BTK and Immunology

Bruton tyrosine kinase (BTK) is involved in both our innate and adaptive immune responses and is a critical signaling molecule in immune-mediated diseases.

Designing drug candidates to treat immune-mediated diseases using Tailored Covalency is best illustrated by our clinical-stage BTK inhibitor pipeline.

BTK is present in the signaling pathways of key cells types of the immune system. Our drug candidates inhibit BTK signaling inside these cells resulting in blockade and down-regulation of several cellular activities key to immune-mediated diseases. The inhibition of BTK rapidly blocks inflammatory immune cells and the destructive signaling associated with autoantibodies, and results in swift blockade of inflammation and tissue destruction. Furthermore, BTK inhibition modifies a key driver of many immune-mediated diseases by preventing new autoantibody production.

We believe this optimizing inhibition of BTK leads to a better risk benefit profile for patients with immune-mediated diseases. With tailored BTK inhibition able to address multiple underlying drivers of immune disorders, our drug candidates were designed for targeted, reversible and refined immune modulation compared to other current treatments of these diseases. Our oral drug candidates should avoid the long-term impact of broad, irreversible immunosuppression (like B cell depletion) as well as the inconvenience of injectable therapies and the potential for infusion reactions.

hexagons

Our portfolio includes three BTK inhibitors that are specifically designed for the types of diseases they are targeted to treat.

We designed rilzabrutinib (formerly known as PRN1008), an oral reversible covalent molecule, for chronic diseases (such as ITP, pemphigus and IgG4-RD) that is optimized for efficacy and safety by delivering high target bonding with low systemic exposure/limited immunosuppression. The company has commenced the clinical development of PRN473 Topical, another reversible covalent BTK inhibitor. Given the abundance of immune cells in skin and their role in immune-mediated diseases, PRN473 Topical is well suited for localized applications. To reach immune cells in the central nervous system (CNS), we created PRN2246 to cross the blood-brain barrier in relatively low doses and with high potency. Our Tailored Covalency platform enables us to purpose-design drug candidates for the specific needs of different immune-mediated diseases. Each of the three molecules were discovered by Principia and each have separate intellectual property estates.

B cells are essential to a healthy immune system

Immune-mediated diseases are characterized by a focused attack by the immune system on a particular organ resulting in significant damage to that organ. A key factor in this destructive process is the B cell, one of several connections in the immune system’s complex network. In preclinical models, autoreactive B cells depend on BTK signaling for survival and autoantibody production. In generating autoantibodies, the human immune system attacks its own body, generating antibodies against its own organs. Because BTK is a key part of the body’s natural B cell control mechanism, researchers have sought ways to inhibit BTK’s function in order to control the impact of B cells, autoantibodies and the resultant organ damage.

The graphic below illustrates several areas where there is scientific rationale and/or clinical data to support the development of BTK inhibitors as a therapeutic modality. The indications shown in blue represent potential areas where we may choose to further develop our BTK franchise. Rheumatology is an area of opportunity; we could internally develop smaller indications, while we would need to partner for larger indications. The indications shown in red represent areas currently well-served by marketed BTK inhibitors.
BTK_Franchise_Tree

Tailoring Performance for Big Impact