Paltusotine (formerly CRN00808)


Paltusotine, our lead product candidate, establishes a new class of oral, selective, nonpeptide, somatostatin receptor type 2 (SST2) agonists designed for the treatment of acromegaly. Somatostatin is a neuropeptide hormone that broadly inhibits the secretion of other hormones, including growth hormone, or GH, from the pituitary gland. Acromegaly arises from a benign pituitary tumor that secretes excess GH that in turn causes excess secretion of insulin-like growth factor-1, or IGF-1, by the liver. This loss of homeostasis in the GH axis results in excess tissue growth and other adverse effects throughout the body.

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For the Treatment of Acromegaly


Somatostatin peptide analogs are the primary pharmacotherapy for those acromegaly patients who are candidates for chronic pharmacological intervention. Currently marketed peptide drugs require painful monthly or daily injections, or a strict twice-a-day oral dosing regimen. In the case of somatostatin peptide drugs, therapies often fail to fully control the disease in many acromegaly patients.

FOR THE TREATMENT OF NEUROENDOCRINE TUMORS (NETs)


Neuroendocrine tumors, or NETs, originate from the neuroendocrine cells commonly found in the gut, lung, or pancreas. NETs are heterogeneic in their behavior, comprising a spectrum of insidious, growing tumors to aggressive, quick-growing tumors. Most NETs express SST2 receptors and injected depots of peptide somatostatin analogs have become the first-line standard of care for many NETs patients, as detailed in National Comprehensive Cancer Network guidelines.

First Half 2021


We will begin Phase 3 trials in acromegaly and anticipate beginning a Phase 2 trial in NETs.

October 2020


Late 2018


Initiated two global Phase 2 clinical trials of paltusotine in acromegaly patients: ACROBAT EVOLVE and ACROBAT EDGE. Both completed their recruitment phase and were conducted at the same centers in the U.S. and globally. Patients who completed either study were eligible to participate in an open-label extension study (ACROBAT ADVANCE).

EVOLVE: Double-blind, placebo-controlled, randomized withdrawal study to evaluate the safety, efficacy, and pharmacokinetics of paltusotine compared to placebo in subjects with acromegaly who respond to octreotide LAR or lanreotide depot monotherapy.

EDGE: Open-label exploratory study to evaluate the safety, efficacy, and pharmacokinetics of paltusotine in subjects with acromegaly treated with somatostatin analog-based treatment regimens but who do not respond completely to monotherapy.

August 2018


Submitted an Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA).

March 2018


Initial results reported from a Phase 1, double-blind, randomized, placebo-controlled, single- and multiple-ascending dose trial to evaluate the safety, pharmacokinetics, and pharmacodynamics of paltusotine in 99 healthy volunteers.

Paltusotine demonstrated POC by potently suppressing stimulated GH and baseline IGF-1 in these subjects. Plasma exposure of paltusotine indicated the drug was well-absorbed with a half-life of 42 to 50 hours, supporting once-daily administration in patients. The safety and tolerability of paltusotine observed in this trial was generally consistent with that of approved peptide somatostatin analogs.

Safety and Efficacy of Switching Injected Peptide Long-Acting Somatostatin Receptor Ligands to Once Daily Oral Paltusotine: ACROBAT Edge Phase 2 Study


Results Support Switching from Injectables to Oral Paltusotine for Acromegaly

Acromegaly-Awareness-Day-2020-Symptoms1

Authors

Monica R. Gadelha, MD, PhD1, Murray B. Gordon, MD2, Mirjana Doknic, MD, PhD3, Emese Mezősi, MD, PhD, DSci4, Miklós Tóth, MD, PhD, DSci5, Harpal Randeva, MBChB, FRCP, FAcadTM, PhD6, Tonya Marmon, PhD7, Rosa Luo, MS8, Michael Monahan, MBA<sup8, Ajay Madan, PhD8, Christine Ferrara-Cook, MD, PhD8, Scott Struthers, PhD8, Alan Krasner, MD8.

