Okay, great. Good morning, everyone. My name is Eric Schmidt, and I'm one of the Senior Biotechnology Analysts at Cantor. I want to welcome you all back to our Global Healthcare Conference, and also welcome, I think, for the very first time perhaps, our next presenting company, Agios, for a fireside chat. We're delighted to have with us pretty much the full senior team at Agios. We have Brian Goff, the company's Chief Executive Officer. Sarah next to me, the company's Sarah Gheuens, the company's Chief Medical Officer. Tsveta Milanova, the company's Chief Commercial Officer. We also have in the front row, Cecilia Jones, the company's CFO. Somewhere around here is Chris Taylor as well from IR. So, we've got the whole group here, and everyone will be around for your questions after our session.
But Brian, let's kick it off with you, maybe just high level for those a little bit less familiar with the story. Give us the elevator pitch on Agios.
Yeah, happy to, and thanks a lot. We're really happy to be here at the Cantor conference, and I'm really pleased to be on stage here with the powerhouse of Sarah Gheuens and Tsveta Milanova. This has been a very exciting year for Agios, and sometimes I describe it as a breathless year in the best way possible. To take a step back and just give the big picture of who we are, our mission at Agios is to develop and deliver transformative therapies to elevate and extend the lives of patients who are living with rare diseases. And the real focal point for us is we're the world leader in a very special mechanism of action, known as pyruvate kinase activation.
Our product, our flagship product, mitapivat, has just delivered and delivered, especially this year, across now three different hemolytic anemias. We're on a pathway to build a multi-billion-dollar franchise with mitapivat. The data has been, as I noted, just compelling and consistent across pyruvate kinase deficiency, thalassemia, where this is a big year for thalassemia, with the readout of two pivotal phase III studies, and sickle cell disease, where last year we had a phase II readout that was very compelling. This year, by the end of the year, we're looking forward to completing enrollment of our pivotal phase III RISE-UP study in sickle cell disease. It's shaping up to be a you know really exciting opportunity with mitapivat having first-in-class and best-in-class potential.
And as I said, the mechanism here of pyruvate kinase activation is all about improving the health of the red blood cell, which we'd be happy to talk more about. We also happen to have another PK activator, and this is a little bit like Prince. It was formerly known as AG-946, and now the INN name is tebapivat, T-E-B-A-P-I-V-A-T. And I'm pleased to announce that just recently, we achieved orphan drug designation for our pursuit of low-risk MDS with tebapivat. I can share today that we have now initiated our phase IIB study in low-risk MDS, which is very exciting and just continues to extend our potential pathway for the mitapivat and tebapivat PK activation franchise.
The last thing I'll mention is that, you noted that in the room is Cecilia Jones, our CFO, who, just really delivered on strengthening our balance sheet this year in that a product that came out of the Agios Labs, vorasidenib, which is now owned by Servier, as a consequence of when we sold off the oncology business. When vorasidenib recently received FDA approval, that triggered, milestone payments that account for $1.1 billion. And so if you look at our... The way we ended our second quarter, on a pro forma basis, our balance sheet, would be $1.7 billion, which puts us obviously in a very, no pun intended, a very rare class of ability for, effective capital deployment. So exciting times.
What we're looking forward to by the end of the year, the highlights will be, first of all, filing with the FDA and regulators with combining our two studies for thalassemia, ENERGIZE and ENERGIZE-T. And also, as I noted, with sickle cell disease, concluding enrollment of our RISE-UP phase III study. So big year, big year already, and we're more excited about what's to come.
Okay, so lots going on, lots to drill down into. Maybe just starting with the mechanism, and Sarah, perhaps you want to address this. A few of us are not necessarily familiar with pyruvate kinase. Why is this an interesting pathway to drug, and why is it important for red blood cell health?
So, pyruvate kinase is an enzyme that is responsible for the last step in the glycolytic pathway, which is the main energy-generating mechanism. Also, what mitapivat does is stimulate that last part of the glycolytic pathway. And so our development program, it started first with a disease called pyruvate kinase deficiency, where that enzyme, that specific enzyme, is mutated. And we were able to show that we were able to increase by stimulating or stabilizing that mutated enzyme. And then we took it forward into thalassemia and sickle cell disease, and we were able to demonstrate there as well that we can improve ATP generation by stimulating wild-type PK enzyme. And that's important because what is a commonality across all of those diseases is that fundamentally, these red blood cells don't have enough energy to be able to survive.
