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Drug designed in San Antonio fights age-related diseases
April 1, 2016

Rapamcyin Holdings Inc., a privately held San Antonio company, is trying to commercialize an improved version of the drug that’s designed to be better absorbed by patients.The company licensed the technology from The University of Texas Health Science Center. Pictured are Rapamycin Holdings CFO Mark Horsey (from left) and Professors Randy Strong and Z. Dave Sharp.  Photo by Edward A. Ornelas / San Antonio Express-News

By Peggy O’Hare, San Antonio Express-News

A San Antonio company is trying to break into the pharmaceutical market with a new version of an old drug that it believes offers hope to two-legged and four-legged patients diagnosed with incurable or life-altering diseases.

Rapamycin, a drug derived from microbes discovered in the early 1970s in the soils of Easter Island in the South Pacific, drew an explosion of renewed attention in 2009 when it was proven to be the first pharmaceutical capable of prolonging the life spans of older mice, according to research done in San Antonio.

Made in laboratory settings today, rapamycin has long been used by transplant patients to help fight organ rejection. It's also used in heart stents to prevent clots from forming in vessels and to treat certain cancers.

Now Rapamycin Holdings Inc. hopes to bring a unique version of the drug to those battling age-related illnesses, such as Alzheimer's disease and dementia patients, people genetically at risk of developing certain cancers, and dogs and cats facing debilitating diseases.

The privately held company, founded in 2012, is trying to capitalize on rapamycin's life-extending benefits, which were first discovered by scientists at the University of Texas Health Science Center in San Antonio and two other research centers in Michigan and Maine. Those findings were heralded by the health science center as a scientific breakthrough when they were published in Nature in 2009. Science and TIME magazines also took notice.

Rapamycin Holdings has secured exclusive rights to market a formula designed by the health science center and Southwest Research Institute to break down in the intestines instead of the stomach so patients can better absorb it.

That formula is known as eRapa. Rapamycin Holdings CEO Randy Goldsmith describes it as "an anti-aging intervention."

"If it makes Nature magazine, then that's the Holy Grail ... I was fascinated to learn about it," Goldsmith recalled of his introduction to the medication's life-extending powers. "There were so many scientists enthralled with the benefits of rapamycin. So it was sort of an evangelistic exercise."

The eRapa formula has the potential to slow the progression of some age-related diseases like Alzheimer's and to prevent certain genetically inherited cancers, according to research at the health science center's Barshop Institute for Longevity and Aging Studies.

Alzheimer's, an incurable brain disorder that affects older people, causes memory loss and erodes cognitive skills. More than 5 million Americans may have the disease, a National Institute on Aging report shows.

A second version of the university's formula, dubbed eRapaNP2g, has significant implications for veterinary care, showing promise in treating feline chronic gingivostomatitis, a painful oral condition in domestic cats.

Rapamycin Holdings estimates a drug that treats this ailment represents a market opportunity totaling $30 million to $50 million a year, based on a study commissioned by the company, Goldsmith said.

Z. Dave Sharp and Randy Strong, professors at the health science center and members of the Barshop Institute, liken rapamycin to aspirin because both medications have so many potential uses.

Both scientists were part of the team that proved rapamycin could extend how long mice lived. Strong also helped design the improved form of the drug that Goldsmith's company is now trying to bring to the commercial market.

"We're in that great place where anything's possible," Strong said of eRapa. "What is exciting, though, is they're actually finding indications now, like for the cat disease. I think we'll find more things over time."

The possibilities are vast, Goldsmith agreed.

"As time has gone on and we've seen more and more research related to rapa - not only at the health science center, but throughout the world - we've seen rapamycin being proposed for macular degeneration, for lupus, a whole variety of diseases that others are working on besides us."

From animals to humans

Rapamycin Holdings has not yet put any of its products on the market, but is working toward that goal. The U.S. Food and Drug Administration must approve any medications intended for people or animals before sales can proceed in the United States.

The company is focusing first on the veterinary medicine market, specifically pursuing FDA approval to treat feline chronic gingivostomatitis. If those efforts are successful, the company will be the first to make rapamycin available to veterinarians.

From there, the company plans to pivot into the human medical market.

"They want to go into the animals first because that's a good revenue stream - and it builds up more data that they can take to the human condition," said John Gebhard, senior executive director of the health science center's Office of Technology Commercialization. "It's a smart strategy. And more companies in therapeutics should do that. They really should."

