Donidalorsen for the Treatment of Hereditary Angioedema: A Review of Clinical Studies

Abstract

Hereditary angioedema (HAE) is a rare disease characterized by recurrent attacks of severe tissue swelling caused by dysregulation of the kallikrein-kinin system. Donidalorsen is a triantennary N-acetyl galactosamine–conjugated antisense oligonucleotide designed to specifically and reversibly reduce plasma prekallikrein production by binding to plasma prekallikrein messenger RNA in the liver. This report reviews donidalorsen’s mechanism of action and data on the pharmacodynamics, efficacy, patient-reported outcomes, and safety of donidalorsen from clinical trials in adolescent and adult participants. In a Phase 1 trial, subcutaneous (SC) administration of donidalorsen led to dose-dependent reductions in plasma prekallikrein concentrations. In a subsequent Phase 2, randomized, placebo-controlled study, donidalorsen 80 mg SC once every 4 weeks (Q4W) for 16 weeks resulted in a 90% mean reduction in monthly HAE attack rate vs placebo, which was sustained for up to 4 years in an open-label extension (OLE). In the Phase 3, randomized, placebo-controlled OASIS-HAE study, patients receiving donidalorsen 80 mg Q4W or once every 8 weeks (Q8W) experienced significant mean reductions in HAE attack rates vs placebo over Weeks 0 to 24 (Q4W: 81%; Q8W: 55%). Mean attack rates were reduced by 87% (Q4W) and 60% (Q8W) vs placebo over Weeks 4 to 24. Reductions in attack rate from OASIS-HAE baseline were sustained for up to 1 year in the OASISplus OLE (Q4W: 94%; Q8W: 95%). A notable study in the clinical program included a cohort of patients who switched from berotralstat, C1 inhibitor, or lanadelumab to donidalorsen for up to 1 year; mean attack rates were reduced by 68% vs baseline (on prior HAE prophylaxis). Donidalorsen treatment improved quality of life at all assessments. Across studies, donidalorsen had an acceptable safety and tolerability profile, with mostly mild to moderate adverse events reported. Overall, the clinical data are promising for donidalorsen as a long-term prophylactic medication for HAE.

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Introduction

Hereditary angioedema (HAE) is a rare disease characterized by unpredictable, frequently severe attacks of cutaneous and submucosal tissue swelling.1 The prevalence of HAE in the United States is estimated to be 2–2.3 per 100,000 individuals.2 Without treatment, HAE attacks typically last from 2 to 5 days and can affect any skin surface, the gastrointestinal tract, and the upper respiratory system, which can be life-threatening.3,4 The tissue swelling associated with HAE attacks can be painful and debilitating and have a substantial negative impact on patients’ quality of life.5 Patients report that HAE can be disruptive to their activities of daily living, particularly regarding work and school productivity.6–8 Patients with HAE have high rates of anxiety and depression, with many patients reporting anxiety about possible pain and suffocation during attacks.7,9 Further, many people with HAE report emergency room and urgent care visits or hospitalization for HAE attacks, which disrupts their lives and poses a considerable economic cost.8,10 Thus, HAE creates a substantial burden on both patients’ physical and mental health.

According to the World Allergy Organization/European Academy of Allergy and Clinical Immunology 2021 guideline for the management of HAE, the primary goals for HAE management are “to achieve complete control of the disease”, such that patients no longer experience HAE attacks, and “to normalize patients’ lives”.11 To this end, the guidelines recommend the use of acute on-demand therapy and the consideration of long-term prophylactic medications (LTPs) for all patients with HAE. While on-demand treatments can minimize the effects of HAE attacks, LTPs are critical for attack prevention and long-term disease control. Current US Food and Drug Administration (FDA)-approved LTPs include plasma-derived C1 inhibitor (C1INH) concentrate,12–15 the plasma kallikrein inhibitors lanadelumab16,17 and berotralstat,18,19 the Factor XIIa inhibitor garadacimab,20,21 and the plasma prekallikrein-directed antisense oligonucleotide (ASO) donidalorsen,22,23 the last of which will be the focus of this review. These treatments differ in their efficacy and safety profiles, dosing frequency, and mode of administration, and patients’ treatment preferences and priorities may vary substantially on these dimensions. For example, a recent study evaluating patient preference through discrete choice experiments revealed that reduction in attack frequency is generally the treatment feature most prioritized by patients, but other features such as risk of side effects, mode of administration, and frequency of dosing are also important.24 Further, per expert consensus, switching LTPs should be considered if treatment targets are not met or if a patient continues to experience a high treatment burden on their current treatment.25 Thus, access to multiple LTP options and a framework for switching among LTPs allow physicians to tailor the choice of treatment based on patient preferences and are significant benefits to patients with HAE.

Donidalorsen, a recently FDA-approved LTP indicated for prophylaxis to prevent attacks of HAE in adult and pediatric patients 12 years of age and older, is a ligand-conjugated ASO designed to reduce plasma prekallikrein production by selectively binding to plasma prekallikrein messenger RNA (mRNA) in the liver.26 Phase 1, 2, and 3 clinical trials have been completed for donidalorsen, and phase 2 and 3 open-label extension (OLE) studies provide long-term clinical data on donidalorsen.22,26–29 Here, we review donidalorsen’s mechanism of action and its efficacy, safety, and pharmacodynamic profile in clinical trials.