And so that is what we're tackling via this mechanism, generating a better balance, creating more energy for the red blood cells, which is important for those cells to be able to withstand stress better and thereby improving their health.
Okay, let's start with the first indication, a quick, quick synopsis of what's going on in PKD. Mitapivat, brand name PYRUKYND in that indication. I don't know, Tsveta or Brian, maybe you just want to give us a quick overview of that market and what, if anything, you've learned from your commercial efforts in-
Tsveta is the rare disease commercialization expert, so let's have her start.
Absolutely. So I've spent a majority of my career in rare diseases, and when I look at PK deficiency, it really has all of the characteristics of an ultra-rare disease and the challenges associated with commercializing those. It's an ultra-rare disease, estimated prevalence of three thousand patients, but diagnosed prevalence significantly lower. So basically, disease, the disease is not diagnosed. There is a very low understanding of the disease within the Hem/Onc community as well. And very importantly, it's not an imminently life-threatening disease, so there is a very low urgency to diagnose, monitor, and treat these patients. So a lot of our commercial efforts have been actually focused on the first part of the patient journey, which is trying to identify clinicians who are potentially having PKD patients and educate them on the disease.
Having said that, as a commercial opportunity, it's a great entry point for us as we expand to meaningfully larger potential indications with thalassemia and sickle cell disease. Because it is still within the Hem/Onc community, it allowed us to build the initial steps of the commercial infrastructure to expand after that with thalassemia and sickle cell disease. And very importantly, it gives us real-life experience with the product. And I can say that we're very pleased with what we are hearing from our customers, being patients, physicians, and payers on the profile of the product.
And what we are very excited and really tracking consistently is the actual experience of patients and the persistency on treatment, which has been very, very strong because of the strong profile in PK deficiency, which potentially we can replicate with thalassemia as well, improving hemoglobin levels, but also having improvement in quality of life.
What has been that compliance, persistency that you would point us to in terms of metrics?
So we haven't given the specific details on continuations on therapy. If you look at the second quarter, we said that we had 201 PEFs or prescription enrollment forms with 128 patients continuing on therapy. That's a net number of patients, so that's patients who have started minus the patients who have discontinued. What I can say is, you know, we are very pleased with what we see in the real world, compared to clinical trials experience as well.
And one thing I would just add is that, what's also really unique about mitapivat and what we've seen so far in the trials consistently is something that's so hard to attain, which is a positive patient PRO, a patient-reported outcome, and the highlight of that is fatigue, which is such a common feature across these hemolytic anemias. And so you can imagine that, what we're trying to do is, with this unique mechanism, is check a number of boxes on behalf of the patient simultaneously, whether it's hemolysis or ineffective erythropoiesis, but also importantly, fatigue, and that is what helps in large part, of course, with patient persistency across these diseases.
Okay, let's move into thalassemia then. Big year, of course, for your development program. As you mentioned, Brian, two positive readouts, ENERGIZE and ENERGIZE-T, in both the transfusion-dependent and non-transfusion-dependent marketplaces, both alpha and beta thal. Sarah, maybe just start with the indication itself. What is the unmet medical need in thalassemia?
Sure. So the unmet medical needs, so there's very few therapies available for patients living with thalassemia, and right now it's actually only beta thalassemia and a subset of patients there that has a therapy available in the U.S. So the vast majority of patients are relying on supportive therapy. So when you're transfusion dependent, it means you get transfusions. If you're a non-transfusion dependent, it truly depends on the comorbidities that you develop of how you are medically managed. But as Brian already alluded to, a commonality across the whole patient population is that they're extremely fatigued. That has an impact on function, on schoolwork, general life, and then because of the disease also having a chronic iron overload, they develop a bunch of organ damage over time as well.
So huge unmet need because there is not really a disease-modifying therapy that it addresses the whole pathophysiology of thalassemia. And that's why we're very excited about our clinical trial program because we now have two trials that encompass the whole thalassemia patient population, in which we were able to demonstrate statistical significance on the hemolytic anemia component, both by reducing transfusions and improving hemoglobin and improving hemolysis. And very importantly, in that specific trial, we also were able to hit on statistical significance for fatigue via measurement by the FACIT-Fatigue. And then another thing that we were able to highlight in that clinical trial data set was that there was also an improvement on the six-minute walk test.
We have, in that specific trial, the improvement on hemolytic anemia, an endpoint that highlights that patients feel better and one that highlights that patient function better.
