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Feature Articles : Jul 1, 2009 (Vol. 29, No. 13)

Competition Mounting in Peptide Market

Renewed Interest in Peptides from Pharmaceutical Firms Heats Up Sector
  • Vicki Glaser

Advances in synthetic chemistry, solid support materials, purification technology, and biological drug delivery strategies have all contributed to strong growth and expanding interest in peptide drugs, especially among large pharma companies. Even with the global economic downturn, the market for GMP peptides continues to grow—albeit at a reduced rate—with the progression of established therapeutic peptide projects through clinical development and the emergence of new peptide drug candidates from discovery research.

In the research sector, demand for peptides also continues to rise at a somewhat slower pace, particularly for peptide libraries used in drug screening, target validation, epitope mapping, and structure-activity studies.

Research-grade peptide producers in the West are facing strong competition from emerging suppliers in the Far East, where lower operating costs are driving down the cost of peptides. Manufacturers in India and China in particular are well positioned to supply the rapidly growing Asian market for research peptides, and some Western producers are gearing up to compete for this growing market base by opening satellite facilities in the Far East.

Companies such as American Peptide Company aim to compete with these lower price points by emphasizing quality and service, and specializing in difficult syntheses such as producing hydrophobic or hydrophilic peptides and modified peptides that offer enhanced stability, solubility, or other desirable characteristics. 

In April, American Peptide completed the first phase of its expansion project, with construction of five new class 100,000 purification suites, doubling the existing purification capacity. This increased capacity is attributable to the addition of purification columns up to 12 inches diameter for large-scale projects. The expansion also included three new class 10,000 packaging suites. The next phase of the expansion will add large-scale synthesis suites and lyophilization capacity for producing multikilogram peptide APIs per batch.

Therapeutic Peptides

The annual growth rate for the therapeutic peptide market is estimated at about 7.5%—down from the double-digit growth the industry enjoyed in recent years. Predictions place the value of the GMP peptides market at more than $13.4 billion by 2010. Some estimates project only 0–5% growth in 2009, with the market beginning to show improvement toward the end of the year.

Therapeutic peptides continue to increase in length and complexity, with 30, 40, and even 50+ amino acid peptides moving into clinical pipelines. Improvements in synthesis and purification technology are allowing for the efficient and cost-effective production of these longer peptides. The development of higher-quality resins for solid-phase synthesis and price reductions for some reagents commonly used in peptide synthesis have also contributed to the lower cost of synthesizing longer peptides.

With 14,500 square feet of new manufacturing capacity now in operation, Bachem’s six production sites in the U.S. and Europe are poised to handle the continuing growth of the peptides market, says Philip Ottiger, president and CEO. While “we are seeing a concentration of projects” by biotech companies, which are focusing their efforts on a few select projects and delaying others until the market heats up, the pharmaceutical industry “is starting to like peptides again,” observes Ottiger. “We are seeing enormous interest from pharma.”

This interest extends beyond peptide drugs to the use of GMP peptides as drug carriers. Ottiger describes a growing interest in cytoconjugation, in which peptides conjugated to cytotoxic drugs such as the chemotherapeutic agent doxorubicin can improve drug selectivity, enhance cell penetration, and reduce drug toxicity. Synthesis of the relatively short peptides used in cytoconjugation—typically 8 to 20 mers—is straightforward, but formation of the cytoconjugate is a complicated process.

Bachem built a facility devoted to cytoconjugation products about two years ago, and Ottiger reports growing demand, with an expanding focus on conjugation to PEGylated peptides or albumin and interest in cytoconjugation to the intestinal peptide glycogen-like peptide-1 for the development of therapeutic compounds targeting diabetes mellitus.

Contributing to the renewed interest in peptide drugs are improvements in pharmaceutical formulation technology, notes Ottiger, which are enabling better stabilization of peptides and more cost-effective methods for large-scale production that can be used in place of lyophilization, such as spray-drying technology and precipitation.

