Sugar Chemistry Finding Markets

In Mary Poppins' time, a spoonful of sugar made the medicine go down. It still does, but today sugars and their derivatives are increasingly medicines themselves as well.

Case in point: the newly patented antitumor product developed by Dextra Laboratories for Glycomed Sciences, both in the U.K., for treating skin cancers. The compound, a mixture of two complex alkaloid glycosides, is showing promise as a treatment that essentially dissolves skin cancer--an attractive proposition for cancers that frequently appear on the face.

For the most part, simple glucose, rather than sucrose, is the raw material of choice for tackling complex carbohydrate chemistry. Dextra's director, Chris Lawson, notes: "Sucrose is a dead end chemically. Many companies have tried to use it as a raw material, but it is not amenable to that. You can ferment it to ethanol, but it is not useful in chemical reactions--there are not really any useful chemical handles. Glucose is far more useful."

That is the simple molecular beginning for a group of companies that have been emerging over the past few years. In comparison with an earlier wave of carbo-chemistry start-ups, both the latest firms and those that have been around for some time are seeking alliances and partnerships on which to base sound growth.

For example, Brisbane, Australia-based Alchemia, formed in 1995, has teamed up with Dow Chemical in an alliance, begun in 2000, to produce synthetic heparin. Alchemia has developed a generic version of a heparin fraction--sodium fondaparinux--a molecule containing five sugar units that is considered among the most difficult carbohydrate-based therapeutics to manufacture.

Heparin, widely used since the 1930s to prevent the formation of blood clots, is mostly extracted from pig intestines. Subsequent research developed processes to split heparin into lower molecular weight components, isolating the active antithrombotic fractions. Synthetic heparin, which arose from a joint venture between Organon and Sanofi-Synthélabo, gives the antithrombotic benefits of heparin while reducing the risk of venous thromboembolism following major surgery.

THE PATENT for the Organon/Sanofi product, trade named Arixtra, expired in August 2003, and U.S. market exclusivity will end in December 2006. Anticipating the expirations, Alchemia has developed and applied for patents on a new and efficient route to synthetic heparin, according to Chief Executive Officer Tracie Ramsdale. The provisional patent, the culmination of three years of research, was filed in 2001, she says.

Alchemia intends to commercialize its synthetic heparin with Dow and American Pharmaceutical Partners. APP will handle product formulation, obtain Food & Drug Administration approval, and market the product in North America. Manufacturing will be carried out at Dow's pharmaceutical chemical operations.

Ramsdale expects Alchemia's product to be ready for the market in 2008. By that time, according to the company's estimates, the heparin family of drugs will account for annual sales of $4 billion, up from $3 billion in 2002. Some 85% of those sales were the low-molecular-weight fractions obtained from natural heparin.

More broadly, the Alchemia-Dow alliance aims for the large-scale custom synthesis of novel or existing carbohydrate compounds for pharmaceutical, nutraceutical, or other applications, particularly against intractable or difficult-to-treat diseases, according to Ramsdale. And the two firms are not stopping at synthetic heparin--they are actively seeking projects for the custom synthesis of other carbohydrate-based molecules.

Similarly, last year Dextra teamed up with life sciences specialist Cambrex to develop new chiral molecules used in active pharmaceuticals ingredients and advanced intermediates.

Dextra, founded in 1989 to exploit the carbohydrate chemistry at British sugar producer Tate & Lyle, specializes in the development of unique sugar and carbohydrate technologies. These technologies are used to synthesize chiral carbohydrate building blocks for pharmaceuticals and to build carbohydrate-based libraries of oligosaccharides, monosaccharides, azo sugars, and locked nucleosides.

Starting with Dextra's building blocks, Cambrex can generate complex molecules using its own enzyme technologies. Its aim is to support combinatorial drug discovery with complex chiral materials of known structure and configuration.

"FOR SOME TIME at Dextra, we have been excited about the potential of carbohydrates as chiral building blocks," says Andrew Hacking, the firm's joint managing director. He says the partnership "can pave the way to new classes of drug candidates through hitherto unavailable chiral structures in quantities suitable for practical development work."

