Vertex Pharmaceuticals Morgan Stanley 24th Annual Global Healthcare Conference

You bet. Well, good morning all, and for you brave souls who've made it here at 7:00 A.M., it's very nice to see you. We have been on a journey. It's more than 10 years now to diversify our company and continue to grow. I do want to make sure that we talk about CF for one minute. CF has been and remains important to us, and we see more growth in CF as we now launch ALYFTREK around the world and get down to lower age groups. We also have our last 5% of patients for which we don't yet have a therapy. That foundational pillar of CF continues to go strong. Outside of CF, over the last three years, we've been bringing CASGEVY to more people around the globe, and you know CASGEVY has a very significant patient journey.

And now we are at a point where we can see patients who are initiating, who have first cell collections and have infusions. We have line of sight into the growth, and it looks very good and I continue to believe CASGEVY is going to grow into a multi-billion dollar asset. Over the last year or so, we have been launching JOURNAVX in acute pain. This is the first non-opioid in more than 2 decades, and I really like what I see in the growth there. Then we were talking about the fourth pillar, which was going to be renal medicine. It is, but I think it is actually going to just switch places with rare endocrine and Crinetics, which is our fourth pillar now with PALSONIFY, which is an approved medicine in the U.S. It is approved in Europe, launched in the U.S. This is a medicine for acromegaly.

Then of course there is the renal pillar. The PDUFA date for our first renal medicine, povetacicept in IgAN is November 30, and I am sure we will get into a little bit more there. There is much more beyond that. In total, there is something like 6 programs in phase III, more than that in phase II, and I like what is coming out of the bench into the clinic as well. So lots going on inside and outside of CF.

Yeah. So when you think about IgA nephropathy, just to level set, you are looking at something like 300,000 patients between the U.S. and Europe, let us say 150,000 inside the U.S., and then add another 1 million or so in Asia where we are going with Zai Lab in China and associated countries and with Ono Pharmaceutical in Japan and a few other countries. So it is one of these rare diseases that is a common rare disease. In terms of coming to market, it turns out that this is an interesting area where there are 3 medicines that are all launching, let us call it within a year or so of each other in the category of APRIL or APRIL/BAFF. In my mind, as I think about IgA nephropathy, and I happen to be a nephrologist, this is a disease that is very well understood in terms of its etiology. It is a B-cell-mediated disease.

It is a disease that results from autoantibody production. When you think about it that way, it makes most sense to have a medicine that works on both APRIL and BAFF, because those are the two cytokines that are most responsible for B-cell development maturation. It wouldn't make sense to me to work on only APRIL or only BAFF unless you saw some concern in the safety profile. We now have the profile. We put out a fairly extensive press release. The safety profile looks really good and the efficacy, and this is numerical and it's cross-trial comparisons. You got to take this with a grain of salt. When I look at the numerical response, povetacicept has the best numerical response in terms of proteinuria, hematuria, Gd-IgA1 levels, and that's important.

But maybe the most important thing which could be surprising to you is the fact that it's also the most patient-friendly dosing. This is a biologic. A patient will be taking this for the rest of their life and their ability to take a small volume, povetacicept is 0.46 mils, in an auto-injector once monthly is a very favorable presentation, and I think that's actually going to be one of the greatest differentiators. I also think our ability to support patients through their journey is going to be important. We've learned a ton doing the same in cystic fibrosis. I think that's going to be important.

The last thing I'll call out is we have built the largest sales force, and that is to serve patients where they are. There are certainly centers of excellence and large clinics, but there's also smaller number of patients in the community setting, and we want to be able to serve all patients.

Yeah. This one has been a rapidly evolving field. 10 years ago, 15 years ago, the FDA wasn't yet comfortable with proteinuria as an accelerated endpoint. The community, the renal community, has been working with the FDA, with academic centers, with industry to get proteinuria to be it. We are now at a point where proteinuria is routinely accepted in IgAN as an accelerated approval endpoint. Your point, Terrence, is around, all right, where are we with GFR? On GFR, the agency has been hinting, and in the spring renal meetings, they all but said they're going to get comfortable with one-year GFR as the endpoint as opposed to 2 years GFR, which is where it was at prior to those meetings with the FDA. Where we are is that we want to launch povetacicept around the globe. That is our ambition. That is what we are going to do.