WO2022187657A1 - Procédés de sélection de sous-populations de patients atteints de la maladie de crohn pouvant faire l'objet d'une thérapie par antagoniste de l'il 23 - Google Patents

Procédés de sélection de sous-populations de patients atteints de la maladie de crohn pouvant faire l'objet d'une thérapie par antagoniste de l'il 23 Download PDF

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WO2022187657A1
WO2022187657A1 PCT/US2022/018957 US2022018957W WO2022187657A1 WO 2022187657 A1 WO2022187657 A1 WO 2022187657A1 US 2022018957 W US2022018957 W US 2022018957W WO 2022187657 A1 WO2022187657 A1 WO 2022187657A1
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crohn
patients
disease
patient
cdai
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PCT/US2022/018957
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Rada M. SAVIC
Nan Zhang
Ming Liang CHAN
Jing Li
Philip Z. BROHAWN
Bo Sun
Inna Vainshtein
Lorin K. ROSKOS
Raffaella Faggioni
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Astrazeneca Collaboration Ventures, Llc
The Regents Of The University Of California
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the disclosed subject matter relates generally to methods and compositions for the medical treatment of disease and more particularly to the treatment of inflammatory bowel diseases such as Crohn's disease.
  • CD Crohn's disease
  • IBD chronic inflammatory bowel diseases
  • Treatment options include chemical steroids, immunosuppressives, such as azathioprine and methotrexate, and biologies such as infliximab, adalimumab, certolizumab, ustekinumab and vedolizumab, which have been shown to be effective for moderate to severe CD by targeting specific pathways implicated in CD 2 .
  • Patients start the treatment of CD using either a “bottom up” (set up) or “top down” approach, and therapy is individualized based on clinical presentation, medical history, prior treatments, severity of disease and the like 3-5 .
  • patients fail to respond or are intolerant to the chemical agents, those patients are switched to the alternative treatment option of biologies 3- 5 .
  • the cause of the non-response can be due to drug-related factors, such as neutralizing antibodies, altered clearance of drug or possibly biological escape mechanisms, or factors unrelated to the drug, including absence of active inflammation, concurrent infection or septic complications 6 .
  • Brazikumab (MEDI2070, AMG139) a human monoclonal antibody (mAh) under clinical development for CD, selectively targets the pl9 subunit of interleukin-23 (IL-23), a pro- inflammatory cytokine implicated in the pathogenesis of CD 14, 15 .
  • IL-23 induces the downstream production of IL-22, which is significantly increased in CD and correlates with disease activity 16 .
  • C-reactive protein is an acute phase protein produced by hepatocytes in response to inflammatory conditions, and its production is stimulated by active IBD-associated cytokines 17 .
  • PK/PD Pharmacokinetic/Pharmacodynamic
  • PK/PD Pharmacokinetic/Pharmacodynamic
  • IL23 antagonists such as the anti-IL23 monoclonal antibody brazikumab in treating Crohn's disease using CDAI as an exemplary efficacy measure.
  • CDAI Crohn's Disease Activity Index
  • the methodology provides a data-driven framework for precision therapy for Crohn's disease. In a phase 2a trial in patients with moderate to severe Crohn's disease, treatment with brazikumab was associated with clinical improvement.
  • Brazikumab treatment effect was determined to be dependent on the baseline IL- 22 (BIL22) or baseline C-reactive protein (BCRP) as predictive biomarkers, and placebo effect was found to be correlated with the baseline CDAI (BCDAI) as a prognostic biomarker.
  • a maximal inhibition (I max ) on CDAI input function of 50.6% and 42.4% was predicted for patients with extremely high BIL22 or BCRP, compared to an inhibition of 20.9% and 17.8% for patients with extremely low BIL22 or BCRP, respectively, which were mainly due to the placebo effect.
  • model-derived IB 50 baseline biomarker level that would achieve 50% of I max
  • I max baseline biomarker level that would achieve 50% of I max
  • the experiments disclosed herein exemplify the utility of pharmacometrics to quantify biomarker-driven responses in biologic therapies and distinguish between predictive and prognostic biomarkers, complementing clinical efforts to identify subpopulations with higher likelihood of response to brazikumab.
  • one aspect of the disclosure is drawn to a pharmacometric method of identifying a sub-population of Crohn's disease patients amenable to treatment with an IL23 antagonist comprising: (a) measuring a baseline level of a biomarker in a plurality of Crohn's disease patients; (b) administering an IL23 antagonist to the plurality of Crohn's disease patents;
  • the method further comprises continued administration of the IL23 antagonist to the patient if the patient has a biomarker level greater than the IB 50 , such as continuing administration of the IL23 antagonist to the patient if the patient has a biomarker level greater than 110% of the IB 50 .
  • the IL23 antagonist is an anti-IL23 antibody.
  • the anti-IL23 antibody is brazikumab, ustekinumab, briakinumab, guselkumab, risankizumab, tildrakizumab, risankizumab, NeutraKineTM IL23 p40 antibody, BI-655066, LY- 3074828, or an antigen-binding fragment thereof.
  • the anti-IL23 antibody specifically binds to the pl9 subunit of IL23 (SEQ ID NO:l), the p40 subunit of IL23 (SEQ ID NO:2), or both subunits.
  • the anti-IL23 antibody or antigen-binding fragment thereof comprises (i) a variable region (VH) comprising or consisting of SEQ ID NO: 3 (SIN5) and/or a light chain variable region (VL) comprising or consisting of SEQ ID NO: 4 (SIN6), or (ii) a variable region (VH) comprising or consisting of SEQ ID NO:5 (SIN43) and/or a light chain variable region (VL) comprising or consisting of SEQ ID NO: 6 (SIN44).
  • VH variable region
  • VL light chain variable region
  • SEQ ID NO: 6 SIN44
  • the anti-IL23 antibody or antigen-binding fragment thereof comprises at least one complementarity determining region selected from SEQ ID NOS: 7-12 (SIN31-36) or SEQ ID NOS: 13-18 (SIN45-50). In some embodiments, the anti-IL23 antibody or antigen-binding fragment thereof is brazikumab. In some embodiments, the inhibition comprises a change in the magnitude of at least one symptom of Crohn's disease. In some embodiments, the inhibition is measured using the Crohn's Disease Activity Index (CDAI).
  • CDAI Crohn's Disease Activity Index
  • the biomarker levels are measured using a patient sample selected from the group consisting of whole blood, blood serum, plasma, saliva, sputum, bronchoalveolar lavage fluid, cerebrospinal fluid, pleural fluid, pericardial fluid, ascites, synovial fluid, epithelial cells, urine, stool, skin, tissue biopsy, and a combination thereof, such as wherein the sample is a blood serum sample.
