Q&A With JP Clancy, VP of Clinical Research at the CF Foundation
Last year, the foundation put a total of $218.1 million toward research and spent $80 million on its Path to a Cure initiative, which focuses on funding efforts centered on repairing and restoring the cystic fibrosis transmembrane conductance regulator (CFTR) protein, or fixing or replacing the faulty CFTR gene, all strategies that address the underlying cause of the disease.
Including other therapeutic categories such as mucociliary clearance, anti-inflammation, anti-infection and nutritional-gastrointestinal, the CF Foundation is backing 38 treatments in the drug development pipeline.
Some of the companies it’s supporting include Arcturus Therapeutics, in preclinical stages for a therapy based on messenger RNA (mRNA, the intermediate molecule between DNA and proteins); 4D Molecular Therapeutics, working on gene therapy delivered in an adeno-associated virus vector (AAV); and Spirovant, with both an AAV- and lentivirus-delivered gene therapy platform, also in preclinical development. The foundation has previously supported Translate Bio, which is developing improved mRNA technology.
JP Clancy, MD, vice president of clinical research, who also is in charge of scientist training programs and leads a working group on racial disparities in CF, said what excites him most about the future of CF research is fixing the genetic mutation that leads to the disease at the source.
“We want to cure CF,” Clancy said. “A cure in our minds typically means that there’s a genetic cure for CF; you no longer have to take a pill to make your CFTR [protein] work better.”
Cystic Fibrosis News Today spoke with Clancy about the progress the foundation is making on its Path to a Cure initiative, the science it is funding, and hope for the future of CF treatments.
Cystic Fibrosis News Today: Can you tell readers about what you do day to day as the vice president of clinical research?
JP Clancy: I oversee a lot of the clinical research that is conducted or sort of funded by the CF Foundation. And so that captures a lot of the activity that happens in the TDN — that’s the therapeutic development network, the big network of 91 centers that does collaborative research. I helped to oversee those grants that come into the CF Foundation from investigators, people from academic institutions who want to conduct either single-site research or multicenter research. I also intersect a fair amount with industry in the sense that those companies are trying to develop new CF therapies.
I help oversee physician and scientist training programs — really trying to make sure that we have a robust pipeline of people who want to do research, but also people who want to provide healthcare. We actually see that the CF population is going to grow. Because of that, we think there’s going to be a need for healthcare providers.
The CF Foundation has leaned in quite a bit on racial justice efforts. One of my activities is to help lead the externally facing working group. It’s in the very early days, but we’re working with members of the CF healthcare and research communities who have expertise in health disparities. Plus, we’re currently working with the Black CF community to really improve their outcomes and their experience related to having CF.
CFNT: What research are you most excited about funding?
Clancy: I’m really very enthusiastic about that work going forward, just because we’ve invested very heavily in a number of different strategies to try to make CFTR [gene] available for everybody. The Path to a Cure work really is focused on sort of three general groups. One is more and better modulators. And we are certainly working with companies to continue to expand the availability of modulators, both more choices, but also to more people based on their mutations.
Two is really trying to restore CFTR, when none is present. It turns out that certain mutations get in the way of the actual biosynthesis of the CFTR protein. A good example of that is nonsense-mediated CF, or stop mutations; when those premature stop signals are in the gene, they basically lead to almost no protein. And so you have to be able to sort of help the cell machinery read past that false stop sign.
The third is really around genetic therapies. And that term can cover a lot of territory. But that includes potentially providing people with a normal copy of the working CFTR gene that is a transient thing that lasts for the life of the cell. That would be, for example, where you give someone a CFTR gene that would actually go and integrate within the person’s own chromosomes, therefore, you’d have long-lasting CFTR.
The ultimate thing would be genetic editing, where you actually use molecular scissors to cut out the mistaken part of the gene and replace it with the correct part of the gene.
So, it’s a long way of saying that I’m excited about all my territory, but Path to a Cure is where I’m most excited for the next 10 years.
CFNT: So, as far as gene therapy, are you funding mainly one project that’s looking into that? Or are there a couple that you’re funding?
Clancy: Being able to give people a working CFTR gene via mRNA by a form that they would breathe in is actually in clinical trials. And we envision at least a couple more companies bringing clinical trials within 2022. So that’s really moving quickly. And from my perspective, I’m excited about that, because I see that as a near-term possibility to get CFTR to a lot of people with CF. I’m also excited about some viral-based gene transfer strategies that are based on a virus called adeno-associated virus, or AAV. But what you can do is tell that AAV which cells to go to and that’s what makes it kind of exciting.
CFNT: A lot of organizations are embracing the venture philanthropy model where they invest early on and then is able to reinvest that money. So is that something that the CF Foundation does with some of the other companies it funds?
Clancy: Yeah, very much. Arguably, I think we may have been, if not the first, one of the first to use that model. In general, the idea is if we really want to attract industry into something like a rare disease and try to provide some funds early, that would help de-risk them getting into the field. And I think a really good example of that is the compounds that ultimately were developed by Vertex. The CF Foundation really provided a lot of seed money back in the late 1990s. The original company was called Aurora, but then it was purchased by Vertex. The idea was to entice them to develop drugs that were relevant to CF patients.
CFNT: What types of therapies are patients telling you they are most interested in, and how are you pursuing those needs?
Clancy: We did do a very big survey in late 2017. The thing that sort of jumped out at that time was infection. People were, by and large, concerned about infection. We know that people with CF often will have chronic infections and they’re hard to manage. Honestly, they’re almost impossible to cure, but we know we can manage them. But it’s often very hard to get rid of them. And so people could use lots of different antibiotics for long periods of time. And as you might guess, that also can create problems with resistance. So that whole sort of principle led to what was called our Infection Research Initiative.
CFNT: What about phage therapy?
Clancy: We are funding a study currently by a company called Armata. I think it’s the first controlled study of phage (NCT04596319), which we think is really exciting, starting with adults with CF who have Pseudomonas, a type of infection that’s pretty common in the adult community, and that is truly enrolling as we speak.
We’re also funding another program that’s being conducted at Yale University, which has been a leader of the phage field. That’s an investigator-initiated approach. Then, we have at least two to three other companies who we are talking with about potentially funding their phage research progress.
So stay tuned. We’ve definitely got started, but we have more to go and we have a lot of people interested. Obviously, this is exciting because it may offer a very precise way to treat infections for people with CF and other diseases.