Alex Weymouth-Wilson, Dextra's director of chemistry, adds that his firm's focus on building blocks fits with its limited capacity. "After that, we will use our partners at Cambrex, who can take production from 1 to 100 kg. They can take the product up to cGMP standards, for lead molecules," he points out. "And they have a sales team promoting our molecules. They get business in for us to develop, and then they can scale it up."

Dextra and Alchemia are just two examples of the current wave of firms working to exploit the versatility of glycochemistry. As components of many drugs and drug intermediates, carbohydrates provide a means to achieve multiple contiguous chiral centers that can be chemically manipulated to form a desired drug or drug intermediate.

Simple sugars can be linked together in numerous ways, resulting in a wide variety of carbohydrates. The challenge is to be able to produce a desired carbohydrate in a pure form, and--anticipating commercial application--using synthetic technology that is cost-effective and scalable.

And that is true whether the company is focused on supplying molecules for customers or on building its own portfolio of products.

Cambridge, Mass.-based Momenta Pharmaceuticals, for example, is applying its expertise in structure and function to improve existing sugar-based products and create new ones. The company's proprietary sequencing technology and capabilities enable it to identify--for what it says is the first time--the specific structures in complex sugars.

Cofounder Ganesh Venkataraman--a chemical engineer formerly on the research faculty at Massachusetts Institute of Technology--explains that Momenta was founded in 2001 on technology developed at MIT. The goal was to "take information encoded in sugars and translate that into therapeutics," he says.

Formation of Momenta, he notes, has been helped by the development of precise methods of characterizing chemical structures. "Precise chemical structure characterization of complex carbohydrates has led us to go back and do analysis on a lot of molecules that have been used in the past," Venkataraman says, citing structure-activity studies of heparin as a prime example. "Now we can rationally engineer drugs."A small pharmaceutical company like Momenta can survive in a world dominated by giants, Venkataraman adds, by balancing long-term technology with near-term opportunities. "By taking existing products and leveraging our knowledge of sugar properties, we can create a second-generation product," he explains. "We can combine that work with work on novel polysaccharide-based therapeutics." Near-term opportunities help cash flow, he points out. And collaborations, partnerships, and similar agreements can help move the basic technology along.

In November, for example, the company formed a strategic alliance with Sandoz, the generic drugs arm of Novartis. Venkataraman says the collaboration will marry Momenta's technological capabilities in complex sugars with Sandoz's expertise in generic pharmaceuticals to commercialize products. The two companies will jointly manage product development and commercialization.

Momenta will receive a profit share based on product sales if the parties are successful. As Alan L. Crane, Momenta's chairman and CEO, points out, "This partnership offers Momenta the potential to realize significant revenue at a very early stage in our company's development."

For zuChem, another sugar chemistry company, the goal of developing its own slate of pharmaceuticals is also being supported with alliances and agreements. The Chicago-based company, founded in 2001, focuses on fermentation and enzyme-catalyzed reactions to cost-effectively produce highly complex or expensive glycochemicals such as modified monosaccharides and l-sugars.

Rajni Aneja, zuChem's vice president and commercial director, was one of the team that founded the company in 2001 based on the premise of now-CEO David Demirjian that technology sitting idle in federal and academic labs could be commercialized. Its first deal, in 2002, with the Peoria, Ill.-based National Center for Agricultural Utilization Research, was to help commercialize a new low-calorie sweetener. A subsequent grant from the Biotechnology Research & Development Organization is helping zuChem commercialize a fermentation process to make the sweetener xylitol.

"One of the lessons we have learned from the biotechnology industry is that those companies went through money quickly," Aneja says. "That is a very risky strategy. So we were looking for quick revenues, and providing products for the food industry was one way. We want to exploit the early opportunities until we can get to the pharmaceutical sector."

Last year, zuChem--a name derived from the German "zucker," or sugar--acquired a portfolio of patents for microbial fermentation of d-mannitol, a reduced-calorie sweetener, from Hydrios Biotechnology of Helsinki. Also last year, zuChem entered a research collaboration with Ingenza of Edinburgh, Scotland, using Ingenza's work in biocatalysts for industrial applications.