  • a patient sample selected from the group consisting of whole blood, blood serum, plasma, saliva, sputum, bronchoalveolar lavage fluid, cerebrospinal fluid, pleural fluid, pericardial fluid, ascites, synovial fluid, epithelial cells, urine, stool, skin, tissue biopsy, and a combination thereof, such as wherein the sample is a blood serum sample.
  • the biomarker is Interleukin 22 (IL22).
  • IL22 IB 50 is about 22.8 pg/ml, including embodiments wherein the IL22 IB 50 is 22.8 pg/ml.
  • the biomarker is C-reactive Protein (CRP).
  • CRP C-reactive Protein
  • the CRP IB 50 is about 8.03 mg/L, including embodiments wherein the CRP IB 50 is 8.03 mg/L.
  • the patient is switched to an alternative Crohn's disease therapy if the biomarker level of the patient is less than 110% the IB 50 , such as wherein the patient is switched to an alternative Crohn's disease therapy if the biomarker level of the patient is less than the IB 50 .
  • Another aspect of the disclosure is directed to a pharmacometric method of identifying a sub-population of Crohn's disease patients having a positive prognosis upon administration of IL23 antagonist therapy comprising: (a) measuring a baseline level of Interleukin 22 (BIL22) and/or a baseline level of C-reactive Protein (BCRP) in a plurality of Crohn's disease patients;
  • BIL22 Interleukin 22
  • BCRP C-reactive Protein
  • the percent reduction in CDAI score for the patient is greater than 20.9% for IL22 or greater than 17.8% for CRP, or both.
  • the percent reduction in CDAI score for the patient is about 50.6% for IL22 and/or about 42.4% for CRP.
  • the percent reduction in CDAI score for the patient is at least 50.6% for IL22 and/or at least 42.4% for CRP.
  • the IL23 antagonist is an anti-IL23 antibody.
  • the anti-IL23 antibody is brazikumab, ustekinumab, briakinumab, guselkumab, risankizumab, tildrakizumab, risankizumab, NeutraKineTM IL23 p40 antibody, BI-655066, LY-3074828, or an antigen-binding fragment thereof.
  • the anti-IL23 antibody specifically binds to the pl9 subunit of IL23 (SEQ ID NO:l), the p40 subunit of IL23 (SEQ ID NO:2), or both subunits.
  • the anti-IL23 antibody or antigen-binding fragment thereof comprises (i) a variable region (VH) comprising or consisting of SEQ ID NO: 3 (SIN5) and/or a light chain variable region (VL) comprising or consisting of SEQ ID NO: 4 (SIN6), or (ii) a variable region (VH) comprising or consisting of SEQ ID NO:5 (SIN43) and/or a light chain variable region (VL) comprising or consisting of SEQ ID NO: 6 (SIN44).
  • VH variable region
  • VL light chain variable region
  • SEQ ID NO: 6 SIN44
  • the anti-IL23 antibody or antigen- binding fragment thereof comprises at least one complementarity determining region selected from SEQ ID NOS: 7-12 (SIN31-36) or SEQ ID NOS: 13-18 (SIN45-50). In some embodiments, the anti-IL23 antibody or antigen-binding fragment thereof is brazikumab. In some embodiments, the inhibition comprises a change in the magnitude of at least one symptom of Crohn's disease.
  • the biomarker levels are measured using a patient sample selected from the group consisting of whole blood, blood serum, plasma, saliva, sputum, bronchoalveolar lavage fluid, cerebrospinal fluid, pleural fluid, pericardial fluid, ascites, synovial fluid, epithelial cells, urine, stool, skin, tissue biopsy, and a combination thereof.
  • the sample is a blood serum sample.
  • the patient is switched to an alternative Crohn's disease therapy if the percent reduction in maximal inhibition of CDAI score is no greater than 20.9% for patients with IL22 levels greater than 22.8 pg/ml.
  • the patient is switched to an alternative Crohn's disease therapy if the percent reduction in maximal inhibition of CDAI score is no greater than 17.8% for patients with CRP levels greater than 8.03 mg/L.
  • FIG. 1 PK and efficacy raw data profiles of subjects in Phase lb and 2a trials.
  • HV healthy volunteers
  • CD Crohn's disease patients
  • IV intravenous.
  • the PK data are stratified by the subject populations and the route of drug administration.
  • the data of HV are all from the phase lb study with three doses in total, administered once every four weeks (i.e ., Q4W), at a large dose range (70-700 mg). All of the data of CD patients with intravenous (IV) infusion at 210 mg and part of the data of CD patients with IV infusion at 700 mg are also from the phase lb study.
  • FIG. 1 Schematic Structure of Final PK and Biomarker/Efficacy Model a) BIL22- dependent efficacy model structure b) BCRP-dependent efficacy model structure.
  • the PK can be described using a two-compartment model and is linked to an indirect response model where the total inhibitory effect accounts for the contribution from a placebo effect and drug effect.
  • the drug effect depends on the baseline level of the serum IL-22 or CRP biomarker described by a hill function are the amount of brazikumab present in the central and peripheral compartments, respectively.
  • V c and V p are the volumes of distribution of the central and peripheral compartments, respectively.
  • a sc represents the amount of brazikumab administered at the subcutaneous injection site and k a and F are the first-order absorption rate constant and bioavailability, respectively.
  • CL is the clearance of brazikumab from the central compartment while Q is the intercompartmental clearance k in is input function for the CDAI scores while k out is the elimination rate.
  • CL is dependent on the gender and disease status of the subjects and V c is dependent on the gender of the subjects.
  • Figure 4 Visual predictive checks for the final population PK model and biomarker/efficacy models a) PK model visual predictive check; b) BIL22 -dependent PD model visual predictive check; c) BCRP-dependent PD model visual predictive check.
  • the PK plots are stratified by study populations and the routes of drug administration.
  • the efficacy plots are stratified by the treatment arms.
  • Figure 5. Re-sampled Relationship between the Decrease in CDAI Scores as a Function of the Baseline level of IL-22 (a) and CRP (b) based on the Efficacy Model, a) BIL22- dependent inhibitory effect; b) BCRP-dependent inhibitory effect.
