From The Editor | July 8, 2014

Fibrotech Knows Translational Research Methodology, Shire and Pharma Industry Agree

By Louis Garguilo, Chief Editor, Outsourced Pharma

Louis Garguilo

Feel-good stories about clinical trial design are rare these days. Those about pharma in-licensing programs from biotechs at Phase I might be even rarer. However, Darren Kelly, Ph.D., founder and CEO of Australia-based Fibrotech Therapeutics, and a recognized thought-leader in translational research, has experienced both recently. Kelly is moving his promising anti-fibrosis program to Shire, who on May 2nd acquired Fibrotech for “an upfront payment of $75 million and certain contingent payments based on the achievement of development and regulatory milestones.”

I first met Kelly and Fibrotech’s operations manager, Ann Hamer, a few years ago when they hired the U.S.-based contract research and development organization I was working for, to scale up their lead candidate, FT011. The compound targets diabetic nephropathy, a form of kidney failure in diabetics as a result of kidney scarring, or fibrosis. FT011 entered the clinic in 2013, and Phase Ia results showed that the compound was very well tolerated. At that point, according to Kelly, “Shire swooped in and outbid a who’s who list of pharma” to win the program.

Kelly, Hamer and I met again recently, at BIO 2014 in San Diego in June, to discuss the Fibrotech-Shire deal and the current state of clinical trial research and methodology.

Lessons From a Biotech Down Under

Why was Fibrotech able to generate so much interest and successfully out-license to pharma so early in the process? Kelly answers this by taking us back to 2006 and through his thought process when he spun Fibrotech out from his work at the University of Melbourne, where he continues to serve as a professor.

“From day one we made a conscious decision to think of our activities on an international scale. First, we benefitted from a nurturing and very supportive environment in Australia for biotechnology,” Kelly says. “We used some of the early funding we received for what I think is one of the keys to our success and should be central to other biotechs: We got ourselves on planes to the U.S. and other countries to meet face-to-face with global pharma companies. We actively engaged them in discussions, learning what it is they want to see. We then worked to tailor our discovery and development program not to one specific company, but a breadth of different pharma.”

I asked Kelly, who decided (somewhat unusually for Australian academia) to lead the new company as its CEO, what about the program pharma liked and what he learned. “If I had to point to one specific item,” he says, “I actually think it is the clinical trial design that we are about to perform in Phase II that made the out-licensing successful early on. Shire is strategically aligned with our trial design, which is focused on molecular pathways, and will result in a more personalized medicine approach.” Kelly adds, “Understanding which patients will have the best outcomes is vital, and it is possible to achieve this knowledge with the right methodology.”

Perhaps because the news regarding the Fibrotech-Shire deal focused on the Phase I trial for FT011 as the main driver, Kelly makes clear that is not entirely accurate. “Yes, Phase Ia was a trial that delivered measurable and important safety results,” he says, “but the entire scientific and clinical package methodology is the real key.”

Kelly further explains: “We have a series of patients that we know have developed fibrosis, and we already understand which pathways are ‘disregulated’ in those patients. Hence when we give them FT011, we know the drug will modulate those pathways. That is the design that will give you the most likely chance of success in the clinic and ultimately as a new drug. We have a database of patients based in North America for our Phase II trial. We collaborated with the most innovative nephrologists in the world to map out the patient profile.”

Among others, Kelly is referring to Adeera Levin, MD, a professor of medicine at the University of British Columbia, Canada, and long-time chair of the U.S. National Kidney Foundation's Kidney Disease Outcomes Quality Initiative; and Matthias Kretzler, MD, a German born and trained scientist who has established labs at the University of Michigan, where he did post-doctoral work, after a long career in Germany. Kretzler, utilizing a unique research group within the European Renal Cell Study Group, initiated what is now a worldwide network of kidney research centers to define the molecular mechanism of renal disease in humans.

“Essentially,” Kelly continues, “Matthias has mapped out the pathways that are disregulated in our patients, and we’ve done studies with him that allow us to show which pathways FT011 modulates. We will overlay that on the ensuing clinical trial to predict which patients will likely respond. Most importantly, this next Phase gets us into personalized targeting and leads to the real promise of personalized medicine.”

We’ll get back to the clinic in a moment, but at this point Kelly also reminds us that “another major incentive for pharma to take our program internal is that our compounds have a novel mechanism of action, which remains undisclosed. We believe this novel MOA is highly selective for fibrosis.”

Hamer, who also works at the University of Melbourne, and has been with Fibrotech from the company’s inception, summarizes for us all the attributes of success that any biotech can benefit from and should emulate: “We started with early support from (in our case Australian) investors and a nurturing environment; a commitment to traveling to meet with global pharma to understand their needs; a strong and comprehensive clinical trial methodology and design; an openness to utilize experts in the field; a novel MOA in our compound, and finally,” she adds, “I should mention that Fibrotech ran a very lean organization.”

Clinical Conservatism

Back to the clinic. I asked Kelly, who as a consultant has advised pharmaceutical companies on translational methodology, if he agreed with the recent criticism leveled at that part of the industry. “One of the things that has slowed advancement of clinical trials is simply the practice of using the same design and endpoints over and over again, for example for chronic kidney disease,” he replies. He laments that “so many trials have drugs fail because of overly conservative clinical trial designs and possibly outdated endpoints,” and then adds, “Absolutely, it is true that clinical trial design has been a major problem over the last 20 odd years.”

“This conservatism” says Kelly, “despite there being new technologies that allow us to do improved, more predictive trials. The cancer biologists are really the ones who have started honing in on more specific and advanced methodologies and design. The cardiovascular area is catching up.”

When asked what or who feeds the conservatism, Kelly says this is a key question. “Is it the chicken or the egg? Is this because of the FDA and regulatory policy, or big pharma not wanting to take a risk? I don’t know the answer; probably some of both. However, what I do know is this can be exactly where small biotechs can take the risk and stand out,” says Kelly.

But are biotechs, who often rely on a single program for survival, really going to be the risk-takers? Kelly concedes that is a fair point, but says if you think about it, biotechs can only survive with a sound and competitive strategy for advancing their program. “If there is a risk, it is an informed risk, since you should have already spoken in depth to pharma and understand what can be done from the biotech perspective,” he says. “I think of it as an educated risk that can lead to a stronger chance of compound progression.”

Of course the best example of this is Kelly’s own program and company. “At Fibrotech, we planned out two or three trials from the very beginning, understanding the need to utilize back-up candidates. Again, one of the key things for us is understanding molecular pathways, so you can understand which patients are more likely to respond to the drug treatment, rather than the current “treat all” thinking that all the patients of chronic kidney disease are a population target. Obviously, this reduces the patient population and also improves the safety profile. It ultimately gives you the best changes of having a successful trial.”

And, as Kelly and Hamer know experientially, gives biotechs the best chances of having pharma take notice, and doing so early in the process. With death valley – the interim when early stage programs have the most trouble obtaining funding to continue in the clinic – a real problem for biotechs, and with clinical trials themselves potentially adding to the problem instead of increasing the potential for advancing programs, the “risk” seems to be in designing trials the way they have always been done in the past.

In part 2 of our interview with Darren Kelly, Ph.D., founder and CEO of Fibrotech, he will help us learn about the growing biotechnology industry in Australia, and the support models for the industry there. We’ll also hear from Michelle Gallaher, CEO, BioMelbourne Network, and others supporting research and biotechnology in Australia.