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Phase I studies of BI 1015550, a preferential phosphodiesterase 4B inhibitor, in healthy males and patients with idiopathic pulmonary fibrosis

Toby M. Maher, Christina Schlecker, Doreen Luedtke, Sebastian Bossert, Donald F. Zoz, Armin Schultz
ERJ Open Research 2022 8: 00240-2022; DOI: 10.1183/23120541.00240-2022
Toby M. Maher
1Inflammation, Repair, and Development Section, National Heart and Lung Institute, Imperial College London, London, UK
2Keck Medicine of USC, Los Angeles, CA, USA
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  • For correspondence: Toby.Maher@med.usc.edu
Christina Schlecker
3Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany
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Doreen Luedtke
4Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
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Sebastian Bossert
4Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
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Donald F. Zoz
5Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT, USA
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Armin Schultz
6CRS Clinical Research Services Mannheim GmbH, Mannheim, Germany
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  • FIGURE 1
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    FIGURE 1

    Phase I study in healthy males: subject flow. #: one patient prematurely discontinued the study after taking 48 mg BI 1015550 due to an adverse event that was not considered drug-related (ligament sprain). SRD: single rising dose; MRD: multiple rising dose.

  • FIGURE 2
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    FIGURE 2

    Geometric mean plasma concentration–time profiles of BI 1015550. Phase I study in healthy males after a) single oral administration of BI 1015550 36 mg or 48 mg under fasted conditions, and b) single and multiple oral administrations of 6 mg or 12 mg twice-daily BI 1015550 under fed conditions. c) Phase Ic study in patients with idiopathic pulmonary fibrosis after single and multiple oral administration of 18 mg twice-daily BI 1015550.

  • FIGURE 3
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    FIGURE 3

    Phase Ic study in patients with idiopathic pulmonary fibrosis: patient flow. Of 10 patients treated with BI 1015550, seven were treated up to a maximum duration of 12 weeks and three up to a maximum of 4 weeks. Of five patients treated with placebo, four were treated up to a maximum duration of 12 weeks and one up to a maximum of 4 weeks. AE: adverse event; PK: pharmacokinetic. #: four patients were screened twice; ¶: other reasons for discontinuations (n=1 each) included no longer willing to participate, administrative reason, randomisation timeline, study closed and unable to perform calprotectin retest.

Tables

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  • TABLE 1

    Phase I study in healthy male subjects: summary of adverse events (AEs)

    SRDMRD
    PlaceboBI 1015550PlaceboBI 1015550
    36 mg48 mgTotal6 mg twice daily12 mg twice dailyTotal
    Number of subjects6 (100.0)6 (100.0)6 (100.0)12 (100.0)8 (100.0)8 (100.0)8 (100.0)16 (100.0)
    Subjects with any AE1 (16.7)4 (66.7)4 (66.7)8 (66.7)3 (37.5)2 (25.0)5 (62.5)7 (43.8)
    Subjects with investigator-defined drug-related AEs1 (16.7)2 (33.3)4 (66.7)6 (50.0)1 (12.5)2 (25.0)4 (50.0)6 (37.5)

    Data are presented as n (%). SRD: single rising dose; MRD: multiple rising dose.

    • TABLE 2

      Phase I study in healthy male subjects: summary of pharmacokinetic parameters of BI 1015550 in the single rising dose part

      Parameter (unit)BI 1015550 36 mg#BI 1015550 48 mg#
      gMeangCV (%)gMeangCV (%)
      Cmax (nmol·L−1)71020.795515.5
      AUC0−∞ (nmol·h·L−1)591021.28700¶17.2
      fe0–120 (%)12.5¶45.212.1+13.4
      CLR,0–120 (mL·min−1)30.5+21.525.2+20.6

      gMean: geometric mean; gCV: geometric coefficient of variation; Cmax­: maximum measured concentration of analyte in plasma; AUC0–∞: area under the concentration–time curve of the analyte in plasma over the time interval from 0 extrapolated to ∞; fe0–120: fraction of administered drug excreted unchanged in urine over the time interval 0–120 h after first drug administration; CLR,0–120: renal clearance of the analyte in plasma over the time interval 0–120 h after first drug administration. #: fasted, n=6; ¶: n=5; +: n=4.

