THU038 Osilodrostat Dosing In Cushing’s Disease: A Pooled Analysis Of The LINC Program
Authors: Newell-Price John , Pivonello Rosario , Lacroix André , Biller Beverly M K , Feelders Richard , Gadelha Mônica , Bertherat Jérôme , Belaya Zhanna , Piacentini Andrea , Pedroncelli Alberto M , Fleseriu Maria 
Published: October 2023

Disclosure: J. Newell-Price: Consulting Fee; Self; HRA Pharmaceuticals, Diurnal, Novartis Pharmaceuticals, Recordati Rare Diseases, Crinetics. Grant Recipient; Self; Crinetics, Diurnal, HRA Pharmaceuticals, Novartis Pharmaceuticals, Recordati Rare Diseases. R. Pivonello: Consulting Fee; Self; Novartis Pharmaceuticals, Recordati, Corcept Therapeutics, Pfizer, Inc., Bresmed Health Solutions, Damor farmaceutici, S&R Farmaceutici SpA, Organon Italia Srl, Siunergos Pharma, Biohealth Italia Srl. Grant Recipient; Self; Novartis Pharmaceuticals, Recordati, Xeris Pharmaceuticals (Strongbridge), Corcept Therapeutics, Takeda, Neurocrine Biosciences, Camurus AB, Pfizer, Inc., Merk Serono, Ibsa. A. Lacroix: Consulting Fee; Self; Novartis Pharmaceuticals, Recordati, Corcept Therapeutics, Ipsen, Novo Nordisk. Grant Recipient; Self; Novartis Pharmaceuticals, Recordati, Corcept Therapeutics, Ipsen, Novo Nordisk. B.M. Biller: Consulting Fee; Self; HRA Pharmaceuticals, Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals (Strongbridge). Research Investigator; Self; served on the LINC 3 steering committee. R. Feelders: Consulting Fee; Self; HRA Pharmaceuticals, Recordati. Grant Recipient; Self; Corcept Therapeutics. M. Gadelha: Advisory Board Member; Self; Novo Nordisk, Recordati, Crinetics Pharmaceuticals. Speaker; Self; Recordati, Ipsen, Crinetics, Novo Nordisk. J. Bertherat: Consulting Fee; Self; Atterocor, Shire, HRA Pharmaceuticals, Novartis Pharmaceuticals, Corcept Therapeutics, Recordati. Grant Recipient; Self; Novartis Pharmaceuticals, Pfizer, Inc., HRA Pharmaceuticals. Z. Belaya: None. A. Piacentini: Employee; Self; Recordati. A.M. Pedroncelli: Employee; Self; Recordati. M. Fleseriu: Consulting Fee; Self; HRA Pharmaceuticals, Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals (Strongbridge). Grant Recipient; Self; Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals (Strongbridge). Research Investigator; Self; served on the LINC 3 steering committee.

Introduction: Phase II (LINC 2, NCT01331239) and Phase III (LINC 3, NCT02180217; LINC 4, NCT02697734) studies showed that osilodrostat, a potent oral 11β-hydroxylase inhibitor, was an effective long-term therapy for Cushing’s disease (CD) patients (pts). Objective: This pooled analysis of the LINC program examined how dosing, including dose uptitration and adjustments during long-term maintenance, can provide rapid, sustained mUFC control, minimize AEs and improve treatment outcomes. Methods: Individual pt data from LINC 2, LINC 3 and LINC 4 were pooled and analyzed. Given differences in study designs across trials, placebo treatment periods were excluded. Pts with mUFC &gt;1.5 times the upper limit of normal (ULN) (LINC 2 and LINC 3) or mUFC &gt;1.3 x ULN (LINC 4) were enrolled. In LINC 2, pts started open-label osilodrostat 2 mg twice daily (bid), with dose increases every 2 weeks (W) if mUFC &gt;ULN. In LINC 3, pts started open-label osilodrostat 2 mg bid, with dose increases every 2W until W12 if mUFC &gt;ULN, then every 4W after W12. In LINC 4, pts were randomized to osilodrostat 2 mg bid or placebo for the first 12W. Dose was increased every 3W until W12 if mUFC &gt;ULN and every 3W after W12. Maximum dose was 30 mg bid in all studies (reduced from 50 mg bid in LINC 2 core phase). Dose adjustments were permitted during the extensions based on efficacy and tolerability. Results: This analysis included 229 pts. Median (min-max) osilodrostat exposure was 100.1 weeks (1–351). Median (min–max) daily osilodrostat dose was 6.8 mg/day (1–47); dose needed to achieve mUFC control varied widely between pts. Median time to first mUFC control was 35 days (D; 95% confidence interval [CI] 34–41) in all pts; according to baseline (BL) mUFC severity: mUFC &lt;2 x ULN, 28D (95% CI 17–34); mUFC 2–5 x ULN, 40D (95% CI 34–42); mUFC &gt;5 x ULN, 52D (95% CI 41–56). Median time to first AE of special interest (AESI) was 12W (95% CI 10–15); AESIs occurred at different osilodrostat doses. AEs related to hypocortisolism (BL to W12, 23%; W12–48, 24%; W48–72, 8%; W72 onwards, 20%) and accumulation of adrenal hormone precursors (BL to W12, 36%; W12–48, 37%; W48–72, 14%; W72 onwards, 18%) were less frequent during long-term maintenance than dose titration. AESIs were mostly manageable with dose interruption and/or additional therapy; few patients discontinued treatment as a result (hypocortisolism-related AEs, n=8; adrenal hormone precursor accumulation-related AEs, n=3). Conclusions: Osilodrostat led to sustained mUFC control in all 3 studies; time to control was shorter in pts with lower BL mUFC values. Median daily osilodrostat dose was low but varied widely. Dose titration regimens differed for each study, but AESIs were less frequent during long-term treatment than dose uptitration and were manageable in most pts without stopping treatment. Personalized therapy during dose titration and lifelong monitoring are needed to optimize clinical outcomes in CD pts.

Presentation: Thursday, June 15, 2023