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Ensysce’s Bet: Combining Two Risky Drug Technologies That Add Up

Xconomy Texas — 

At one edge of the sprawling Texas Medical Center in south central Houston, near a slew of hospitals and research hubs including the renowned MD Anderson Cancer Center, three floors of an office tower are reserved to nurture startup companies.

The incubator is one of the initiatives that have sprung up in Texas to expand the state’s community of life sciences companies, a sector that is growing but can’t yet match the established business ecosystems around cities such as San Francisco and Boston.

However, fledgling companies such as Ensysce Biosciences have taken root at the incubator space, the Biotechnology Commercialization Center at the University of Texas Health Science Center at Houston. There, Ensysce researchers can maintain their close collaboration on nanotechnology drug delivery tactics with scientists at Rice University and other nearby labs.

Ensysce is working on experimental cancer treatments that combine two cutting edge technologies: RNA interference and carbon nanotubes. The company is trying to prove that nanotubes offer a superior drug delivery system that will help fulfill the somewhat tarnished promise of the compounds known as siRNA’s, or small interfering RNA molecules. These chains of about 20 to 25 nucleotides can be designed to short-circuit the expression of damaging genes that cause disease.

Just five years ago, when Ensysce was founded, the scientific world was galvanized by the potential of siRNA’s, which silence the messages sent out by genes in the form of messenger RNA. A siRNA can interfere with the production of proteins from the coded instructions in messenger RNA molecules transcribed from a target gene. As one sign of the excitement over the new technology in 2006, Merck (NYSE: MRK) bought San Francisco-based startup Sirna Therapeutics for the stunning price of $1.1 billion to acquire its pioneering program in siRNA’s. The compounds were seen as a way to fight diseases that couldn’t be effectively treated with existing small-molecule chemical drugs, or biotech products made through conventional genetic engineering.

Even so, drug developers knew they’d need to find a way to get the bulky siRNA nucleotide chains delivered inside cells, where they could go to work. And hitches with drug delivery have in fact hindered progress with siRNA therapies.

Carbon nanotubes seemed like the perfect siRNA delivery vehicle to Ensysce founder Bob Gower, who financed the startup himself in 2008. It was a spinout of a company, Carbon Nanotechnologies, that he had formed in 2000 with Richard Smalley, who shared the Nobel Prize in Chemistry in 1996 for the discovery of the “buckyball,” a hollow sphere of 60 carbon atoms that looks like a soccer ball because the carbon atoms form the points of six-sided hexagons. Carbon nanotubes are made of curled sheets of these hexagons, so they look like rolled-up chicken wire.

Lynn Kirkpatrick, CEO of Ensysce Biosciences

Gower saw the thin, minuscule carbon nanotube as a lattice where chemists could attach drug molecules such as siRNA’s for protected transport through the bloodstream to a target tissue or tumor. The lattice, he hoped, would shield the siRNA from enzymes in the bloodstream that would otherwise chop it up and render it ineffective before it could get inside cells. In addition, the nanoscale ends of the tubes could penetrate cell membranes like a needle—a phenomenon later nicknamed “nanospearing.”

In 2009, Gower recruited CEO Lynn Kirkpatrick, a medicinal chemist who had co-founded small molecule drug developer ProlX Pharmaceuticals, which was sold in 2006 to become part of a merged company Oncothyreon (NASDAQ: ONTY) of Seattle, WA. Kirkpatrick says she was intrigued by Ensysce’s cutting-edge goals, but she faced a significant learning curve.

“I knew nothing about carbon nanotubes,” says Kirkpatrick, who has since presided over Ensysce’s work to adapt the nanotubes as elements of a drug preparation.

The potential of carbon nanotubes is easy to see in fields such as electronics—their molecular structure is a hundred times stronger than steel, they conduct heat, and no liquid can dissolve them. But the idea of piercing cells with “nanospears” in medical treatment can be instinctively alarming, Kirkpatrick acknowledges, because people imagine the cells would die after being punctured. However, she says, Ensysce has shown in animal studies that its modified, soluble nanotubes can be absorbed safely by cells.

The company is now in preclinical testing for a nanotube complex that contains two types of siRNA designed to block a pair of cell elements implicated in cancer. The first siRNA aims at the protein EGFR, the target of cancer drugs such as Genentech’s erlotinib (Tarceva). The second siRNA acts against a mutant form of the KRAS gene, which can make cancer cells resistant to drug treatment.

Binding the siRNA molecules to a nanotube guards them from being broken down by ribonucleases and other bodily mechanisms as they pass through the bloodstream and penetrate cells, Kirkpatrick says. As a transport system into cells, nanotubes may prove better than the lipid nanoparticle capsules often used as vehicles for siRNA’s in drug development, Kirkpatrick says. Those lipid complexes can be as much as 150 nanometers wide, while the diameter of Ensysce’s single-walled carbon nanotube is one nanometer—about half the width of a strand of human DNA.

“We hope in the next twelve months to start testing this material in clinical trials,” Kirkpatrick says. The company has not yet chosen a cancer indication to focus on first, but the possibilities include colorectal, lung, and pancreatic cancer. The company now has eight employees and works with contract labs and manufacturers.

Ensysce was awarded $1.5 million from the State of Texas Emerging Technology Fund in 2010, and last year raised another $1 million from individual investors. The company is setting out to raise another $5 million to $10 million in its first outside funding round, Kirkpatrick says.

The fundraising effort could be challenging, Kirkpatrick says. Not only are carbon nanotubes a relatively untried technology in the drug arena, but siRNA’s are now also seen as risky bets.

The early excitement over siRNA’s has flagged in recent years as drug developers hit roadblocks. In 2010, two big pharma investors in RNA interference, Roche and Novartis, dropped their collaborations with Cambridge, MA-based Alnylam Pharmaceuticals (NASDAQ: ALNY). In 2011, Merck shut down the RNA interference research facility that came with the purchase of Sirna. However, Alnylam is one of the companies still betting on the potential of RNA interference. It now has partners including Genzyme and The Medicines Company, and regained investor confidence last year as it showed some promising results with its RNAi drug for the treatment of a rare disease called TTR amyloidosis. As its stock climbed on those results, Alnylam was able to cash in on favorable financial terms, reaping $174 million in a public stock offering this year.

Kirkpatrick says Ensysce appeals to investors who want to take a chance on something truly novel. Carbon nanotubes could become a “universal carrier’’ of therapeutic drugs, she says. Nanotubes a few hundred nanometers long offer a huge surface area where a variety of functional molecules can be stowed, including multiple copies of active drugs. Complementary drugs could be loaded onto the nanotubes together to make combination therapies, and other molecules could be added to selectively bind the complex to tumor cells, she says.

“We have many, many directions to go,” Kirkpatrick says.