Donidalorsen is an investigational ligand-conjugated antisense (LICA) drug designed to target and reduce the production of prekallikrein (PKK), a precursor of plasma kallikrein. PKK plays a role in activating inflammatory mediators associated with HAE attacks. 

The global, multicenter, randomized, double-blind, placebo-controlled OASIS-HAE study (ClinicalTrials.gov Identifier: NCT05139810) enrolled 91 patients 12 years of age and older with type 1 and type 2 HAE. Study participants were randomly assigned 2:1 to receive either donidalorsen 80mg or placebo via subcutaneous injection once every 4 or 8 weeks for 24 weeks. Within each cohort participants were randomly assigned 3:1 to receive donidalorsen or placebo. 

Findings showed the study met its primary endpoint demonstrating a significant reduction in the rate of HAE attacks in patients who received donidalorsen every 4 weeks (P <.001) or every 8 weeks (P =.004) compared with placebo. No serious adverse events were observed with donidalorsen. 

“We are very pleased with the positive topline results from the phase 3 OASIS-HAE study of donidalorsen,” said Kenneth Newman, MD, senior vice president, head of clinical development at Ionis. “Based on these results and the durable efficacy and favorable safety data seen in the ongoing phase 2 open-label extension study, we believe donidalorsen, if approved, could be an attractive new treatment option for patients with HAE, many of whom continue to experience unpredictable, painful and severe breakthrough attacks despite currently available prophylactic treatments.”

Data from OASIS-HAE, as well as the OASIS-Plus extension study (ClinicalTrials.gov Identifier: NCT05392114), are expected to be presented at an upcoming medical congress.

Garadacimab is a first-in-class, recombinant monoclonal antibody designed to inhibit activated factor XIIa, a plasma protein responsible for initiating the kallikrein-kinin cascade of HAE attacks. 

The application is supported by data from the randomized, double-blind, parallel-group, placebo-controlled, phase 3 VANGUARD trial (ClinicalTrials.gov Identifier: NCT04656418), which evaluated the efficacy and safety of garadacimab in patients 12 years of age and older with type I or II HAE. 

Study participants were randomly assigned 3:2 to receive garadacimab (n=39) 400mg subcutaneously (SC) as a loading dose on day 1 followed by 200mg SC once monthly or placebo (n=25) for 6 months. The primary endpoint was the time-normalized number of HAE attacks per month during the treatment period.

Findings showed the number of investigator-confirmed HAE attacks per month was significantly lower in patients treated with garadacimab vs those who received placebo (0.27 [95% CI, 0.05-0.49] vs 2.01 [95% CI, 1.44-2.57]; P <.0001). This result corresponded to a mean attack rate reduction of 87% (95% CI, -96, -58; P <.0001). The median number of HAE attacks per month was 0 in the garadacimab arm and 1.35 in the placebo arm.

The most common treatment-emergent adverse events reported with garadacimab were upper respiratory tract infections, nasopharyngitis, and headaches. 

“We believe that garadacimab has the potential to become a promising therapy in the prevention of HAE attacks and we look forward to working closely with global health regulators throughout the review process,” said Emmanuelle Lecomte Brisset, Pharm D, Senior Vice President and Global Head of Regulatory Affairs at CSL.

Sebetralstat is a novel oral plasma kallikrein inhibitor designed to target the kallikrein-kinin system cascade. Researchers assessed the efficacy and safety of sebetralstat for on-demand treatment of angioedema attacks in 136 patients aged 12 years and older with hereditary angioedema (HAE) in the randomized, double-blind, placebo-controlled, 3-way crossover, phase 3 KONFIDENT trial (ClinicalTrials.gov Identifier: NCT05259917). 

Eligible study participants included those with a confirmed diagnosis of HAE type I or II. Study participants were randomly assigned to self-administer a single dose of sebetralstat 300mg (n=87), 600mg (n=93), or placebo (n=84) after recognizing the start of an attack (any location of the body and any severity, except severe laryngeal attacks, which were treated with conventional therapy). A second dose at least 3 hours after the first dose was allowed if the patient determined it was necessary.

The primary endpoint was the time to the beginning of symptom relief (defined as at least “a little better”) based on the Patient Global Impression of Change score (for ≥2 time points in a row) within 12 hours after the first dose. Key secondary endpoints included time to first incidence of decrease in severity from attack onset (≥1 level decrease on Patient Global Impression of Severity [PGI-S] for ≥2 time points in a row) within 12 hours and time to complete attack resolution (PGI-S rating of “none”) within 24 hours after the first dose.

Of the 136 participants included in the analysis, 110 patients treated at least 1 HAE attack; 87 attacks were treated with 1 to 2 doses of sebetralstat 300mg, 93 attacks were treated with 1 to 2 doses of sebetralstat 600mg, and 84 attacks were treated with 1 to 2 doses of placebo. 

Findings showed patients experienced significantly faster symptom relief from HAE attacks with sebetralstat 300mg (P <.0001) and 600mg (P =.0013) compared with placebo. Median time to beginning of symptom relief was reported to be 1.61 hours with sebetralstat 300mg (95% CI, 0.78-7.04), 1.79 hours with sebetralstat 600mg (95% CI, 1.02-3.79) and 6.72 hours with placebo (95% CI, 1.34, >12).

An analysis of secondary endpoints showed that attacks treated with sebetralstat 300mg (P =.0036) or 600mg (P =.0032) led to a significantly faster time to reduction in attack severity from baseline compared with placebo. Complete attack resolution was also found to be significantly faster with the 300mg (P =.0022) and 600mg (P <.0001) dosages compared with placebo.

