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PEPTIDE TRENDS OCTOBER 2016

MEET US AT THE EUROPEPTIDES IN BERLIN

The Europeptides, part of Tides Europe is a unique forum for professionals from pharma, biotech and academia to meet and discuss key challenges in peptide therapeutics.

 

It is our pleasure to inform you that we will be attending the Europeptides, which will take place on November 15 – 16, 2016, at booth 10 at the Estrel Berlin Hotel in Berlin, Germany. We would like to meet with you to discuss how Bachem can help you with your peptide API custom manufacturing needs.

 

Bachem‘s pipeline contains more than 200 customer projects in preclinical and clinical phases. They all have promising potential: in the last two years, a number of products in phase III trials received marketing authorization and phase II projects progressed to pivotal phase III clinical trials. Some of our services include pegylated peptides, lipidated peptides, various other peptide conjugates, and sterile fill and finish (Clinalfa®).

 

A new service in our portfolio is the selective chemical glycosylation. The technology is applicable to large scale and has the potential to be applied to a variety of peptides, where we can pioneer the concept of improving current and future drugs. To view our recent webinar please click here.

 

Downstream Process Development of Aggregation-Prone Peptides will be presented by Thomas Meier, Vice-President Manufacturing at BACHEM AG, Switzerland at the Keynote area on November 16, 2016 at 9:40 AM.

 

As the Industry leader and pioneering partner, we promise to meet the expectations of our customers. We would be glad to arrange a meeting with you at Europeptides.

 

To schedule a personal meeting in advance please contact us.

SOMATOSTATIN

Somatostatin-14 and -28

The peptide hormone somatostatin was first discovered in hypothalamic extracts and identified as an inhibitor of the secretion of growth hormone secretion. Somatostatin is also called somatotropin release-inhibiting factor (SRIF). Its name is derived from this activity. Subsequently, somatostatin was shown to be an essential regulatory hormone of the gastrointestinal tract. It also acts as a modulator of neurotransmission in the CNS and affects cell proliferation. Somatostatin inhibits the release of various hormones such as growth hormone, TSH, glucagon, VIP, insulin, CCK, and gastrin.

Somatostatin is produced by the δ-cells of the pancreas and, to a lesser extent, in the hypothalamus and by paracrine cells in the gastrointestinal tract. Somatostatin exists in two active isoforms:

 

Somatostatin-14 (SRIF-14)

AGCKNFFWKTFTSC

 

Somatostatin-28 (SRIF-28)

SANSNPAMAPRERKAGCKNFFWKTFTSC

 

Preprosomatostatin

MLSCRLQCAL AALSIVLALG CVTGAPSDPR LRQFLQKSLA AAAGKQELAK YFLAELLSEP

Signal peptide                                           Propeptide (bold: neuronostatin-19)

NQTENDALEP EDLSQAAEQD EMRLELQRSA NSNPAMAPRE RKAGCKNFFW KTFTSC     

                                           Somatostatin-28/14      

 

 

Both SRIF isoforms contain a disulfide bridge. Somatostatin-14 and -28 are produced by alternate cleavage of preprosomatostatin. Additionally, the 116 amino acid protein is the precursor of the neurohormones neuronostatin-13 and -19.

 

The relative amount of the somatostatin variants depends on the type of tissue releasing them. SRIF-14 is secreted especially in the nervous system and by pancreatic δ-cells, whereas intestinal cells predominantly produce the larger peptide. Somatostatin-14 and -28 may also differ in activity. Whereas SRIF-28 more efficiently inhibits the release of growth hormone, SRIF-14 is more potent in inhibiting secretion of glucagon.

 

 

Both SRIF isoforms contain a disulfide bridge. Somatostatin-14 and -28 are produced by alternate cleavage of preprosomatostatin. Additionally, the 116 amino acid protein is the precursor of the neurohormones neuronostatin-13 and -19.

The relative amount of the somatostatin variants depends on the type of tissue releasing them. SRIF-14 is secreted especially in the nervous system and by pancreatic δ-cells, whereas intestinal cells predominantly produce the larger peptide. Somatostatin-14 and -28 may also differ in activity. Whereas SRIF-28 more efficiently inhibits the release of growth hormone, SRIF-14 is more potent in inhibiting secretion of glucagon.

 

Somatostatin receptors

Somatostatin triggers numerous physiological processes by binding to G-protein-coupled receptors located on the surface of various cell types. Five somatostatin receptor subtypes are known, SST1 –SST5, to which the hormone (both isoforms) binds with equally high affinity. The cyclic structure and the FWKT motif of the ring are essential for receptor binding. The somatostatin-related neuropeptides cortistatin-17 and -29 are further endogenous ligands for the five receptors.

