Principia Biopharma Presents Full Phase 1 Clinical Trial Results For PRN1008, A Novel Reversible Covalent BTK Inhibitor, Supporting Further Clinical Development In Autoimmune And Inflammatory Diseases

--Phase 1 and Preclinical Data Presented at EULAR 2015--

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Principia Biopharma Inc., a private, clinical-stage biopharmaceutical company, today announced results from a Phase 1 clinical trial of PRN1008, its investigational oral, reversible covalent Bruton’s Tyrosine Kinase (BTK) inhibitor. Results showed that PRN1008 was well tolerated after single and 10-day dosing and demonstrated sustained therapeutic levels of BTK receptor occupancy following a brief period of systemic drug exposure. The data were presented at the European League Against Rheumatism Annual Congress (EULAR 2015) in Rome. Principia also presented preclinical data at the Congress demonstrating that PRN1008 had a dose-dependent therapeutic effect in an animal model of collagen-induced arthritis.

“Principia plans to continue evaluating PRN1008 in Phase 2 clinical programs for multiple autoimmune and inflammatory diseases.”

“The data from our Phase 1 trial demonstrated that PRN1008 was well tolerated, and the sustained inhibition of BTK suggests that it could have a clinical effect in patients with autoimmune and inflammatory diseases. Because therapeutic levels of BTK occupancy were achieved without sustained systemic exposure, PRN1008 also may have a therapeutic margin desirable for long-term treatment in patients with chronic diseases,” said Steve Gourlay, MBBS, FRACP, Ph.D., chief medical officer of Principia Biopharma.

“We are pleased that these Phase 1 results support continued clinical development of PRN1008,” said Martin Babler, chief executive officer of Principia Biopharma. “Principia plans to continue evaluating PRN1008 in Phase 2 clinical programs for multiple autoimmune and inflammatory diseases.”

Phase 1 Study Design and Results

The double-blind, placebo-controlled Phase 1 trial evaluated the pharmacokinetics, pharmacodynamics, BTK occupancy, and safety and tolerability of PRN1008 given orally to 80 healthy volunteers in single ascending dose (SAD) cohorts, and in multiple ascending dose (MAD) cohorts over 10 days of treatment.

Results showed a rapid effect on BTK target occupancy. Daily doses of PRN1008 of 300 mg and above reached therapeutic levels of BTK target occupancy. Full inhibition was rapidly achieved and therapeutic levels of BTK occupancy, indicative of sustained inhibition of BTK activity, were maintained over 24 hours. A reduction of basophil activation was observed within four hours of PRN1008 administration, consistent with BTK pathway inhibition in these cells.

In the study, PRN1008 was well tolerated without clinically significant changes in vital signs, ECGs or laboratory measurements across all dose groups even at supra-therapeutic doses. No serious adverse events were observed. Mild gastrointestinal adverse events were more common at higher doses of PRN1008 than with placebo. At the PRN1008 dose of 300 mg twice daily, at which therapeutic BTK occupancy was maintained well above 70 percent for 10 days, few treatment-related adverse events were reported.

Preclinical Study Design and Results

The preclinical study was conducted to characterize the biochemical properties of PRN1008, its binding to BTK, functional effects in B-cells, and in vivo efficacy in an animal model of collagen-induced arthritis.

PRN1008 is a very potent and selective BTK inhibitor when tested against a panel of 251 kinases. Cellular selectivity for BTK was demonstrated by lack of potency against a range of off-target cell-based assays. When dosed orally in rats, PRN1008 demonstrated enduring pharmacodynamic effects after it had cleared from circulation, consistent with extended target occupancy. In an animal model, PRN1008 reversed and completely suppressed collagen-induced arthritis in a dose-dependent manner.

About Bruton’s Tyrosine Kinase (BTK)

BTK is a protein important to the proper function of the immune system. It functions as a signaling element downstream of the B-cell receptor (BCR) and Fc receptors (FcRy and FcRe), which are present on multiple cell types, including osteoclasts (bone cells). Inhibition of BTK activity results in the down-regulation of various cellular activities that are activated in autoimmune and inflammatory diseases, including cell proliferation, differentiation, maturation and survival.

BTK plays a crucial role in BCR signaling during normal B-cell development and activation. Aberrant BCR signaling is associated with autoimmune diseases, including rheumatoid arthritis. BTK is also involved in the activation of other hematopoietic cells, such as mast cells, macrophages and neutrophils. These cells infiltrate the synovial cavity and produce inflammatory cytokines, which contribute to disease and aggravate arthritic symptoms. Mice that lack BTK function have decreased susceptibility to developing collagen-induced arthritis. For these reasons, BTK is an attractive therapeutic target for rheumatoid arthritis.

About PRN1008

PRN1008 is an oral, reversible covalent BTK inhibitor. This investigational, small molecule therapy acts by blocking BTK. It was designed using Principia’s proprietary Tailored Covalency™ technology to optimize its safety and efficacy profile, resulting in a prolonged and reversible action while being rapidly eliminated from the body. This approach gives PRN1008 antibody-like specificity for BTK, reversible covalent bonding, and potentially enables a safety profile suitable for the treatment of chronic diseases.

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 PRN1371, 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.