By President and CEO Anthony J. Castaldo, HAEi

The global HAE community has achieved something unprecedented for an ultra-rare condition: regulatory approval of eight different treatments. Remarkably, the pace of development for next-generation HAE medicines is nothing short of extraordinary. There is a very good reason why HAE continues to attract significant interest in new treatments. Our community has always understood that achieving a better quality of life for ourselves, our children, and grandchildren starts with participating in clinical trials. 

Before going into details regarding each potential new medicine, we must first acknowledge that far too many of our Member Organizations do not have adequate access to and reimbursement for HAE medicines that have already been approved. Therefore, it is important to emphasize that HAEi’s primary goal (as reflected in our programs, training initiatives, and services) is to provide Member Organizations with the tools necessary to win access to the modern treatments that are already available. Our kind, compassionate, and knowledgeable Regional Patient Advocates are the “boots on the ground” forces ready to apply their expertise and bring the full range of HAEi’s resources to help Member Organizations organize and implement successful advocacy efforts.  

At the same time, however, it is also sensible, and in our community’s best long-term interests, to encourage investment in next-generation treatments by continuing to enroll in clinical trials.

Right now, nine companies are developing new HAE therapies. In all, there are thirteen treatments at various stages of clinical development that include:

  • Five orally administered preparations – two for treating attacks and three for preventing HAE swelling,
  • Two new monoclonal antibodies to be injected subcutaneously,
  • A medicine for subcutaneous injection that has been developed using messenger RNA technology, and 
  • Five prospective gene therapies. 

Before we get started with the details, I want to make it very clear that all of the information presented today has been derived solely from public sources such as websites and press releases. Please visit each company’s website for updates and additional information on their individual HAE clinical development programs.

CSL Behring already has two approved HAE medicines: Berinert® for treating attacks and HAEGARDA®/Berinert® 2000-3000 for attack prevention. The company is developing an HAE treatment called garadacimab, delivered once a month by subcutaneous injection. The medicine is a monoclonal antibody targeted to block Factor XIIa, which research shows is the fuel in human plasma that ignites an HAE attack. The results of a phase 2 trial announced in June 2020 revealed that garadacimab was well tolerated and reduced the average number of HAE attacks when compared to placebo by as much as 99% in one of the dosing levels being tested. According to Clinical, CSL Behring is now conducting a phase 3 clinical trial at 37 sites worldwide. 

KalVista is developing three oral HAE treatments. The company’s drug candidate for treating attacks when they occur, KVD-900, works by blocking kallikrein, which is a key component in the HAE attack biology. KalVista reported the results of their Phase 2 trial in February 2021 and noted that KVD-900, when compared to placebo, significantly reduced the use of rescue medicine and the time it takes for symptoms to begin resolving. On 8 March 2022, the company announced the initiation of KONFIDENT, a Phase 3 worldwide, double-blind, placebo-controlled crossover trial to evaluate the efficacy of two dose levels of KVD900 compared to placebo in 84 adults and adolescents during acute HAE attacks. According to KalVista, the study is being conducted at approximately 60 sites in 20 countries. 

KalVista is also conducting KOMPLETE, a Phase 2 clinical trial of KVD824, a twice-daily oral preparation for preventing HAE attacks. The trial is a randomized, double-blind study evaluating the safety and effectiveness of twice-daily administration against placebo for 12 weeks at varying doses of 300 mg, 600 mg, and 900 mg. According to, the trial will include 48 people with HAE types 1 and 2. It is being conducted at 30 clinical trial sites.

In addition, KalVista is in the early stages of researching a pill to inhibit Factor XIIa, which, as we mentioned earlier, is the protein that initiates HAE attacks.  

Pharvaris is another company developing an oral form of HAE treatment called PHVS416. This medicine is designed to have the same biological effect as Icatibant, the generic name for a treatment most HAEi friends might also know under the brand name Firazyr®. According to a March 2022 presentation that is on the company’s website, a phase 2 trial called RAPIDe-1 for treatment of HAE attacks with PHVS416 is looking to recruit 72 people with HAE types 1 and 2 from 30 clinical trial sites in the United States, Canada, Europe, Israel, and the United Kingdom. 