HAE Pathophysiology

HAE is an autosomal dominant disorder most often caused by mutations of the SERPING1 gene, which encodes the C1INH protein.1,30,31 HAE-C1INH-Type1 is caused by mutations that result in quantitative C1INH deficiency and makes up approximately 85% of cases of HAE-C1INH.32 HAE-C1INH-Type2 is caused by mutations that result in C1INH dysfunction and accounts for approximately 15% of cases of HAE-C1INH. A third type of HAE, HAE with normal C1 inhibitor (HAE-nC1INH), exists in patients with normal quantitative and functional C1INH and has similar clinical presentation to HAE-C1INH. HAE-nC1INH is very rare, with an unclear prevalence due to the lack of standardized, validated diagnostic tests.32,33

The swelling attacks associated with HAE are caused by overproduction of bradykinin, a potent vasodilator that increases vascular permeability and fluid extravasation.34,35 In HAE-C1INH-Type1 and HAE-C1INH-Type2, the overproduction of bradykinin results from a loss of C1INH regulation of the kallikrein-kinin system.3,36,37 Kallikrein-kinin system activation is initiated by autoactivation of Factor XII to Factor XIIa upon contact with negatively charged surfaces.36–38 Factor XIIa can then cleave plasma prekallikrein, resulting in active plasma kallikrein.39 Plasma prekallikrein may also be activated by Factor XII–independent pathways.40 Prior to activation by Factor XIIa, plasma prekallikrein is synthesized in the liver.1,41 In circulation, plasma prekallikrein molecules form 1:1 complexes with high-molecular-weight kininogen.42 Plasma kallikrein releases bradykinin from high-molecular-weight kininogen and additionally activates Factor XII to Factor XIIa, resulting in further conversion of plasma prekallikrein to plasma kallikrein in a positive feedback cycle.36,42 Bradykinin B2 receptor activation in endothelial cells results in nitric oxide production, which leads to vascular smooth muscle cell relaxation and the degradation of vascular endothelial cadherin molecules. Together, these cause vascular leakage between endothelial cells, leading to tissue swelling. C1INH is an inhibitor of both Factor XIIa and plasma kallikrein, among other components of the fibrinolysis, coagulation, and complement systems.3 Thus, in HAE-C1INH, C1INH deficiency or dysfunction leads to both uncontrolled activation of plasma prekallikrein to kallikrein by Factor XIIa and excess kallikrein-mediated release of bradykinin from high-molecular-weight kininogen, resulting in attacks of angioedema.36,43

Long-Term Prophylactic Treatment Approaches for HAE

LTPs for HAE aim to restore regulation of the kallikrein-kinin system and reduce bradykinin overproduction, thereby preventing excessive vasodilation and fluid extravasation. Historically, attenuated androgens were commonly used for the long-term prophylactic management of HAE.44 However, because of the numerous side effects associated with androgen use and the consequent requirement for careful surveillance, androgens are no longer recommended as a first-line LTP for HAE.11 Current approaches to long-term management of HAE target specific components of the kallikrein-kinin system, including C1INH (C1INH supplementation), kallikrein (lanadelumab and berotralstat), Factor XIIa (garadacimab), and plasma prekallikrein (donidalorsen).11,20,22

As HAE is primarily caused by C1INH deficiency or dysfunction, supplementation with a C1INH protein concentrate to restore functional levels of C1INH activity addresses the fundamental cause of HAE attacks directly. The introduction of exogenous C1INH protein can restore control over the physiological cascades that lead to bradykinin release, thereby reducing HAE attacks.11–13 For long-term prophylaxis, plasma-derived C1INH can be administered intravenously or subcutaneously (SC) twice weekly.11,14,15 Another approach to HAE treatment is to inhibit plasma kallikrein to reduce bradykinin release from high-molecular-weight kininogen. Lanadelumab, a fully human monoclonal antibody, inhibits plasma kallikrein by binding to its active site, preventing the proteolysis of high-molecular-weight kininogen.45 Lanadelumab is administered SC every 2 to 4 weeks.11,17 Berotralstat is a synthetic small molecule that also inhibits kallikrein’s proteolytic activity, but is administered orally once daily.19,46 Garadacimab, a fully human antibody administered SC once monthly, binds to and inhibits Factor XIIa and reduces the eventual production of bradykinin.20,47 The rest of this report focuses on the mechanism of and clinical data for donidalorsen, an ASO that reduces plasma prekallikrein production.

Donidalorsen Mechanism of Action

Donidalorsen, formerly known as IONIS-PKK-L_Rx and ISIS 721744, takes a unique approach to the prevention of HAE attacks by specifically targeting the production of plasma prekallikrein in the liver, its primary site of production (Figure 1).26,27 Donidalorsen is an ASO conjugated to a triantennary N-acetyl galactosamine (GalNAc) moiety. The GalNAc moiety enables targeted uptake of donidalorsen into the liver via the asialoglycoprotein receptor, which is highly expressed on hepatocytes.48,49 Uptake into hepatocytes occurs via receptor-mediated endocytosis.1 After uptake, the GalNAc moiety is cleaved from the ASO, which is released into the cytosol.48–50 Targeted delivery to hepatocytes with GalNAc conjugation can increase ASO potency by up to 30 times compared with unconjugated ASOs.26,51 GalNAc conjugation also increases the duration of effect of ASOs, allowing for reduced dosing frequency, and can improve their safety and tolerability.52–54

Figure 1.

(A) Donidalorsen mechanism of action; (B) the kallikrein-kinin system. (A) Donidalorsen is a GalNAc-conjugated ASO. It binds to the ASGR on hepatocytes and is taken into the cell by receptor-mediated endocytosis. The ASO is cleaved from the GalNAc moiety inside the endosome and enters the nucleus, where it binds to plasma prekallikrein mRNA. The ASO:mRNA duplex is recognized by RNase H1 endonucleases that cleave plasma prekallikrein mRNA, leading to its degradation and ultimately reducing the synthesis of plasma prekallikrein. (B) The kallikrein-kinin system, which is dysregulated in HAE. After autoactivation of Factor XII, in the absence of inhibition by C1INH, Factor XIIa activates plasma prekallikrein to plasma kallikrein. Plasma kallikrein, if not inhibited by C1INH, cleaves high-molecular-weight kininogen to release the bradykinin peptide. Bradykinin binds to the bradykinin B2 receptor on vascular endothelial cells, which ultimately leads to fluid extravasation and tissue swelling. The reduction of circulating plasma prekallikrein by donidalorsen activity in the liver leads to decreased kallikrein-mediated bradykinin release, thereby reducing HAE attacks. Figure created using BioRender (https://www.biorender.com/).

Abbreviations: ASGR, asialoglycoprotein receptor; ASO, antisense oligonucleotide; C1INH, C1 inhibitor; GalNAc, triantennary N-acetyl galactosamine; HAE, hereditary angioedema; mRNA, messenger RNA; RNase H1, ribonuclease H1.

