CLINALFA STERILE PEPTIDES FOR CLINICAL TRIALS

Transcription

1 CLINALFA STERILE PEPTIDES FOR CLINICAL TRIALS

2 Clinalfa CLINALFA YOUR PARTNER IN CLINICAL RESEARCH Products of highest quality Manufactured under GMP conditions Sterile and pyrogen-free Ready for use in approved clinical studies Released by QP with CofA signed by QP Fast delivery from stock Documentation for ethical committees and regulatory authorities available We invite you to discuss your specific needs with us 2

3 APIs We are the leading independent supplier of peptidic active pharmaceutical ingredients (APIs) for the human and veterinary pharmaceutical markets. With our high capacity and the outstanding quality of our products Bachem holds a unique position. Our expertise is in large-scale solid-phase peptide synthesis (Boc- and Fmoc-strategies) and solutionphase peptide synthesis. Purification procedures include large-scale preparative high performance liquid chromatography (preparative HPLC), conventional chromatography (ion exchange, gel chromatography) and countercurrent (Craig) distribution. Our GMP compliant manufacturing facilities for APIs fulfill the highest standards and are regularly inspected by the FDA and/or local authorities. Additionally, Bachem has a production unit for the custom synthesis of small organic molecules. cgmp PRODUCTION More than 40 Years of Expertise in Peptide Chemistry Fully Independent Company Quality You Can Trust Full Range of Technical and Regulatory Support Excellent customer and technical service 3

4 Clinalfa ST. HELENS (UK) WEIL AM RHEIN (D) VIONNAZ (CH) BUBENDORF (CH) TORRANCE (CA) VISTA (CA) GLOBAL BUSINESS Bachem s facilities are located in Switzerland, Europe and in the USA. All cgmp manufacturing sites are inspected by the US-FDA and national authorities. GMP sites 4

5 OUR PRODUCTS AND SERVICES Clinalfa basic Clinalfa basic peptides are sterile freeze-dried medicinal products for use in clinical trials. The supply of Clinalfa basic peptides is accompanied by Bachem s Certificate of Analysis (CofA), which is signed by Bachem s Qualified Person (QP). The manufacturing process and the analytical methods might not be fully validated and only limited stability data are available. Product Prod. Nr. Pack Size Page Angiotensin II Acetate* U μg/vial 8 (Pyr 1 )-Apelin-13 Acetate* U mg/vial 8 Angiotensin I/II (1-7) (human) Acetate* U mg/vial 9 BQ-123 Sodium salt* U mg/vial 9 BQ-788 Sodium salt U mg/vial 9 Bradykinin Acetate* U μg/vial 10 CCK-4 Acetate U μg/vial 10 CRF (ovine) Acetate U μg/vial 10 Exendin (9-39) Acetate* U mg/vial 11 Ghrelin (human) Acetate (formulated)* U μg/vial 11 (Des-octanoyl)-Ghrelin (human) Acetate* U μg/vial 11 GIP Acetate* U μg/vial 12 GLP-1 (7-36) amide Acetate* U μg/vial 12 Neuropeptide Y (human, rat) Acetate U μg/vial 13 L-NMMA Acetate* U mg/vial 13 Pentagastrin U μg/vial 13 Substance P Acetate U μg/vial 14 *Clinalfa basic peptides available from stock. 5

6 Clinalfa Clinalfa plus Clinalfa plus products are sterile freeze-dried or ready-to-use liquid formulations made according to customer requirements. In many cases, the active pharmaceutical ingredients (APIs) and the resulting Clinalfa products are proprietary products of Bachem s customers. Based on agreements between the customer and Bachem, Bachem s Qualified Person (QP) may release the products for use in a specific clinical study approved by the competent authority, and also for market approval (see page 15). Clinalfa Services Bachem offers related services to Clinalfa basic and Clinalfa plus products, i.e. formulation development, compatibility studies, stress test and post-release stability studies, CMC documentation for IMPD and IND, drug master file and other services (see page 15). 6

