July 1, 2005 (Vol. 25, No. 13)

Pharma’s Interest in Peptide Drugs Drives this Market

If you were to listen in at a gathering of executives from the contract peptide manufacturing sector, you might hear phrases like “extremely busy,” or “saturated until well into next year,” or “cautiously optimistic about the future.”

Manufacturers of GMP peptides for therapeutic applications are echoing a common theme: strong growth in the peptide therapeutics market and expanding interest in peptides for drug discovery will continue for the foreseeable future.

They paint a rosy picture overall, yet despite widespread optimism, their image of the future is tinged with caution, as peptide suppliers are well aware of the inherent risks involved in dedicating manufacturing space and resources to a drug candidate that may or may not ever become a commercial product.

A peptide in Phase I clinical studies has perhaps a 1020% chance of reaching the market. Even though those odds improve to 6080% for peptide drugs that make it into Phase III trials, the risks also rise.

If a product fails at this stage, a significant amount of time and resources will have already been invested in the product, and the manufacturer will be left with a large-scale synthesis facility lying empty and unproductive.

The bottom line is that the GMP peptide industry shows great potential for growth, but how many of the products currently moving through and coming into the pipeline will make it to the market, and on how large a scale they will ultimately be manufactured will determine the level of actual, sustainable growth in this industry sector.

Contract manufacturers are expanding their manufacturing capacity to meet the increased demand for pilot-scale and small-scale synthesis projects; however, there may currently be overcapacity for large-scale projects.

Peptide manufacturers point to an increase in pharmaceutical clients as the most significant trend in the evolution of their customer base, a trend driven by the focus on peptide APIs for therapeutics and vaccines.

Progress in the areas of novel peptide formulations, innovative delivery systems that enable oral administration of therapeutic peptides, advances in inhaled drug delivery, and novel strategies for intranasal delivery of peptide vaccines are largely credited with reviving interest among Big Pharma in peptide drugs.

In the area of intranasal vaccine delivery, for example, Carrington Laboratories (Irving, TX) recently reported positive results from human safety trials of its GelVac powder intranasal system for vaccine delivery.

According to Kenneth Yates, president of Delsite Biotechnologies, a wholly owned subsidiary of Carrington Labs established to commercialize its polymer drug delivery technology, “studies showed that nasal deposition was consistent with quantifiable and reproducible amounts of powder delivered to the nasal cavity.”

Technology Driving Market

During the past year, Pepscan (Lelystad, The Netherlands) has demonstrated success in using its CLIPS (chemically linked peptides on scaffolds)-based peptide mimics of discontinuous protein domains as immunogens in synthetic vaccines.

With CLIPS, peptides are organized into a single, constrained, spatially defined molecule using small chemical scaffolds. The resulting molecules bear a closer resemblance to the native structure of a protein domain than would a typical linear synthetic peptide.

Pharmaceutical companies are developing more complex peptides with defined structural characteristics designed to achieve a specific biological function. Producing these sophisticated therapeutics requires expertise beyond conventional peptide synthesis capabilities. Similarly, value-added technology will be the key to survival in the highly competitive non-GMP peptide industry.

Simply having a peptide synthesizer and being able to churn out peptides for the research market will not be sufficient to ensure a company’s ability to compete in this market, in the view of Peter van Dijken, chief commercial officer at Pepscan.

Pepscan recently announced a research collaboration with ServiceXS (Leiden, The Netherlands) and Solvay Pharmaceuticals (Weesp, The Netherlands) focused on the de-orphanization of a series of proteases proprietary to Solvay. The project involves applying peptide array and microarray technology for the identification of novel peptide substrates for proteases.

“We think there will be a consolidation of suppliers of non-GMP peptides in the coming years,” says van Dijken. Price pressure continues to fuel competition in the research peptides marketplace and to drive improvements in synthesis and purification technology. Despite declining prices for standard peptides, though, the market will accommodate higher price points for more complex, value-added peptides.

