QOTW – “If type 3 has normal C1 level and normal C1 function, what is the treatment for type 3?”

Nov 23, 2015

Dr. C:I can certainly see why this is a confusing topic. Even the name is problematic. The accepted nomenclature for Type 3 is now ‘HAE with normal C1 inhibitor’ (HAE-nl-C1INH). This has been further subdivided into ‘HAE-nl-C1INH with Factor XII mutation’ (HAE-nl-C1INH-XII) and ‘HAE-nl-C1INH unknown’ (HAE-nl-C1INH-U). We believe that there may be a number of different abnormalities in the latter group with similar clinical disease expression. I have spoken with many patients about the categories and have been told ‘we are not normal’. Indeed this is true—we need a better name. We hope to have an improved categorization as we identify discriminating tests and genetic markers. Turning to our readers question, as is the case for Type I and II we divide treatment into prophylactic and on demand treatment. Marc, would you like to comment about on-demand treatment of HAE-nl-C1INH?

Dr R:Because HAE with normal C1INH (Type III) appears to be bradykinin-mediated, the most rational treatment approach is to use bradykinin-targeted drugs including some of as those used in HAE due to C1INH deficiency. However, there are nuances specific to the management of HAE with normal C1INH and due to the rarity of the condition, we simply have fewer published studies on the effects of various medications. Thus, my view is that it’s currently difficult to make strong treatment recommendations for HAE with normal C1INH. This is a specific area where I think each individual with this diagnosis benefits from evaluation and management discussions with an experienced angioedema specialist. The Angioedema Center and other research groups are actively studying HAE with Normal C1INH in an effort to improve knowledge of the underlying pathophysiology as well as pursue additional treatment studies in the near future.

Dr C:Yes, I agree that until we have improved diagnostic tests and controlled trials that the approach to care needs to be very individualized for HAE-nl-C1INH. There have been several reports showing that bradykinin is likely to be the mediator of HAE-nl-C1INH, and published literature reports that C1 inhibitor, Firazyr and Kalbitor have each been effective for some patients. As Firazyr will block the action of bradykinin at the receptor and Kalbitor will prevent the generation of bradykinin by blocking the enzyme plasma kallikrein these both make sense. Bruce would you care to speculate why C1 inhibitor would be an effective treatment for some HAE patients with “normal” C1 inhibitor?

Dr. Z:That does sound rather paradoxical, doesn’t it? I believe that there are at least two possible explanations why C1 inhibitor concentrate might work in a patient with HAE-nl-C1INH. The first possibility is that normal or near-normal levels of C1 inhibitor can be overcome by whatever is provoking the swelling attack but that supra-normal (higher than normal) levels of C1 inhibitor protein provide enough extra control to prevent activation of the bradykinin-generating proteases. The second possibility (which I favor) is that C1 inhibitor levels are normal or near-normal between attacks but that during attacks the C1 inhibitor is transiently consumed, allowing a burst of bradykinin to be generated. We previously showed that activation of the contact system proteases could cleave C1 inhibitor into a slightly smaller but non-functional protein. Therefore, enhanced activation of factor XII recently shown for HAE-nl-C1INH-XII could cleave C1 inhibitor into the non-functional form, providing the rationale for the use of C1 inhibitor replacement during an attack. It’s also worth pointing out that the cleaved C1 inhibitor protein remains measurable in the blood, so unless you measure C1 inhibitor function you can miss the transient fall in C1 inhibitor activity.

Dr. C:Excellent explanation for this observed ’paradox’. To get to the next level we also critically need to continue research efforts to dissect the pathophysiology and thereby approach to care. We are getting a clearer picture for prophylactic therapy for HAE-nl-C1INH. Some HAE-nl-C1INH patients are on Cinryze however the perception (again no controlled data) is that it is working less well for this group vs the Type I and II. Again your comments are helpful in understanding why it does seem to work in some patients with ‘normal’ C1inh. We have seen quite successful outcomes with Tranexamic acid, an anti-fibrinolytic medicine. This is quite different that in Type I & II where it is not a very effective therapy. This difference may be explained by the growing evidence that plasmin activation may be important in triggering the contact system cascade and generation of bradykinin in HAE-nl-C1INH. There is also an important relationship to estrogen in the HAE-nl-C1INH group influencing swelling. “Countering” this influence by treatment with Progestin has also been very helpful for some patients. There are case reports of attenuated androgens being used however this makes less sense then the other therapies from what we are starting to understand about the mechanisms of swelling. We unfortunately have no controlled studies on any of these treatments to draw upon. Bruce what has been your experience with the available prophylactic therapies for HAE-nl-C1INH?

Dr. Z:Like you, I’ve been impressed that tranexamic acid and progestins do often help patients when used prophylactically for HAE-nl-C1INH. It will be very interesting to see whether the newest medicines that are currently being studied for prophylactic use in HAE due to C1 inhibitor deficiency will be helpful for HAE-nl-C1INH. I strongly agree with your comment that progress in treating HAE-nl-C1INH will depend on figuring out the underlying pathophysiology of the disease.

Dr C:I completely agree. What do you think will be the role for drugs under development for HAE-nl-C1INH patients? I am particularly interested in the fully human antibody to factor XII developed by CSL Behring that was shown to be efficacious in the mouse model for HAE-nl-C1INH-XII patients. There is also the oral inhibitor of plasma kallikrein under study by BioCryst and going into trials the fully human antibody to plasma kallikrein developed by Dyax. There’s even an antisense oligonucleotide that can ‘knock down’ prekallikrein that has passed safety studies (phase I). Where do you think these will come into use for the patients like our reader?

Dr Z:If our supposition that HAE-nl-C1INH is mediated by contact system generated bradykinin is correct, then each of these treatments ought to work for HAE-nl-C1INH.

Dr. C:Thank you Bruce and Marc. I always enjoy our discussions. I hope this is helpful for our reader and others struggling with HAE-nl-C1INH. We are clearly making progress with more encouraging developments on the horizon. We look forward to hearing from you and our next ‘Question of the Week’.

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