16 June 2003 00:00 [Source: ICB Americas]Riding on the coattails of protein drugs, peptides have returned to prominence, generating new op-portunities for contract manufacturers possessing the required combination of small- and large-molecule expertise. Some of these companies have emerged from the catalog market; others are offshoots of industrial-scale manufacturers. Together they are demonstrating that synthetic chemistry can be the best ap-proach to manufacturing peptide-based active pharmaceutical ingredients (APIs), even very long ones.
A hot area in the 1980s, the development of peptide drugs was put on the back burner by pharmaceutical companies be-cause the only mode of delivery available was injection, a factor that seriously limited market potential. In the mid-1990s, however, peptides were given a boost when recombinant proteins reached the market. Proteins suffer the same drawbacks as peptides, but many address previously unmet medical needs. This and their high activity at very low dosage with low toxicity make a winning combination that has driven increased research into more convenient forms of delivery. This work has also benefited peptides, which are, like proteins, chains of amino acids. In fact, only chain length distinguishes them from each other: chains shorter than 100 amino acids are peptides, while anything over is a protein. Patches, inhalers and extended release delivery systems developed for proteins are therefore just as useful for peptides. Pharmaceutical companies have consequently revived or begun peptide programs, and biotech companies focused on proteins have also directed their resources at peptides.
There are now about 35 peptide drugs on the market, with the largest category being the LHRH-agonists, oncologic drugs that include TAP Pharmaceuticals' Lupron (leuprorelin), AstraZeneca's Zo-ladex (goserelin) and Aventis's Supre-fact (buserelin). The most recent FDA approval for a peptide has gone to Tri-meris and Roche's Fuzeon (enfuvirtide, formerly known as T-20), a 36-mer (i.e., a 36-amino acid polymer) fusion in-hibitor for the treatment of HIV infection. Fuzeon is a milestone of sorts in that Roche will produce tons per year, demonstrating that the large-scale production of such long peptides is feasible. Peptides recently made their way into the headlines when David Ho, a re-searcher at the Aaron Diamond AIDS Research Center, announced that fusion-inhibiting peptides were being tested for the treatment of SARS (severe acute respiratory syndrome).
From a manufacturing perspective, peptides are a peculiar cross between small and large molecules. Their synthesis draws on the chemistry used to make small molecules, while their purification, characterization and handling draw on techniques developed for proteins. The combination is unusual. Pharmaceutical companies typically focus on either end of the spectrum, and even many with expertise in both are "lost in between," says one producer. "They've found that this unique know-how is worth outsourcing."
There are two general approaches to peptide synthesis: solution-phase and solid-phase. Solution-phase synthesis, carried out in stirred reactors, is not so different from ordinary fine chemicals synthesis. Solid-phase synthesis, in-vented by the Nobel laureate Bruce Merrifield in the 1960s, entails anchoring the peptide to a resin. The advantage of solution-phase is its scalability. Solid-phase, on the other hand, can be developed more quickly.
The size of the market for peptide APIs is unclear. Estimates based on sales of finished drugs suggest that the value of APIs consumed lies between $200 million and $400 million. However, most peptide drugs are currently produced in house, so that the actual market for APIs is less. (Outsourced APIs include Millenium's Integrilin (eptifibatide) and the Medicine Company's Angiomax.) By the same token, most developmental work is contracted, as are many intermediates, notes one source, who suggests that this more inclusive market likewise totals between $200 million and $400 million. Growth of the cGMP market is generally put near 15 percent, though estimates range from 10 to 20 percent. "Each year there are more projects, and their size is growing," says one manufacturer. About 150 peptides are reportedly in the pipeline worldwide.
