Hereditary angioedema (HAE) is a rare and potentially life-threatening genetic disease that occurs in approximately 1 in 10,000 to 1 in 50,000 people, according to HAEi.
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, nausea and may be life-threatening in case of airway blockage.
Depending on the severity of the disease, some people will have many attacks each month, while others may go months without an attack.
treatment of HAE consists of
- Long-term prophylaxis
- Management of acute attacks
- Intermittent episodic prophylaxis in advance of known triggers
Multiple therapies are available, acting at different points in the bradykinin-forming cascade. Only one approved therapy, icatibant, acts directly at the bradykinin B2 receptor to treat all types of HAE by inhibiting bradykinin interaction with its bradykinin B2 receptor target, and hence by putting a halt to bradykinin-mediated signaling.
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.
the bradykinin-B2 Receptor interaction causes angioedema
therapeutic focus: PHA121 in hereditary angioedema (HAE)
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 resulting in localized swelling and pain.
PHA121 by inhibiting bradykinin signaling through the bradykinin B2 receptor, has the potential to treat all clinical signs of an HAE attack and also to prevent the occurrence of attacks.
In preclinical studies, PHA121 demonstrated highly potent and selective competitive antagonism of the B2 receptor and, in clinical studies, PHA121 has shown rapid and potent activity at multiple oral doses in a bradykinin-mediated challenge model. PHA121 has been observed to be safe and well-tolerated at the doses studied to date.
We recognize the need for acute fast-onset treatment and preventive treatment—whether long term or intermittent – which we aim to address through optimized formulations, PHVS416 and PHVS719.
PHA121, the chemical entity in both PHVS416 and PHVS719, is the only oral B2-receptor antagonist compound currently in clinical development. We aim to optimally formulate the compound to ensure fast onset of activity in acute treatments, and prolonged efficacy in preventive treatment.