Abstract CRN04894 is a potent orally bioavailable MC2R (adrenal cortex specific ACTH receptor) antagonist (Kb=0.34 nM) that is >1000-fold selective for MC2R over other melanocortin receptor subtypes. In rats receiving continuous administration of ACTH via subcutaneously implanted osmotic pumps, oral administration of CRN04894 over 7 days has previously been shown to result in dose-dependent suppression of basal and ACTH stimulated corticosterone levels. This compound is in clinical development for the treatment of diseases of ACTH excess including congenital adrenal hyperplasia (CAH) and Cushing's Disease. We report initial results from a randomized double-blinded, placebo-controlled single ascending dose study evaluating the safety, pharmacokinetics and pharmacodynamics of CRN04894 in 39 healthy volunteers. After an overnight fast, single doses of CRN04894 were administered at approximately 8 am, 2 hours prior to an IV bolus of ACTH 1-24 (cosyntropin). Serial cortisol over 600 minutes and pharmacokinetics over 168 hours post CRN04894 dose were measured. Two different challenge doses of ACTH 1-24 were studied: 250 μg (supra-pharmacological) and 1 μg (comparable to ACTH concentrations encountered in CAH and Cushing's Disease). CRN04894 was rapidly orally absorbed (median tmax 0.5-1.5 hour), and demonstrated a dose dependent increase in systemic exposure, with an apparent terminal elimination t1/2 of approximately 20 hours. Unstimulated (basal) cortisol measured 2 hours after CRN04894 administration fell in a dose-dependent manner, resulting in reduction near the theoretical maximum with the 80 mg dose cohort (-56.1% [SEM 4.0%, n=12] vs +17.4% in placebo [SEM=18.1%, n=9]). Dose-dependent cortisol suppression following a supra-pharmacological ACTH-stimulated (250 μg) was also observed, with a 41% reduction in the area under the curve (AUC60-600min) post-stimulation at the 80 mg dose. Furthermore, a single dose of 80 mg of CRN04894 reduced the cortisol response (AUC15-120 min) to a disease relevant 1 μg ACTH challenge by 48%, maintaining cortisol concentrations within the normal range seen prior to dosing in a basal unstimulated state. Single doses of CRN04894 were well tolerated with no need for glucocorticoid supplementation. All adverse events (AEs) were considered mild or moderate and there were no serious AEs. The data from this single-dose, proof-of-concept study show that MC2R antagonist CRN04894 was well tolerated after oral delivery in healthy volunteers and demonstrated dose-dependent increases in exposure with lowering of basal and ACTH-stimulated cortisol secretion, including in the presence of disease relevant excess ACTH exposure. Multiple ascending dose evaluations are underway in anticipation of studies in patients with diseases of ACTH excess. Presentation: Sunday, June 12, 2022 11:15 a.m. - 11:30 a.m.

Abstract Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in neonates, infants, and children, and is caused by genetic mutations in the insulin secretion pathway in pancreatic beta-cells. Current medical and surgical treatments are often highly burdensome, only partially effective, and associated with significant morbidity. CRN04777 is a potent orally bioavailable SST5 agonist (EC50=0.41 nM) that is >1300 fold selective over other SST receptor subtypes. CRN04777 has been shown to suppress both glucose- and sulfonylurea (SU)-induced insulin secretion in rats. The latter is a model for the most common known monogenic form of human congenital HI. We report initial results from a randomized, double-blinded, placebo-controlled single ascending dose study evaluating the safety, pharmacokinetics and pharmacodynamics of CRN04777 in 74 healthy volunteers. Endogenous insulin secretion was stimulated using intravenous glucose tolerance tests (IVGTT) or SU challenges in separate cohorts of volunteers. In the IVGTT cohorts, single doses of CRN04777 (0.5-120 mg) were administered after an overnight fast and 1 hour prior to an IV bolus of 300 mg/kg glucose, followed by serial measurements of blood glucose and insulin over 180 minutes. The SU-challenge cohorts received single doses of CRN04777 (30 and 60 mg) one hour after SU administration (5 mg of glibenclamide/glyburide), followed by measurement of the IV glucose infusion rate (GIR) over 8 hours under automated euglycemic clamp conditions (ClampArt®). CRN04777 was orally absorbed (Tmax 1-3 hours) and demonstrated a dose dependent increase in systemic exposures with an apparent terminal elimination t1/2 of approximately 40 hours. Basal insulin secretion was reduced dose-dependently, with a 73% reduction following 120 mg of CRN04777. Likewise, glucose stimulated insulin secretion during the IVGTT (plasma insulin AUC) was reduced dose-dependently by approximately 50% with a parallel doubling of plasma glucose AUC following 120 mg of CRN04777. CRN04777 resulted in dose-dependent reversal of SU-induced insulin secretion, with 79% and 90% reductions in insulin AUC5-180min, respectively, at 30 and 60 mg doses. At the 60 mg dose of CRN04777, no exogenous glucose infusion was needed to prevent SU-induced hypoglycemia. CRN04777 was well tolerated across the dose range evaluated. All adverse events (AEs) were considered mild or moderate and there were no serious AEs. The data from this single-dose, proof-of-concept study show that the selective SST5 agonist CRN04777 is well tolerated after oral administration in healthy volunteers, is suitable for once daily dosing and suppresses insulin secretion under basal and stimulated conditions, including in a pharmacologic model of congenital HI. Multiple ascending dose evaluations in healthy volunteers are underway to support future studies in congenital HI patients. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Abstract 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)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

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.

