QOTW “Can you explain why we need to take C1 inhibitor regularly to prevent attacks of swelling?”

Feb 3, 2016

Dr. C: Greetings, we are glad to be back from the WSAAI meeting. Hopefully you enjoyed the posts from the gathering.
I can see where this question can be puzzling for our reader. It would seem that if you replace something that is should just fix the problem. As we have discussed for patients with HAE related to C1 inhibitor deficiency it is the lack of sufficient C1 inhibitor that allows for contact system activation, generation of bradykinin with ensuing vascular leak and swelling. The availability of plasma derived C1 inhibitor beginning in 2008 has been transformational in the approach to care in the US. Given at the onset of an attack it effectively arrests the swelling. IV plasma derived C1 inhibitor, Cinryze, was approved for prophylactic use to prevent swelling attacks. The recommended dosing is every 3-4 days. The reason for this is that the C1 inhibitor protein will be degraded and cleared over a period of time and needs replenishment. The technical term is half-life or the time until the active protein is “half gone”. For IV plasma derived C1 inhibitor this is in the range of 32.7 hours.
There are some recent reports on effectiveness with a range of dosing with Cinryze as well as exciting developments with a subcutaneous form of C1 inhibitor. Bruce, you were the primary author on the original Cinryze study, open label extension as well as the phase II study for subcutaneous C1 inhibitor. Would you like to comment on our reader’s question?

Dr. Z: Picture a shark’s tooth! When we inject C1INH intravenously into a HAE patient, the blood level of C1INH instantaneously increases to near normal levels – which is what we want. However, over the next 3-4 days the blood C1INH level falls back to essentially the same level that it was prior to the injection. If we graph this, it looks like an upside down V (or a shark’s tooth). We were interested in developing a subcutaneous C1INH product because the absorption of C1INH from the subcutaneous space into the blood is relatively slow. What we see after subcutaneous injection of C1INH is a much slower increase in the blood level. Once the C1INH protein reaches the blood, however, it disappears just as quickly as after intravenous administration. The difference is that the C1INH protein keeps slowly moving from the subcutaneous tissue into the blood over a much longer period. With repeated subcutaneous injections, a certain magic happens – the blood level of C1INH stays in the normal or near-normal range continuously. This is very much like what we see in normal subjects without HAE. For this reason we have very high hopes for subcutaneous C1INH and are eagerly looking forward to seeing the Phase III study results.

Dr C: It is possible that the shark analogy was inspired by our recent trip to Hawaii… The subcutaneous product does sound very interesting—hopefully the phase III results will indeed be magical. Turning back to our question, Marc, could you further clarify why regular dosing with C1 inhibitor is necessary to prevent swelling for our reader?
Dr R: C1INH is a protein that inhibits or regulates a number of other protein pathways in the body. For HAE, the most of important of these inhibitory actions is controlling the activity of kallikrein and Factor XII and thereby preventing excessive bradykinin production. But C1INH has regulatory functions on other pathways such as the complement and coagulation systems. All of these functions require that C1INH is constantly produced by the liver and other cells types – this production doesn’t occur normally in HAE Types 1 and 2 due to gene mutations which leads to C1INH deficiency and the recurring angioedema symptoms. We can address this therapeutically by improving the C1INH levels with infusions of protein concentrate, and a plasma-derived C1INH product has been shown to effectively prevent HAE attacks. However, after each infusion, the C1INH protein is gradually metabolized or used up by the body as it provides it’s inhibitory function. C1INH is known as a “suicide” protein because each molecule irreversibly binds to its targets (other proteins). So it’s a “one and done” case for each C1INH molecule. Because of this, it’s necessary to repeatedly infuse the plasma-derived C1INH every 3 or 4 days on average to keep the protein level at a point where it can effectively provide enough inhibitory function to prevent swelling attacks.

Dr. C: Thank you Bruce and Marc—I hope that our discussion was helpful for our reader and followers with HAE. We look forward to hearing from you and our next “Question of the Week”.

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