  • the placebo effect is shown as the red ribbon (red line representing the typical placebo effect and shaded area representing the 90% confidence interval), while the total inhibitory effect from both the placebo effect and drug effect is shown as the blue ribbon (blue line representing the typical total inhibitory effect and shaded area representing the 90% confidence interval of the drug effect together with the typical placebo effect).
  • This confidence interval is derived from 5000 simulations using the parameters in the covariance matrix output from NONMEM.
  • FIG. 6 Statistical analysis of the difference in changes of CDAI scores at week 8 between high and low biomarker groups, a) BIL22-dependent efficacy response; b) BCRP- dependent efficacy response. The p-values are compared between the t-tests using biomarker median and model-based estimate (IB 50 ) as the cutoff for BIL22 and BCRP individually. Dash lines are the means of the changes of CDAI scores at week 8 of each biomarker subgroup.
  • Figure 7 Statistical correlation between CDAI score at baseline and placebo effect of patients with brazikumab treatment or placebo in the final BCRP-dependent efficacy model.
  • Figure 8. Shows patient disposition up to Week 24.
  • the chart summarizes the number and disposition of enrolled and randomized patients in a phase 2a study (clinicaltrials.gov identifier: NCT01714726) evaluating MEDI2070 in patients having moderate or severe CD.
  • mITT Modified Intent-to-Treat Population
  • PP per protocol
  • OL Open Label.
  • Figure 9A shows clinical efficacy at Week 8 in the Modified Intent-to-Treat Population as indicated by CDAI clinical effect, CDAI remission, and CR100.
  • Figure 9B shows clinical efficacy at Week 8 in the Modified Intent-to-Treat Population as indicated by composite end points.
  • CDAI Crohn's Disease Activity Index
  • Cl confidence interval
  • CRP C-reactive protein
  • FCP fecal calprotectin
  • p p- value.
  • Figure 11 Shows percent of patients with CDAI- 100 response over time by baseline IL22 levels.
  • IL22 LO baseline IL22 ⁇ 15.6 pg/mL;
  • IL22 HI baseline IL22>5.6 pg/mL.
  • Cl confidence interval.
  • 116 patients had evaluable baseline IL22 values.
  • Patients with baseline serum IL22 levels >15.6 pg/mL had a statistically significant increased CDAI- 100 response compared to placebo at week 8.
  • Figure 12 Shows percent of patients with CDAI- 100 response over time by baseline LCN2 Levels.
  • LCN2 LO baseline LCN2 less than 215 ng/mL;
  • LCN2 HI baseline LCN2 of at least 215 ng/mL. Cl, confidence interval.
  • Figure 13A-C show the differential clinical response rate between subjects treated with MED 12070 compared to placebo as measured by: (Figure 13A) the difference between the percentage (%) of subjects achieving a CDAI score less than 150 or a reduction in CDAI score of greater than 100); ( Figure 13B) the difference between the percentage (%) of subjects achieving a 100-point improvement in CDAI score; or ( Figure 13C) the difference between the percentage (%) of subjects achieving a CDAI score less than 150 or a reduction in CDAI score greater than 100, + also achieving a greater than 50% reduction in either FCP or CRP compared to baseline FCP or CRP, respectively, between subjects treated with MED 12070 and placebo at Week 8 as a function of baseline IL22 and LCN2 levels.
  • Clinical Response rates are reported as the delta or difference between the rate observed for MEDI2070-treated subjects and the rate observed for subjects treated with placebo ("Response Rate Differential").
  • Response Rate Differential For the set of baseline values of IL22 or LCN2 across the entire study population, each distribution was divided into 10 levels, or deciles, such that each of the 11 analyte cut-offs (noted as “quantile” in Figure 13A-C) progressively segmented the study population into groups with 10% less of the total study population.
  • Subjects with high levels of IL22 or LCN2 had greater clinical response rate differences from placebo (irrespective of which of the three different clinical response measurements was used) compared to the IL22 or LCN2 low subjects (including, e.g., subjects with IL22 or LCN2 levels at the 1 st or 2 nd deciles (0.1 or 0.2 quantiles)).
  • IL22 or LCN2 low subjects including, e.g., subjects with IL22 or LCN2 levels at the 1 st or 2 nd deciles (0.1 or 0.2 quantiles).
  • Figure 14 Shows percent reduction from baseline in serum IL22 levels in MEDI2070 and placebo groups. Error bars represent median absolute deviation (MAD). Compared to treatment with placebo, treatment with MED 12070 was associated with a significantly greater drop in serum IL-22 levels by Week 8. "N" corresponds to the number of subjects at week 0.
  • Figure 15 Compares the differential clinical response rate (defined as the difference in the percentage (%) of subjects achieving a CDAI-100 response between treatment and placebo ("CDAI Response Delta vs. Placebo")) (y axis) and the differential clinical remission rate (defined as the difference in the percentage (%) of subjects achieving a total CDAI score of below 150 points between treatment and placebo ("CDAI Remission Delta vs. Placebo”)) (x axis) for patients treated with various molecules administered for 4-10 weeks, as shown.
  • CDAI Response Delta vs. Placebo the differential clinical remission rate
  • a phase 2a clinical study was conducted to investigate the efficacy of brazikumab, where an association between baseline serum IL-22 levels (BIL22) and the therapeutic effect of brazikumab was found: higher BIL22 levels were associated with an increased likelihood of response compared to placebo, suggesting that BIL22 may be a potential predictive biomarker to select the patients who most likely will benefit from brazikumab treatment 14 .
  • BIL22 baseline serum IL-22 levels
  • placebo placebo
  • BIL22 may be a potential predictive biomarker to select the patients who most likely will benefit from brazikumab treatment 14 .
  • CDAI Crohn's Disease Activity Index
  • CDAI scores of less than 150 indicate a clinical remission or inactive disease and scores over 450 indicate severely active disease.
  • patients with high BCDAI >292
  • had low response in both treatment and placebo arms p-value ⁇ 0.05
  • BCDAI BCDAI-associated adalimumab
  • adalimumab BCDAI-associated adalimumab
  • the need for a more frequent dosing of adalimumab was discussed 9 .
  • the underlying relationship of BCDAI and treatment response has not been quantitatively studied.
  • a quantitative relationship between BCDAI and therapeutic effect and/or disease progression is required to demonstrate the role of BCDAI as a predictive or prognostic factor.
  • Precision medicine as one of the five challenges to IBD research, is designed to utilize specific clinical and biological characteristics to predict the course of disease development and treatment outcome in order to optimize clinical care 20 .
