Bachem : What are somatostatin and somatostatin analogues?

Somatostatin (SST) was isolated and characterized by researchers working in the laboratory of Guillemin at the Salk Institute in 1973¹Burgus, R et al. Proc. Natl. Acad. Sci. U. S. A. 70(3), 684-688 (1973). Somatostatin is a hormone produced by the hypothalamus and some other tissues such as the pancreas and the gastrointestinal tract. It is an inhibitor of growth hormone release from the anterior pituitary gland and suppresses the release of a variety of other hormones involved in the regulation of important physiological functions of the gastrointestinal tract.

What does somatostatin look like?

Somatostatin is a cyclic polypeptide containing a disulfide bridge, between Cys-3 and Csy-14 for somatostatin-14 (SST-14) and between Cys-17 and Cys-28 for somatostatin-28 (SST-28). Somatostatin peptides are derived from a precursor protein of 116 amino acids (Figure 1). The precursor is processed into several peptide hormones, including SST-14, SST-28 at the N-terminal, and neuronostatin, which is a 13-residue amidated peptide flanked with the signal peptide.

Figure 1 - Somatostatin precursor molecule and location of the disulfide bridges

What role does somatostatin play in the body?

In the body, there exists five somatostatin receptor (SSTR) subtypes, SSTR₁ to SSTR₅ to which their natural ligands SST-14 and SST-28 bind. SST-14 and SST-28 bind with equal affinity to SSTRs 1-4. However, SST-28 has a 10- to 30-fold higher affinity for SSTR₅ than other SSTs, whereas SST-14 has reduced affinity at SSTR5.

The two somatostatin forms are together considered a global counter regulatory hormone, with inhibitory effects in multiple target tissues. Somatostatin inhibits gastric acid secretion and motility, intestinal absorption, pancreatic bicarbonate and enzyme secretion, and selectively decreases splanchnic and portal blood flow in dogs and humans without affecting mucosal blood flow. Moreover, somatostatin inhibits the secretion of growth hormone (GH), prolactin (PRL), thyrotropin (TSH), cholecystokinin (CCK), gastric inhibitory peptide (GIP), gastrin, motilin, neurotensin, secretin, glucagon, insulin, and pancreatic polypeptide (PP)²Brown, M at al. Fed. Proc. 40(11), 2565-2569, (1981).

SST-14 is the predominant form in the central nervous system and in most peripheral organs, including the gastrointestinal tract, where it can be found in the stomach, duodenum, colon, and pancreas. In contrast, SST-28 is produced mainly by intestinal enteroendocrine cells and represents >50% of the somatostatin content in the small intestine. Furthermore, SST-28 could be used to treat a range of disorders, mostly relating to hormone hypersecretion.

Somatostatin is characterized as a regulatory-inhibitory peptide with exocrine secretion; for example, of gastric acid, intestinal fluid and pancreatic enzymes and endocrine secretion, or for example, of growth hormone, insulin, glucagon, gastrin, cholecystokinin, vasoactive intestinal peptide (VIP) and secretin. Somatostatin has great potential for the treatment of somatotropinomas, thyrotropinomas, and functioning and non-functioning gastroenteropancreatic neuroendocrine tumors. The short half-life of somatostatin however limits its usefulness as an efficient therapeutic modality. Therefore, research has been conducted in the development of new tuned somatostatin derivatives to offer patients a more efficient treatment.

Somatostatin analogues: What role do they play for patients?

A somatostatin analogue (SSA) is a synthetic version of somatostatin. It slows down the production of hormones, especially the growth hormone and serotonin. This helps to control the symptoms of carcinoid syndrome such as diarrhoea and flushing of the skin. Furthermore, SSAs are of considerable utility in the diagnosis and treatment of gastroentero-pancreatic neuroendocrine tumors (NETs). These synthetic analogs of somatostatin have longer half-lifes. To date, three of them have been approved by the agencies: lanreotide and octreotide are considered first-generation SSAs, and pasireotide is considered a second-generation SSA.

The first synthetic SSA that was approved by the Food and Drug Administration (FDA) was the octapeptide octreotide (SMS 201-995) marketed as Sandostatin^®. Octreotide (scheme 1) shows high affinity for SSTR₂ and inhibits the proliferation of the cells expressing SSTR2 gene by activating the tyrosine phosphatase pathway³Buscai, l L et al. Proc. Natl. Acad. Sci. U. S. A. 91(6), 2315-2319 (1994). Octreotide acts through four mechanisms to decrease abnormal growth hormones (GH) secretion in acromegaly. First, octreotide suppresses GH secretion from the pituitary gland and from GH-secreting adenomas. Second, it decreases GH binding to hepatocytes. Third, it inhibits hepatic IFG-1 production and finally it controls tumor growth⁴Murray, R D et al. J. Clin. Invest. 114(3), 349-356 (2004).

