And then when you move to Phase 3, again positive studies against placebo. In the grand scheme of things, this is remarkable, because as you know, the conduct of clinical trials in the pain field is notoriously difficult. Placebo effects move around significantly. The effect of any comparator group moves around significantly. So when I look at the totality of the data and for me that means looking at the data from Phase 2 to Phase 3, and it also means looking at the SPID48, let’s focus on bunionectomy in bunionectomy and connecting that with the NPRS. Remember the NPRS is the actual score that feeds the SPID48, which is an integration of NPRS over time. So if you look at the NPRS data, the decrease in the NPRS is 3.4 points in bunionectomy, it’s 3.4 points in abdominoplasty start to hour 48, and it’s about a 50% decrease in terms of the relative decrease.
And when you look at that in comparison to Norco, the opioid we used in the trial, that number is 3.2 in abdominoplasty, 3.6 in bunionectomy, and it’s approximately a 50% reduction in terms of the relative change. So I put that all together and I see quite a bit of consistency and very good therapeutic effectiveness and efficacy. On sweat chloride, so it’s a really, really great question. In order to sort of really understand this you have to triangulate a couple of different data points, one data point is around just the natural history and the genetics of this disease. So, take for example, patients who are FMS versus those who are FRF. FMS patients have very high sweat chloride and have more severe disease. FRF patients, the residual function patients have relatively better sweat chloride levels and relatively less severe disease, that’s one set of data.
And then to your point, if you look at interventional data, the data that we have the greatest reduction in ppFEV1, sweat chloride, and long term evidence is TRIKAFTA. And if you compare that to KALYDECO for example, you can see where TRIKAFTA does even better than KALYDECO, and the best example I can give you is on rate of decline. The TRIKAFTA real-world data on rate of decline shows, there is no decline. And until we got the TRIKAFTA what we could show is, we slowed the rate of decline. And so, I have every reason in the world to believe as the vanzacaftor triple is used over a longer time point and we get CFTR protein function to higher levels, and the vanza triple has given us the best highest achieved CFTR protein levels, I do think we’re going to see long-term benefit.
And yes, you can do all of that math and triangulation from the available data.
Phil Nadeau: Perfect. Thank you.
Operator: Your next question will come from Robyn Karnauskas with Truist. Please go ahead.
Robyn Karnauskas: Hi, thank you. So, commercialization, I know it’s really hard switching from one drug to the next, can you walk me through switching from TRIKAFTA to the next drug? And like, given that people are stable, their lung punctures are great, how would you think about — what motivates commercial, Europe as well as U.S., to allow people to stay on drug and like move to next-generation drug? And I think I’m coming from the point of, like I remember from a long time ago that people had a hard time switching from one drug to the other, and I want to understand like more — like how you actually help people, help commercial organization switch from one to the next?
Reshma Kewalramani: Stuart?
Stuart Arbuckle: Yes, Robyn. Thanks. So I must confess, our experience is a little bit different to that. We’ve seen very rapid transitions from medicines as we’ve serially innovated and delivered better and better medicines, and even, for instance, when we introduced TRIKAFTA and patients who had been on KALYDECO for instance for a very long time, and obviously, KALYDECO had set a very, very high bar for efficacy, we did see rapid adoption with TRIKAFTA even in those patients given that it had a clear benefit-risk profile. So, I think we’ve seen relatively rapid transitions for our medicines as we’ve serially innovated. And interestingly, the design of the study actually gives a proof for the fact that patients can effectively transition from TRIKAFTA to vanzacaftor because as Reshma mentioned in her remarks, the design of the study was to have people stable on four weeks of TRIKAFTA therapy to establish a baseline, and they were then randomized to either continue on TRIKAFTA or transition to vanzacaftor.
So we have within the study real-world evidence of people being able to transition. And then you asked me, what do I think is going to motivate people to want to consider the vanzacaftor triple combination? I think it’s the benefit-risk profile that we’ve been able to demonstrate here with achieving higher levels of sweat chloride reduction and with any of our previous medicines, including now TRIKAFTA, and the fact that this is a once-a-day therapy. So as I’ve said a number of times, I think with this profile we’re going to see a lot of enthusiasm from the CF community.
