Changing Tides

Though they are highly potent and generally less toxic than small-molecule pharmaceuticals, peptide-based drugs have had trouble hitting their stride. A handful of naturally occurring peptides—insulin and calcitonin to name two—are high-volume sellers, but synthetic peptides have traditionally been challenged by delivery and formulation problems, manufacturing hurdles, and cost constraints.

Over the past several years, however, the tide has started to change. Pharmaceutical and biotechnology companies are acknowledging that the specificity and safety of peptides could allow them to address previously unattainable drug targets. Their interest in peptides coincides with technological breakthroughs that have made producing peptides, particularly longer sequences of amino acids, far more economical.

Those developments have translated into a heavier flow of peptide-based drugs through the development pipeline: At any given time, approximately 200 peptides are in clinical trials, with one to two approvals each year, according to data from peptides manufacturer American Peptide Co. Currently, more than 20 peptide-based drugs are in Phase III development, according to a study released last month by the market research firm Drug & Market Development.

The D&MD study also found that drug and biotech companies are pursuing peptides for a far wider scope of indications than previously studied. Of the 39 preclinical peptide drug candidates tracked in the study, 35 address new therapeutic targets entirely different from those of currently launched peptides. Some later stage candidates or recently launched products, in contrast, are more conveniently deliverable versions of naturally occurring peptides such as insulin.

Further evidence of heightened interest in peptides is the hefty codevelopment deal Affymax secured last month for its lead product, Hematide, a peptide that is in Phase IIb trials to treat anemia. Takeda Pharmaceutical laid out $105 million to share U.S. rights to Hematide and will pay another $430 million in milestones if the drug actually wins Food & Drug Administration approval.

Jane Salik, president of the contract manufacturer PolyPeptide Laboratories, attributes some of the recent interest in peptides to drug company recognition that certain indications can be attacked only by a peptide or protein.

"Big Pharma has come back in a big way to peptides," Salik says. "There was a period of maybe 10 years when they were not seriously considered for new pharmaceutical indications."

Peptides had been overlooked in no small part because they have been generally administered by injection, rather than orally, and tend to have short half-lives. "We now find more interest in peptides at big pharma companies, based on new technology in delivery and formulation," Salik adds.

Another major hindrance was cost. Peptides are made either by recombinant biotechnology or by liquid- or solid-phase synthesis, and large-scale manufacture proved economically prohibitive for some of them, particularly those composed of longer amino acid chains.

In recent years, however, a vast improvement in production economics has spurred increased use of solid-phase technology. The process, which involves building a string of amino acids off a resin support, is considered the most straightforward route to making medium- and long-chain sequences. "Over the past 10 years, cost of goods has come down dramatically," says Jim Hampton, vice president of business development at American Peptide.

Before then, recombinant technology was the only commercially viable option for a long-chain peptide drug that demanded large-scale quantities. "Ten years ago, peptides weren't as easily synthesized and scalable," Hampton says. "If you needed more than a half a kilo of product, you'd probably look at recombinant technology."

But the recombinant approach is limiting, peptide producers say, because it does not allow the introduction of unnatural amino acids. Furthermore, process development had to begin with a protracted program of selecting the right cell line to efficiently express the desired gene.

Solid-phase production, in contrast, is much more direct. "You can move into the clinic more quickly with a chemical process. We can have a few hundred grams in the clinic in four to five months, whereas with a recombinant approach it would be 18 months before that is possible," says Rodney Lax, sales and marketing director at PolyPeptide Labs.

Development speed limitations aside, recombinant manufacturing has a different set of quality issues compared with synthetic syntheses. "A synthetic universe is a known universe. You don't get anything out of it that you don't put into it," Hampton adds.

The growing prominence of solid-phase technology is driven by the need for a more economical manufacturing process to accomodate changing peptides requirements. Decades ago, peptide drug development was focused on small chain lengths that could be easily and economically manufactured through liquid-phase technology.

Today's peptides of 20 or more amino acids can't readily be manufactured in the liquid phase, says Lukas Utiger, head of exclusive synthesis at Lonza. Moreover, they typically require chemical modification, such as disulfide bridges, and are often required in volumes greater than 100 kg per peptide active pharmaceutical ingredient. "The trend toward solid-phase syntheses was a logical step for both customers and CMOs," or contract manufacturing organizations, Utiger notes.

Peptide manufacturers all agree that the shift to solid-phase synthesis of longer-chain peptides was made possible by Fuzeon, the HIV medication launched by Roche and Trimeris in 2003.

The drug, a 36-amino acid peptide formerly referred to as T-20, required production capacity magnitudes beyond that of previously approved synthetic peptides. That volume—some 45 tons of raw materials are needed to make 1 ton of Fuzeon—not only brought down the prices of raw materials for Roche but changed the cost equation for all peptide contract manufacturers.

"Synthetics were given a new life because of T-20," American Peptide's Hampton notes. "We spend more now on solvents than we do on amino acids."

