Therapeutic Pipeline For Specialty Endocrine Disorders And endocrine related cancers
Acromegaly is caused by pituitary tumors that secrete excess growth hormone, which in turn cause elevated circulating levels of Insulin-like Growth Factor-1 (IGF-1). IGF-1 is a hormone that plays a vital role in childhood growth and adult homeostasis. Left untreated, acromegaly can result in serious illnesses and premature death.
Acromegaly is an orphan disease affecting more than 20,000 individuals in the U.S.
The pituitary neuropeptide somatostatin naturally inhibits growth hormone production, and synthetic somatostatin analogs have been used routinely to treat acromegaly.
However, these somatostatin analogs are only effective in about half of patients with acromegaly. In addition, somatostatin analogs require frequent doctor’s office visits for painful injections that can often lead to injection site reactions.
To overcome these treatment limitations, Crinetics is developing an orally available small molecule for the treatment of acromegaly. Crinetics is currently preparing for clinical trials to show that our once-a-day pill will improve treatment efficacy and tolerability in acromegalics.
Resources & Links
Acromegaly consensus group. Expert consensus document: A consensus on the medical treatment of acromegaly.
Giustina A, Chanson P, Kleinberg D, Bronstein MD, Clemmons DR, Klibanski A, van der Lely AJ, Strasburger CJ, Lamberts SW, Ho KK, Casanueva FF, Melmed S. Nature Reviews. Endocrinology. 2014; 10:243-8.
A Critical Analysis of Clinically Available Somatostatin Analog Formulations for Therapy of Acromegaly.
Murray RD, Melmed S. Journal of Clinical Endocrinology and Metabolism.2008; 93:2957-68.
AcromegalyAcromegaly Community NORD Pituitary Network Association Acromegaly symptoms, causes and diagnosis
Melmed S. New England Journal of Medicine. 2006; 355:2558-73.
Gastrointestinal neuroendocrine tumors (NETs) are a heterogeneous group of carcinomas that commonly arise in either the gut or pancreas. In the U.S., more than 100,000 people are living with NETs and it is estimated that approximately 12,000 new patients are diagnosed each year. Surgical resection is the only potentially curative treatment, but the majority of NETs present at a metastatic stage and median overall survival of patients with metastatic disease is 2-4 years. Patients with carcinoid syndrome commonly suffer from incapacitating diarrhea, flushing, and skin rashes due to hormones secreted by the tumor.
NETs over-express somatostatin receptors, and consequently peptide somatostatin analogs are used to inhibit the tumor’s aberrant secretory activity improving quality of life. However, many patients taking somatostatin analogs experience a loss of efficacy and breakthrough symptoms, and increasing the dose is limited by the injection volumes required.
Crinetics is developing an orally-available small molecule drug for the treatment of NETs. This drug candidate represents the first oral small molecule designed specifically to provide an improved responder rate for patients with NETs and carcinoid syndromes. This oral pill will do away with painful injections and limitations on daily administration.
Resources & Links
Somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine tumors.
Delaunoit T, Rubin J, Neczyporenko F, Erlichman C, Hobday TJ. Mayo Clinic Proceedings. 2005; 80:502-6.
Illuminating somatostatin analog action at neuroendocrine tumor receptors.Carcinoid Cancer Foundation Neuroendocrine Tumor Research Foundation Neuroendocrine Cancer Awareness Network (NCAN) North American Neuroendocrine Tumor Society United Kingdom NET Patient Foundation Neuroendocrine tumor overview
Reubi JC, Schonbrunn A. Trends Pharm Sciences. 2013; 34:676-88.
Hyperinsulinemic hypoglycemia (HH) is one of the most frequent causes of persistent hypoglycemia in infants. It is a heterogeneous condition caused by increased insulin secretion from pancreatic β-cells. HH can result in apneas, seizures, developmental delays, learning disabilities, epilepsy, and even death. The most severe form of HH is inherited and referred to as congenital hyperinsulinism (CHI). The incidence of CHI is approximately 1 in 30,000–50,000, though can be higher in certain populations. As with many rare diseases, there are no current drugs specifically tailored for patients with CHI.
The pancreas is a principal site of somatostatin action, and there it inhibits the synthesis and secretion of the two major hormones that control glucose homeostasis: glucagon and insulin. Different somatostatin receptor subtypes control these vital processes: sst2 receptors suppress glucagon, while sst2 and sst5 are responsible for the suppression of insulin.
At Crinetics, we will employ our expertise in somatostatin receptor drug discovery to develop an orally-available, sst5-selective small molecule therapeutic to treat CHI and other diseases of hyperinsulinemia. Crinetics sst5 agonist program represents the first small molecule drug candidate specifically designed to help this vulnerable population.