Richard Lauricella, business development manager at Mimotopes (Clayton, Australia and Raleigh, NC), sees a growing demand for peptide providers that offer specialty peptides and have the capability to do more sophisticated types of syntheses, for example, production of primary screening and analog libraries of FRET peptides for use in kinase studies.

Mimotopes, a producer of specialty custom peptides and peptide libraries for the research market, was acquired by Western Australia-based PharmAust in March of this year.

Lauricella also cites a trend toward miniaturization in synthesis capabilities, enabling the production of small quantities of specialty peptides arrayed in formats suited to high throughput screening systems. He also sees strong demand for peptide libraries for screening projects linked to functional genomics, peptide therapeutics, diagnostics, and vaccine development programs.

Solid- vs. Solution-phase Synthesis of GMP Peptides

In a year marked by expansion of its cGMP-compliant manufacturing facilities in Torrance, CA, Peptisyntha (Brussels, Belgium; a member of the Solvay group) has multiple synthesis projects under way for peptides in various phases of clinical development, including in Phase III testing.

Together with the company’s established, large-scale (>100 kg/yr) program to produce eptifibatide (Integrilin) for Millennium Pharmaceuticals, Peptisyntha’s pilot plant and manufacturing facilities are “saturated,” at least through the end of the year, according to Pierre Barthlemy, Ph.D., general manager of Peptisyntha.

Construction under way at the Torrance site will add two manufacturing suites for large-scale cGMP peptide production using solid-phase synthesis. Solution-phase synthesis is the specialty of the group in Brussels. Ongoing manufacturing projects range from very small peptides of 3 to 5 amino acids, to the synthesis of long peptides, exceeding 40 amino acids in length.

Selecting an optimal synthesis strategy, whether that is solid-phase or solution-phase synthesis, depends in large part on the characteristics of the peptide being produced.

For example, Dr. Barthlemy describes one project at Peptisyntha in which peptide fragments are being made in solid phase and then combined in liquid phase; whereas the approach taken for another synthesis project is just the oppositesolution-phase synthesis to produce peptide fragments followed by a solid-phase process to connect the fragments.

The choice depends largely on the amino acid composition of the peptide and the presence of modifications or protective groups. Advances in solid supports and synthesis techniques have made solid-phase chemistry increasingly competitive with solution-phase synthesis. Each continues to offer unique capabilities and advantages.

“There is a misperception in the market that solid-phase synthesis is the ideal choice whatever the project,” says Dr. Barthlemy. “Although SPSS has evolved significantly and is a must have’ technology in the toolbox, it is a complement, and not a replacement for liquid phase.”

Robert Hagopian, director of business development at NeoMPS (San Diego), echoes the growing popularity of solid-phase synthesis for larger-scale projects. Ten years ago, once production levels exceeded 5 kilograms, people would switch to solution-phase synthesis, notes Hagopian. Now, however, the declining cost of scale-up and large-scale synthesis on solid supports has made solid-phase synthesis competitive with solution-phase methods.

Multiple Peptide Systems (San Diego) became part of Neosystem (Strasbourg, France) in 1999, but it was only recently that both companies adopted the common name NeoMPS to reflect that change.

NeoMPS has seen a shift in its customer base over the past year or so from small biotech firms to large pharma, with companies moving therapeutic peptide projects forward and into various stages of clinical development.

In Hagopian’s view, the peptide industry has not yet fully matured and is still in a growth phase, which will get a boost as new peptide drugs receive regulatory approval and begin to make their way to the marketplace.

Showing Signs of Success

Dr. Barthlemy points to recent registrations of two peptide drugs as “good news for peptide APIs.” Earlier this year, Amylin Pharmaceuticals (San Diego) and Eli Lilly (Indianapolis) announced FDA approval of Byetta (exenatide) for injection, an adjunctive therapy intended to improve blood sugar control in patients with type 2 diabetes who have not achieved adequate control with the use of metformin and/or sulfonylurea.

Exenatide is the first approved compound from the new drug class of incretin mimetics. These compounds stimulate insulin secretion and restore the body’s ability to respond to increased blood sugar levels, which is compromised in type 2 diabetes. Amylin formulated Byetta for use as a fixed-dose, subcutaneous self-injectable given before the morning and evening meals.

