Dori Thomas-Karyat, PhD, founder and CEO of Synthis Therapeutics, and her fellow investigators are an XSeed Award finalist team for their development of SYN301, a novel drug candidate for idiopathic pulmonary fibrosis (IPF). This progressive lung scarring disease has limited therapeutic options. The compound shows promise in preclinical studies for blocking and potentially reversing the progression of this disease.
The XSeed Award provides critical funding to translate scientific discoveries into commercially successful drug therapies. The 2024 XSeed awards will provide two winning teams up to $250,000 for New York City minority- and women-led life science and healthcare startups working on novel drug development projects. The winners will be announced in September 2024.
This conversation has been edited for length and clarity.
Cure: What is idiopathic pulmonary fibrosis and how common is it?
Dori Thomas-Karyat: Idiopathic pulmonary fibrosis causes a buildup of fibrotic tissue in the lungs, causing them to stiffen. As the disease progresses, oxygen exchange does not occur efficiently. Patients present with a persistent cough and have a very difficult time breathing. Once it starts, there's really no stopping it. About 150,000 people are diagnosed with IPF in the United States every year. The average life expectancy after diagnosis is only about five years.
Cure: How is IPF currently treated?
Thomas-Karyat: Nintedanib and pirfenidone were both approved in 2014 by the FDA for the treatment of patients with IPF. They are designed to slow down the rate of lung scarring. However, they are highly toxic, with side effects that lead to a drug discontinuation rate of 40 to 50 percent for patients who take these medications.. The only real cure for IPF is lung transplantation, but that is not an option for everyone.
What we really need are drugs that stop the disease and, ideally, reverse it. That is our goal.
Cure: What is the new compound you have developed and how does it work?
Thomas-Karyat: SYN301 is a targeted antibody-drug conjugate that inhibits a signaling pathway called transforming growth factor-beta (TGF-beta). Existing TGF-beta inhibitors are systemic, meaning they block TGF-beta everywhere. But TGF-beta has fundamental roles to keep your tissues in balance. Blocking TGF-beta everywhere is both unnecessary and ineffective. Simply put,, if you block it everywhere, the treatment becomes very toxic and can actually destroy the heart.
TGF-beta is a dominant factor in driving the IPF disease process. It binds to a protein called the ALK5 receptor to turn on the gene responses that drive fibrosis. TGF-beta levels are upregulated within lung lesions of people with IPF. We designed SYN301, a selective TGF-beta inhibitor, as an antibody-drug conjugate. Its antibody binds to a target on fibroblasts (the lung cells affected by IPF) to deliver a drug payload that selectively blocks TGF-beta signaling in the fibroblasts. Because our drug candidate -localizes to the lung, we believe SYN301 will have a better safety profile and be more effective against IPF than existing medications.
Cure: What has your laboratory research demonstrated so far?
Thomas-Karyat: We constructed the antibody-drug conjugate, which consists of an antibody plus a linker and a TGF-beta inhibitor payload. We've shown in mouse models that SYN301 effectively and safely binds to its target and selectively blocks TGF-beta signaling in vitro. We recently began evaluating SYN301 in a widely used mouse model of lung fibrosis, and we should have the initial results of those studies in early fall 2024. Our goal is to block collagen and fibronectin deposition, so we'll be looking for evidence of that.
Cure: If SYN301 turns out to be a successful and effective medication, what would that mean for patients?
Thomas-Karyat: I think it would be game changing because we've never had a targeted TGF-beta inhibitor like this before. It offers brand new and safer opportunities for IPF treatment. The clinicians we've spoken with so far are telling us it could change everything for their patients. Our work might also be relevant to other fibrotic diseases, such as scleroderma and myelofibrosis, which arise through similar mechanisms.
Cure: If you win the XSeed Award, what would that mean for this project?
Thomas-Karyat: Winning an XSeed Award would be a validation of everything we've been doing. It would provide funds for the next stages of our research, and increase our network so more people can learn about our work. Being a small biotech company in New York, it can be -challenging to stand out amongst the crowd. People tell me I should move to Boston, but we’re in New York for a reason. So, winning an XSeed Award would be very beneficial.
Cure: Who is on your team?
Thomas-Karyat: My team includes Robert Lutz, PhD, Chief Development Officer for Synthis; Glenn Crater, MD, a consulting pulmonary specialist; John McPherson, PhD, a member of our scientific advisory board; and Synthis scientist Doug Burtrum.