Pet Dogs Help Biotech Startups Find New Weapons to Fight Cancer

7/25/12Follow @arleneweintraub

A few weeks back, a black-and-white terrier mix named Chance entered a clinical trial for a drug that may offer a completely new way to combat cancer—not only in dogs, but in people, too. The drug, made by San Diego-based Genelux, uses a genetically engineered virus to annihilate tumor cells. Genelux made two different versions of the drug and is now testing one in people and other in dogs, as part of a wide-ranging research strategy designed to yield cutting-edge cancer treatments for both man and man’s best friend.

Why dogs? “Cancer as a disease in dogs is as significant as it is in humans,” says Aladar Szalay, founder and CEO of Genelux. “We expect that humans will benefit from the information we obtain from canines.”

Genelux is part of a growing branch of cancer research called comparative oncology. The idea behind comparative oncology is simple: Dogs get many of the same cancers that strike humans, including lymphoma, breast cancer, and bone cancer. But unlike genetically altered laboratory rodents and other animals that are used to test potential new cancer treatments, dogs develop the disease naturally.

There are other reasons that dogs make good study subjects, says Gregory Ogilvie, director of the Angel Care Cancer Center in Carlsbad, CA, and the lead veterinary investigator for the Genelux trial. “We can measure the same things in dogs that we do in people, like blood pressure, heart changes, and organ function,” Ogilvie says. “These data can be applied directly to people.”

The National Cancer Institute (NCI) estimates that about 10 percent of the 65 million pet dogs in the United States will be diagnosed with cancer each year. The NCI has sponsored several comparative oncology studies through a network of 20 veterinary schools that trade research insights with each other—and with their human-oncology counterparts at medical schools and pharmaceutical companies.

Genelux, which was founded in 2001, is one of several biotech companies that are enlisting pet dogs in the war on cancer. Genelux’s San Diego neighbor, Polaris Group, is sponsoring a dog trial at the University of California at Davis’s veterinary school. And Boston-area biotechs Karyopharm and Synta Pharmaceuticals (NASDAQ: SNTA) are both working with Ohio State University’s veterinary college to test new therapeutic approaches in cancer.

In most cases, the companies are not testing exactly the same drug they intend to develop for humans, but rather a different molecule with the same mechanism of action as the human version. The reasons for that are both ethical and commercial: First of all, testing a drug and getting it approved can be a much quicker process on the veterinary side than it is on the human side, offering companies the potential for a more immediate market opportunity.

More importantly, says Szalay, biotech companies don’t want to create the perception that they’re using people’s pets merely as tools for advancing human medicine. “We’ve come to the realization that animals also need our help,” he says.

Ogilvie began recruiting dogs for a trial of Genelux’s veterinary drug, called V-VET1, in late June. Both V-VET1 and its human counterpart, GL-ONC1, are modified versions of vaccinia, the virus that causes cowpox and is the basis of the smallpox vaccine in humans. Genelux modified the virus to boost its therapeutic ability, Szalay says, and to imbue it with targeting and diagnostic capabilities. V-VET1 and GL-ONC1 were constructed to be able to locate, burrow into, and then destroy tumor cells while leaving healthy tissues intact. The drugs also have light-emitting properties that allow oncologists to track their activity in the body using imaging technologies.

Genelux scientific advisory board member Yumon Fong, chief of gastric and mixed tumor service at Memorial Sloan-Kettering Cancer Center in New York, says the idea of using viruses to kill cancer cells—a field of research known as oncolytic virology—has been around for several decades. But only recently has genetic engineering advanced to the point where viruses can be modified to be made safe and to carry extra tumor-killing payloads. And because vaccinia doesn’t normally affect humans (or dogs for that matter), it may score extra points on the safety front. “Vaccinia as a smallpox vaccine has been given to millions of people in the western world,” he says. “Therefore to talk to regulatory agencies about it is reasonably straightforward.”

Veterinarian Gregory Ogilvie

The initial Genelux dog trial will enroll 25 canines with a variety of tumors, Ogilvie says. Chance, for example, has a relatively common tumor type called an adenocarcinoma under his tail.

Ogilvie’s clinic will use several different imaging scans and tissue tests to determine exactly what the drug is doing in the dogs’ bodies. Ogilvie will share his insights with human oncologists at the Moores Cancer Center at the University of California San Diego, where he serves on the faculty. Genelux CEO Szalay is also on the faculty at Moores, and one of the early-stage trials of the human version of the drug is taking place there, he says.

One of the advantages for dog owners who participate in comparative oncology trials is that their pets’ care is usually subsidized by the drug company, the veterinary clinic, or some combination of the two. Chance’s owner, Ken Willcut, says the only alternative for him would have been to spend more than $2,000 to have his dog’s tumor surgically removed. “For a guy just trying to get by, that’s not an option for me,” says Willcut, who adds that he was concerned about subjecting his 14-year-old dog to major surgery. “He’s got so much life in him. He’s still bouncing off the walls like terriers do. I just wanted to be able to maintain his quality of life.”

 

More Realistic Than Mice

Natick, MA-based Karyopharm is testing its cancer-fighting technology in both dogs and humans, and like Genelux, it’s examining two separate molecules that act on the same target. Karyopharm is developing compounds that inhibit a protein called CRM1, which prevents the body’s tumor-fighting mechanisms from working properly inside cells.

Karyopharm CEO Michael Kauffman says the dog trials have been particularly valuable for understanding the side effects that can result from blocking CRM1. “From a tolerability standpoint, knowing what this drug does in dogs is immeasurably beneficial for humans,” Kauffman says. That’s because dogs are part of families, he says, and family members can play an important role in observing and reporting how their pets are responding to treatments. “We have no idea with [laboratory] rats and mice, frankly. They’re caged. It’s a very artificial situation,” Kauffman says. “Dogs are in domestic situations. Their owners are extremely attentive.”

