QOTW – Can you provide some suggestions for those patients that benefit from the C1inh but have problems with veins so are unable to self infuse? Not all physicians agree with ports or are ready to introduce C1 inh subcutaneously as of yet–not approved of available in other countries?

Jun 8, 2016

Dr. C: Another excellent question from the HAEi gathering in Madrid. I think that we sort of missed the boat when C1 inh first became available for treatment. The Hemophilia model of self-infusion with emphasis on protection of the veins should have been immediately adopted. We still have much to learn from their example. Multiple injections in the same site can cause scarring as can mismatch of the needle to the vein size. There is no one more invested in the long-term success of a treatment than the affected patient—it only makes sense to educate them and put them in charge. That being said sometimes the damage has been done with too many injections in a site, lack of care and mismatch of needle-vein sizes. We are certainly opposed to ports as an “easy solution” given the risk of infection and thrombosis. It is another matter however when a port is a necessity to provide access for delivery of the drug. In these circumstances a port may be the best option. In the same way as peripheral veins it is critical to educate the patient regarding techniques and self care of the port. Marc would you like to share your thoughts with our reader on this topic?

Dr R: A very difficult question because the answer depends entirely on the specific circumstances of the patient as well as the shared discussions with their angioedema specialist. Certainly at times C1INH therapy can present challenges due to the fact that the efficacy and safety data we have in hand is almost entirely for intravenous (IV) dosing. For the purposes of this discussion, I’ll assume this C1INH use is for long-term prophylaxis since there are reasonable SQ alternatives (ecallantide and icatibant) for treating acute HAE attacks. With frequent IV C1INH use, vein care is extremely important over time in an effort to preserve the option of IV administration using peripheral veins. If self-infusing, reviewing techniques regularly with an infusion specialist (nurse or physician) can be helpful. In instances where IV access is becoming difficult, there are basically 5 options in my view:

  1. Have an expert infusion nurse or center assist with the infusions. Skill counts in this arena and at times the right person will be able to reliably access veins such that scheduled infusions can continue.
  2. Port placement. This option is fraught with potential complications and I personally view this as a ‘last resort’ – but there are rare occasions where this is necessary to continue needed C1INH therapy. The data on C1INH and ports suggests that a large number of the thrombosis (blood clots) that occur with C1INH therapy occur in people with ports, so this signal along with the potentially serious infectious and technical complications have raised considerable and appropriate concern about port placement as a long-term solution. In my view, ports should never be used as a ‘convenience’ but rather as a necessary evil if no other treatment option is acceptable.
  3. Subcutaneous C1INH treatment. To be very clear, this is not currently a FDA-approved way to give C1INH concentrate. Though a clinical study has been completed, the safety and efficacy data has not been released. So we await that information and FDA consideration of this treatment option. In the meantime, there are published reports and anecdotes of this strategy being successfully used in selected patients when absolutely necessary. This requires a protracted discussion between the doctor and the patient since this is ‘off-label’ treatment. So this path requires an experienced physician willing to prescribe in this fashion and a patient who is comfortable with an approach very rarely used to date.
  4. Use of a different prophylactic medication. This would involve switching from C1INH to another preventative med – usually low-dose androgens (which have considerable possible adverse side effects to consider), or less commonly tranexamic acid or progestins.
  5. Forgoing prophylactic treatment altogether and using only an optimizing on-demand treatment plan with a non-IV medication. This is a shift in treatment strategy, but can sometimes work effectively even with frequent attacks, depending on the individual circumstances. To reiterate – the road taken in these situations entirely depends on the individual circumstances as every person and situation is different.
  6. Lastly, this question clearly highlights the potential benefits of non-IV medications to prevent HAE attacks. As many people know, there’s a lot of research action in the HAE prophylaxis space currently, aiming to bring either subcutaneous or oral preventative medications to the HAE community. Involvement in the clinical studies investigating these newer medications is critical to providing more treatments down the road, options which hopefully will put the intravenous challenges behind us.

Dr C: Thank you Marc. I would like to return to the second part of the question, which brings up an exciting new chapter in HAE care. Subcutaneous infusion of C1 inh has the advantage of ease of delivery for everyone obviating the need for venous access and thereby ports. The expectation with subcutaneous delivery of a “steady state” (sustained C1 inh level) vs “shark tooth” (rapid rise, rapid drop) pattern seen with intravenous C1 inhibitor may also translate into improved therapy for the prevention of swelling in HAE.
Bruce, you have been the Chair of the the CSL Behring C1 inhibitor subcutaneous trials — can you update us as to how these are going and what to expect in the US and other parts of the world?

Dr Z: I’m happy to comment on these studies. CSL Behring has developed a new C1INH product (CSL 830) that is being studied for prophylaxis use in HAE. There are several differences between the Berinert product that is currently being used for on-demand treatment and this new CSL 830 product. First, while Berinert is labeled for intravenous administration, CSL 830 is being studied for subcutaneous (i.e. below the skin) administration – which is much simpler and easier to do. Second, the formulation of CSL 830 is more concentrated than Berinert, allowing the volume of drug that needs to be given to be reduced. CSL Behring has indicated that they expect to file for licensing of subcutaneous prophylactic use of CSL 830 in both the United States and Europe sometime in the second half of 2016. As Marc indicated, we are still awaiting the results of the Phase III study, however the results of the earlier Phase II study have been published. The outcomes from the Phase II study were very encouraging, to put it mildly. Those of us on the scientific planning committee were actually very surprised to see how well subcutaneous CSL 830 was able to maintain relatively constant levels of C1INH, and how easy it was to predict the C1INH level based on the dose of CSL 830 used. While this Phase II study was not designed to prove efficacy, the information we could glean from the results was highly encouraging and suggested that CSL 830 was likely to be highly effective. We’ll have to await the final results from the Phase III study, however, before we know for certain. I should also mention, that Shire is also studying giving Cinryze by subcutaneous injection but these studies will come later than the CSL 830 studies. Finally, there are a number of additional novel subcutaneous and oral prophylactic treatments that are being studied for prophylactic use in HAE. I feel quite confident in predicting that the need for ports for HAE prophylaxis will be ending in the near future.

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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