Analyses suggested that treatment with Takhzyro reduced the rates of HAE attack by 46–73% as compared with Cinryze in an indirect comparison of previous studies.
Titled “Indirect Comparison of Lanadelumab and Intravenous C1-INH Using Data from the HELP and CHANGE Studies: Bayesian and Frequentist Analyses,” the new study was published in the journal Drugs in R&D.
HAE is caused by the overproduction of bradykinin, a signaling molecule that promotes swelling. In HAE types 1 and 2, the overproduction of bradykinin is caused by the lack of functional C1-inhibitor, a protein that normally blocks the activity of kallikrein and other proteins that are involved in the production of bradykinin.
Takhzyro and Cinryze are both approved first-line treatments marketed by Takeda for HAE. While Cinryze is administered intravenously (directly into the bloodstream) twice weekly to replenish C1-inhibitor levels, Takhzyro is an antibody that works by blocking the activity of kallikrein. Takhzyro is given by a subcutaneous (under-the-skin) injection.
To date, no clinical trial has directly compared the effectiveness of these two medications. In the absence of such a direct comparison, researchers from Takeda and ICON, a medical device company, now used statistical analyses to compare results from separate trials that had tested these medications.
Specifically, the researchers analyzed data from two Phase 3 trials involving HAE patients. HELP (NCT02586805) evaluated the safety and efficacy of Takhzyro while CHANGE (NCT01005888) examined the effectiveness and safety of Cinryze.
Participants in HELP were randomly assigned to receive Takhzyro — either at a dose of 300 mg every two or every four weeks, or at a dose of 150 mg every four weeks — or were given a placebo, for a total of 26 weeks (six months).
However, the recommended starting dosage for this medication is 300 mg every two weeks, with the possibility of a reduction to once every four weeks in individuals who remain attack-free. Due to that, patients who received Takhzyro at a dose of 150 mg every four weeks in the trial were excluded from this analysis.
In CHANGE, patients were given either Cinryze at a dose of 1,000 units (U) every three to four days, or a placebo, for 12 weeks (about three months). After that, they were switched from Cinryze to a placebo or vice versa for an additional period of 12 weeks.
Here, the investigators used two kinds of statistical analyses to compare data from the two trials: a Bayesian approach and a frequentist approach. Conceptually, the Bayesian approach compares combined patient data from each trial, whereas the frequentist assesses data for individual participants in each trial.
Based on the two approaches, both Takhzyro and Cinryze were found to significantly reduce the frequency of swelling attacks, compared with a placebo.
From the Bayesian approach, treatment with Takhzyro resulted in a statistically significant decrease in the rates of swelling attacks compared with treatment with Cinryze. Specifically, the rates were 73% less when given every two weeks and 46% less when given every four weeks.
Treatment with Takhzyro also significantly reduced the risk of a first attack zero and 70 days following treatment initiation, compared with Cinryze using the Bayesian approach.
The frequentist approach yielded generally similar results. Compared with Cinryze, treatment with Takhzyro reduced the rates of swelling attacks by 73% when the medication was given every two weeks and by 46% when it was administered every four weeks. The risk of a first attack after zero or 70 days also was significantly reduced in this approach among those given Takhzyro compared with a placebo.
Additional analyses that took into account possible confounding factors, such as participants’ ages and weights, found “nearly identical” results, the researchers reported.
“Bayesian and frequentist approaches both indicated that [Takhzyro] dosages were associated with a favorable and statistically significant reduction in HAE attack rate compared with [intravenous Cinryze],” the team concluded.
“The findings from these respective methodologies are consistent, and support the efficacy of [Takhzyro] in reducing HAE attack rate and extending attack-free periods in patients with HAE,” they added.
The researchers also noted that this study — like any comparison that uses data from two different clinical trials — is limited by differences between the two trials, which could have impacted the results.
“Although HELP and CHANGE were broadly similar in terms of age, sex, and number of enrolled patients with HAE, residual heterogeneity [variation] in the included trials may have influenced the findings,” they wrote.
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