7 CLINALFA BASIC PRODUCTS Clinalfa basic products are sterile freeze-dried peptides available from stock. The supply of Clinalfa basic peptides is accompanied by Bachem s Certificate of Analysis (CofA) signed by Bachem s Qualified Person (QP). 7

8 Clinalfa ANGIOTENSIN II 50 μg/vial U-1050, Synonym Ang II H-Asp-Arg-Val-Tyr-Ile-His-Pro- Phe-OH acetate salt C 50 H 71 N 13 O 12 : g/mol CAS No: (net) The octapeptide angiotensin II (Ang II) binds to both the AT1 and the AT2 receptors. Ang II interaction with the AT1 receptor results in strong vasoactive effects, the stimulation of aldosterone synthesis and the elevation of blood pressure via direct vasoconstriction of arteriole smooth muscles. The role of the AT2 receptor is not fully understood. Ang II can be metabolized by aminopeptidase into angiotensin III (Ang 2-8) and angiotensin IV (Ang 3-8). H-1705 Angiotensin II (PYR 1 )-APELIN mg/vial U-1270, Pyr-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly- Pro-Met-Pro-Phe-OH acetate salt C 69 H 108 N 22 O 16 S : g/mol CAS No: (net) Apelin-36 was shown to be the specific endogenous ligand of the orphan G protein-coupled receptor APJ. APJ and the precursor peptide of apelin-36 are expressed in a variety of tissues including the heart, brain, breast, and lung; both are effective in the CNS and in the periphery. The metabolization products of apelin-36, e.g. (Pyr 1 )-Apelin-13, are considerably more active than the native peptide. Apelin-36 and its C- terminal fragments are involved in cell proliferation, vessel formation (regulation of the caliber size of blood vessels), and fluid homeostasis. (Pyr 1 )-Apelin-13, which has been identified as the predominant apelin isoform in the human heart, is a potent regulator of cardiovascular functions and a hypotensive. Apelin is also secreted by mature adipocytes, acting as an adipokinin. Plasma levels of apelin and its metabolites are altered in obese and hyperinsulinemic humans and in case of heart failure. (Pyr 1 )-Apelin-13 was shown to stimulate glucose utilization in normal and obese insulin-resistant mice. First positive results have been obtained in studies applying the apelin fragment in humans with chronic heart failure. (Pyr 1 )-Apelin-13 is a valuable tool in obesity, diabetes and, especially, cardiovascular research. This product is available in research H-4568 (Pyr 1 )-Apelin-13 (human, bovine, mouse, rat) 8

9 ANGIOTENSIN I/II (1-7) (HUMAN) 10 mg/vial U-1280, H-Asp-Arg-Val-Tyr-Ile-His-Pro-OH acetate salt C 41 H 62 N 12 O 11 : g/mol CAS No: (net) Angiotensin I/II (1-7) is a biologically active endogenous angiotensin. It is a product of a pathway independent of the angiotensin I processing by an angiotensin converting enzyme (ACE). Angiotensin I/II (1-7) may play an important role in the regulation of blood pressure as it has possible antihypertensive actions being a specific non-competitive antagonist of angiotensin II. Its vasodilator activity is mediated by stimulation of vasodilator prostaglandins and/ or the release of nitric oxide. Moreover the heptapeptide was shown to inhibit growth of human lung cancer cells in vitro and to reduce the size of human lung cancer xenografts in vivo. This product is available in research H-1715 Angiotensin I/II (1-7) BQ-123 SODIUM SALT 5 mg/vial U-1070, Cyclo(-D-Trp-D-Asp-Pro-D-Val-Leu) sodium salt C 31 H 42 N 6 O 7 : g/mol CAS No: (net) BQ-123 is a highly selective ET-A receptor antagonist. This product is available in research H-1252 BQ-123 BQ-788 SODIUM SALT 1 mg/vial U-1060, N-cis-2,6-Dimethylpiperidino- carbonyl-4-methyl-leu-d-trp(1- methoxycarbonyl)-d-nle-oh sodium salt BQ-788 is a highly selective ET-B receptor antagonist. This product is available in research H-2492 BQ-788 C 34 H 51 N 5 O 7 : g/mol CAS No: (net), (sodium salt) 9

