To Jonathan Nyce, the difference between curing asthma his way and the traditional way can be likened to stopping the gears on a piece of machinery. Traditional therapies throw a monkey wrench in a "machine" that is doing harm. You stop the gears, but you have not eliminated the problem. With Nyce’s "antisense" therapies, he can go to the back of the machine and flip the switch to "off."

Nyce, CEO and founder of EpiGenesis Pharmaceuticals, says that these therapies have been called "the pharmacology of the future." He hopes to tap the potential that sequencing of the human genome has promised for so long.

Nyce’s company is one of the most recent arrivals to the Princeton biotech community; EpiGenesis moved from North Carolina to Exit 8A last fall. By using antisense therapies to disable the harmful genes, he is working on making the treatment of respiratory diseases as easy as flipping a genetic switch. Early this week EpiGenesis floated its second private placement, for $6 million.

The key, according to Nyce, is to deliver the drug directly to thetarget tissue; this makes the drug less toxic and more potent. Only EpiGenesis Pharmaceutical, he says, can rapidly and accurately reduce disease genes in the respiratory tract. It is working to discover the genetic basis for an amazing array of diseases, starting with asthma — a $9 billion worldwide market — plus chronic obstructive pulmonary disease, chronic bronchitis, respiratory infections, and lung cancer.

Once it finds a genetic target for a particular disease it can try to treat these diseases by delivering RASONS (respirable antisense oligonucleotides) to the target. Of three clinical candidates already in the pipeline, the first one might go into Phase 1 clinical trials within a year.

"We are focusing on medically unmet needs," says Nyce. Of his three candidates for clinical trials, two are for asthma and one is for cancer.

The name EpiGenesis implies something that is "near to" genes that does not mutate genes. If DNA is the road map, says Nyce, EpiGenesis reads the road map. Or, DNA is the score, and when a musician plays out of tune (as with disease), EpiGenesis corrects the musical discord by teaching the pianist how to play better. The antisense oligonucleotides that EpiGenesis uses can block the disease gene’s "messenger" RNA.

The firm’s "cash cows" or revenue sources are its database of genes and its "Target Validation" technology — for which Nyce was unwilling to give specific projections, saying only, "it will be very significant." In addition to Nyce’s personal money, the company already had a private placement of stocks with $2.5 million in cash and another $2.5 million in warrants to be exercised

this year. Last year it received a National Institutes of Health Phase I Small Business Innovation Award, and Nyce heard in early February that it will receive approximately $1 million with a Phase II award this year.

Although the money from the NIH is a victory, it is the attention the science is receiving that Nyce cherishes more. "The most important thing was the scientific validation for RASONs," said Nyce. "The reviewers made embarrassingly nice comments." The NIH even went as far as to ask permission to include EpiGenesis’s research in its report to Congress this year.

Nyce has a personal interest in the success of his products: as a child he and his brother both suffered from asthma. Recently he experienced a severe reoccurrence — coughing fits while he was trying to give a paper at a professional meeting. Thus he can empathize first-hand with asthma sufferers. Citing that each year approximately 7,000 people die from asthma, he adds, "It’s hard to imagine something worse than not being able to breathe."

Nyce, 44, is the son of a machine designer who worked in Collegeville, Pennsylvania. "My father influenced me because of something he didn’t do," says Nyce. "He worked around the clock one night to design the machinery to knit the first pair of pantyhose. But because he had a new family, he was unable to capitalize on that discovery, whereas his partner was able to run with it. He told me that if I were ever in a similar position, to be sure I could capitalize on it."

The first of his family to attend college, Nyce soon discovered a knack for doing dissections in biology labs. His undergraduate degree is from Temple University, and he earned his PhD from the Fels Research Institute at Temple University’s School of Medicine. He did post graduate work in the Children’s Hospital of Los Angeles and then moved to the Kenneth Norris Cancer Center in Los Angeles. In 1987 he returned to the East Coast, this time to North Carolina, as assistant professor at the School of Medicine, East Carolina University. He reached full professor there in the department of molecular pharmacology and therapeutics.

The scientific advisory board includes Peter Barnes of Imperial College in London; James Metzger, director of the Asthma & Allergy Center of Eastern North Carolina; Gioria Feuerstein, director of cardiovascular pharmacology at SmithKline Beecham; Ken Lloyd of Salk SIBIA in La Jolla; and Genoviffa Franchinni of National Institutes of Health in Bethesda.

David J. Sorin and Perry Pappas of Buchanan Ingersoll in Princeton are the firm’s attorneys, and Michael McGinnis is the accountant.

Today Nyce lives with his wife and three young children in Princeton. The only drawback to the business so far has been the separation from his family during frequent business trips. "My driving force," said Nyce of his work, "is that I want to help sick people." After three years in Greenville and Durham, North Carolina felt too small and had too few opportunities for the growing company.

Nyce thinks the corridor between New York and Maryland is conducive to the growth of pharmaceutical companies both big and small. He compares it to California’s Silicon Valley, saying that this corridor is earning the nickname "Carbonyl Valley" (carbonyl being an organic ingredient often used in pharmaceutical products).