Rapamycin Holdings has raised nearly $5 million so far from mostly San Antonio-based angel investors - independent financiers serving as the first round of funding for new ideas - and from the UT Horizon Fund and McDermott Legacy Fund.

The UT Horizon Fund is a venture capital fund for companies commercializing University of Texas innovations, while the McDermott Legacy Fund provides seed money to early-stage bioscience and technology companies. The latter is managed by the Texas Technology Development Center.

Those funds have been used for various pilot studies, eRapa's product development, patent filings and patent prosecutions, said Chief Financial Officer Mark Horsey.

Rapamycin Holdings is working to finalize a worldwide exclusive licensing agreement that will allow an animal health drug company to manufacture, sell and distribute eRapa for various veterinary uses if the FDA approves, Goldsmith said. A non-disclosure agreement has kept the veterinary pharmaceutical company's name under wraps.

The company is raising a bridge round of $2 million from the same angel investors to support preparations for human clinical trials. It plans to raise an additional $5 million from institutional investors, like private equity firms, later this year to test the safety of people taking eRapa. That clinical trial will most likely focus on cancer prevention, Horsey said.

Rapamycin Holdings has been attractive to investors for several reasons, Horsey said.

"We're getting strong validation by having interest in this animal health license," he said. "It's exciting that a company that's only been in business for three years already has a product that's attracting commercial interest in acquisition or license.

"They're also very excited about the applications in human health, both cancer prevention and Alzheimer's disease."

The company's recent hiring of Dr. George Peoples as its chief medical officer stirred interest as well, Horsey said.

Peoples, a cancer researcher, is the founder and director of the Cancer Vaccine Development Program associated with the Uniformed Services University of the Health Sciences in Bethesda, Maryland. He's also an adjunct professor of surgical oncology at MD Anderson Cancer Center in Houston and past chair of the San Antonio Military Medical Center's cancer program.

Rapamycin Holdings believes its novel design of the medication gives it a unique position in the pharmaceutical market.

"What we've learned is, the gastric acid in the stomach is very detrimental to the effectiveness of the drug. It just tears it all up," Goldsmith said. "So in order to get it into an environment of effective bioavailability, it needs to be absorbed in the intestines."

Strong worked with Bert Wheeler, a chemist at Southwest Research Institute, to come up with a new way for animals and people to take the drug. By late 2006, they had encapsulated the antibiotic to pass through the stomach without being destroyed by gastric acids. This enables rapamycin to reach the intestines, where it is absorbed through the intestinal walls into the bloodstream.

As a result, the medication is more effective, and its levels in a patient's blood can be predicted with greater accuracy, Rapamycin Holdings officials said in U.S. patent application filings.

The drug is compressed in a pH-sensitive polymer matrix that remains stable while passing through the acidic conditions of the stomach. That matrix unfolds, releasing the rapamycin, once it reaches the intestines, where pH conditions rise above 7 and become basic instead of acidic, said chief scientific officer Dana Vaughn.

The company has packaged eRapa into oral tablets that can be swallowed, Vaughn said.

Treating disease in cats

ERapa's first potential use, for feline chronic gingivostomatitis, is a significant opportunity because there are no medications approved by the FDA specifically to treat this disease.

Cats with this condition frequently have most or all of their teeth surgically removed, but that doesn't always relieve the symptoms, said Dr. M.J. Redman, a veterinary dentist at Mission Veterinary Specialists in San Antonio.

Nearly 1 million cats worldwide suffer from the condition, more than 350,000 of them in the United States, Goldsmith said. It can affect cats of any age.

The condition is painful and gruesome. Its hallmark symptoms are inflamed gums, oozing and bleeding gum lines, drooling, bad breath or an overgrowth of tissue in the mouth. Sometimes cats cry out while chewing their food or stop eating completely. "For some reason, their immune system goes on the attack," Redman said.

What causes the disease is not known. Steroids can provide temporary relief, but typically become less effective the longer they're used, Redman said.

A preclinical pilot study done in Canada found Rapamycin Holdings' eRapa compound achieved remarkable success in alleviating those symptoms in 16 cats diagnosed with the disease. Nearly half of them went into complete remission. The average improvement rate among all of the cats was 78 percent, according to data shared by the company.

Those findings were provided to the FDA's Center for Veterinary Medicine last year.

"We were able to show every animal responded to our formulation," Vaughn said.

The study also found symptoms usually had not returned about two and a half months after the cats stopped taking eRapa. "We got very little re-inflammation," Vaughn said.

Getting clearance from the FDA to go to market is typically a long process. Vaughn and Horsey estimate it will be another two years before the medication becomes commercially available to cats.

