Annexon, Inc. Common Stock Wells Fargo 21st Annual Healthcare Conference

Thanks for having us. Delighted to be here.

Yeah, happy to do so. Yeah, exciting indeed. We're in our 11th year here at Annexon, and more excited than ever about the technology that underpins the company. After 11 years, we've got two major opportunities to deliver game-changing therapies to millions of patients worldwide. The first in Guillain-Barré syndrome, which we'll talk more about. Obviously, a resounding win on the phase III. We're on file for approval in Europe, and we anticipate filing very shortly for the BLA in the U.S. That's coming, and we're really excited by that. Followed shortly behind that will be the geographic atrophy phase III study with vonaprument separate drug candidate, where we're really excited about the outlook at month 15, which I'm sure we'll talk a great deal about. Last but not least, is our small molecule program.

First in kind, oral tablet targeting the classical pathway for a host of antibody-mediated autoimmune disorders, where we will update on a proof of concept study this fall on that program. After 11 years into it, one thing we can say consistently is that this platform and this mechanism that we are targeting by blocking upstream inflammation right on disease tissue is really showing very unique functional benefit in patients, which is different from a symptomatic outcome, which we think is really important. We are encouraged by it across the board.

Yeah, 100% offensive. Really thrilled by this. For those who are less familiar with the program, this is a 24-month study with the primary endpoint being month 15. We got 12 months through the study, and what we realized is we picked up additional alpha or power over the course of the study, and I will have Lloyd Clark talk more specifically about how we did that. Anyway, suffice to say, we had the option to either add additional power to month 15 or apply it to a second endpoint, an independent endpoint at month 24. We chose the latter, primarily because month 15 is so well-powered. Month 15 is powered at greater than 90%, even higher, I mean, really high, plus 90% at the single study level and 90-plus percent at the sub-study level. We felt really good about where that endpoint is.

That was our first call to action was to make sure we do no harm and to protect the primary endpoint at month 15. Then to apply the additional outcome to month 24 really was centered around building a franchise that is dominant, candidly. We recognize that month 15 is an important and an attractive number, but month 24 is even better for the treating physicians, for the patient populations, certainly for the payers, et cetera. Anyone following us will now need to run a study after with 24 months or greater data on an endpoint of BCVA 15 letter loss, which is an exceedingly high bar. We in effect, were able to build a moat around this franchise by adding in month 24. Maybe, Lloyd, talk a bit about how we picked up power over the course of the study.

Yeah, Doug, we did a 12-month review of the study, and we really found that we had a larger study at the end of the first year than we anticipated due to four factors. First, we made our powering assumptions based on 12-month data, but we extended the trial early in the course of ARCHER II to month 15. So we had more events at that point. As a reminder, we over-enrolled the study at the outset by 30 patients, which gave us more patients, more time, more events. One of the key factors that we learned during the course of the study, though, was that we had significantly better patient retention than we anticipated, significantly better than our phase II study, and much better historically than other phase III dry AMD studies. So again, more patients, more time, more events.

So the size of a study like ours is sort of predicated on the number of sham events that you have in a study. We essentially found ourself at the end of the first year with a larger study operationally than we anticipated, which gave us more statistical power. The fourth piece was then looking at that and then putting alpha at month 24. That gives us more time, which gives us a larger treatment effect. A widening treatment effect is a significant variable to increase powering in a clinical trial. So this was sort of operational statistical power that we recovered with the combination of time as our friend in the second half of the study to give us the opportunity to add a second endpoint.

Yeah, really good question. So for us and for the regulators, what's really important is data integrity out to month 24. So what that means is, from a company perspective, we could not unmask ourselves at month 15, yet we still wanted an answer. So we assembled the DMC, which has been running over the course of the studies. It's a very experienced group of retina specialists. They will look at the data at month 15 and make a determination on whether or not the study is feasible to continue, if we've hit our statistical bar, or end/or to continue. So those will be the three options that they will give us. So that's all we will know, and we will report out at that point.

Assuming success at month 15, they will then unmask and look at the sub-studies, which we will have at the beginning of next year. Assuming success on that, the company will then be unmasked as we pull a package together to file for approval while the study is still running for month 24. It is a really stepped approach to really align ourselves with the regulators to do this in a way where we protect the integrity of the data.