Oral HAE therapy may improve control after patients switch treatments
Orladeyo was used after injectable treatments or androgen-based prevention
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In seven cases involving people with hereditary angioedema (HAE) who had challenges with existing treatment options, doctors in Italy reported generally good disease control, adherence or treatment satisfaction after patients started oral Orladeyo (berotralstat).
The cases covered three main topics: switching from injectable drugs to oral therapy, moving away from hormone-based therapies, and Orladeyo treatment while managing other health conditions and multiple medications.
Oral therapy expands first-line options for HAE prevention
“Significant progress has been achieved in the development of oral therapies for HAE, with [Orladeyo] standing out as the sole oral option among the three first-line choices for [long-term preventive treatment],” the researchers wrote.
The study, “Clinical experience with berotralstat in patients with hereditary angioedema: an Italian case series from the ITACA cohort,” was published in the European Annals of Allergy and Clinical Immunology. BioCryst Italy Srl, now a Neopharmed Gentili company, provided unconditional support for the overall project. BioCryst Pharmaceuticals developed Orladeyo. In 2025, Neopharmed Gentili acquired BioCryst Pharmaceuticals’ European Orladeyo business.
Most cases of HAE are caused by deficient levels or reduced activity of C1 esterase inhibitor (C1-INH), a protein that controls bradykinin, a signaling molecule that regulates swelling. Without enough functional C1-INH, bradykinin levels can rise too high and trigger a swelling attack in any part of the body.
The latest international guidelines recommend three first-line options for long-term preventive treatment: C1-INH replacement therapy, Takhzyro (lanadelumab), and Orladeyo. Both C1-INH therapy and Takhzyro are given by injection.
Orladeyo, in contrast, is taken by mouth. Because it became available in Italy only in 2023, clinical experience with the drug there has been limited.
To provide guidance on using Orladeyo, the Italian Network for Hereditary and Acquired Angioedema (ITACA) convened clinicians to discuss seven cases involving people with HAE who were treated with the drug.
The first three cases focused on choosing oral therapy over injectable drugs.
Patients switched from injectable or androgen-based treatments
A 27-year-old woman with an extensive family history of HAE was having up to four attacks a month, which were treated as needed with injectable Firazyr (icatibant). When offered long-term preventive treatment, she declined injectable Takhzyro because of her fear of needles and chose oral Orladeyo. She had no further attacks during about six months of follow-up and experienced brief nausea during the first week of treatment.
A 12-year-old girl, also afraid of needles, received several treatments, including injectable Firazyr, oral tranexamic acid, injectable Takhzyro, and injectable C1-INH. These treatments were associated with significant injection-site pain or a high treatment burden. After her weight had increased to 65 kg, she switched to Orladeyo, with good disease control, high treatment satisfaction and adherence.
In the third case, a 72-year-old woman had lived with undiagnosed symptoms for years before her HAE diagnosis. She began experiencing abdominal pain and digestive symptoms at age 10. When she was in her 20s, she had two full-term pregnancies without complications. During the same period, she experienced monthly or twice-monthly swelling of her limbs or face that did not improve with steroids or antihistamines.
She received an HAE diagnosis at age 47 and used intravenous C1-INH to treat attacks as they occurred. When her attacks later became more frequent, she declined preventive treatment with subcutaneous Takhzyro or C1-INH because of concerns about adherence and injection-site effects. After she started Orladeyo, her attacks decreased and eventually stopped. Early stomach problems resolved with antacids and by taking Orladeyo with her main meal.
The next two cases illustrated the transition from androgens such as danazol to Orladeyo. Danazol is a synthetic steroid related to the male sex hormone testosterone and has historically been used to prevent HAE attacks.
A 66-year-old woman had lived with severe, long-undiagnosed symptoms before receiving an HAE diagnosis at 22. She initially received C1-INH for acute abdominal and throat attacks, but weekly attacks continued. She later began danazol, and attempts to reduce or stop it resulted in rapid recurrences, including severe attacks. Doctors started Orladeyo while gradually tapering danazol. No attacks occurred after September 2024, and moderate morning abdominal cramps resolved after about a month.
In the second case, a 58-year-old man began experiencing recurrent angioedema episodes at age 17, affecting his face, hands, feet, abdomen, and genitals. He received an HAE diagnosis at 43 and began danazol. He later showed poor adherence to both treatment and follow-up appointments. Because of his fear of needles, he also did not treat acute attacks, which delayed their resolution. Doctors proposed starting Orladeyo while slowly tapering danazol, but he abruptly stopped danazol on his own. He reported no side effects, adhered well to Orladeyo and achieved good disease control.
Doctors weigh drug interactions and surgical planning
The final two cases addressed managing HAE in a patient taking multiple medications and planning for another patient’s surgical procedure.
In one case, a 76-year-old woman with diabetes, high blood pressure, and a prior stroke was taking six other medications, including the cholesterol drug atorvastatin, sold as Lipitor. After learning that Orladeyo may increase blood levels of atorvastatin, potentially raising the risk of liver or muscle damage, her doctors decided to discontinue the statin rather than Orladeyo.
She later showed abnormal liver test results that were considered likely related to the combination of medications and discontinuation of the androgen treatment. After the statin was stopped, her liver test results gradually improved, and the improvement persisted even after the statin was later restarted. Her swelling attacks, which had occurred about once a month during the danazol taper, fell to zero after she started Orladeyo.
In the second case, a 56-year-old man who was diagnosed at 35 had poor adherence to his HAE care. He had previously discontinued danazol because he could not tolerate it. He experienced three to four unpredictable abdominal attacks per month, which affected his work, free time and social relationships. The attacks were treated with on-demand Firazyr.
He began Orladeyo under a compassionate use program but still experienced two attacks over two months, both of which were treated with Firazyr. He later underwent cataract surgery without receiving additional short-term preventive treatment beforehand, and no postoperative attacks were reported.
“Patient engagement, awareness of androgen risks, transition strategies and drug-interaction evaluation are essential to guide individualized [long-term preventive treatment] choices,” the researchers concluded.
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