10 Clinalfa BRADYKININ 50 μg/vial U-1080, H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe- Arg-OH acetate salt C 50 H 73 N 15 O 11 : g/mol CAS No: (net), (acetate) The pharmacological effects of bradykinin include smooth muscle contraction, vasodilation and hypotension, increase in capillary permeability with oedema formation and induction of pain. Bradykinin induces bronchoconstriction in asthmatic subjects and symptoms of rhinitis on nasal provocation. H-1970 Bradykinin (BK, Kallidin I, Kallidin-9, BRS-640) CCK-4 50 μg/vial U-1000, Synonyms Gastrin Tetrapeptide, Cholecystokinin Octapeptide (5-8), Cholecystokinin Tetrapeptide, Gastrin (14-17) (human) H-Trp-Met-Asp-Phe-NH 2 acetate salt C 29 H 36 N 6 O 6 S : g/mol CAS No: (net) CCK-4 reliably and dose-dependently induces panic-like symptoms both in healthy volunteers and patients with panic disorders. H-3110 Gastrin Tetrapeptide (Cholecystokinin Tetrapeptide, Cholecystokinin Octapeptide (5-8), CCK-4, Gastrin (14-17) (human)) CRF (OVINE) 100 μg/vial U-1170, H-Ser-Gln-Glu-Pro-Pro-Ile-Ser-Leu- Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu- Val-Leu-Glu-Met-Thr-Lys-Ala-Asp-Gln- Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg- Lys-Leu-Leu-Asp-Ile-Ala-NH 2 acetate salt C 205 H 339 N 59 O 63 S : g/mol CAS No: (net) Corticotropin-releasing factor (CRF) is a hypothalamic peptide which stimulates the release of adrenocorticotropic hormone (ACTH) and β-endorphin from the anterior pituitary. CRF also shows effects on reproductive functioning at local, neuroendocrine and behavioral levels, and depression. Ovine CRF produces a longer lasting ACTH response in humans than human CRF, mainly due to its longer plasma half-life. H-2445 CRF (ovine) (Corticorelin (ovine)) 10

11 EXENDIN (9-39) 10 mg/vial U-1160, H-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu- Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp- Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly- Ala-Pro-Pro-Pro-Ser-NH 2 acetate salt C 149 H 234 N 40 O 47 S : g/mol CAS No: (net) Exendin (9-39) is a GLP-1 (glucagon-like peptide-1) receptor antagonist and a competitive inhibitor of exendin-3 and exendin-4. H-8740 Exendin (9-39) GHRELIN (HUMAN) 100 μg/vial (FORMULATED) U-1250, H-Gly-Ser-Ser(octanoyl)-Phe-Leu-Ser- Pro-Glu-His-Gln-Arg-Val-Gln-Gln-Arg- Lys-Glu-Ser-Lys-Lys-Pro-Pro-Ala-Lys- Leu-Gln-Pro-Arg-OH acetate salt C 149 H 249 N 47 O 42 : g/mol CAS No: (net) Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor and is involved in regulating growth hormone (GH) release. Apart from GH release ghrelin stimulates appetite and weight gain. H-4864 Ghrelin (human) (DES- OCTANOYL)- GHRELIN (HUMAN) 100 μg/vial U-1300, H-Gly-Ser-Ser-Phe-Leu-Ser-Pro-Glu- His-Gln-Arg-Val-Gln-Gln-Arg-Lys-Glu- Ser-Lys-Lys-Pro-Pro-Ala-Lys-Leu-Gln- Pro-Arg-OH acetate salt C 141 H 235 N 47 O 41 : g/mol CAS No: (net) Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor. Most circulating ghrelin is des-octanoyl ghrelin. The non-acylated ghrelin was considered inactive at first, though biological activities such as stimulation of adipogenesis and control of cell growth could be demonstrated more recently. Both ghrelin and the more abundant endogenous form des-octanoyl ghrelin could play a role in the paracrine regulation of vascular tone in humans. This product is available in research H-5946 Des-octanoyl)-Ghrelin (human) 11