  • the precision medicine approach involves stratifying patients into distinct subgroups using the clinical or biological characteristics and determining the optimal treatment strategies 15 . Therefore, identifying such clinical or biological characteristics and determining the optimal cutoff to stratify patients can be critical in the process of drug development and clinical practice.
  • this work demonstrates that pharmacometrics can be used to quantitatively evaluate potential predictive and prognostic biomarkers for biologic therapies for CD. Optimization of the biomarker cutoffs by pharmacometric analysis potentially will increase the power of detecting the efficacy of brazikumab, improve the probability of clinical trial success and accomplish the precision medicine objective of identifying the patients likely to benefit from treatment.
  • phase lb study was a randomized, double-blind, placebo-controlled, sequential multiple- ascending- dose design in 34 subjects.
  • the study was designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and effects on disease activity of brazikumab.
  • Investigational product doses ranged from 70 mg to 700 mg; routes of administration were subcutaneous (SC) injections or intravenous (IV) infusion. Extensive sampling was conducted after the first and third dose.
  • the phase 2a study was a two-part study comprising a 12-week, double-blind, placebo- controlled, treatment period followed by a 100- week, open-label, treatment period to evaluate the short-term efficacy and the short- and long-term safety of brazikumab in 119 patients with moderate to severe, active CD who have failed or are intolerant to anti-TNFoc therapy.
  • Placebo or 700 mg of brazikumab was administered as an IV infusion over a period of at least 60 minutes on day 1 and day 29 during the 12-week induction period, while subjects enrolled in the open- label period received SC injections of 210 mg brazikumab once every four weeks (i.e., Q4W) from week 12 through week 112. Sparse sampling was conducted before or after the dose during both the double-blinded and open-label periods 14, 15 .
  • the population efficacy model was built using collected data from the double-blind placebo-controlled period of the phase 2a trial.
  • An indirect response (IDR) model with inhibition or stimulation was investigated as a potential model to describe the longitudinal CDAI score data.
  • the temporal relationship of the placebo effect was explored using a linear, step or mono-exponential decay function.
  • a sigmoidal function was used to investigate the potential biomarker level-dependent drug effect.
  • VPCs Visual Predictive Checks
  • CDAI Crohn's Disease Activity Index
  • PK/biomarker/efficacy model The Crohn's Disease Activity Index (CDAI) is the main efficacy endpoint used in the PK/biomarker/efficacy model.
  • CDAI is a widely used measurement to evaluate CD activity since it was developed in the late 1970s 8 .
  • Clinicians will give a weighted score on 8 aspects of an individual patient, such as whether the patient had abdominal pain or used anti-diarrheal drugs and hematocrit and body weight and the total score - the CDAI score - indicates the severity of disease in the patient.
  • the following cut-offs have been used: Below 150 for CD patients who are in remission, 150-219 for mild activity, 220-450 for moderate activity, and above 450 (to about 600) as severe disease.
  • CDAI had been the gold standard for evaluating disease activity and most frequently used in clinical trials 9 until recently where patient-reported outcomes are reportedly being increasingly favored by the US Food and Drug Administration (FDA) as primary endpoints in clinical trials of IBD 10 .
  • FDA US Food and Drug Administration
  • PK samples were assayed using a validated ECL immunoassay method with a lower limit of quantitation (i.e., LLOQ) of 12.5 ng/mL. The quantitative range was 12.5 to 12,800 ng/mL.
  • LLOQ lower limit of quantitation
  • study samples were added to a plate that had been passively coated with a mouse anti-brazikumab monoclonal antibody. After capture of brazikumab to the immobilized antibody, unbound materials were removed by a wash step. Ruthenium-labelled mouse anti- brazikumab monoclonal antibody was added for detection of captured brazikumab.
  • a tripropylamine read buffer (MSD ® , MD) was added to the buffer to enhance the electro-chemi-luminescent signals (ECL counts).
  • ECL counts were directly proportional to the amount of brazikumab bound by the capture reagent.
  • the conversion of ECL counts for study samples to concentrations was performed using Watson LIMS (v7.3.0.01, Thermo Lab Systems, Inc., PA, USA) data reduction software.
  • IL-22 samples were assayed using a quantitative ELISA-based immunoassay method with quantifiable range from 10 pg/mL-800 p/mL in 100% serum. The assay is reproducible and precise. Briefly, A mouse monoclonal antibody specific to human IL-22 was pre-coated onto a microplate. Standards, controls, and samples were added to the wells and allowed to incubate. Following a wash step, horseradish peroxidase-conjugated (i.e., HRP-conjugated) monoclonal antibody specific to human IL-22 was added to each well and allowed to incubate. IL-22 protein was bound by the immobilized antibody and the HRP-conjugated monoclonal antibody.
  • HRP-conjugated horseradish peroxidase-conjugated
  • Serum CRP concentration were measured using the immunoturbidimetric high sensitive assay (Roche Integra) with upper limit of normal of 3.00 mg/L. This method has been approved by the PDA for clinical use and the details of the assay method 24 are incorporated herein by reference. Modeling Inter-individual Variabilities
  • the population PK analysis included data pooled from a total of 34 subjects from the phase lb study and 119 subjects from the phase 2a study, whereas the biomarker/efficacy analysis included only data from the phase 2b study of brazikumab.
  • the demographics of the study population are summarized in Table 1. Briefly, among all 34 subjects (4 females and 30 males) in the phase lb study, 4 subjects had mild to severe CD, while the remaining 30 subjects were healthy volunteers (HV). For the phase 2a study, all the subjects (74 females and 45 males) had moderate to severe, active CD who failed or were intolerant to anti-TNFa therapy.
  • N Number of subjects; %: percent of the total subjects; NA: not available; ND: not determined; FCP: Fecal Calprotectin; LCN2: Lipocalin-2; MIP3A: Macrophage inflammatory protein-3
  • a c and A p are the amount of brazikumab present in the central and peripheral compartments, respectively;
  • V c and V p are the volumes of distribution of the central and peripheral compartments, respectively; Asc represents the amount of brazikumab administered at the subcutaneous injection site; k a and F are the first-order absorption rate constant and bioavailability respectively;
  • CL is the clearance of brazikumab from the central compartment
  • brazikumab is a monoclonal antibody specifically binding to IL-23 and blocking the binding of IL-23 to its receptor
  • IDR indirect response
  • CDAI is the CDAI score over time; k in is zero-order input rate; k out is first-order elimination rate;
  • I total is total inhibitory effect accounting for the placebo effect and/or the drug effect, for the data from only placebo arm, I total is fixed as 0;
  • HL is the half-life to describe the remission rate.