"Every time there's something in the press, all three of us get emails from people around the country, saying, ‘Please help me - I'm so glad to hear that you're doing something that will save my cat.' And they go into these long, heart-wrenching stories about how they love their cats," Goldsmith said. Inevitably, the pleading letters ask how soon the drug will hit the commercial market.

ERapa has other potential uses in veterinary medicine as well. Another pilot study done for Rapamycin Holdings showed the compound improved the memories of dogs suffering from canine cognitive dysfunction, which mirrors the symptoms seen in people diagnosed with dementia.

The condition is widespread among older dogs. In 1997, when drugmaker Pfizer Inc. acquired Anipryl, a medication used to treat this syndrome, it reported more than 1 million dogs over 10 years old suffered from the condition in the U.S. More than 8 million dogs and cats worldwide may suffer from the condition, according to market data shared by Rapamycin Holdings.

Another of Rapamycin Holdings' pilot studies showed eRapa had positive effects on dogs suffering from intervertebral disc herniation. The company couldn't provide more details since it hasn't yet received the formal data analysis.

Intervertebral disc herniation is seen most commonly in dachshunds, but the painful condition occurs in other breeds as well. A study published in the Journal of Neurotrauma in 2011 reported disc herniation in the thoracic or lumbar regions of dogs' spines accounted for more than 2 percent of "all admissions to veterinary teaching hospitals."

The human market

Rapamycin Holdings has secured seven exclusive licenses with the health science center to use eRapa for a wide range of ailments in the human medical market as well. If the FDA approves, the company likely will begin with cancer prevention, which Vaughn describes as "one of the biggest unmet medical needs" in the pharmaceutical industry.

"It's practical reasoning ... We decrease our risk by going into cancer" first, Vaughn said, explaining the company's strategy. "There's not been a new Alzheimer's disease (drug) approved in over a decade. And huge pharma is trying to do this without success. So we're a small group of men and women here that think our odds are better to start in cancer."

The oral tablet containing eRapa would be unique since most cancer-related medications are injected, he said.

Scientists at the Barshop Institute, like Dave Sharp, have shown rapamycin has potential to keep certain cancers from returning or to prevent some genetically inherited cancers from occurring in mice predisposed to such diseases. This suggests promising benefits for humans.

Research at the health science center showed eRapa prevented polyps from forming in mice at risk of developing a hereditary type of colon cancer known as Familial Adenomatous Polyposis. As a result, those mice had normal life spans and did not die young, Sharp said.
FAP typically causes thousands of polyps to form in a person's colon, typically during the teen years. Patients with this condition usually must have their colons surgically removed or the polyps can progress to cancer, which can become lethal.

The market opportunity for a medication capable of preventing FAP is projected to reach $435 million a year just in the U.S. alone, Goldsmith said. Statistics vary on the prevalence of FAP. Its occurrence ranges from one in 7,000 people to one in 22,000 people, according to the U.S. National Library of Medicine's Genetics Home Reference website.

"The oncologists who specialize in the GI tract cancers, they're real excited that there's something for these people," Sharp said.

Barshop Institute researchers also showed eRapa can slow the progression of neuroendocrine tumors in mice, a rare type of cancer that can surface in a variety of places, such as the lungs, brain or digestive system, Sharp said.

ERapa rejuvenated breast tissue in older mice in another study, indicating the drug has potential to prevent breast cancer in patients at risk of developing the disease, Goldsmith said.

"We think rapamycin is a really good cancer prevention agent," Sharp said. "It hasn't worked real well as a cancer treatment agent ... But as a preventive, it's really good, we think."

The drug also shows promise for patients suffering from Alzheimer's disease and dementia.

Research by scientists affiliated with the Barshop Institute showed eRapa restored vascular function and brain blood flow in mice that had been genetically manipulated to have impaired cognition, mimicking Alzheimer's disease.

Their research showed eRapa also prevented memory loss in mice suffering from symptoms similar to Alzheimer's - and even restored their memories if the drug was given to them after they began to experience cognitive deficits, according to an article published in Experimental Gerontology last year.

More than 1,000 clinical trials have been done on Alzheimer's disease, but only five medications are approved to treat the condition, according to the Experimental Gerontology article. None of those drugs have slowed the progression of Alzheimer's, according to the scientists who published that report.

Research suggests rapamycin is more likely to succeed on that front because the drug improves and restores vascular function and blood flow in the brain and because it slows the aging process, a major risk factor for the disease.

pohare@express-news.net

 

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