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With Fluorine Tech, SciFluor Aims to Vindicate “Me-Too” Drugs

Xconomy Boston — 

Me-too drugs, knockoffs, copycats, retreads—they’re all names for new pharmaceuticals patterned after drugs already proven to work. The number of such labels alone signals the type of passionate commentary surrounding these products.

Critics have charged pharmaceutical companies with churning out these modified drugs to fight common ailments like high cholesterol or heartburn without proving that they perform any better than the first drug to work by the same pathways.

In the climate of resistance to such follow-on products, many pharmaceutical companies are adopting the tactics of innovative biotechnology startups by pursuing novel drug modes of action in a quest for breakthrough treatments, says Arthur Hiller, CEO of the startup SciFluor Life Sciences in Cambridge, MA.

But the drug firms may be sacrificing their best opportunities to improve healthcare and make significant revenues, says Hiller (pictured above). Some of the industry’s biggest success stories have come from important refinements of first-in-class drugs that led to best-in-class drugs, Hiller maintains.

“The most fruitful basis for the discovery of a new drug is to start with an old drug,” says Hiller, whose company is acting on that theory.

Innovations in medicinal chemistry—the art of optimizing a drug’s structure—led to SciFluor’s founding in 2011 by Harvard professor Tobias Ritter and his former student Takeru Furuya, who is now the company’s director of chemistry. SciFluor licensed the methods developed at Harvard for inserting the element fluorine into the structure of an existing drug to reshape its key chemical groups and enhance its value.

SciFluor’s chemists have been tweaking the composition of small molecule drugs by placing atoms of fluorine in strategic spots, such as the site where a drug binds to a target cellular molecule linked to disease. Fluorine, when substituted in for a smaller atom of hydrogen, can improve the “fit” of the drug to the target and thus make it more effective, says Ben Askew, SciFluor’s vice president of research. The binding affinity can increase by 10-fold, he says.

Changing the spatial contours of the drug with fluorine atoms can also prevent the drug from binding with off-target molecules, Askew says. That can prevent the side effects that often come with a medicine that’s not selective enough in its action, he says.

Such molecular tweaking can open a less risky path to valuable new drugs than exploring an exciting new cellular pathway revealed by cutting-edge research, Hiller says. Indeed, researchers have significant advantages when they tinker with drugs already proven to have health benefits, he says. For example, the design of clinical trials and the path toward regulatory approval have already been worked out to a large extent.

The knock on such follow-on drugs is that they’re merely a drug firm’s tactic to prevent a drop in revenues when a product’s patent life expires and generic forms enter the market. The company’s next-generation drug may not be better, but it can be sold at the higher price of a branded drug, critics say.

Hiller, on the other hand, says pharmaceutical companies often bypass a chance to make valuable improvements on their own drugs, only to see a competitor do so and reap the rewards.

As an example, Hiller points to GlaxoSmithKline’s dutasteride (Avodart), a drug for the urinary tract symptoms linked to a benign enlargement of the prostate gland. The drug is similar to the Merck product finasteride (Proscar), but with the addition of fluorine atoms, Hiller says. Sales of dutasteride exceeded $1 billion in 2010.

“Had Merck done that, they would have had a great life cycle story and been able to maintain their franchise,” Hiller said.

A competitor can patent new molecules based on a rival’s older drugs. But the competitor must make changes to the original drug that are truly novel, and that would not have been obvious innovation routes for the creators of the original drug, Hiller says. SciFluor is filing for patents on the new compounds it has created, and is seeking partners for their development.

SciFluor’s first deals so far, however, have come from a second technology unit based on discoveries also licensed from Harvard. The company is using radioactive isotopes of fluorine to create custom tracers to find out how a drug spreads throughout the body, and whether it reaches its targets. SciFluor is making tracers for a large Cambridge biotech company and a midwestern pharmaceutical company, Hiller says. He says he can’t divulge the company names at this point.

