Lanreotide Depot An Antineoplastic Treatment of C

Authors: Edward M Wolin Amandine Manon Christophe Chassaing Andy Lewis Laurent Bertocchi Joel Richard Alexandria T Phan

Publish Date: 2016/09/13

Volume: 47, Issue: 4, Pages: 366-374

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Abstract

Peptide drugs for antineoplastic therapies usually have low oral bioavailability and short in vivo halflives requiring less preferred delivery methods Lanreotide depot is a sustainedrelease somatostatin analog SSA formulation produced via an innovative peptide selfassembly method Lanreotide is approved in the USA and Europe to improve progressionfree survival PFS in patients with unresectable gastroenteropancreatic neuroendocrine tumors GEPNETs and also approved in Europe for symptom control in carcinoid syndrome associated with GEPNETs This review discusses how the distinct molecule and formulation of lanreotide depot provide advantages to patients and health care providers as well as the most recent clinical evidence demonstrating the safety and efficacy of lanreotide depot in inhibiting tumor growth and controlling hormonal symptoms in GEPNETsThe lanreotide depot formulation confers a remarkable pharmacokinetic profile with no excipients comprised only of lanreotide acetate and water Of note lanreotide depot constitutes an example for peptide selfassembly based formulations providing insights that could help future development of sustainedrelease formulations of other antineoplastic peptides Most patients with GEPNETs will present with inoperable or incurable disease thus medical management for symptoms and tumor control plays a crucial role Recent longterm clinical studies have demonstrated that lanreotide depot is well tolerated prolongs PFS in GEPNET patients and significantly reduces symptoms related to carcinoid syndromePeptides are attractive therapeutic molecules due to their significant activity and low toxicity profile It is not surprising that the number of peptidebased drugs being evaluated in clinical trials has been steadily increasing over the years Currently many peptide drug candidates are in clinical or preclinical development phases and many are being evaluated in the oncology setting 1 However peptide drugs usually have low and variable oral bioavailability and short in vivo halflives Therefore 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 2 3Fortunately an intrinsic biophysical property of some peptides may help overcome the problems associated with peptide drug delivery Under specific conditions of pH concentration and salts many peptides and proteins will selfassemble into filamentous structures such as hollow nanotubes or densely packed fibers that have all the properties of an ideal sustainedrelease formulation 2 4 Firstly they only contain the densely packed peptide commonly as an acetate salt and water which enable very small injection volumes even for high doses Secondly they form highly organized and stable structures The active drug ie the peptide is very stable in these structures and is released in a controlled manner over an extended period of time This stability also enables sustainable supply and storage of prefilled readytoinject syringes Furthermore release of the active drug from the depot can provide a rapid response 2Lanreotide is an analog of human somatostatin and lanreotide depot Somatuline Depot Ipsen Pharma SAS Paris France is the first marketed sustainedrelease formulation produced via peptide selfassembly Lanreotide depot has been used by patients with acromegaly for more than 13 years 5 and has recently been approved in the USA for the treatment of patients with unresectable well or moderately differentiated locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors GEPNETs to improve progressionfree survival PFS 6 Lanreotide depot has also been approved in Europe since 2003 for symptom control in carcinoid syndrome associated with GEPNETs 5NETs are a group of malignancies that arise from the secretory cells of the neuroendocrine system NETs can develop in virtually any organ but are predominantly found in the gastrointestinal system particularly the pancreas and gastrointestinal tract 7 GEPNETs are rare however the ageadjusted incidence of GEPNETs has been steadily increasing with a 36fold increase observed between 1973 and 2007 7 8 9 Improved disease awareness and improved diagnostic imaging technologies 10 may play a role in the apparent increase in incidence 7 Based on the most updated data from the Surveillance Epidemiology and End Results program of the National Cancer Institute the incidence of GEPNETs was 365/100000 individuals per year between 2003 and 2007 9While indolent in nature advanced welldifferentiated NETs remain incurable with overall poor prognosis and only a few treatment options can effectively inhibit their growth 11 12 13 Goals of therapy in managing patients with GEPNETs are twofold symptoms and tumor control The majority of NETs are nonfunctioning ie they do not secrete excess hormones that cause clinical symptoms This lack of symptoms in nonfunctioning NETs may delay diagnosis until after the disease has advanced and metastasized when patients will exhibit symptoms relating to their bulky/advanced disease burden Conversely functioning NETs are characterized by excessive hormone secretion resulting in distinct clinical syndromes depending on the hormone secreted A common example is the carcinoid syndrome which is caused by systemic release of serotonin and tachykinins by gastrointestinal NETs and characterized by severe gastrointestinal symptoms including flushing and diarrhea 11 13 Functioning and nonfunctioning NETs are histologically indistinguishable as they are clinically defined/classified and goals of treatment remain the same—controlling of tumor and controlling of symptoms from hormone oversecretion or from bulky tumor burden

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