 

Somatostatin-14              AGCKNFFWKTFTSC

Cortistatin-17              DRMPCRNFFWKTFSSCK

Octreotate                                fCYwKTCT     

 

Though all of them inhibit adenyl cyclase, the five somatostatin receptor subtypes activate different signaling mechanisms in the cell.

Somatostatin analogs as (D-Trp8)-somatostatin-14 are more resistant to enzymatic degradation and show different abilities to inhibit the production of growth hormone, insulin or glucagon.

 

Somatostatin-14

 

Somatostatin-14

 

OctreotideLanreotideVapreotide

 

Octreotide                                                    Lanreotide                            Vapreotide

 

 

 

Use of somatostatin and analogs as drugs

In addition to the downregulation of gastrointestinal hormones, somatostatin inhibits the production of pancreatic and gastric enzymes. For this reason it has been employed in the treatment of gastrointestinal disorders such as bleeding peptic ulcers and gallbladder fistulae. As the hormone has a half-life of merely 1-3 minutes, stable analogs such as octreotide (with a half-life of ca. 100 min in plasma) and vapreotide have been developed for treating these conditions.

Somatostatin agonists could be tools in the management of obesity, as SRIF counteracts the expression of hormones involved in the uptake of nutrients including the orexigenic hormone ghrelin. Octreotide has been evaluated for the treatment of hypothalamic obesity, a condition caused by insulin hypersecretion.

The somatostatin analogs octreotide and lanreotide are approved drugs for treating acromegaly, a disorder resulting from excessive production of growth hormone. In most cases, GH hypersecretion is caused by a benign pituitary tumor.     

Somatostatin is involved in the proliferation of both normal and tumorigenic cells. As somatostatin receptors are overexpressed in various types of tumors, the hormone became a target in cancer research and a lead for developing receptor-specific agonists. These compounds found use in cancer therapy.

Most tumors carrying somatostatin receptors may express multiple subtypes. Amongst them, SST2 is predominantly expressed. The somatostatin agonists octreotide, lanreotide and vapreotide preferably bind to SST2.

 

 

 

 

Due to the high affinity and specificity of the compounds for SST2 they were modified by attaching chelators enabling them to transport radionuclides to the target cancerous growth. Edotreotide (DOTATOC, DOTA-(Tyr)-octreotide), the even more SST2-specific DOTATOC analog DOTATATE (DOTA-(Tyr)-octreotate), pentetreotide (DTPA-octreotide, “octreoscan”) and DOTALAN (DOTA-Lanreotide) have found use as radiodiagnostics and imaging agents or as radiotherapeutics, e.g., for the treatment of neuroendrocrine tumors such as somatotropin- and thyrotropin-secreting pituitary adenomas and carcinoids. Macrocycles as DOTA form extraordinarily stable chelates with radioisotopes such as 68Ga, 111In, 90Y, or 177Lu and carry them to malignant tissue to be located or destroyed by radiation whilst keeping damage to healthy tissue low. The radionuclide has to be generated and complexed by the peptide immediately before use.

PBD: 1SOC

 

 

NMR STUDY OF THE BACKBONE CONFORMATIONAL EQUILIBRIA OF SANDOSTATIN, MINIMIZED AVERAGE BETA-SHEET STRUCTURE

Multiconformational NMR analysis of sandostatin (octreotide): equilibrium between beta-sheet and partially helical structures. Melacini, G., Zhu, Q., Goodman, M. (1997) Biochemistry 36: 1233-1241

 

DotatateDOTATATE

 

 

Pasireotide, a somatostatin agonist approved for the treatment of Cushing’s disease, preferably binds to SST5. The cyclopeptide inhibits corticotropin secretion and thus reduces cortisol levels.

 

PasireotidePasireotide

 

 

Literature

R.Guillemin and J.E.Gerich, Somatostatin: physiological and clinical significance, Annu. Rev. Med. 27,379-88 (1976)

A.V.Schally, Oncological applications of somatostatin analogues, Cancer Res. 48 6977-85 (1988)

R.Deghenghi, M.Papotti, E.Ghigo, G.Muccioli, V.Locatelli, Somatostatin octapeptides (lanreotide, octreotide, vapreotide, and their analogs) share the growth hormone-releasing peptide receptor in the human pituitary gland

Endocr. 14, 29–33 (2001)

L.N. Møller, C.E. Stidsen, B.Hartmann, J.J.Holst, Somatostatin receptors, Biochim. Biophys. Acta 1616, 1-84 (2003)

