

EP4423126B1EP 4423126 B1EP4423126 B1EP 4423126B1EP-4423126-B1

Inventors

  • GERMINARO, Matthew
  • OLURINDE, Mobolaji
  • SAHOO, Aparna
  • YEE, Jacqueline
  • ADEDOKUN, Omoniyi

Dates

Publication Date
20260506
Application Date
20221027

Claims (8)

  1. An antibody specific to IL23 for use in a method of treating moderately to severely active Crohn's disease in a patient, wherein the antibody is guselkumab; and wherein the method comprises administering to the patient an initial subcutaneous dose of 400 mg of the antibody, a 400 mg subcutaneous dose 4 weeks after the initial dose and a 400 mg subcutaneous dose 8 weeks after the initial dose.
  2. The antibody for use according to claim 1, further comprising administering a dose of 100 mg or 200 mg of antibody every 4 weeks or every 8 weeks after the dose at 8 weeks after the initial dose.
  3. The antibody for use according to claim 1, further comprising administering a dose of 200 mg of antibody every 4 weeks after the dose at 8 weeks after the initial dose.
  4. The antibody for use according to claim 1, further comprising administering a dose of 100 mg of antibody every 8 weeks after the dose at 8 weeks after the initial dose.
  5. The antibody for use according to claim 1, wherein the antibody is formulated as a composition comprising 7.9% (w/v) sucrose, 4.0mM Histidine, 6.9 mM L-Histidine monohydrochloride monohydrate; and 0.053% (w/v) Polysorbate 80; wherein the diluent is water at standard state.
  6. The antibody for use according to any preceding claim, further comprising administering to the patient one or more additional drugs used to treat Crohn's disease, optionally wherein the additional drug is selected from the group consisting of: immunosuppressive agents, non-steroidal anti-inflammatory drugs (NSAIDs), methotrexate (MTX), anti-B-cell surface marker antibodies, anti-CD20 antibodies, rituximab, TNF-inhibitors, corticosteroids, and co-stimulatory modifiers.
  7. The antibody for use according to any preceding claim, wherein the patient is considered: (a) a biologic therapy failure or intolerance for Crohn's disease (Bio-Failure); or (b) a conventional therapy failure or intolerance for Crohn's disease (Con-Failure).
  8. The antibody for use according to any preceding claim, wherein the patient has: (a) endoscopic evidence of active Crohn's disease prior to administration of the initial dose; and/or (b) moderately to severely active Crohn's disease for at least three months prior to administration of the initial dose.

Description

FIELD OF THE INVENTION The present invention is directed to methods of treating Crohn's Disease with guselkumab, which is an antibody that binds human IL23. In particular, it relates to dosing regimens for administration of guselkumab and specific pharmaceutical compositions of guselkumab. BACKGROUND OF THE INVENTION Interleukin (IL)-12 is a secreted heterodimeric cytokine comprised of 2 disulfide-linked glycosylated protein subunits, designated p35 and p40 for their approximate molecular weights. IL-12 is produced primarily by antigen-presenting cells and drives cell-mediated immunity by binding to a two-chain receptor complex that is expressed on the surface of T cells or natural killer (NK) cells. The IL-12 receptor beta-1 (IL-12Rβ1) chain binds to the p40 subunit of IL-12, providing the primary interaction between IL-12 and its receptor. However, it is IL-12p35 ligation of the second receptor chain, IL-12Rβ2, that confers intracellular signaling (e.g., STAT4 phosphorylation) and activation of the receptor-bearing cell (Presky et al, 1996). IL-12 signaling concurrent with antigen presentation is thought to invoke T cell differentiation towards the T helper 1 (Th1) phenotype, characterized by interferon gamma (IFNy) production (Trinchieri, 2003). Th1 cells are believed to promote immunity to some intracellular pathogens, generate complement-fixing antibody isotypes, and contribute to tumor immunosurveillance. Thus, IL-12 is thought to be a significant component to host defense immune mechanisms. It was discovered that the p40 protein subunit of IL-12 can also associate with a separate protein subunit, designated p19, to form a novel cytokine, IL-23 (Oppman et al, 2000). IL-23 also signals through a two-chain receptor complex. Since the p40 subunit is shared between IL-12 and IL-23, it follows that the IL-12RB1 chain is also shared between IL-12 and IL-23. However, it is the IL-23p19 ligation of the second component of the IL-23 receptor complex, IL-23R, that confers IL-23 specific intracellular signaling (e.g., STAT3 phosphorylation) and subsequent IL-17 production by T cells (Parham et al, 2002; Aggarwal et al. 2003). Recent studies have demonstrated that the biological functions of IL-23 are distinct from those of IL-12, despite the structural similarity between the two cytokines (Langrish et al, 2005). Abnormal regulation of IL-12 and Th1 cell populations has been associated with many immune-mediated diseases since neutralization of IL-12 by antibodies is effective in treating animal models of psoriasis, multiple sclerosis (MS), rheumatoid arthritis, inflammatory bowel disease, insulin-dependent (type 1) diabetes mellitus, and uveitis (Leonard et al, 1995; Hong et al, 1999; Malfait et al, 1998; Davidson et al, 1998). However, since these studies targeted the shared p40 subunit, both IL-12 and IL-23 were neutralized in vivo. Therefore, it was unclear whether IL-12 or IL-23 was mediating disease, or if both cytokines needed to be inhibited to achieve disease suppression. Recent studies have confirmed through IL-23p19 deficient mice or specific antibody neutralization of IL-23 that IL-23 inhibition can provide equivalent benefit as anti-IL-12p40 strategies (Cua et al, 2003, Murphy et al, 2003, Benson et al 2004). Therefore, there is increasing evidence for the specific role of IL-23 in immune-mediated disease. Neutralization of IL-23 without inhibition of IL-12 pathways could then provide effective therapy of immune-mediated disease with limited impact on important host defense immune mechanism. This would represent a significant improvement over other therapeutic options. Currently, there are three classes of biologic agents approved for the treatment of moderately to severely active Crohn's disease: tumor necrosis factor (TNF) antagonist therapies (infliximab, adalimumab, certolizumab), integrin inhibitors (natalizumab and vedolizumab), and an IL-12/23 inhibitor (ustekinumab). Although the introduction of biologic agents has significantly improved the clinical management of patients with moderately to severely active Crohn's disease, a sizable proportion of the target patient population is non-responsive or will lose response over time. A review of the available data for approved biologic agents highlighted the unmet need in achieving and maintaining long-term remission, especially among patients who have previously failed biologic treatments. In all-treated patients (i.e., all patients who were randomized at Week 0 of the studies evaluated), the estimated rates of clinical remission at 1 year in the biologic failure or intolerance (BIO-Failure) population is around 20%, and ranges from 20% to 50% in the conventional therapy failure or intolerance (CON-Failure) population. In summary, there remains considerable unmet medical need for new treatment options, especially therapies with novel mechanisms of action that have the potential to raise the efficacy bar and maximize the proportion of patients who ac