Advancing the Peptide Pipeline

Biopharmaceuticals are increasingly important in the pipelines of major pharmaceutical companies, but key technical issues exist in bringing certain biopharmaceuticals such as peptides to market. Improving delivery technologies, developing peptides with increased stability and half-life, and synthesizing long-chain peptides are some challenges in advancing commercialization.

Compared with other therapeutic proteins, peptides are a niche area. Roughly 430 proteins are in clinical development compared with130 peptides, and 70 proteins are in Phase III and registration compared with 20 peptides (1).

Lured by potential in clinical efficacy, however, the pharmaceutical majors and emerging drug companies are building their pipelines with peptide-based drugs and with technology to optimize the synthesis and delivery of peptides.

Pharma majors target peptides

Pfizer. A case in point is Pfizer, Inc. (New York, NY), which earlier this year agreed to acquire BioRexis Pharmaceutical Corporation (King of Prussia, PA), a biopharmaceutical company with several diabetes drug candidates and a protein-engineering technology based upon human transferrin designed to provide therapeutic agents with longer duration of action than synthetic peptides.

BioRexis's technology produces biopharmaceuticals by genetically engineering protein and peptide drugs into the scaffold of a natural variant of the human plasma protein transferrin. The engineered fusion protein is designed to enhance drug half-life from minutes or hours to several days or weeks, thus overcoming the problem of short half-life associated with peptide drugs. The engineered-fusion technology allows the drugs to be manufactured in yeast and genetically fuses therapeutic proteins and peptides to the N or C terminus, or both, of the carrier protein, nonglycosylated transferrin, according to the company.

Peptide Resources

BioRexis's lead candidate is a fusion of the well-known glucagon-like peptide (GLP-1), a 30-amino-acid peptide, to transferrin, for treating Type 2 diabetes. Pfizer also is developing a GLP-1 compound (PF 734200) to treat diabetes.

Sanofi-Aventis and Wyeth. Zealand Pharma (Copenhagen, Denmark) is another company specializing in peptide development and technology. Its stabilization of peptide ("SIP") technology is designed to increase biological half-life and improve product stability. Zealand is partnered with Sanofi-Aventis SA (Paris, France) for developing AVE0010, a GLP-1 for treating Type 2 diabetes, and with Wyeth (Madison, NJ) for developing rotigaptide, a peptide cardiovascular drug.

Eli Lilly. Eli Lilly and Company (Indianapolis, IN) has a global development and commercialization pact with Amylin Pharmaceuticals, Inc. (San Diego, CA) for "Byetta" (exenatide), a 39-amino-acid peptide amide with incretin-mimetic actions to treat Type 2 diabetes. The drug received US regulatory approval in 2005 and European approval in 2006.

Amlyin obtains exenatide, the active ingredient in Byetta from peptide supplier Bachem (Torrance, CA) and Mallinckrodt, Inc. (St. Louis, MO) under long-term supply agreements , according to Amylin's 2006 annual report.

The Eli Lilly–Amylin pact includes the development of a long-acting release (LAR) formulation of exenatide. Amylin is working with Alkermes, Inc. (Cambridge, MA) to develop a once-weekly dosing of exenatide. Amylin expects to complete the commercial-scale manufacturing process for the LAR formulation of exenatide and commission a new manufacturing facility in West Chester, Ohio in the second half of 2008, according to Amylin's annual report.

The partnership with Amylin is one aspect of an overall strategy by Eli Lilly to build its manufacturing base for biotechnology-based drugs. In October 2006, Eli Lilly completed the first phase of a $560-million expansion to its biotech complex in Indianapolis, Indiana. The first phase included the opening of a bioproducts pilot manufacturing plant that manufactures small-scale amounts of drug for use in clinical trials and a research-support facility. Construction of a third facility, a bioproducts research and development laboratory was scheduled for completion in the first quarter of 2007.

Also, in January, Eli Lilly announced plans to expand its site in Kinsale, County Cork, Ireland to manufacture active ingredients for future biotech products and to expand its parenteral operations in Indianapolis so that site can convert the biotech active ingredients made in Kinsale into their final dosage form.

Eli Lilly, however, decided not to proceed with a planned insulin manufacturing plant in Prince William County, Virginia because it expects to meet expected growth in insulin demand with existing sites and new insulin capacity that is being built in Sesto, Italy.

