076: First-in-Human Phase 1 SAD, MAD, Food Effect & DDI Study of SGR-1505, a Mucosa-Associated Lymphoid Tissue Lymphoma Translocation Protein 1 Inhibitor, in Healthy Volunteers

Statement of Purpose, Innovation or Hypothesis: SGR-1505 is a rationally designed, potent, orally bioavailable small molecule allosteric inhibitor of Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) enzymatic activity that demonstrates anti-proliferative activity in multiple ABC-DLBCL cell lines and patient-derived xenograft models1,3. MALT1 is a therapeutic target for several subtypes of non-Hodgkin B-cell lymphomas. This work summarizes the pharmacokinetics (PK), safety and tolerability of SGR-1505 from a clinical pharmacology study conducted in healthy volunteers.

Description of Methods & Materials: This study was a 4-part, open-label, dose-escalation (single ascending dose (SAD) and multiple ascending dose (MAD)), food effect (FE), and drug-drug interaction (DDI) study (with and without posaconazole, a strong CYP3A inhibitor) conducted at a single investigational site  (ACTRN12623000358640p). Each cohort of the study consisted of a screening, treatment, and follow-up phase. Each SAD and MAD cohort consisted of 6 healthy volunteers per cohort. The FE and DDI cohorts enrolled 12 healthy volunteers per cohort. Extensive PK samples were collected at predetermined time points to characterize SGR-1505 PK. Plasma samples were assayed for SGR-1505 concentrations using a validated LC-MS/MS assay. SGR-1505 PK parameters were obtained by non-compartmental PK analysis.

Data & Results: The median age for the participants was 26 years (SAD), 30 years (MAD), 29 years (FE), and 28 years (DDI). The mean BMI (kg/m2) for SAD, MAD, FE, and DDI cohort participants was 24.3, 24.5, 26.0, and 24.9, respectively. There were no serious treatment emergent adverse events (TEAEs), most TEAEs were mild (Grade 1 in severity), and there were no clinically concerning trends in the changes in serum chemistry parameters, 12-lead ECG, or urinalyses following dosing with SGR-1505. SGR-1505 was rapidly absorbed, with a median tmax between 2 and 4 hours, and slow elimination (half-life geometric mean: 34.1 to 42.5 hours), with low-to-moderate inter-participant variability in PK parameters. SAD cohorts results suggested a dose proportional increase in SGR-1505 Cmax and exposure up to the 100 mg dose (Table 1). In the MAD cohorts, at steady state, 1.8-fold accumulation was noted with QD dosing (75 and 150 mg) and a 3.3-fold accumulation was observed with 100 mg Q12h dosing for 10 days. With high fat, high calorie food, SGR-1505 C_max and AUC were approximately 1.6 and 1.3 -fold higher; respectively in comparison to fasted state. SGR-1505 coadministration with posaconazole resulted in increased plasma exposure (approximately 1.4-fold for C_max and 3.6-fold for AUC_0-inf) in healthy volunteers.

Interpretation, Conclusion or Significance: This healthy volunteers study has demonstrated that SGR-1505, when administered orally as a single dose (up to 225 mg) or multiple daily doses (75 mg or 150 mg QD or 100 mg Q12h) for 10 days, was safe and well tolerated in healthy adults. SGR-1505 exhibited dose-proportional increase in exposure up to 100 mg, rapid absorption and a long half-life. Moderate accumulation (1.8 to 3.3-fold) was observed with multiple doses of SGR-1505. Food increased SGR-1505 exposure moderately (approximately 1.3 fold increase in AUC_0-inf). Co-administration with a strong CYP3A inhibitor increased SGR-1505 C_max (1.4-fold ) and AUC0-inf (3.6-fold). Clinical data generated from this study supports the ongoing development of SGR-1505.

Disclosures: All Schrödinger Inc authors are full time employees and hold Schrödinger shares. Jason Lickliter is the principal investigator of the study that was conducted by Schrödinger Inc.

Citations/References: 1. SGR-1505 Is a Potent MALT1 Protease Inhibitor with a Potential Best-in-Class Profile. Blood. Volume 142, Supplement 1, 2 November 2023, Page 2997 2. Characterization of Potent Paracaspase MALT1 Inhibitors for Hematological Malignancies. Blood. Volume 138, Supplement 1, 23 November 2021, Page 1187 3. Identification of Potent Paracaspase MALT1 Inhibitors for Hematological Malignancies. Blood. Volume 136, Supplement 1, 5 November 2020, Page 30

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