The FDA also granted approval to Amylin’s drug Symlin, or injectable pramlintide, a synthetic analog of human amylin for use in combination with insulin to treat diabetes. Amylin is a hormone that helps regulate appetite and food intake.

In recent weeks, the company presented data from a 16-week Phase II clinical study of pramlintide for the treatment of obesity. The company reported significant, progressive weight loss of 3.6% with pramlintide compared to placebo and no evidence of a plateau effect at 16 weeks. Amylin has initiated a Phase II dose-ranging study in 400 obese subjects.

With plans under way to expand manufacturing capacity at both its Torrance, CA, and Malmo, Sweden, facilities, PolyPeptide Laboratories (Hillerod, Denmark) is preparing for the increased demand that will result largely from Big Pharma’s renewed interest in peptides as viable therapeutic candidates, according to Jane Salik, Ph.D., president of PolyPeptide’s U.S. operations.

Not only is pharma developing peptide products they have acquired through partnerships, but they are also “bringing us projects from their own discovery,” notes Dr. Salik.

And even though it was dogma in the industry only 510 years ago that longer peptides were too expensive to produce as therapeutics, we are seeing “some larger peptides now being considered quite seriously as therapeutic candidates,” she adds.

Dr. Salik attributes this trend to improvements in chemistry, purification, and large-scale synthesis strategies and equipment, as well as, in part, to the example set by the Trimeris/Roche drug enfuvirtide, or Fuzeon, a long peptide that requires a complex synthesis process and is being produced in amounts exceeding 3,500 kg/year.

Fuzeon has not only established a benchmark for the production of longer, more complex peptide drugs, but it has also demonstrated success in navigating the regulatory approval process.

Dr. Salik would like to see more definitive regulatory guidelines established for peptide molecules, in particular with regard to impurities. Looking ahead, though, she foresees no regulatory issues facing peptide therapeutics as a whole and believes that current separation and purification technologies are quite adequate and readily scalable.

However, she suggests the need to explore new methods for isolating peptide products, as lyophilization will likely become a rate-limiting factor in therapeutic peptide manufacturing.

With its issuance of a guidance encouraging manufacturers of cGMP peptides to adopt Process Analytical Technology (PAT), the FDA emphasized the need for a more scientific and analytical approach to the art of synthesizing peptide drugs.

More Science Thank Art

This marked a shift in philosophy from the traditional approach of post-process quality control, in which peptides were produced and the product was then purified from contaminants and product variants in the process stream, to a focus on improving innate process qualities and, as a result, enhancing product quality from the top down and improving manufacturing efficiency.

TechniKrom (Evanston, IL) recently presented its Adaptive PAT to the FDA. Adaptive PAT is the company’s real-time application of PAT to the process of peptide synthesis and purification. “The payback for our clients is both reduced regulatory oversight, by demonstrating true process knowledge and control, and increased yield of product, which can create a return on investment during the first run,” explains Lou Bellafiore, president of TechniKrom.

Adaptive PAT helps drug manufacturers apply the principles of PAT to reagent and buffer delivery during peptide synthesis and liquid chromatography-based purification processes.

A key advantage it confers is the ability to monitor and adjust a range of parameters of the process stream, including pH, concentration, and conductivity, enabling real-time process optimization and documentation of these critical process parameters to support regulatory submission.

TechniKrom is applying Adaptive PAT in a variety of ways, including in synthesizer design, in which PAT-driven monitoring and decision-making permit either single pass or recirculating solid-phase synthesis.

A PAT module analyzes, adjusts, and controls the reagent feedstream entering the reaction vessel and monitors the process fluid coming off the synthesis column. It then decides whether to recirculate the process stream until the reaction is complete.

Another application of Adaptive PAT is in monitoring dynamic axial compression reaction vessels and controlling piston action to accommodate the shrinking and swelling of the solid-phase support resin. The end result is to ensure uniform flow and pressures throughout the process cycle by maintaining intimate contact of the pistons with the solid-phase support.

