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Adrenocorticotropic hormone (ACTH) is an important modulator of steroidal hormone synthesis and secretion from the adrenal gland and its selective activity at the melanocortin type 2 receptor (MC2) dictates the synthesis and secretion of cortisol (corticosterone in rats). Excess ACTH action contribute to the pathophysiology of Cushing’s disease (CD), ectopic ACTH secreting tumors (EAS), and Congenital Adrenal Hyperplasia (CAH). Cushing’s disease results from a microadenoma derived from pituitary corticotrophic cells that secretes excess ACTH, whereas EAS arises from nonpituitary ACTH secreting tumors. Excess ACTH action at the adrenal gland and resulting hypercortisolemia presents in a myriad of symptoms that result in high morbidity. CAH results from inactivating mutations in steroid synthesis pathways, resulting in lack of cortisol and aldosterone production. Lack of negative feedback by cortisol at the level of the pituitary causes the over-secretion of ACTH, and overproduction of adrenal androgens, causing significant virilization and reduction in quality of life. We hypothesize that blocking ACTH action directly via a selective MC2 receptor antagonist may provide an important new therapeutic mechanism for these patients. To test this hypothesis, Crinetics launched an iterative medicinal chemistry program to identify potent and selective nonpeptide ACTH antagonists with pharmaceutical and safety characteristics suitable for evaluation in human clinical trials. Unlike most other G protein coupled receptors, MC2 requires the presence of an accessory protein (MRAP) for cell surface expression and recognition of ACTH. Using CHO-K cells stably expressing this MC2-MRAP complex, iterative optimization led to the discovery of multiple chemical classes of highly potent, nonpeptide MC2 receptor selective antagonist leads, which were then further optimized for drug-like characteristics. We identified multiple compounds that exhibit high potency for human and rat MC2 receptors (hMC2 Kb

Cushing’s disease (CD) and Ectopic ACTH syndrome (EAS) stem from excess circulating adrenocorticotropic hormone (ACTH) and resulting hypercortisolemia. In CD, excess ACTH is secreted from pituitary tumors, whereas excess ACTH in EAS arises from nonpituitary tumors. ACTH acts on the adrenal melanocortin type 2 (MC2) receptor to control the synthesis and secretion of adrenal hormones, including the stress hormone cortisol (corticosterone in rats) which accounts for the comorbidities of CD and EAS. Availability of a potent ACTH antagonist that can normalize cortisol in patients with diseases of excess ACTH will be a major advance in endocrinology. Additionally, an ACTH antagonist will have utility in congenital adrenal hyperplasia (CAH) because of its ability to block production of excess adrenal androgens. Crinetics is evaluating and developing ACTH antagonists for the treatment of diseases of excess ACTH. To our knowledge, these compounds represent the first potent nonpeptide ACTH antagonists to demonstrate in vitro potency and in vivo efficacy. As a result, the direct effects of sustained MC2 receptor blockade on the structure and function of the adrenal gland have never been able to be assessed. We examined the effects of several orally bioavailable ACTH antagonists across a range of doses on Sprague-Dawley rat adrenal gland weight, histology, and hormone levels in repeat dosing (7-14 days) studies. Sustained MC2 receptor antagonism dose dependently blocked activity of ACTH at the level of the adrenal gland and reduced plasma corticosterone levels. In the normal rat, this resulted in dose-dependent atrophy of the adrenal gland as assessed by organ weights and microscopically. The atrophy was primarily observed in the cortisol producing zona fasciculata, as well as in the zona reticularis, with smaller reductions noted in the aldosterone producing zona glomerulosa. Additionally, hypertrophy of the adrenal glands caused by continuous subcutaneous administration of exogenous ACTH was reversed by treatment with an ACTH antagonist. The adrenal effects were accompanied by expected changes in corticosterone levels. These preclinical findings demonstrate the therapeutic potential of ACTH antagonism and provide a strong rationale for development of an orally bioavailable drug that can be used to combat CD, EAS, and CAH.

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 {"type":"entrez-protein","attrs":{"text":"CRN00808","term_id":"1048626668","term_text":"CRN00808"}}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 ({"type":"clinical-trial","attrs":{"text":"NCT03789656","term_id":"NCT03789656"}}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 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.