Proximity to potential clients and strategic partners was only part of the appeal of the area. As the company poised to expand from its facility in Greenville, it found sufficient lab space a daunting goal. With the help of Tom Sullivan (of CB Richard Ellis) and Bruce Simons (representing Eastern Properties’ holdings of more than a million square feet at Exit 8A) it found its current space of between 5,000 and 6,000 square feet. When it expands again to 15,000 to 20,000 square feet — as soon as next year — New Jersey will again be able to offer appropriate facilities, Nyce believes.

Expanding again was built into the initial thinking of the move up north, says Nyce. The search for employees to fill that space will more than triple the company’s employee roster in the next year. Seven PhD and two technical positions will add to the six scientists now in the laboratory. Nyce is also actively interviewing for a president and will be looking for a full time chief financial officer soon.

Nyce’s vice president of operations, Amanda Gillum, returned to biomedical research when she accepted the position at EpiGenesis Pharmaceuticals last July. She had studied chemistry at Indiana University before gaining her Ph.D. in biochemistry at MIT with post doctoral work at Stanford. She worked at Squibb, Kodak, Sterling Winthrop, and MDL Information Systems. She and her husband have lived in Pennington for 20 years, and they have two high school-age daughters.

The company recognizes the important role adenosine plays in the condition of asthma. With an asthmatic lung, there is an overabundance of receptors for adenosine, and the lung makes more adenosine for all the receptors. Too much adenosine can shut the lung down, making it impossible to breathe.

Drugs break down in tissue, and any antisense oligonucleotide containing adenosine would produce free adenosine — toxic to the asthmatic lung. Virtually all of the oligonucleotides in the company’s library do not have adenosine, and so Epigenesis can avoid such toxic effects. EpiGenesis has the intellectual property rights to all those "adenosine lacking" sequences for the asthma gene and has patents pending.

One of EpiGenesis’s three candidates for clinical trials, EPI-2010, knocks out the receptor that causes the adenosine problem. Tests so far have shown that EPI-2010 may be available as a drug administered weekly, which may help in supervision of pediatric patients. It also has the potential of being the only single drug to address all three common problems of asthmatic lungs: inflammation, broncho-constriction, and "drying out" of lung tissue, known as surfactant reduction.

Instead of taking a pill or getting a shot this drug can be administered with an aerosol: you breathe in the medication and the lung actually helps to deliver the drug. "The lung is kind enough to repackage it for us and distribute it," says Nyce.

This repackaging also uses the therapies more effectively, resulting in a smaller dose, possibly 1,000 times smaller than the usual. Other companies’ attempts to administer antisense oligonucleotides into the blood stream have used such a large amount that random reactions and toxicity have become major problems. The use of this therapy is also more the way nature stops the machinery too, says Nyce. Cells use the same antisense techniques, so the main problem for scientists is how to get the antisense into the cells and let the cells do their work. Lipids in the cells aid the antisense oligonucleotides across the barrier of the cell wall and into the cell.

Another company, Isis, is also delivering antisense oligonucleotides directly to the target tissue, but to a different organ, the eye. Isis’ Fomivirsen, an antisense oligonucleotide for the treatment of drug-refractory CMV retinitis in AIDS patients, is injected into the eye. Fomivirsen has been approved as a new drug and helps to prove Nyce’s point about the effectiveness of local delivery.

EpiGenesis’s second clinical trial candidate, the more traditional EPI-12322 asthma therapy, shows the good therapeutic features of glucocorticoids (traditional antiinflammatory steroids) but without their side effects. Coupled with the technology to find and then validate genes for asthma, the company also has an improved animal model to continue development of their drugs in the pipeline. This model should dramatically improve the ability to predict drug efficacy in humans, according to the firm.

The third potential drug is EpiCyte (EP1163) which is supposed to take advantage of cancer cells "over expressing" an enzyme. Unlike other anticancer drugs, EpiCyte is completely non toxic until it is activated by the enzyme. Once activated it suppresses tumor growth.

Overall, the company has two issued patents, three allowed and seven applications pending in the US and abroad.

If imitation is the sincerest form of flattery then the scientists at EpiGenesis Pharmaceuticals must be blushing from all the attention. Although EpiGenesis is an innovator in antisense therapeutics for respiratory diseases, many companies, such as Boehringer Ingleheim and Novartis have expressed their intent to work in this area, which James Watson (discoverer of the structure of DNA) says is "the next great wave of the biotechnology revolution."

"These companies immediately let us know that, ‘this is a great idea and we’re going to do it too,’" says Nyce. "Our work has not gone unnoticed." No fewer than 12 other companies are working on other new genetic approaches to asthma treatment, according to Genetic Engineering News (March, 1998).

What gives EpiGenesis Pharmaceuticals the edge and Nyce his confidence of success is that his company has been the only one with the proven ability to selectively attack a particular "villain" gene in the respiratory system — to knock out the target gene.

EpiGenesis Pharmaceuticals, Box 7007, Princeton, 08543-7007; 2005 Eastpark Boulevard, Cranbury, NJ 08512-3515. 609-409-6080; fax, 609-409-6126. Home page: http://www.epigene.com.

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