HAE

Hereditary angioedema (HAE) is a rare and potentially life-threatening genetic condition that occurs in approximately 1 in 50,000 people. HAE patients are susceptible to sudden and prolonged attacks of edema (swelling), which often occur in the hands, feet, face, gastrointestinal tract, and airway resulting in severe swelling and pain, life-threatening airway blockage, and nausea. Depending on the severity of the disease, some people will have many attacks each month, while others may go months without an attack.

Bradykinin and B2 Receptor

HAE most commonly occurs as a result of insufficient levels or function of a protein called C1 esterase inhibitor (C1-INH), a naturally occurring inhibitor of the plasma kallikrein enzyme. C1-INH deficiency enables uncontrolled plasma kallikrein activity which leads to elevated levels of bradykinin. The pharmacologically active peptide bradykinin activates the bradykinin B2 receptor, a G-protein-coupled receptor expressed in vascular endothelial cells, resulting in increased permeability of blood vessels and release of fluid into surrounding tissue (the typical edema or swelling). 

Multiple other scenarios can excessively increase bradykinin levels, including mutations of factor XIIa, plasminogen, angiopoietin 1, and kininogen1 (together referred to as HAE-nC1-INH, as C1-INH is normal in this patient group). Elevated bradykinin levels can also occur as a side effect of medications, such as ACE inhibitors, resulting in drug-induced angioedema. 

Blocking signaling at the B2 receptor has the potential to treat angioedema attacks resulting from all sources of bradykinin. A selective peptidomimetic, icatibant, inhibits bradykinin from binding the B2 receptor to treat rapidly all clinical signs and symptoms of an HAE attack. The co-founders of Pharvaris include an inventor of icatibant and the leadership from Jerini AG that developed icatibant, now sold by Takeda under the brand name Firazyr®.

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Current Therapies

Treatment of HAE consists of long-term prophylaxis, management of acute attacks, and intermittent episodic prophylaxis in advance of known triggers. Multiple therapies are available to patients, acting at different points in the enzymatic/signaling pathway. Only one approved therapy, icatibant, acts directly at the bradykinin B2 receptor to treat all types of HAE by blocking the bradykinin signal.

All current therapies, including icatibant, are limited by invasive routes of drug administration (injection or infusion), inconvenient dosing regimens, or undesired side effects. Surveys of patients with HAE overwhelmingly show that they seek additional treatment options. A first-in-class, oral small-molecule antagonist of the bradykinin B2 receptor may provide an effective and more convenient way to manage HAE and improve quality of life.

Our Approach

PHA121 is a novel small molecule with drug-like properties. In preclinical studies, PHA121 demonstrates highly potent and selective competitive antagonism of the B2 receptor, and shows rapid and potent activity on oral dosing in a bradykinin-mediated disease model.

Despite efforts by pharmaceutical and academic researchers over the last 30 years, the challenge has remained unresolved to identify orally bioavailable small-molecule B2 receptor antagonists with appropriate drug-like properties. Pharvaris identified a core binding motif for the B2 receptor with favorable physicochemical properties and optimized this core binding motif using deep structure-activity relationship analysis (SAR), in silico modeling, and mutational studies.

The core motif contains structural features that uniquely interact with B2 receptor to improve the antagonist potency of our lead series into the sub-nanomolar range, the highest potency yet disclosed for a small molecule at this target. In our preclinical work, we further optimized physicochemical properties, metabolic stability, and oral absorption yielding orally active B2 receptor antagonists with high therapeutic potential.