Cops and firefighters who raced to the scene on 9/11, in many cases, came down with what doctors call idiopathic pulmonary fibrosis. It’s a fancy way of describing “scarring of the lungs we don’t understand very well biologically, and don’t know how to treat.”
The biology of fibrosis, and treatment, has come a long way. Third Rock Ventures, one of biotech’s aggressive early-stage investors, is now plunking down $45 million on a startup that thinks it can make a pill to halt fibrosis of the lungs, liver and kidneys.
The company, Redwood City, Calif.-based Pliant Therapeutics, is getting started with the big venture round and technology in-licensed from the University of California, San Francisco. The idea is to start by developing an oral pill for idiopathic pulmonary fibrosis. The cause is unknown, but the disease is irreversible, fatal and affects an estimated 100,000 people in the U.S. and Europe. Based on growing knowledge of the ways scarring works in different tissue types, the company hopes to branch out and treat more patients with fibrosis of the liver and kidneys.
“We and others are trying to identify targets that can stop the progression of fibrosis,” said Bernard Coulie, the startup’s CEO. “It may be possible even to reverse it, to regress the fibrosis. Not only do we think we can maintain a patient with a certain amount of lung function, but we may be able to help them improve. That’s our goal.”
The science underneath Pliant, and other drugmakers, has been advancing quickly in recent years. Dean Sheppard, a scientific co-founder of the company and chief of the Division of Pulmonary, Critical Care, Allergy and Sleep at UCSF, said he’s spent more than 15 years studying the basic biology of a family of protein receptors, called integrins, that play key roles in the excessive signal activation of a protein called transforming growth factor beta (TGF-beta).
The genesis of Pliant goes back a couple years, when Sheppard and his team at UCSF used genetic "knock-out" mice to delete all the members of an integrin family, known as alpha V. When they did that, they prevented fibrosis of the lungs, liver and kidneys of the mice.
Then it was time to go a step further. Sheppard spoke to Bill DeGrado, a medicinal chemistry professor at UCSF, who said “it wouldn’t be that hard” to synthesize a small-molecule chemical compound to bind with a specific alpha V receptor, Sheppard recalled. Last May, Sheppard and DeGrado said in Science Translational Medicine that an experimental drug was able to hit the target and slow down fibrosis of the lung and liver in mice. Importantly, they achieved that result while only targeting a subset of TGF-beta activity–not completely shutting it down, which would likely cause problematic side effects.
That set of findings perked up the ears of pharmaceutical companies and biotech venture capitalists, Sheppard said. A recent Keystone Symposia for fibrosis researchers in Colorado was packed with drug company officials, he said. “I think half the people there were from a pharma and biotech companies,” Sheppard said. “It’s a dramatic change over the last 3-4 years.”
Drug companies have become more interested in part because the FDA approved the first two products for idiopathic pulmonary fibrosis in 2014. Roche is marketing pirfenidone (Esbriet) and Boehringer Ingelheim sells nintedanib (Ofev). Pliant considers those drugs a good thing for the field, Coulie said. They helped clear up some of the uncertainty about how to conduct clinical trials in the field, establishing precedents with the FDA. The drugs themselves were originally designed for other diseases, and have only a modest effect against fibrosis. There is plenty of room for improvement, especially for drugs designed specifically for pulmonary fibrosis from the get-go, Coulie said.
Naturally, other companies see similar opportunity.
Michael Gilman, the former CEO of Stromedix, who now runs another company called Padlock Therapeutics in Cambridge, Mass., said the success with the first two drugs could be a double-edged sword. While those trials set a precedent for what kind of parameters are necessary for a successful pulmonary fibrosis development program, other issues could make clinical trials difficult. He wrote in an email:
I'm gratified that interest in fibrosis remains strong--I suppose we were a bit ahead of our time at Stromedix--and there's no question that the medical need remains high. I would say that the clinical development path is a bit more complicated than it was a few years ago, especially in IPF where there are already two approved therapies--which makes trial design and patient recruitment potentially challenging. There's also quite a bit of development activity in IPF now, which suggests that much of the risk here is not technical but commercial--if the drug works, will it work better than drugs already on the market when they get there?
A further point I'd make is that integrins have historically been very tricky targets for small molecules--I've been personally associated with several over the years that came out of the gate on fire but then fizzled out later. But, that said, these guys (Pliant) know what they're doing and I wish them luck!
Gilman added that liver scarring may be an even bigger market opportunity, particularly as awareness has grown of the emerging epidemic of non-alcoholic steatohepatitis (NASH). It's a fatty liver condition that leads to scarring. Subscribers to Timmerman Report may read more on the companies, and different scientific approaches being taken to combat NASH, in this article--NASH is the next Monster Pharmaceutical Market: Here are the Players.
