A New Coat Makes The Difference in Rapamycin’s Disease Prevention

Xconomy Texas — 

San Antonio — Drugs that can cure a disease inevitably draw the most attention. But San Antonio, TX-based Rapamycin Holdings is hoping that its drug’s potential to prevent the recurrence of diseases like cancer, among others, will at least draw the interest of a Big Pharma company with money to spend.

By 2017, Rapamycin Holdings hopes to begin testing a formulation of a decades-old drug known as rapamycin in clinical trials—early stage trials that may be focused on bladder and pancreatic cancers. The company is expecting that work to take place locally, betting that there will be a couple of reasons that researchers at the University of Texas Health Science Center at San Antonio may have interest in working on the Phase 1 and Phase 2a clinical trials.

First, scientists at the health science center are experts in indications Rapamycin will focus on. Rapamycin Chief Medical Officer George Peoples says that he has already tentatively discussed the design of the early trials with Ian Thompson, the director of the health science center’s Cancer Therapy & Research Center and an urologic oncologist who has studied prostate cancer for more than three decades, including in a 20,000-person study. Others from the center’s department of urology, of which Thompson is the chair, may help the company explore in early trials how rapamycin could impact bladder cancer, Peoples says.

The second reason there might be interest from the health science center? The formulation of rapamycin, called eRapa (for encapsulated rapamycin), was developed at the UT Health Science Center. Rapamycin Holdings licensed the rights to the drug from the center for seven fields of use in humans related to diseases of aging, including a variety of cancer prevention and treatment applications, as well as for use in treating certain diseases for animals.

“You have this trifecta going between rapa being discovered at UT, RHI is commercializing it, and now bringing it back to UT Health Science [for clinical trials], with prostate cancer being the first indication,” Peoples says. “You know the FDA has approved the drug substance before. All you have to show is that your reformulation provides for sustained blood concentration levels without the toxicity, and provides some benefit.”

Rapamycin, a natural product discovered 44 years ago, has been best known for its role as an immunosuppressant drug called sirolimus (marketed as Rapamune) for organ transplants, but has been increasingly used as a potential cancer treatment. There are other derivatives or analogues of rapamycin that are structurally similar but not the same, called rapalogs. Some have also found some success, like Novartis’ everolimus (Afinitor), which had one alcohol subgroup added to the rapamycin’s chemical structure, says Dana Vaughn, Rapamycin Holdings’ chief scientific officer.

The company’s rapamycin and some other rapalogs aim to be a buzzkill for overactive cells, such as cancer cells, which have been ramped up to divide and multiply at a faster rate than normal cells, Vaughn says. Rapamycin drugs inhibit a kinase—a type of signaling molecule for cells—called mTOR, standing for mammalian target of rapamycin. That blocks genetic information in a cell from being replicated, and prevents those cancerous cells from “multiplying and growing into larger, malignant tumors,” Vaughn says.

The drug doesn’t kill the cancer cells, and instead merely reduces their ability to become malignant, Vaughn says. Other companies are developing their own drugs to target mTOR, including Cambridge, MA-based Navitor Pharmaceuticals, which is working on indications in metabolic and neurodegenerative diseases.

“Since the genetic information cannot be replicated, the cells do not divide and you get an anti-cancer, anti-proliferative effect,” Vaughn wrote in an e-mail. “The drug is called as ‘cytostatic’ inhibitor in that it does not kill (cancer) cells—it just turns their activation steps off which decreases their malignancy capabilities.”

For Rapamycin Holdings, its differentiating factor is in the delivery mechanism of the drug. Rather than altering the chemical structure of rapamycin slightly to create a new rapalog, like Novartis, the creators developed a coating for rapamycin that would allow the drug to pass through the stomach before being released. It’s a microencapsulated, nanoparticle version of rapamycin, Vaughn says.

By passing through the stomach and into the intestines, the company can better control (or predict) the actual amount of the drug that will be released in a patient’s blood, Vaughn says. The company can adjust when its pill, which is taken orally, will dissolve and release the drug based on acidity, or pH level, in the intestines, according to Peoples, the chief medical officer.

“You can kind of dial it up, dial it down,” he says of the coating and the pill’s controlled release. “The enteric formulation is where the IP exists.”

Other formulations of rapamycin made it difficult to predict how much would be released in the bloodstream because they can often break down and release the drug in the highly acidic stomach, Vaughn says.

The company is in the process of raising a round of funding—a $2 million convertible note meant to finance it to the point of starting clinical trials, according to Chief Financial Officer Mark Horsey. Rapamycin Holdings may seek around $5 million more after that to actually start the clinical trials. It has already raised about $5 million so far, including namely from the UT Horizon Fund.

After the company develops its clinical trial plan, it hopes to submit an investigational new drug application to the FDA so that it can begin trials in late 2016 or early 2017. The company will be testing the safety of the drug in the early stage trials—hopefully showing it has a diminished toxicity profile compared with other rapamycin—while also determining the impact the drug has on the reoccurance of bladder and pancreatic cancer, Peoples says.

The company was founded in 2012 by a group of scientists and entrepreneurs, including Randy Goldsmith, the former president and CEO of the Texas Technology Development Center and a former employee of the UT Health Science Center’s technology transfer and economic development office. By the next year, Goldsmith had taken over as CEO, he had recruited the core management team, and the company was studying rapamycin’s use in animals.

That’s actually where the drug has so far found success, as the San Antonio Express-News first reported. The company is seeking to gain regulatory approval using the drug to treat an oral disease in cats, and it is finalizing a licensing deal with the animal health divisions of an unnamed pharmaceutical company with multiple drug targets, Horsey says. That company, which Horsey declined to name until the deal is finalized, is aiming to get the drug on the market in 18 to 24 months, he says.

The animal data is supporting the path to clinical trials for the drug’s use in humans, says Peoples, who also runs his own cancer immunotherapy research company, called Cancer Insight.

If one, or both, of the Phase 1/2a trials for bladder or prostate cancer—likely 20 to 30 patient trials, Peoples says—meets the goals of both short-term and long-term toxicity, among others, Rapamycin Holdings will follow it with a 200- to 300-patient Phase 2b trial, he says.

“From a company standpoint, that will highly likely be the potential of an exit,” he says. “If we have randomized Phase 2b data in an indication like prostate that shows the potential of affecting these people who are on active surveillance, that’s something a Big Pharma is going to be very interested in.”

That’s the benefit of working with the UT Health Science Center on the trials, Peoples says: The center is already tracking progress of patients in both indications of cancer. In bladder cancer, patients are checked for progression of the disease every three months. The same goes for pancreatic, though they also receive biopsies every six to 12 months, he says. By potentially providing those patients with the company’s formulation of rapamycin, the company will be able to easily study the net effect, he says.

“It’s kind of a beautiful thing,” says Peoples, who joined the company in February. “I couldn’t be happier with the way this has all come together.”

The company believes eRapa has more potential than just cancer. The drug may potentially be able to treat autoimmune diseases or age-related diseases like Alzheimer’s, stemming its progression, Goldsmith says.