Lanreotide

Lanreotide (D-2Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2; CAS 108736-35-2 free base; molecular formula C54H69N11O10S2; molecular weight 1096.33) is a synthetic cyclic octapeptide analog of native somatostatin-14, developed by Beaufour-Ipsen (now Ipsen) and introduced clinically in the early 1990s as the second somatostatin analog to reach the market after octreotide. The compound exhibits high-affinity agonism at somatostatin receptor subtypes 2 and 5 (SSTR2, Ki approximately 0.54 to 0.75 nM; SSTR5, Ki approximately 5.2 nM) with moderate affinity at SSTR3 and low affinity at SSTR1 and SSTR4, a selectivity profile that mediates suppression of growth hormone, insulin-like growth factor 1, and multiple gastrointestinal and pancreatic hormones through inhibition of adenylyl cyclase and reduction of intracellular cyclic adenosine monophosphate [1, 2]. The compound is formulated as lanreotide acetate in the Autogel (marketed as Somatuline Depot in the United States), a supersaturated aqueous gel in which lanreotide molecules self-assemble into hollow nanotubes of highly uniform diameter stabilized by beta-sheet hydrogen bonding, hydrophobic packing, and aromatic pi-pi stacking, producing a deep subcutaneous depot that releases active peptide over 28 days with a terminal elimination half-life of 23 to 30 days and absolute bioavailability of approximately 60 to 70 percent [3, 4]. The Autogel formulation, first approved in Europe in 2001 and in the United States in 2007, was the first marketed sustained-release pharmaceutical product produced by peptide self-assembly rather than by polymer microsphere encapsulation. Three indications are registered in the United States: long-term treatment of acromegaly in patients who have had an inadequate response to or cannot be treated with surgery and radiotherapy (FDA approved August 2007); treatment of unresectable, well- or moderately-differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors to improve progression-free survival (FDA approved December 2014, on the basis of the CLARINET trial); and treatment of carcinoid syndrome in adults to reduce the frequency of rescue somatostatin analog therapy (FDA approved February 2018, on the basis of the ELECT trial) [5, 6, 7]. In acromegaly, lanreotide Autogel at 60 to 120 mg every 28 days normalizes growth hormone to below 2.5 micrograms per liter in approximately 58 percent and age-adjusted insulin-like growth factor 1 in approximately 48 percent of treatment-naive patients, with tumor volume reduction in approximately 60 percent of evaluated patients on long-term treatment [8, 9]. In the CLARINET trial, lanreotide 120 mg every 28 days versus placebo produced a hazard ratio for progression or death of 0.47 (95 percent confidence interval 0.30 to 0.73; P less than 0.001) in 204 patients with nonfunctioning, somatostatin-receptor-positive, grade 1 or 2 enteropancreatic neuroendocrine tumors, with estimated 24-month progression-free survival of 65.1 percent versus 33.0 percent [6]. In the ELECT trial, lanreotide 120 mg every 28 days significantly reduced the need for rescue short-acting octreotide for symptomatic carcinoid syndrome control and reduced patient-reported days with moderate or severe diarrhea and flushing [7]. The principal adverse events at registered doses are gastrointestinal (diarrhea 26 to 65 percent, abdominal pain 7 to 34 percent, nausea 5 to 11 percent), cholelithiasis and gallbladder sludge (14 to 20 percent), injection site reactions (5 to 22 percent), dysglycemia (hyperglycemia 5 to 14 percent, hypoglycemia 2 to 7 percent), and sinus bradycardia (3 to 8 percent) [10]. This monograph reviews the chemistry, synthesis, and self-assembly of lanreotide; the somatostatin receptor pharmacology in molecular detail; the comprehensive human pharmacokinetic record; the preclinical antiproliferative pharmacology; the clinical evidence base across acromegaly, neuroendocrine tumor, and carcinoid syndrome indications; reconstitution and handling; sourcing and quality verification; stack-interaction considerations; adverse-event signal; and a comparative assessment of five somatostatin receptor ligands against lanreotide on five competency standards.