Safety, pharmacokinetics, and pharmacodynamics of sofnobrutinib, a novel non‐covalent BTK inhibitor, in healthy subjects: First‐in‐human phase I study
Bruton's tyrosine kinase (BTK) is a potential therapeutic target for allergic and autoimmune diseases. This first‐in‐human phase I study evaluated safety, pharmacokinetic, and pharmacodynamic profiles of sofnobrutinib (formerly AS‐0871), a highly selective, orally available, non‐covalent BTK in...
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| Published in | Clinical and translational science Vol. 17; no. 11; pp. e70060 - n/a |
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| Main Authors | , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
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John Wiley & Sons, Inc
01.11.2024
John Wiley and Sons Inc Wiley |
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| Abstract | Bruton's tyrosine kinase (BTK) is a potential therapeutic target for allergic and autoimmune diseases. This first‐in‐human phase I study evaluated safety, pharmacokinetic, and pharmacodynamic profiles of sofnobrutinib (formerly AS‐0871), a highly selective, orally available, non‐covalent BTK inhibitor, in healthy adult subjects. Single ascending doses (SAD; 5–900 mg) and multiple ascending doses (MAD; 50–300 mg twice daily [b.i.d.] for 14 days [morning dose only on Day 14]) of sofnobrutinib were tested. In the entire study, all adverse events (AEs) were mild or moderate, and no apparent dose‐proportional trend in severity or frequency was observed. No serious treatment‐emergent AEs, cardiac arrythmias, or bleeding‐related AEs were reported. In the SAD part, sofnobrutinib exhibited approximately dose‐dependent systemic exposures up to 900 mg with rapid absorption (median time to maximum concentration of 2.50–4.00 h) and gradual decline (mean half‐lives of 3.7–9.0 h). In the MAD part, sofnobrutinib showed low accumulation after multiple dosing (mean accumulation ratios of ≤1.54) and reached a steady state on ≤Day 7. Single dosing of sofnobrutinib rapidly and dose‐dependently suppressed basophil and B‐cell activations in ex vivo whole blood assays. Multiple dosing of sofnobrutinib achieved 50.8%–79.4%, 67.6%–93.6%, and 90.1%–98.0% inhibition of basophil activation during the dosing interval of 50, 150, and 300 mg b.i.d., respectively. Based on pharmacokinetic‐pharmacodynamic analysis, half‐maximal inhibitory concentration (IC50) of sofnobrutinib for basophil activation was 54.06 and 57.01 ng/mL in the SAD and MAD parts, respectively. Similarly, IC50 for B‐cell activation was 187.21 ng/mL. These data support further investigation of sofnobrutinib in allergic and autoimmune diseases. |
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| AbstractList | Bruton's tyrosine kinase (BTK) is a potential therapeutic target for allergic and autoimmune diseases. This first‐in‐human phase I study evaluated safety, pharmacokinetic, and pharmacodynamic profiles of sofnobrutinib (formerly AS‐0871), a highly selective, orally available, non‐covalent BTK inhibitor, in healthy adult subjects. Single ascending doses (SAD; 5–900 mg) and multiple ascending doses (MAD; 50–300 mg twice daily [b.i.d.] for 14 days [morning dose only on Day 14]) of sofnobrutinib were tested. In the entire study, all adverse events (AEs) were mild or moderate, and no apparent dose‐proportional trend in severity or frequency was observed. No serious treatment‐emergent AEs, cardiac arrythmias, or bleeding‐related AEs were reported. In the SAD part, sofnobrutinib exhibited approximately dose‐dependent systemic exposures up to 900 mg with rapid absorption (median time to maximum concentration of 2.50–4.00 h) and gradual decline (mean half‐lives of 3.7–9.0 h). In the MAD part, sofnobrutinib showed low accumulation after multiple dosing (mean accumulation ratios of ≤1.54) and reached a steady state on ≤Day 7. Single dosing of sofnobrutinib rapidly and dose‐dependently suppressed basophil and B‐cell activations in ex vivo whole blood assays. Multiple dosing of sofnobrutinib achieved 50.8%–79.4%, 67.6%–93.6%, and 90.1%–98.0% inhibition of basophil activation during the dosing interval of 50, 150, and 300 mg b.i.d., respectively. Based on pharmacokinetic‐pharmacodynamic analysis, half‐maximal inhibitory concentration (IC