The donidalorsen ASO binds to a 20-nucleotide sequence in exon 9 of plasma prekallikrein mRNA through Watson-Crick base pairing.1,55 The 5 nucleotides at each end of the ASO are 2′-O-(2-methoxyethyl)–modified ribonucleotides, which increase the affinity for the target mRNA and resistance to nucleases. The central portion of the donidalorsen ASO is composed of 10 deoxynucleotides; thus, binding of the ASO to plasma prekallikrein mRNA triggers the recruitment of endogenous ribonuclease H1, which degrades the plasma prekallikrein mRNA in the mRNA:ASO duplex. This reduces the availability of plasma prekallikrein mRNA for translation, ultimately reducing plasma prekallikrein protein synthesis and circulating plasma prekallikrein concentrations.26,55 Within the kallikrein-kinin system, reduction of plasma prekallikrein leads to less kallikrein, and therefore reduced release of bradykinin from high-molecular-weight kininogen.55 As bradykinin signaling causes the vasodilation, increased vascular permeability, and fluid extravasation associated with HAE attacks, reduction of bradykinin is expected to reduce HAE attack incidence and severity.56

Clinical Studies of Donidalorsen

Phase 1

The first clinical study of donidalorsen was a phase 1, randomized, double-blind, placebo-controlled, dose-escalation study (NCT03263507) to assess the safety, tolerability, and pharmacodynamics of donidalorsen in healthy volunteers.27,51 In this study, 32 adults were randomized 3:1 to donidalorsen or placebo in 4 sequential cohorts with ascending doses of 20, 40, 60, and 80 mg SC. Data from the phase 1 study were reported in tandem with a compassionate-use pilot study, which provided early efficacy data in 2 patients with severe bradykinin-mediated angioedema, including 1 patient with HAE-nC1INH.

Phase 2

With no safety concerns identified in the phase 1 study, a phase 2, randomized, double-blind, placebo-controlled trial (NCT04030598) was conducted to study the efficacy and safety of donidalorsen in patients with HAE-C1INH-Type1 or HAE-C1INH-Type2.26 Twenty adult patients with documented HAE-C1INH-Type1 or HAE-C1INH-Type2 diagnoses were assigned to receive donidalorsen 80 mg (n = 14) or placebo (n = 6) once every 4 weeks (Q4W) for 16 weeks (Figure 2). Three patients with HAE-nC1INH (confirmed based on a threshold-stimulated kallikrein activity assay and investigator-confirmed response to acute treatment for bradykinin-mediated angioedema) were also enrolled in a parallel open-label study to receive donidalorsen 80 mg Q4W. The primary endpoint was the time-normalized number of investigator-confirmed HAE attacks per month, and safety, pharmacodynamics, and quality of life were also assessed. Seventeen (85%) of the patients continued into the corresponding OLE of the phase 2 study (NCT04307381).28 In the OLE, all patients received donidalorsen 80 mg Q4W for the first 12 weeks. Then, a flexible dosing period began at Week 16, in which patients could change dose to 80 mg with once-every-8-weeks (Q8W) dosing if they were attack-free for at least 12 weeks, after which they could revert to Q4W dosing if attacks were not adequately controlled. Data have been published for up to 4 years of the phase 2 OLE.28,57

Figure 2.

Study design of phase 2 and phase 3 clinical trials of donidalorsen.

Abbreviations: C1INH, C1 inhibitor; HAE, hereditary angioedema; LTP, long-term prophylactic medication; nC1INH, normal C1INH; Q4W, once every 4 weeks; Q8W, once every 8 weeks.

Phase 3

A phase 3, global, double-blind, randomized, placebo-controlled trial (OASIS-HAE; NCT05139810; Figure 2) to evaluate the efficacy and safety of donidalorsen was completed in 2024.22 In OASIS-HAE, patients 12 years of age or older with HAE-C1INH-Type1 or HAE-C1INH-Type2 received donidalorsen 80 mg or placebo SC for 24 weeks. In addition to the Q4W dosing schedule used in the phase 2 study, OASIS-HAE included a Q8W dosing regimen to evaluate the efficacy and safety of less frequent dosing. Of 90 patients dosed, 45 received donidalorsen Q4W, 23 received donidalorsen Q8W, and 22 received placebo (pooled across Q4W and Q8W). The primary endpoint was the time-normalized number of investigator-confirmed HAE attacks (per month) from Week 0 to Week 24 (monthly attack rate). Safety, pharmacodynamics, and multiple patient-reported outcomes were also assessed.

The phase 3 program for donidalorsen also includes the ongoing OASISplus study (NCT05392114), which is composed of 2 cohorts (Figure 2): the OLE cohort and the Switch cohort.29 The OLE cohort consists of 83 patients (94% of eligible patients; Q4W, n = 69; Q8W, n = 14) who rolled over from OASIS-HAE.58 All patients, including those in the placebo group, received donidalorsen 80 mg Q4W in the OLE cohort, unless they were on the Q8W dosing schedule in OASIS-HAE and were attack-free for ≥8 weeks, in which case they continued with Q8W dosing. Six of the patients in the Q4W group had received donidalorsen Q8W in OASIS-HAE and changed dosing for the OLE. Thus, 14 of 21 patients who completed OASIS-HAE in the Q8W group enrolled in OASISplus and continued Q8W dosing. Results for this ongoing study have been published for up to 1 year of treatment.58

The safety and efficacy of transitioning to donidalorsen from another LTP are under evaluation in the OASISplus Switch cohort.59 In this cohort, a group of patients who were on stable doses of berotralstat (n = 11), intravenous or SC C1INH (n = 22), or lanadelumab (n = 31) remained on their prior LTP dose during a 10-week screening period prior to switching directly to donidalorsen 80 mg Q4W.60 To avoid increases in attacks during the transition period between LTPs, patients switched from their prior LTP to donidalorsen with no washout, per a prespecified algorithm that varied according to the half-life of the prior LTP (Table 1). Patients previously on lanadelumab took their last dose approximately 2 weeks prior to the first dose of donidalorsen, while patients previously on C1INH or berotralstat continued on their prior treatment for approximately 2 weeks after their first dose of donidalorsen. To date, data have been published for up to 1 year of donidalorsen treatment for this cohort.60

Table 1.