      • TABLE 3

        Phase I study in healthy male subjects: summary of pharmacokinetic parameters of BI 1015550 in the multiple rising dose part

        Parameter (unit)BI 1015550 6 mg twice daily#BI 1015550 12 mg twice daily#
        gMeangCV (%)gMeangCV (%)
        Cmax (nmol·L−1)10328.222929.9
        AUCτ,1 (nmol·h·L−1)56424.8137015.9
        Cmax,ss (nmol·L−1)16421.334814.1
        AUCτ,ss (nmol·h·L−1)105025.7230015.8
        RA,Cmax1.6035.01.5223.6
        RA,AUC1.859.911.6814.8

        gMean: geometric mean; gCV: geometric coefficient of variation; Cmax­: maximum measured concentration of analyte in plasma; AUCτ,1: area under the concentration–time curve for the analyte in plasma over a uniform dosing interval τ after the first dose; Cmax,ss: maximum measured concentration of analyte in plasma at steady state over a uniform dosing interval τ; AUCτ,ss: area under the concentration–time curve of the analyte in plasma at steady state over a uniform dosing interval τ; RA,Cmax: accumulation ratio of the analyte in plasma after multiple dose administration over a uniform dosing interval τ, expressed as a ratio of Cmax at steady state and after a single dose; RA,AUC: accumulation ratio of the analyte in plasma after multiple dose administration over a uniform dosing interval τ, expressed as a ratio of AUC at steady state and after a single dose. #: fed, n=8.

        • TABLE 4

          Phase Ic study in patients with idiopathic pulmonary fibrosis: summary of adverse events (AEs)

          PlaceboBI 1015550
          18 mg twice daily
          Total on treatment
          Patients treated5 (100.0)10 (100.0)15 (100.0)
          Any AE5 (100.0)10 (100.0)15 (100.0)
          Severe AEs0 (0.0)1 (10.0)1 (6.7)
          Investigator-defined drug-related AE3 (60.0)9 (90.0)12 (80.0)
          AE leading to discontinuation of study drug0 (0.0)1 (10.0)1 (6.7)
          Patients with AESI#0 (0.0)0 (0.0)0 (0.0)
          Patients with other significant AEs according to ICH E30 (0.0)1 (10.0)1 (6.7)
          Patients with SAEs0 (0.0)1 (10.0)1 (6.7)
           Patients requiring or prolonging hospitalisation0 (0.0)1 (10.0)1 (6.7)

          Data are presented as n (%). AESI: adverse event of special interest; ICH: International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use; SAE: serious adverse event. #: hepatic injury was defined as an AESI.

          • TABLE 5

            Phase Ic study in patients with idiopathic pulmonary fibrosis: pharmacokinetic parameters of BI 1015550 18 mg twice daily

            Parameter (unit)gMean+gCV (%)
            Day 1#
             Cmax (nmol·L−1)27723.1
             AUCτ,1 (nmol·h·L−1)199018.2
            Day 14¶
             Cmax,ss (nmol·L−1)46041.7
             AUCτ,ss (nmol·h·L−1)372049.5

            n=10. gMean: geometric mean; gCV: geometric coefficient of variation; Cmax: maximum measured concentration of the analyte in plasma; AUCτ,1: area under the concentration–time curve of the analyte in plasma over a uniform dosing interval τ after administration of the first dose; Cmax,ss: maximum measured concentration of analyte in plasma at steady state over a uniform dosing interval τ; AUCτ,ss: area under the concentration–time curve of the analyte in plasma at steady state over a uniform dosing interval τ at steady state. #: after the first dose; ¶: at steady state; +: n=10.

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              Supplementary material 00240-2022.SUPPLEMENT

              Plain language summary 00240-2022_PlainLanguageSummary

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            Phase I studies of BI 1015550, a preferential phosphodiesterase 4B inhibitor, in healthy males and patients with idiopathic pulmonary fibrosis
            Toby M. Maher, Christina Schlecker, Doreen Luedtke, Sebastian Bossert, Donald F. Zoz, Armin Schultz
            ERJ Open Research Oct 2022, 8 (4) 00240-2022; DOI: 10.1183/23120541.00240-2022

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            Phase I studies of BI 1015550, a preferential phosphodiesterase 4B inhibitor, in healthy males and patients with idiopathic pulmonary fibrosis
            Toby M. Maher, Christina Schlecker, Doreen Luedtke, Sebastian Bossert, Donald F. Zoz, Armin Schultz
            ERJ Open Research Oct 2022, 8 (4) 00240-2022; DOI: 10.1183/23120541.00240-2022
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