The market for catalog and research peptides is no more certain, one estimate putting its size at $100 million to $150 million, while another ventures "several hundred million," with growth of 10 to 20 percent. Part of the difficulty of putting a figure on this segment is the number of small players-every major center of medical research will have two or three nearby, many with only a few employees and revenues of $2 million or so, but together they make a major contribution to the market. The largest player in catalog and research peptides is Basel, Switzerland-based Bachem AG, which leaped into first place with the purchase of Bachem California Inc. in 1996. In late 1999, the company also acquired Peninsula Laboratories Inc. of San Carlos, Calif. Other major players include Neosystem (and its subsidiary, Multiple Peptide Systems, or MPS), Sigma-Genosys and American Peptide.
Bachem is also a major player in the cGMP market, having grown into that role to serve research customers whose projects were moving through development. Neosystem, a subsidiary of Iso-chem, SNPE's fine chemicals business, is taking a similar path. Founded in 1986, the company was acquired by SNPE in 1992. Between 1996 and 1998, the company added a cGMP production unit for the supply of gram and kilogram quantities of API at its primary site in Strasbourg, France. More recently, Neo-system invested $7.5 million in a production and research facility in San Diego, Calif., that is the new home of Multiple Peptide Systems (MPS), which became a Neosystem subsidiary in 2001. The facility includes 13,000 square feet of clean room space designed for large-scale cGMP manufacturing, with room for expansion.
In 2001, custom manufacturing of development peptides accounted for 51 percent of Neosystem's 10 million in sales, research peptides for 26 percent, and a catalog business of peptides and raw materials for 23 percent, according to CEO Serge Plau'. The company does not yet produce commercial APIs, he says, though it does have some pharmaceutical products-peptides for diagnostics-in production. About 15 APIs are in Phase I and II development, nearing Phase III. Subsidiary MPS, also founded in 1986, has sales of 6.5 million, of which cGMP grade peptides contribute about 60 percent. Over the past ten years, about 250 cGMP peptides have been produced at the San Diego facility, with about five now in Phase III and four in commercial production. Both solution- and solid-phase synthesis are practiced in Strasbourg, while the San Diego facility works primarily with solid-phase synthesis.
For other companies, a catalog has never been a large business. "We use the catalog almost exclusively as a marketing tool," says Rodney Lax, sales manager at PolyPeptide Laboratories (PPL) in Torrance, Calif. "Our core business is very definitely manufacturing APIs, primarily proprietary, and second line, generic peptides." PPL is a privately-held group of companies founded in 1996 specifically to pursue the growing market for cGMP peptide manufacturing. It has grown through acquisition, beginning with the Denmark-based bulk peptide business of Peptech, and now has five facilities. Large-scale production is done in Hillerod, Denmark, and Malm", Sweden, primarily by solution-phase. A newer facility in Torrance, Calif., can produce cGMP peptides in lots from 100 grams to multi-kilograms, primarily by solid-phase. The US facility, which has four APIs approved in the US, including Leuprolide, recently acquired another 10,000 square feet of space, increasing its capacity by almost 50 percent to meet ongoing production demands. PPL also has facilities in Prague, the Czech Republic, and Wolfenbttel, Germany.
Mr. Lax says that PPL, with its current expansion of both the US and Swedish subsidiaries, will have the capacity to produce about 300 to 500 kilograms of peptide APIs per year. "In addition to a number of approved proprietary peptides, we also make 15 to 20 peptide generics, and we believe these alone are present in about 50 registered drugs, worldwide," he adds.
An early participant in the contract manufacture of peptide APIs, UCB-Bio was founded in 1981, when UCB Pharma turned its attention away from peptides and shed the unit, which be-came a separate business within the UCB Group. After serving the catalog market for a few years, UCB-Bio found its mission in 1984 when UCB Pharma asked the spin-off to work on somatostatin, a 14-mer indicated for bleeding and esophageal ulcers, says Sophie Egholm, global marketing manager. UCB-Bio drew on its pharmaceutical background to implement cGMP compliant production, and in 1989 began a "breakthrough" scale-up project for Biogen that led to the 20-mer Angiomax (bivalirudin). UCB-Bio now produces the API commercially for the Medicine Company at its primary manufacturing facility in Brussels, Belgium, which has a capacity of 500 kilograms per year.