OASISplus Switch Cohort Switching Procedure

Prior Long-Term Prophylactic Medication	Final Dose
Berotralstat	14 ± 3 days after the first dose of donidalorsen
C1INH	14 ± 3 days after the first dose of donidalorsen
Lanadelumab	14 ± 3 days before the first dose of donidalorsen

Abbreviation: C1INH, C1 inhibitor.

Donidalorsen Pharmacokinetics and Pharmacodynamics

The pharmacokinetic properties of donidalorsen have been evaluated in both healthy subjects and in patients with HAE.55,61 Donidalorsen is rapidly absorbed into systemic circulation after SC administration, with a median time to maximum plasma concentration of approximately 2 hours.23 Once absorbed, donidalorsen is expected to distribute primarily to the liver and kidney cortex. The half-life of the initial rapid clearance phase, which reflects tissue distribution, is approximately 5 hours. The terminal elimination half-life of donidalorsen is approximately 1 month. The oligonucleotide moiety of donidalorsen is expected to be metabolized to short oligonucleotide fragments by endo- and exonucleases in the liver. The linker that connects the oligonucleotide to the GalNAc moiety is cleaved by hydrolysis followed by dephosphorylation and oxidative metabolism to form inactive metabolites. Donidalorsen is not a substrate of cytochrome P450 (CYP) enzymes based on in vitro studies; however, the most abundant linker-related metabolite is a substrate of CYP3A4.

All available pharmacodynamics data from clinical studies indicate that donidalorsen reduces plasma prekallikrein concentrations. In the phase 1 dose-ranging study in healthy volunteers, donidalorsen resulted in a dose-dependent reduction in plasma prekallikrein concentrations. The highest dose, 80 mg, produced a 94% reduction from baseline to 2 weeks after the last dose, and plasma prekallikrein concentrations remained suppressed by 75% at 3 months after the last dose, highlighting the potential for a low-frequency, Q8W dosing schedule.27 Since donidalorsen targets plasma prekallikrein mRNA rather than acting directly on the plasma prekallikrein protein, the full clinical effects of donidalorsen would not be expected until the plasma prekallikrein produced prior to the first dose of donidalorsen has degraded.22 In circulation, plasma prekallikrein is bound to high-molecular-weight kininogen, which has an estimated half-life of 144 hours (6 days).62–64 After the passage of 5 half-lives, or approximately 4 weeks, the majority of preexisting plasma prekallikrein protein will be degraded by endogenous pathways.26 Therefore, HAE attack rate data beginning 4 weeks after the first dose of donidalorsen may be more representative of its clinical efficacy at steady state. Based on the observed reduction in plasma prekallikrein, and with no safety concerns identified, the 80-mg dose was chosen for use in the phase 2 study.26 In patients with HAE-C1INH-Type1 or HAE-C1INH-Type2 in the phase 2 study, plasma prekallikrein concentration was reduced by a mean of 61% over 16 weeks. A corresponding mean decrease of 58% in cleaved high-molecular-weight kininogen, a biomarker for bradykinin release that is increased during HAE attacks, was also observed.65 The reduction in plasma prekallikrein was correlated with the reduction in HAE attack rate, supporting donidalorsen’s mechanism of action. The plasma prekallikrein reduction in the phase 2 study was sustained in the OLE study, with a mean 51% reduction through 3 years.22 After 3 years of treatment, reductions in plasma prekallikrein were similar between patients who received donidalorsen Q4W and Q8W in the flexible treatment period. These data support the idea that less frequent Q8W dosing after initial Q4W dosing can be viable long-term, which could be important for patients due to the chronic nature of HAE. Plasma prekallikrein concentrations in the phase 3 OASIS-HAE study demonstrated a mean 73% reduction in the Q4W group and a 47% reduction in the Q8W group over 24 weeks.22 Overall, the clinical data collected to date indicate that donidalorsen substantially reduces plasma prekallikrein concentrations, as expected based on its mechanism of action.

Efficacy of Donidalorsen

Early clinical evidence for the efficacy of donidalorsen came from a compassionate-use pilot study of 1 patient with HAE-C1INH-Type1 and 1 patient with HAE-nC1INH of unknown genetic cause.27 Treatment with donidalorsen resulted in reduced HAE attack rates in both patients, with a complete cessation of HAE attacks for 30 weeks in the patient with HAE-C1INH-Type1. Though interpretation is limited because only 2 patients were studied, this pilot provided the first clinical data on donidalorsen’s efficacy as an LTP for preventing angioedema attacks.

Results of the phase 2 and phase 3 studies of donidalorsen provided robust evidence of its efficacy in reducing HAE attack rates (Table 2). In the phase 2 clinical trial, the mean HAE attack rate in the patients who received donidalorsen was 90% lower compared to patients who received placebo over Weeks 0 to 16 (P <0.001).26 Over study Weeks 4 to 16, corresponding to the period after existing plasma prekallikrein would have been degraded, the HAE attack rate in the donidalorsen group was 97% lower compared to the placebo group. All patients in the donidalorsen group except one (92%) were attack-free during this period. Notably, HAE attack rates also decreased in all 3 patients with HAE-nC1INH in the parallel open-label phase 2 study, though interpretation is limited by the small sample size.

Table 2.