Brian indicated your goal is to file a supplemental, I assume, NDA this year.
Mm-hmm.
What's rate limiting for that?
... We have a goal to deliver on that by the end of the year, and so far, we're on track to do so.
I don't think you need the word rate limiting-
Yeah.
We're on track. Yeah.
Rate limiting means you'll file tomorrow? Nothing's rate limiting.
No, so there is. Well, if you look at it that way, the filing has very many technical components and building of modules and integrating data sets, taking other data cuts, like there is a lot involved. So there's a whole project plan, and that project plan is on track to deliver to the corporate milestone we had mentioned.
Okay, typical execution stuff. Okay. Maybe then, Tsveta, we'll turn it over to you. I mean, this is a marketplace that, again, investors don't have a lot of familiarity with. If anything, you know, there's some skepticism that it's a real market. Why should we care about thalassemia?
So we talked a little bit about the challenges with the ultra-rare PK deficiency. When you look at thalassemia, it's almost the complete opposite, and it ticks so many of the boxes for an excited potential commercial launch. First and foremost, there are 6,000 diagnosed patients with thalassemia in the U.S., and I wanna underscore the word diagnosed, which is a big difference versus PK deficiency. And as well, there are established ICD-10 codes, so we have a very good visibility and understanding where these patients are treated and managed, which allows us to deploy our commercial activities in an efficient and effective manner to reach these patients and physicians. Second, again, in contrast to PK deficiency, there is definitely a better understanding of the disease as a totality, especially in the KOL community.
I think there is a clear understanding of the unmet need in the transfusion-dependent thalassemia. What is very interesting is that over the past five to seven years, there is an increased body of evidence of the unmet need in the non-transfusion-dependent thalassemia, led by the KOL community. Having said that, in terms of our launch preparation activities, we know that the majority of the patients are still managed in the community hematology setting, so we are actively actually educating on the disease, and our three main points of emphasis on disease education are around the pathophysiology of the disease, highlighting that it involves not only ineffective erythropoiesis, but also hemolysis.
And we know, as some of the KOLs say, hemolysis is deadly, linking it to the complications, morbidity, and mortality, as well as the low quality of life, which is experienced not only in the transfusion-dependent populations, but is very prevalent in the non-transfusion dependent population as well. And last but not least, we are also educating on the fact that the thalassemia red blood cells have an increased need of energy and ATP, which directly links to the mechanism of action. Last but not least, this patient community is a lot more connected compared to the PK deficiency.
Brian and I had the opportunity to actually attend the Cooley's Anemia Foundation meeting earlier in the year, and we heard it loud and clear from patients of the unmet need in that disease, and the opportunity for us to make a difference with the potential launch in thalassemia across all the thalassemia subtypes.
So the last drug launch I think we saw here was Reblazyl from Bristol Myers Squibb. What's how would you compare and contrast what you have with Pyrukynd, either clinically or in terms of your commercial approach to the marketplace?
I think when we think about Reblazyl, the first thing I'll say is we don't see it as a good analog and a comparator of the potential of Pyrukynd in thalassemia, for several reasons. The first one, Sarah mentioned it already. Reblazyl is approved only in the beta thalassemia transfusion-dependent segment, while we are aiming to have a potential label across all the thalassemia subtypes: transfusion-dependent, non-transfusion-dependent, alpha, and beta. The second aspect for us is two-thirds of the population is non-transfusion-dependent thalassemia, and we have a clinical study which has demonstrated, as Sarah mentioned, not only a hemoglobin improvement, but improvement in quality of life, and we know that also from PK deficiency, quality of life improvement is a very strong motivator for patients to initiate and stay on therapy.
We're excited about the opportunity there, as well. The third aspect when we think about Reblazyl, again, we are an oral therapy, which does not add to the overall treatment burden. Reblazyl is once every three weeks, subcutaneous physician-administered infusion, that's not ideal for patients. Last but not least, Reblazyl is approved also for MDS, which has been BMS's primary drive and focus, so they don't have a lot of emphasis commercially on thalassemia.
The thing is, every, every one of those statements you could put first in front of. This is, I mean, this is the core of Agios, is we love pioneering in these rare diseases, and to be the first, to have the opportunity, I should say, to be the first to cover all subtypes so no one gets left behind in this population is really special. First oral, we haven't talked about it yet, but also in the ENERGIZE-T data, which is the transfusion-dependent population, we were really proud to see that mitapivat was the first to show, and this is the maximum we could have shown in the study, 36 weeks of durable effect in terms of this transfusion reduction. So we, we check a lot of boxes on firsts, and, that's something we're especially proud of and excited about.
