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Cover Story

March 15, 2010
Volume 88, Number 11
pp. 16 - 19

Patently Right Process Chemistry

Case Study #1: Cytokinetics turns to Irix for help with a tough synthesis

Michael McCoy

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CONTAINED: Irix manufactures highly potent drugs at its Greenville, S.C., site. Irix Pharmaceuticals
CONTAINED Irix manufactures highly potent drugs at its Greenville, S.C., site.

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Since its start in 1996, Irix Pharmaceuticals has helped its clients in the drug industry win 34 patents, most related to process chemistry. This is the story of one of them: U.S. patent number 7009049, awarded to Cytokinetics, a South San Francisco-based biotech firm.

Irix was founded by J. Guy Steenrod and Panos Kalaritis, two ex-Roche executives who wanted to offer big-pharma-caliber R&D and manufacturing services to drug companies that couldn’t, or didn’t want to, expend the resources themselves.

One of their first hires was George Yiannikouros, their chief scientific officer. Yiannikouros earned a Ph.D. at City University of New York and was a postdoc under the famed total synthesis chemist K. C. Nicolaou. Like Steenrod and Kalaritis, Yiannikouros is a veteran of Roche, where his claim to fame was devising a new route to the osteoporosis drug Rocaltrol, a change that saved millions of dollars in annual manufacturing costs.

In its early days, Irix operated out of lab space in Florence, S.C., leased from Francis Marion University. By 1998, the firm had become big enough to build its own labs in Florence, and in 2002, the partners bought a brand-new commercial pharmaceutical chemical plant in Greenville, S.C.

Starting with its first customer, for which it earned two patents, Irix has sought to develop technology that saves its clients money and sets up barriers to potential competitors. “Our strategy is to expeditiously solve problems using advanced chemical tools,” Yiannikouros says. “It keeps us in the game when everyone is rushing to India and China to take advantage of cheap labor.”

Cytokinetics knocked on Irix’ door in the middle of 2000, Yiannikouros recalls. It was referred, as is often the case in pharmaceutical chemical manufacturing, by an Irix client.

The person doing the knocking was David J. Morgans Jr., who today is Cytokinetics’ executive vice president of preclinical R&D. After his meeting with Steenrod and Kalaritis, Morgans came away impressed by the company’s big pharma pedigree and its ability to manufacture cytotoxic compounds.

A newcomer to Cytokinetics, Morgans had been tasked with the critical job of obtaining multiple kilograms of high-quality active pharmaceutical ingredient for the firm’s first clinical trial.

Cytokinetics was one-and-a-half years old at the time. Backed by venture capitalists, it had been launched to commercialize discoveries made by scientists at Stanford University’s School of Medicine and the University of California campuses in San Diego and San Francisco.

The scientists were all experts on the cytoskeleton, the multicomponent framework upon which the cell interior is ordered. The firm likens the cytoskeleton to a city plan, with highways made of protein structures called microtubules and enzyme cars known as molecular motors. Its plan was to develop small-molecule drugs that would inhibit or activate the components of this framework to treat ailments as diverse as heart failure, cancer, and muscle wasting.

The compound that Morgans needed was the anticancer agent ispinesib. It works by inhibiting kinesin spindle protein, a mitotic kinesin that plays a role in cell division, and was the first such inhibitor to be advanced to clinical development, according to Cytokinetics. Data from animal studies show that inhibiting this motor protein can arrest cancer cell division without affecting other cellular functions.

Although kinesin spindle protein was a novel drug target, Morgans says, ispinesib was discovered through traditional high-throughput compound library screening followed by lead optimization with medicinal chemistry techniques.

The resulting route, however, was problematic. As with most medicinal chemistry syntheses, the goals were speed and ease of preparing multiple analogs. Cost and commercial viability were not yet considerations.

