C1 Esterase Inhibitor (Human) (ViroPharma)

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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The FDA has signed off on three drugs in the last two months to treat the rare genetic condition hereditary angioedema. The newest to come online is Ionis Pharmaceuticals' Dawnzera. Since 2008, the FDA has approved 11 treatments for a rare genetic condition called hereditary angioedema (HAE), three of which have occurred in the last two months.The latest drug to join this cohort of medicines arrived Thursday with the FDA approval of Ionis Pharmaceuticals’ Dawnzera (donidalorsen). Despite entering a competitive, crowded market, it shouldn’t be difficult for Dawnzera to differentiate itself. As the first RNA-targeted treatment for HAE, it is a first-in-class therapy and further distinguishes itself with its dosing schedule and ability to be injected at home.The U.S. regulator has signed off on Dawnzera for prophylactic use by those age 12 years and older to reduce the likelihood of the sudden, unpredictable episodes of severe swelling in the limbs, face, abdomen and larynx that characterize HAE. The disorder, which affects 7,000 people in the U.S., can be fatal when it strikes the airways and inhibits breathing.Dawnzera was designed to target plasma prekallikrein, a protein that activates inflammatory mediators associated with acute attacks of HAE.Paving the way for approval was a phase 3 trial in which Dawnzera reduced the HAE attack rate by 81% compared to placebo over 24 weeks. The attack rate reduction increased to 87% when measured beyond the second dose of Dawnzera.Dawnzera is the third in a run of recent approvals that give patients new options to combat the disease. The products will take on Takeda’s blockbuster standard of care, an injected treatment called Takhzyro, and BioCryst Pharmaceuticals’ fast-rising oral challenger Orladeyo.“Orladeyo has less benefit than Takhzyro, with respect to reducing attack rates, and it has tolerability issues, particularly (gastrointestinal) because it is oral,” Ionis CEO Brett Monia, Ph.D., said in an interview with Fierce. “With those two drugs alone, we’re seeing that patients are switching from one drug to another trying to get a better treatment. My point is—they’re unsatisfied.”Last month, the FDA endorsed Ekterly, the first approved product from small Massachusetts biotech KalVista Pharmaceuticals, which has become the first oral on-demand medicine to address the symptoms of HAE, while others are delivered by intravenous or subcutaneous administration.Adding to the competition in the HAE prophylactic space is CSL, which scored a June FDA nod for Andembry, a self-administered prefilled pen. The treatment is dosed monthly and inhibits factor XIIa, a plasma protein that plays a key role in triggering the swelling episodes.“It’s a quite different mechanism of action, with respect to the targets its going after—we’re targeting RNA, they’re targeting a protein with an antibody,” Monia said of Andembry. “It looks like a good drug. We think donidalorsen has an overall profile that will be more attractive to many patients.” CSL will be a formidable rival as it has vast experience in the HAE space. Its drugs Berinert and Haegarda, which were approved in 2009 and 2017, respectively, were the premier HAE treatments before Takhzyro became a blockbuster in 2022.Ionis believes Dawnzera’s advantage is in its dosing regimen, which calls for patients to begin with one injection every four weeks, with an option to switch to dosing every eight weeks. In an extension study of Ionis’ phase 3 trial, eight-week dosing performed at the same level as four-week dosing, limiting swelling episodes by 94% versus placebo.Meanwhile, Takhzyro starts patients on a two-week dosing schedule, with the option to switch to every four weeks. Andembry follows a monthly dosing regimen.Ionis will charge $57,462 per dose, which works out to a $747,000 price tag for annual injections, assuming a patient stays on the four-week schedule. While the annual pricing exceeds that charged by Takeda and CSL for their prophylactic treatments, it will be significantly less for patients who shift to the eight-week dosing plan.“We’re right in line with where the market is today,” Kyle Jenne, Ionis’ chief global product strategy officer, said during a post-approval webcast Thursday. “We expect the majority of (physicians) to start patients at every four weeks and then if they’re performing well and are well controlled, they could potentially have the option of moving them to every eight weeks. We’ll have to see what that split looks like over time.” Ionis also pointed to a switch cohort in its phase 3 study that evaluated the performance of Dawnzera in patients previously treated with Takhzyro, Orladeyo or Takeda's C1 inhibitor Cinryze. In switching to Dawnzera, patients reduced their mean HAE attack rate by 62% from prior prophylactic treatment over 16 weeks, with no mean increase in breakthrough attacks observed during the switch.Additionally, a total of 84% of patients surveyed preferred Dawnzera over their prior prophylactic treatment, citing better disease control, less time to administer and less injection site pain or reactions.The switch data are not included on Dawnzera’s label but will “remain important for Ionis’s messaging on market positioning and reimbursement,” according to William Blair analyst Myles Minter, Ph.D.“Overall, we see Dawnzera’s profile as superior to current prophylactic options, with less frequent dosing and at-home auto-injector dosing being further differentiators. We also view Dawnzera’s profile as comparable to CSL Behring’s Andembry,” Minter added in an Aug. 21 note.