12 Clinalfa GIP 500 μg/vial U-1240, Synonyms Gastric Inhibitory Polypeptide (human), Glucose-Dependent Insulinotropic Polypeptide (human) H-Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp- Tyr-Ser-Ile-Ala-Met-Asp-Lys-Ile-His- Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu- Ala-Gln-Lys-Gly-Lys-Lys-Asn-Asp-Trp- Lys-His-Asn-Ile-Thr-Gln-OH acetate salt C 226 H 338 N 60 O 66 S : g/mol CAS No: (net) Gastric inhibitory polypeptide (GIP; also, and more adequately, designated as glucose-dependent insulinotropic polypeptide) is related to glucagon-like peptide-1 (GLP-1). Both are incretins, gastrointestinal hormones which regulate glucose homeostasis. GIP and GLP-1 stimulate insulin production after the ingestion of a meal. GIP is generated from a 153-amino acid precursor protein in the K cells of the duodenum mucosa and the jejunum. GIP induces insulin secretion by docking to the GIP receptors on the surface of pancreatic β-cells, though it is (contrary to GLP-1) inactive in type II diabetes. GIP receptors have also been detected in adipose tissue, the guts, the heart, adrenal cortex, and brain, suggesting further functions of the peptide hormone. In adipocytes, GIP enhances the metabolism of fatty acids by stimulating lipase activity. GIP alone and in combination with GLP-1 has gained interest in the secondary prevention of insulin resistance and in the management of obesity. H-5645 Gastric Inhibitory Polypeptide (human) GLP-1 (7-36) AMIDE 100 μg/vial U-1190, H-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser- Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln- Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu- Val-Lys-Gly-Arg-NH 2 acetate salt C 149 H 226 N 40 O 45 : g/mol CAS No: (net) This GLP-1 fragment is secreted from the lower small intestine and shows a strong insulinotropic effect. It is presently considered as the most important incretin hormone. Its action is mediated by receptors expressed by the endocrine pancreatic B-cells. Recent interest has focused on the development of this peptide as a novel therapeutic strategy for non-insulin-dependent (type 2) diabetes mellitus and associated neuropathy. H-6795 GLP-1 (7-36) amide (human, bovine, guinea pig, mouse, rat) (Glucagon- Like Peptide 1 (7-36) amide (human, bovine, guinea pig, mouse, rat)) 12

13 NEUROPEPTIDE Y (HUMAN, RAT) 200 μg/vial U-1230, H-Tyr-Pro-Ser-Lys-Pro-Asp-Asn-Pro- Gly-Glu-Asp-Ala-Pro-Ala-Glu-Asp-Met- Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His- Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg- Tyr-NH 2 acetate salt C 189 H 285 N 55 O 57 S : g/mol CAS No: (net) Neuropeptide Y (NPY) is one of the most potent neurotransmitters in reproductive endocrine functions and endocrine functions regulating stress, metabolism, and eating behavior. H-6375 Neuropeptide Y (human, rat) (NPY (human, rat)) L-NMMA 250 mg/vial U-1090, Synonym L-NMA H-Arg(Me)-OH acetate salt C 7 H 16 N 4 O 2 : g/mol CAS No: (net), (acetate) L-NMMA inhibits the synthesis of nitric oxide (NO) in a dose-dependent and enantio-specific fashion. Intravenous or intra-arterial injections of L-NMMA produce a powerful and prolonged vasoconstrictor effect, which can be reversed by L-Arg in a dosedependent manner. E-3745 H-Arg(Me)-OH (L-NMMA, Tilarginine, Targinine) PENTAGASTRIN 50 μg/vial U-1100, Boc-β-Ala-Trp-Met-Asp-Phe-NH 2 C 37 H 49 N 7 O 9 S : g/mol CAS No: Pentagastrin stimulates the secretion of gastric acid. It is a highly selective CCK- 8 receptor agonist with panicogenic and anxiogenic properties. The peptide elicits symptoms and cardiovascular responses similar to those produced by CCK-4. A-1130 Pentagastrin (AY 6608, ICI 50123, NSC ) 13

