Donidalorsen

Donidalorsen is a 2'-O-methoxyethyl–modified antisense oligonucleotide (ASO) conjugated to a triantennary N-acetylgalactosamine (GalNAc₃) moiety that causes ribonuclease H1 (RNase H1) mediated degradation of prekallikrein (PKK) mRNA through selective binding to PKK mRNA, which results in reduced production of PKK protein. PKK is a pro-enzyme for plasma kallikrein, which results in the release of bradykinin, a potent vasodilator causing inflammation and swelling in HAE.

In Trial 1, a 24-week multicenter, randomised, double blind, placebo-controlled trial in adult and paediatric patients (≥12 years) with HAE 1 or HAE 2, a decrease in plasma PKK concentrations was observed. The mean percentage change from baseline to 7 Week 24 in trough plasma PKK concentrations indicated reductions of 73% and 47% following treatment with donidalorsen 80 mg every 4 weeks and every 8 weeks, respectively, compared with 2% in the placebo group.

The pharmacokinetic properties of donidalorsen were evaluated following subcutaneous administration of multiple doses every 4 weeks in healthy subjects and every 4 weeks or every 8 weeks in patients with HAE.

Donidalorsen exposure (area under the plasma concentration time curve [AUC]) increased in a dose dependent manner following subcutaneous doses ranging from 20 to 80 mg in healthy volunteers but was greater than dose proportional over the entire dose range.

Population estimates (geometric mean) of steady state maximum plasma concentration (C_max,ss), trough plasma concentration (C_trough,ss), and area under the plasma concentration time curve over the dosing interval (AUC_τ,ss) are presented in Table 4. No accumulation of donidalorsen C_max and AUC was observed in plasma after repeated dosing every 4 weeks.

Table 4. Summary of simulated pharmacokinetic parameters from population pharmacokinetic analysis following dosing of donidalorsen 80 mg q4wks or 80 mg q8wks in patients with HAE at steady state:

AUC_τ,ss = area under the plasma concentration time curve over the dosing interval at steady state; C_max,ss = maximum plasma concentration at steady state; C_trough,ss = trough plasma concentration at steady state; q4wks = every 4 weeks; q8wks = every 8 weeks.

Absorption

Following subcutaneous administration, donidalorsen is absorbed with the time to maximum plasma concentration of approximately 2.5 hours post dose, based on population estimates.

Distribution

Donidalorsen is expected to distribute primarily to the liver and kidney cortex after subcutaneous dosing. The population estimate of apparent volume of distribution for the central (Vc/F) and peripheral (Vp/F) compartment were 69.8 L and 1 840 L, respectively. Donidalorsen is highly bound to human plasma proteins (>98% bound) in vitro.

Biotransformation

Donidalorsen is metabolised by endo- and exonucleases to short oligonucleotide fragments of varying sizes within the liver.

Elimination

The population estimate of the terminal elimination half-life of donidalorsen in a typical patient with HAE is approximately 1 month.

The mean fraction of unchanged ASO eliminated in urine was less than 1% of the administered dose in healthy subjects within 24 hours. Linker related metabolites are minimally released to circulation and subsequently rapidly excreted to urine or faeces.

Special populations

Population pharmacokinetics and pharmacodynamics analyses showed no clinically meaningful differences in the pharmacokinetics or pharmacodynamics of donidalorsen based on age (12 to 74 years), sex, mild renal impairment (eGFR ≥60 to <90 mL/min/1.73 m²), or mild hepatic impairment (total bilirubin ≤1 × ULN and AST >1 × ULN, or total bilirubin >1 to 1.5 × ULN and any AST). Regarding body weight, donidalorsen AUC predicted values for the 30‑40 kg body weight range were >17 500 ng·h/mL, >10 000 ng·h/mL for 40‑50 kg and around 10 000 ng·h/mL for 50‑60 kg. The corresponding values for patients with body weights >60 kg were <7 500 ng·h/mL.

Donidalorsen has not been studied in patients with moderate or severe renal impairment, end stage renal disease, or moderate or severe hepatic impairment.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction and development.

Carcinogenicity

In a 6 month carcinogenicity study in transgenic (Tg.rasH2) mice, subcutaneous administration of donidalorsen (5, 10, 20, or 60 mg/kg) or a rodent specific surrogate (10 mg/kg) once every 2 weeks did not result in an increase in malignant tumors, indicating a lack of human carcinogenic risk.

Genotoxicity

Donidalorsen was negative for genotoxicity in in vitro (bacterial reverse mutation, chromosomal aberration in Chinese hamster lung cells) and in vivo (mouse bone marrow micronucleus) assays.

Pregnancy, lactation and fertility

Subcutaneous administration of donidalorsen (0, 5, 10, or 20 mg/kg/week) or a rodent active inhibitor of PKK (5 mg/kg/week) to mice every other day throughout pregnancy and weekly throughout lactation produced no adverse effects on pre- and postnatal development.

In the mouse pre- and postnatal development study, the concentrations of donidalorsen in breast milk from lactating mice increased in a dose dependent manner at doses ≥10 mg/kg/week, but these concentrations of donidalorsen in breast milk were >3 000 fold lower than the observed tissue concentrations. Even though donidalorsen was detected in the maternal mouse milk, systemic exposure in pups was not expected due to the lack of oral absorption of donidalorsen.

In animal studies, administration of donidalorsen or a pharmacologically active rodent specific surrogate in a combined fertility and embryofetal development toxicity study in mice did not result in effects on male and female fertility or embryofetal development.

Subcutaneous administration of donidalorsen (0, 1, 4, or 10 mg/kg/week) or a rodent active inhibitor of prekallikrein (PKK) (4 mg/kg/week) to male and female mice weekly, prior to and during mating, and continuing every other day in females throughout the period of organogenesis, resulted in no adverse effects on fertility, pregnancy, or embryofetal development.