Patients with cystic fibrosis can expect to live until their late 30s or early 40s. It’s a big improvement over the life expectancy they had a decade or two ago. But now a biotech startup in Austin, TX, has put itself into position to find out, in the next year, if it has another way to improve the outlook for patients with this deadly genetic disease.
Savara Pharmaceuticals, a little company that has scraped together $19 million in angel investment since its founding in 2007, is entering a critical proving ground this year in clinical trials to test its idea for treating cystic fibrosis. It is enrolling 80 patients in a clinical trial that will give it a clear idea of whether it has come up with important new inhalable antibiotic, or whether it has to go back to the drawing board. The answer should arrive in less than a year.
“We’ve already shown safety. Once we show efficacy, we believe this will be a game-changer for us,” says Savara co-founder and CEO Rob Neville.
Cystic fibrosis, for those new to the story, is a genetic condition that affects about 30,000 people in the U.S. It’s known for leading to the buildup of thick, sticky mucus in the lungs that makes it hard to breathe. The mucus also becomes a haven for dangerous infections from bugs like pseudomonas aeruginosa and MRSA. Patients used to get intravenous antibiotics in the hospital once they had a severe infection, by which point it was often getting late in the game. Then pharmaceutical companies developed inhalable antibiotics that could be delivered more effectively to the lungs where the bugs reside, and which patients could take themselves on a regular basis at home.
What Savara noticed, about five years ago, was that those innovative products weren’t killing all the bugs that CF patients ought to be worried about. Novartis’ inhalable tobramycin (TOBI) and Gilead Sciences’ inhalable aztreonam (Cayston) won FDA approval for their ability to fight pseudomonas. But no one has come up with an inhalable version of vancomycin, the go-to antibiotic for MRSA. Savara’s big bet is that it can create such a drug, that it will be an important weapon against an infection increasingly viewed as troublesome, and that the rising incidence of MRSA is going to make it a widely prescribed product for CF.
Data from a 2010 study published in the Journal of the American Medical Association suggested that patients die sooner when they have chronic MRSA infections that are left untreated. That has provided some added urgency for the doctors and patients participating in the ongoing study of Savara’s inhalable vancomycin, which it calls AeroVanc.
The Savara story actually traces its roots back to 2007 in Kansas, with technology licensed from Cory Berkland’s lab at Kansas University. But Neville got involved the next year as CEO. He moved the company to Texas, which was where he had his home and a lot of business contacts. The original idea for Savara was to develop a platform technology for making inhalable drugs, which could be broadly applied to many products, but it ultimately didn’t prove commercially viable or scalable, and Savara is in the process of handing it back to KU, Neville says.
While Savara was looking at opportunities for inhalable drugs, it sized up a promising one in cystic fibrosis. The patients, physicians, and insurers were already well versed with the transition from IV to inhalable products, through the past experience with Novartis, Gilead, and others. Those drugs started with killing pseudomonas, which made sense, because it’s dangerous and affects about 60 percent of the cystic fibrosis population. The market appeared smaller for MRSA infections, because as recently as a few years ago, fewer than 20 percent of patients were thought to have this bug. Plus, converting vancomycin to an inhalable form presented technical challenges, and there wasn’t a consensus on how important MRSA was to treat, Neville says.
As Savara was working on its own inhalable form of vancomycin, a key paper in JAMA came out in 2010. It looked at patients in the Cystic Fibrosis Foundation’s database, and saw that those with MRSA infections had a significantly higher risk of death than those without. The study, although retrospective in nature, suggested that life expectancy for MRSA-infected patients was about 31, compared with 37 for those without, Neville says.
Suddenly, there was newfound urgency for someone to come up with the first inhaled version of vancomycin, especially as MRSA infection rates started to climb to more than 30 percent of patients. A few aggressive physicians were already acting on their own to turn IV vancomycin into a nebulized form that patients could take at home, suggesting they might also be interested in a more convenient commercial product that could do the same thing.
“I’d like to think we had a crystal ball, but we didn’t,” Neville says.