50
) of sofnobrutinib for basophil activation was 54.06 and 57.01 ng/mL in the SAD and MAD parts, respectively. Similarly, IC
50
for B‐cell activation was 187.21 ng/mL. These data support further investigation of sofnobrutinib in allergic and autoimmune diseases. Abstract Bruton's tyrosine kinase (BTK) is a potential therapeutic target for allergic and autoimmune diseases. This first‐in‐human phase I study evaluated safety, pharmacokinetic, and pharmacodynamic profiles of sofnobrutinib (formerly AS‐0871), a highly selective, orally available, non‐covalent BTK inhibitor, in healthy adult subjects. Single ascending doses (SAD; 5–900 mg) and multiple ascending doses (MAD; 50–300 mg twice daily [b.i.d.] for 14 days [morning dose only on Day 14]) of sofnobrutinib were tested. In the entire study, all adverse events (AEs) were mild or moderate, and no apparent dose‐proportional trend in severity or frequency was observed. No serious treatment‐emergent AEs, cardiac arrythmias, or bleeding‐related AEs were reported. In the SAD part, sofnobrutinib exhibited approximately dose‐dependent systemic exposures up to 900 mg with rapid absorption (median time to maximum concentration of 2.50–4.00 h) and gradual decline (mean half‐lives of 3.7–9.0 h). In the MAD part, sofnobrutinib showed low accumulation after multiple dosing (mean accumulation ratios of ≤1.54) and reached a steady state on ≤Day 7. Single dosing of sofnobrutinib rapidly and dose‐dependently suppressed basophil and B‐cell activations in ex vivo whole blood assays. Multiple dosing of sofnobrutinib achieved 50.8%–79.4%, 67.6%–93.6%, and 90.1%–98.0% inhibition of basophil activation during the dosing interval of 50, 150, and 300 mg b.i.d., respectively. Based on pharmacokinetic‐pharmacodynamic analysis, half‐maximal inhibitory concentration (IC50) of sofnobrutinib for basophil activation was 54.06 and 57.01 ng/mL in the SAD and MAD parts, respectively. Similarly, IC50 for B‐cell activation was 187.21 ng/mL. These data support further investigation of sofnobrutinib in allergic and autoimmune diseases. Bruton's tyrosine kinase (BTK) is a potential therapeutic target for allergic and autoimmune diseases. This first‐in‐human phase I study evaluated safety, pharmacokinetic, and pharmacodynamic profiles of sofnobrutinib (formerly AS‐0871), a highly selective, orally available, non‐covalent BTK inhibitor, in healthy adult subjects. Single ascending doses (SAD; 5–900 mg) and multiple ascending doses (MAD; 50–300 mg twice daily [b.i.d.] for 14 days [morning dose only on Day 14]) of sofnobrutinib were tested. In the entire study, all adverse events (AEs) were mild or moderate, and no apparent dose‐proportional trend in severity or frequency was observed. No serious treatment‐emergent AEs, cardiac arrythmias, or bleeding‐related AEs were reported. In the SAD part, sofnobrutinib exhibited approximately dose‐dependent systemic exposures up to 900 mg with rapid absorption (median time to maximum concentration of 2.50–4.00 h) and gradual decline (mean half‐lives of 3.7–9.0 h). In the MAD part, sofnobrutinib showed low accumulation after multiple dosing (mean accumulation ratios of ≤1.54) and reached a steady state on ≤Day 7. Single dosing of sofnobrutinib rapidly and dose‐dependently suppressed basophil and B‐cell activations in ex vivo whole blood assays. Multiple dosing of sofnobrutinib achieved 