Mimotopes continues to benefit from its alliance with Genzyme Pharmaceuticals, aimed at providing seamless peptide synthesis, scale-up, and GMP manufacturing from discovery and development through to clinical testing. Nicholas Ede, Ph.D., CEO of Mimotopes, points to the use of pseudoproline dipeptides as a competitive advantage.

Pseudoproline technology prevents secondary structure formation during peptide synthesis, enhancing coupling efficiency and chain elongation, and resulting in higher purity of crude peptides and better overall synthesis yields. Mimotopes uses pseudoproline reagents in the synthesis of its research-grade peptides, and Genzyme further developed the technology and demonstrated the advantages of these reagents in large-scale GMP synthesis. Genzyme also offers these reagents in bulk—in quantities from 100 g to hundreds of kilograms—for large-scale production; these include high-purity Fmoc- or Z-protected pseudoproline dipeptides.

In response to rising competition from India and China, Mimotopes established a relationship with the Chinese company Venturepharm Laboratories, which provided a facility that now houses Mimotopes China. The new facility employs Mimotopes’ peptide-synthesis technologies, follows the company’s standard operating procedures, and its staff is trained by Mimotopes employees. It can not only take advantage of the lower cost base of employment in China, but it has also tapped “the incredible local talent pool of peptide chemists,” says Dr. Ede.

Mimotopes recently launched, in collaboration with GlaxoSmithKline and the University of Leeds (U.K.), REPLI, a fluorescence resonance energy transfer (FRET) rapid endopeptidase profiling library for use in identifying protease substrates. PepSet peptide libraries consist of fluorescently labeled tripeptide analogs that span the sequence surrounding the cleavage site of the substrate.

Improvements

Other recent advances in peptide synthesis that Dr. Ede feels have contributed to the quality, efficiency, and cost-effectiveness of peptide synthesis are improvements in automated peptide synthesizers, such as Protein Technologies’ line of instruments that includes the Symphony®, Sonata®, Prelude™, and Tribute™.

“What they have achieved in the last two years—with the development of fast synthesis protocols using HCTU highly activated coupling agents—has helped us enormously,” he says. Dr. Ede also credits the development of microwave-synthesis technology, pioneered by CEM with its Liberty™ automated synthesizer, as having “a profound effect on the ability to synthesize hydrophobic peptides.”

Protein Technologies recently introduced the Sonata XT peptide synthesizer, doubling the scale of the original Sonata instrument, with a capacity for 400 g of resin and 0.5 to 200 mmol scale synthesis.

The Sonata XT is GMP compliant, compatible with batch or continuous flow syntheses, offers amino acid delivery options for either in situ activation or preactivation (to minimize unwanted side reactions), and features dual waste streams for reduced disposal costs.

The new instrument was developed in response to customer demand for increased capacity. As products move through the pipeline and peptide quantities increase, companies want to be able to produce a GMP peptide in a single, larger batch rather than in two or more batches, thereby simplifying traceability and accountability and eliminating the need to duplicate QA/QC and validation protocols, according to Mahendra Menakuru, COO.

He highlights several key features of the company’s automated synthesizers, primarily the core fluidics technology that minimizes moving parts and is based on a soft-seat membrane valve design; the instruments’ minimal down-time for cleaning and other internal machine processing enabling fast cycle times; and the use of HCTU, a potent coupling reagent that accelerates Fmoc synthesis.

Also new on the market from Protein Technologies is the IntelliSynth UV-monitoring and feedback control attachment for the Tribute two-channel peptide synthesizer. The system “takes the mystery out of the deprotection reaction,” says Menakuru. It monitors the efficiency of Fmoc removal in real-time by measuring the concentration of dibenzofulvene-piperidine adduct formed. Users can select from two feedback control options that automatically modify deprotection and/or coupling cycles based on the reaction data.

Despite the increasing strength of the dollar in overseas markets, Menakuru has not seen a decline in business from Europe or Asia. Furthermore, he reports early signs of a reversal in last year’s decline in grant-funded projects, with a substantial rise in inquiries from academia in the early part of 2009 that he attributes to anticipation of NIH stimulus dollars making their way down to funded laboratories.