14 Clinalfa SUBSTANCE P 50 μg/vial U-1180, H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe- Gly-Leu-Met-NH 2 acetate salt C 63 H 98 N 18 O 13 S : g/mol CAS No: (net) Substance P (SP) is a modulator of pain transmission. As an extremely potent vasodilator, SP produces significant bronchodilation in normal and asthmatic subjects and a maximal increase in forearm blood flow. H-1890 Substance P 14

15 CUSTOM MANUFACTURING: CLINALFA PLUS Clinalfa is Bachem s brand for its clinical trial materials and related services. Clinalfa plus products are sold exclusively to Authorized Persons and Companies. Clinalfa plus products are available as sterile freeze-dried products or as readyto-use liquid formulations. The products are manufactured and released based on the requirements laid down in the European Commission Directives 2001/20/EC and 2003/94/EC and the EU GMP guide including annex 13. The products contain active substances manufactured and released according to ICH Q7. Clinalfa plus products can be used in preclinical or clinical studies (clinical trials) provided that such clinical studies fully comply with the international ethical and scientific standards as stated in the ICH guideline for Good Clinical Practice E6 (R1). Clinalfa plus products are manufactured and released on a customized basis. Based on agreements between the customer and Bachem, Bachem s Qualified Person (QP) may relate the release of the products to the use in a specific clinical trial approved by the competent authority. For Clinalfa plus products the level of validation of the manufacturing process and analytical methods, the design and duration of post-release stability studies and the content of CMC documentation is customized based on the developmental stage and intended use of the products. Clinalfa products are manufactured under cgmp conditions. Please have a look at the respective certificates. For offers and supply of Clinalfa products and Clinalfa services, the General Conditions of Sale of the Bachem Group apply. CLINALFA SERVICES Bachem offers related services to Clinalfa basic and Clinalfa plus products, i.e. formulation development, compatibility studies, stress test and post-release stability studies, CMC documentation for IMPD and IND, drug master file and other services. Please contact us for more information. 15

16 Clinalfa SITE CERTIFICATIONS BACHEM AG Development and manufacturing of active pharmaceutical ingredients (APIs) Registered with and inspected by the FDA, Swissmedic, and other national authorities Licensed for the manufacture of APIs for the Japanese market Peptides and small organic molecules Manufacturing of catalog products Custom synthesis Production of peptides by solid-phase peptide synthesis (SPPS) and solution-phase chemistry BACHEM DISTRIBUTION SERVICES GMBH Production and release of sterile products for use in approved clinical trials (Clinalfa brand) Intra-Community tax supply Registered with and inspected by the Regierungspräsidium Tübingen 16

17 PRODUCT DISCLAIMER AGREEMENT Bachem Distribution Services GmbH, Hegenheimer Straße 5, Weil am Rhein, Germany Product Disclaimer Agreement between Bachem Distribution Service GmbH, Hegenheimer Strasse 5, Weil am Rhein, Germany (the Supplier) and ( full name and address ) (the Investigator). Whereas the Investigator wishes to buy from Supplier and Supplier wishes to sell to Investigator the following Clinalfa product (the Product): Product Category : Clinalfa basic Product Name : Product Number : To be used in the following the following study (the Study): Study Number/Name : EUDRACT Number : (for Europe only) IND Number : (for USA only) The Investigator acknowledges having been informed by the Supplier about general terms and conditions of sale, in particular that Clinalfa basic products - are not authorized for marketing and - must be used exclusively in human studies (clinical trials) that fully comply with the international ethical and scientific quality standards as stated in the ICH Guideline for Good Clinical Practice E6 (R1). The Investigator has also been informed and is aware that an equivalent medicinal product authorised for marketing may be on the market. The Investigator acknowledges that experimental conditions of the clinical trial (study) are to be established by, and are the sole and exclusive responsibility of the Investigator. The product is for use in trials where the product is not taken home by subjects. The supplier assumes no liability whatsoever for damage and/or loss resulting from the use of the product, except where such damage and/or loss arise from the failure of the Product to meet the specifications. The Investigator shall ensure that the documentation taken into account by Bachem s qualified person (QP) when certifying the batch is consistent with the information submitted to the competent authorities for clinical trial approval (study). Place and Date : Signature : (of the Principal Investigator or Sponsor) Name and Position: BW Bank Lörrach Steuer-Nr /09863 Konto-Nr UST.-Id.-Nr: DE BLZ Handelsregister Freiburg i. Br., HRB IBAN DE Geschäftsführer: Dr. Wolfgang Fritzen, BIC: SOLADEST Dr. Thomas Früh, Christian Schütz 17