Injected depot formulations of somatostatin peptide analogs are routinely used to treat acromegaly and neuroendocrine tumors (NETs). CRN00808 is a small molecule nonpeptide selective somatostatin receptor 2 agonist whose safety, pharmacokinetics (PK), and pharmacodynamics (PD) has been characterized in preclinical studies. This study describes the final results from a first-in-human, single and multiple ascending dose Phase 1 study in healthy volunteers to measure the safety, PK, PD, and midazolam drug interaction potential of CRN00808 (NCT03276858; preliminary results with blinded safety data presented at ENDO 2018). In the single dose arm of the study, cohorts of 8 subjects (6 active: 2 placebo) received CRN00808 as an oral solution or capsules (1.25 mg to 60 mg, or placebo). The effect of food on CRN00808 PK was also evaluated. In the multiple dose arm, cohorts of 9 subjects (6 active: 3 placebo) received CRN00808 capsules once daily (5 mg to 30 mg, or placebo) for 7-10 days. In the drug-interaction arm, a single cohort of 8 subjects received 20 mg of CRN00808 for 7 days; midazolam PK was assessed before (Day -2) and after (Day 7) administration of CRN00808. Safety and PK were assessed in all phases of the study. Suppression of GHRH-induced GH secretion and suppression of serum IGF-1 were measured as PD endpoints in the single and multiple dose phases of the study, respectively. Once daily administration of 5-30 mg CRN00808 capsules exhibited dose-dependent increases in peak (Cmax) and total (AUC) plasma exposures. The apparent terminal elimination half-life was determined to be of 42-50 hours and steady state was achieved in 3-5 days. Capsules taken with a standard high fat, high calorie meal resulted in a markedly lower plasma CRN00808 AUC (83%). Oral administration of CRN00808 resulted in dose-dependent suppression of both GHRH stimulated GH and IGF-1 secretion; a single 10 mg dose was found to cause 91% suppression of GHRH-stimulated GH and 10 mg once per day for 10 days resulted in maximal suppression of serum IGF-1. Midazolam PK was unaffected by co-administration of 20 mg CRN00808, suggesting little or no risk of drug interaction with CYP3A4/5 substrates. Treatment emergent adverse events associated with CRN00808 were generally mild and transient, and consistent with those reported with other somatostatin agonists. In conclusion, results from this Phase I clinical trial in healthy volunteers support further clinical development of CRN00808 as a once-daily oral treatment of patients with acromegaly.

Congenital hyperinsulinism (CHI) results from mutations within the insulin secretion pathway and is characterized by excessive and/or inappropriate insulin secretion by pancreatic islet β-cells. CHI is the most common cause of persistent hypoglycemia in newborns and infants and is estimated to affect 1/30,000 to 1/50,000 live births. Prompt recognition and treatment are vital to prevent coma, long-term neurological complications, and even death. If medical control of CHI is unsuccessful, near-total pancreatectomy may be required. The neuropeptide somatostatin is an important modulator of pancreatic hormonal signaling and activity at different somatostatin receptor (sst) subtypes dictates the suppression of insulin and/or glucagon. Glucagon secretion from α-cells is inhibited through sst2 receptors and insulin secretion from β-cells is inhibited through activation of sst2, sst3, and sst5. The injectable peptide drugs octreotide and lanreotide are potent agonists at sst2 and are often deployed as the last medical intervention to prevent or delay pancreatectomy. These peptides’ sst2 activity leads to inhibition of glucagon secretion, potentially reducing their effectiveness and compromising a key defense mechanism against hypoglycemia. We hypothesize that agonists targeting sst5 but lacking sst2 activity will possess an optimal efficacy/safety profile for patients with hyperinsulinemic hypoglycemia. Using iterative medicinal chemistry, Crinetics has discovered several classes of highly potent, orally bioavailable, small molecule sst-subtype selective agonists with drug-like pharmaceutical properties. Our discovery efforts aimed at finding a compound to treat CHI have yielded potent and selective nonpeptide sst5 agonists with sub-nanomolar EC50s in cell-based assays of receptor activation. These compounds also typically possess similar potency for the rat sst5 receptor. To probe their physiological consequences and to gain mechanistic insights, we compared the acute and chronic effects of these agonists to the peptide pasireotide, a pan-sst agonist that is most potent at sst5, on glycemic control in several rat models, which generally demonstrate a high degree of translation to humans. These preclinical studies evaluated the effects of the sst5 agonists during oGTT, ipGTT, sulfonylurea-induced hypoglycemia, and on blood glucose levels in both the fed and fasted states. In each model, selective nonpeptide sst5 agonists suppressed insulin secretion and raised blood glucose levels while having minimal effects on glucagon secretion, as predicted by their in vitro pharmacology. These results support our efforts to develop potent nonpeptide selective sst5 agonists with pharmaceutical and safety profiles suitable for evaluation in human clinical trials.