Recognizing increasing market demand for an expanded range of peptide substrates for long-wavelength fluorescence resonance energy transfer assays, AnaSpec developed a series of fluorogenic FRET pairs for evaluating protease inhibitors in drug discovery. The assays are commonly used for studying protease activity and screening for protease inhibitors. The company’s FRET peptides incorporate its QXL™ quenchers, which are optimized to pair with AnaSpec’s HiLyte Fluor™ dyes as well as commercial fluorescent dyes.

The long absorption wavelengths of AnaSpec’s FRET pairs, such as carboxyfluorescein/QXL 520, “eliminate a lot of the autofluorescence” that contributes to background noise and compromises assay sensitivity, according to Cecilia Po, technical support specialist. The company’s most recent product introduction, early this year, featured fluorimetric cathepsin FRET assay kits.

Po also highlights the company’s hydrocarbon-stapled peptides, in which the modified amino acids are artificially “stapled” together to create an alpha-helical secondary structure. This increases peptide chemical stability and may offer biological stability by making the peptide resistant to protease activity, offering protection from proteolytic enzymes. The modification may also enhance the cell permeability of short peptides, while improving their target-binding affinity.

For luciferase-based assays, AnaSpec offers custom synthesis of peptide-aminoluciferin substrates, which are amenable for use in high-throughput screening assays. Substitution of an amino group for the 6-position hydroxyl group transforms a luciferin molecule into aminoluciferin, allowing the molecule to form amide bonds with a peptide while retaining the bioluminescent properties of luciferin.

Expanding Capacity

With recent economic conditions, Peptisyntha has seen “a more discriminative funding approach” across GMP peptide programs.  “Successful drug projects seemed to have attracted partnering attention of big pharma more rapidly, while some other drug projects with higher uncertainty profiles are put on hold or discontinued altogether,” says Johan Devenyns, Ph.D., head of Solvay Peptides, the parent company of Peptisyntha.

The company has continued to expand its capacity, with the recent completion of new QA/QC laboratories and offices at its California site. The company has also leased a fourth building on the same premises, providing space for a future expansion of its solid-phase production capacity, according to Satish Joshi, president of Peptisyntha.

At its Brussels site, home of the company’s solution-phase manufacturing capability, Peptisyntha finished validation and took into operation new lyophilization capacity and, in April, commissioned a new pilot installation using organic electrochemical processes for the production of non-natural beta-amino acids. A recent cGMP inspection of the Brussels facility by the U.S. Food and Drug Administration for commercial peptide APIs manufactured for the U.S. market was completed successfully and generated no written or oral observations or discrepancies, according to Joshi.

Work continues on the installation and validation of hardware and software for a manufacturing execution system that will automate a series of workflow processes involved in peptide production. “This will include automated follow-up of the flow of materials moving in and out of the company’s new warehouses and will allow a significant productivity upgrade in an environment with multiple product streams,” says Dr. Devenyns.
According to Peptisyntha, key market trends include a growing focus on PEGylation; increasing interest in peptide drug projects in the areas of diabetes, obesity, and cancer; and more projects that may benefit from hybrid strategies that combine solid-phase and solution-phase synthetic processes.

The PolyPeptide Group (PPL) also reports a market decline stemming from the biotech sector, with gains continuing from the pharmaceutical industry. Progress continues on PPL’s newest production site in Mumbai, and Rodney Lax, director of business development, reports that the facility will begin manufacturing generic peptides by the end of 2009.

Corporate expansion is still under way in Scandinavia as well, and PPL has begun to look for a new facility to allow for additional growth in the South Bay region in California.

While the market for short peptides (<10 amino acids) remains relatively stable, companies such as PPL report a rise in orders for peptides that require increasingly complex syntheses, whether due to increased length or a variety of modifications. In addition to growing demand for PEGylated peptides, Lax describes interest in complex structures that may contain more than one peptide (for activity against dual targets) or incorporate nonpeptide organic moieties.

“I am quite upbeat about 2010,” says Lax. “A lot of companies are holding back right now waiting to see how quickly the economy recovers.”