In addition, Pharvaris has started another Phase 2 study of PHVS416 called CHAPTER-1 to test the medicine as an HAE preventive therapy. The company is looking to enroll 30 HAE patients across 24 sites in the United States, Canada, Europe, Israel, and the United Kingdom.

Pharvaris expects to report data on the effectiveness and safety from both the Rapide 1 and CHAPTER 1 trials is expected in the 4th quarter of 2022.

Ionis Pharmaceuticals announced (on 18 November 2021) a phase 3 study called OASIS-HAE designed to test the safety and effectiveness of a medicine called donidalorsen. This treatment will be given as either a monthly or bi-monthly subcutaneous injection to prevent HAE attacks. Ionis is looking to recruit 84 people with type 1 or type 2 HAE. In brief, this medicine works by employing messenger RNA to suppress pre-kallikrein, a protein that figures prominently in the biological cascade causing an HAE attack. In March 2021, the company announced the results of a Phase 2 study indicating that donidalorsen demonstrated a 90% reduction of HAE attacks in weeks one to 17 of the study, with a 97% reduction observed in weeks five to 17.

Astria Therapeutics is researching a STAR-0215, a monoclonal antibody to inhibit kallikrein given once every three months or longer. According to the company’s website, Astria plans to file an Investigational New Drug application for STAR-0215 in mid-2022 and initiate a Phase 1 clinical trial with initial results anticipated by year-end 2022.

Pharming NV is the manufacturer of Ruconest®, a recombinant C1-inhibitor concentrate approved for treating HAE attacks. In July 2021, the company announced plans to research, develop, manufacture, and commercialize a gene therapy called OTL-105. The concept for this therapy involves drawing blood from a person with HAE and then taking this blood to a laboratory where a “healthy” copy of the C1-inhibitor gene is inserted into the person’s blood stem cells. Once this process is completed, the patient is infused with the stem cells containing the “working” C1-inhibitor gene. 

BioMarin is developing a gene therapy for HAE called BMN 331. According to, the company is conducting a Phase 1/2 Open-Label, Dose-Escalation Study to determine the safety, tolerability, and efficacy of BMN 331 in 34 people with HAE due to C1-inhibitor deficiency. People receiving this therapy will be followed for five years. 

Intellia Therapeutics is pursuing a gene therapy for HAE using a technology called CRISPR-Cas 9 to knock out (which means to inactivate and stop) the gene that ultimately produces kallikrein. CRISPR-Cas 9 edits genes by removing, adding, or altering sections of the DNA sequence. According to Clinical, Intellia is running a multi-national Phase 1/2 study that will evaluate the safety, tolerability, and biological activity of its gene therapy medicine called NTLA-2002 in 55 adults with Type I or Type II HAE. In December 2021, Intellia reported that the first clinical trial dose of NTLA-2002 had been given to a person participating in the clinical trial.

Spark Therapeutics is another company researching gene therapy for HAE. According to the company’s website, Spark is in the early stages of developing an investigational gene therapy for the treatment of HAE using liver-directed gene therapy for C1-Inhibitor replenishment. 

RegenxBio is the fifth company developing an HAE gene therapy using AAV technology. In a November 2021 press release, RegenxBio said it continues to conduct research and pre-clinical studies to advance its gene therapy candidate for the treatment of HAE. The company’s website shows that the HAE program is in the pre-clinical stage.

Working Towards a Better Future

The incredible and special “can do” and “will do” attitude of the global HAEi community has been noticed and has a lot to do with why there are so many new therapies being researched. There is little doubt that HAEi friends will continue our longstanding tradition of fiercely advocating for access to modern therapies while also enabling a better future for us and future generations through participation in clinical trials. 

For more information, feel free to contact your Member Organization or HAEi’s Clinical Trial Project Leader at gro.ieah@slairtlacinilc.