Much of the research work in the sugar chemistry field has been aided by companies willing to make small quantities for tests and analyses.

Sometimes it is a side area of work. Although zuChem, for example, is primarily interested in building its own portfolio of proprietary products, "because of the expertise we have, we've been approached by others looking for processes: 'Can you make molecule X?'" Aneja says.

"One of our core strengths is in fermentation," she adds. "But eventually we may have to combine enzyme catalysis with classic chemistry. We have built a good scientific advisory board, which can tell us what problems we have to beat, or how we maybe don't need to do this or that because it is easier to do by classical chemistry."

ON THE OTHER HAND, at Dextra, custom chiral chemical synthesis joins small-scale chemical production as an integral part of the company's business. "We want to make things," Hacking emphasizes, "in quantities from 10 g to 1 kg. We want to make multistep process chemicals for drug evaluations and so on."

For example, Dextra has long maintained a catalog business featuring a range of carbohydrate chemicals such as the complex sugars found on surfaces of glycoproteins. These, Lawson says, "have a vastly important role to play. For example, we are selling them in 20-µg batches for use in mass spectrometry and research." Other catalog compounds include blood group trisaccharides, important in the xenotransplantation field; glycoconjugates, used in diagnostic kits; and heparin-derived oligosaccharides.

And Dextra has developed analytical services for carbohydrates, including methylation, mass spectrometry, and chromatography.

As part of this effort, the firm has put several hundred nuclear magnetic resonance (NMR) spectra on a website. "These are the real McCoy," Hacking says. "We have digitally scanned our carbohydrate NMR spectra into an archive, so researchers can compare what we have here with what they have."

According to Lawson, rapidly expanding areas include oligonucleotides, as well as nucleosides that feature nonnatural sugars and are used mainly for antiviral compounds or for cholesterol-reducing drugs. "We are recruiting at the moment to get people to do this. With the amount of work we see on the horizon, we are going to have to expand."

Weymouth-Wilson adds: "Each carbohydrate chemical is a different chemical, but once you set up the reaction conditions, it comes down to consistent chemistry. You must get the impurities out--it just won't work otherwise." Moreover, "you can't telescope through a process. These are very sensitive and unpredictable compounds. Some of these oligonucleotides [require] 30 steps. That's an awful lot of chemistry."

Hacking relates that the worst process Dextra has had to work with was one for which the client's R&D labs had devised the route. "They said there was a 40% yield. We couldn't reproduce it. The cost was two-and-a-half times what it would otherwise have been because there was only a 16% yield. It was a very tough job."

Lawson notes: "The commercial carbohydrate chemist is very rare. The academic carbohydrate chemist can do all sorts of things and not be worried about the yield. As long as he can find [the desired product] in the spectra, he can write an academic paper on it. Or he can work with exotic reagents. Industrial people have to come to grips with a reaction that scales well and that does not use exotic reagents or solvents or conditions. Some things you just wouldn't touch on an industrial basis--we must evaluate the chemistry before we start."

Founded in 1989, Dextra is one of the longest lived companies in the sugar chemistry sector. On the other end of the spectrum is zuChem, one of the latest entrants. But Aneja has paid attention to the sector's past. "Technology goes in waves--look at combinatorial chemistry, for instance. There was a glycochemistry wave a while ago, but most of the companies seemed to fail," she says.

However, "other areas all have been tapped out, which is why companies have come back to this field."

Moreover, Alchemia's Ramsdale says, "the recent advances in sequencing and synthesis mean that carbohydrates are just starting to come into their own as a range of compounds offering potential opportunities."

Glycochemistry, Aneja notes, is seeing a wide range of "novel structures, novel scaffolds, and novel ways of modifying them. There are a bunch of little companies, each with a unique approach. We are not competing directly, or all trying to get to the same place."

How much space there is, though, for all those little companies, remains unclear. In fact, she predicts, "within three to five years, there will be a lot of mergers and acquisitions: The industry will mimic what happened in combinatorial chemistry--and other sectors--before."