Ecallantide

Hereditary Angioedema (HAE) is a rare genetic disorder characterized by recurrent episodes of localized subcutaneous and mucosal edema. Patients with HAE have reduced levels of an important protein, C1 Inhibitor (C1-INH), in their blood, or this C1-INH is nonfunctional. These forms of hereditary angioedema are distinct from allergic angioedema, which is a type of skin reaction typically associated with hives (urticaria). Hereditary Angioedema is a potentially life-threatening condition caused by a genetic defect. Hereditary Angioedema can cause painful swelling, usually occurring in the face, hands, feet, or genitals. Dangerous swelling can also occur in the airways of the lungs or the walls of the intestines. In the same episode, these symptoms can migrate from one location to another. Most attacks are unpredictable, and the triggering factors vary from person to person. Potential triggers may include stress, surgical procedures, dental work, medications, and illnesses such as the common cold. Many individuals have early warning signs of an HAE attack, such as extreme fatigue, skin tingling, hoarseness, or sudden mood changes that may herald an impending attack. Accurately diagnosing HAE can be difficult because the disease is very rare, and doctors may initially rule out more common diseases with similar symptoms. Besides physical examination and medical history, HAE can also be diagnosed by measuring the level and function of C1-INH in the blood. As early as the 19th century, scientists first described the clinical manifestations of this disorder and classified it as an autosomal dominant genetic disease. In the past 40 years, scientific research has identified the fundamental defect in hereditary angioedema as a deficiency of functional C1-INH protein and identified bradykinin as the biological mediator of the edema. In hereditary angioedema with C1-INH deficiency, the activation of the plasma contact system produces bradykinin, which exerts its biological effects through the interaction with bradykinin B2 receptor, a member of the G protein-coupled receptor family. DOI: 10.1056/NEJMra1808012The bradykinin B2 receptor is continuously expressed on endothelial cells and is thought to be primarily responsible for actively transporting fluid into local tissues, leading to vascular edema. Mechanistically, activation of the bradykinin B2 receptor leads to the disassembly of adherens junctions, which play a crucial role in limiting vascular permeability. Following the involvement of the bradykinin B2 receptors, downstream signaling results in the phosphorylation of transmembrane vascular endothelial adhesion molecules, leading to their internalization and degradation. The subsequent contraction of the actin cytoskeleton increases the size of the gaps between endothelial cells, causing vascular leakage. The figure below summarizes the first-line treatment methods for hereditary angioedema (HAE) due to C1-INH deficiency, including the blood-derived product Berinert developed by CSL Behring, approved in 1986; recombinant C1-INH developed by Pharming, approved in 2010; recombinant C1-INH by Takeda Pharmaceuticals, approved in 2008; the recombinant peptide Ecallantide, approved in 2009; the small molecule compound Icatibant, approved in 2008; and monoclonal antibody Lanadelumab, approved in 2018. DOI: 10.1056/NEJMra1808012About Pharvaris and DeucrictibantPharvaris is a clinical-stage company, leveraging its profound expertise in the field of hereditary angioedema (HAE) to develop novel oral bradykinin B2 receptor antagonists for treating and preventing HAE attacks. Pharvaris aims to provide a safe, effective, and convenient treatment option for patients with all subtypes of HAE by utilizing novel small molecules targeting this clinically validated therapeutic goal, enabling both on-demand treatment and prophylactic management of attacks. Deucrictibant is a new, potent oral small-molecule bradykinin B2 receptor antagonist, originally developed by the Pharvaris team. The company is currently developing two oral formulations with the same active ingredient - Deucrictibant (PHVS416 and PHVS719) - for on-demand treatment and prophylaxis of hereditary angioedema (HAE). PHVS416 is an experimental soft capsule formulation containing Deucrictibant. PHVS416 is designed as a convenient, compact oral dosage form that alleviates symptoms quickly and reliably through a rapid onset of action for attack relief. In a phase 2 study, PHVS416 consistently demonstrated positive effects across all endpoints and evaluations, confirming the efficacy and tolerability of PHVS416 in the treatment of HAE attacks. Currently, PHVS416 is undergoing phase 2 clinical development outside the United States for both on-demand and prophylactic concept-validation treatment of HAE. PHVS719 is an experimental sustained-release tablet containing Deucrictibant. PHVS719 is designed for the prevention of HAE attacks, with a conveniently small oral dosage form. PHVS719 is currently in Phase 1 clinical development for prophylactic treatment of HAE. In healthy volunteers, PHVS719 demonstrated good tolerability with a single dose, and its sustained-release properties support once-daily dosing.