  • BIL22, BCRP and BCDAI were the three biomarkers identified based on the screening criteria.
  • Final models included BCDAI- correlated placebo effect plus BIL22- or BCRP-dependent drug effect ( Figure 2).
  • a linear function was used to describe the relationship between BCDAI and model-estimated placebo effect (p-value ⁇ 0.01, Figure 3, Figure 7), while a sigmoidal function was used to describe the relationships between BIL22 or BCRP and drug effect (Eq. 5).
  • I max is the maximum inhibition of baseline biomarker level on the CDAI production rate caused by the drug effect
  • IB 50 is the baseline level of biomarker that would achieve 50% of l max', ⁇ is the hill coefficient to describe the steepness of the biomarker-dependent drug effect;
  • CB is the baseline biomarker level of BIL22 or BCRP.
  • the typical values of maximal inhibition (I max ) on k in caused by drug effect was 29.7%
  • the biomarker level achieving 50% maximal inhibition ⁇ IB 50 ) was 22.8 pg/mL
  • the steepness of the sigmoidal curve ( ⁇ ) was 20 (fixed in the final model due to large uncertainty in the initial model estimation).
  • the typical values of I max , IB 50 and ⁇ were 24.6%, 8.03 mg/L and 2.07 (fixed in the final model due to large uncertainty in the initial model estimation), respectively.
  • the biomarker/efficacy relationship parameters in the final models were estimated with good precision, with relative standard error (RSE) of no more than 30%.
  • RSE relative standard error
  • the absolute change of CDAI scores from week 0 to week 8 shows a statistically significant difference between high and low biomarker groups for both BIL22 (high group vs low group: -169.8 (60% relative standard deviation (RSD)) vs -72.3 (137% RSD), p-value ⁇ 0.01) and BCRP (high group vs low group: - 131.5 (71% RSD) vs -29.9 (396% RSD), p-value ⁇ 0.01).
  • a Phase 2a study was conducted to evaluate the efficacy and safety of multiple IV doses of MED 12070 (700 mg) or placebo administered on Week 0 (Day 1) and Week 4 (Day 29) during an initial 12-week treatment period in subjects with moderate to severe CD who have failed or are intolerant to anti-TNFa therapy.
  • the following clinical trial protocol was carried out in human patients. Results of the clinical trial are presented in Example 5.
  • the Phase 2a study evaluated the efficacy and safety of multiple IV doses of MEDI2070 (700 mg) or placebo administered on Week 0 (Day 1) and Week 4 (Day 29) during an initial 12-week treatment period in subjects with moderate to severe CD who failed or are intolerant to anti-TNFa therapy.
  • a 100-week, open-label, treatment period was included to allow evaluation of the long-term safety of MED 12070 (administered at 210 mg SC Q4W) and to provide information on PK and efficacy data.
  • the primary objective of this study was to evaluate the efficacy of MEDI2070 versus placebo to induce a clinical effect (defined as at least a 100-point reduction in CDAI from baseline) or remission (defined as CDAK150)) at Week 8 in subjects with moderate to severe CD.
  • Secondary objectives of this study included evaluating: the efficacy of MEDI2070 versus placebo in achieving CDAI remission at Week 8; the effect of MEDI2070 versus placebo in achieving at least a CDAI 100-point reduction from baseline at Week 8; the effect of MEDI2070 versus placebo in achieving at least a CDAI 70-point reduction from baseline at Week 8; the effect of MEDI2070 versus placebo in achieving CDAI remission or at least a CDAI 100-point reduction from baseline at Week 12; the effect of MEDI2070 versus placebo on the change from baseline in CDAI at Week 8; the safety and tolerability of MEDI2070; and the PK and immunogenicity (IM) of MED 12070.
  • IM immunogenicity
  • Exploratory objectives of this study included evaluating: the effect of MEDI2070 on other measures of clinical effect including but not limited to CDAI response, change from baseline in CDAI at other timepoints, and sustained CDAI response; the effect of treatment on inflammatory markers in blood and stool; the predictive value of blood or fecal biomarkers with respect to subject response to MED 12070; and the effect of MEDI2070 on Patient Reported Outcomes (PROs).
  • Subjects at various centers worldwide were randomized in a 1:1 ratio to initially receive a fixed IV dose of MED 12070 (700 mg) or placebo on Week 0 (Day 1) and Week 4 (Day 29) during the 12-week, double-blind, placebo-controlled, treatment period.
  • subjects At the completion of the double-blind, placebo-controlled, treatment period (Week 12), subjects had the option to enter a 100- week, open-label, treatment period where they received open-label MEDI2070 (210 mg SC) Q4W (Week 12 through Week 112) as described in Figure 8 .
  • MEDI2070 or placebo was administered as an IV infusion over a period of at least 60 minutes via an infusion pump on Week 0 (Day 1) and Week 4 (Day 29).
  • Subjects who completed the 12-week, double-blind, placebo-controlled, treatment period and entered the 100- week, open-label, treatment period received MEDI2070 at a fixed dose of 210 mg SC injection Q4W for 26 doses (through Week 112).
  • the primary analysis of the study was conducted after the last subject in the study completed the 12-week, double-blind, placebo-controlled, treatment period or was withdrawn from the study prior to completing the 12-week, double-blind, placebo- controlled, treatment period.
  • the doses of MED 12070 in this study were 700 mg IV Q4W in the 12-week, double- blind, placebo-controlled, treatment period (Weeks 0 and 4) and 210 mg SC Q4W in the 100- week, open-label, treatment period (Week 12 to Week 112).
  • MEDI2070 predicted a greater than 99% mean suppression of plasma IL23 throughout the duration of the study for both the 700 mg IV and 210 mg SC dosing regimens. Furthermore, (potency-corrected) serum concentrations of MEDI2070 at these dosing regimens were predicted to be higher than those of the anti-IL12/23p40 antibody ustekinumab shown to be efficacious in CD (Sandbom et al. Gastroenterol. 135:1130-41 (2008)). Administration of 700 mg IV was predicted to rapidly achieve steady-state target suppression.
  • MEDI2070 was administered by subcutaneous (SC) injection during the 100-week, open-label, treatment period. Each SC dose was administered to the subject's anterior abdominal wall by an experienced and qualified staff member. Each SC injection was no more than 1.0 mL in volume (i.e., 3x1.0 mL injections for the 210 mg SC dose). As the MEDI2070 dosage volume exceeds 1.0 mL, the dose was equally divided in 3 syringes and administered as multiple SC injections on alternating (left or right) sites on the subject's anterior abdominal wall with no more than approximately 30 seconds of time between each injection and at a distance of at least 2 cm apart.
