CRN00808 and CRN01941
For the Treatment of Acromegaly and Neuroendocrine Tumors (NETs)
Paltusotine, our lead product candidate (also known as CRN00808), establishes a new class of oral selective nonpeptide somatostatin receptor type 2, or sst2, biased 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 metabolic effects throughout the body.
More than 25,000 people in the United States suffer from acromegaly, and an estimated 40% to 60% are candidates for chronic pharmacological intervention, of which somatostatin peptide analogs are the primary pharmacotherapy. Currently marketed peptide drugs require painful monthly or daily injections and, in the case of somatostatin peptide drugs, often fail to fully control the disease in many acromegaly patients.
Neuroendocrine tumors, or NETs, originate from the neuroendocrine cells commonly found in the gut, lung, or pancreas, and are the second most common gastro-intestinal cancer after colon cancer. Typically, NETs are only diagnosed at a time of extensive metastatic disease and will often progress to liver failure. NETs are present in approximately 171,000 adults in the United States. Most NETs overexpress 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.
In March 2018, we reported initial results from a Phase 1, double-blind, randomized, placebo-controlled, single- and multiple-ascending dose trial to evaluate the safety, pharmacokinetics, or PK, and pharmacodynamics, or PD, of paltusotine (CRN00808) in 99 healthy volunteers. Paltusotine (CRN00808) demonstrated clinical proof-of-concept by potently suppressing stimulated GH and baseline IGF-1 in these subjects. The plasma exposure of paltusotine (CRN00808) 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 (CRN00808) observed in this trial was generally consistent with that of approved peptide somatostatin analogs.
In August 2018, we submitted an Investigational New Drug, or IND, application to the U.S. Food and Drug Administration, or FDA. In late 2018, we initiated two global Phase 2 clinical trials of paltusotine (also known as CRN00808) in acromegaly patients, the ACROBAT EVOLVE, or EVOLVE, and ACROBAT EDGE, or EDGE, trials. The EVOLVE trial is double-blind, placebo-controlled, randomized withdrawal study designed to evaluate the safety, efficacy and pharmacokinetics of paltusotine (CRN00808) compared to placebo, in subjects with acromegaly that respond to octreotide LAR or lanreotide depot monotherapy. The EDGE trial is an open label exploratory study designed to evaluate the safety, efficacy and pharmacokinetics of paltusotine (CRN00808) in subjects with acromegaly that are treated with somatostatin analog based treatment regimens but do not respond completely to monotherapy. The EVOLVE and EDGE studies will be conducted at the same centers in the U.S. and globally. Patients that complete either EVOLVE or EDGE will be eligible to participate in an open-label extension study.
More information and links to ACROBAT EDGE and ACROBAT EVOLVE can be found on our study site theacrobatstudies.com
CRN01941 is a separate oral, nonpeptide sst2 biased agonist that is currently being evaluated in a double-blind, randomized, placebo-controlled, single- and-multiple-dose Phase 1 study in healthy volunteers to evaluate its safety, pharmacokinetics, and pharmacodynamics. We expect results from this trial in early 2020.
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.