Industry veteran with late-stage clinical development, medical affairs, and regulatory experience; well-positioned to advance losmapimod towards a potential regulatory submission and approval Interim Chief Medical Officer, Iain Fraser, MBChB, DPhil, will continue to serve on Fulcrum’s executive leadership team as senior vice president (SVP) of early development CAMBRIDGE, Mass., March 18, 2024 (GLOBE NEWSWIRE) -- Fulcrum Therapeutics, Inc.® (Fulcrum) (Nasdaq: FULC), a clinical-stage biopharmaceutical company focused on developing small molecules to improve the lives of patients with genetically defined rare diseases, today announced the appointment of Patrick Horn, M.D., Ph.D., as chief medical officer, effective immediately. Dr. Horn is a seasoned executive with over 20 years of end-to-end drug development experience spanning multiple therapeutic areas, with an emphasis on rare diseases, across both large pharmaceutical and biotech companies. Interim chief medical officer, Iain Fraser, MBChB, DPhil, will continue to serve on Fulcrum’s executive leadership team as SVP of early development. Together, Drs. Horn and Fraser will be responsible for leading clinical development and overseeing regulatory strategy and execution. “I am very pleased to enrich our leadership team with Pat, an accomplished industry veteran who has successfully guided multiple therapies—including rare disease programs lacking existing regulatory pathways—through late clinical development, regulatory approval, and commercial launch,” said Alex C. Sapir, Fulcrum’s president and chief executive officer. “This is a key moment for Fulcrum as we continue to advance our Phase 3 REACH trial of losmapimod for patients with facioscapulohumeral muscular dystrophy and reinitiate our Phase 1b PIONEER trial of pociredir in sickle cell disease. We believe both Pat and Iain’s complementary expertise will be invaluable as we near several pivotal milestones for our two key clinical programs and advance our early-stage pipeline.” Dr. Horn added, "Joining Fulcrum is an exciting opportunity to bring potentially transformative therapies to patients especially as we advance towards near-term inflection points for losmapimod, a late-stage clinical program with first-to-market potential, and pociredir, a highly differentiated oral treatment option that may shift the current standard of care. Building on the encouraging clinical data generated to date, I, alongside Iain, look forward to working with the management team to deliver on the promise of Fulcrum’s differentiated pipeline of rare disease programs.” Dr. Patrick Horn is a distinguished professional with over 20 years of experience in the field of rare disease drug development, encompassing all stages from initial research to regulatory approval and commercial launch. His most recent role was as the Chief Medical Officer at HemoShear Therapeutics, specializing in rare metabolic diseases. Previously, he held the position of Chief Medical Officer at Albireo Pharma where he led the team that achieved marketing approvals in the US and Europe for Bylvay™ in progressive familial intrahepatic cholestasis (PFIC). Before his tenure at Albireo, he served as the Senior Vice President of Medical and Clinical Development at Orphan Technologies, directing the advancement of novel treatments for homocystinuria. Prior to this, he was the Chief Medical Officer at Tetraphase Pharmaceuticals, where he oversaw the clinical development of antibiotic candidates, including the program leading to the New Drug Application for eravacycline. Before Tetraphase, Dr. Horn led the clinical program at Dyax Corp. that resulted in the approval of Kalbitor® for the treatment of hereditary angioedema. Dr. Horn received his M.D., and Ph.D., from the University of Chicago and completed his pediatric residency at Boston Children’s Hospital. Prior to transitioning to industry, Dr. Horn was a practicing pediatrician at major academic institutions in Chicago. About Fulcrum Therapeutics Fulcrum Therapeutics is a clinical-stage biopharmaceutical company focused on developing small molecules to improve the lives of patients with genetically defined rare diseases in areas of high unmet medical need. Fulcrum’s two lead programs in clinical development are losmapimod, a small molecule in development for the treatment of facioscapulohumeral muscular dystrophy (FSHD), and pociredir (formerly known as FTX-6058), a small molecule designed to increase expression of fetal hemoglobin and in development for the treatment of sickle cell disease (SCD). Fulcrum uses proprietary technology to identify drug targets that can modulate gene expression to treat the known root cause of gene mis-expression. For more information, visit and follow us on Twitter/X (@FulcrumTx) and LinkedIn. Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this press release are forward-looking statements, including express or implied statements regarding advancement of losmapimod towards regulatory submission and approval;; reinitiation of the Phase 1b trial; advancement of Fulcrum’s early-stage pipeline; Fulcrum’s ability to deliver an FDA-approved therapy for FSHD patients; and the potential for pociredir to shift the standard of care;; among others. The words “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “will,” “would” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements are based on management’s current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in, or implied by, such forward-looking statements. These risks and uncertainties include, but are not limited to, risks associated with Fulcrum’s ability to continue to advance its product candidates in clinical trials; initiating and enrolling clinical trials on the timeline expected or at all; obtaining and maintaining necessary approvals from the FDA and other regulatory authorities; replicating in clinical trials positive results found in preclinical studies and/or earlier-stage clinical trials of losmapimod, pociredir and any other product candidates; obtaining, maintaining or protecting intellectual property rights related to its product candidates; managing expenses; managing executive and employee turnover, including integrating a new CMO; and raising the substantial additional capital needed to achieve its business objectives, among others. For a discussion of other risks and uncertainties, and other important factors, any of which could cause Fulcrum’s actual results to differ from those contained in the forward-looking statements, see the “Risk Factors” section, as well as discussions of potential risks, uncertainties, and other important factors, in Fulcrum’s most recent filings with the Securities and Exchange Commission. In addition, the forward-looking statements included in this press release represent Fulcrum’s views as of the date hereof and should not be relied upon as representing Fulcrum’s views as of any date subsequent to the date hereof. Fulcrum anticipates that subsequent events and developments will cause Fulcrum’s views to change. However, while Fulcrum may elect to update these forward-looking statements at some point in the future, Fulcrum specifically disclaims any obligation to do so. Contact: Chris Calabrese LifeSci Advisors, LLC ccalabrese@lifesciadvisors.com 917-680-5608