Principia Biopharma And University of California, San Francisco (UCSF) Scientists Announce Publication Of Seminal Paper On Reversible Covalent Drugs In Nature Chemical Biology
SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Principia Biopharma Inc., a private, clinical-stage biopharmaceutical company, today announced the publication of a seminal paper establishing a new category of oral small molecule drugs, which are able to form reversible covalent bonds with antibody-like specificity. The article, co-authored by scientists from Principia and UC San Francisco (UCSF) titled “Prolonged and tunable residence time using reversible covalent kinase inhibitors,” was published online Monday, May 25, 2015 and will appear in the July issue of Nature Chemical Biology.
“This represents a significant step forward for the development of treatments for chronic diseases, including inflammatory and autoimmune disorders.”
“Principia has built on the foundation of our work on reversible covalent inhibitors and created a generalizable approach to discovering and developing novel reversible covalent drugs,” said Jack Taunton, Ph.D., professor of Cellular and Molecular Pharmacology at UCSF. “The Nature Chemical Biology publication shows the promise of this approach to developing highly selective drugs with long residence time, but also low exposure.”
Traditional oral drug development has been limited to two primary methods: reversible non-covalent binding and irreversible covalent binding of a drug to its target. The paper describes a novel approach, using Principia’s Tailored Covalency™ technology, to discovering and developing reversible covalent oral small molecule drugs, including inhibitors of Bruton’s tyrosine kinase (BTK). These reversible covalent drugs are highly potent, orally administered molecules that exhibit both enhanced selectivity, similar to antibodies, and have long lasting effect.
“Prolonged inhibition of drug targets with minimal drug exposure is a long sought goal of drug discovery to minimize drug side effects. This is particularly critical for patients with diseases that require ongoing treatment but may not be able to tolerate the long-term side effects from their therapy,” said David Goldstein, Ph.D., senior vice president, Drug Discovery of Principia Biopharma. “This represents a significant step forward for the development of treatments for chronic diseases, including inflammatory and autoimmune disorders.”
In the published paper, broad applicability of Tailored Covalency technology is illustrated with two high-profile therapeutic drug targets, BTK and Fibroblast Growth Factor Receptor (FGFR). A series of highly selective reversible covalent inhibitors were created, containing doubly-activated electrophiles with a dramatic range of target residence times - from minutes to days. The extended residence time seen in vitro was also demonstrated in vivo, with BTK target occupancy achieved with an inhibitor 24 hours after oral dosing despite being rapidly cleared from circulation.
Principia’s lead product candidate utilizing Tailored Covalency technology is PRN1008, a reversible covalent BTK inhibitor, for the treatment of autoimmune and inflammatory diseases. The Company will present data from a Phase 1 clinical trial at the upcoming European League Against Rheumatism Annual Congress (EULAR) in June 2015. In addition, Principia plans to initiate a Phase 1 clinical trial with PRN1371, a covalent FGFR 1-4 inhibitor drug candidate for oncology, later this year.
About Tailored Covalency
Principia’s proprietary Tailored Covalency technology enables the formation of a covalent bond between the drug and a specific cysteine amino acid in the therapeutic target without making that bond permanent. The synergy of the reversible covalent bond coupled with the “lock and key” drug protein interactions of classical small molecule drugs imparts profound efficacy and selectivity. When the “lock and key” interactions are disrupted during the natural protein turnover and recycling process, the cysteine bond breaks, and the drug is released from the protein. This intrinsic property avoids the potential for side effects resulting from permanently modified drug-bound proteins.
While traditional drug discovery focuses on sustained drug exposure, Tailored Covalency technology optimizes on drug target inhibition and therefore should lead to lower potential side effects. This approach can be applied to numerous targets across therapeutic areas, and Principia has utilized this technology for both kinase and non-kinase targets.
About Principia Biopharma
Principia Biopharma Inc., a private, clinical-stage biopharmaceutical company, has created a revolutionary new way to design and develop oral small molecule therapies that are more potent, selective, durable and safer than currently available drugs. The Company has utilized its proprietary Tailored Covalency™ technology to develop a portfolio of drug candidates that exhibit antibody-like specificity to benefit patients with autoimmune and inflammatory diseases and cancer. Its most advanced drug candidate, PRN1008, a reversible covalent BTK inhibitor, is in Phase 1 development for the treatment of autoimmune and inflammatory diseases. The Company anticipates initiating a Phase 1 clinical trial for PRN 1371, a covalent FGFR 1-4 inhibitor drug candidate for oncology, later this year. For more information, please visit the company's website at www.principiabio.com.