The synthesis was 11 steps long, Yiannikouros says, and had an overall yield of only about 8%. Moreover, it had other shortcomings that would be problematic during commercial-scale manufacturing. As a cancer drug, ispinesib is cytotoxic, and Irix was equipped to handle it. The properties of several precursors, however, presented an unexpected challenge to successful scale-up.

Other issues with the synthesis included a need for undesirable reagents such as bromine and azide compounds, reliance on a classical chiral resolution late in the game, and a side chain that was not stable and had to be used in small quantities immediately upon preparation.


Using the medicinal chemistry process, Irix manufactured several hundred grams of ispinesib in a facility that met the Food & Drug Administration’s current Good Manufacturing Practices standards. But both partners knew that a new approach was needed. “So in parallel, Cytokinetics approved our proposal to investigate an alternative route,” Yiannikouros says.

Although he provides scientific oversight to 100 scientists and technical staffers, Yiannikouros is a hands-on manager in the most literal sense. “Every time there’s an opportunity with a client for new chemistry, new approaches, I go into the lab myself,” he says. “It’s a joy for me, a passion.”

There, he convened a team to brainstorm on a new synthesis. The key to the problem, Yiannikouros recalls, was finding a better way to create ispinesib’s chiral center. The chemists settled on a novel method of introducing the chiral center with a d-amino acid. Then they devised a new synthetic route that shared a late-stage intermediate with the existing route.

It was around this time that a third partner joined the mix. In June 2001, Cytokinetics launched a collaboration with GlaxoSmithKline to discover and develop small-molecule drugs that address cancer and other diseases by targeting mitotic kinesins. Cytokinetics got more than $50 million in funding and the opportunity to work with one of the world’s largest drug companies.

“Our strategy is to expeditiously solve problems using advanced chemical tools.”

For Irix, having GSK aboard meant a visit to its site by the big pharma company’s quality managers and scrutiny of their new process by its scientists. GSK approved it, Yiannikouros says, with one request: Develop a new side chain to eliminate the problematic intermediates from the last few steps of the synthesis.

In the end, Irix trimmed the process to six chemical steps. It also succeeded in avoiding the chromatographic resolution, the undesirable reagents, and the troublesome intermediates. Overall, the yield rose to about 40%, Yiannikouros says, and the cost of manufacturing was cut to many times less than it would have been with the medicinal chemistry route.

Awarded in 2006, the patent covers use of an amino acid to introduce chirality into quinazolinones, the class of compound to which ispinesib belongs. Process patents such as this one don’t only protect technology improvements, Yiannikouros notes. They can also deter potential competitors and even extend the life of a drug once composition-of-matter patents have 

Unfortunately, it takes more than good chemistry to bring a drug to market. In December 2008, GSK informed Cytokinetics that it would not exercise its option to license ispinesib. By the following December, the two firms had ended their collaboration, and Cytokinetics had halted all oncology research.

Last June, Cytokinetics disclosed interim results from the Phase I portion of a Phase I/II clinical trial evaluating ispinesib in patients with locally advanced or metastatic breast cancer. The firm reported that the trial generated “encouraging signs of clinical activity.” Since then, it hasn’t revealed any more about ispinesib’s future, other than to say it is seeking partners that can help conduct clinical trials on its oncology drug candidates.

Although it has ended its cancer research efforts, Cytokinetics is still developing drugs that act on cytoskeletal proteins involved in muscle function. Its lead candidate, the heart-failure treatment omecamtiv mecarbil, is the subject of a partnership with Amgen, and Cytokinetics has several other compounds in development.

Irix continues to be part of the effort in a manner that reflects 10 years of close cooperation. “Our guys call up their guys on a regular basis to talk about what’s going on,” Morgans says. “We go out there and spend time with the working scientist in the lab and the plant operator on the floor.”

Over his years in the pharmaceutical industry, Morgans has learned a few lessons about how to succeed in business. One comes from Cytokinetics’ partnership with Irix. “Build that bond between people who are responsible for the work,” he says. “It will get done, and it will get done well.”

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