Abstract Injected depot formulations of somatostatin peptide analogs are routinely used to treat acromegaly and neuroendocrine tumors (NETs). CRN00808, a small molecule nonpeptide selective somatostatin receptor 2 (sst2) agonist, is being evaluated for efficacy and safety in patients with acromegaly. The current Phase 1 study was conducted in two Parts: In Part A, the absorption, metabolism, excretion, and mass balance of a single oral dose of 20 mg [14C]-CRN00808 (3.0 MBq) oral solution was characterized in six healthy male subjects. Plasma, blood, urine, and feces were collected for up to 432 hours, and were analyzed for total radioactivity and CRN00808 concentrations (plasma only). Metabolite profiling was conducted on the plasma, urine, and feces samples. In Part B, the absolute bioavailability of CRN00808 was determined by administering a single oral dose of 20 mg CRN00808 compared with a single micro-tracer intravenous (IV) bolus injection of 50 µg [14C]-CRN00808 (0.0185 MBq) in five healthy male subjects. The IV dose was administered approximately 90 minutes after the oral dose. Plasma samples were collected for up to 144 hours and were analyzed for total radioactivity and CRN00808 concentrations (plasma only). Key data from Part A and Part B will be presented. Available data from Part A of the study show that >90% of radioactivity was recovered within 7 days of dosing. The primary route of excretion was the feces (>90%) with minimal excretion in the urine (<10%). Absorption of total [14C]-CRN00808-derived radioactivity in plasma was rapid (median Tmax=1 hour), and the mean Cmax, AUC0-∞, and t1/2 were determined to be 194 ng-equivalents/mL, 3340 ng-equivalents.hr/mL, and 31 hours, respectively. The pharmacokinetic parameters of unchanged CRN00808 in plasma were similar, suggesting that majority of the circulating drug-derived radioactivity is accounted for by unchanged CRN00808 and there are no abundant circulating metabolites. 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 clinical trial in healthy volunteers confirm that CRN00808 has excellent drug-like properties for chronic once-daily oral treatment of patients with acromegaly.

Abstract 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.

Abstract 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 1:2500 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, a near-total pancreatectomy may be required, but hypoglycemia often persists. 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. The injectable peptide drugs octreotide and lanreotide are potent sst2 agonists used to treat CHI, but in addition to suppressing insulin, the sst2 activity of these peptides may also inhibit glucagon secretion, potentially reducing effectiveness and compromising a key defense against hypoglycemia. Glucagon secretion from α-cells is inhibited through activation of sst2 receptors, while insulin secretion from β-cells is inhibited through activation of sst2 and sst5. We therefore hypothesize that agonists selectively targeting sst5 and lacking sst2 activity will offer an improved efficacy/safety profile for patients with hyperinsulinemic hypoglycemia. Using iterative medicinal chemistry and pharmacology, 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. Insulin secretion from isolated human and rat islets was suppressed upon exposure to sst5 agonists. Potent and selective sst5 agonists were then evaluated in a number acute and repeat dose in vivo models (e.g., oGTT, fed/fasted conditions, sulfonylurea-induced hypoglycemia) to assess physiological effects and to gain mechanistic insights. As predicted by the in vitro pharmacology, selective nonpeptide sst5 agonists suppressed insulin secretion and raised blood glucose levels in each model, while having minimal effects on glucagon secretion. Leading sst5 agonists were also evaluated for drug like characteristics, including stability in liver microsomes, lack of inhibition of cytochromes P450 and the hERG ion channel, and were shown to exhibit good exposure upon oral dosing in both rats and dogs. The culmination of these studies has led to a subset of candidate molecules that are being evaluated in genotoxicity, safety pharmacology, and general toxicity studies to determine the molecule most suitable for evaluation in human clinical trials.