Efficacy of Donidalorsen in the Phase 2 and Phase 3 Randomized Clinical Trials

Endpoint	Phase 2 Trial		Phase 3 Trial
	Donidalorsen n = 14	Placebo n = 6	Donidalorsen Q4W n = 45	Donidalorsen Q8W n = 23	Placebo n = 22
Primary endpoint
Number of attacks per month (95% CI)a,b	0.23 (0.08, 0.39)	2.21 (0.58, 3.85)	0.44 (0.27, 0.73)	1.02 (0.65, 1.59)	2.26 (1.66, 3.09)
Percent difference vs placebo (95% CI)	−90 (−96, −76)	—	−81 (−89, −65)	−55 (−74, −22)	—
P-value	<0.001	—	<0.001	0.004	—
Secondary endpoints
Number of attacks per month, following Week 4 (95% CI)a,c	0.07 (−0.08, 0.23)	2.06 (0.41, 3.72)	0.30 (0.15, 0.58)	0.90 (0.53, 1.52)	2.25 (1.59, 3.18)
Percent difference vs placebo (95% CI)	−97 (−100, −69)	—	−87 (−94, −72)	−60 (−79, −25)	—
P-value	—	—	<0.001	0.004	—
Clinical response, following Week 4c
Reduction in attack rate ≥50% per month, n (%)	13 (100)d	2 (33)	42 (93)	19 (83)	6 (27)
Odds ratio vs placebo (95% CI)	—	—	310 (12, 8280)	15 (3, 69)	—
P-value	—	—	—	—	—
Reduction in attack rate ≥70% per month, n (%)	12 (92)d	1 (17)	37 (82)	15 (65)	4 (18)
Odds ratio vs placebo (95% CI)	—	—	35 (7, 165)	9 (2, 41)	—
P-value	—	—	<0.001	0.004	—
Reduction in attack rate ≥90% per month, n (%)	12 (92)d	0	28 (62)	11 (48)	2 (9)
Odds ratio vs placebo (95% CI)	—	—	17 (3, 86)	9 (2, 49)	—
P-value	—	—	—	—	—
Attack-free status, following Week 4, n (%)c	12 (92)d	0	24 (53)	8 (35)	2 (9)
Odds ratio vs placebo (95% CI)	—	—	12 (2, 59)	3 (0.5, 23)	—
P-value	—	—	0.003	NS	—
Change in AE-QoL total scorea	−26.8	−6.2	−24.8	−19.9	—
Difference vs placebo (95% CI)	20.7 (8.7, 32.7)	—	18.6 (9.5, 27.7)	13.7 (3.3, 24.0)	—
P-value	—	—	<0.001	—	—
Well-controlled disease on the AECT, n (%)	—	—	41 (91)	—	9 (41)
Odds ratio vs placebo (95% CI)	—	—	14.8 (3.9, 56.1)	—	—

Notes: Dashes indicate data that have not been reported. ^aPhase 2, mean; phase 3, least-squares mean. ^bPhase 2, over Weeks 0 to 16; phase 3, over Weeks 0 to 24. ^cPhase 2, Weeks 4 to 16; phase 3, Weeks 4 to 24. ^dPercentage calculated using a denominator of n = 13.

Abbreviations: AECT, Angioedema Control Test; AE-QoL, Angioedema Quality of Life Questionnaire; CI, confidence interval; NS, not significant; Q4W, once every 4 weeks; Q8W, once every 8 weeks.

Based on its promising clinical efficacy in the phase 2 study, donidalorsen was advanced to a pivotal phase 3 trial.22 Over the full treatment period from Week 0 to Week 24, mean HAE attack rates were 81% lower in patients who received donidalorsen Q4W (P <0.001) and 55% lower in patients who received donidalorsen Q8W (P = 0.004) compared with those who received placebo. From Weeks 4 to 24, corresponding to the period in which plasma prekallikrein produced prior to the study treatment would likely have been degraded, attack rates were reduced by a mean of 87% in the Q4W group (P <0.001) and 60% in the Q8W group (P = 0.004) vs placebo. The rates of moderate to severe attacks and attacks that required on-demand therapy were also significantly reduced by 89% and 92%, respectively, in the Q4W group vs placebo (both P <0.001). While Q4W dosing appeared to be more effective than Q8W dosing in reducing HAE attack rates over the course of the study treatment, at Week 24, the reductions in attack rate in the Q4W and Q8W groups were similar. These data suggest that the difference in efficacy between dosing regimens may be explained by the longer time to reach steady state with Q8W dosing. Accordingly, patients may benefit from starting on a Q4W dosing regimen to more rapidly reduce HAE attack rates, then changing to the potentially more convenient Q8W dosing regimen for maintenance if they are attack-free. Patients could then revert to Q4W dosing if needed. Based on these data, dosing may be individualized for each patient based on shared decision-making with the HAE specialist and regulatory guidance.

Long-Term Efficacy of Donidalorsen

The long-term efficacy of donidalorsen was studied in the completed phase 2 OLE and is under study in the ongoing phase 3 OASISplus OLE. Published data from up to 4 years of the phase 2 OLE show that the reductions in HAE attack rate during the randomized trial have been sustained for an extended period.57 Among all patients in the study, there was a mean 97% reduction in attack rate from baseline of the phase 2 randomized study through the 4-year on-treatment period. As noted above, the phase 2 OLE included a flexible dosing period in which patients could change to Q8W dosing if they were attack-free for at least 12 weeks. Over the course of the study, 8 patients changed from Q4W to Q8W dosing. Efficacy was dependent on the dosing frequency; there was a mean reduction in HAE attack rate of 83% in patients who received donidalorsen Q8W vs 97% in patients who received donidalorsen Q4W. The median longest attack-free interval was 990 days, or approximately 2.7 years. Up to the completion of this trial after 4 years, 5 of 17 (29%) patients remained on Q8W dosing until the end of the study, 2 of whom remained attack-free for the entire on-treatment period. Thus, a substantial proportion of patients were able to transition from Q4W to Q8W dosing and maintain complete disease control for an extended period of time. Though the sample size is small, this provides support for the idea proposed above that some patients may benefit from a regimen in which they start with Q4W treatment, then move to a Q8W dosing schedule if they are attack-free.

The HAE attack rate reductions in the phase 3 OASIS-HAE study were sustained in the phase 3 OASISplus OLE for up to 1 year (Figure 3).58 Compared to baseline HAE attack rates prior to OASIS-HAE, there were mean 94% and 95% reductions in patients who rolled over to donidalorsen Q4W or Q8W, respectively. These reductions were accompanied by a median longest attack-free duration of 282 days as of Week 52. The rates of moderate or severe HAE attacks and attacks requiring on-demand treatment from Weeks 4 to 52 were both reduced by 94%. Overall, data from the OLE studies indicate that the strong efficacy observed in the phase 2 and phase 3 randomized studies can be sustained long-term with continued donidalorsen treatment.