As the story started to get more focused, Neville was able to corral more and more financing to support the work. While most biotech companies eventually have to turn to venture capital firms with deep enough pockets to finance serious clinical trials, Savara has gotten all of its money to date from angel investors.
Tech Coast Angels, Keiretsu Forum, and the Central Texas Angel Network ended up being part of the $19 million in financing Savara has pulled together. Neville says he was able to get the unusually large amount from angels partly because he had a significant investment in the company himself, and his previous company, Austin, TX-based Evity, was sold to BMC Software for $100 million in 2000. That deal delivered a 27-fold return on investment for angels, Neville says.
With the money in hand, Savara put it to work on developing a dry powder form of vancomycin for inhalation. There were plenty of technical challenges to overcome. The company had to make the particles the right size (about 1-3 microns in diameter) so they could be breathed in efficiently and get concentrated in the lungs. It needed to think about how to manufacture the product in a way that could be done in the future at commercial scale. It needed to make the particles in such a way that they don’t cause coughing, a common tolerability problem with other dry powder formulations. The IV version of vancomycin is acidic, and Savara needed to balance that out to make a tolerable product to be inhaled into the lungs.
Bruce Montgomery, the Seattle-based entrepreneur who spearheaded development of both the CF antibiotics sold by Novartis and Gilead today, ticked off a list of three challenges that he and others considered around making inhalable vancomycin for treating MRSA. Here’s what he said via e-mail.
—Dry powders can cause cough. Can an effective dose be tolerated?
—Not all CF patients have MRSA, and pseudomonas infections may be a bigger driver of outcomes than MRSA.
—Scaling up manufacturing for the TOBI podhaler took years and repeat clinical trials as the process was changed to make it to scale.
Since vancomycin is a widely used generic drug, Savara was able to move pretty quickly with its inhaled version into clinical trials. Its first study of 18 healthy volunteers showed that its drug was tolerable at a variety of doses, and appeared to cause fewer adverse events than other inhaled antibiotics, including Novartis’ TOBI, Neville says. The drug was effectively distributed into the lungs, and stayed there 24 hours, which is important, Neville says, because research suggests vancomycin needs some time to deliver maximum punch against MRSA.
The next small trial for Savara was in 12 cystic fibrosis patients. That one showed, again, that the drug appeared well tolerated. Importantly, when patients coughed out sputum from their lungs, researchers found that the AeroVanc had gotten into the sputum (where the MRSA bugs reside) at concentrations as much as 50 times higher than the minimum dose considered necessary to kill the bug. That’s far greater than the lung concentrations patients typically get of vancomycin after taking an IV form that circulates throughout the bloodstream. The AeroVanc, again, stayed in the lungs for as long as 24 hours, Neville says.
But now a much more rigorous test is underway to find out if Savara has a real drug. The earlier studies only gave patients a single administration of the drug, and Savara needs to prove its product works chronically. So this ongoing study of 80 patients is designed to randomly assign people to a low or high dose of the new drug, or a placebo. The new drug will be taken twice a day, for 28 days.
The main goal of the study is to show it can cut down on the number of MRSA colonies that form in the lungs.
“I’m willing to put my life on the fact that we’ll kill the bug,” Neville says.
True success in the trial, however, will be measured by the secondary questions researchers are seeking to answer. Researchers will want to see that patients report they are feeling better on questionnaire, and that they have increased lung capacity—measured through the volume of air they can force out of their lungs in one second. And patients will also be followed to see if using the inhalable antibiotic can keep them off IV antibiotics for a longer period of time, and delay any exacerbation of their disease.
If enrollment stays on schedule, Savara expects to have results from the study before the end of March 2014, Neville says. If the data are positive, then Savara will face a whole new set of strategic questions. It will need to design a couple of pivotal-stage clinical trials to win FDA approval, which will take considerably more time and money. It may opt to raise more money to run those trials, or to join forces with a partner to help foot the bills. Either way, if Savara looks like it has a real drug, the pressure will be on for it to nail the next set of clinical trials to get it on the market as soon as possible. It’s an exciting time for the company, Neville says.
“We’re going as fast as we can,” Neville says.