Hereditary angioedema (HAE) is a genetic disorder characterized by episodes of edema (swelling) in the extremeties (hands and feet), face, gastrointestinal tract and airway passages. The majority of patients experience periods of severe abdominal pain, nausea and vomiting caused by swelling in the intestinal wall.
Attacks that involve the face and throat can result in closure of the airway passages and cause death by suffocation. The mortality rate from untreated airway obstruction has been reported to be over 30%, with death most frequently caused by asphyxiation due to airway closure.
The course of the disease is diverse and unpredictable, even within a single patient over his lifetime. Swelling caused by HAE usually lasts for 24-72 hours, but the length of an attack can range from four hours to four days [this would be me]. On average, patients experience approximately one attack per month, but the frequency is highly variable. As many as five to 10% of patients are severely affected [again, this would be me], experiencing attacks one to three times per week. HAE affects between 1:10,000 and 1:50,000 individuals worldwide, and there are thought to be 6,000 or more people with HAE in the United States [not a heck of a lot of us in the larger scheme of things].
HAE is caused by a defective gene for C1-INH, and this defect is passed on in families – a child has a 50% chance of inheriting this disease if one parent is affected. The absence of family history, however, does not rule out HAE diagnosis, and as many as 20% of HAE cases involve patients who appear to have had a spontaneous mutation of the C1-INH gene at conception. The genetic defect results in production of either inadequate [me again] or nonfunctioning C1-INH protein.
Normal C1-INH helps to regulate the complex biochemical interactions of blood-based systems involved in inflammation and coagulation, and C1-INH is known to be either a major or minor inhibitor of at least seven proteins involved in these systems. More specifically, C1-INH is known to inhibit three key biochemical pathways underlying inflammation and/or coagulation – the complement system, the contact pathway of intrinsic coagulation and the fibrinolytic system. Excessive activity of each of these systems has been demonstrated in HAE, as evidenced by increased levels of components of the complement system, kallikrein, coagulation Factors XIa and XIIa, and plasmin. The biochemical imbalance that results from reduced levels of functional C1-INH leads to the production of proteins and peptides that cause fluids to be released from the capillaries into surrounding tissues thereby causing edema.
Treatment of HAE can be categorized as: (i) preventive treatments for patients severely affected by HAE; and (ii) mitigation treatments to remedy the symptoms of infrequent episodic acute attacks. The only currently available treatments in the United States for severe attacks are anabolic steroids, pain control and rehydration. Restriction of the inciting activity (e.g. repetitive motion such as typing or hammering) is also advised. Current treatments for HAE in the United States do not prevent all attacks and have adverse side effects.
Long-term prevention therapy is recommended for patients who experience more than one attack per month, or who believe the disease significantly interferes with their quality of life. Most of these patients are currently treated with anabolic steroids that act as prophylactics to prevent attacks of edema. The most commonly used steroids are alpha-alkylated androgens such as stanozolol and danazol [brand names worked fine for me for 25 years; when generics became available and brand names stopped production, found that generics don’t work on me because (possibly) of absorption problems]. Although these drugs are effective in reducing the number and severity of the most serious attacks, they do not prevent all attacks [this was true for me, but 3 or 4 hospitalizations a year was preferable to once a week]. In addition, use of such anabolic steroids can have numerous side effects ranging from hepatotoxicity (liver toxicity) [nope], virilization (development of male sexual characteristics in a female) [nope], weight gain [yep, avg 5 lbs/year], acne [yep] and hirsutism (unwanted hair growth) [another nope]. Another preventive treatment is the use of freshly frozen plasma, or FFP, which contains C1-INH, but which also contains a wide variety of other factors that may activate multiple inflammatory pathways and exacerbate an attack [and gives me hives all over my body].
There are currently no approved treatments for acute attacks available in the United States. Rather, current therapies primarily focus upon treating the symptoms of an acute attack. For swelling of the intestinal wall, which can cause debilitating pain, narcotics such as morphine and antiemetics for nausea are given, but these medications only address the symptoms and not the underlying cause. For severe laryngeal swelling, which can be life threatening, rescue therapy such as intubation or tracheotomy may be required. There are no treatments available for swelling of the face or extremities. [And good luck finding an ER doctor who “gets it” in time to treat you properly or in a timely fashion! Because you can’t possibly know what is wrong with your own body or what disease you are suffering from, bloody arses.]
Our first product candidate, C1-INH, prepared from human plasma, is being developed both to treat acutely [me], when there is an attack, or prophylactically [me again], to prevent attacks, depending on the severity of the case. The treatment concept is similar to hemophilia, in which a patient is treated regularly with the particular clotting factor in which he is deficient. C1-INH is given by intravenous administration [through a port in my chest]. Published studies by others have shown C1-INH treatment to resolve angioedema in 30 minutes to two hours [does for me], compared to 24-72 hours when untreated. A research study published in the New England Journal of Medicine in 1996, provided evidence that this treatment was safe and effective for both prevention of attacks and as an acute attack therapy – rapid resolution of laryngeal, facial, abdominal and extremity swelling was observed. A study published in the Archives of Internal Medicine in 2001 concluded C1-INH to be highly effective in treating the laryngeal edema of HAE with rapid resolution of symptoms. We believe these studies, and others showing comparable efficacy, are representative of the extensive European clinical experience using C1-INH as a treatment for HAE for more than 30 years [lucky SOBs].
In the first quarter of 2005, we initiated a Phase III clinical trial of C1-INH for treating HAE in the United States. The Phase III trial is a multi-center, placebo-controlled, double-blind study designed to examine the use of C1-INH in both treating acute attacks of angioedema and in preventing the onset of such attacks. In July 2004, we received orphan drug designation from the FDA for C1-INH (human) in treating angioedema. Upon product licensure, orphan drug designation could provide us with seven years of marketing exclusivity for our C1-INH product as a treatment for HAE in the United States as well as certain tax credits and eligibility for certain government grants.
The current good news is that the FDA decision (which is expected to be favorable) is expected in early 2008. “Early,” in Government lingo, could be in the first quarter, so perhaps before the end of March 2008. Yippe-ki-yay!