The startup now has eight full-time employees, three chemists working in India, and an annual budget of about $5 million. It was founded with an initial $5 million investment from its owner Allied Minds of Boston, MA, an investment firm that forms startup subsidiaries based on university technology.

Hiller, a former executive at Merck, Millennium Pharmaceuticals, and the device maker Heartscape Technologies, has become an avid evangelist for follow-on drug development. He points to success rates detailed in a 2002 McKinsey paper by Bruce Booth, who is now a partner at Atlas Venture in Cambridge, MA. Booth and his McKinsey colleagues concluded that most of the drug industry’s profits in the 1990s came from modified versions of first-in-class drugs that delivered better efficacy or lower side effects than the original product.

What Booth called “precedented drugs” also delivered 35 percent more revenues than drugs based on new scientific approaches, according to his study. Among those high-earning follow-on drugs were the antihistamine Allegra, the antidepresant Paxil, and the blockbuster cholesterol drug Lipitor, Booth said.

Booth and his co-authors concluded that drug companies should continue to include follow-on drug candidates in their development pipelines, along with novel experimental therapies.

Lipitor, Prozac, and Cipro are among the successful drugs that contain fluorine atoms, according to SciFluor. The highly reactive element forms intensely strong bonds with the carbon atoms in proteins and other biological molecules. SciFluor chemists use this property of fluorine to slow the breakdown of their modified drugs by enzymes in the liver, Askew says. This increases the drug’s life span in the body, and may allow patients to take lower doses, he says.

Other startups are pursuing similar strategies. Auspex Pharmaceuticals in San Diego, CA, strengthens chemical bonds by replacing hydrogen atoms with deuterium, a heavier isotope of hydrogen. The stable, naturally occurring variant of hydrogen is embedded in Auspex’s lead drug candidate SD-809, which is similar to the approved drug tetrabenazine (Xenazine). Tetrabenazine is marketed by the Danish firm Lundbeck as a treatment for the involuntary movements associated with Huntington’s disease and other disorders.

Auspex is hoping that SD-809 can be used at lower doses than tetrabenazine because its stronger bonds will protect it from breakdown in the body.

SciFluor uses fluorine rather than deuterium to modify drugs because the fluorine-carbon bond is much stronger than the deuterium-carbon bond, Askew says. Chemists have incorporated at most about seven fluorine atoms into their drugs, he says.

“We wouldn’t propose making a drug molecule with every hydrogen replaced by fluorine,” Askew says. “It would be Teflon.”

Fluorine has another useful characteristic: it eases a drug’s ability to mix in with fatty compounds called lipids, which are key ingredients in cell membranes. SciFluor is taking advantage of this property to make drugs that can penetrate into the brain by getting past the blood-brain barrier.

Hiller says his researchers have used fluorine modification to create eight new chemical entities based on drugs used against cardiovascular disorders, nervous system diseases, and cancer.

One of the new SciFluor compounds is an analog of ezogabine (Potiga), an epilepsy medication developed by Valeant Pharmaceuticals North America of Durham, NC, and distributed by GlaxoSmithKline of Research Triangle Park, NC.

Ezogabine was the first epilepsy drug designed to work by influencing cell structures called neuronal potassium channels, which are believed to regulate nerve signals. The drug’s side effects can include changes in heart rhythm and an inability to fully empty the bladder. Hiller says SciFluor’s redesigned version of the drug addresses both of those side effects, and two others.

The company is in discussions with a number of companies about potential partnerships, Hiller says. SciFluor’s scientists are using innovations in fluorine chemistry not only from Harvard, but also from the Scripps Research Institute in La Jolla, CA, the University of Michigan at Ann Arbor, and other research centers.

“Fluorine is becoming one of the most important ways of evolving molecules,” Hiller says.

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  • Jens

    One important pioneer you cannot leave out in this context is Concert Pharmaceuticals in Lexington which actually has two programs in the clinic (http://www.concertpharma.com/).