Dawnzera (donidalorsen)

A third mechanism for HAE prevention alongside the kallikrein antibody Takhzyro and the Factor XII antibody Andembry, distinguished by acting on production rather than on circulating protein and by the every-8-weeks option. Its 81% attack reduction sits between Orladeyo's 44% and the antibodies' 87% to 89%.

Most other HAE preventive medicines act on proteins already in the blood, either blocking them or replacing missing C1 inhibitor. Donidalorsen works one step earlier. It is an antisense oligonucleotide, a short strand of synthetic RNA-like material, attached to a GalNAc sugar tag that steers it to liver cells. Inside the liver it binds the messenger RNA that carries the instructions for prekallikrein and marks it for destruction by an enzyme called RNase H1, so the liver produces less prekallikrein. Less prekallikrein means less plasma kallikrein to activate, less bradykinin, and fewer attacks. Because the effect is on production rather than on circulating protein, one injection lasts 4 to 8 weeks.

The label's one warning is hypersensitivity reactions including anaphylaxis, with the instruction to stop the drug and seek immediate care if a serious reaction occurs. The most common reactions, in at least 5% of patients, were injection site reactions, upper respiratory infections, urinary tract infections and abdominal discomfort. Suspected reactions can be reported to Ionis at 1-833-644-6647.

A chronic antisense therapy for a rare disease, dosed 6 to 13 times a year, in the cost tier of other HAE biologics. The every-8-weeks interval, where appropriate, halves the number of doses per year.

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Approved for prophylaxis in adults and children aged 12 and older. It prevents attacks and does not treat one in progress. The every-8-weeks option gave a smaller attack reduction in the trial (55% versus 81% with every-4-weeks dosing), which is worth knowing before choosing the longer interval for convenience.

Source: FDA Drugs@FDA (NDA 219407)

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The OASIS-HAE trial (NCT05139810) randomized 90 patients aged 12 and older with type I or II HAE, each with at least 2 attacks during an 8-week run-in, to donidalorsen 80 mg every 4 weeks, 80 mg every 8 weeks, or placebo for 24 weeks. The every-4-weeks dose reduced the attack rate by 81% relative to placebo (95% CI 65% to 89%), from 2.26 to 0.44 attacks per 4 weeks; the every-8-weeks dose reduced it by 55% (95% CI 22% to 74%). Most patients had type I disease, and only 18% had been on prior prophylaxis.

Developed by Ionis as IONIS-PKK-LRx using its GalNAc-conjugated antisense platform, and approved by the FDA on August 21, 2025 as the first RNA-targeted therapy for HAE, completing a summer in which 3 new HAE drugs reached the market.