Connect Biopharma Holdings Limited Ordinary Shares H.C. Wainwright 28th Annual Global Investment Conference

Yeah. No doubt. I think that the study, from our perspective, is very successful in terms of taking us to the next stage of development. You have to remember that we are, in terms of the acute indication, going down a path that nobody else has gone before us. There is no guidance in terms of what data you need for approval. The FDA has not given out an acute indication in asthma or COPD. When we met with them, they could not give us explicit guidance in what is the endpoint, how many patients they want to see, et cetera. We had no way of powering a phase II study for FEV1 change because there is really basically no data on what happens to patients in the middle of an exacerbation, how fast does their FEV1 recover on background therapy, because these patients are aggressively treated, bronchodilators, prednisone.

How much more can we benefit? The purpose of this study was to really answer those questions. What's a useful endpoint for acute? How much benefit can we show? Therefore, how do you power a phase III study? I think we confirmed unequivocally the drug works very rapidly to improve lung function, and to improve it on top of aggressive background therapy. That was a big question because we normally present data pre-bronchodilator. Patients at a trough, they're at their lowest level of airway function. Then you give them the drug or placebo, and lo and behold, airway improves. You've got a pretty significant amount of head space to show an improvement. Here, we're taking patients, we're maxing them out on bronchodilator, and then saying, "Okay, 20 minutes later, now do a test.

Are you breathing better because you had this drug 3 days ago than with just the high-dose beta-agonist that they're receiving?" We were able to demonstrate certainly at day 7, statistically significant improvement over that background therapy. I think the study was very successful from our perspective on demonstration of benefit and giving us a pathway to design a phase III program. Yes, we're disappointed that the background rate of treatment failure was lower than projected, and as such, even with a 66% reduction, we missed statistical significance. Unfortunate, but I think what's important is it wouldn't have changed our path if we'd had those 2 or 3 more people on placebo with a treatment failure.

We still would not be going to the FDA with a treatment failure endpoint for an acute indication, because what's clear from our study, what's clear from ABRA is you don't see treatment failures in the first week. People are on prednisone. They're maxed out on therapy. Very difficult to see treatment failures in that first week, 10 days. That's the window that the FDA would be interested in in terms of acute benefit. Maybe even sooner. At the very least, you're not going beyond a week to show a benefit to get an acute indication. Treatment failure was, we thought, a smart, in retrospect, maybe not so smart, way to power the study. We had a very contemporary publication of the ABRA study exactly when we were setting this trial up. That gave us, theoretically, a perfect opportunity to power a study.

We theoretically knew what the background rate was, what kind of improvement we should show, powered the study, took a conservative approach of 50% benefit. We saw much better than that, but if you don't have enough events, it's hard to reach a stat sig. That was unfortunately the outcome that we had to describe today. But if you look at it in the perspective of in the phase II study that was completed a few years ago, 24-week trial, we showed excellent improvement in FEV1 very rapidly, which is why we're going after an acute indication. We saw about a 63% reduction in annualized exacerbation rate. Here, we're seeing fairly similar improvement in exacerbations, and the same kind of rapid improvement in FEV1. I think it totally validates the previous observations, and now is the time to design the phase III.

We plan to meet with the FDA late this year. Hopefully, we get calendared in a timely fashion, and then we'll be able to move forward into phase III early next year.

Yeah. Look, we just unblinded and analyzed the top line results literally within the last few days. We have not had time to drill into it to the extent that we will over the next several weeks and months. But some of the things that clearly pop out when you look at the data are that even though we use the same entry criteria for one of the key issues would be how many exacerbations has the patient had in the last year. So we set it at least one. I can tell you that KOLs pushed back and said, "Don't even ask for one, because that's going to be hard." We stood by it because we wanted to match the ABRA data, and we ended up with about 1.6 in both groups in terms of exacerbations in the prior year, which is pretty good.

We now look at ABRA, and it's 4 to 5. So it's a population of very rapid and frequent exacerbations. I think from that perspective, it's probably an anomalous outcome to see that rate of treatment failure. Easy to say in retrospect, but I think that that rate we now know is definitely higher than what is seen normally in the real world in the U.S. We have data that it's 17%-20%. So if we were ever going to do a treatment failure study, we'd certainly have a much more realistic expectation of what we should see. We did not even see that 17%-20%, obviously. I think that has to do with a lot of factors related to the majority of patients coming out of Eastern Europe. Those patients they tend to be a little more compliant, I think, with medication.

If you use your inhaler more regularly, you take all of your prednisone, probably have a lower expectation of recurrence. I am sure there are other factors that we will find as we drill into the data.