SUN-052 Effects of Paltusotine Treatment on Patient-Reported Symptoms of Acromegaly in Phase 3 Randomized Placebo-Controlled Studies (PATHFNDR-2 and PATHFNDR-1)

Abstract Disclosure: A.A. Rizio: A. Rizio is an employee of IQVIA QualityMetric, which received funding from Crinetics to conduct these analyses. M.K. Carty: M. Carty is an employee of IQVIA QualityMetric, which received funding from Crinetics to conduct these analyses. A. Krasner: A. Krasner is an employee of Crinetics and owns shares/stock in the company. I. Paulson: I. Paulson is an employee of Crinetics and owns shares/stock in the company. S.K. Rattana: S. Rattana is an employee of Crinetics and owns shares/stock in the company. M. Kosinski: M. Kosinski is an employee of IQVIA QualityMetric, which received funding from Crinetics to conduct these analyses. T.P. Quock: T. Quock is an employee of Crinetics and owns shares/stock in the company. Acromegaly is a chronic rare disease typically caused by a benign growth hormone (GH) secreting tumor in the pituitary gland. The Acromegaly Symptom Diary (ASD) is a new daily diary developed to fill a gap in the availability of patient-reported measures of acromegaly symptoms. The ASD evaluates the severity of 7 core acromegaly symptoms and 2 additional health experiences over the past 24 hours (symptoms: headache, joint pain, sweating, fatigue, leg weakness, swelling, numbness/tingling; additional experiences: sleep difficulty, short-term memory difficulty), using 0 to 10 numeric rating scales. A weekly average ASD total score reflects the sum of the weekly average scores obtained from the 7 symptom items. Higher scores indicate greater symptom severity. Two randomized, blinded, placebo-controlled phase 3 studies in patients with acromegaly (PATHFNDR-2 [PF-2, n=111]; PATHFNDR-1 [PF-1, n=58]) included a secondary endpoint defined as change from baseline in ASD total scores. Patients completed the ASD daily throughout the randomized treatment phase. Both studies demonstrated statistically significant reductions in acromegaly symptom burden as measured by a decrease in ASD total scores. To provide additional insight into patients’ symptom experience, retrospective analyses were conducted to further examine the impact of paltusotine on acromegaly symptoms, as measured by the ASD. Empirical cumulative distribution functions (eCDFs) were plotted to show the cumulative percentage of patients with change at or above each ASD total change score. Patients were stratified according to treatment group and treatment history. A range of meaningful within-patient change (MPWC) thresholds (3-15 points) was identified to further interpret group differences in the distribution of ASD change scores. For both PF-2 and PF-1, a larger percentage of patients treated with paltusotine showed improvement on the ASD compared to patients on placebo; this was observed across the full range of change scores indicating symptom improvement. For example, in PF-2, 28.9% of patients on paltusotine improved by ≥8 points on the ASD, compared to 7.1% of patients on placebo. Likewise, in PF-1, 11.1% of patients on paltusotine improved by ≥8 points, compared to 0% of patients on placebo. Similar patterns were observed across the range of potential MWPC thresholds. ECDFs also showed that in PF-2, greater percentages of patients treated with paltusotine – regardless of prior treatment history – experienced improvement or stability of acromegaly symptoms, as compared to patients on placebo.Treatment with oral paltusotine promotes improvement and/or stability of acromegaly symptoms relative to placebo, as measured by the ASD. These findings demonstrate the benefit of paltusotine in addressing core symptoms of acromegaly that are most relevant to patients, in addition to its GH and IGF-1 lowering effects. Presentation: Sunday, July 13, 2025