R.E.Weiner and M.L. Thakur, Radiolabeled peptides in oncology: role in diagnosis and treatment, BioDrugs 19,145-63 (2005)

I.M.Modlin, M.Pavel,M.Kidd, B.I.Gustafsson, Review article: somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours, Aliment. Pharmacol. Ther. 31, 169-88 (2010)

Z.Csaba, S.Peineau, P.Dournaud, Molecular mechanisms of somatostatin receptor trafficking, J. Mol. Endocrinol. 48, R1-12 (2012)

R.A.Feelders, W.W.de Herder, S.J.Neggers, A.J.van der Lely, L.J.Hofland, Pasireotide, a multi-somatostatin receptor ligand with potential efficacy for treatment of pituitary and neuroendocrine tumors. Drugs Today (Barc).49, 89-103 (2013)

C.Lambertini, P.Barzaghi-Rinaudo, L.D'Amato, S.Schulz, P.Nuciforo, H.A.Schmid, Evaluation of somatostatin receptor subtype expression in human neuroendocrine tumors using two sets of new monoclonal antibodies,

Regul. Pept.187, 35-41 (2013)

SOMATOSTATIN-RELATED DRUGS IN CLINICAL DEVELOPMENT

For decades, somatostatin-related drugs have been of interest in the areas of endocrinology and oncology. Somatostatin was initially viewed as an attractive candidate for the treatment of cancer due to its ability to block hormone release and cell growth after binding to its receptors; however, the native somatostatin peptide exhibited disadvantages such as a short half-life and rebound hypersecretion upon discontinuation. To overcome these obstacles, somatostatin analogs (SSAs) were designed with longer half-lives and improved pharmacologic efficacy and have continued to be a focus of drug development (1). Octreotide (Sandostatin®), the first SSA to be developed was approved by the U.S. Food and Drug Administration (FDA) in 1988. More recently, lanreotide (Somatuline®) was approved for the treatment of acromegaly in 2007 and for the treatment of neuroendocrine tumors in 2014. Pasireotide (Signifor®) was approved for the treatment of Cushing’s disease in 2012. There are several somatostatin-related drugs currently in various phases of clinical development as shown in Table 1.

 

Product Name

Active Ingredient

Condition Treated

Highest Phase

Company Name

Mechanism of Action (MOA)

Octreotide Depot MAR

octreotide

Diarrhea(I)

Phase I

GP Pharm

Somatostatin Receptor 2 (SSTR2) Agonist

PT201

octreotide

Acromegaly(I), Carcinoid Tumors(I)

Phase I

Peptron Inc,
AZAD Pharma AG

Somatostatin Receptor 2 (SSTR2) Agonist

Tozaride

rhenium-188 somatostatin analog

Lung Cancer(I), Melanoma(PC), Pancreatic Cancer(PC)

Phase I

Bayer Ag,
Andarix Pharmaceuticals, Diatide Inc,
Xanthus Pharmaceuticals, Inc.,
Schering AG,
Bryan Oncor

Somatostatin Receptor (SSTR) Agonist

CAM2029

octreotide chloride

Acromegaly(II), Neuroendocrine Tumor(II), Carcinoid Tumors(I)

Phase II

Camurus AB, Novartis AG

Somatostatin Receptor 2 (SSTR2) Agonist

COR005

somatoprim

Acromegaly(II), Carcinoid Tumors(I), Cushing's Syndrome(I), Diabetic Retinopathy(I)

Phase II

DeveloGen AG, Aspireo Pharmaceuticals Limited, Strongbridge Biopharma Plc

Somatostatin Receptor 2 (SSTR2) Agonist, Somatostatin Receptor 4 (SSTR4) Agonist, Somatostatin Receptor 5 (SSTR5) Agonist

ITF2984

--

Acromegaly(II)

Phase II

Italfarmaco SpA

Somatostatin Receptor (SSTR) Agonist

Octreotide SDI

octreotide acetate

Acromegaly(II), Neuroendocrine Tumor(II)

Phase II

Glide Pharmaceutical Technologies Limited,
Albany Molecular Research Inc., Paladin Labs Inc.

