PHA121 (PHA-022121), Pharvaris‘ oral therapy for hereditary angioedema (HAE), outperformed Firazyr (icatibant acetate) — an approved therapy with a similar mechanism of action — in a small study of healthy volunteers, the company announced in a press release.
That finding was presented in a poster, “Bradykinin Challenge Provides Surrogate Endpoints For Hereditary Angioedema Treatment Using Bradykinin-B2-Receptor Antagonists,” at the virtual American College of Asthma, Allergy and Immunology (ACAAI) Annual Scientific Meeting.
HAE is a disorder characterized by the excess production of the inflammatory molecule bradykinin, which causes blood vessels to dilate (widen) and fluid to accumulate in tissues. This brings about sudden and frequent bouts of swelling, the hallmark of the disease.
Firazyr, marketed by Takeda, is an approved, on-demand medicine administered by subcutaneous (under-the-skin) injection to ease these painful and potentially severe swelling attacks. It works by blocking the bradykinin B2 receptors so bradykinin can no longer cause inflammation. However, in some patients, the effect lasts for only six hours.
Pharvaris is developing PHA121 as an oral-based alternative treatment option to Firazyr.
In an earlier study, the company demonstrated that PHA121 is as effective as Firazyr at reversing bradykinin-induced changes in monkeys. The proof-of-concept, non-human primate model was created via multiple bradykinin injections — a procedure called a bradykinin-challenge — to mimic the changes in blood pressure that cause attacks in patients.
In the recent study, researchers conducted a similar bradykinin-challenge in 16 healthy volunteers, who were given six bradykinin injections over 24 hours to induce changes in blood pressure and heart rate.
After the first bradykinin dose, participants received PHA121 (12 and 22 mg) or placebo, and then were further challenged with bradykinin after one, four, eight, 12, and 24 hours. Blood samples were withdrawn to measure concentrations of PHA121 over time.
Bradykinin triggered an immediate reduction in blood pressure that was dampened following PHA121 treatment.
Using statistical models to evaluate blood test results, the effective treatment duration from both doses of PHA121 exceeded the published duration of subcutaneous Firazyr (30 mg). The duration of 22 mg PHA121 in the blood lasted approximately twice as long as Firazyr.
To achieve the concentration in blood that produces 50% of the maximum effect (EC50), PHA121 was approximately fourfold more potent than Firazyr.
When corrected for the molecular weight and blood protein binding levels, the estimated blood PHA121 concentration needed to block bradykinin B2 receptors by 50% (IC50) was 170 picomolar (pM), and for Firazyr, 4,100 pM. Thus, 24 times less PHA121 was required to achieve the same result as Firazyr.
“When we scale the observed clinical potencies in this human bradykinin challenge by the molecular weight and plasma protein binding for PHA121 and [Firazyr], we find that PHA121 is 24-fold more potent than icatibant on a molar basis, consistent with our preclinical in vitro and ex vivo measurements,” said Jochen Knolle, PhD, chief scientific officer of Pharvaris.
“This agreement between clinical and preclinical studies gives us confidence in the models and approach that Pharvaris has used in developing PHA121,” Knolle added.
Poster lead author and professor Hartmut Derendorf, PhD, at the University of Florida College of Pharmacy, said the “data show that the BK [bradykinin]-challenge test, which was used intensively in the dose-finding of [Firazyr], allows an estimation of the therapeutically relevant target concentrations of PHA121.
“[Firazyr] has good efficacy; however, for some attacks, the effect dissipates after six hours,” he added. “The investigated doses of PHA121 provide equivalent BK-antagonism for a longer time than the currently approved dose of [Firazyr], which is therapeutically relevant given the previous use of the BK challenge to predict therapeutic outcome.”
A second poster presented at the same meeting, “PHA-022121, a Selective Bradykinin-B2-Receptor Antagonist, Is Safe and Shows Rapid Oral Bioavailability in Humans,” described data that assessed the new therapy’s safety, pharmacokinetics (PK), and pharmacodynamic (PD) properties — how it behaves and how it affects the body, respectively — up to 72 hours after dosing.
This study included 48 healthy participants, given single increasing doses of PHA121 or placebo. Under fasting conditions, PHA121 was very rapidly absorbed and reached peak blood concentration within 30 to 60 minutes after dosing in all subjects.
With or without food, PHA121 levels reached the therapeutic threshold within 15 minutes and were sustained for about 12 hours after 12 and 22 mg.
All doses tested were well-tolerated, with a total incidence of adverse events (AEs, or side effects) similar in both PHA121 (23%) and placebo groups (31%). All adverse events were mild and resolved rapidly.
“PHA121 is an oral bradykinin-B2-receptor antagonist that is rapidly absorbed with dose-proportional pharmacokinetics, and has been well-tolerated in studies to date,” said Peng Lu, MD, PhD, chief medical officer of Pharvaris. “The PK/PD profile suggests that rapid onset of action and prolonged efficacy with a single dose of PHA121 can be expected in the treatment of acute HAE attacks.”
Pharvaris is planning a Phase 2 clinical trial (NCT04618211) to evaluate PHA121 as an on-demand treatment for HAE acute attacks in adult patients who experienced at least three attacks in the last four months. The trial will recruit about 56 participants who will self-administer PHA121 or a placebo at home to treat three of their attacks.
The company also is formulating PHA121 in soft capsules (PHVS416) to provide a rapid and convenient on-demand HAE treatment using a small oral dosage.
“Pharvaris is preparing to initiate an on-demand study of PHVS416, a soft capsule formulation of PHA121, for the treatment of HAE attacks in 2021,” added Lu.
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