β peptides and chemical litigation advance peptide research

Takeda. Takeda Pharmaceutical Company Limited (Osaka, Japan) is partnered with the biopharmaceutical company Affymax, Inc. (Palo Alto, CA) for developing "Hematide," a synthetic, pegylated peptide functioning as an erythropoiesis-stimulating agent. The drug is in Phase II studies.

Affymax and Takeda are collaborating on the development of Hematide and will cocommercialize the product in the United States. Takeda has been granted an exclusive, royalty-bearing license to develop and commercialize Hematide outside the United States, including Japan. Under the pact, Affymax received $132 million in upfront and milestone payments, $10 million from the sale of equity, and is eligible to receive development and regulatory milestone payments of as much as an additional $345 million and commercial milestone payments of up to $150 million.

Affymax is responsible for manufacturing the active ingredient in Hematide, and it intends to establish long-term commercial supply agreements with at least two contract manufacturing organizations, according to company information. Takeda is responsible for the fill-and-finish of Hematide.

Last year, American Peptide Company (APC, Sunnyvale, CA) formed a clinical supply agreement with Affymax for production under current good manufacturing practices (CGMP) of Hematide. APC had previously manufactured preclinical lots of Hematide for Affymax.

Affymax and Takeda are positioning Hematide in the $13-billion market for recombinant erythropoietic proteins (EPOs). This market is led by Amgen, Inc.'s (Thousand Oaks, CA) "Aranesp" (darbepoetin alfa) and Johnson & Johnson's (New Brunswick, NJ) "Procrit" (epoetin alfa).

Although Hematide has the erythropoietic activity characteristic of naturally occurring EPOs, its amino-acid sequence is unrelated to EPO, recombinant EPO, or other known naturally occurring erythropoietic proteins. Two current types of ESAs, epoetin alfa and epoetin beta, are biologically engineered hormones produced in mammalian cells by recombinant DNA technology. Both are relatively short-acting forms of recombinant EPO that typically require frequent dosing. Darbepoetin alfa is a biologically engineered hormone product closely related to and functionally similar to epoetin alfa. Darbepoetin alfa, however, has a terminal half-life approximately three times longer than epoetin alfa, as a result of the addition of sialic acid to stabilize the protein, according to Affymax's annual report.

Roche and Novo Nordisk. Roche (Basel, Switzerland) is partnered with Ipsen (Paris, France) to license, develop, and market "BIM 51077," an analogue of the peptide hormone GLP-1 to treat diabetes. Ipsen's technology platform involves the ability to combine the engineering of therapeutic peptides with parenteral sustained-release delivery technologies. Roche is responsible for manufacturing the product. A Phase II study to confirm the efficacy and safety of this compound in a sustained-release formulation is expected for this year.

Novo Nordisk (BagsvE6rd, Denmark) also is developing a GLP-1 analog, liraglutide, which is in Phase II development.

Novo Nordisk's long-acting insulin "Levemir" shows how chemical modification can alter the properties of a protein to prolong its effect. The chemical modification can be performed on the isolated protein by linking a small molecule or side chain to the protein. In the case of Levemir, the activated lipid acid is synthesized and coupled to the primary amino group of lysine in the protein, resulting in an insulin analogue with tailored properties, says Novo Nordisk.

Company Web sites

Other players target peptides

Certain generics companies are positioning in peptides. Last month, Ranbaxy Laboratories Ltd. (Gurgaon, India) and Jupiter Biosciences Limited (JBL, East Marredpally, Secunderabad, India), a contract manufacturer of peptides, agreed in principle to form a strategic business alliance under which Ranbaxy would acquire a 14.9% share of JBL. JBL's board approved the alliance in principle, according to a JBL filing with the Bombay Stock Exchange.

Jupiter Bioscience (US), a JBL subsidiary, is setting up a CGMP facility in Frederick, Maryland for manufacturing custom peptides, clinical peptides, and peptide-based generic APIs with an initial investment of $4 million. The facility is scheduled to open in August 2007.

In 2006, JBL acquired a manufacturing facility in Khazipally, India with capabilities for bulk production of APIs and drug intermediates. Jupiter will use this facility to produce advanced organic and chiral intermediates and and bulk supplies of peptide raw materials.