50.8%–79.4%, 67.6%–93.6%, and 90.1%–98.0% inhibition of basophil activation during the dosing interval of 50, 150, and 300 mg b.i.d., respectively. Based on pharmacokinetic‐pharmacodynamic analysis, half‐maximal inhibitory concentration (IC50) of sofnobrutinib for basophil activation was 54.06 and 57.01 ng/mL in the SAD and MAD parts, respectively. Similarly, IC50 for B‐cell activation was 187.21 ng/mL. These data support further investigation of sofnobrutinib in allergic and autoimmune diseases. Bruton's tyrosine kinase (BTK) is a potential therapeutic target for allergic and autoimmune diseases. This first-in-human phase I study evaluated safety, pharmacokinetic, and pharmacodynamic profiles of sofnobrutinib (formerly AS-0871), a highly selective, orally available, non-covalent BTK inhibitor, in healthy adult subjects. Single ascending doses (SAD; 5-900 mg) and multiple ascending doses (MAD; 50-300 mg twice daily [b.i.d.] for 14 days [morning dose only on Day 14]) of sofnobrutinib were tested. In the entire study, all adverse events (AEs) were mild or moderate, and no apparent dose-proportional trend in severity or frequency was observed. No serious treatment-emergent AEs, cardiac arrythmias, or bleeding-related AEs were reported. In the SAD part, sofnobrutinib exhibited approximately dose-dependent systemic exposures up to 900 mg with rapid absorption (median time to maximum concentration of 2.50-4.00 h) and gradual decline (mean half-lives of 3.7-9.0 h). In the MAD part, sofnobrutinib showed low accumulation after multiple dosing (mean accumulation ratios of ≤1.54) and reached a steady state on ≤Day 7. Single dosing of sofnobrutinib rapidly and dose-dependently suppressed basophil and B-cell activations in ex vivo whole blood assays. Multiple dosing of sofnobrutinib achieved 50.8%-79.4%, 67.6%-93.6%, and 90.1%-98.0% inhibition of basophil activation during the dosing interval of 50, 150, and 300 mg b.i.d., respectively. Based on pharmacokinetic-pharmacodynamic analysis, half-maximal inhibitory concentration (IC ) of sofnobrutinib for basophil activation was 54.06 and 57.01 ng/mL in the SAD and MAD parts, respectively. Similarly, IC for B-cell activation was 187.21 ng/mL. These data support further investigation of sofnobrutinib in allergic and autoimmune diseases. Bruton's tyrosine kinase (BTK) is a potential therapeutic target for allergic and autoimmune diseases. This first‐in‐human phase I study evaluated safety, pharmacokinetic, and pharmacodynamic profiles of sofnobrutinib (formerly AS‐0871), a highly selective, orally available, non‐covalent BTK inhibitor, in healthy adult subjects. Single ascending doses (SAD; 5–900 mg) and multiple ascending doses (MAD; 50–300 mg twice daily [b.i.d.] for 14 days [morning dose only on Day 14]) of sofnobrutinib were tested. In the entire study, all adverse events (AEs) were mild or moderate, and no apparent dose‐proportional trend in severity or frequency was observed. No serious treatment‐emergent AEs, cardiac arrythmias, or bleeding‐related AEs were reported. In the SAD part, sofnobrutinib exhibited approximately dose‐dependent systemic exposures up to 900 mg with rapid absorption (median time to maximum concentration of 2.50–4.00 h) and gradual decline (mean half‐lives of 3.7–9.0 h). In the MAD part, sofnobrutinib showed low accumulation after multiple dosing (mean accumulation ratios of ≤1.54) and reached a steady state on ≤Day 7. Single dosing of sofnobrutinib rapidly and dose‐dependently suppressed basophil and B‐cell activations in ex vivo whole blood assays. Multiple dosing of sofnobrutinib achieved 50.8%–79.4%, 67.6%–93.6%, and 90.1%–98.0% inhibition of basophil activation during the dosing interval of 50, 150, and 300 mg b.i.d., respectively. Based on pharmacokinetic‐pharmacodynamic analysis, half‐maximal inhibitory concentration (IC50) of sofnobrutinib for basophil activation was 54.06 and 57.01 ng/mL in the SAD and MAD parts, respectively. Similarly, IC50 for B‐cell activation was 187.21 ng/mL. These data support further investigation of sofnobrutinib in allergic and autoimmune diseases. Bruton's tyrosine kinase (BTK) is a potential therapeutic target for allergic and autoimmune diseases. This first-in-human phase I study evaluated safety, pharmacokinetic, and pharmacodynamic profiles of sofnobrutinib (formerly AS-0871), a highly selective, orally available, non-covalent BTK inhibitor, in healthy adult subjects. Single ascending doses (SAD; 5-900 mg) and multiple ascending doses (MAD; 50-300 mg twice daily [b.i.d.] for 14 days [morning dose only on Day 14]) of sofnobrutinib were tested. In the entire study, all adverse events (AEs) were mild or moderate, and no apparent dose-proportional trend in severity or frequency was observed. No serious treatment-emergent AEs, cardiac arrythmias, or bleeding-related AEs were reported. In the SAD part, sofnobrutinib exhibited approximately dose-dependent systemic exposures up to 900 mg with rapid absorption (median time to maximum concentration of 2.50-4.00 h) and gradual decline (mean half-lives of 3.7-9.0 h). In the MAD part, sofnobrutinib showed low accumulation after multiple dosing (mean accumulation ratios of ≤1.54) and reached a steady state on ≤Day 7. Single dosing of sofnobrutinib rapidly and dose-dependently suppressed basophil and B-cell activations in ex vivo whole blood assays. Multiple dosing of sofnobrutinib achieved 50.8%-79.4%, 67.6%-93.6%, and 90.1%-98.0% inhibition of basophil activation during the dosing interval of 50, 150, and 300 mg b.i.d., respectively. Based on pharmacokinetic-pharmacodynamic analysis, half-maximal inhibitory concentration (IC50) of sofnobrutinib for basophil activation was 54.06 and 57.01 ng/mL in the SAD and MAD parts, respectively. Similarly, IC50 for B-cell activation was 187.21 ng/mL. These data support further investigation of sofnobrutinib in allergic and autoimmune diseases.Bruton's tyrosine kinase (BTK) is a potential therapeutic target for allergic and autoimmune diseases. This first-in-human phase I study evaluated safety, pharmacokinetic, and pharmacodynamic profiles of sofnobrutinib (formerly AS-0871), a highly selective, orally available, non-covalent BTK inhibitor, in healthy adult subjects. Single ascending doses (SAD; 5-900 mg) and multiple ascending doses (MAD; 50-300 mg twice daily [b.i.d.] for 14 days [morning dose only on Day 14]) of sofnobrutinib were tested. In the entire study, all adverse events (AEs) were mild or moderate, and no apparent dose-proportional trend in severity or frequency was observed. No serious treatment-emergent AEs, cardiac arrythmias, or bleeding-related AEs were reported. In the SAD part, sofnobrutinib exhibited approximately dose-dependent systemic exposures up to 900 mg with rapid absorption (median time to maximum concentration of 2.50-4.00 h) and gradual decline (mean half-lives of 3.7-9.0 h). In the MAD part, sofnobrutinib showed low accumulation after multiple dosing (mean accumulation ratios of ≤1.54) and reached a steady state on ≤Day 7. Single dosing of sofnobrutinib rapidly and dose-dependently suppressed basophil and B-cell activations in ex vivo whole blood assays. Multiple dosing of sofnobrutinib achieved 50.8%-79.4%, 67.6%-93.6%, and 90.1%-98.0% inhibition of basophil activation during the dosing interval of 50, 150, and 300 mg b.i.d., respectively. Based on pharmacokinetic-pharmacodynamic analysis, half-maximal inhibitory concentration (IC50) of sofnobrutinib for basophil activation was 54.06 and 57.01 ng/mL in the SAD and MAD parts, respectively. Similarly, IC50 for B-cell activation was 187.21 ng/mL. These data support further investigation of sofnobrutinib in allergic and autoimmune diseases. |