One of the pet owners who volunteered her dog for the Karyopharm study is also the study’s lead investigator, Cheryl London, associate professor of canine medicine at Ohio State University. London noticed the same side effect in her dog, a foxhound named George, that other participants in the study were reporting: the dogs lost their appetites on Karyopharm’s experimental cancer pill, KPT-335. “When my dog quit eating, he quit eating for days,” London says. “It took a long time for his appetite to come back.” (George was suffering from lymphoma and ultimately died of a complication of conventional chemotherapy, London says.)

OSU veterinarian Cheryl London

London has since dropped the dose of KPT-335 being used in the dog trial, which she says has helped alleviate the appetite issues. Karyopharm’s Kauffman says that in addition to running the lymphoma trial at Ohio State, the company is working with Texas A&M’s veterinary school to study KPT-335 in osteosarcoma, a form of bone cancer that strikes children and dogs. The company is also gearing up to test the human version of the drug, KPT-330, in non-Hodgkin’s lymphoma, multiple myeloma, leukemia, and solid tumors.

Kauffman says he was inspired to test Karyopharm’s technology in dogs by London’s success with a cancer pill called toceranib phosphate (Palladia), which was developed by New York-based Pfizer alongside a human version, sunitinib (Sutent). Both drugs inhibit proteins called receptor tyrosine kinases, and London led the charge to test the power of the technology in pet dogs. Toceranib phosphate, which hit the market in 2009, is the first and so far only cancer drug approved by the FDA specifically for dogs. Prior to its approval, veterinarians had no choice but to use the same chemo and radiation drugs given to people.

Sales estimates are hard to come by in veterinary medicine, but Kauffman says he has learned enough about the demand for effective cancer treatments in pets to convince him KPT-335 is worth pursuing. “We do think there’s a market there,” he says. “And the investment required for approval in veterinary medicine is substantially lower than what’s required for humans,” which helps make it feasible for cash-poor startups to pursue the companion-animal market, he adds.

 

“Science as Serendipity”

For Lexington, MA-based Synta, dog trials have been essential to fine-tuning an emerging class of drugs called heat shock protein 90 (Hsp90) inhibitors. Hsp90 is what’s known as a chaperone protein, says Synta scientist David Proia, because it shuttles thousands of other proteins around inside cells—including some that cause cancer.

In studies, Synta has shown that its lead drug, ganetespib, accumulates in cancerous tissues, but is rapidly cleared out of normal cells, which may help lessen toxicities, Proia says. Determining the best dosing schedule to achieve a response has been challenging, though. So Proia has been working with Ohio State’s London to study what’s called a “pro-drug” of ganetespib—a separate molecule that is converted in the bloodstream to something that’s equivalent to the actual drug.

One of the dogs that participated in the early Synta dog trials at Ohio State demonstrated both the perils and promise of working with canines. The dog, a high-strung Belgian Teruven, was supposed to get a one-hour infusion of the drug into a vein. But he was so frisky that he pulled his catheter out, and the drug ended up going under his skin, London recalls.

Much to London’s surprise, the rowdy dog was the only one in the trial whose cancer responded well to Synta’s drug.

With the help of London, scientists at Synta figured out that giving Synta’s drug outside of the vein completely changes its behavior in the body. “This is science as serendipity,” London says. “To me, the challenge lies in figuring out how to give the drug so you can get biologic activity.” Ohio State is now doing a second study with Synta to look more closely at dosing regimens, London says.

Proia says Synta plans to measure dozens of variables in the dogs, ranging from how specific genetic mutations affect their response to how long the drug continues working in the body after it’s infused. Drug companies can do experiments like that in lab mice—say by taking tumor samples from humans and injecting them into the rodents—but dogs offers a more realistic model, Proia says. “I cannot think of a better model than a dog that comes into the clinic with an equivalent disease,” Proia says. “[London’s] animals really can mimic what’s occurring in human patients.”

Synta is currently studying ganetespib in two lung cancer trials and a breast cancer trial in people, with hopes of moving into the pivotal trials that are required for FDA approval by the end of the year. As a small company, Synta does not have the resources to pursue a veterinary approval at the same time, though the insights the company is gaining from the dog trials have been invaluable, Proia says. “If we see very clearly [in the dogs] that one dosing schedule stands out, we’ll think about whether we should implement it in our patients,” he says. “There may be different dosing strategies for different tumor types. That’s really important.”

Szalay of San Diego’s Genelux says that although his company is also strapped for resources, he is considering several options for pursuing the veterinary market. “We may license [V-VET1] or co-develop it with a large veterinary hospital,” he says.

The use of pet dogs in early research is bound to intensify, as the FDA becomes more comfortable with the role of comparative oncology in drug development. Both Ogilvie and London report that some companies they’re working with have included data from trials in pet dogs in packages they’ve submitted to the FDA for approval to start human trials—even when the drug being tested in dogs is different than the human version. “The FDA values real-life models,” London says.

As for Chance, the first dog to enroll in Genelux’s trial, he has had two injections of the experimental drug so far and is not showing any major side effects, Willcut says. And Ogilvie says he’s constantly trading notes on the Genelux trial and others he’s working on with the oncologists at UCSD’s Moores Cancer Center. “I’ll get an e-mail or a call every week asking what I’ve found,” he says. “They want to know how they can use the information to benefit people.”

“First and foremost we’re working for the animals,” Ogilvie adds. “But our objective is to take these discoveries and bring them to people with cancer.”

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