Amylin. In addition to Byetta, Amylin's other commercial peptide is "Symlin" (pramlintide), a synthetic analog of human amylin for treating Types 1 and 2 diabetes. The drug is a synthetic 37-amino-acid polypeptide. The contract manufacturer Lonza (Basel, Switzerland) and Bachem supply the peptide to Amylin, according to Amylin's annual report.

Contract manufacturers expand

As the pipelines of Big Pharma, emerging drug companies, and generics players fill with select peptide-based drug candidates, several contract manufacturers of peptides are expanding manufacturing internally and by acquisition.

Peptisyntha. Earlier this year, Peptisyntha SA (Brussels, Belgium) launched the expansion of its pilot-scale production capacity for bulk peptides based onsolution-phase technology at its plant in Brussels, Belgium. The expansion includes an additional pilot high-performance liquid chromatography unit, an additional pilot freeze-dryer, and an additional pilot plant for the chemical synthesis of peptides. All the units are scheduled to be fully operational during 2007. Peptisyntha completed construction and validation of CGMP quality-control laboratories at the same site in 2006.

Peptisyntha's expansion in Brussels follows its recent expansion of solid-phase peptide synthesis capacity at its site in Torrance, California, which came on stream in 2006.

Peptisyntha is part of the Solvay Group (Brussels, Belgium), the chemicals and pharmaceuticals company, which also includes Solvay's contract manufacturing activities in small molecules. Solvay holds a controlling interest in Girindus SA (Bensberg, Germany), is a producer of oligonucleotides and radiolabeling services. It operates laboratories and pilot-plant facilities in Cincinnati, Ohio, which also is the site for its commercial-scale oligonucleotide production.

PolyPeptide Laboratories. PolyPeptide Laboratories (Torrance, CA) is building a new peptide plant in Ambernath, India, which is scheduled to be operational in 2008. Last year, it increased its peptide manufacturing capacity in Torrance, California; Malmo, Sweden; and Hillerod, Denmark. These expansions increased solid-phase peptide synthesis capacity, complementing its large-scale, solution-phase synthesis capabilities in Malmo and Hillerod. The company also expanded its preGMP development capabilities in the United States.

NeoMPS. NeoMPS (Strasbourg, France) is planning to invest EUR10 million ($13.6 million) to expand peptide capacity at its facility in Strasbourg, France, with completion scheduled for mid-2008. The investment more than triples the company's large-scale manufacturing capacities (solid and liquid phases) in Strasbourg. The company has multi kilogram-scale CGMP peptide capacity at its facilities in Strasbourg and San Diego.

Bachem. Bachem (Bubendorf, Switzerland) invested $10 million to expand production capacity by 40% for the CGMP manufacture of peptide active ingredients at its facilities in Torrance, California. The company added a new production unit for solid-phase peptide synthesis and purification that become operational in July 2006.

Almac Sciences. Last year Almac Sciences (Craigavon, Northern Ireland) commissioned a £500,000 ($993,000) package of new assets at its facilities in Northern Ireland and Scotland. New investment at its large-scale, multi-product site at Craigavon, Northern Ireland included automated peptide synthesis equipment, a freeze-drying suite, and preparative high-performance liquid chromatography. New equipment for small-scale peptide synthesis was added to its production and research and development center in Edinburgh. Almac specializes in long-chain peptides and has developed synthesis and purification techniques to make peptides up to 170 amino acids in length.

Lonza. In 2006, Lonza acquired UCB Bioproducts and its peptide manufacturing facility in Braine-l'Alleud, Belgium and completed its integration into Lonza in December 2006. The facility has manufactured over 400 preclinical and clinical peptide drug candidates, estimates Lonza. Examples of generic peptide APIs manufactured at the Braine facility include somatostatin and desmopressin.

Genzyme Pharmaceuticals. Genzyme Pharmaceuticals (Cambridge, MA), a contract peptide manufacturer, is partnered with Brookwood Pharmaceuticals, Inc. (Birmingham, Alabama) to offer customized solutions for parenteral formulations by combining expertise in peptide delivery and synthesis. The companies formed a pact last year.

References

1. J. Lakshmikanthan, "Outsouricng: Biologics: The CMO Advantage," BioPharm Intl. 20 (2) 40–48 (2007).