12531 Long-term Safety And Efficacy Of Once-daily Oral Paltusotine In The Treatment Of Patients With Acromegaly: Update From Acrobat Advance

Abstract Disclosure: M. Gadelha: Consulting Fee; Self; Crinetics, Ipsen, Novo Nordisk, and Recordati. Grant Recipient; Self; Crinetics and Recordati. Speaker; Self; Ipsen, Novo Nordisk, and Recordati. H.S. Randeva: None. M.B. Gordon: Consulting Fee; Self; Crinetics Pharmaceuticals, HRA Pharma, Novo Nordisk, and Recordati Rare Diseases. Grant Recipient; Self; Ascendis, Camurus, Chiasma, Corcept, Crinetics, Ipsen, Novartis, Novo Nordisk, Opko, Pfizer, and Strongbridge. M. Doknic: Research Investigator; Self; Crinetics Pharmaceuticals. Speaker; Self; Merck, Novartis, Novo Nordisk, Pfizer, and Sandoz. E. Mezosi: Research Investigator; Self; Crinetics Pharmaceuticals. M. Toth: Consulting Fee; Self; Pfizer, Ipsen, Novo Nordisk, and Recordati. Research Investigator; Self; Crinetics Pharmaceuticals. Other; Self; Pfizer, Ipsen, Novo Nordisk, and Recordati. C.L. Boguszewski: Advisory Board Member; Self; Novo Nordisk and Recordati. Consulting Fee; Self; Ipsen, Novo Nordisk, and Recordati. Other; Self; Ipsen, Novo Nordisk, and Recordati. C. Davidson: Employee; Self; Crinetics Pharmaceuticals. C.T. Ferrara-Cook: Employee; Self; Crinetics Pharmaceuticals. A. Casagrande: Employee; Self; Crinetics Pharmaceuticals. A. Krasner: Employee; Self; Crinetics Pharmaceuticals. Paltusotine is a non-peptide, highly selective SST2 receptor agonist in development as a once-daily, oral treatment for patients with acromegaly or carcinoid syndrome. ACROBAT Advance is an ongoing, 6-year, single-arm, open-label extension study of paltusotine in the treatment of patients with acromegaly. Interim results as the first enrolled patients approach 4 years of treatment are reported here. Enrolled patients had completed either the ACROBAT Edge or Evolve phase 2 parent studies. In Edge, at enrollment all patients were candidates for combination drug therapy: either sub-optimally controlled on an injected SRL (octreotide or lanreotide) alone or in combination with cabergoline, or required combination therapy or pasireotide to achieve normal IGF-I levels. In Evolve, enrolled patients had normal IGF-I levels on injected SRL monotherapy. When the Advance study was initiated, paltusotine was formulated as a capsule (dose range, 10-40 mg); all patients were switched to the tablet formulation (dose range, 20-60 mg) during the third year of the study. As of this analysis, all patients had at least 2 assessments after switching to tablet formulation. Adjunctive treatment with cabergoline or pegvisomant was allowed in patients who did not attain normal IGF-I levels on the maximum dose of paltusotine. Forty-three patients were enrolled in Advance (Edge, n=32; Evolve, n=11; 88% of eligible patients): at baseline, mean (±SD) age 53.0±11.6 years, 56% female, 86% previous pituitary surgery, and none had prior radiotherapy. IGF-I control in Edge and Evolve subsets remained stable at parent study baseline values. For all patients pooled, median (IQR) IGF-I levels were 1.15× ULN (0.84, 1.46; n=43) at parent study baseline; in Advance, 1.14× ULN (0.89, 1.29; n=40), 1.06× ULN (0.87, 1.24; n=35), and 1.08× ULN (0.87, 1.57; n=10) at months 12, 24, and 42, respectively. As expected, patients receiving adjunctive medication during Advance largely derived from the Edge study. Acromegaly symptoms, as measured using the patient-reported Acromegaly Symptom Diary (score range, 0-70; higher values indicate greater symptom burden), were stably controlled: median (IQR) score of 8.6 (3.6, 20.1; n=21) at parent study baseline; in Advance, 10.5 (5.0, 18.5; n=40), 10.0 (5.0, 25.0; n=34), and 13.5 (6.0, 22.0; n=10) at months 12, 24, and 42, respectively. The most common AEs reported through month 42 were arthralgia (37.2%), headache (30.2%), and fatigue (23.3%). One serious drug-related AE (cholelithiasis) was reported. Of the 8 patients who discontinued the study, 2 were due to AEs (mild or moderate). Glycemic control, as measured by HbA1c, was stable during paltusotine treatment. In conclusion, long-term results show that once-daily oral paltusotine treatment was well tolerated, with stable biochemical and symptom control relative to that observed with injected SRLs. Support: Crinetics Pharmaceuticals. Presentation: 6/3/2024