Since 2008, the FDA has given the nod to 11 therapies for hereditary angioedema (HAE), a rare genetic disorder. What’s interesting is that three of those nods have come in just the past two months.
The newest addition arrived as the agency approved Ionis Pharmaceuticals’ Dawnzera (donidalorsen). Even in a crowded and competitive field, Dawnzera is expected to stand apart as the first RNA-based therapy for HAE. Its status as a first-in-class drug, along with its convenient dosing schedule and at-home injection option, provides further differentiation.
The FDA has authorized Dawnzera for preventive use in patients aged 12 and older, aiming to lower the risk of unexpected and random swelling episodes in the face, limbs, abdomen, and throat that define HAE. The rare disorder, which impacts around 7,000 individuals in the U.S., can become life-threatening if it obstructs the airways and restricts breathing.
Mechanism and Efficacy
Dawnzera works by inhibiting plasma prekallikrein, a protein involved in triggering inflammatory mediators that drive severe HAE attacks.
Dawnzera secured approval on the back of a phase 3 study showing the drug cut the frequency of HAE attacks by over 80% versus placebo over 24 weeks. Looking past the second administration of the therapy, the reduction shot up to 87%.
A Crowded Market
This marks the third consecutive regulatory clearance in the past few months to broaden treatment choices for HAE patients. Ionis’ newcomer will now face competition from Takeda’s injected mainstay Takhzyro and BioCryst’s rapidly growing oral option Orladeyo.
Ionis CEO Brett Monia stated in an interview that Orladeyo offers fewer advantages than Takhzyro in lowering attack rates and also faces tolerability challenges, especially gastrointestinal ones due to its oral form. He noted that with only these two therapies available, patients often switch between them in search of improved treatment, which, in his view, reflects their overall dissatisfaction.
In July, the FDA cleared Ekterly, marking the first approved therapy from Massachusetts-based KalVista Pharmaceuticals. The drug is notable as the first oral, on-demand option for HAE symptoms, contrasting with other therapies that require intravenous or subcutaneous delivery.
Meanwhile, CSL has added further competition in the preventative market with the June approval of Andembry. The once-monthly, self-injected pen blocks factor XIIa, a plasma protein central to initiating the swelling episodes associated with the disease.
Monia explained that Andembry works through a very different mode of action, noting that while the rival drug targets a protein with an antibody, their approach focuses on RNA. He acknowledged that Andembry appears to be a strong candidate but emphasized that Ionis believes donidalorsen’s overall profile will prove more appealing to many patients.
Key Differentiator
Ionis is positioning Dawnzera’s dosing schedule as its key differentiator. Patients start with a shot every four weeks, and can later move to an eight-week interval. Data from an extension of the phase 3 study showed that the less frequent regimen worked just as well as the monthly one, cutting swelling attacks by 94% compared to placebo.