Robyn Karnauskas: So follow-up question for you is, what about the payers of the governments in Europe, do they believe in like, you’ve had very stable levels of lung function with TRIKAFTA, do you think that people focus on like that or do they need more data moving forward?
Stuart Arbuckle: Well, I mean, I think we’ve had a long track of working with payers on cystic fibrosis for kind of well over a decade now, so I think there’s a significant amount of understanding about the disease. Obviously, we’ll be presenting the data to vanzacaftor to payers in a compliant manner at the right time. The one other thing I would note about the vanzacaftor triple combination, is it’s likely to be indicated for a very similar population of patients to TRIKAFTA, which I do think is going to make this launch from a payer perspective a bit different to previous launches as you will recall, because you’ve been on this journey with us for a while. When we launched ORKAMBI, we were moving from kind of single-digit numbers of eligible patients to a medicine that could potentially treat up to 50% of CF patients.
When we then brought TRIKAFA forward, we’re moving it towards being able to treat 90% of patients. Vanza is going to likely have a very similar label to TRIKAFTA and so it’s not likely to be as scary I would suggest to payers in terms of a big budget impact here.
Robyn Karnauskas: Great. Thank you so much.
Operator: Your next question will come from Jessica Fye with J.P. Morgan. Please go ahead.
Jessica Fye: Great. Good evening. Thanks for taking my question. Can you set expectations around how you see the cadence of patients initiating the CASGEVY journey for us? Thank you.
Reshma Kewalramani: First thing, Stuart.
Jessica Fye: Yes, Jess. So I think we’ve described the patient journey for CASGEVY, it has kind of these multiple phases from patients being evaluated by their physician and deciding with their physician that this is a journey that they want to go on. You then have to go through the cell [Technical Difficulty] manufacturing process and then the cells are infused, each of those steps can take a number of months. And as you know, we’ve said that we’ll be recognizing revenue at the point of infusion. So in contrast to our cystic fibrosis launches, which have really seen incredibly rapid uptake, we have said that we are expecting this launch to be more like a traditional biopharma launch, but we are expecting this — and we have said, we are expecting this to be a foundational year for us as we build momentum around CASGEVY.
Having said that, in terms of the destination, we continue to believe the destination for CASGEVY is going to be used in thousands of patients and represents a multi-billion dollar opportunity.
Jessica Fye: Thank you.
Operator: The next question will come from Evan Seigerman with BMO Capital. Please go ahead.
Evan Seigerman: Hi, guys, thank you so much for taking my question. I know there’s a lot on the vanza triple, but kind of — can you maybe walk us through some of the clinical considerations as you would get to maybe have a physician switch patient? And then thinking about kind of potential TRIKAFTA [indiscernible] returning on drug, what does that conversation look like? And I guess maybe more specifically, why would a patient discontinue TRIKAFTA and why would they want to reinitiate with the vanza triple? Thank you.
Reshma Kewalramani: Sure. Evan, I think Stuart has talked about this and maybe I’ll shorthand it by saying, we have the approximately 6,000 patients who are in the system, they are known to have CF. They’re seen by a CF provider. They used to be on TRIKAFTA, so they’re not lost. They simply have discontinued it either because of an adverse event or perhaps because of compliance [Technical Difficulty] vanza is of course once today. So we see those 6,000 patients potentially coming back and the short version of the conversation would be, they’re coming to see their doctor. Usually, CF patients are seen by their doctor once a quarter. So when they return the conversation might be something like if and when vanza is approved, there is a new drug, it has this safety, it has this efficacy, do you want to try it, you had tried a medicine before, this is a new one, and the doctor and patient would have a communication about that.
So the patients who are already on TRIKAFTA and are doing well, I suspect it’s going to be just like it was from SYMDEKO and ORKAMBI to TRIKAFTA or from KALYDECO to TRIKAFTA. Our CF patients are very educated patients. They know what clinical trials are going on. They know what potential medicines might be coming down the pipe and they are interested in being treated with the most effective medicine, the medicine with the best benefit-risk. And they do this because it is a disease that starts at birth and is with them their entire life. Now with the life expectancy based on modeled data being in the [ADs] (ph), I do think the idea is that we can get patients to as close to normal as possible, at least we’re on that journey with vanza is an attractive option for physicians and patients.
