Rapid and Sustained Response of Biochemically Uncontrolled Acromegaly to Once-daily Oral Paltusotine Treatment

Paltusotine is a nonpeptide, selective somatostatin receptor 2 agonist in development as once-daily oral treatment for acromegaly.

To evaluate efficacy and safety of paltusotine in patients with biochemically uncontrolled acromegaly not currently receiving medical therapy.

In this phase 3, randomized, double-blind, placebo-controlled trial, adults with medically untreated acromegaly at randomization (stratum 1: medication-naïve or off acromegaly medications ≥4 months [IGF-I ≥ 1.3 × upper limit of normal {ULN}]; stratum 2: controlled on a somatostatin receptor ligand and underwent washout [IGF-I increase ≥30% to ≥1.1 × ULN]) received paltusotine or placebo for 24 weeks.

A total of 111 patients (stratum 1, n = 82; stratum 2, n = 29) enrolled (paltusotine, n = 54; placebo, n = 57). The primary endpoint of IGF-I normalization at 24 weeks was met in 55.6% of paltusotine-treated patients vs 5.3% for placebo (odds ratio [OR]: 42.81; 95% CI, 8.44-455.82; P < .0001), with superiority to placebo in both strata. Paltusotine treatment decreased IGF-I in 92.6% of patients within the first 4 weeks. All secondary endpoints were met: mean (±SE) change in IGF-I of -0.82 ± 0.08×ULN with paltusotine vs 0.09 ± 0.08×ULN with placebo (P < .0001); IGF-I < 1.3×ULN in 66.7% vs 14.0% of patients (OR: 18.32; 95% CI, 5.64-79.16; P < .0001); GH (5-sample mean) < 1.0 ng/mL in 57.4% vs 17.5% (OR: 7.59; 95% CI, 2.78-23.48; P < .0001); mean (±SE) change in Acromegaly Symptom Diary score of -2.7 ± 1.4 vs 2.8 ± 1.4 (P = .004). Most adverse events were acromegaly symptoms or mild, transitory gastrointestinal effects characteristic of somatostatin receptor ligands (eg, diarrhea, abdominal pain). Pituitary tumor volume was stable or reduced in paltusotine-treated patients.

IGF-I normalized in significantly more patients with uncontrolled acromegaly treated with paltusotine vs placebo. Paltusotine was associated with rapid, sustained IGF-I reduction, significant symptom improvement and stable or reduced pituitary tumor size and was well tolerated.