Oral Drug Effective for On-Demand Treatment of HAE Attacks

The investigational oral drug sebetralstat provided on-demand relief during tissue swelling attacks from hereditary angioedema (HAE), according to a phase III study reported at the recent American Academy of Allergy, Asthma & Immunology (AAAAI) annual meeting.

In this exclusive MedPage Today video, Paul Audhya, MD, of KalVista Pharmaceuticals in Cambridge, Massachusetts, which developed the drug, shares key findings from the various endpoints of the so-called KONFIDENT trial.

Following is a transcript of his remarks:

I think a good starting place is just trying to understand how we could validate the outcome of our phase II. So we had a great phase II trial we published in The Lancet, and it basically is the first oral drug to make it to this stage of development for on-demand treatment in HAE. That space has really been occupied for really the entirety of time with injectables. So you’ve got either IV drugs or you’ve got a subcutaneous drug, which itself is actually quite painful. And so there’s been a huge interest in trying to move this forward to oral.

So in that regard, we had to first figure out what was the best endpoint, how could we even measure the benefit? So we talked to patients, we talked to physicians, and we took our own phase II data to come up with our primary endpoint, which is the Patient Global Impression of Change. We also looked at other, what we call patient-relevant endpoints. We asked patients how they interpreted different scales that were out there in the literature that had been used in trials, and so we used those key secondary endpoints on that basis. Then we designed a trial that really would be large enough to power all of those different endpoints.

So the primary endpoint of when do you start to feel improvement, when does that relief occur, when does that symptom burden actually start to go down, and when does resolution happen? So we designed the trial around that, and ultimately the KONFIDENT trial was designed as the largest on-demand trial and actually the largest trial in HAE to date. We enrolled 136 patients around the world, and of those, 110 of those patients actually had at least one attack on the study. The way that we powered the trial was that we made an estimate of how many patients might have three attacks, so we could shoot for about 264 attacks.

So that’s sort of the first part of the poster. We then basically blinded the trial. They could receive either 300 mg, 600 mg, or placebo. And it was all two pills. So it was all matching what we call a double dummy design.

Ultimately, we were really pleased to see, firstly that, and this is one of the major benefits of an oral, is that the barriers to taking the treatment were basically reduced or even eliminated for many patients. They’re able to take the drug very quickly. So the median time to treatment was 41 minutes, but if we look at the first 25% of patients, they were treated within 6 minutes and that’s after having scanned a QR code and figured out which drawer to open and then take blinded medication. We already know that that’s going to improve as we look ahead.

The second piece was that we did create a lot of flexibility for patients. They made all the decisions when to treat, whether to use an optional second dose, ultimately how to interact with their physician. So a very real-world type of trial.

So I guess the next piece is what we saw. So the actual outcomes on the primary endpoint we saw were basically a much faster time to relief than with placebo. So it was 1.6 hours for the 300-mg group. And we saw something very similar for the 600-mg group, which was about 1.79 hours. We expected that this would be in the range of 1 to 2 hours, which is effectively what we saw in the phase II trial. So that was really encouraging.

The next key secondary endpoint, we measured them in order. We had to follow a certain fixed sequence in order to maintain statistical power. We basically also saw that the time to a reduction in severity was also reduced much faster than we did see with placebo for both groups.

And then the last endpoint, which is the hardest endpoint to hit, is actually to complete resolution. This is the first time that any on-demand trial looks at that endpoint, which is basically no symptoms, the complete shutdown of that attack to the point where a patient is back to themselves. And we also saw a much faster time to improvement than placebo. So those are the main endpoints of the trial.

We also did an analysis where we looked at the proportion of patients who achieved those outcomes with just one pill. Remember they had the optional second dose, and even though quite a few of them took that second dose, we observed that over 90% of them achieved their outcomes with just that single pill. So that’s something that was very encouraging for us too.

The last piece is the safety, and some could argue that the safety is the most important. In this case, it’s pretty much just as important, but the reality was we saw outcomes similar to what we saw with placebo, and that differs really radically from the injectable drugs. There are lots of side effects that we observe in those settings from anaphylaxis for some of those in rare circumstances, but still something to worry about. And then on the other side, almost universally, injection site reactions for a drug like icatibant [Firazyr] — almost 100% of patients. So here we’ve seen placebo basically had the same rate of adverse events.

So overall, really, really compelling data. We think that it’s going to be supportive of submission to FDA in the first half of this year, and we’re excited to get their feedback, frankly, on the outcome.

Please enable JavaScript to view the

comments powered by Disqus.