... Okay, ex-U.S., especially in the Gulf regions, may also be an important marker. The market here, we know you. Well, why don't you tell us about the deal you've signed with NewBridge and how you intend to address this opportunity?
Absolutely. We are very excited about the GCC opportunity. As always, the U.S. remains our core priority, but when we start looking at ex-U.S. based on prevalence, GCC comes next. There are about 70,000 patients with thalassemia in that region. We recently signed an agreement with NewBridge, which is a really leading specialty distributor in the region with a very strong experience and expertise in launching in those countries. We're gonna sit down with them now and further refine the commercial opportunity there and the approach to launch, as Sarah and the team are preparing for a submission in the regions from a regulatory perspective, and we are preparing for launch.
When I think about the region, two things to keep in mind: The biggest country in the region is Saudi Arabia, where we'll be focusing a lot of our efforts with the majority of the patients there. We have a breakthrough designation, which is a new pathway , for approval, highlighting that the authorities see thalassemia as a high unmet medical need area. And the second thing, commercially, I would compare the region in terms of pricing, reimbursement, and product uptake, a little bit more similar to Europe compared to the U.S.
How quickly could we see a launch in the Gulf Cooperation Council?
Oh, Sarah, maybe you can comment on the regulatory process to start with.
This is a relatively new regulatory process. This is something that we are pioneering, I would say, in. I think the team is definitely ready to take a similar approach to that region as what we take to the U.S. and to Europe. The difference is there that the regulatory approval timelines, plus the reimbursement timelines are integrated.
Just one comment is, but on the receiving end, for KSA, for Saudi Arabia, we were really proud of the fact that recently we were granted, and it's new in the region.
That's right
... Breakthrough Medicines Designation. So at least as an indicator from the regulator vantage point of demand and interest in having this new oral therapeutic option, we're really proud to have that.
Would the Gulf Coast be your first geographic launch?
It's hard to say. I mean, I guess the best way to answer it is, our ambition is with urgency. If that happened, that would be the first that I can think of, where you have that kind of an order of entry. But I, you know, again, credit to Sarah and the team with just managing the interest level that exists from regulators.
Mm-hmm.
Sarah took time out of her very busy preparation for filing schedule to be at this conference, which we're pleased about. But we would be delighted if we could compress the timeline that so classically has long delays between the U.S. and elsewhere.
Okay, let's talk about sickle cell. You mentioned, Brian, earlier that you had some nice phase II data out late last year, sort of proof of mechanism, proof of concept in sickle cell, and that we're hoping to finish enrollment in the pivotal study this year and read out pivotal data next year. Sarah, perhaps you just paint us a quick picture of the unmet need in sickle cell, which obviously is very substantial, but how you view Pyrukynd or mitapivat fitting into that unmet need.
It's a horrible, horrible disease with lots of morbidity and increased mortality, very reduced lifespan in those patients, and they really don't have any therapeutic options that hits on the totality of the disease, because the disease has a hemolytic anemia component and then has vaso-occlusion and pain crisis components that lead to all of this morbidity and mortality together. And so our program is designed to deliver data that can speak to all of those aspects of the disease, so we have two primary endpoints. One is hemoglobin, so hitting on that hemolytic anemia component, and then annualized rate of sickle cell pain crisis, which hits on that vaso-occlusion component.
And then, because of the, you know, it being two primary endpoints, we can move on to secondary endpoint testing when we hit on one or both of the primary endpoints, and within those secondary endpoints, we have other parameters that can speak to feel and function in the context of the sickle cell disease manifestations. Because for this population as well, consistent as what we hear for thalassemia and for PKD, fatigue is really very important, and so that is also something we've incorporated in our secondary endpoints.
With your co-primary endpoints, what's gonna be required for approval? My guess is that investors are feeling quite confident in hemoglobin, since you've achieved that in multiple hemolytic anemias already.
Right.
Maybe more questions around VOCs, but perhaps not.
