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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.