Figure 3.

HAE attack rates in OASIS-HAE and the OASISplus OLE cohort. ^aIncludes patients who received donidalorsen Q4W in OASIS-HAE and continued Q4W dosing in the OLE (n = 44) and those who changed from placebo (n = 19) or donidalorsen Q8W (n = 6) in OASIS-HAE to donidalorsen Q4W in the OLE.

Abbreviations: HAE, hereditary angioedema; OLE, open-label extension; Q4W, once every 4 weeks; Q8W, once every 8 weeks; SEM, standard error of the mean.

Efficacy of Donidalorsen in Patients Who Switched From Another LTP

As the goal of LTP treatment is for patients to be attack-free, but all available LTPs are associated with breakthrough HAE attacks in some patients, switching between therapies is an important option that should be considered.11,13,16,18,20,22 Specifically, it is important to understand whether it is safe to switch, if there is a benefit to switching LTPs, and how that switch should be managed.11,66 The ongoing OASISplus study includes an independent cohort of patients who switched directly from a previous LTP (berotralstat, C1INH, or lanadelumab) to donidalorsen.59,60

When patients switched from their previous LTP to donidalorsen, no transient increase in overall mean attack rate was observed during the transition, suggesting that patients can switch from other LTPs to donidalorsen without a washout period.60 Mean HAE attack rate was reduced by 68% overall from baseline on the prior LTP in patients who switched directly from a prior LTP to donidalorsen for 1 year. The largest reduction in HAE attack rate (83%) was observed for patients switching to donidalorsen from berotralstat, with substantial reductions also observed in patients switching from lanadelumab (64%) and C1INH replacement (51%). Overall, these data indicate that switching to donidalorsen could be an effective option for patients seeking alternative LTP options and provide a potential procedure for making this switch in a safe manner.

Safety of Donidalorsen

In all clinical studies to date, donidalorsen had an acceptable safety and tolerability profile (Table 3). Across studies, most adverse events were mild to moderate.22,26–28,57,58,60 One serious adverse event related to the study drug has been reported across all studies; a patient receiving donidalorsen Q4W in the OASISplus OLE experienced a serious type 1 hypersensitivity reaction after their 29th dose (approximately 27 months) of donidalorsen, which resolved on the same day following acute treatment, after which the patient discontinued donidalorsen. One patient in the phase 2 OLE, 1 patient in OASIS-HAE, 3 patients in the OASISplus OLE cohort, and 1 patient in the OASISplus Switch cohort discontinued due to adverse events; no patients discontinued from the compassionate-use pilot study or the phase 2 randomized study due to adverse events. The most common treatment-emergent adverse events (≥10%) in OASIS-HAE were headache (Q4W, 13%; Q8W, 9%; placebo, 18%), injection-site erythema (Q4W, 13%; Q8W, 4%; placebo, 0), nasopharyngitis (Q4W, 11%; Q8W, 13%; placebo, 18%), influenza (Q4W, 4%; Q8W, 17%; placebo, 9%), and limb injury (placebo, 18%). The only adverse events considered possibly related to the study treatment reported by ≥5% of patients in OASIS-HAE were injection-site reactions (Q4W, 20%; Q8W, 4%; placebo, 0) and headache (Q4W, 7%; Q8W, 0; placebo, 14%). Specific injection-site reactions included erythema, discoloration, pruritus, and pain.67 In OASIS-HAE, all injection-site reactions were mild. Other than the single serious hypersensitivity event, no major safety concerns have been identified in donidalorsen clinical trials, and the primary side effects that can be expected based on these trials are mild injection-site reactions or headache.

Table 3.

Safety of Donidalorsen in the Phase 2 and Phase 3 Clinical Trials

Event, n (%)	Phase 2 Trial		Phase 3 Trial
	Donidalorsen n = 14	Placebo n = 6	Donidalorsen Q4W Group n = 45	Donidalorsen Q8W Group n = 23	Placebo n = 22
Any AE	10 (71)	5 (83)	33 (73)	14 (61)	18 (82)
Drug-related AEs	4 (29)	4 (67)	19 (42)	4 (17)	6 (27)
AEs leading to treatment discontinuation	0	0	0	1 (4)	0
Serious AEs	0	0	0	0	1 (5)
Drug-related serious AEs	0	0	0	0	0

Abbreviation: AE, adverse event; Q4W, once every 4 weeks; Q8W once every 8 weeks.

While plasma prekallikrein plays a critical role in the coagulation and fibrinolytic systems, plasma prekallikrein deficiency is not associated with increased thrombotic or bleeding risk in vivo, although complete plasma prekallikrein deficiency is associated with prolonged activated partial thromboplastin time.68,69 Notably, no coagulation abnormalities have been reported with donidalorsen treatment in any clinical study.22,26–28 Further, a specific post-hoc analysis of coagulation and fibrinolytic activity assays from the phase 2 study did not identify any significant changes between measurements taken at baseline and after donidalorsen treatment, or between the donidalorsen and placebo groups.68 Consistent with these observations, donidalorsen has not been reported to increase thrombotic or bleeding risk.

