Acromegaly Disease Control Maintained After Switching From Injected Somatostatin Receptor Ligands to Oral Paltusotine

Abstract

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

Objective: To evaluate the efficacy and safety of paltusotine in the treatment of patients with acromegaly previously controlled with injected somatostatin receptor ligands (SRLs).

Methods: This phase 3, randomized, double-blind, placebo-controlled trial enrolled adults with acromegaly who had IGF-I ≤1.0 times the upper limit of normal (×ULN) while receiving a stable dose of depot octreotide or lanreotide. Patients were switched from injected SRLs and randomized to receive paltusotine or placebo orally for 36 weeks. The primary endpoint was proportion of patients maintaining IGF-I ≤1.0× ULN. Secondary endpoints were change in IGF-I level, change in Acromegaly Symptom Diary score, and maintenance of mean 5-sample GH <1.0 ng/mL.

Results: The primary endpoint was met: 83.3% (25/30) of patients receiving paltusotine and 3.6% (1/28) receiving placebo maintained IGF-I ≤1.0× ULN (odds ratio, 126.53; 95% CI, 13.73->999.99; P < .0001). Paltusotine was also superior to placebo for all secondary endpoints: mean (± SE) change in IGF-I of 0.04 ± 0.09× ULN vs 0.83 ± 0.1× ULN (P < .0001); mean (± SE) change in Acromegaly Symptom Diary score of -0.6 ± 1.5 vs 4.6 ± 1.6 (P = .02); mean GH maintained at <1.0 ng/mL in 20/23 (87.0%) vs 5/18 (27.8%) patients (odds ratio, 16.61; 95% CI, 2.86-181.36; P = .0003). The most common adverse events were acromegaly symptoms and gastrointestinal effects characteristic of SRLs.

Conclusion: Replacement of injected SRLs by once-daily oral paltusotine was effective in maintaining both biochemical and symptom control in patients with acromegaly and was well tolerated.

Keywords: IGF-I; acromegaly; clinical trial; paltusotine; somatostatin; somatostatin receptor 2.

Figure 1.

Study design.

Figure 2.

Patient disposition. ^aSponsor decision to discontinue participation of Russian study sites because of logistical study operation difficulties related to international conflict. Abbreviations: CYP, cytochrome P450; ULN, upper limit of normal.

Figure 3.

Primary endpoint: proportion of patients with IGF-I ≤1.0× ULN at the end of the randomized controlled phase. The primary endpoint was based on average of IGF-I values at weeks 34 and 36. Odds ratio is from an exact logistic regression model with categorical covariates of prior treatment (octreotide, lanreotide) and screening IGF-I level (<0.86× ULN, ≥0.86× ULN).

Figure 4.

IGF-I levels at baseline and end of treatment (week 36 or last assessment before rescue) for individual patients. Red lines represent patients who received rescue medication; blue (paltusotine) and gray (placebo) lines represent patients who completed the core phase without rescue.

Figure 5.

Mean IGF-I level at baseline and end of treatment. *P < .0001 for paltusotine vs placebo. Error bars indicate standard error.

Figure 6.

Proportion of patients with mean 5-sample GH <1.0 ng/mL at screening who maintained mean 5-sample GH <1.0 ng/mL at week 34 (secondary endpoint). Odds ratio is from an exact logistic regression model with categorical covariates of prior treatment (octreotide, lanreotide) and screening IGF-I level (<0.86× ULN, ≥0.86× ULN).

Figure 7.

Least-squares mean change in ASD total score from baseline at end of treatment (week 36 or last assessment before rescue) (secondary endpoint). Higher scores indicate worsening. Change from baseline values (reported as least-squares means) and treatment difference are from analysis of covariance. Error bars indicate standard error. Abbreviation: ASD, Acromegaly Symptom Diary.

Figure 8.

Least-squares mean change in ASD item scores from baseline at end of treatment (exploratory endpoint). Higher scores indicate worsening. Dashed line separates core items (left) from additional items and most bothersome symptom (right). Change from baseline values (reported as least-squares means) and P values are from analyses of covariance. Error bars indicate standard error. *P < .05 for paltusotine vs placebo; **P < .01 for paltusotine vs placebo. Abbreviation: ASD, Acromegaly Symptom Diary.