The New England Journal of Medicine recently published research done at the University of California on a new treatment for hereditary angioneurotic edema (HANE) also called hereditary angioedema (HAE).
HANE or HAE is a rare genetic disorder that leads to unpredictable, disabling and occasionally fatal episodes of swelling. The swelling can occur in any part(s) of the body. It is caused by uncontrolled activity of the contact system components factor X11a and plasma Kallikrein which leads to excessive release of a bradykinin which in turn causes leaky blood vessels (vascular permeability) with the resultant swelling from the fluid that leaks out of the blood vessels.
The most common form is due to reduced production or reduced functionality of a controller protein called C-1-esterase inhibitor. But there are other forms including ones with normal C-1-inhibitor.
This latter group has been difficult to treat with most current therapies because they work by increasing production of function of C-1-inhibitor replace it directly or inhibit Kallikrein or block the bradykinin receptor. The currently available therapies can be used either to treat/stop acute attacks or prophylactically. In general, they work quite well but not 100%. That is why improved therapies are being researched.
The new drug being researched is donidalorsen which is an antisense oligonucleotide that selectively inhibits plasma prekallikrein production. (Say what?) Donidalorsen inhibits the production of plasma prekallikrein by means of ribonuclease (RNase) enzyme that degrades messenger RNA that would otherwise lead to prekallikrein production. The idea is by moving a step earlier in the domino-like chain of events by reducing prekallikrein this will prevent kallikrein and eventually bradykinin.
The UC researchers have conducted a small trial in 32 patients with a 90% reduction in attacks. Moreover, the medication was not prone to causing side effects. Larger trials are underway.
Hereditary Angioedema (HAE) is an inherited deficiency of functional C-1-esterase inhibitor (C-1-INH) and is characterized by unpredictable recurrent episodes of painful often disabling swelling of the abdomen or face or extremities.
In the recent past several new drugs have become available to treat this condition. One of the most exciting ones is Ruconest,
which is a C-1-esterase inhibitor made by recombinant technology. Thus, it works by replacing what the patient fails
to make (or fails to make in a functional protein). By way of explanation C-1-esterase inhibitor is a “gate-keeper” or “watch-dog” for inappropriate activation of our complement system proteins. If the complement system is activated when it is not needed, it makes the individual sick by causing the tissue swelling which is the hallmark of HAE.
In women with HAE, variations in hormones such as the menstrual cycle or pregnancy can bring on attacks. A case in point was recently published in the medical literature of a 23-year-old woman who experienced multiple attacks of angioedema during her pregnancy. Because Ruconest is technically not a drug but a pure replacement protein it is felt to be safe to use during pregnancy. At 38 weeks the woman had a severe attack as she was going into labor. Because of concern for the fetus an ultrasound was done and the baby was also having an attack of facial angioedema. The woman received Ruconest and as her swelling subsided so too did her infant sons swelling. By the time he was delivered he was back to normal. This is the first documented account of fetal angioedema successfully treated while treating the mother.
A new treatment for hereditary angioedema has become available: Ruconest. It is a recombinant (man-made) C1-esterase inhibitor, and the first available not derived from a blood product such as plasma. Infusion of Ruconest replaces the deficiency of C1-esterase inhibitor which is the cause for hereditary angioedema attacks.
It is hoped that recent research into expanding the use of a targeted, expensive drug could bring financial relief to many who share symptoms with those covered by the drug’s current restrictive application.
At issue are serious symptoms caused by ACE-inhibitor-induced angioedema. The drug studied is Icatibant (brand name Firazyr), but its only approved application at present is for Hereditary Angioneurotic Edema, or HAE — a rare, but significant disease.
People with HAE suffer repeated bouts of swelling (angioedema) of different body parts, from lips and tongue to throat and even the intestines. The attacks can be severe and occasionally life-threatening when the airway is compromised. They are caused by the build-up and release of bradykinin, a powerful vasodilator. Icatibant works by blocking the tissue receptor where bradykinin exerts its mischief.
Not so rare is ACE-inhibitor-induced angioedema, which also occurs because of a build-up and release of bradykinin. Unlike HAE in which any part of the body is susceptible to swelling, ACE angioedema tends to occur primarily around the head and neck — lips, tongue, face, palate and throat.
Also unlike HAE which is caused by a genetic deficiency in an enzyme, ACE angioedema is caused in susceptible individuals by the medications called ACE-inhibitors, which are antihypertensives. At the current time the only FDA-approved use of Icatibant is in HAE; therefore, using it in ACE-angioedema would be an “off-label” use.
Which comes around to the crazy world of insurance. At this point insurance carriers will only cover the cost (roughly $8,000 per dose) for people with HAE. Hopefully, this research study will change things, as ACE-angioedema is a common reason for emergency room visits.