Abstract 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 <1 nM), while having no activity at the MC1, MC3, MC4, or MC5 receptors. Leading ACTH antagonists were also evaluated for drug like characteristics, including good stability in liver microsomes, lack of inhibition of cytochromes P450 and the hERG ion channel, and were shown to exhibit good exposure upon oral dosing in both rats and dogs. These ACTH antagonists acutely suppress corticosterone secretion in an ACTH-challenge model in rats. In a 7-day hypercortisolemia model in which rats receive an implanted minipump that continually secretes ACTH, corticosterone levels were decreased, and body weight loss and adrenal hypertrophy were prevented with ACTH antagonist treatment. The culmination of these studies has led to a subset of candidate molecules that are being evaluated in genotoxicity, safety pharmacology, and general toxicology studies to enable evaluation in human clinical trials.

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.

Abstract Cushing’s disease is most commonly the result of a microadenoma derived from pituitary corticotrophic cells that secretes excess adrenocorticotropic hormone (ACTH). 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). The resulting hypercortisolemia in Cushing’s patients presents in a myriad of symptoms that include growth of fat pads, excessive sweating, dilation of capillaries, thinning of the skin, muscle weakness, hirsutism, depression/anxiety, hypertension, osteoporosis, insulin resistance, hyperglycemia, and heart disease, among others that result in high morbidity. We hypothesize that blocking ACTH action directly via a selective MC2 receptor antagonist may provide an important new therapeutic mechanism to help better manage Cushing’s disease in patients. To test this hypothesis, we launched an iterative medicinal chemistry program to identify potent and selective nonpeptide MC2 receptor 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 and our effort led to small molecule nonpeptides with antagonist activity in CHO-K cells stably expressing the MC2-MRAP complex. Iterative optimization led rapidly to the discovery of multiple chemical classes of highly potent, nonpeptide MC2 selective antagonist leads, which were then further optimized for drug-like characteristics. We have identified multiple compounds that exhibit high potency for human and rat MC2 receptors (hMC2 Kb <1 nM), while having little activity at the MC1, MC3, MC4, or MC5 receptors. In rat and dog pharmacokinetic studies, many of these selective MC2 antagonists exhibit good oral bioavailability. In rat models to probe their efficacy, these selective MC2 antagonists acutely suppress corticosterone secretion in an ACTH-challenge model in male Sprague-Dawley rats and the degree of suppression is proportional to their activity at the rat MC2 receptor. In a 7-day hypercortisolemia model in which rats receive an implanted minipump that continually secretes ACTH, corticosterone levels were decreased, and body weight loss and adrenal hypertrophy were prevented. To our knowledge, these compounds represent the first potent nonpeptide MC2 receptor antagonists to demonstrate in vitro potency and in vivo efficacy and we are actively pursuing preclinical safety and toxicology studies to select the optimal molecule(s) suitable for evaluation in human clinical trials.

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.

Hyperinsulinemia is a heterogeneous condition in which dangerously low blood sugar levels are caused by improperly regulated insulin secretion from pancreatic ß-cells. The most severe form of hyperinsulinemia arises from congenital hyperinsulinism (CHI), a set of genetic disorders in which the underlying pathology is driven by mutations in key genes that regulate insulin secretion. CHI is the most common cause of persistent hypoglycemia in newborns and infants, and prompt recognition and treatment are vital to prevent coma, long-term neurological complications, and even death. The neuropeptide somatostatin is an important modulator of hormonal signaling from the pancreas mediated by different somatostatin receptor (sst) subtypes. Glucagon secretion from α-cells is inhibited through sst2 receptor activation and insulin secretion from β-cells is inhibited through sst2, sst3, and sst5. The injectable peptide drugs octreotide and lanreotide are primarily agonists at sst2 and are often prescribed for these patients in an attempt to reduce insulin secretion, but their efficacy is limited, and they carry the risk of impairing glucagon secretion, an important defense mechanism against hypoglycemia. We hypothesize that an orally available selective sst5 agonist may be a useful new approach to managing hyperinsulinemia. We launched an iterative medicinal chemistry program that led to the discovery of selective sst5 agonists, with multiple nonpeptide series possessing EC50s < 1 nM in cell-based assays of receptor activation (these compounds also routinely possess similar potencies for the rat sst5 receptor). We have shown that these sst5 agonists potently suppress insulin and raise plasma glucose in multiple glycemic studies in rats. To explore the mechanism of selective sst agonism and its translation from rat studies to humans, we undertook a series of studies using pancreatic islets isolated from human donors and from naïve Sprague Dawley rats. Selective sst5 agonists were compared to selective sst2 and selective sst3 agonists as well as somatostatin peptides for their capacity to suppress insulin and/or glucagon from islets under various conditions including increasing glucose concentrations and the presence of a sulfonylurea (the increased insulin secretion mimics many CHI patients). In both human and rat islets, we found that selective sst5 agonists potently suppressed insulin secretion more effectively than selective sst2 or sst3 agonists, while having little effect on glucagon secretion, demonstrating their potential efficacy in the human condition. These studies support our program to identify and develop potent nonpeptide selective sst5 agonists with pharmaceutical and safety characteristics suitable for evaluation in human clinical trials.