VOCs is a sort of classical endpoint in the context of sickle cell disease. Now, as you know, there are other options available in the U.S. Voxelotor is a hemoglobin improvement agent, so did not hit on VOCs, versus crizanlizumab is not a hemoglobin improvement agent, but had an impact on sickle cell pain crises. So there are multiple ways to tackle the unmet need in sickle cell disease, and I think that's the beauty of our design, because it really tries to hit on all of those. In regards to sickle cell pain crisis as a primary endpoint, it is a harder endpoint in general, not just in the context of this drug, but in general for sickle cell disease.
As proven by other development plans, but I think this is where our phase II data is really unique. It's the first phase II placebo-controlled clinical trial data set that actually delivered on hemoglobin and showed a dose dependent improvement trend on end hemolysis and on VOC. So the data goes all together in the same direction against placebo. So that's why we feel confident about that data set. And then the other aspect that I think is important is that because the way we designed the trial, which was an operationally seamless design, meaning we went from phase II took those results into then a phase III separate patient population.
But because of that seamless nature, we didn't change anything on our inclusion criteria, we didn't change anything on the way we assessed sickle cell pain crisis, and we didn't change anything around the adjudication of the endpoint. And those are things that are, I think, very logistically important when you measure an endpoint like that.
But from a regulatory perspective, could the trial be a success on either of the two primary endpoints?
So from the regulators, it's always a matter of review, right? It's like whatever the data actually ultimately presents, it's their assessment on the data set that they will independently make. But we have created a package that can deliver on the feeling component and the functioning component multiple ways.
Yeah, I think that's the point. I just want to reinforce how complex this disease is, and certainly at the patient level, and so if we talk less about a hypothetical scenario and more about our ambition, our ambition is to not have the patient or the clinician have to make a choice between these very important attributes that Sarah talked about. And in today's world, certainly in the oral therapy world, you're kinda stuck with the push and pull between, are you gonna go after hemoglobin or fatigue or VOCs? And we're going after a package that would have all three.
Fair enough, but as we've talked about, VOCs probably are the more challenging of the endpoint to hit. What gives you confidence? You mentioned the phase II results, of course, but what other factors in the drug, the data, the history with mitapivat give you-
So-
hope or confidence that you're going to hit on VOCs?
I think the golden standard, this is a placebo-controlled phase II, and you see that pattern as related to those. So I think that is one that is very important. We also have two investigator-sponsored trials that are open label, smaller data sets, but those data sets also continue to support the development in sickle cell disease, and then mechanistic work that has happened in the past around understanding the mechanism of action with improvements on point of sickling, all pointing to the same direction.
Thank you, so, Tsveta, if you're fortunate to be in position to commercialize this drug in the sickle cell market, how do you think about this opportunity?
I really hope that we're gonna be in the position to have two back-to-back potential launches with sickle cell disease. As Sarah said, the unmet medical need in that disease is really really strong. If we deliver on the profile, which Sarah and Brian mentioned, which is improvement in hemoglobin, reduction in VOCs, as well as improvement in quality of life and fatigue, this is gonna be the only product that delivers on all of the endpoints relevant, not only to physicians, but what we hear from market research, to payers and patients as well. So I think we'll be very, very well positioned.
Sarah mentioned currently there is no option, available that addresses all these, endpoints, and when we look at it competitively, we'll be the first, and best-in-class therapy, addressing these unmet needs across the board. There... Again, patients are diagnosed in sickle cell disease. There are about a hundred thousand patients in the U.S., total adults and pediatrics. There is a good understanding of the unmet medical need, and a lot stronger urgency to treat. So commercially, that launch really ticks all the boxes for us to be successful.
I think you make a compelling argument that you're checking all the boxes with mitapivat in sickle cell, where others competitively haven't. But investors have also seen sickle cell be a, you know, I think a difficult or challenging market to penetrate, maybe based on socioeconomic factors or patient disenfranchisement and things like that. How do you view maybe some of the sickle cell-specific factors when you're thinking about commercializing?
So the first thing is we haven't seen a launch where the product really addresses the unmet medical needs, and this is why we are aiming so high. The second thing is, of course, as with every disease, we'll approach the market comprehensively, addressing the patients, the physicians, and the payer opportunities that exist in that space. We are very well positioned, I think, as an organization culturally, to engage with patients early on in every aspect of everything we do. Sarah has great examples of how they helped us really inform the design of our clinical studies. We're taking the same approach commercially, so we get the patients' feedback early. We engage with the communities to make sure that we approach the launch in the most impactful and successful manner.
Well, team, I could go on all day and maybe into the night, and maybe we will offline.
Could we?
But, we're out of time, so thank you very much for this.