Biocryst showed the PK profile of their oral kallikrein inhibitor in one of their investor presentations showing that the max drug absorption is achieved within an hour or two after administration. Does this mean that this also has the potential of being used as an acute treatment therapy?

Jun 24, 2015

Dr C: This is an exciting new area of drug development using an oral agent for inhibition of plasma kallikrein to prevent generation of bradykinin and thereby attacks of angioedema. Given the kinetics of the drug I did check with the investigators at Biocryst to see what their take on the possibility of usage for acute therapy would be.

They did consider whether to investigate acute therapy however oral/facial and GI acute attacks seemed to pose quite a challenge for an oral therapy, and reiterated as our questioner notes, that it also takes one or two hours to reach peak levels. They felt that immediate exposure and parenteral route might be better approaches for acute treatment. They thought that the oral route would be very suitable for chronic prophylaxis. Given the menu of current therapeutic options for on demand care I would agree with their conclusion. Marc and Bruce do you have any further thoughts on this?

Dr Z: As much as we’d love to have an orally available option for on-demand treatment of HAE attacks, I would have to echo the cautious response from Biocryst. The entire point of on-demand therapy is to rapidly stop swelling before there is significant extravasation of fluid into the tissue. Waiting ~2 hours for the drug to reach maximal concentration in the plasma would certainly not be ideal. Furthermore, there would be additional time from then until when the patient begins to experience relief.

Dr R: Yes, my take is very much in line with Bruce’s. The oral BioCryst compound (BCX 4161) currently in clinical trials shows maximal concentrations in the bloodstream about 2 hours after dosing. While it’s tempting to believe this may be rapid enough to be useful in treating acute HAE attacks by shutting off kallikrein activity, there are several potential issues that could affect this: 1) The baseline blood levels of the drug increase by about 30% after repeated dosing (every 8 hours for 7 days) compared to a single dose. It’s not currently known if this drug accumulation is important for the effect on HAE symptoms, but it would be of little benefit for acute attacks if it takes days to reach a steady state important for the clinical effect. 2) In the early human studies, food intake appears to affect absorption of medication doses to some extent. This may vary based on the person and the fat content of the food, but is a clear concern since HAE attacks are rarely predictable and meals might affect the absorption and therefore the effect of the drug. 3) Airway and intestinal HAE attacks may potentially affect the ability to take or absorb oral medications. Certainly, it’s interesting and important to consider ways to improve acute HAE treatments, and I suspect this will likely be explored in the future with oral kallikrein inhibitors, but these important questions will require more investigation.

Dr. Z: I’d like to emphasize the problem of drug absorption. The phase 1 BCX 4161 study showed that there was significant variability in the blood levels of the drug between normal subjects as well as a substantial impact of fatty food on absorption. This implies that we would have to be concerned that the efficacy of treatment would be affected by what a given person had eaten earlier in the day not to mention being variable between patients. While we can compensate for these types of differences in prophylaxis by varying the dose, we really do need the on-demand treatment to work every time.

Dr C: Very illuminating. On a different note I also raised the question as to whether the oral agent would be a consideration for short term prophylaxis for a predictable trigger for attacks such as dental surgery. I received the following response:

“Could be – but difficult to see those types of uses fitting into a regulatory development pathway. Once an oral plasma kallikrein inhibitor is approved and marketed there will likely be the basis for evaluating other ideas such as these.”

I again agree. While it would be difficult to shepherd this through the FDA for an indication, I believe that this usage would be important to consider for patients who do not need chronic prophylactic therapy but would want to just have the short term coverage. Bruce and Marc, any thoughts here?

Dr R: Agree that this approach for short-term prophylaxis could be helpful. But it will be difficult to study from a regulatory and practical perspective since it is tough to do controlled trials for these events given all the other variables.

Dr. Z: In keeping with Marc’s comment, there haven’t been good studies addressing the efficacy of short-term prophylaxis. To demonstrate why this is true, consider a recent paper that showed that facial or throat swelling occurred 21.5% of the time following tooth extractions in HAE patients who did not receive prophylaxis. Treating patients with C1 inhibitor prophylactically only reduced the incidence of facial or throat swelling to 12.5%. Since only about 1/5th of extractions result in swelling, designing a study to show a significant effect of prophylactic treatment would be very difficult and require a very large number of treatments with both placebo and BCX-4161.

Dr C: When I read this paper, I was struck by the fact that C1 inhibitor prophylaxis wasn’t more effective, especially considering that this was a retrospective study.

Dr. Z: To me, this paper indicated that there is still an unmet need for safe and effective short-term prophylaxis. It will be fascinating to see if a specific plasma kallikrein inhibitor can be more effective than C1 inhibitor for this indication.

Dr C: Excellent, I appreciate your thoughtful inputs. I hope that this provides some clarity for our readers in the HAE community. I forward to our next discussion of ‘The Question of the Week’.

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