December 03, 2025
3 min read
Key takeaways:
- Around 6 months after lonvoguran ziclumeran infusion, researchers reported a –86% change in plasma kallikrein from baseline.
- At 6, 12, 18, 24 and 30 months, more than 80% of patients were attack-free.
ORLANDO — Among adults with hereditary angioedema, a one-time infusion of lonvoguran ziclumeran immediately lowered the average monthly attack rate and was well tolerated up to 3 years, according to pooled study results.
These data on lonvoguran ziclumeran (lonvo-z, NTLA-2002; Intellia Therapeutics) were presented at the American College of Allergy, Asthma & Immunology Annual Scientific Meeting.
“Lonvoguran ziclumeran … is designed to inactivate the KLKB1 gene and prevent production of kallikrein, and thereby reducing bradykinin to reduce angioedema attacks in patients with hereditary angioedema,” Danny M. Cohn, MD, PhD, medical specialist of vascular medicine at Amsterdam UMC, said during his presentation.
In a pooled analysis of ongoing phase 1 (open-label, single ascending dose) and phase 2 (randomized, double-blind, placebo-controlled) study data, Cohn and colleagues assessed 32 adults (median age, 48.5 years; 50% women) with hereditary angioedema (HAE) type 1 or 2 who received an IV infusion of investigational one-time lonvo-z 50 mg to determine the drug’s impact on kallikrein and attack rate over 2 years.
The infusion takes 2 to 4 hours and is done in an outpatient setting, according to Cohn.
The primary objective of each study differed, with Cohn highlighting that safety and tolerability was the primary endpoint for the phase 1 study, whereas the number of HAE attacks per month at 16 weeks was the primary endpoint for the phase 2 study.
The doses of lonvo-z used in phase 1 included 25 mg, 50 mg and 75 mg. In phase 2, only the 25 mg and 50 mg doses were studied.
“After unblinding of phase 2 and determining that 50 milligram was the optimal biological dose, all eligible patients that had previously received 25 milligrams or placebo could receive lonvo-z 50 mg [for the 88-week observation period],” Cohn said.
Notably, patients could enroll in a long-term follow-up study after completing the 2-year study period. Cohn highlighted that there are already 17 patients in this study as of the data cutoff date of Aug. 29.
Results
In the immediate time before entering the phase 1 or 2 study, Cohn noted that 56% of patients were taking a long-term prophylaxis treatment.
“Patients in phase 1 were allowed to continue their long-term prophylactic treatment, but patients in phase 2 needed to wash out immediately prior to their entry,” Cohn said.
In the phase 1/2 studies and long-term follow-up studies, 12.2 months was the median follow-up period, according to the presentation.
Around the 6-month mark, researchers reported a –86% change in plasma kallikrein from baseline. Cohn said this “deep, stable and durable reduction” continued to be seen when evaluated around the 11-month mark (–87%) and the 24-month mark (–89%).
When assessing attack-related outcomes, researchers found that the monthly rate of 3.4 at baseline immediately fell and stayed low. The monthly rate was 0.2 at 6 and 12 months, 0.1 at 18 months, 0.2 at 24 months and 0 at 30 months.
Further, at each of the above points, more than 80% of patients were attack-free.
In terms of long-term prophylaxis (LTP), Cohn reported that all patients who became attack-free and LTP-free for at least 6 months stayed this way over the follow-up period.
“Twenty-four patients have been attack-free and LTP-free for 7 to 32 months of follow-up and remain so at the last follow-up,” he said. “Seven patients have been attack-free and LTP-free for less than 6 months and follow-up is ongoing.
“One patient who has not yet achieved attack-free and LTP-free status still experienced a 59% reduction in angioedema attack rate as compared to baseline,” Cohn continued.
Safety
Researchers divided the reported treatment-emergent adverse events by time from infusion.
Within 28 days of infusion, 84% of patients experienced a treatment-emergent adverse event. The most frequent event was infusion-related reaction (53%), followed by fatigue (34%) and headache (19%). Cohn highlighted that most infusion-related reactions resolved within 24 hours.
Events only reported by one or two patients included abdominal pain, nasopharyngitis, upper respiratory tract infection, arthralgia and COVID-19. No serious adverse events occurred in this timeframe.
After the 28-day mark, researchers found that 94% of patients reported a treatment-emergent adverse event. The most frequent event in this timeframe was nasopharyngitis (25%), followed by upper respiratory tract infection (19%), back pain (16%), arthralgia (13%) and COVID-19 (13%). Events only reported by one or two patients included abdominal pain and headache.
“There were no clinically significant shifts in liver enzymes or coagulation parameters,” Cohn said. “One patient had a grade two event of elevated [aspartate aminotransferase] at the day of infusion, but that resolved without any intervention within 4 days.”
There was one serious adverse event reported 1 year after infusion, but Cohn noted that this pulmonary embolism event was resolved shortly after.
Notably, Cohn said there have been no serious or treatment-related adverse events reported by the 17 patients in the long-term follow-up study.
“We observed a well-tolerated safety profile with no long-term risks identified,” Cohn said.
“The ongoing HAELO phase 3 trial is further evaluating lonvo-z 50 mg and is fully enrolled as of this September,” Cohn continued.
Sources/Disclosures
Source:
Cohn DM, et al. Two-year durability/safety of one-time lonvoguran ziclumeran (lonvo-z, NTLA-2002) 50 mg in patients with hereditary angioedema. Presented at: ACAAI Annual Scientific Meeting; Nov. 6-10, 2025; Orlando.
Disclosures:
Cohn reports receiving speaking fees from CSL Behring, Ionis Pharmaceuticals, Pharvaris and Takeda; consultancy fees from Astria, BioCryst, CSL Behring, Ionis Pharmaceuticals, KalVista, Pharming, Pharvaris and Takeda; and research support from Ionis Pharmaceuticals, KalVista, Pharvaris and Takeda.
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