On-demand treatment of swelling attacks in HAE patients
How does Kalbitor work?
Angioedema is a type of swelling that occurs when fluid builds up in the deeper layers of the skin, or in the mucus membranes lining the surface of internal organs and cavities in the body.
In HAE, a type of angioedema, this is due to genetic mutations that ultimately lead to the production and release of high levels of a signaling molecule called bradykinin. Too much bradykinin causes blood vessels to widen and leak fluid into tissues, resulting in recurrent swelling attacks that can arise suddenly in any part of the body.
Kalbitor contains ecallantide, a recombinant or lab-made protein that blocks the action of an enzyme in the blood called kallikrein. This enzyme is needed for the production of bradykinin. By inhibiting or blocking it, Kalbitor is expected to lower bradykinin levels and bring swelling under control.
Who can take Kalbitor?
Kalbitor was first approved by the U.S. Food and Drug Administration in December 2009 to treat acute swelling attacks in people with HAE, ages 16 and older. With that decision, Kalbitor became the first subcutaneous HAE treatment to earn approval in the country.
Kalbitor is contraindicated, or not recommended, for people who have a known hypersensitivity, or allergy, to the drug or its ingredients.
The therapy’s prescribing information also comes with a boxed warning noting that Kalbitor may cause anaphylaxis, or a severe, whole-body allergic reaction. Due to the risk of anaphylaxis, Kalbitor should only be administered by a healthcare professional who has access to proper medical support to deal with HAE and with anaphylaxis should it take place. At the same time, patients on the therapy should be closely monitored, and physicians should keep in mind the similarities of HAE symptoms and those of allergic reactions.
How is Kalbitor administered?
Kalbitor is supplied in single-use glass vials containing 10 mg/mL of a clear, colorless solution for injection. The recommended dose of Kalbitor is 30 mg (3 mL), given as three separate 10 mg (1 mL) subcutaneous injections in the abdomen, thigh, or upper arm. If symptoms persist, an additional dose of 30 mg may be given within 24 hours.
Injections may be given in the same or in different parts of the body, but should be spaced by at least five centimeters (about two inches) from each other and away from the site of swelling. They should only be administered by a doctor or nurse in a healthcare setting with appropriate medical support to manage both HAE and an allergic reaction, should it occur.
Kalbitor in clinical trials
Kalbitor was first approved based on results from two pivotal Phase 3 clinical trials, one called EDEMA3 (NCT00262080) and another called EDEMA4 (NCT00457015). The therapy’s label expansion to include patients as young as 12 also was supported by data from an open-label Phase 3 trial called DX-88/19 (NCT00456508).
Sponsored by Dyax, EDEMA3 assessed the safety and efficacy of Kalbitor against a placebo in 72 people with HAE type 1 or 2. The participants, ages 11 to 77, were randomly assigned to receive either 30 mg of Kalbitor or a placebo given as three subcutaneous injections within eight hours of experiencing an HAE attack.
The results showed that Kalbitor worked better than a placebo at easing symptoms. After four hours, the median Treatment Outcome Score (TOS), a patient-reported measure of response to treatment, was significantly higher in patients treated with Kalbitor than in those given a placebo (50 vs. 0 points).
The Mean Symptom Complex Severity (MSCS) score also dropped significantly more in patients treated with Kalbitor than in those on the placebo (median of 1 vs. 0.5 points), indicating less severe symptoms. While the difference was not significant, the median time to significant improvement, or feeling a little better, was shorter with Kalbitor than it was with the placebo (2.8 vs. 4 hours).
EDEMA4 was designed in very similar way to EDEMA3. It included 96 people with HAE type 1 or 2, ages 13 to 72, who were randomly assigned to either 30 mg of Kalbitor or a placebo, given as three subcutaneous injections within eight hours of experiencing an attack of HAE.
After four hours, the MSCS score dropped significantly more in patients treated with Kalbitor than in those on the placebo (0.8 vs. 0.4 points). Average TOS was significantly higher with Kalbitor than with placebo (53.4 vs. 8.1 points). The benefit of Kalbitor was apparent within two hours and maintained for up to an entire day. Fewer patients in the Kalbitor-treated group required medical intervention to treat unresolved symptoms compared with the placebo-treated group (33% vs. 50%).
Other analyses from EDEMA3 and EDEMA4 indicated that Kalbitor continued to be safe and ease symptoms after repeated dosing.
In DX-88/19, 147 patients with HAE type 1 or 2 received 30 mg of Kalbitor, given as three subcutaneous injections, to treat the symptoms of acute attacks. There was no limit on the number of treated attacks.
Consistent with findings from EDEMA3 and EDEMA4, MSCS scores dropped by more than 1 point after four hours, while mean TOS increased by at least 56.2 points. No new safety concerns were identified and there were no signs indicating that Kalbitor’s efficacy decreased with repeated dosing.
Common side effects of Kalbitor
The most common side effects that have been reported with Kalbitor during clinical testing are:
injection site reactions
inflammation of the nose and throat.
Allergic reactions, including anaphylaxis, may occur with Kalbitor within one hour after dosing. Symptoms of an allergic reaction may include chest discomfort, flushing, a swollen or sore throat, itching, a runny or blocked nose, sneezing, rashes or hives, known as urticaria, wheezing, and low blood pressure. Because some of these symptoms overlap with those of angioedema, patients should be monitored closely for signs of hypersensitivity for an appropriate period of time following dosing.
Use in pregnancy and breastfeeding
Available data from a Kalbitor pharmacovigilance database did not indicate that use of the therapy was associated with an increased risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, studies in rats indicated a potential risk of harm to the fetus.
It, therefore, is not known if Kalbitor is safe to use during pregnancy. Similarly, it also is unknown if the therapy passes into breast milk, affects milk production, or is safe for the breastfed infant.
Women who are pregnant, planning to become pregnant, or breastfeeding should consult their doctor before taking Kalbitor.
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