Somatostatin Receptor 2 (SSTR2) Agonist

SomaDEX

--

Hormone Refractory Metastatic Prostate Cancer(II), Solid Tumors(I)

Phase II

DexTech Medical AB

Somatostatin Receptor (SSTR) Agonist

Lutathera

lutetium Lu 177 dotatate

Neuroendocrine Tumor(PA)

Pending Approval

BioSynthema Inc  (Originator, Developer),

Advanced Accelerator Applications SA  (Co-Developer),

FUJIFILM RI Pharma Co Ltd  (Distributor, Sales/Marketing),

Covidien  (Sales/Marketing)

Not Applicable

Mycapssa

octreotide acetate

Acromegaly(PA),

Hypertension(II),

Neuroendocrine Tumor(R)

Pending Approval

Chiasma Inc  (Primary Owner, Developer)

Somatostatin Receptor 2 (SSTR2) Agonist

Table 1: Somatostatin-Related Drugs in Clinical Development (2)

 

Phase I Candidates

GP Pharm is developing a controlled release depot formulation of octreotide. Octreotide Depot MAR is polymer matrix micro-encapsulated and this formulation is being developed as a one week treatment of chemo-therapy induced diarrhea. It has finished pre-clinical development. GP Pharm is seeking a partner for co-development or divestment of the project (3)

Peptron is developing a generic version of Sandostatin LAR® known as PT201. This product contains octreotide as the active ingredient and is being developed for the treatment of acromegaly and carcinoid tumors. In collaboration with AZAD Pharma, Peptron has completed a pilot bioequivalence study in healthy volunteers (2).

Tozaride is a cancer therapy being developed by Andarix Pharmaceuticals. The product is a high affinity somatostatin analog labeled with the radioisotope rhenium-188, which specifically targets tumors over expressing somatostatin receptors. A phase I trial has been completed for Tozaride for the treatment of advanced lung cancer. In addition, Tozaride has been granted orphan drug designation by the FDA for the treatment of small cell lung cancer (2).

 

Phase II Candidates

Novartis and Camurus are developing CAM2029, a long-acting octreotide FluidCrystal® formulation. The product is being developed as an alternative to existing long-acting somatostatin analog formulations for the treatment of acromegaly, neuroendocrine tumors and other indications. CAM2029 is designed as a ready-to-use injection for self-administration. In 2016, Camurus completed a Phase II study of CAM2029 in patients with acromegaly and neuroendocrine tumors. Phase III trials are expected to commence in 2017 (4).

Strongbridge Biopharma is developing COR005 or somatoprim, a novel somatostatin analog for the treatment of acromegaly, Cushing’s disease, neuroendocrine tumors and diabetic retinopathy. The initial indication for somatoprim is acromegaly and Phase II clinical trials are underway. In 2015, Stongbridge Biopharma reported that it received orphan designation for COR005 from both the European Medicines Agency (EMA) and the FDA (2).

Italfarmaco is developing ITF2984, a somatostatin analog, for the treatment of acromegaly and cancer. In 2016, Italfarmaco completed a Phase II trial of ITF2984 for the treatment of acromegaly (2)

Glide Technologies is developing Octreotide SDI®, a solid dose formulation of octreotide acetate, for the treatment of acromegaly and neuroendocrine tumors. The product is delivered via Glide’s needle-free solid dose injection system (SDI). In 2016, Glide Technologies reported results from a clinical proof-of-concept study that showed Octreotide SDI achieved bioequivalence to Sandostatin®, the currently marketed immediate release liquid injectable product (2).

SomaDex is a stabilized form of somatostatin with an extended-half life that is being developed by DexTech AB. The product consists of somatostatin coupled to a modified hydroxypolymer conjugate. A clinical phase II/pilot study was conducted between 2006 and 2009 on castration resistant prostate cancer patients with results showing a good symptom relieving effect regarding skeletal related pain (5).

 

Pending Approval

Advanced Accelerator Applications is developing Lutathera®, a Lu-177-labeled somatostatin analog for the treatment of gastroenteropancreatic neuroendocrine tumors. Lutathera has received orphan drug designation from both the EMA and the FDA. In 2016, the company submitted a New Drug Application (NDA) to the FDA and Priority Review was granted for Lutathera. The company also submitted a Marketing Authorization Application (MAA) to the EMA and Accelerated Assessment was granted for Lutathera; however, the review period was recently modified to a standard review period (1).

In 2015, Chiasma completed a Phase III trial of Mycapssa®, the company’s oral formulation of octreotide, in acromegaly and later submitted an NDA to the FDA. In 2016, the FDA completed their review of Chiasma’s NDA for Mycapssa and indicated that the NDA is not ready for approval in its present form. The company is conducting an additional Phase III trial in acromegaly to support a potential MAA with the EMA (1).

