On March 22, 2021 Crinetics Pharmaceuticals, Inc. (Nasdaq: CRNX), a clinical stage pharmaceutical company focused on the discovery, development, and commercialization of novel therapeutics for rare endocrine diseases and endocrine-related tumors, reported details of four presentations that were made at the Endocrine Society’s annual ENDO 2021 congress on the company’s product pipeline (Press release, Crinetics Pharmaceuticals, MAR 22, 2021, View Source [SID1234576990]). A late-breaking e-poster and oral presentation provided details of the preclinical findings supporting the company’s development of CRN04894 and CRN04777. In addition, a summary of the previously announced ACROBAT Edge Phase 2 results as well as details of an improved tablet formulation of paltusotine were presented:

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Selective Somatostatin 5 (SST5) and Somatostatin 2 (SST2) Nonpeptide Agonists Potently Suppress Glucose- and Tolbutamide-Stimulated Dynamic Insulin Secretion from Isolated Human Islets
Effects of CRN04894, a Nonpeptide Orally Bioavailable ACTH Antagonist, on Corticosterone in Rodent Models of ACTH Excess
Pharmacokinetics and Safety of an Improved Oral Formulation of Paltusotine, a Selective, Nonpeptide Somatostatin Receptor 2 (SST2) Agonist for the Treatment of Acromegaly
Safety and Efficacy of Switching Injected Peptide Long-Acting Somatostatin Receptor Ligands to Once Daily Oral Paltusotine: ACROBAT Edge Phase 2 Study
"I have never been more excited to share our data with the audience at ENDO. We believe CRN04894, which is now in Phase 1 development, represents an important advancement in the field of the endocrine stress axis. We also presented encouraging findings from our SST5 agonist program, from which we developed CRN04777. I am especially excited about this candidate, which I believe , if successfully developed and approved, has the potential to offer real benefit to kids with congenital HI and their families," stated Scott Struthers, Ph.D., president and CEO of Crinetics. "In addition to our early-stage pipeline programs, we presented information from the Phase 2 ACROBAT Edge study and the new formulation of paltusotine to be used in our Phase 3 acromegaly program."

Crinetics presented a late-breaking e-poster describing the potential of SST5 receptor agonists to regulate glucose-stimulated insulin secretion from human islet cells. One of somatostatin’s roles in maintaining blood glucose concentrations is to regulate insulin secretion, yet the lack of highly selective agonists has previously hampered efforts to identify the role of the individual somatostatin receptor subtypes in this process. In its preclinical efforts, Crinetics observed that SST5 receptor agonists were potent inhibitors of insulin secretion in the healthy pancreas and under conditions that stimulate excess insulin secretion. Based on these results, the company believes that a selective SST5 agonist may have therapeutic value in the treatment of congenital HI, which is a condition associated with dysregulated insulin secretion. Based on these preclinical findings, Crinetics advanced CRN04777, an experimental oral nonpeptide SST5 agonist, into a clinical program for congenital HI. CRN04777 is currently being evaluated in a Phase 1 trial designed to evaluate safety, pharmacokinetics, and clinical proof-of-concept by employing well-established methods for evaluating insulin secretion.

Crinetics also discussed preclinical results related to CRN04894, an oral nonpeptide ACTH antagonist, during a live oral presentation at ENDO 2021. CRN04894 recently advanced into a Phase 1 clinical program in healthy volunteers that is designed to evaluate safety, pharmacokinetics, and clinical proof-of-concept by measuring the ability of CRN04894 to suppress cortisol, cortisol precursors and adrenal androgens following exogenous ACTH stimulation. Preclinical data featured in the oral presentation showed that repeat dosing of CRN04894 suppressed plasma corticosterone levels in a robust and dose-dependent manner in animal models of ACTH excess. Results also showed that after seven days, the weight gain and adrenal gland hypertrophy caused by excess ACTH were reduced. This evidence supports the further evaluation of CRN04894 in conditions such as Cushing’s disease and congenital adrenal hyperplasia (CAH), which are associated with excessive ACTH.

"ENDO 2021 was our first opportunity to present the entirety of our growing clinical-stage pipeline, including the supportive evidence for our emerging programs in congenital HI and diseases of ACTH excess like Cushing’s disease and CAH," added Alan S. Krasner, M.D., Crinetics’ chief medical officer. "We are extremely excited to expand our development efforts to three clinical programs with more expected from our experienced in-house discovery team."