  • SC subcutaneous
  • CDAI The CDAI is the oldest and most widely used of several multi-item instruments that have been developed and is validated for use in clinical studies to measure disease activity in CD (Best et al. Gastroenterology 70:439-44 (1976); Sands et al. N Engl J Med. 350(9):876-85 (2004)).
  • the CDAI measures the severity of active disease using symptom scores that are monitored over the previous week and includes patient-reported symptoms, physician-assessed signs, and laboratory markers.
  • the CDAI score is calculated by summing weighted scores for subjective items (number of liquid or very soft stools, abdominal pain and general well-being) recorded by a diary during a 1-week period, and objective items (associated symptoms, taking anti-diarrheals such as loperamide/opiates, abdominal mass, hematocrit, daily morning temperature, and body weight).
  • the CDAI scores range from 0 to 600, with higher scores indicating greater disease activity. Subjects with scores less than 150, 150 to 219, and 220 to 450 represent remission, mild disease, and moderate to severe disease, respectively, whereas subjects with scores greater than 450 have very severe disease (Buxton et al. Value Health. 10:214-20 (2007)).
  • the CDAI was calculated at the site in order to determine the eligibility for the study. For statistical analysis, CDAI for all visits was also calculated.
  • IBDQ Inflammatory Bowel Disease Questionnaire
  • the IBDQ has been frequently used in drug approval applications to assess treatment efficacy in IBD.
  • the IBDQ was designed to be self-administered and completed in 5 minutes.
  • the primary endpoint of the study was CDAI response at Week 8, defined by either a CDAI score greater than 150 or a CDAI reduction from baseline of at least 100 points. Baseline was defined as the latest non-missing observation prior to first administration of the investigational product.
  • Missing data were imputed by non-responder imputation approach; i.e., any subject with missing information on primary endpoint was assumed to be a non-responder.
  • subjects with a clinically meaningful increase in steroid use were assumed to be a non-responder for the primary analysis perspective.
  • a sensitivity analysis was performed by adjusting for baseline CDAI score and/or other baseline covariates by extending the model planned above for subjects in mITT population.
  • a mixed effect longitudinal logistic regression model was implemented on the observed responses. This logistic random- effect model includes a random intercept to account for the variability between subjects. Fixed categorical effects include stratification factor, treatment, visit, and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline score.
  • a sensitivity analysis was performed by adjusting for baseline CDAI score and/or other baseline covariates by extending the model planned above for subjects in the PP Population.
  • Secondary Endpoints included: 1) CDAI remission at Week 8, as defined by a CDAI score less than 150; 2) A reduction of at least 100 points from baseline in CDAI at Week 8; 3) A reduction of at least 70 points from baseline in CDAI at Week 8; 4) CDAI response (either remission defined by CDAI less than 150 or a CDAI reduction from baseline of at least 100 points from baseline) at Week 12. Secondary endpoints 1, 2, 3, and 4 were analyzed in a similar way to the primary endpoint. In addition, a sensitivity analysis was performed by carrying forward the last response on or before the Week 8 visit to Week 12 for subjects who had increased steroid (defined as 5 mg/day prednisolone, or equivalent, or 3 mg/day budesonide).
  • MEDI2070 Subjects randomized to placebo with at least one dose of MEDI2070 were included in the active arm; also the subjects randomized to the MED 12070 arm without any active dose were included in the placebo arm.
  • the Medical Dictionary for Regulatory Activities (MedDRA) was used to code all AEs. Treatment-emergent AEs were defined as any AE with onset on or after the administration of the first dose of investigational product up to and including 36 weeks post-last dose. 7)
  • IM immunogenicity
  • phase 2a study (clinicaltrials.gov identifier: NCT01714726) described in Example 4 included a 12- week, double-blind, placebo-controlled treatment period followed by a 100- week open-label treatment period to evaluate short-term efficacy and short- and long-term safety of MEDI2070 in patients with active moderate to severe Crohn's disease who failed prior anti- TNFa therapy. Conducted at 60 centers worldwide, the study included adults aged 18 to 65 years diagnose with ileal, ileo-colonic, or colonic Crohn's disease for at least 6 months.
  • Patients must have received at least one anti-TNFa therapy at approved doses for Crohn's disease, with primary nonresponse (signs and symptoms of active disease, despite at least 1 induction regimen, including at least 2 doses of anti-TNF-a therapy at least 2 weeks apart) or secondary nonresponse (recurrence of symptoms of persistently active disease during maintenance anti-TNFa therapy following initial clinical benefit) or intolerance (including but not limited to infusion-related reaction, demyelination, congestive heart failure, or infection).
  • primary nonresponse signals and symptoms of active disease, despite at least 1 induction regimen, including at least 2 doses of anti-TNF-a therapy at least 2 weeks apart
  • secondary nonresponse recurrence of symptoms of persistently active disease during maintenance anti-TNFa therapy following initial clinical benefit
  • intolerance including but not limited to infusion-related reaction, demyelination, congestive heart failure, or infection.
  • Exclusion criteria included having an allogeneic bone marrow transplant or cell-based transplantation; short-bowel syndrome; obstructive stricture within 3 months of study; bowel surgery within 12 weeks of study; ileostomy or colostomy; a clinically significant concomitant disease; or prior treatment with a biologic agent targeting IL12 or IL23.
  • washout of other prior therapies was required, including infliximab for 8 weeks before study, adalimumab or certolizumab for 10 weeks, natalizumab for 12 weeks; cyclosporine, mycophenolate mofetil, sirolimus, thalidomide, or tacrolimus for 4 weeks; intravenous or intramuscular corticosteroids for 2 weeks; or topical mesalamine or rectal corticosteroids for 2 weeks.
  • Concomitant use of 5-aminosalicylates and glucocorticosteroids was permitted if doses were stable for at least 2 weeks before randomization and remained stable through week 8.
  • immunomodulators e.g., azathioprine
  • azathioprine was permitted if the dose remained stable from 8 weeks before randomization through week 8.
  • Use of oral antibiotics for Crohn's disease, probiotics, and antidiarrheals were allowed.
  • the primary outcome measure was the proportion of patients achieving clinical effect, defined as at least a 100-point CDAI score reduction from baseline or CDAI score less than 150 at week 8.