18 Clinalfa GENERAL INFORMATION General Conditions of Sale and Delivery The general terms and conditions of sale and delivery currently in force at the Bachem Group of Companies in the USA and in Europe can be obtained from the following sources: 1. Bachem website The information is contained at our website and a pdf file can be downloaded via the link General Conditions of Sale at the footer of the web page or under Service & Support. 2. Bachem Customer Service on request For Europe, Asia, Australia, Africa Tel [email protected] For North and South America Tel Tel [email protected] 3. Quotations and invoices (on the reverse side of the page) Qualified Person All Clinalfa products are released by a qualified person (QP) in full compliance with the EU GMP requirements (Eudralex Vol. 4 - Guidelines for good manufacturing practices for medicinal products for human and veterinary use) for investigational medicinal products. Storing and Handling of Clinalfa Products The required storage temperature is clearly indicated on the label of each vial, on the Certificate of Analysis, and on the box in which the product is shipped. The reconstituted product can be kept for a few days if stored in a freezer at -18 C (please check with us). The freeze/thaw cycle may be repeated only once. The unused portion must be discarded. The reconstituted solution can only be maintained sterile and pyrogen-free if kept in the original Clinalfa vial. Use-by Date The use-by dates stated on the vials, boxes and Certificates of Analysis are the retest dates in accordance with our scheduled stability tests. Beyond this date a revised Certificate of Analysis is available upon request. Product Disclaimer Agreement By purchasing a Clinalfa product, the buyer acknowledges having been informed by the producer that the product sold has been designed and manufactured exclusively for and therefore may only be used in clinical research under conditions to be established by buyer under his sole and exclusive responsibility. Producer and supplier assumes no liability whatsoever for injury and/or loss resulting from the use of the products. Calculations (g versus mol) amount (g) / MW (g/mol) = mol Example: compound with MW=1 000 g/mol g 1 mol 1 g 1 mmol 1 mg 1 μmol 1 μg 1 nmol 1 ng 1 pmol References The publications where Clinalfa products have been used are constantly updated on our website. Please use these references to support your ethical committee applications. 18

19 1 1 PRODUCT BROCHURES AMYLOID PEPTIDES ANTIMICROBIAL PEPTIDES CALCITONIN GENE-RELATED PEPTIDES CASPASE SUBSTRATES INHIBITORS CYSTEINE DERIVATIVES DAP AND DAB DERIVATIVES DIABETES PEPTIDES ENDOTHELINS FRET SUBSTRATES GHRELIN, LEPTIN AND OBESTATIN LHRH AGONISTS AND ANTAGONISTS MATRIX METALLO- PROTEINASES MELANOMA PEPTIDES N-METHYLATED AMINO ACID DERIVATIVES NEUROPEPTIDE Y NON-IONIC DETERGENTS ORTHOGONALITY OF PROTECTING GROUPS PAR ACTIVATING PEPTIDES PEPTIDE YY PEPTIDES IN COSMETICS PRION PEPTIDES PSEUDOPROLINE DIPEPTIDES SECRETASE SUBSTRATES INHIBITORS VETERINARY PEPTIDES VIP/PACAP 19

20 Marketing & Sales Contact Europe, Africa, Middle East and Asia Pacific Bachem AG Tel Americas Bachem Americas, Inc. Tel (toll free in USA & Canada) Visit our website or shop online shop.bachem.com All information is compiled to the best of our knowledge. We cannot be made liable for any possible errors or misprints. Some products may be restricted in certain countries. shop.bachem.com published by Global Marketing, Bachem Group,November 2015