140: Pharmacokinetic-Pharmacodynamic Analysis of Cytokines in First-in-Human Phase 1 Dose Escalation Study of the MALT-1 Inhibitor, SGR-1505, in Healthy Volunteers

Statement of Purpose, Innovation or Hypothesis: Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a therapeutic target for several subtypes of non-Hodgkin B-cell lymphomas. SGR-1505 is an oral MALT1 inhibitor in Phase 1 clinical development. This abstract summarizes evaluation of SGR-1505 target engagement and pharmacokinetic-pharmacodynamic (PK-PD) relationships using changes in cytokine levels upon ex vivo stimulation after single and repeat doses in healthy participants.

Description of Methods & Materials: This study was a 4-part, dose-escalation open-label study (no placebo control) designed to evaluate the safety, tolerability, PK, food effect, and drug-drug interaction potential of SGR-1505 in healthy participants (ACTRN12623000358640p). For PD assessment, whole blood samples were collected at various time points across cohorts and processed to measure target engagement and pathway modulation markers. Cytokine productions at pre- and post-SGR-1505 administration were measured quantitatively in whole blood using Meso Scale Discovery Multiplex panels upon ex vivo T cell stimulation. SGR-1505 plasma concentrations were measured using a validated LC-MS/MS assay. The PK-PD analysis was performed using the R statistical software, version 4.04. Nonlinear regression methods were used to assess the degree of correlation between SGR-1505 concentration and the time-matched PD endpoint values. The functional form for the nonlinear regression was a sigmoidal E_max function.

Data & Results: A total of 424 samples, each assayed for IL-2, IFN-γ, and TNF-α, from 46 participants were utilized for the descriptive statistics. A total of 392 samples, each assayed for IL-2, IFN-γ, and TNF-α, had time-matched SGR-1505 plasma concentrations and were used for the PK-PD correlation analyses. The estimated parameters from the fits of the sigmoidal E_max models and associated IC₅₀ and/or IC₉₀ values are provided in Table 1. IL-2 demonstrated the best correlation with SGR-1505 concentration (r² =0.371) among the three cytokines with an IC₉₀ value of 1340 ng/mL (Figure 1).

Interpretation, Conclusion or Significance: PK-PD correlation analyses indicated that SGR-1505 is a potent MALT1 inhibitor in humans. Increasing SGR-1505 plasma concentrations were associated with decreasing percent changes in all three cytokines measured with IL-2 demonstrating the strongest relationship with SGR-1505 concentrations. These results are useful in determining the potential clinical dosing regimen of SGR-1505 based on the inhibition of cytokines associated with the MALT1 pathway.

Disclosures: Schrödinger affiliated authors are full time employees and own Schrödinger stocks. Jo Tan also owns Schrödinger stocks. Jason Lickliter is the principal investigator for this Schrödinger study.

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