CRN04894 is an orally administered nonpeptide that is a potent and selective antagonist for adrenocorticotropic hormone (ACTH) acting at the melanocortin 2 receptor (MC2R) and is currently under development for the treatment of diseases of ACTH excess such as Cushing’s disease, congenital adrenal hyperplasia, and ectopic ACTH-secreting tumors. Cushing’s disease results from an adenoma derived from pituitary corticotropic cells that secrete excess ACTH, whereas ectopic ACTH syndrome arises from nonpituitary ACTH secreting tumors. Congenital adrenal hyperplasia is a genetic disease that results in cortisol deficiency leading to high levels of ACTH and adrenal androgens. Each of these indications is characterized by high ACTH levels that act on MC2R expressed in the adrenal cortex to drive pathological elevations of adrenally derived steroid hormones. CRN04894 blocks the action of ACTH at MC2R, providing a potential novel treatment for these diseases. Preclinical models of chronic hypercortisolemia include implantation of ACTH-secreting pituitary tumor cells in mice and continuous administration of ACTH via subcutaneously implanted osmotic pumps in rats. These models induce features consistent with human diseases of ACTH excess including hypercortisolemia and hypertrophy of the adrenal glands. We employed both rodent models to examine the pharmacodynamic effects of CRN04894 on corticosterone levels and adrenal gland morphology. In the mouse pituitary tumor model, subcutaneous inoculation of the ACTH-secreting mouse pituitary tumor cell line, AtT-20, into immunodeficient mice resulted in formation of tumors and increased plasma ACTH and corticosterone levels. Repeated daily oral administration of CRN04894 for 14 days dose-dependently and robustly suppressed plasma corticosterone levels in mice with AtT-20 tumors. In the rat model, subcutaneous implantation of osmotic pumps delivering ACTH resulted in increased corticosterone levels, reduction in body weight, and hypertrophy of the adrenal glands after 7 days. Daily oral administration of CRN04894 over 7 days dose-dependently suppressed corticosterone levels, mitigated the effect of ACTH excess on body weight, and rescued the adrenal gland hypertrophy. These findings provide evidence that CRN04894 functions as an effective ACTH antagonist at MC2R to suppress adrenal corticosterone secretion in both mouse and rat models of ACTH excess and hypercortisolemia, thus providing a strong rationale for its potential therapeutic utility in diseases of ACTH excess. This work was supported in part by an SBIR grant from the NIH awarded to Dr. Struthers (R43- DK115245)

Objective: There are five situations in a women’s life during which hormone fluctuations make them more susceptible to oral health problems – during puberty, at certain points in the monthly menstrual cycle, when using birth control pills, during pregnancy, and at menopause. The present study aimed at evaluating the effect of menstruation, pregnancy and menopause on salivary flow rate, pH and gustatory function. Materials and Methods: The study was carried out on 120 patients including 30 controls (with normal menstrual cycle of 28 to 30 d) and 90 cases (30 patients within three days of menstruation, 30 pregnant and 30 postmenopausal). Paraffin-stimulated saliva samples were obtained by expectoration to calculate salivary flow rate, pH was measured electrometically and patients were prospectively evaluated for gustatory function. Then, whole mouth taste test was performed in which the quality identification and intensity ratings of taste solutions were measured. Results: No statistically significant difference was found between the groups with respect to salivary flow rate but pH values were significantly lower in post menopausal women (p