C1 Esterase Inhibitor (Human)

iStock, natrot This year has seen the approval of several first-in-class therapies for HAE, but in a fragmented space, experts question whether they will be enough to net their developers a significant share of the entrenched market. The drug development landscape for hereditary angioedema—a potentially lethal condition characterized by severe swelling, including of the airways—has evolved rapidly in recent decades, with at least one investigational therapy touted to be potentially curative. The disease’s dire nature necessitated the development of both acute treatments for individual attacks and prophylactic therapies designed to reduce the overall number and severity of attacks. The creation of the first FDA-approved prophylactic and on-demand treatments in 2008 and 2009, respectively, changed the outlook for patients with hereditary angioedema (HAE). In the intervening years, progress has continued, with 2025 marked by several novel approvals and the emergence of late-stage candidates that could again change the treatment of the disease. In August, Ionis Pharmaceuticals received FDA approval for Dawnzera, the first RNA-targeting therapy for the prophylactic treatment of HAE. This followed closely behind FDA greenlights in July for KalVista Pharmaceuticals’ Ekterly , the first on-demand pill for the condition, and in June for CSL’s prophylactic factor XIIa inhibitor Andembry , again, the first in its class. Waiting in the wings to join this latest cohort is Intellia Therapeutics’ NTLA-2002, also known as lonvo-z, a CRISPR-based gene therapy aiming to prevent HAE attacks with a single dose. Phase I/II data presented at the American College of Allergy, Asthma & Immunology (ACAAI) 2025 conference last month showed that 97% of patients receiving a 50-mg dose of the therapy were attack-free and long-term prophylaxis-free as of the data cutoff of Aug. 29. Patients in the pooled readout were followed for up to 32 months. All this movement in the pipeline should mean a range of treatments for patients to choose from, but the reality is quite different. Patients are often “sticky” with their existing treatments, Myles Minter, biotech equity research analyst at William Blair, told BioSpace, and often view switching treatments as an unnecessary risk if their current therapies are working. “That’s why investors consider it a fragmented market,” Minter said, “Because great work has been done to keep HAE patients under control, as most people who have access are taking an effective therapy. Any other treatments are just fighting to get a smaller piece of the pie, and there are lots of different therapeutic options here.” That “pie” is projected to be worth nearly $6 billion by 2030, according to Grand View Research. Takeda’s Takhzyro, approved in 2018 , surpassed incumbents to become the market leader and now generates full-year sales of approximately $1.7 billion, according to Minter. “It’s still attractive,” Minter continued, “because if you can command a lion’s share of the market, you can have a blockbuster on your hands.” A Penetrable Market HAE is a rare disease, affecting approximately 1 in 50,000 people globally and around 7,000 in the U.S. About one-third of these patients are still taking C1 esterase inhibitors, Minter said, representing some of the earliest modern therapies for HAE, having been used for on-demand and preventive treatment since 2008. Shire’s Cinryze was approved in 2008 for prophylactic care, with CSL’s Berinert following in 2009 for acute treatment. CSL now has three treatments in its HAE portfolio. This includes the newly approved Andembry, which, according to a company spokesperson, inhibits the protein that plays a key role in attacks of swelling, effectively preventing the HAE cascade “at the top.” Andembry also comes with the advantages of being offered in a once-monthly dosing regimen and delivered in 15 seconds or less via an autoinjector, the spokesperson told BioSpace . In comparison, Takhzyro, administered subcutaneously, has a recommended dosing schedule of every two weeks. This fits the “treat-and-extend paradigm,” as Minter described, where drug developers vie for market share by boosting convenience. Although treatment efficacy is relevant for FDA approval, he explained that it is rare for this to be a deciding factor when it comes to switching therapies. For patients, time between dosing, safety or tolerability are typically more important. But companies in the space beg to differ. In one Ionis-sponsored poll, 9 of 10 patients with HAE who responded to the survey expressed interest in trying a new prophylactic therapy, “with nearly two-thirds reporting they hadn’t yet found the best treatment option for them,” Kyle Jenne, chief global product strategy officer at Ionis, told BioSpace by email. “In the U.S., many people living with HAE remain unsatisfied with their current treatment, continuing to experience painful, unpredictable attacks.” A Truly Differentiated Approach The emergence of new treatment modalities such as RNA-targeting therapies and gene therapies, alongside a deeper understanding of the underlying mechanisms of HAE, have created different angles of attack, Minter said. Ionis’s Dawnzera, an RNA-targeting therapy, achieved a “compelling set of data” because it achieved a high rate of attack freedom, with a 90% reduction over 24 weeks of follow-up, he noted. In addition, Ionis reported a 94% mean reduction in attack rate from baseline after one year in an open label extension study. The treatment is also dosed every four weeks and is delivered by autoinjector in 10 seconds. Dawnzera works by limiting the production of PKK, a protein that plays a role in the cascade that triggers HAE attacks, Jenne explained. Minter noted that Ionis’ launch of Dawnzera would be watched closely by analysts, as the knockdown approach is differentiated to some other treatments that have emerged in the space. On Dawnzera’s uptake so far, Jenne said only that it has been “encouraging.” Intellia’s lonvo-z, which has been said to have “potentially curative” potential, could be another differentiated option, though optimism around the candidate was slightly blunted after two recent setbacks. Earlier Phase II data reported last October showed mean monthly attack reduction of 77% and 81%, which, though effective, meant that not all patients were completely under control with one dose. Then, perhaps more significantly for the company, last month Intellia paused Phase III trials for a separate CRISPR therapy, nexiguran ziclumeran, due to safety concerns. This led Minter to ask whether patients would be interested in a permanent solution, such as gene therapy, if safety risks are present—especially if there are safer and equally effective dosed options. Overall, Minter believes the HAE pipeline is promising, particularly as analysts keep a close eye on a series of new launches to determine patient uptake. “I would never wish a disease on anyone, but if you have HAE and you’re living with the disease today, you have a much, much better prognosis than you did 15 years ago,” he concluded. “The next goal is to make these patients basically forget that they’re living with this rare disease.” .responsive-container { display: flex; flex-wrap: wrap; border: 1px solid #ededed; font-family: Helvetica, Arial, Sans-Serif; padding: 20px 20px 10px 20px; } .column-left { flex: 1; max-width: 45%; padding: 20px 20px 10px 20px; } .column-right { flex: 2; padding: 20px 20px 10px 20px; } @media (max-width: 768px) { .column-left, .column-right { max-width: 100%; flex: 100%; padding: 10px 0; } } Subscribe to ClinicaSpace! 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