A Transatlantic Polymeric Solution

A START-UP started by a start-up, California-based Ilypsa is a biopharmaceutical company that in just four years has brought a drug into Phase II clinical trials. Now, with the help of the German custom manufacturer Saltigo, Ilypsa is looking ahead to the product's final stage of clinical testing and potential commercial launch.

Although a robust 70-person company today, Ilypsa was just two people and a good idea in May 2003, when it was spun off of Symyx Technologies. At the time, Symyx, a specialist in materials research and high-throughput experimentation (HTE), had been a public company for only four years.

Gerrit Klaerner, a German polymer chemist, remembers that time well. Now Ilypsa's chief business officer, he had come to the U.S. in 1997 for a postdoctoral fellowship at the Center on Polymer Interfaces & Macromolecular Assemblies, a National Science Foundation-sponsored partnership among Stanford University, IBM's Almaden Research Center, and the Davis and Berkeley campuses of the University of California.

Following the scientific ties that ran between the center and Symyx, Klaerner joined the company in 1998. Symyx was just hitting its stride in commercializing the idea that got it started. Inspired by UC Berkeley chemistry professor Peter G. Schultz, the company was taking the HTE philosophy of miniaturization, automation, and parallel processing beyond pharmaceutical research and into the materials realm.

Symyx tackled the challenge with a vengeance. Before long, it had struck deals with ExxonMobil and Dow Chemical to apply HTE to commodity polymer catalysis. It launched its initial public stock offering in 1999 and has been profitable since 2001.

Klaerner's charge at Symyx was to apply HTE techniques at the interface of biology and polymer chemistry. Together with Schultz, a small group of company scientists was determined to bring HTE back to its pharmaceutical roots. In the drug industry, polymers acted mainly as drug delivery agents or inert ingredients. "But we realized that, in the end, the ultimate prize is the drug itself," Klaerner says.

The trouble was, although Symyx had developed high-throughput techniques for polymorph screening and other pharmaceutical research protocols, company managers were loath to confuse investors by suddenly diving into the risky world of drug discovery. Their solution was to spin off the pharma effort with $10 million in financing from venture capital backers.

The resulting company, Ilypsa, was small, but it enjoyed the advantage of access to Symyx's HTE technology and its experience in controlled polymer synthesis. "In my five years at Symyx, I probably made hundreds of thousands of polymers," Klaerner says. "Normally a person in a good career might make tens of thousands."

Ilypsa also enjoyed a six-month honeymoon, during which it stepped back and thought broadly about the medical possibilities for polymers. Schultz connected the Ilypsa team with Nobel Laureates and other gifted thinkers who helped develop a list of 40 to 50 medical needs that could be addressed with nonabsorbed pharmaceuticals acting via surface mechanisms.

THE PROBLEM that rose to the top of the list was the inability of patients with chronic kidney disease to eliminate phosphorus. "Every year in the U.S., about 20% of the patients on dialysis die, and one of the contributing factors is the phosphate disease cascade," Klaerner says.

In the series of events that define the syndrome, the kidneys stop removing phosphorus, prompting the body to pull calcium out of the bones in an effort to bind the excess phosphorus in circulation. The body next tackles the calcium depletion by stepping up production of parathyroid hormone to spur bone growth. However, some of this bone growth occurs in the arteries and irreversibly hardens them.

Aluminum compounds started to be used in the 1970s to artificially bind phosphorus but fell out of favor after they were found to be potentially neurotoxic. Calcium compounds came next, and they are still used today, but the introduction of extra calcium into the body can create separate problems in the kidneys, bones, and arteries.

Today, the top-selling phosphorus treatment is Renagel, a polymer-based drug marketed by Genzyme. Approved by the Food & Drug Administration in 1998, Renagel is manufactured by cross-linking polyallylamine hydrochloride with epichlorohydrin. It had sales last year of $515 million, a 23% increase over 2005.

Renagel effectively binds and removes phosphorus without the use of damaging metals. A chief drawback is that patients must take as many as four 800-mg tablets with each meal, for a total of 7 g or more of active ingredient per day. "Compliance is a major challenge," Klaerner says.