In February, UCB-Bio completed a 10,000 square foot customer appli-cation laboratory in North Augusta, S.C., increasing its global capacity for pilot production by 50 percent. Large-scale manufacturing capacity, now being planned, will follow, timed to suit growing demand for commercial APIs already in production in Brussels, says Ms. Egholm. She notes that the facility will be fully integrated and mirror the capabilities of the Brussels facility. "What we have put in place is dual-site sourcing-both sites have the same technology, the same pro-cesses, and an integrated quality system," she says. "No one else has that." UCB-Bio has also included small-scale flexibility in the facility. "We recognize the need to be there earlier and work with customers in preclinical," she explains.
The company has given equal emphasis to both solid-phase and solution-phase synthesis, Ms. Egholm says. "We're using the benefits of both in more and more combined approaches, making pieces by solid-phase to use its flexibility, then putting things back into solution for yield purposes." For example, three 10-mers might be prepared by solid-phase, then linked to form a 30-mer using solution-phase. Another advantage of this approach is the ability to characterize intermediates.
Diosynth, Akzo Nobel's active pharmaceutical ingredient manufacturing unit, has done peptide synthesis at its main site in Oss, the Netherlands, for over 30 years. The company has two facilities there, where it does some solid-phase synthesis while concentrating on solution-phase processes, manufacturing at scales in the hundreds of kilograms per year. According to a spokesperson, Diosynth has developed a new process, DioRaSSP (Diosynth Rapid Solution Syn-thesis of Peptides), that combines the advantage of rapid development provided by solid-phase with the scalability of solution-phase. Details of the new technology were made public for the first time at the recent Oligonucleotide and Peptide Technology Conference (Tides), but it has already been used in contract work. "It is expected that most of the new peptide processes Diosynth will develop in the future will be based on the DioRaSSP technology," he says.
Other major players are Peptisyntha, Avecia and Mallinckrodt. Peptisyntha, a Brussels-based subsidiary of Solvay with revenues over 30 million, has focused on solution-phase synthesis, for which it has developed a proprietary process based on persilylated amino acids. Among the advantages that the company claims for its technology are reduced risk of racemization and a sim-plified, milder production scheme. Among peptides manufactured by Pepti-syntha are cetrorelix, a 10-mer gonado-trophin-releasing hormone (GnRH) an-tagonist, says a Solvay spokesperson. "Peptisyntha's expertise is best illustrated by the development of eptifibatide, the active ingredient of a cardiovascular drug now on the market," he adds. Eptifibatide (Millenium's Integrilin) is a cyclic heptapeptide. In late 2001, an expansion lifted Peptisyntha's annual capacity to between 150 and 200 kilograms. The same year, a subsidiary specializing in solid-phase technology, Peptisyntha Inc., was established in Tor-rance, Calif., where it has R&D facilities and cGMP manufacturing capabilities.
Avecia, a leader in Fmoc solid-phase synthesis chemistry, has production facilities in Grangemouth, Scotland, and Milford, Mass. In February 2002 the company extended a collaboration with Gryphon Sciences for the development and supply of Gryphon's "performance-enhanced" protein therapeutics using native chemical ligation, a proprietary Gryphon technology for joining peptides to form proteins.
It has long been assumed that economical proteins could only be manufactured fermentatively using recombinant technology, but advances such as Gry-phon's native chemical ligation point to a time when the synthetic chemistry developed by peptide companies might provide a competitive alternative that offers particular advantages. "With re-gard to regulation, chemistry is more robust," notes one producer, who also points to its flexibility. "It seems there is a lot of progress being made in the production of longer and longer peptides, and researchers, when they look at a protein, are not limited by how the bugs make it. If they want to modify it, they have much easier access."
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