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

Abstract

Context Paltusotine is a once-daily, oral, non-peptide small-molecule somatostatin receptor type 2 (SST2) agonist in clinical development for treatment of acromegaly. Objective To evaluate change in IGF-I levels in patients switched from octreotide LAR or lanreotide depot monotherapy to paltusotine. Design Phase 2, open-label, prospective, multicenter, multinational, non-randomized, single-arm exploratory study in which dosage up-titrations were performed in a double-blinded manner. Setting 26 global sites. Participants Patients with acromegaly switched to paltusotine from injected SRL-based therapy. Interventions Patients received 13-week treatment with once-daily oral paltusotine (10-40 mg/day). Main Outcome Measures Primary endpoint was change from baseline to week 13 in IGF-I for patients who switched from long-acting octreotide or lanreotide monotherapy to paltusotine (Group 1). All patients underwent a 4-week paltusotine washout at end of treatment period (weeks 13-17). IGF-I, 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 = 0.6285; GH = -0.05 ng/mL, P = 0.6285). IGF-I and GH rose significantly in the 4 weeks after withdrawing paltusotine (median change in IGF-I = 0.55×ULN, P < 0.0001 [median increase 39%]; GH = 0.72 ng/mL, P < 0.0001 [109.1% increase]). No patients discontinued due to adverse events; no treatment-related serious adverse events were reported. Conclusions These results suggest once daily, oral paltusotine is 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.

Discovery of Paltusotine (CRN00808), a Potent, Selective, and Orally Bioavailable Non-peptide SST2 Agonist

“…These examples of pharmacodynamic efficacy were mirrored in a Phase 1 clinical study in healthy volunteers, in which paltusotine acutely suppressed GHRH-stimulated GH secretion and lowered IGF-1 levels over the course of several days . In a Phase 2 study, paltusotine was shown to maintain IGF-1 levels in acromegaly patients that switched from their parentally administered depots to oral paltusotine . Currently, paltusotine is being evaluated in Phase 3 trials in acromegaly patients and a Phase 2 study in NETs patients with carcinoid syndrome.…”

“… 23 In a Phase 2 study, paltusotine was shown to maintain IGF-1 levels in acromegaly patients that switched from their parentally administered depots to oral paltusotine. 30 Currently, paltusotine is being evaluated in Phase 3 trials in acromegaly patients and a Phase 2 study in NETs patients with carcinoid syndrome.…”

“…Analogues bearing other functional groups on this phenyl ring were prepared, as exemplified by compounds 30−32. It appears that the electron-donating methyl (30) and methoxy (31) groups were well-tolerated, exhibiting EC 50 values of 0.17 and 0.12 nM, respectively, but the electron-withdrawing cyano group (32) was found to be detrimental (EC 50 = 10 nM). Finally, replacing phenyl with its isostere pyridine to improve the physicochemical properties generated compound 33 with only moderate human SST2 activity (EC 50 = 50 nM).…”

Development and evaluation of the Acromegaly Symptom Diary

“…The psychometric properties of the ASD were evaluated using pooled data from two clinical trials, ACROBAT Evolve [ 16 ] (NCT03792555; n = 13) and ACROBAT Edge [ 17 , 18 ] (NCT03789656; n = 47). ACROBAT Evolve was a phase 2, double-blind, placebo-controlled, multicenter, randomized withdrawal study to evaluate the safety, pharmacokinetics, and efficacy of paltusotine in patients with an IGF-I within the age-related reference range while on SRL therapy in the form of octreotide long-acting release (LAR) or lanreotide depot.…”

Oral Octreotide Capsules and Paltusotine in Management of Acromegaly

“…The recently published phase II ACROBAT Edge study provides the first data assessing the safety and efficacy of paltusotine in patients with acromegaly. 35 Patients were enrolled into the primary analysis cohort and four additional exploratory groups. The primary analysis cohort (Group 1) comprised patients who were partial responders to stable iSRL.…”