12535 Efficacy And Safety Of Once-daily Oral Paltusotine In Medically Untreated Patients With Acromegaly: Results From The Phase 3, Randomized, Placebo-controlled Pathfndr-2 Study

Abstract Disclosure: B.M. Biller: Consulting Fee; Self; Amolyt, Amryt, Camurus, Crinetics, and Recordati. Research Investigator; Self; Crinetics and Ionis. A. Casagrande: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. A. Elenkova: Grant Recipient; Self; Pfizer, Novartis, and Novo Nordisk. Research Investigator; Self; Corcept Therapeutics, Crinetics Pharmaceuticals, Xeris Pharmaceuticals, and Recordati Rare Diseases. 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. R.S. Jallad: Grant Recipient; Self; Crinetics Pharmaceuticals. B. Hu: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. E. Hubina: None. P. Fazeli: Advisory Board Member; Self; Amryt, Camurus, Crinetics, and Xeris. Consulting Fee; Self; Regeneron and Quest Diagnostics. Grant Recipient; Self; Crinetics and Corcept. M. Fleseriu: Consulting Fee; Self; Camurus, Crinetics Pharmaceuticals,and Recordati. Grant Recipient; Self; Crinetics Pharmaceuticals. P.J. Snyder: Grant Recipient; Self; Crinetics Pharmaceuticals. C.J. Strasburger: Consulting Fee; Self; Amolyt Pharma, Crinetics Pharmaceuticals, Novo Nordisk, Pfizer, Recordati, and Sandoz-Hexal. Grant Recipient; Self; Crinetics Pharmaceuticals. Speaker; Self; Amolyt Pharma, Crinetics Pharmaceuticals, Novo Nordisk, Pfizer, Recordati, and Sandoz-Hexal. M. Bidlingmaier: Consulting Fee; Self; Crinetics, Ionis, Novo Nordisk, Pfizer, Roche, and Sandoz. Grant Recipient; Self; Amolyt, Camurus, Chiasma, Crinetics, IDS, Ionis, Lumos, and OPKO. Speaker; Self; Euroimmun, Novo Nordisk, and Pfizer. M. Buchfelder: Grant Recipient; Self; Crinetics Pharmaceuticals. P.J. Trainer: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. S. Struthers: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. A. Krasner: Employee; Self; Crinetics Pharmaceuticals. M. Gadelha: Consulting Fee; Self; Crinetics, Ipsen, Novo Nordisk, and Recordati. Grant Recipient; Self; Crinetics and Recordati. Speaker; Self; Ipsen, Novo Nordisk, and Recordati. 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. The first phase 3, randomized, placebo-controlled trial (PATHFNDR-1; NCT04837040) demonstrated maintenance of biochemical and symptom control in patients with acromegaly converted from injected depot somatostatin receptor ligands (SRLs) to once-daily paltusotine. Here, we report results from PATHFNDR-2, a phase 3, randomized, placebo-controlled trial of paltusotine in medically untreated patients with active acromegaly (NCT05192382). Eligible patients were stratified as: (1) medication naïve (IGF-I ≥1.3 ×ULN and ≥1 pituitary surgery ≥3 months prior) or previously treated but stopped medications ≥4 months prior (IGF-I ≥1.3 ×ULN), or (2) previously controlled on injected octreotide or lanreotide and underwent washout (IGF-I increase ≥30% to ≥1.1 ×ULN). Patients were randomized to paltusotine or placebo for 24 weeks. The starting dose was 20 mg once-daily, with titration to 40 mg (if tolerated) at Wk 2 and then to 60 mg (Wks 6-12) if IGF-I was >0.9 ×ULN. A total of 111 patients (stratum 1, n=82; stratum 2, n=29) were randomized and received study medication (paltusotine, n=54; placebo, n=57). Fixed sequential testing was performed for primary and secondary endpoints. The primary endpoint was met: 55.6% of paltusotine-treated patients had IGF-I ≤1.0 ×ULN (mean of Wks 22 and 24) vs 5.3% for placebo (OR: 42.81; 95% CI: 8.44, 455.8; P<0.0001). Primary endpoint results were consistent within both strata in a pre-specified sensitivity analysis: stratum 1 (medication naïve or previously treated), 42.5% vs 2.4% (P<0.0001); stratum 2 (washed out), 92.9% vs 13.3% (P<0.0001). All secondary endpoints were met. Mean (±SE) change from baseline IGF-I was -0.82±0.08 ×ULN with paltusotine vs 0.09±0.08 ×ULN with placebo (P<0.0001). IGF-I was <1.3 ×ULN in 66.7% vs 14.0% of patients (OR: 18.32; 95% CI: 5.64, 79.16; P<0.0001) Mean (±SE) change from baseline Acromegaly Symptom Diary score improved (-2.7±1.4) with paltusotine vs worsening (+2.8±1.4) with placebo (P=0.004). GH (5-sample mean) was <1.0 ng/mL in 57.4% vs 17.5% of patients (OR: 7.59; 95% CI: 2.78, 23.48; P<0.0001). In the paltusotine group, IGF-I was reduced in 92.6% of patients at end of treatment, with the majority of the effect seen by Wks 2 to 4. The most common AEs were characteristic of SRLs or acromegaly symptoms. There were no serious AEs in the paltusotine group. No new safety signals were observed. In conclusion, paltusotine demonstrated rapid and sustained response in patients with active acromegaly and was well tolerated. Taken together with the findings of PATHFNDR-1, these results indicate that paltusotine has the prospect of being a once-daily, oral alternative to injected SRLs in patients who require medical therapy for acromegaly. Support: Crinetics Pharmaceuticals. Presentation: 6/3/2024