Ilypsa set out to design a phosphate binder that could be delivered in far fewer pills. In the process, Klaerner says, "we violated every rule of usual pharmaceutical polymer science—on purpose." Although many pharmaceutical polymers are designed to fall apart in the body, "we went through great pains to make sure our polymer stays intact and is not systemically absorbed," he says.

Ilypsa calls the polymer that came out of that effort ILY101. The firm isn't disclosing its chemical makeup yet, so Klaerner will only say it has a "three-dimensional structure to allow higher capacity and more selective binding of phosphate ions in the gastrointestinal tract." It is now in Phase II clinical trials, and he expects Phase III trials to begin by year-end.

During the second half of 2004, Ilypsa began searching for outside help to make the polymer for use in the trials and for eventual commercial launch. Even though Ilypsa had designed an efficient binding agent, significant amounts would be needed for preclinical research and clinical trials. Klaerner estimates that the amount of active ingredient consumed in Renagel every year is about the same as in Pfizer's Lipitor, the world's top-selling drug.

Ilypsa sought a custom drug manufacturer with enough existing production capacity to undertake such a project. Because the basic mechanism of phosphate binding is ion exchange, the firm also wanted a company experienced with ion-exchange polymers.

One of the few firms to meet both requirements was Lanxess. Bayer had just created Lanxess as a new industrial chemicals subsidiary, and Lanxess had yet to set up Saltigo as its stand-alone custom manufacturing arm.

Wilhelm Stahl, now the head of Saltigo's pharmaceutical business, recalls the first meeting with Klaerner and his colleagues. It was around the time that Lanxess executives were realizing big pharmaceutical companies are not the only source of custom manufacturing business. Smaller biotech companies like Ilypsa were discovering a host of interesting compounds but often didn't have the manufacturing know-how to make them in large quantities and up to FDA standards.

According to Klaerner, this appreciation came through. "We showed up at Willi's office with only a bunch of great ideas, and he had the vision to go with us," he says. "They took a small early-stage California biotech company seriously."

After meeting with a few potential suppliers, Ilypsa decided to hire Saltigo. Representatives from both firms met next to think through the anticipated development, scale-up, and commercial manufacturing of ILY101. Follow-up meetings were conducted by conference calls scheduled to account for the nine-hour time difference between the two companies.

Looking back, Klaerner is glad that Ilypsa and Saltigo started their collaboration with enough time to turn a laboratory synthesis into a process that was scalable, economical, and up to regulatory standards. "We did a lot of things wrong, but one thing we did right was getting Saltigo on board shortly after we discovered the compound," he says.

According to Stahl, Saltigo conducted preclinical and process development work in a small-scale facility, called Q17, at its main site in Leverkusen, Germany. Synthesis to FDA's current Good Manufacturing Practices standards is taking place at Saltigo's ZeTO pilot plant at the same location. Klaerner says Saltigo is a likely partner for commercial manufacturing, which would also occur at the ZeTO plant.

Stahl says his team doesn't mind that Ilypsa needs more hand-holding than a big drugmaker does. "It's a fun project for our people; they feel like they are part of a drug development team," he says. "It's not, 'Here's the technology package; you deliver the compound.' "

THE TWO COMPANIES are now collaborating on the manufacturing of Ilypsa's second polymeric drug, ILY105, which is in preclinical testing. Also developed with HTE techniques, ILY105 treats hyperkalemia, an elevated potassium condition faced by some kidney disease patients.

An advantage of developing drugs for mineral-related conditions is that efficacy is quickly determined by drawing blood from patients and measuring mineral levels. Renagel, Klaerner notes, went from Phase I trials to a New Drug Application in just about three years.

With financial backers pushing for results and options such as a stock offering on the table, Ilypsa is operating on an equally compressed timeline. It needs significant quantities of the ILY101 active ingredient next year in preparation for possible market launch in 2010. "We are not an easy partner," Klaerner says. "Our timelines are very different than big pharma's timelines."

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