In liquid chromatography applications, Adaptive PAT for mobile-phase blending ensures reproducible linear gradient formation.

By achieving linear gradients within +0.1% of the set point, which is more than one order of magnitude greater than is achieved with other commercial chromatography systems, according to Kimo Sanderson, engineering manager at TechniKrom, the technology enhances the ability to resolve closely related peptides and to separate product from impurities, thereby improving yield and first pass recovery of product.

High-Energy Microwaves

CEM (Matthews, NC) replaced its Odyssey System for solid-phase peptide synthesis with the new Liberty System, launched in mid-April, which incorporates improvements based on market feedback. These include accelerated cycle times of less than 20 minutes and enhanced ease of use.

Researchers are finding that “microwave energy significantly speeds the synthesis process, results in better purity, higher yields, and the ability to make longer peptides,” says Michael Collins, president and CEO of CEM. People have made up to 67mers and are now looking to make 90 to 120mers.

“We believe that microwave will become the preferred way to synthesize peptides,” says Collins, adding that the field has reached a critical point at which there is enough experience with microwave synthesis to recognize its value and to attain a certain comfort level with the technology.

Additionally, hybrid synthesis strategies that rely on solid-phase synthesis to produce peptide fragments and solution-phase processes to link the fragments are becoming more common. “Microwave looks to be ideal for linking fragments together,” says Collins.

He anticipates that as companies look to develop longer peptides, the faster synthesis times and greater efficiency of coupling and deprotection that can be achieved with microwave energy will yield savings in the cost of solvents and reagents needed and in processing time.

Greater product purity will also save on downstream processing. Suppliers of research peptides strive for at least 90% product purity. But with conventional processes, purity tends to drop below 90% as peptide chains extend beyond 10 amino acids. With microwave synthesis, “we’re seeing crude 30mers in excess of 90% purity,” says Collins, eliminating the need for additional purification steps.

The Case for PEG Conjugation

American Peptide Co. (APC; Sunnyvale, CA) offers selections of premanufactured catalog peptides in convenient aliquots, a spectrum of custom synthesis services from array screens to mg and kg of research-grade peptides, and cGMP manufacturing of pharmaceutical-grade peptides for clinical trials. APC is experienced in solid-phase and solution-phase peptide synthesis and organic conjugations to proteins, toxoids, and PEG.

“We are producing milligrams to multikilograms of Active Pharmaceutical Ingredients (APIs) in our newest large-scale cGMP peptide manufacturing plant located in Vista, CA,” says Jim Hampton, vp, business development – GMP.

APIs based on synthetic peptides are recognized as potentially potent and selective drugs. Endogenous peptide sequences evolved in vivo to initiate and participate in complex biological processes in a specific and precise manner. Many thousands of these peptides are sequenced and manufactured synthetically.

“However, since 1970 only about 30 of these highly potent compounds have been synthetically manufactured at multigram, multikilogram, or tonne scales for approved pharmaceutical applications. One reason for the low participation of peptides in the pharmaceuticals market is the high cost of administration in therapeutic settings,” says Hampton.

For any given clinical utility of a drug, reducing cost-of-goods at the point of use and increasing bioavailability in vivo are major factors in determining the drug’s cost and success or failure in the marketplace.

Several studies are currently investigating therapeutic peptides that have been PEGylated and found to increase circulating half-life 100-fold or more. This could reduce the cost of the dose/ patient/year by several orders of magnitude, says Hampton.

In general, the direct cost of labor and materials of PEGylating a peptide under cGMP conditions will require a 2025% premium. In addition, the license fees for various proprietary PEG technologies from manufactures and suppliers of PEG may be 15% in royalties.

However, these royalty costs are usually paid at or after commercialization, and the PEGylation strategy may carve a potentially faster track through clinical testing than the naked peptide.

PEGylation strategies should be considered in primary proof of concept clinical studies with peptides. A 2025% increase in the cost-of-goods of a peptide API by chemical modification with PEG is a cost-effective trade-off for the benefits of potential decreases in dosing frequency and lower patient costs compared to the injected naked peptide, according to Hampton.

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