Pharvaris N.V. operates as a clinical-stage biopharmaceutical company. The company focuses on the development and commercialization of innovative therapies for rare diseases with significant unmet need, initially focused on angioedema and other bradykinin-mediated diseases.
The company’s first molecule, deucrictibant (PHA121, PHA-022121), is a novel, small-molecule bradykinin-B2-receptor antagonist for the treatment of hereditary angioedema, or HAE. Bradykinin-B2-receptor inhibition is a clini...
Pharvaris N.V. operates as a clinical-stage biopharmaceutical company. The company focuses on the development and commercialization of innovative therapies for rare diseases with significant unmet need, initially focused on angioedema and other bradykinin-mediated diseases.
The company’s first molecule, deucrictibant (PHA121, PHA-022121), is a novel, small-molecule bradykinin-B2-receptor antagonist for the treatment of hereditary angioedema, or HAE. Bradykinin-B2-receptor inhibition is a clinically validated mechanism for the treatment of HAE, as demonstrated by icatibant, which is a bradykinin-B2-receptor antagonist approved in Europe in 2008 and in the United States in 2011 (as FIRAZYR). PHA121 demonstrated over 4000-fold selectivity for the bradykinin-B2-receptor when compared to approximately 170 other molecular targets, including the bradykinin-B1-receptor. The company designed deucrictibant to improve upon the therapeutic profile of existing therapies and, through oral delivery, to provide patients with quality of life and ease-of-administration that is superior to standard-of-care HAE treatments, which are injectables.. The company’s product candidates may address a broader range of angioedema attacks than other available treatments since deucrictibant blocks the actual signal that leads to angioedema (the interaction of bradykinin, or BK with the bradykinin-B2-receptor), rather than an upstream signal.
The company has successfully demonstrated proof-of-concept through a clinical pharmacodynamics, or PD assessment with the bradykinin challenge, which had been utilized as a validated surrogate assessment for dose selection in the icatibant development program.
The company has demonstrated clinical efficacy and tolerability in a Phase 2 study (RAPIDe-1) treating attacks of HAE. The data allowed the company to compare the projected therapeutic performance of deucrictibant with that of icatibant. The company plans to efficiently progress deucrictibant through clinical development for on-demand and prophylactic use with its on-demand immediate-release product candidate, PHVS416, and prophylactic extended-release product candidate, PHVS719, respectively. The company commenced its RAPIDe-1 Phase 2 clinical trial of PHVS416 in February 2021 and reported topline Phase 2 data for the acute treatment of patients with HAE attacks in December 2022. The company has also demonstrated clinical efficacy and tolerability in a Phase 2 study (CHAPTER-1) for prophylaxis of HAE attacks. The company commenced the CHAPTER-1 Phase 2 clinical trial for prophylaxis in 2021 using twice-daily dosing of the PHVS416 soft capsules and announced positive topline data in December 2023. The company’s primary objective with this trial was to assess the efficacy and safety profile of PHVS416 dose regimens for prophylactic treatments in HAE patients. In February 2022, the company reported Phase 1 clinical data with PHVS719 demonstrating pharmacokinetics of the extended-release formulation and the potential for once-daily dosing. In healthy volunteers, a single dose of PHVS719 was well tolerated with an extended-release profile supporting once-daily dosing. PHVS719 is a prophylactic extended-release tablet designed to be taken in small, daily doses.
Deucrictibant (PHA121, PHA-022121) is a novel, highly potent inhibitor and selective small molecule bradykinin-B2-receptor antagonist and, to the company’s knowledge, the only orally available bradykinin-B2-receptor antagonist in development. Deucrictibant has been observed to be a potent inhibitor in vitro as assessed using human recombinant bradykinin-B2-receptors (150 pM); ex vivo as studied against endogenous bradykinin-B2-receptors in a human umbilical vein model (350 pM); and in vivo in the human bradykinin-challenge model (170 pM). The company designed deucrictibant as a new chemotype with properties compatible with oral delivery. The company is developing deucrictibant for the on-demand indication as PHVS416, which is delivered in a softgel capsule designed to rapidly treat symptoms with a single dose. The company is also developing deucrictibant for the prophylactic indication as PHVS719, which is a small daily dose tablet with an extended-release formulation designed for the patient to maintain therapeutic levels for at least 24 hours and to achieve a steady-state plasma concentration within 72 hours. The company has released topline data from its RAPIDe-1 study demonstrating efficacy and tolerability in its Phase 2 clinical trial for the treatment of HAE attacks on demand using PHVS416 and topline data from its CHAPTER-1 study demonstrating efficacy and tolerability of deucrictibant for the prophylactic treatment of HAE attacks. CHAPTER-1 used twice daily dosing of PhVS416 for proof-of-concept. The company intends to use PHVS719 extended-release deucrictibant in further trials and commercially for prophylaxis.
In its Phase 2 placebo-controlled trial evaluating the efficacy and tolerability of PHVS416 for on-demand treatment of attacks in patients with HAE type 1 and 2 (RAPIDe-1), a statistically significant and clinical meaningful reduction of the patient-reported symptoms of HAE was observed for the attacks treated with all doses of PHVS416 (10, 20, 30 mg) compared to placebo-treated attacks. The study’s primary endpoint—symptom relief at four hours after treatment with study drug—as well as all key secondary efficacy endpoints were met. Consistently with its pharmacokinetic profile, PHVS416 demonstrated rapid onset of action, symptom relief, and resolution of the manifestations of HAE attacks as well as sustained clinical effects, with consistent findings across outcome measures. In addition, PHVS416 substantially reduced the use of rescue medication compared to the placebo. PHVS416 was generally well tolerated at all dose levels with three treatment-related adverse events (TRAEs) reported for one PHVS416 30-mg-treated attack (2.8%) and one TRAE reported for one placebo-treated attack (1.9%); there were no treatment-related serious adverse events (SAEs), no treatment-related adverse events (AEs) of severe severity, and no AEs leading to treatment discontinuation.