No clinically significant changes in laboratory liver function tests were reported in the phase 1, phase 2, or phase 2 OLE studies.22,26–28 In OASIS-HAE, 2 patients receiving donidalorsen had transient increases in alanine aminotransferase (ALT) greater than 3 times the upper limit of normal (ULN).22 However, 1 patient had a history of liver disease, and their ALT levels resolved during the study. The other patient had been receiving androgen treatment for over 15 years before study entry, which is known to affect liver function.44,70,71 In the OASISplus OLE, 3 patients had ALT elevations greater than 3 times the ULN; the study drug was withdrawn for 1 of these patients and ALT levels recovered, and the transient ALT increases recovered without discontinuation in the other 2 patients.58

Reproductive safety data for donidalorsen remain very limited, with a small number of patient pregnancies across the clinical program. Among 5 patient pregnancies, 2 resulted in normal healthy baby deliveries, 2 were terminated in elective abortions, and 1 patient had a spontaneous abortion, which the investigator judged as unlikely to be related to the study drug due to the patient’s weight, comorbidities, concomitant medications, and advanced maternal age, which is a demonstrated risk factor for spontaneous abortion.72,73 In all cases, female patients discontinued from the study drug upon confirmation of pregnancy. In animal reproduction studies in mice, donidalorsen doses up to 5 times the maximum recommended human dose did not result in any adverse effects on embryofetal development, or behavioral, fertility, and reproductive development in F1 offspring.23 Moreover, donidalorsen did not cross the placental barrier.

Impact of Donidalorsen Treatment on Patient-Reported Outcomes

While prevention of HAE attacks is the primary goal of LTPs, based on guidelines that include the goal of normalizing life for patients, quality of life and disease control are also important aims of treatment for HAE. Moreover, while high attack rates are often associated with poor quality of life, some patients experience impaired quality of life even with low attack rates, indicating that quality of life should be assessed specifically and separately from assessments of HAE disease activity.10,11 Therefore, clinical studies of donidalorsen have integrated an extensive series of patient-reported outcome measures.

Quality of life was assessed using the Angioedema Quality of Life Questionnaire (AE-QoL) in the phase 2 and phase 3 studies.22,26,28,74 Patients reported improvements in quality of life across all of these studies. AE-QoL total scores decreased by 26.8 points (out of 100) in patients receiving donidalorsen Q4W in the phase 2 study, which was sustained for up to 3 years of treatment in the phase 2 OLE study (mean decrease of 21.3 points).26,28 In OASIS-HAE, a least-squares mean improvement of 24.8 points was observed in patients who received donidalorsen Q4W (P <0.001), and patients in the donidalorsen Q8W group also reported better improvement in overall quality of life vs placebo (19.9 points).22 The positive impact on quality of life has been sustained for up to 1 year in the OASISplus OLE (mean decreases of 28.1 [Q4W] and 26.7 [Q8W] points).58 Patients who switched to donidalorsen from another LTP in OASISplus also reported better quality of life on the AE-QoL at 1 year vs baseline on their prior LTP (12.2 points).60 In all of these studies, changes in AE-QoL total scores exceeded the minimum clinically important difference (≥6 points)75 in the donidalorsen groups, indicating patients experienced clinically meaningful improvements in overall health-related quality of life after treatment with donidalorsen. On a more granular level, the AE-QoL produces scores for 4 domains of quality of life: Functioning, Fatigue/Mood, Fears/Shame, and Nutrition.74 In the phase 2 donidalorsen study, numerical improvements were observed across all AE-QoL domains in patients receiving donidalorsen, and were sustained for up to 4 years in the OLE study.26,57 In OASIS-HAE, patients reported nominally significant improvements in the Functioning, Fears/Shame, and Nutrition domains in both the donidalorsen Q4W and Q8W groups vs placebo.76 Overall, the clinical data show that patients broadly report increased quality of life while receiving donidalorsen treatment.

While changes in HAE attack rate provide an objective measure of the efficacy of LTPs, patients’ subjective perception of disease control can be captured using the validated Angioedema Control Test (AECT).77 In OASIS-HAE, patients reported improvements on the AECT, indicating that the aforementioned decrease in HAE attack rate with donidalorsen was accompanied by an improvement in patients’ perception of their control over HAE. Changes in AECT scores were clinically meaningful (>3 points)78 in both donidalorsen groups. Using a categorical assessment of disease control based on AECT total scores, 91% of patients in the donidalorsen Q4W group and 74% of patients in the Q8W group reported well-controlled disease (AECT score ≥10) at Week 24, compared with only 41% of placebo-treated patients.22,79 Moreover, approximately half of patients in both donidalorsen groups (Q4W, 51%; Q8W, 48%) reported complete disease control (maximum AECT score = 16) at Week 24, achieving the consensus primary goal of treatment for HAE, vs only 18% of patients in the placebo group.76 Improvements in disease control were sustained in the OASISplus OLE, with 97% of patients reporting well-controlled disease at Week 52.58 Further, 90% of patients in the OASISplus Switch cohort reported well-controlled disease on the AECT 1 year after they switched to donidalorsen, an increase from 67% of patients at baseline on their prior LTPs.60

In addition to the AE-QoL and AECT, OASIS-HAE and OASISplus also included several other patient-reported outcomes. Patients in the donidalorsen Q4W group reported that treatment with donidalorsen improved their work/school productivity and ability to participate in normal activities of daily living based on the Work Productivity and Activity Impairment Questionnaire plus Classroom Impairment Questions.76,80,81 Moreover, over 90% of patients in both donidalorsen groups reported overall improvements on the Patient Global Impression of Change scale, with approximately 80% of patients in each group reporting feeling “much better” at Week 24 on donidalorsen.22,82 Finally, 82% of patients receiving donidalorsen Q4W reported less severe disease at Week 24 compared with baseline on the Patient Global Impression of Severity scale. In OASISplus, patients switching from any of the prior LTPs to donidalorsen reported numerically higher global satisfaction with donidalorsen compared to their previous LTP on the Treatment Satisfaction Questionnaire for Medication II.59 Overall, 84% of patients preferred donidalorsen over their prior LTP at Week 16, with the majority of patients preferring donidalorsen regardless of which prior LTP they used. Common reasons for patients’ preference for donidalorsen included that it worked better to control their disease, took less time for administration, or resulted in a lower level of injection-site pain or reactions. Thus, in addition to objective decreases in investigator-confirmed HAE attack rates, donidalorsen produced substantial improvements in patients’ self-reported disease status across multiple assessments.

