144: A Concentration-QT Analysis Identifies No Meaningful Effect of Nirogacestat or Itraconazole on QTcF Interval

Statement of Purpose: Nirogacestat is a γ-secretase inhibitor currently under investigation as monotherapy for the treatment of desmoid tumors (DT) and ovarian granulosa cell tumors, as well as in combination with B cell maturation antigen-targeting agents for multiple myeloma. Nirogacestat was evaluated for clinical risk of QT prolongation via a concentration-QT (C-QT) model developed using data from seven clinical studies involving healthy volunteers and participants with advanced malignancies or DT. A pooled modeling approach to estimate risk of drug-related QT prolongation was required because safety considerations precluded the ability to reach steady-state therapeutic exposures in a dedicated thorough QT study.

Description of Methods & Materials: Concentration-time, electrocardiogram (ECG), and demographic data were combined from one single and one multiple ascending dose study; two absorption, distribution, metabolism, and excretion studies; a drug-drug interaction (DDI) study; a dose-range finding study in participants with advanced malignancies; and a phase 3 study in participants with DT. In total, 359 participants contributed data to the model. Nirogacestat concentrations ranged from zero to 6,180 ng/mL. All ECGs were triplicate 12-lead collections and values were derived from automatic or centrally read manual measurements by study. A total of 2,587 paired concentrations and QT measurements were used in the analysis. A base model was developed using only data following placebo administrations. After selection of the base model, the effect of itraconazole concentration was evaluated using data from placebo- and itraconazole-only periods in the DDI study. Additional covariates were evaluated using the full analysis dataset and, after selection of the full covariate model, the effect of nirogacestat concentration on Fridericia-corrected QT (QTcF) was evaluated. Nirogacestat-related effects on QTcF were predicted from the final model using a bias-corrected nonparametric bootstrap procedure to derive the two-sided 90% confidence interval (CI) of the predicted effect. A secondary analysis of the effect of itraconazole on QTcF using the pre-specified model was performed.

Data & Results: Exploratory analyses confirmed that key assumptions were met prior to model development. A significant positive effect for female sex on baseline QTcF and an effect for increased QTcF with increased age were identified. Notably, data from placebo-controlled evaluations of itraconazole in the DDI study showed no meaningful effect of 200 mg once daily (QD) itraconazole at steady state on QTcF relative to baseline (concentration-related slope 0.0005 msec/ng/mL). The nirogacestat concentration-related slope for QTcF (0.00111 msec/ng/mL) was not significant, and the predicted nirogacestat-related mean ΔQTcF and 90% CI for exposures at 150 mg twice daily nirogacestat were 1.33 msec (0.307, 2.23) at steady state, and 4.67 msec (1.08, 7.81) at the predicted exposure with strong CYP3A4 inhibition. The prespecified model for itraconazole also demonstrated no effect of itraconazole on QTcF.

Interpretation, Conclusion or Significance: An effect of nirogacestat on QTcF interval can be ruled out at the therapeutic exposure and at the clinical worst-case exposure (concomitant dosing with strong CYP3A4 inhibition). Additionally, itraconazole at 200 mg QD had no meaningful effect on the QTcF interval, suggesting that itraconazole drug-drug interaction studies may be a feasible method for collecting data for use in a C-QT analysis.

Disclosures: Shearer: SpringWorks Therapeutics: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company, Patents & Royalties: 63/263,635. Williams: SpringWorks Therapeutics: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: Minor unrelated stock positions in PFE, VTRS, MBIO, RIGL, SNDL, SRNE and various mutual funds, Patents & Royalties: USPTO Application 63/263,635 (Compositions and Treatments with Nirogacestat ) -- Assigned to SpringWorks. Lohmer: Paid consultant for SpringWorks Therapeutics as an employee of Allucent. Curd: Paid consultant for SpringWorks Therapeutics as an employee of Allucent. Schmith: Paid consultant for Springworks Therapeutics.