In August 2022, the FDA placed a hold on the clinical trials of deucrictibant in the U.S. based on its review of nonclinical data. The FDA requested that the company conduct an additional long-term rodent toxicology study and update the Investigator’s Brochure. The company participated in a Type A meeting with the FDA to discuss paths to address the on-demand and prophylactic holds and aligned on a protocol for a 26-week rodent toxicology study. Following review of data from a preplanned interim analysis of the ongoing 26-week nonclinical rodent study, the FDA lifted the clinical hold on the IND application for deucrictibant for the on-demand treatment of HAE in June 2023. In January 2024, the FDA lifted the clinical hold on the IND application for deucrictibant for the prophylactic treatment of HAE attacks following review of the full data set from the completed 26-week rodent toxicology study.
The company plans to develop separate products for on-demand and prophylactic use, PHVS416 and PHVS719 respectively, with both products utilizing the same active ingredient, deucrictibant. PHVS416 will be a softgel capsule, and PHVS719 will be an extended-release tablet.
Strategy
The key elements of the company’s strategy are to continue to advance deucrictibant through clinical development for on-demand treatment of HAE utilizing a fast-onset formulation, known as PHVS416; advance the development of deucrictibant for prophylactic treatment of HAE utilizing an extended-release formulation, known as PHVS719; expand the range of bradykinin-mediated angioedema indications to which PHVS416 and PHVS719 can be applied; expand upon our expertise in the bradykinin-B2-receptor pathway; and commercialize its product candidates.
Intellectual Property
As of March 1, 2024, the company owned three U.S. patents, one European patent and 82 national/regional patents, including in Australia, India, Indonesia, Japan, Mexico, South Korea, France, Germany, Italy, Netherlands, Spain and United Kingdom, that expire on November 23, 2038 or later, and 62 pending patent applications worldwide, including five pending U.S. applications, 57 pending non-U.S. applications, including applications in Europe and Japan, and three pending PCT applications. The U.S. and national/regional patents and 23 of the company’s pending patent applications contain composition-of-matter claims to the deucrictibant small molecule and derivatives thereof; deucrictibant is the active pharmaceutical ingredient (API) in, and therefore extends its patent applications to, its PHVS416 and PHVS719 product candidates. Each such patent application can generally be categorized into one of three patent families: those relating to the novel bradykinin-B2-receptor antagonists, those relating to the cyclic bradykinin-B2-receptor antagonists, and those relating to the new cyclic bradykinin-B2-receptor antagonists. 11 of its pending applications contain claims directed to the use of deucrictibant in on- demand treatment of HAE and in prophylaxis for HAE, and accordingly extend the patent applications to methods of use of the PHVS416 and PHVS719 product candidates. The granted European patent and 22 of the company’s pending patent applications contain claims directed to the formulation of its PHVS416 product candidate. Two of the company’s applications that are pending in the U.S. and Europe contain claims directed to the crystal form of the API. Three pending international (PCT) applications and one pending national application are directly or indirectly directed to the formulation of the company’s PHVS719 product candidate and its use in chronic or prophylactic treatment of HAE.
License Agreement
On March 31, 2016, the company entered into a license agreement (the AnalytiCon License), and a research agreement with AnalytiCon to collaborate for the development of an orally available bradykinin-B2-receptor antagonist. Pursuant to the AnalytiCon License, the company acquired a worldwide, exclusive license from AnalytiCon to use a certain proprietary substance class of bradykinin-B2-receptor antagonists with the potential of oral activity (OB2RA), and any derivatives, improvements, analogs, isomers, metabolites, or conjugates therefrom (together, the OB2RA Class), in each case, for the purpose of developing, manufacturing and marketing compounds on a global basis from the OB2RA Class for the treatment of, among others, hereditary angioedema. Certain rights associated with deucrictibant, PHVS416 and PHVS719 are subject to the AnalytiCon License.
Sales and Marketing
The company has experience in developing and commercializing drug products for rare diseases, including HAE specifically. The company intends to develop a fully integrated sales and marketing organization ahead of marketing approval for PHVS416 or PHVS719.
Research and Development
The company’s research and development expenses included €65.6 million for the year ended December 31, 2023.
Government Regulation
Among others, the FDA, the EMA and the national Competent Authorities of each Member State of the European Union are the key regulatory agencies that exercise oversight over all aspects of the company's products. In the United States, the company's activities are potentially subject to regulation by various federal, state and local authorities in addition to the U.S. Food and Drug Administration (FDA), including but not limited to, the Centers for Medicare and Medicaid Services, or CMS, other divisions of the U.S. Department of Health and Human Services (e.g., the Office of Inspector General), the U.S. Department of Justice, or DOJ, and individual U.S. Attorney offices within the DOJ, and state and local governments.
In addition to the foregoing, state and federal laws regarding environmental protection and hazardous substances, including the Occupational Safety and Health Act, the Resource Conservancy and Recovery Act and the Toxic Substances Control Act, affect the company's business. These and other laws govern the company's use, handling and disposal of various biological, chemical and radioactive substances used in, and wastes generated by, the company's operations.
History
Pharvaris N.V. was founded in 2015. The company was incorporated in 2015.