In addition to the company’s pipeline programs, Crinetics presented two posters on paltusotine, (formerly CRN00808) for the treatment of acromegaly, including results from the Phase 2 ACROBAT Edge study. Edge was a single-arm study designed to evaluate the impact of switching patients with acromegaly from monthly injected somatostatin receptor ligands (SRLs) to paltusotine, an experimental oral, once-daily, nonpeptide SST2 receptor agonist. Edge enrolled individuals who had not achieved normal insulin-like growth factor-1 (IGF-1) levels despite receiving long-acting octreotide or lanreotide. As previously reported, after 13 weeks of treatment 20 of 23 participants who completed the dosing period maintained their IGF-1 to levels within 20% of their baseline or lower. 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.

Crinetics plans to advance paltusotine into a Phase 3 clinical program in acromegaly in the first half of 2021 using a new tablet formulation. Results of a Phase 1 pharmacokinetic study reported at ENDO 2021 demonstrated that this new once-daily tablet formulation of paltusotine had a fasting requirement of only 0.5-1 hour, compared to the 2-hour requirement of the prior capsule formulation. The tablet formulation also showed improved dose-proportional exposure up to 80 mg, which offers the potential for greater dosing flexibility compared to the prior formulation. In addition, the new tablet formulation was observed to be less sensitive to effects of acid lowering drugs, such as proton pump inhibitors (PPIs). In planned Phase 3 studies of paltusotine, the new tablet formulation will be administered with a 1-hour post-dose fast without the exclusion of acid lowering drugs.

All presentations made at the annual ENDO 2021 congress may be accessed in the virtual conference environment through April 30, 2021. In addition, they will be available on the Crinetics website.

ABOUT PALTUSOTINE
Paltusotine (formerly CRN00808) is an investigational, orally available nonpeptide agonist that is designed to be highly selective for the somatostatin receptor type 2 (SST2). It was designed by the Crinetics discovery team to provide a once-daily option for patients with acromegaly and neuroendocrine tumors, which are currently treated by injected therapies that have approximately $3.2 billion in revenues annually. A previously completed Phase 1 trial of paltusotine showed clinical proof of concept by providing evidence of potent suppression of the growth hormone (GH) axis in healthy volunteers. In Phase 2 trials, paltusotine maintained insulin-like growth factor-1 (IGF-1) levels in acromegaly patients who switched from injectable depot medications to once-daily oral paltusotine. IGF-1 is the primary biomarker endocrinologists use to manage their acromegaly patients. Based on these findings, Crinetics plans to advance paltusotine into a Phase 3 program for acromegaly in the first half of 2021.

ABOUT CRN04777
CRN04777 is an investigational, orally available selective nonpeptide somatostatin receptor type 5 (SST5) agonist designed to reduce insulin secretion and is intended to be a universal treatment for patients with congenital hyperinsulinism (HI). Congenital HI is a severe form of hyperinsulinism that, if not identified and treated early, can lead to life-threatening hypoglycemia, severe neurological sequelae and developmental delay. Congenital HI is driven by mutations in certain genes involved in regulating insulin secretion and occurs in approximately 1 in 30,000 to 50,000 new births in the United States. In 2020, the U.S. Food and Drug Administration granted rare pediatric disease designation for CRN04777 for the treatment of congenital HI. CRN04777 is being evaluated in a Phase 1 study in healthy volunteers to assess safety, tolerability, and clinical proof of concept.

ABOUT CRN04894
CRN04894 is an investigational, orally available, nonpeptide adrenocorticotropic hormone (ACTH) antagonist designed to selectively block the interaction of ACTH at the melanocortin type 2 receptor (MC2R), which is predominantly expressed in the adrenal gland. ACTH is synthesized and secreted by the pituitary gland and binds to MC2R to stimulate the production of cortisol, a stress hormone that is involved in the regulation of many systems. Cortisol is involved in the regulation of blood sugar levels, metabolism, inflammation, blood pressure, and memory formulation. Diseases associated with excess of ACTH, therefore, can have significant impact on physical and mental health. Crinetics’ ACTH antagonist, CRN04894, exhibited strong binding affinity for MC2R and demonstrated suppression of adrenally derived glucocorticoids that are under the control of ACTH, while maintaining mineralocorticoid production in preclinical models. CRN04894 is being evaluated in a Phase 1 study in healthy volunteers to assess safety, tolerability, and clinical proof of concept.