Discussion

Data from the clinical studies indicate that reduction of plasma prekallikrein with donidalorsen substantially reduced HAE attack rates with an acceptable profile of safety and tolerability. While all LTPs for HAE target components of the kallikrein-kinin system, donidalorsen is unique in its targeting of plasma prekallikrein, upstream of the kallikrein dysregulation and bradykinin overproduction that causes HAE attacks.11,26,36 Donidalorsen is also first in class as an RNA-targeted treatment for HAE that reduces plasma prekallikrein production at the source. As a GalNAc-conjugated ASO, donidalorsen is designed to specifically reduce the production of plasma prekallikrein by degrading plasma prekallikrein mRNA in the liver, thereby reducing the circulating concentration of plasma prekallikrein in the blood.1 In patients with HAE, this reduction in plasma prekallikrein ultimately leads to reduced bradykinin release and decreased incidence and severity of HAE attacks.26 The effectiveness of this mechanism of action as an LTP for HAE has been supported by the clinical studies to date.

Although several approved LTPs that reduce HAE attack rate exist, more safe and effective options benefit patients with HAE. Patients have heterogenous treatment preferences, and many switch medications due to breakthrough attacks or treatment burden.66,83 Major factors that could affect patients’ treatment preferences include the magnitude of reduction in HAE attack rate, side effect/adverse event type and rate, route of administration, and frequency of administration.24 Data from the clinical studies show that donidalorsen has a favorable treatment profile. Donidalorsen reduced HAE attack rates and improved patients’ self-reported quality of life and disease control with Q4W or Q8W dosing regimens, and no major safety concerns were identified. In particular, for the best clinical outcome, the data support a dose-switching regimen in which patients start on Q4W dosing to drive down HAE attack rates before transitioning to Q8W dosing if they experience no attacks for 12 weeks. The potential for Q8W dosing is a distinguishing factor for donidalorsen among LTPs for HAE, with other approved LTPs ranging in dosing frequency from daily to monthly. For patients who may choose to switch to donidalorsen from another LTP, data from the Switch cohort of the OASISplus study provides a potential procedure for making the switch based on the patients’ previous LTP, while avoiding transient increases in HAE attacks and without major safety concerns. Importantly, patients may have entered the OASISplus study Switch cohort for a variety of reasons related to their prior LTP: lack of efficacy, the side effect profile, the schedule/route of dosing, or another reason. Therefore, the study population may not be representative of patients on these other LTPs as a whole, but of the subgroup of those patients who are motivated to change their therapy. Future studies should provide more data on donidalorsen’s long-term efficacy and safety. Overall, the clinical data support donidalorsen as a treatment for the management of HAE.

Conclusion and Perspective

The clinical development program for donidalorsen represents a significant advancement in prophylactic treatment for HAE. Across phase 2 and phase 3 studies, donidalorsen consistently demonstrated robust and sustained reductions in HAE attack rates, along with meaningful improvements in health-related quality of life and high patient satisfaction. Additionally, donidalorsen’s favorable safety profile, low dosing frequency, and targeted mechanism of action that selectively reduces plasma prekallikrein offer a differentiated therapeutic option for patients with HAE. As the field of HAE treatment continues to evolve, donidalorsen highlights the value of RNA-targeted technology in precisely addressing the pathophysiology of rare genetic diseases with a low propensity for immunogenicity and drug-drug interactions.84,85 With the recent FDA approval of donidalorsen,23 future research directions may include evaluating its long-term safety in broader real-world populations and assessing its efficacy in specific subgroups. In summary, donidalorsen shows great promise as a next-generation prophylactic therapy for HAE that comprehensively addresses challenges with treating this chronic disease. Its continued clinical development and post-marketing evaluations are expected to influence future standards of care for patients with HAE.

Funding Statement

This work was funded by Ionis Pharmaceuticals, Inc.

Abbreviations

AECT, Angioedema Control Test; AE-QoL, Angioedema Quality of Life Questionnaire; ALT, alanine aminotransferase; ASO, antisense oligonucleotide; C1INH, C1 inhibitor; CYP, cytochrome P450; FDA, US Food and Drug Administration; GalNAc, triantennary N-acetyl galactosamine; HAE, hereditary angioedema; LTP, long-term prophylactic medication; mRNA, messenger RNA; nC1INH, normal C1 inhibitor; OLE, open-label extension; Q4W, once every 4 weeks; Q8W, once every 8 weeks; SC, subcutaneous(ly); ULN, upper limit of normal.

Disclosure

M.A.R. has received research grants from Astria, BioCryst, BioMarin Pharmaceutical, CSL Behring, Intellia Therapeutics, Ionis, KalVista, Pharvaris, and Takeda; consulted for ADARx, Astria, BioCryst, BioMarin Pharmaceutical, Celldex, CSL Behring, Cycle Pharma, Grifols, Intellia Therapeutics, Ionis, KalVista, Novartis, Pharming, Pharvaris, Sanofi-Regeneron, and Takeda; and provided speaker presentations for BioCryst, CSL Behring, Grifols, Pharming, Pharvaris, and Takeda. T.C. has received research support from ADARx, Argo, Astria, BioMarin Pharmaceutical, CSL Behring, Intellia Therapeutics, Ionis, KalVista, Pharvaris, and Takeda; consulted for ADARx, Astria, BioMarin Pharmaceutical, CSL Behring, Grifols, Intellia Therapeutics, Ionis, KalVista, Pharvaris, and Takeda; and provided speaker presentations for Astria, CSL Behring, Grifols, Ionis, KalVista, and Takeda. W.R.L. has received honoraria and/or research grant support from AstraZeneca, Astria, BioCryst, BioMarin Pharmaceutical, CSL Behring, Eli Lilly, Grifols, GSK, Intellia Therapeutics, Ionis, KalVista, Pharming, Pharvaris, Sanofi-Regeneron, Shire/Takeda, Teva, and Upstream Bio; and is a member of the US Hereditary Angioedema Association Medical Advisory Board. L.B., S.T., A.Y., and K.B.N. are employees of Ionis and hold shares and/or options in Ionis. D.M.C. has received speaker or consultancy fees from Astria, BioCryst, CSL Behring, Intellia Therapeutics, Ionis, KalVista, Otsuka Pharmaceutical Europe Ltd., Pharvaris, and Takeda.

The authors report no other conflicts of interest in this work.