H. Randeva*a (Prof), M. Gadelhab (Prof), M. Gordonc (Dr), E. Mezosid (Dr), M. Doknice (Dr), M. Tothf (Prof), C. Boguszewskig (Prof), R. Luoh (Dr), A. Krasnerh (Dr), A. Casagrandeh (Dr), S. Struthersh (Dr)

a University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UNITED KINGDOM ; b Neuroendocrinology Research Center/Endocrinology Division, Medical School and Hospital Universitario Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeirol, Rio De Janeiro, BRAZIL ; c Allegheny Neuroendocrinology Center, Allegheny General Hospital, Pittsburgh, UNITED STATES ; d 1st Department of Internal Medicine, University of Pecs, Pecs, HUNGARY ; e Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Centre Serbia, Belgrade, SERBIA ; f Department of Internal Medicine and Oncology, Semmelweis University, Budapest, HUNGARY ; g Endocrine Division, Department of Internal Medicine, Federal University of Parana, Curitiba, BRAZIL ; h Crinetics Pharmaceuticals, San Diego, UNITED STATES

* harpal.randeva@uhcw.ac.uk

Paltusotine is a once daily, oral, nonpeptide, somatostatin receptor agonist highly selective for subtype 2 receptor currently being evaluated for the treatment of acromegaly and carcinoid syndrome. We report the interim long-term safety and efficacy data from the ACROBAT Advance (NCT04261712) an ongoing, phase 2, non-randomized, multicenter, open-label, long-term extension study. Eligible subjects have participated in the previously reported phase 2 parent studies, ACROBAT Edge (EudraCT 2018-002230-20), and Evolve (EudraCT 2018-001833-42).

Of 49 eligible subjects, 41 [(23 female, median age of 52 (IQR 46-62) years, 85% previous pituitary surgery, no patient had RT] were enrolled in the study. Pre-trial all subjects were on the somatostatin receptor ligands (SRLs), as monotherapy or in combination therapy with cabergoline or pegvisomant. Most subjects were on the maximum approved dose of SRL prior to study entry.

Subjects started oral paltusotine at 10 mg daily with the option of titration up to 40 mg based on IGF-1 levels and toleration. Adjunctive medication was allowed for subjects with IGF‑1 values above the upper limit of normal (ULN) on 40 mg of paltusotine monotherapy.

At the time of this data cut, IGF-1 levels were equivalent to study entry, either as paltusotine monotherapy (n=29) or in combination with cabergoline (n=112:

IGF-1 (median (IQR)x ULN))

Study entry (n=41) 1.15 (0.84, 1.46)

Week 31 (n=31) 1.06 (0.81, 1.41)

Week 51 (n=23) 1.13 (0.86, 1.39)

Paltusotine was generally well tolerated. The most common treatment-emergent adverse events reported were consistent with symptoms of acromegaly (headache 29.3%, arthralgia 22%, and fatigue 14.6%) or the known GI side effects of SRLs.

During the study, there were three non-study-drug related SAEs reported in two subjects (gallstone pancreatitis, worsening of coronary artery disease followed by sinus arrest postcoronary artery bypass surgery) and four non-drug related discontinuations.

In conclusion, once-daily, oral paltusotine lowered and maintained IGF-1 at levels comparable to prior injected SRL therapy for up to 51 weeks. Data from the second cut will be presented at the congress.

The author has declared the following conflict(s) of interest:

Harpal Randeva - no conflicts

Monica Gadelha - Principal Investigator - clinical trials: Crinetics, Novartis and Recordati Rare Diseases.  Speaker fee: Crinetics, Novo Nordisk, Ipsen, Recordati Rare Diseases, Novartis.  Advisory board member: Ipsen, Recordati Rare Diseases, Novo Nordisk, Crinetics

Murray Gordon - Investigator for Crinetics trials.  Research support: Ascendis, Camurus, Chiasma, Crinetics, Ibsen, Novartis, Novo Nordisk, Pfizer

Scientific Consultant: Crinetics, HRA Pharma, Ibsen, Novo Nordisk

Emese Mezosi - no conflicts

Mirjana Doknic - no conflicts

Miklos Toth -consulting fees from Novartis, Ipsen, Recordati and Pfizer

Cesar Boguszewski - Clinical Investigator Ipsen, Crinetics and Recordati. Speaker fee Novartis Consultant Ipsen, Novartis

Rosa Luo - employee and stock holder in Crinetics Pharmaceuticals

Alan Krasner - employee and stock holder in Crinetics Pharmaceuticals

Alessandra Casagrande - employee and stock holder in Crinetics Pharmaceuticals

Scott Struthers - employee and stock holder in Crinetics Pharmaceuticals