| Author | Oosterhaven, Jart A. F. Voors‐Pette, Christine Sato, Yuji Kirita, Shirou Dobbelsteen, Marieke Miyamoto, Kyoko Mihara, Katsuhiro Geldof, Marian Miller, Robert M. Matsuda, Naomi Sawa, Masaaki Arimura, Akinori |
| AuthorAffiliation | 6 Carna Biosciences, Inc. Kobe Japan 2 Artemida Pharma, Ltd. Hertfordshire UK 4 ICON plc Groningen The Netherlands 5 Venn Life Sciences ED B.V. Breda The Netherlands 3 QPS Netherlands BV Groningen The Netherlands 1 CarnaBio USA, Inc. South San Francisco California USA |
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| Author_xml | – sequence: 1 givenname: Kyoko orcidid: 0009-0001-3157-2824 surname: Miyamoto fullname: Miyamoto, Kyoko organization: CarnaBio USA, Inc – sequence: 2 givenname: Robert M. orcidid: 0000-0003-2030-1778 surname: Miller fullname: Miller, Robert M. organization: Artemida Pharma, Ltd – sequence: 3 givenname: Christine surname: Voors‐Pette fullname: Voors‐Pette, Christine organization: QPS Netherlands BV – sequence: 4 givenname: Jart A. F. orcidid: 0000-0001-7214-7528 surname: Oosterhaven fullname: Oosterhaven, Jart A. F. organization: ICON plc – sequence: 5 givenname: Marieke surname: Dobbelsteen fullname: Dobbelsteen, Marieke organization: Venn Life Sciences ED B.V – sequence: 6 givenname: Katsuhiro orcidid: 0009-0005-8746-619X surname: Mihara fullname: Mihara, Katsuhiro organization: Venn Life Sciences ED B.V – sequence: 7 givenname: Marian surname: Geldof fullname: Geldof, Marian organization: Venn Life Sciences ED B.V – sequence: 8 givenname: Yuji surname: Sato fullname: Sato, Yuji organization: Carna Biosciences, Inc – sequence: 9 givenname: Naomi surname: Matsuda fullname: Matsuda, Naomi organization: Carna Biosciences, Inc – sequence: 10 givenname: Shirou surname: Kirita fullname: Kirita, Shirou organization: Carna Biosciences, Inc – sequence: 11 givenname: Masaaki orcidid: 0000-0002-0077-2188 surname: Sawa fullname: Sawa, Masaaki organization: Carna Biosciences, Inc – sequence: 12 givenname: Akinori orcidid: 0009-0009-0167-3868 surname: Arimura fullname: Arimura, Akinori email: akinori.arimura@dd.carnabio.com organization: Carna Biosciences, Inc |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/39523516$$D View this record in MEDLINE/PubMed |
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| Copyright | 2024 Carna Biosciences, Inc. published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. 2024 Carna Biosciences, Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. 2024. This work is published under http://creativecommons.org/licenses/by-nc/4.0/ (the "License"). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. |
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| PublicationDecade | 2020 |
| PublicationPlace | United States |
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| PublicationTitle | Clinical and translational science |
| PublicationTitleAlternate | Clin Transl Sci |
| PublicationYear | 2024 |
| Publisher | John Wiley & Sons, Inc John Wiley and Sons Inc Wiley |
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| Snippet | Bruton's tyrosine kinase (BTK) is a potential therapeutic target for allergic and autoimmune diseases. This first‐in‐human phase I study evaluated safety,... Bruton's tyrosine kinase (BTK) is a potential therapeutic target for allergic and autoimmune diseases. This first-in-human phase I study evaluated safety,... Abstract Bruton's tyrosine kinase (BTK) is a potential therapeutic target for allergic and autoimmune diseases. This first‐in‐human phase I study evaluated... |
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| Title | Safety, pharmacokinetics, and pharmacodynamics of sofnobrutinib, a novel non‐covalent BTK inhibitor, in healthy subjects: First‐in‐human phase I study |
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