  • Secondary measures included the proportion of patients achieving CDAI remission (defined as CDAI score lower than 150) at week 8, at least a 100-point CDAI score reduction (CR100) from baseline at week 8, at least a 70-point CDAI score reduction (CR70) from baseline at week 8, clinical effect at week 12, CDAI remission at week 12, and the safety and tolerability of MEDI2070, including adverse events, serious adverse events, and significant changes in laboratory values and vital signs. Serum MEDI2070 concentrations and the presence of ADAs were evaluated at baseline, week 4, week 8, week 12, week 24, and end of study.
  • Exploratory outcome measures included inflammatory markers in the blood and stool (CRP and FCP), responses of other biomarkers and their predictive value for clinical effects, sustained clinical effect between weeks 8 and 24, and sustained CDAI remission assessed at weeks 8 and 24.
  • Biomarker assessments included changes in IL22 serum levels (expressed in high levels in Crohn's disease patients and a marker of disease activity [Schmechel et al., Inflamm Bowel Dis, 14:204-212 (2008)]) from baseline after treatment with MEDI2070 versus placebo at weeks 8 and 12; association of change from baseline in IL22 levels with clinical effect and CDAI remission after treatment with MEDI2070 versus placebo at weeks 8 and 12; and assessment of higher IL22 serum levels at baseline as a predictor of clinical effect and CDAI remission after treatment with MEDI2070 compared with placebo at weeks 8 and 12.
  • the modified intent-to-treat population included all randomized patients who received at least one dose of study treatment during the double-blind period.
  • the safety population comprised patients who received any study treatment during the double-blind period.
  • the per- protocol population included patients who received all treatment doses and had no major protocol deviations.
  • the open-label population included all patients who received at least 1 dose of MEDI2070 during the open-label period.
  • Clinically meaningful increase in steroid dose was defined as an increase of at least 5 mg/day for at least 3 days of prednisone or equivalent, or an increase of at least 3 mg/day for at least 3 days of budesonide. Missing data for continuous measures were handled using the inverse probability weighting generalized estimating equations method, adjusting for prior anti-TNFa agent use. [0094] Pharmacokinetic data were summarized. Exploratory analyses were performed for patients in the open-label period. Efficacy data from the double-blind and open-label periods up to week 24 for these patients were combined and reported by treatment arms in the double-blind period.
  • the proportion of patients in the placebo/MED 12070 group achieving both composite end points at week 24 was similar to those in the MEDI2070/MEDI2070 group.
  • changes from baseline in FCP and CRP levels were maintained between weeks 12 and 24; in the placebo/MED 12070 group, decreases in FCP and CRP levels were observed between weeks 12 and 24.
  • Treatment-emergent adverse events were observed in 67.3% of patients in the MED 12070 group and 65.4% of those in the placebo/MED 12070 group, with treatment- related adverse events observed in 25.0% and 21.2% of patients, respectively.
  • Treatment- emergent adverse events of at least grade 3 severity occurred in 13.5% of patients in the MEDI2070 group and 3.8% of patients in the placebo/MEDI2070 group; serious adverse events were observed in 15.4% and 7.7% of patients, respectively.
  • Anti-drug antibodies were detected in two of 119 patients. One patient receiving MEDI2070 had anti-drug antibodies at baseline, but not in subsequent assessments. The other patient, who received placebo during the double -blind period, had anti-drug antibodies at week 24.
  • Clinical efficacy was consistent with the biologic effects observed with MEDI2070.
  • Patients in the MEDI2070 group had greater decreases from baseline in FCP and CRP relative to placebo.
  • the beneficial effects of MEDI2070 on FCP and CRP are remarkable given that this patient population was previously heavily treated with anti-TNF-a therapies; more than 65% of patients had received two or more prior anti-TNFa agents.
  • MEDI2070 was well tolerated, with rates of treatment-emergent adverse events, grade 3 or greater adverse events, serious adverse events, and discontinuations owing to treatment- emergent adverse events similar to those of placebo at 12 weeks. Rates of serious or severe infections were less than 10% in the MED 12070 group at week 12. At week 24, overall rates of treatment-emergent adverse events were similar between the MEDI2070 and placebo/MEDI2070 groups; rates of grade 3 or greater adverse events and serious adverse events were numerically greater in the MEDI2070 group versus the placebo/MEDI2070 group (13.5% vs. 3.8% and 15.4% vs. 7.7%, respectively), as were rates of discontinuations attributable to treatment- emergent adverse events (9.6% vs. 3.8%, respectively). Rates of serious or severe infections were the same in both treatment groups at 24 weeks (13 events). One patient had anti-drug antibodies at baseline; presumably, this was a false-positive result and was not detected on follow-up assessment.
  • MEDI2070 is specific for IL23 and does not inhibit IL12.
  • IL22 expressed at high levels in Crohn's disease, is an effector cytokine that supports mucosal barrier integrity and is an indicator of IL23 axis activity [Schmechel et al., Inflamm Bowel Dis, 14:204- 212 (2008)]. Serum IL22 levels were reduced in the MEDI2070 group compared with the placebo group. Additionally, baseline serum IL22 levels greater than or equal to 15.6 pg/mL were associated with an increased likelihood of clinical effect in the MEDI2070 group, whereas MEDI2070-treated patients with baseline IL22 levels less than 15.6 pg/mL had CR100 responses similar to those in the placebo group.
  • MED 12070 treatment demonstrated consistently robust efficacy, with an acceptable safety profile in patients with Crohn's disease who failed prior anti-TNFa therapies.
  • IL23 is expressed primarily from activated dendritic cells and macrophages (see Gaffen et al (2014) Nature Revs Immunol 14: 585-600; Oppmann et al (2000) Immunity 13: 715-251) and acts directly on a variety of hematopoietic cell types including Thl7, Th22, yo T cells and innate lymphoid cells (ILCs) to induce cytokines including IL22, IL21, IL17A, IL17F, IF17A/F, TNF alpha and GM-CSF (see, e.g., Gaffen et al (2014) Nature Revs Immunol 14:585-600; Zheng et al (2007) Nature 445: 648-51; El-Behi et al (2011) Nature Immunol 12: 568-575).
  • IL23-induced IL22 can stimulate IL22-receptor expressing epithelial cells and keratinocytes to secrete antimicrobial proteins such as LCN2 (Sonnenberg et al (2010) Adv Immunol 107: 1-29; Stallhofer et al (2015) Inflamm Bowel Dis 2015 Aug. 7; Behnsen et al (2014) Immunity 40:262-73).