Results also showed the proportions of attacks that reached the beginning of symptom relief without a second dose were 93.9% with sebetralstat 300mg and 95.8% with sebetralstat 600mg. The proportions of attacks reaching a reduction in severity without a second dose were 90.9% and 95.9% with sebetralstat 300mg and 600mg, respectively. For complete attack resolution, the proportions were 91.9% and 84.8%. 

“Given the unrestricted use of a second dose of oral sebetralstat in KONFIDENT, it was important to understand the proportion of attacks that achieved the primary and key secondary endpoints without a second dose,” said principal investigator Marc A. Riedl, MD, Professor of Medicine and Clinical Director, US Hereditary Angioedema Association Center at the University of California, San Diego. “What we observed was that the vast majority of attacks that successfully met the 3 endpoints did so with a single dose of sebetralstat.”

Sebetralstat was reported to have a similar safety profile to placebo, with adverse events occurring in 2.3%, 3.2%, and 4.8% of the 300mg, 600mg, and placebo groups, respectively.

The long-term safety and efficacy of sebetralstat is currently being investigated in a 2-year open-label extension trial (KONFIDENT-S; ClinicalTrials.gov Identifier: NCT05505916).

Disclosure: Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

The randomized, double-blind, event-driven, crossover study (ClinicalTrials.gov Identifier: NCT05259917) evaluated sebetralstat, an oral plasma kallikrein inhibitor, vs placebo for the on-demand treatment of HAE (type 1 and type 2) in adult and adolescent patients (N=136). Participants were randomly assigned to receive either sebetralstat 300mg or 600mg or placebo. The primary endpoint was the time to the beginning of symptom relief (defined as at least “a little better”) within 12 hours of administration based on the Patient Global Impression of Change score.

Findings showed patients experienced significantly faster symptom relief from HAE attacks with sebetralstat 300mg (P <.0001) and 600mg (P =.0013) compared with placebo. Median time to beginning of symptom relief was reported to be 1.61 hours with sebetralstat 300mg (95% CI, 1.28-2.27), 1.79 hours with sebetralstat 600mg (95% CI, 1.33-2.27) and 6.72 hours with placebo (95% CI, 2.33, >12).

An analysis of secondary endpoints showed that attacks treated with sebetralstat 300mg (P =.0036) or 600mg (P =.0032) led to a significantly faster time to reduction in attack severity from baseline compared with placebo. Complete attack resolution was also found to be significantly faster with the 300mg (P =.0022) and 600mg (P <.0001) dosages compared with placebo.

Sebetralstat was reported to have a similar safety profile to placebo, with adverse events occurring in 2.3%, 2.2%, and 4.8% of the 300mg, 600mg, and placebo groups, respectively.

“With no new on-demand therapies for HAE approved for nearly a decade, having a safe and effective oral, on-demand treatment for HAE attacks could be immensely valuable in addressing unmet needs and reducing the treatment burden associated with current injectable treatments,” said Marc A. Riedl, MD, professor of medicine and clinical director, US Hereditary Angioedema Association Center at the University of California, San Diego, and an investigator for the KONFIDENT phase 3 trial. “Against the backdrop of patient needs and opportunities, the results of this trial with sebetralstat are extremely encouraging for the HAE community.”

Findings from the KONFIDENT trial will be included in the New Drug Application that will be submitted to the Food and Drug Administration in the first half of 2024, according to KalVista Pharmaceuticals.

The Food and Drug Administration (FDA) has expanded the approval of Takhzyro^® (lanadelumab-flyo) for prophylaxis to prevent attacks of hereditary angioedema (HAE) in pediatric patients 2 to less than 12 years of age. Previously, the treatment was only approved for patients 12 years of age and older.

The approval was supported extrapolation of efficacy data from the phase 3 HELP study (ClinicalTrials.gov Identifier: NCT02586805), which included patients 12 to less than 18 years of age, along with safety and pharmacodynamic data from the open-label phase 3 SPRING study (ClinicalTrials.gov Identifier: NCT04070326). 

The SPRING study evaluated the safety and pharmacokinetics of lanadelumab to prevent acute HAE attacks in 21 patients 2 to less than 12 years of age. Lanadelumab was administered at a dose of 150mg subcutaneously every 4 weeks in patients 2 to less than 6 years of age and every 2 weeks in patients 6 to less than 12 years of age.

Findings from the SPRING study showed that treatment with lanadelumab reduced the rate of HAE attacks by a mean of 94.8% compared with baseline, from 1.84 attacks per month to 0.08 attacks during treatment. Moreover, 76.2% of patients were attack-free over the 52-week treatment period with an average of 99.5% attack-free days. No new safety signals were observed in these patients.

Takhzyro is currently supplied as a 300mg/2mL (150mg/mL) strength solution for subcutaneous injection in single-dose vials and prefilled syringes. A new single-dose prefilled syringe containing 150mg/1mL solution is expected to be available in the coming months.

References

1. US FDA approves Takeda’s Takhzyro^® (lanadelumab-flyo) to prevent hereditary angioedema (hae) attacks in children 2 years of age and older. News release. Takeda. February 3, 2023. Accessed February 6, 2023. https://www.businesswire.com/news/home/20230203005431/en/U.S.-FDA-Approves-Takeda%E2%80%99s-TAKHZYRO%C2%AE-lanadelumab-flyo-to-Prevent-Hereditary-Angioedema-HAE-Attacks-in-Children-2-Years-of-Age-and-Older.
2. Takhzyro. Package insert. Takeda; 2023. Accessed February 6, 2023. https://www.shirecontent.com/PI/PDFs/TAKHZYRO_USA_ENG.pdf.