Dawnzera (donidalorsen sodium)

Donidalorsen sodium is a prekallikrein-directed antisense oligonucleotide.

Donidalorsen is a N-acetylgalactosamine conjugated (Ga1NAc) antisense oligonucleotide that binds to prekallikrein mRNA resulting in ribonuclease H1-mediated degradation and reduced prekallikrein protein production. Because prekallikrein is the precursor of plasma kallikrein, which generates bradykinin, a vasodilator responsible for swelling and pain in hereditary angioedema (HAE), lowering prekallikrein limits bradykinin formation. In HAE, C1-inhibitor deficiency or dysfunction leads to excessive kallikrein activity and bradykinin-driven angioedema attacks; donidalorsen mitigates this by reducing prekallikrein levels.

Donidalorsen produces rapid reductions in plasma prekallikrein, with a mean 48% decrease at the first assessment (week 4), and sustained trough reductions by week 24 of 73% with every 4 week dosing and 47% with every 8 week dosing, compared with a 2% increase with placebo. No clinically significant QTc prolongation was observed at the recommended 80-mg dosage every 4 weeks.

The pharmacokinetics of donidalorsen were similar between healthy subjects and patients with HAE. Following subcutaneous administration, donidalorsen reaches peak plasma concentrations in a median of 2 hours (range, 0.25-8 hours) and exhibits greater than dose proportional increases in exposure across the evaluated dosage range. At steady state, peak plasma concentrations were similar between the 4- and 8-week regimens, while trough plasma concentration was approximately 3-fold higher with every 4-week dosing, consistent with a 2-fold accumulation in trough concentrations but no accumulation in peak plasma concentrations or AUC.

The drug distributes primarily to the liver and kidney cortex, has a large peripheral volume of distribution, and is highly protein bound (>98%). Donidalorsen displays a terminal elimination half-life of roughly 1 month, with an initial distribution phase of about 5 hours. Donidalorsen is metabolized by endo- and exonucleases to oligonucleotide fragments, while the GalNAc linker undergoes hydrolysis and oxidative metabolism; neither pathway relies on cytochrome P-450 (CYP) enzymes, although the linker metabolite M8 is a CYP3A4 substrate.

Renal elimination of unchanged drug is minimal (<1%). No clinically meaningful pharmacokinetic differences were observed across age, sex, race, body weight, disease status, or mild renal or hepatic impairment, but the drug has not been studied in moderate or severe renal or hepatic dysfunction.

USES: This medication is used to help prevent severe swelling attacks due to a certain inherited immune disease (hereditary angioedema-HAE). Donidalorsen works by decreasing the amount of a natural substance made by the body (prekallikrein). This effect lowers the amount of another natural substance (bradykinin) that causes symptoms during a sudden HAE attack.

Generic name: donidalorsen sodium
Drug class: Prophylaxis Hereditary Angioedema Treatment Agents
Therapeutic class: Cardiovascular Therapy Agents

The following indications are listed for Dawnzera:

• Prevention Of Angioedema Attacks In Patient With Hereditary Angioedema

Also known as: Prevention Of Angioedema Attack In Hereditary Angioneurotic Edema, Prevention Of Angioedema Attacks In Patient With Hae, Prophylaxis Against Angioedema Attacks In Patient With Hae.