  • the CDAI response rate at week 8 (as measured by the percentage (%) of subjects achieving a CDAI score less than 150 or a reduction in CDAI score of greater than 100) in those subjects exposed to MEDI2070 and with baseline IF-22 levels of at least 12.7 pg/mF, i.e., above the 4th decile, was 58.3%.
  • subjects with high levels of IL22 had greater clinical response rate differences from placebo (irrespective of which of the three different clinical response measurements was used) compared to the IL22 low subjects (including, e.g., subjects with IL22 levels at the 1st or 2 nd deciles (0.1 or 0.2 quantiles)).
  • IL22 low subjects including, e.g., subjects with IL22 levels at the 1st or 2 nd deciles (0.1 or 0.2 quantiles)
  • Figure 13A-C These IL22-high subjects also had increased CDAI response rates compared to all comers treated with MED 12070 (see, e.g., Figure 15).
  • the CDAI response rates and CDAI remission rates observed in IL22-high subjects treated with MEDI2070 in the Phase 2a study are amongst the highest clinical response rates to biologies therapy for CD reported to date.
  • the CDAI- 100 response rate differential (defined as the difference in the percentage (%) of subjects achieving a CDAI- 100 response between treatment and placebo) and/or CDAI remission rate differential (defined as the difference in the percentage (%) of subjects achieving a reduction in total CDAI score to below 150 points between treatment and placebo) achieved in patients having elevated baseline serum IL22 treated with MED 12070 for 8 weeks were highly increased compared to the published CDAI- 100 response and/or CDAI remission rates of patients treated with a number of other compounds currently approved or under development to treat CD including: Ustekinumab (response rates after 6 weeks or 8 weeks of treatment with a 6 mg/kg dose as reported in Figure 1 of Sandbom et al., N Engl J Med
  • Vedolizumab (response rates after 6 weeks or 10 weeks of treatment as reported in Figure 3 of Sands et. al., Gastroenterology. 2014 September; 147 (3): 618-627); or Adalimumab (response rates after 4 weeks of treatment in patients who are secondary failures to infliximab as reported in Sandborn et. al, Ann Intern Med. 2007; 146:829-838).
  • CDAI-100 response rate differential (“CDAI Response Delta vs. Placebo")
  • Placebo achieved in patients treated with MED 12070 for 8 weeks who had a baseline CRP of at least 5 mg/L; baseline IL-22 of at least 11.3 pg/mL; baseline IL-22 of at least 15.6 pg/mL; or baseline IL-22 of at least 11.3 pg/mL + CRP of at least 5 mg/L (as measured by IL22 immunoassay) were greater than the reported CDAI-100 response rate differential and/or the CDAI remission rate differential for Ustekinumab, Vedolizumab and Adalimumab reported in Figure 15.
  • MEDI2070 having increasingly higher levels of baseline LCN2 achieved higher clinical response rates (as measured using any of the three different clinical response measurements shown in Figure 13A-C) at week 8 compared to placebo, supporting the position that MEDI2070 induced better clinical responses in patients with high baseline LCN2 serum levels.
  • LCN2-high subjects including, e.g., subjects with LCN2 levels at the 5th 6th or 7th deciles (0.5, 0.6 or 0.7 quantiles)
  • had greater clinical response rate differences from placebo irrespective of which of the three different clinical response measurements was used
  • the LCN2 low subjects including, e.g., subjects with LCN2 levels at the 1st or 2 nd deciles (0.1 or 0.2 quantiles)).
  • IL22 serum levels and/or high LCN2 serum levels can be used to identify a patient having an IL23- mediated disease or disorder suitable for treatment with an IL23 antagonist (including, e.g., an anti-IL23 antibody or fragment thereof such as MED 12070).
  • an IL23 antagonist including, e.g., an anti-IL23 antibody or fragment thereof such as MED 12070.
  • IL23-induced IL22 induces cells to secrete LCN2.
  • baseline serum levels of two separate IL23 pathway members i.e ., elevated IL22 or LCN2
  • MEDI2070 e.g., CDAI-100 Response Rate at week 8
  • other IL23 pathway biomarkers may also predict an increased likelihood of clinical effect in response to treatment with MEDI2070.
  • serum baseline levels of IL22 and/or LCN2 or any other IL23 pathway analyte including, e.g., CCL20, IL17F, IL17A/F, IL23R, IL12B, IL6, IL21, TNF, CCR6, CCL22,
  • IL1R1, IFN-y, S100A12, DEFB-2, DEFB-4, IF1, SERPINB3, PI3/Elafin, LL37, RORy, RORyT, IL26, S100A7, DEFB103B, or GM-CSF reflects increased IL23 axis activity
  • a patient determined to have increased IL23 pathway activity is expected to be more likely to benefit from treatment with an IL23 antagonist (including, e.g., an anti-IL23 antibody or an antigen-binding fragment thereof such as MEDI2070).

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Abstract

La présente divulgation fournit des procédés pharmacométriques basés sur des modèles incorporant des données pharmacocinétiques et pharmacodynamiques pour identifier les patients atteints de maladies inflammatoires de l'intestin, tels que les patients atteints de la maladie de Crohn, répondant à un traitement par antagoniste de l'interleukine 23 (IL23) en mesurant les niveaux de biomarqueurs de l'interleukine 22 et/ou de la protéine C-réactive dans des échantillons prélevés sur les patients. L'invention concerne également des procédés de pronostic permettant d'affiner l'identification de ces patients en distinguant les effets induits par le traitement des effets placebo sur la base des changements de l'indice d'activité de la maladie de Crohn résultant du traitement par antagoniste de l'IL23.
PCT/US2022/018957 2021-03-05 2022-03-04 Procédés de sélection de sous-populations de patients atteints de la maladie de crohn pouvant faire l'objet d'une thérapie par antagoniste de l'il 23 WO2022187657A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020102244A1 (fr) * 2018-11-14 2020-05-22 Beyondspring Pharmaceuticals, Inc. Méthodes de traitement du cancer à l'aide d'agents de liaison à la tubuline
WO2021035129A1 (fr) * 2019-08-21 2021-02-25 Astrazeneca Collaboration Ventures, Llc Utilisation de brazikumab pour traiter la maladie de crohn

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020102244A1 (fr) * 2018-11-14 2020-05-22 Beyondspring Pharmaceuticals, Inc. Méthodes de traitement du cancer à l'aide d'agents de liaison à la tubuline
WO2021035129A1 (fr) * 2019-08-21 2021-02-25 Astrazeneca Collaboration Ventures, Llc Utilisation de brazikumab pour traiter la maladie de crohn

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