 

Disclosures

M.R. Gadelha: Advisory Board Member; Self; Ipsen, Novartis Pharmaceuticals, Crinetics. Research Investigator; Self; Crinetics, Novartis Pharmaceuticals. Speaker; Self; Novartis Pharmaceuticals, Ipsen, Pfizer,
Inc. M.B. Gordon: Research Investigator; Self; Crinetics. M. Doknic: Research Investigator; Self; Crinetics. E. Mezősi: Research Investigator; Self; Crinetics. M. Tóth: Research Investigator; Self; Crinetics. H. Randeva: Research Investigator; Self; Crinetics. T. Marmon: Consulting Fee; Self; Crinetics. R. Luo: Employee; Self; Crinetics. M. Monahan: Employee; Self; Crinetics. A. Madan: Employee; Self; Crinetics. C. Ferrara-Cook: Employee; Self; Crinetics. S. Struthers: Employee; Self; Crinetics. A. Krasner: Employee; Self; Crinetics.

Abstract

Patients with acromegaly not cured by surgery are often initially treated with injected peptide long-acting somatostatin receptor ligands (SRLs). Non-peptide small molecules can also activate the somatostatin receptor and do so with a high degree of precision for the target therapeutic receptor subtype.

Paltusotine (formerly CRN00808) is a small molecule somatostatin type 2 (SST2) receptor agonist with high oral bioavailability (70%) and pharmacokinetic profile suitable for once daily dosing. In healthy volunteers, paltusotine has been shown to lower growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels. We hypothesized that patients with acromegaly could switch from injected SRLs to once daily oral paltusotine while maintaining baseline IGF-1 levels. ACROBAT Edge (NCT03789656) was a single-arm study designed

to evaluate the safety and efficacy of switching from injected SRLs to paltusotine in patients with acromegaly. The primary analysis population consisted of those who had not achieved normal IGF-1 levels despite stable therapy with long-acting octreotide or lanreotide. Eligible patients received their last injection of SRL 4 weeks prior to switching to once daily oral paltusotine monotherapy for a 13-week treatment period. The starting dose of 10 mg per day was uptitrated in 10 mg increments at specified study visits to a maximal dose of 40 mg per day based on protocol specified study drug toleration and IGF-1 criteria.

The primary endpoint was change in IGF-1 from baseline to the completion of the 13-week treatment period. Statistical testing was based on non-parametric Wilcoxon Sign Rank test of whether the median change is different from zero. In addition, the rise in IGF-1 during a 4-week washout period was used to provide supportive evidence of efficacy. Twenty- five patients were enrolled in the primary analysis group, three patients discontinued from the study for non-study drug related reasons, two during the treatment period and one during the washout period after completing treatment. The primary endpoint was achieved as paltusotine treatment resulted in no significant change in IGF-1 levels at week 13 compared to baseline [change in IGF-1 =-0.034 (-0.107, 0.107), median (IQR), p>0.6]. Of the 23 patients who completed the dosing period, 20 (87%) achieved IGF-1 levels at the end of treatment that were within 20% of baseline or lower. Median IGF- 1 values rose significantly after paltusotine washout (p<0.0001). The most common treatment-emergent adverse events (>10%) included: headache, arthralgia, fatigue, peripheral swelling, paresthesia and hyperhidrosis. There were no discontinuations due to adverse events and no treatment related serious adverse events. These results suggest that patients with acromegaly treated with injected SRLs can switch to oral paltusotine while maintaining IGF- 1 and that paltusotine appeared to be well tolerated.

1Neuroendocrinology Research Center/Endocrinology Division – Medical School and Hospital Universitario Clementino Fraga Filho-Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil, 2Allegheny General Hospital, Pittsburgh, PA, USA, 3Clinical Center of Serbia, Belgrade, Serbia, 4University of Pécs Medical School, Pécs, Hungary, 5Semmelweis University, Budapest, Hungary, 6University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom, 7Marmon Biostatistics, Seattle, WA, USA, 8Crinetics Pharmaceuticals Inc., San Diego, CA, USA.

Pharmacokinetics and Safety of an Improved Oral Formulation of Paltusotine, a Selective, Non-Peptide Somatostatin Receptor 2 (SST2) Agonist for the Treatment of Acromegaly


Improved Oral Formulation of Paltusotine for the Treatment of Acromegaly

Authors

Rosa Luo, MS1, Gerald Burke, PhD1, Cosina Mui, BSc1, Sepehr Shakib, Prof2, Christine Ferrara-Cook, M.D., Ph.D.1, Alan Krasner, MD1, Ajay Madan, PhD11Crinetics Pharmaceuticals, Inc., San Diego, CA, USA, 2CMAX Clinical Research Pty Ltd, Adelaide, Australia.