Octreotide or Sandostatin^® was approved for use in the United States in 1988. It is used for the reduction of growth hormone and insulin-like growth factor 1 (somatomedin C) in adults with acromegaly who have had inadequate response to or cannot be treated with surgical resection, pituitary irradiation, and bromocriptine mesylate at maximally tolerated doses. In addition, Sandostatin^® is applied for the treatment of severe diarrhea and flushing episodes associated with metastatic carcinoid tumors in adults as well as profuse watery diarrhea associated with vasoactive intestinal peptide tumors (VIPomas) in adults.

Scheme 1 Structure of octreotide

Lanreotide (scheme 2) is a cyclic octapeptide that was developed in the 1990s with the intent to develop a longer acting SSA⁵Morange, I et al. J. Clin. Endocrinol. Metabol. 79(1), 145-151 (1994). Like octreotide, lanreotide is used in adults to treat acromegaly that cannot be treated with surgery or radiation, carcinoid syndrome and a certain type of pancreatic or digestive tract tumor that may spread to other parts of the body. First approved for use in the United States by the FDA in 2007, lanreotide is marketed under the trade name Somatuline^®.

Scheme 2 Chemical structure of lanreotide

Pasireotide, a novel SSA, that is sold under the brand name Signifor^®, is an orphan drug approved by the FDA in 2014 for the treatment of Cushing's disease in patients who fail or are ineligible for surgical therapy. Pasireotide activates a broad spectrum of somatostatin receptors, and binds with higher affinity to SSTR₁ (30-fold), SSTR₃ (5-fold), and SSTR₅ (39-fold), and with the same affinity to SSTR2 (three-fold) when compared with octreotide; and with higher affinity to SSTR1 (19-fold), SSTR3 (nine-fold), and SSTR5 (106-fold), but with the same affinity to SSTR2 (two-fold) when compared with lanreotide⁶Bruns, C et al. Eur. J. Endocrinol.146(5), 707-716 (2002); Hofland, LJ et al. Eur. J. Endocrinol. 152(4), 645-654 (2005). The binding and activation of the somatostatin receptors causes inhibition of ACTH secretion and results in reduced cortisol secretion in Cushing's disease patients. Also this agent is more potent than somatostatin in inhibiting the release of human growth hormone (HGH), glucagon, and insulin.

Scheme 3 Chemical structure of pasireotide

For these drugs to be efficient, they require delivery methods such as infusion, frequent injections, implantable devices, or intramuscular injection of large drug volumes, which are not always preferred by health care providers and patients.

A huge improvement for diagnosis and treatment of tumors

So far, three SSAs have been approved and launched in the market for treatment of tumors secreting vasoactive intestinal peptide, carcinoid tumors, glucagonomas and various pituitary adenomas, and acromegaly in where there is over secretion of growth hormone in an adult. Furthermore, they are an invaluable therapeutic option in the diagnosis of these diseases.

The formulations of somatostatin analogues have been improved over time and new longer acting versions were introduced, Sandostatin LAR^® Depot for octreotide and Somatuline^® Depot or Autogel for lanreotide.

In the case of Sandostatin LAR^® octreotide is encapsulated in microspheres that are formed with a biodegradable glucose star polymer, D,L-lactic and glycolic acids copolymer. Sterile mannitol is added to the microspheres to improve suspensibility.

Somatuline^® Depot contains lanreotide acetate in a prefilled syringe that is fitted with an automatic needle guard. The formulation is based on the peptide self-assembly, which provide an innovative solution to sustain a therapeutic dose over a long period of time. Indeed, Somatuline^® Depot is the first marketed sustained-release formulation produced via peptide self-assembly.

Somatuline^® and Sandostatin^® are used as treatment for symptoms and slow tumor progression in patients with neuroendocrine tumors (NETs), carcinoid syndrome and to reduce hormone secretion and reduce pituitary tumor volume in patients with acromegaly. These are chronic conditions requiring long-term treatment⁷Oberg, K et al. Endocr. Relat. Cancer. 23, 551-566 (2016). Therefore, optimizing patients' treatment experience is essential to improve their quality of life. These highly complex formulations also depend on an API of the highest quality. At Bachem, we have the experience with these complex compounds that allow us to deliver them with consistently high specifications.

The latest development, and still under investigation, are non-parenteral formulations. They will help to further facilitate the therapy. For these formulations the availability of large volumes of API at competitive price is of vital importance. At Bachem, we have strong expertise in API manufacturing. In our pipeline we have lanreotide, octreotide and somatostatin with the compiled documentation for Drug Master File and Certificates of Suitability. We work with passion and dedication to support our customers in achieving breakthrough medical advances that will significantly improve the life of patients.