CAMBRIDGE, Mass.—Opening the door to a different school of thought in treating autoimmune disease, cancer and fibrosis, biotech prodigy Scholar Rock has gone against the grain in discovering and developing “niche modulators” that actually target growth factor activation in the disease microenvironment—and it has paid off.
Scholar Rock shed light on its novel theory July 14 with its presentation of preclinical data at the Federation of American Societies for Experimental Biology conference in Snowmass, Colo., demonstrating the effective targeting of the latent complex of transforming growth factor β1 (TGFβ1)—the most-studied family member of the TGFβ superfamily of proteins.
“We believe that the data Scholar Rock reported at this meeting represented the first demonstration of targeting and modulating the latent form of TGFβ1,” Nagesh Mahanthappa, Scholar Rock president and CEO, stated in a news release. “This opens the door to a whole new approach to addressing a wide variety of diseases by modulating the latent forms of TGFβ1 and other drug targets in this superfamily of growth factors.
“We rapidly expanded our niche modulator discovery and development platform across a number of different TGFβ superfamily members, and the positive preclinical results on these targets are leading us toward selection of our first development candidate that we expect to announce in the coming months,” he said.
In its preclinical study and presentation, Scholar Rock reported for the first time that TGFβ1’s primary form, an inactive latent complex, can be targeted and modulated as a therapeutic approach, which is distinct from the traditional drug development approach of solely inhibiting the active form of TGFβ1, Mahanthappa says.
Traditional therapeutic approaches “directly target a growth factor everywhere in the body, thus shutting down its harmful function in disease, but also causing undesirable side effects on normal body functions that depend on the same growth factor,” Mahanthappa tells DDNews.
Scholar Rock’s therapeutics “are designed to target activation of latent growth factors located in the microenvironment of specific types of cells and tissues,” he says. “In this way, for the first time our niche modulators are able to result in highly specific therapeutic effects at the site of disease.”
TGFβ1 is a key growth factor in a wide number of physiological processes, and dysregulation of its activity underlies a number of diseases, he notes. The ability to modulate the latent form of TGFβ1 offers an important new way to treat autoimmune disease, cancer and fibrosis, and it may be generalizable to modulating activation of members of the TGFβ superfamily and other growth factor families for therapeutic applications.
“TGFβ1 is known to control many biological processes, including roles in immune homeostasis and tissue remodeling,” Mahanthappa explains. “TGFβ1 is produced by white blood cells and controls proliferation, differentiation and function of immune cells.”
Genetic deletion of TGFβ1 “causes severe inflammation, and mice deficient in TGFβ1 succumb to multi-organ failure by four weeks of age,” he adds. “In contrast, uncontrolled TGFβ1 activity has been attributed to fibrotic diseases.”
“The purpose of presenting [in Colorado] was to share our findings with our scientific colleagues and to receive their feedback, which was very positive,” Mahanthappa says. “There was general enthusiasm for the new findings and appreciation for the therapeutic potential.”
“We’re not yet at a point to provide a case study for how a niche modulator can change the way patients are treated with a specific disease,” Mahanthappa acknowledges. “The latent complex is relevant for multiple members of the TGFβ1 superfamily—not only TGFβ1—so that these growth factors are involved in many different diseases.”
Scholar Rock’s approach “should yield therapies with much greater selectivity of action (which relates to fewer unintended side effects for a drug’s safety), potentially greater potency (thus needing less drug and hence better tolerability) and also potentially greater duration of therapeutic effect (which would imply less frequent dosing),” he says. “This stands in contrast to traditional approaches for drugs that target TGFβ growth factors that tend to be less selective, which can result in therapeutic shortcomings.”
“We are designating our first drug candidate this year to enter clinical trials, and plan to file an IND application with the FDA by the end of 2016,” Mahanthappa notes. “At the same time, we will continue to expand our platform and bring additional product candidates forward in our earlier R&D pipeline.”
“We are currently focused on fibrotic diseases and musculoskeletal diseases,” he says. “In these therapeutic areas there are a number of diseases for which current therapies are either inadequate or nonexistent. Scholar Rock intends to advance the development of drugs for significant diseases in these areas such as fibrosis of lung, liver and kidney, as well as muscle-wasting and muscle atrophy disorders.
“Cancer is not the near-term focus,” he adds.