 

Conclusion

Somatostatin analogs hold promise for the treatment of cancers, acromegaly and other conditions. To support companies and organizations developing somatostatin-related drugs, Bachem offers generic APIs such as octreotide, lanreotide, pasireotide, somatostatin and the production of peptide-based new chemical entities. In addition, Bachem offers a selection of over 30 somatostatin peptides and analogs for research at shop.bachem.com.

 

References

(1)  E. Wolin, The expanding role of somatostatin analogs in the management of neuroendocrine tumors, Gastrointest Cancer Res. 5, 161-168 (2012)

(2)  Medtrack (2016)

(3)  Products, GP Pharm (2016)

(4)  Camurus announces completion of Phase 2 study of CAM2029 in patients with acromegaly and neuroendocrine tumors, Nasdaq GlobeNewswire. July 12 (2016)

(5) SomaDex, DexTech (2016)

MEET BACHEM: SILKE WETZENSTEIN, BUSINESS DEVELOPMENT MANAGER

PT: What is your official job title at Bachem?

Silke: Business Development Manager

 

PT: How long have you been with Bachem? Where did you work before Bachem?
Silke: I have worked for Bachem since July 2015 and prior to my Bachem time I was working for Clariant, Switzerland in the field of regional development, business development and global procurement.

 

PT: Briefly, what do you do at Bachem?

Silke: In my role as Business Development Manager I work very closely with our customers on their NCE (new chemical entities) projects, and I am responsible for all commercial activities of the project. I represent internally the customer’s requirements and special needs. Another important part of my job is business relationship management and to identify new business opportunities.

 

PT: What is your academic background/degrees or training?

Silke: I am a Chemist by education and completed my doctoral thesis in physical chemistry and trained in business administration.

 

PT: What do you like to do outside of work (interests, hobbies)?

Silke: I enjoy different outdoor activities (running, cycling, hiking and taking photos).

 

PT: What makes a perfect day for you?  

Silke: A good start in the morning, substantial success during the day and a satisfied, relaxed evening to be eager for the next day.

 

PT: What is your business motto?

Silke: Be authentic, positive, creative and take changes as further opportunities.

 

PT: What do you do for fun?

Silke: I sing in a chorus and taking singing classes.

 

PT: What is your preferred peptide?

Silke: I like any peptides which address unmet medical need.

 

PT: Thank you very much Silke.

PEPTIDE HIGHLIGHTS

LITERATURE CITATIONS

Bachem peptides and biochemicals are widely cited in research publications. Congratulations to all our customers with recent publications!

 

Choi, S. G., Wang, Q., Jia, J., Chikina, M., Pincas, H., Dolios, G., Sasaki, K., Wang, R., Minamino, N., Salton, S. R. and Sealfon, S. C.

Characterization of Gonadotrope Secretoproteome Identifies Neurosecretory Protein VGF-derived Peptide Suppression of Follicle-stimulating Hormone Gene Expression.

J. Biol. Chem., Sep 2016; 291: 21322 - 21334. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=27466366

 

James, T. D., Cardozo, T., Abell, L. E., Hsieh, M. L., Jenkins, L. M., Jha, S. S. and Hinton, D. M.

Visualizing the phage T4 activated transcription complex of DNA and E. coli RNA polymerase.

Nucleic Acids Res., Sep 2016; 44: 7974 - 7988. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=27458207

 

Lai, C. Y., Ho, Y. C., Hsieh, M. C., Wang, H. H., Cheng, J. K., Chau, Y. P. and Peng, H. Y.

Spinal Fbxo3-Dependent Fbxl2 Ubiquitination of Active Zone Protein RIM1alpha Mediates Neuropathic Allodynia through CaV2.2 Activation.

J. Neurosci., Sep 2016; 36: 9722 - 9738. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=27629721

 

Naylor, J., Suckow, A. T., Seth, A., Baker, D. J., Sermadiras, I., Ravn, P., Howes, R., Li, J., Snaith, M. R., Coghlan, M. P. and Hornigold, D. C.

Use of CRISPR/Cas9-engineered INS-1 pancreatic beta cells to define the pharmacology of dual GIPR/GLP-1R agonists.

Biochem. J., Sep 2016; 473: 2881 - 2891. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=27422784

 

Sosna, J., Philipp, S., Fuchslocher Chico, J., Saggau, C., Fritsch, J., Foll, A., Plenge, J., Arenz, C., Pinkert, T., Kalthoff, H., Trauzold, A., Schmitz, I., Schutze, S. and Adam, D.

Differences and Similarities in TRAIL- and Tumor Necrosis Factor-Mediated Necroptotic Signaling in Cancer Cells.

Mol. Cell. Biol., Oct 2016; 36: 2626 - 2644. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=27528614