ACROBAT Edge: Safety and Efficacy of Switching Injected SRLs to Oral Paltusotine in Patients With Acromegaly

Abstract

Context: Paltusotine is a once-daily, oral, nonpeptide small-molecule somatostatin receptor type 2 (SST2) agonist in clinical development for treatment of acromegaly.

Objective: This work aimed to evaluate change in insulin-like growth factor I (IGF-I) levels in patients switched from octreotide long-acting release or lanreotide depot monotherapy to paltusotine.

Methods: A phase 2, open-label, prospective, multicenter, multinational, nonrandomized, single-arm exploratory study was conducted in which dosage uptitrations were performed in a double-blinded manner. At 26 global sites, patients with acromegaly switched to paltusotine from injected somatostatin receptor ligand (SRL)-based therapy. Patients received 13-week treatment with once-daily oral paltusotine (10-40 mg/d). The primary end point was change from baseline to week 13 in IGF-I for patients who switched from long-acting octreotide or lanreotide depot monotherapy to paltusotine (group 1). All patients underwent a 4-week paltusotine washout at end of treatment period (wk 13-17). IGF-I, growth hormone (GH), patient-reported outcome, and safety data were collected.

Results: Forty-seven patients enrolled. In group 1 (n = 25), IGF-I and GH showed no significant change between SRL baseline and end of paltusotine treatment at week 13 (median change in IGF-I = -0.03×upper limit of normal [ULN]; P = .6285; GH = -0.05 ng/mL; P = .6285). IGF-I and GH rose significantly in the 4 weeks after withdrawing paltusotine (median change in IGF-I = 0.55×ULN; P < .0001 [median increase 39%]; GH = 0.72 ng/mL; P < .0001 [109.1% increase]). No patients discontinued because of adverse events (AE); no treatment-related serious AEs were reported.

Conclusion: These results suggest once-daily oral paltusotine was effective in maintaining IGF-I values in patients with acromegaly who switched from injected SRLs. Paltusotine was well tolerated with a safety profile consistent with other SRLs.

Keywords: acromegaly; clinical trial; paltusotine; phase 2; somatostatin receptor ligands; somatostatin receptor type 2; somatotropinoma.

Figure 1.

Study design. EoT, end of treatment; IGF-I, insulin-like growth factor I; med, medication; SRL, somatostatin receptor ligands; ULN, upper limit of normal; V, visit. *IGF-I measurements. **If study drug tolerated and previous IGF-I > 0.9×ULN at wk 2 and 5 or >1.0×ULN at wk 8.

Figure 2.

Patient disposition. IGF-I, insulin-like growth factor I; med, medication; SRL, somatostatin receptor ligands. *Efficacy analysis set.

Figure 3.

Median (interquartile range) IGF-I levels over time for patients in group 1. EoT, end of treatment; IGF-I, insulin-like growth factor I; ULN, upper limit of normal; V, visit. Efficacy analysis set.

Figure 4.

Median IGF-I levels for patients in group 1 at baseline, treatment week 13 (end of treatment, EoT), and 4 weeks after EoT (week 17). A, Median ± IQR IGF-I levels for patients in group 1 at baseline, week 13 (EoT), and 4 weeks after EoT (week 17). B, Percentage change in IGF-I from baseline to EoT and 4 weeks after EoT for individual patients in group 1. ETs, patients who terminated treatment early; IGF-I, insulin-like growth factor I; IQR, interquartile range; ULN, upper limit of normal. Efficacy analysis set. Baseline was calculated as a mean of the measurements from screening visits 1b and 2 and predose week 1. Data are presented as median (interquartile range: 25th percentile-75th percentile) EoT was defined as week 13 (visit 14) or the last on-treatment value for those who discontinued treatment. Four weeks after EoT was defined as week 17 or at least 22 days after the last dose. The shaded area represents expected biologic variability associated with IGF-1 measurements. P values were based on nonparametric Wilcoxon sign rank test of whether the median change was different from zero.

Figure 5.

Median ± IQR GH levels for patients in group 1 at baseline, treatment week 13 (end of treatment, EoT), and 4 weeks after EoT (week 17). Efficacy analysis set. Baseline was calculated as a mean of the integrated GH measurements from screening visits 1b and 2 and treatment week 1. Data are presented as median (interquartile range: 25th percentile-75th percentile). EoT was defined as week 13 (visit 14) or the last on-treatment value for those who discontinued treatment. EoT was defined as week 17 or result at least 22 days after last dose. P values were based on the nonparametric Wilcoxon sign rank test of whether the median change is different from zero. EoT, end of treatment; GH, growth hormone.

Figure 6.

Median ± IQR IGF-I levels for patients treated with SRL + cabergoline (groups 2 and 3) at baseline, treatment week 13 (end of treatment, EoT) and 4 weeks after EoT (week 17). Baseline was calculated as a mean of the measurements from screening visits 1b and 2 and treatment week 1. Data are presented as median (interquartile range: 25th percentile-75th percentile). EoT was defined as week 13 (visit 14) or the last on-treatment value for those who discontinued treatment. Four weeks after EoT was defined as week 17 or at least 22 days after the last dose. P values were based on the nonparametric Wilcoxon sign rank test of whether the median change was different from zero. EoT, end of treatment; IGF-I, insulin-like growth factor I; SRL, somatostatin receptor ligands; ULN, upper limit of normal.