"The key here is bulk shopping; we are the price club of peptides," says Ralph DiLibero, director of business development at Roche Colorado, the subsidiary that manufactures Fuzeon. He notes that Roche worked with suppliers to develop the chemistry that, in turn, enabled the drop in raw material and resin costs.

Although raw materials are important to the economics of peptide production, Roche says improving downstream processing has been even more critical to its ability to manufacture large quantities of synthetic peptides.

After being cleaved from the support resin, peptides are traditionally purified and then lyophilized—dehydrated through freeze-drying—for stable storage. Because of capacity limitations and time constraints, lyophilization can create a manufacturing bottleneck. Roche's response was to develop a precipitation method to replace it.

"Lyophilization is not only a very costly technique for bulk materials, but it also does not allow you to upgrade the purity of the peptide or the peptide intermediate," explains Gary W. Erickson, director of Roche Colorado's Boulder Technology Center.

In other words, "whatever is in the oven is what's going to end up in your cake," DiLibero adds. Any impurities, such as residual solvents, cannot be extracted, and the integrity of the product could even worsen if any degradation occurs during lyophilization.

Perhaps the greatest boon of the precipitation method is that it allowed Roche to synthesize certain peptide fragments in the solid phase, isolate them, and then join them with solution-phase chemistry. This hybrid approach addressed both cost and efficiency issues, and it permitted the synthetic production of longer-chain peptides that previously had been relegated to recombinant technology, peptide producers say.

To build long peptides via solid-phase chemistry alone, reactors need to be "humongous," and the coupling efficiency drops off as the chain gets longer, explains Satish Joshi, executive vice president at Peptisyntha, the peptides arm of Belgian chemicals group Solvay. The yield of a solid-phase synthesis drops exponentially as the length of the peptide increases, PolyPeptide's Lax adds.

In the hybrid process, "We can make small pieces on the solid-phase resin where coupling is very high and get extremely pure fragments," Joshi says. "Because you have large resolution, it's easy to take various fragments and put them in solution-phase mode."

Chemists can also reverse the process, making smaller pieces in solution phase and then assembling the peptide on a solid-phase resin. In either case, peptide producers say the hybrid process can be more efficient and less expensive, and it can result in a cleaner end product.

Furthermore, Roche has shown that the process can work at a large scale. With Fuzeon, "Roche Colorado has shown that you can easily make up to a ton of peptide using solid phase combined with solution phase," Joshi says.

The evolution of a more cost-effective process has more producers turning to solid-phase synthesis as a relatively quick and less expensive route to bringing peptide pharmaceuticals to market. And as the late-stage pipeline of peptide drugs fills, contract manufacturers are investing to support an expected need for commercial-scale manufacturing.

NeoMPS, the peptide manufacturing unit of SNPE's Isochem custom chemicals arm, is tripling solid-phase capacity at its Strasbourg, France, site. The company currently has peptides capacity of tens of kilograms in both Strasbourg and San Diego.

With a customer's product advancing into later stage clinical trials, NeoMPS may need "over 100-kg quantities," says Robert Hagopian, director of business development at NeoMPS. Construction of a new building adjacent to the existing peptides facility in Strasbourg is expected to begin at the end of the year.

PolyPeptide recently expanded solid-phase capacity at its Torrance, Calif., facility and expects over the next few years to double capacity to enable production in the 10-100-kg range. The firm is also upgrading its European facilities, which focus on solution-phase synthesis, to add both capacity and enhanced purification capabilities.

Peptisyntha began construction on an expansion of solid-phase capacity in 2005, adding two production trains to its Torrance facility. The $2.5 million expansion enables the firm to simultaneously manufacture multiple compounds and to support projects that are poised to progress into Phase II or III trials, Joshi says.

American Peptide is spending about $10 million to expand its Vista, Calif., facility. The company produces two commercial peptide drugs and expects a customer will file a New Drug Application for a third product later this year. It recently secured the contract to supply clinical quantities of Affymax's Hematide. The new equipment will enable peptide production up to the 50-kg scale.

Lonza significantly fortified its position in the peptides arena in January through the $145 million acquisition of rival producer UCB Bioproducts. In addition to adding significant capacity, the company says, the deal makes Lonza the sole peptides producer to offer all three technologies employed in peptide manufacturing.

Lonza has also boosted internal capacity at its own facility in Visp, Switzerland. The $20 million investment, initiated in April 2005, included the construction of a midscale plant for clinical trial supplies of both peptides and oligonucleotides and the addition of related purification and lyophilization equipment.

The rash of investment is supported by growth expectations for peptides: Producers expect the market for bulk peptides to grow at roughly 15-20% per year. Successful peptide launches such as Amylin's diabetes drug Byetta, which hit the market last year and is expected to achieve blockbuster status, provide some affirmation for those lofty targets.

"Five years ago, nobody was talking about peptides being needed as much as they are needed now," NeoMPS's Hagopian says. "I'm the eternal optimist, but I think we haven't really seen the full impact of the market growth on peptides yet."