Acquired angioedema can be treated with off-label use of HAE therapies

Benefit with Firazyr, C1-INH concentrates seen in study for very rare condition

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A person looks at two different medicine choices, one an injection, the other a pill, held in each hand.

On-demand and preventive treatment with either icatibant injection or C1 inhibitor (C1-INH) concentrates — which are approved for hereditary angioedema (HAE) — also can help people with acquired angioedema keep swelling under control, according to a small study in Germany.

People severely affected with acquired angioedema and no “underlying condition or no indication for treatment could benefit from off-label therapy,” the researchers wrote,

The study, “Acquired angioedema due to C1-inhibitor-deficiency (AAE-C1-INH) — a bi-center retrospective study on diagnosis, course and therapy,” was published in the Journal of Allergy and Clinical Immunology: In Practice.

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Acquired angioedema often due to an underlying disease or condition

Angioedema is swelling that happens due to a buildup of fluid in the deeper layers of the skin or the mucosal lining of the digestive and respiratory organs.

Acquired angioedema, like HAE types 1 and 2, can occur with low levels of C1-INH, a protein that helps to control swelling. But unlike HAE, it is not caused by genetic mutations; typically, it’s due to an underlying condition, usually a cancer or an autoimmune disease.

“Being about 10-fold rarer than HAE there is limited knowledge and no licensed therapy [for acquired angioedema],” the researchers wrote.

“Because no controlled clinical trials have been done for this extremely rare disease, off-label treatment of [acquired angioedema] follows the principles for HAE treatment, with good effectiveness reported by several studies,” they added.

Researchers in Germany looked at the medical records of 20 adults (12 women and eight men) given a diagnosis of acquired angioedema at a median age of 63 at one of two centers in southern Germany.

Their goal was to describe the disease’s clinical and molecular features and the diagnostic delay in these patients, as well as to assess potential underlying conditions and treatment efficacy.

Patients’ symptoms started no earlier than age 40, and it took them a median of 7.5 months to be diagnosed. At these two centers, there were 194 patients with HAE, resulting in an acquired to hereditary angioedema ratio of 1 to 9.7, “which is in accordance to the data reported in literature,” the team wrote.

The most commonly reported site of swelling was the face (85%), followed by the abdomen (60%), and the hands and feet (55%). Throat swelling in three patients (15%) required admission to an intensive care unit.

Most patients (70%) showed very low C1-INH levels, one quarter (25%) had moderately low levels, and one patient (5%) had levels toward the low end of the normal range.

An underlying condition was identified in 14 patients (70%).

Nine had an underlying blood condition, including blood cancers, that for most was diagnosed a median of two months after that of acquired angioedema. For two of them, angioedema symptoms began after a blood condition diagnosis. The other five patients had a solid tumor or a history of a solid cancer.

“The diagnostic delay for [acquired angioedema] is decreasing and even shorter in case of an underlying [blood] condition as the potential cause,” the researchers wrote.

Treating the underlying condition was “the first-choice therapy,” they added, resulting in swelling control.

‘Good’ symptom control seen with HAE treatments used in small study

“For patients where no underlying disease could be identified or the disease had no indication for therapy, as well as for patients still suffering from [acquired angioedema] attacks waiting for the effects of the standard therapy, off-label treatment was offered,” the researchers wrote.

This consisted in on-demand therapy with icatibant injection (brand name Firazyr, sold by Takeda Pharmaceuticals; generic available) given to 19 patients, and into-the-vein C1-INH concentrate given to three.

Icatibant injection, given as an under-the-skin (subcutaneous) injection into the abdomen, works by stopping the aberrant signaling cascade that causes swelling in HAE. C1-INH concentrates, such as CSL Behring’s Haegarda and Berinert, provide the deficient protein to patients.

One patient did not respond to icatibant injection and switched to a C1-INH concentrate, given directly into the bloodstream.

In patients with particularly frequent attacks, off-label prophylaxis was given, consisting of into-the-vein or subcutaneous C1-INH concentrate in four patients, Orladeyo (berotralstat) in two, or Takhzyro (lanadelumab) in one.

“After switching to prophylaxis therapy, a good symptom control was reported by all patients,” the researchers wrote.

Three of these patients “were able to taper off prophylactic therapy and come back to on-demand treatment after several months being free of symptoms, especially after effective treatment for the underlying condition,” they added.

Study findings demonstrated that “the off-label use of acute and prophylactic treatment available for HAE had good symptom control in this [group] of patients with [acquired angioedema],” the researchers concluded.