Resources & Links
Dillon, P.A. Curr Opin Pediatr, 2013. 25(3): p. 357-61.
Congenital hyperinsulinism: current status and future perspectives.Congenital Hyperinsulinism International Children’s Hospital of Philadelphia CHI Center Cook Children’s Hospital, Fort Worth, Texas, CHI Center Great Ormond Street, London, England CHI Center
Yorifuji, T. Ann Pediatr Endocrinol Metab, 2014. 19(2): p. 57-68.
Clinical signs of Cushing’s syndrome include growth of fat pads (collarbone, back of neck, face and trunk), excessive sweating, dilation of capillaries, thinning of the skin, muscle weakness, hirsutism, depression/anxiety, hypertension, osteoporosis, insulin resistance, hyperglycemia, heart disease, and a range of other metabolic disturbances resulting in high morbidity. The most common form of Cushing’s syndrome is Cushing’s disease which is caused by microadenomas of pituitary corticotropic cells that secrete excess adrenocorticotropic hormone (ACTH). If inadequately controlled in its severe forms, Cushing’s disease is associated with high mortality.
First line treatments for Cushing’s disease are surgical and involve removal of either the ACTH-secreting tumor in the pituitary or the adrenal glands themselves. As this is often unsuccessful, contraindicated, or delayed, medical therapy for these patients becomes necessary. Current treatment options include inhibitors of steroid synthesis enzymes that can prevent the production of cortisol and improve symptoms, but these treatments also induce a host of unwanted side effects due to the accumulation of other steroid products.
Crinetics is developing a novel class of small molecule, oral drugs to normalize cortisol levels, without the excess production of adrenal androgens or hepatotoxicity found with currently available drugs.
Resources & Links
Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Lancet 2015, 386, p. 913-27
Diagnosis and complications of Cushing's syndrome: a consensus statement.The Pituitary Society, Cushing’s Syndrome and Cushing’s Disease Cushing’s Support & Research Foundation (CSRF)
Arnaldi G1, Angeli A, Atkinson AB, Bertagna X, Cavagnini F, Chrousos GP, Fava GA, Findling JW, Gaillard RC, Grossman AB, Kola B, Lacroix A, Mancini T, Mantero F, Newell-Price J, Nieman LK, Sonino N, Vance ML, Giustina A, Boscaro M. J Clin Endocrinol Metab
2003. 88, p. 5593-602
Chronic pain imposes an enormous emotional and socioeconomic burden on patients and their care-givers. In the US, the annual cost of health-care expenditure and work days lost due to chronic pain was estimated in 2009 to be > US$100B. The prevalence of chronic pain is as high as ~20% of the population. Examples include sciatica, painful diabetic neuropath, and cancer chemotherapy induced peripheral neuropathy. Neuropathic pain is often intractable as no more than 40-60% of patients achieve even partial relief. Prescribed drugs often lack efficacy and have dose-limiting side-effects. The over-prescription and abuse of opioids has precipitated a national addiction crisis.
Somatostatin signaling is known to modulate pain pathways. Somatostatin receptors are expressed at multiple neuronal sites including peripheral nerve terminals, DRG neurons, and in the dorsal horn of the spinal cord. Clinical studies demonstrate that administration of peptide somatostatin analogs reduce pain in patients with advanced gastrointestinal cancer, and are opioid sparing in patients following abdominal surgery. These analogs are only available as injectables and so are poorly suited for patients dealing with chronic pain every day.
At Crinetics, we are developing a novel class of sst4 receptor selective agonists for the treatment of chronic neuropathic pain. The development of these drugs represent an important new non-addictive therapeutic option for patients suffering from intractable neuropathic pain states.
Resources & Links
Neuropathic pain in the general population: a systematic review of epidemiological studies.
van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N. Pain. 2014, 155, p. 654-62.
Somatostatin 4 receptor activation modulates G-protein coupled inward rectifying potassium channels and voltage stimulated calcium signals in dorsal root ganglion neurons.
Gorham L, Just S, Doods H. Eur J Pharmacol. 2014;736, p. 101-6.
Effect of somatostatin analogue octreotide on pain relief after major abdominal surgery.International Association for the Study of Pain Neuropathy Action Foundation Support Network Neuropathy American Chronic Pain Association
Dahaba AA, Mueller G, Mattiassich G, Rumpold-Seitlinger G, Bornemann H, Rehak PH, Linck G, Mischinger HJ, Metzler H. Eur J Pain. 2009, 8, p, 861-4.