Patient with HAE and normal C1-INH treated with Takhzyro
Takhzyro reduced frequency, severity of swelling attacks, case report shows
Treatment with Takhzyro (lanadelumab) led to a more than 80% reduction in swelling attacks in a woman with hereditary angioedema (HAE) and normal C1-inhibitor (C1-INH) activity, a case study reports.
The medication effectively reduced both the frequency and severity of the attacks, leading to ongoing benefits for this patient, although Takhzyro is not currently approved for the treatment of HAE with normal C1-INH activity (HAE-nC1).
“Typically, HAE-nC1 patients are treated similarly to those with [HAE type 1 and 2] based on case reports or observational studies, and hence we believe it is reasonable to trial lanadelumab in highly symptomatic patients with HAE-nC1,” the researchers wrote.
The case report, “Successful use of lanadelumab in a patient with hereditary angioedema with normal C1 inhibitor and negative genetic testing,” was published in the Journal of Allergy and Clinical Immunology: Global.
HAE is characterized by sudden and recurrent swelling attacks in the deeper layers of the skin, the upper airways, and the gastrointestinal tract. They are caused by high levels of a molecule called bradykinin, which makes fluid leak from blood vessels into surrounding tissues. Bradykinin production is stimulated by two proteins — plasma kallikrein and coagulation factor 12 — that are controlled by C1-INH.
Depending on the genetic cause of the disease, HAE can be divided into three types. Type 1 and 2 are caused by mutations in the SERPING1 gene, which is responsible for the production of C1-INH. In type 1 HAE, mutations lower the production of C1-INH, whereas in type 2 the body maintains normal C1-INH levels, but its activity is reduced. When C1-INH activity or its levels decrease, bradykinin production increases, which can trigger a swelling attack.
The less common HAE type 3, or HAE-nC1, is not caused by SERPING1 mutations, and people with this type of HAE have normal levels and activity of C1-INH. Several mutations and genes have been linked to this type of HAE, including mutations in the F12 gene leading to an overactive coagulation factor 12, which results in the overproduction of bradykinin.
“However, many patients with HAE-nC1 remain without a genetic diagnosis and the disease mechanisms in these patients are unclear,” the researchers wrote.
Case report description
In this report, researchers described the case of a 62-year-old woman who had frequent swelling attacks since adolescence affecting her tongue, larynx, limbs, and abdomen. The episodes developed in the course of several hours, were not accompanied by hives (urticaria), and took two to three days to resolve.
Past treatments with antihistamines or glucocorticosteroids were not effective in controlling or preventing the episodes. The patient has two daughters, one of whom also has recurrent swelling episodes that do not respond to antihistamines.
Blood analyses showed that the woman had normal C1-INH levels and function, including during swelling episodes. Her daughter’s blood tests also were normal.
A genetic analysis of genes commonly associated with HAE, including SERPING1, F12, PLG, and ANGPT1, did not detect any disease-causing mutations in the patient. Based on these tests and their symptoms, both mother and daughter were diagnosed with HAE-nC1.
For many years, swelling episodes occurred about three times per week. The patient used icatibant (an injected medication sold under the brand name Firazyr) to treat acute episodes, but although the treatment helped with her symptoms in each episode, they were so frequent and unpredictable that they greatly affected her quality of life.
Treatment with plasma-derived C1-INH was offered to both to treat her acute attacks and to prevent future ones. However, this was not a feasible option for the patient because the therapy needed to be injected directly into a vein and she had uveitis — a type of inflammation in the eyes — causing her vision to be impaired and making it too difficult for her to inject herself.
In 2018, she started treatment with Takhzyro, which was given at a dose of 300 mg by an under-the-skin injection every two weeks. After two months, the frequency of swelling episodes had gone down by more than 80% — from about 12 per month to two — and the episodes were mild enough that she didn’t need icatibant for most of them.
Target HAE-nC1 in trials
She maintained treatment with Takhzyro and, at her last visit, her HAE-nC1 was considered to be well-controlled. This, along with the lack of clinical trials targeting HAE-nC1, led the research team to suggest that Takhzyro should be tested in trials focused on people with this form of HAE.
Because Takhzyro targets the protein kallikrein as its method of action, researchers hypothesized that kallikrein may play a key role in the disease mechanisms of HAE-nC1 in this woman, and most likely in other HAE-nC1 patients as well.
“Future studies of lanadelumab and other novel targeted therapeutics in HAE-nC1 may therefore help identify patient subgroups in whom alternate mechanisms should be investigated,” the researchers wrote.
About the Author