Disclosures

R. Luo: Employee; Self; Crinetics Pharmaceuticals. G. Burke: None. C. Mui: Employee; Self; Crinetics Pharmaceuticals. S. Shakib: None. C. Ferrara-Cook: Employee; Self; Crinetics Pharmaceuticals. A. Krasner: Employee; Self; Crinetics Pharmaceuticals. A. Madan: Employee; Self; Crinetics Pharmaceuticals.

Abstract

Depot injection formulations of peptide somatostatin receptor ligands (SRLs) are routinely used to treat acromegaly and neuroendocrine tumors (NETs). Paltusotine (CRN00808), an orally administered small molecule nonpeptide selective somatostatin receptor 2 (SST2) agonist has been shown to maintain GH and IGF-1 levels in acromegaly patients previously on depot SRLs (ACROBAT Edge NCT03789656). In this study, a capsule formulation was used, which did not exhibit dose proportional pharmacokinetics (PK) at doses >40 mg, required a 2-hour post-dose fast in overnight fasted patients, and had the potential for reduced bioavailability when taken with proton-pump inhibitors (PPI). A spray-dried dispersion (SDD) tablet formulation was developed with improved solubility in the physiological pH range and its performance was evaluated in healthy volunteers. Male and female healthy volunteers who met inclusion/exclusion criteria were enrolled in a single-center Phase 1 study (ANZCTR registration ACTRN12619001562167). A Cohort of 12 subjects was administered a single dose of paltusotine in a four-period cross-over design. Periods 1 and 2 assessed the effect of lansoprazole (a PPI) on PK of 20 mg dose of paltusotine SDD tablets.

In Period 3, 20 mg dose of paltusotine SDD tablets was co-administered with a high fat, high-calorie meal. In Period 4, a 60 mg dose of paltusotine SDD tablets was administered to assess dose proportionality. In a separate cohort of subjects (n=12; also, a 4-period cross- over design), the relative bioavailability of capsules and SDD tablets was assessed, and the effect of food administration 0.5, 1, and 2 hour post-dose was evaluated. Subsequently, in another cohort of 12 subjects (a 3-period cross-over design), dose proportionality of the SDD tablets was evaluated at 40 mg and 80 mg dose with a 1-hour post-dose fast. A 4 hours post-dose fast was also assessed for the 80 mg dose. Pharmacokinetics and safety of paltusotine were evaluated.

Paltusotine was generally well tolerated in this study. SDD tablets exhibited dose proportional increase in total systemic exposure (AUC) up to a dose of 80 mg. Healthy volunteers pretreated with the PPI, lansoprazole (15 mg bid for 3 days), and co-administered with paltusotine SDD tablets exhibited a small decrease (approximately 25%) in systemic exposure to paltusotine compared with the same subjects that had washed out from the PPI-pretreatment. SDD tablets exhibited significant reduction in systemic exposure when co-administered with a high-fat, high-calorie meal. However, the SDD formulation was less sensitive to timing of post-dose food administration compared to the capsule formulation. These data suggest that the SDD tablet formulation of paltusotine improves flexibility in dose administration, can be co-administered with PPIs and other agents that increase stomach pH, and reduces the post-dose fasting requirement.

1) Crinetics Pharmaceuticals, Inc., San Diego, CA, USA, and 2) CMAX Clinical Research Pty Ltd, Adelaide, Australia.

Absolute Oral Bioavailability and Absorption, Metabolism, Excretion of [14C]-Labeled Paltusotine (CRN00808), an Orally Bioavailable, Nonpeptide, Selective, Somatostatin Receptor 2 (sst2) Biased Agonist for the Treatment of Acromegaly

Ajay Madan, Rosa Luo, Christine Ferrara-Cook, R. Scott Struthers, Sjoerd van Marle, and Alan Krasner Crinetics Pharmaceuticals, San Diego, CA, USA. PRA Health Sciences, Groningen, The Netherlands.

Final Results From the First in Man Phase 1 Clinical Trial of CRN00808, an Orally Bioavailable sst2-Selective, Nonpeptide Somatostatin Biased Agonist for the Treatment of Acromegaly: Safety, Pharmacokinetics, Pharmacodynamics, and Midazolam Drug Interaction in Healthy Volunteers

Ajay Madan, Yun Fei Zhu, Stacy Markison, Stephen F. Betz, Alan Krasner, Rosa Luo, Tilman Oltersdorf, Theresa Jochelson, Jason Lickliter, R. Scott Struthers. ENDO 2019. March 23-26, 2019; New Orleans.