With a prevalence of 1 in every 10,000 to 50,000 people, hereditary angioedema (HAE) is a condition that few health care professionals will ever see in a patient. This autosomal dominant genetic disorder presents with recurrent, unpredictable, self-limiting attacks of edema.
Known triggers include hormonal changes, stress, and surgical procedures. But many patients experience attacks with no known stimuli, increasing the condition’s overall complexity. The attacks usually last two to five days and can occur up to 100 times per year, although some patients experience them as infrequently as yearly.
The severity and location of edema during an HAE event can vary between attacks but generally the edema presents in three areas: beneath the skin, within the abdomen, and in the laryngeal region. Laryngeal edema can lead to obstruction of the upper airways and death in up to 50 percent of patients if undiagnosed and/or untreated. Even with current treatment, death can result.
The cause of the clinical symptoms of HAE is a defective or deficient C1 inhibitor (C1-INH), which is a modulator of coagulation pathways, complement activation, and bradykinin. In particular, C1-INH prevents C1 complement autoactivation, inactivates coagulation factors XIIa, XIIf, and XIa, and inhibits activated kallikrein. The main clinical effects of C1-INH deficiency ultimately involve accelerated release of bradykinin, which in turn enters the circulation and mediates rapid vascular permeability, leading to swelling, the hallmark of HAE.
HAE is unpredictable, and since it can be fatal, patients experience an increase in clinical depression as well as anxiety, absence from school and work, pain, and increased use of psychotropic and antidepressant medication.
There are both approved and off-label drugs used to treat patients with HAE. Current approved therapies include plasma-derived C1-INH replacements for long-term prophylaxis to prevent attacks, short-term prophylaxis before elective surgical procedures, and treatment of acute attacks.
Current approved therapies include marginally efficacious, intravenously administered, plasma-derived C1-INH replacements for long-term prophylaxis to prevent attacks, short-term prophylaxis before elective surgical procedures, and treatment of acute attacks. The only other approved drug is an inhibitor of kallikrein — ecallantide. It must be administered by a health care professional because of the risk of hypersensitivity and anaphylaxis.
Thus, until recently, there were no products that could be self-administered safely.
Antifibrinolytics such as tranexamic acid, E-aminocaproic acid and attenuated androgens such as danazol and stanozolol have been historically used off label for prevention and for treatment of acute attacks.
Despite the variety of drugs in use, there is still an unmet need in patients with HAE. In particular, early intervention has been linked with attenuation of attacks in that the severity is lessened and the likelihood of progressing to secondary anatomic sites is decreased. It is hoped that a new therapy, icatibant, marketed under the brand name Firazyr, will help these patients, as it may be self-administered by patients who have been trained to detect the signs and symptoms of HAE. In August of this year, the FDA approved this first-in-class drug for the treatment of acute attacks in people age 18 or older.
Icatibant is a synthetic decapeptide with a structure similar to bradykinin and a potent competitive bradykinin (B2) receptor antagonist. The B2 receptor is a protein receptor that is expressed in multiple tissues and once activated by bradykinin leads to the production of nitric oxide, prostacyclin, and cGMP, resulting in the characteristic clinical findings of HAE, namely vascular edema.
Although icatibant received orphan drug designation in November 2003, the FDA did not approve it until August 2011. Two phase III clinical trials (FAST-1 and FAST-2) were presented to the FDA in 2008, with the FDA making a determination that an additional phase III trial was needed to prove efficacy. A third trial, FAST-3, was completed and along with a self-administration study were subsequently submitted.
A total of 1,055 HAE attacks were treated with 30 mg of icatibant in clinical trials. This number included 115 laryngeal attacks.
All three clinical trials (FAST-1, -2, -3) were multicenter, randomized, double-blind, controlled parallel-group studies with open-label extensions. FAST-1 and -3 used isotonic sterile buffered solution as the placebo. FAST-2 used a common European treatment, tranexamic acid, as the comparator drug. For a number of patients, but not all, icatibant was used as an open-label drug for ethical reasons.
Consistent with other HAE drug studies, the endpoints for all icatibant clinical trials used a visual analog scale that measured self reported symptoms of primary importance to patients with HAE: skin and abdominal pain followed by skin swelling, voice change, and difficulty swallowing. There was a physician-assessed score of skin swelling, erythema, skin pain, abdominal pain, nausea, abdominal tenderness, vomiting, diarrhea, difficulty swallowing, voice change, breathing difficulty, stridor, and asphyxia.
Of great interest to patients and clinicians was the significant improvement in patients suffering from laryngeal attacks. Some of these patients received icatibant in an unblinded fashion because of the severity of the laryngeal edema.
There were no deaths in patients treated with icatibant during the clinical trials. There were also no discontinuations of icatibant because of adverse events for patients treated for up to five attacks. Most recorded adverse events were consistent with the disease process itself. Although a smattering of other adverse events was recorded, none appeared to be a result of the drug.
Local skin reactions are common, self limiting, not serious, and appeared to decrease over subsequent treatments with icatibant.They are thought to be due to the local histamine release caused by high local concentration of icatibant. Absorption from the subcutaneous site and time to peak plasma concentration are rapid.
There is a theoretical possibility that this drug may attenuate the antihypertensive effect of ACE inhibitors. Therefore patients using ACE inhibitors were excluded from the clinical trials. In addition, bradykinin has been characterized experimentally as cardioprotective in the presence of ischemia; caution must be exercised when considering icatibant in the presence of cardiac ischemia.
HAE is very rare. Icatibant has been clinically proven to be safe and effective. Icatibant is a first-in-class B2 bradykinin receptor antagonist. Managed care is going to take notice of a self-administered drug at $6,800 per dose. Given the variability of the clinical presentation for each attack, the prior authorization process is likely to be rather challenging to administer. Theracom is distributing the drug. The manufacturer is offering individual training and patient assistance programs.
As the understanding of rare genetic disorders continues to grow through molecular and cellular advances, that knowledge is likely to continue to challenge the decision makers who attempt to manage the ever increasing cost of medical care.