Business Of Biotech
The Business of Biotech is the pod dedicated to leaders of emerging biopharma firms. SUBSCRIBE to our new newsletter at www.bioprocessonline.com/bob. We bring you insight into organizational, finance and funding, HR, clinical, manufacturing, regulatory, and commercial challenges you’ll face as you navigate your company from an idea to success in the clinic and beyond. Each episode features guest commentary and best practices from accomplished founders and biopharma industry luminaries. The Business of Biotech is produced by Life Science Connect.
Business Of Biotech
Commercializing RNAi Therapies With Alnylam's Tolga Tanguler
We love to hear from our listeners. Send us a message.
On today's episode, Tolga Tanguler, EVP and Chief Commercial Officer at Alnylam Pharmaceuticals, talks about commercializing RNAi therapies, how they fit into health insurance reimbursement systems, the company's use of value-based contracts, and building therapeutic franchise "skyscrapers." Tangular also shares his thoughts on commercializing RNAi therapies for larger patient populations, compared with rare disease populations, and reflects on changes in the biopharmaceutical sales and promotion model.
This episode is brought to you by Avantor. For more information, visit avantorsciences.com
Access this and hundreds of episodes of the Business of Biotech videocast under the Business of Biotech tab at lifescienceleader.com.
Subscribe to our monthly Business of Biotech newsletter.
Get in touch with guest and topic suggestions: ben.comer@lifescienceleader.com
Find Ben Comer on LinkedIn: https://www.linkedin.com/in/bencomer/
This episode of the Business of Biotech is brought to you by Avantor. Every day, science has the power to change lives for the better. Avantor partners with the scientific community - pioneers and innovators in the lab and in bioprocessing - to help solve complex scientific and operational challenges. Avantor delivers end-to-end support, from discovery to commercialization, for the global biotech and biopharma ecosystem, providing mission-critical products and services that are integral to advancing life-changing innovations for patients. Visit avantorsciencescom for more information.
Ben Comer:Welcome back to the Business of Biotech. I'm your host, Ben Comer, chief editor at Life Science Leader, and I'm pleased to speak today with Tolga Tanguler, Executive Vice President and Chief Commercial Officer at Alnylam Pharmaceuticals, an innovator in the RNA interference or RNAi, therapeutic space. Tolga is a commercial leader with deep industry experience who has helped commercialize some blockbuster brands you may have heard of, such as Viagra and Eliquis. He also led Pfizer's rare disease group for North America before joining Alexion Pharmaceuticals as senior vice president and head of Alexion's U. S. organization. Tolga joined Alnylam in 2020 and has been a key player in expanding the company's footprint globally to more than 60 markets and dramatically increasing patient access to Alnylam's therapies. Thanks for being here today, Tolga.
Tolga Tanguler:Great to see you, Ben. Thank you for having me.
Ben Comer:Absolutely. I wanted to start with how you got into this line of work. What attracted you initially to pharmaceutical drug marketing and commercialization?
Tolga Tanguler:Yeah, thank you Ben, and I wish I could tell you that there was this great, great grand plan for me to join the industry, but it came a bit of, I think, a happenstance, and I feel very fortunate to be part of the industry, looking back after 25, 30 years.
Tolga Tanguler:Essentially, my family is a good mix of a business executive and my mom is a psychologist who has been in the medical industry, so medicine was not a new territory for me. While I was at business school, I had a number of offers, one of which was actually an offer from Merck that was part of the leadership development program, which really fit very nicely with something that my father always used to say, which is, if you want to do something and if you want to lead something, learn from the bottom and understand how actually the sausage is being made. So Merck Leadership Program was actually a great opportunity and that's why I actually picked it. And, of course, again, science, medicine, technology were in areas that were too unfamiliar for me. So that was actually a great start. And again, I've been very fortunate being associated with great companies like Pfizer, Merck in the beginning, Pfizer throughout my formative career, and then, as you mentioned, I had the opportunity to join the biotech world, first with Alexion and now last four or five years with Alnylam, which has been just a phenomenal ride.
Ben Comer:Yeah, you went from gigantic drugs to rare drugs and now you know Alnylam might be heading back. The pendulum may be swinging back towards some larger patient audiences. I have to ask you about working on Viagra. What was that experience like? Was that the first big brand that you worked on?
Tolga Tanguler:It was. And, frankly, what's really interesting, I was given an opportunity to work either with Celebrex or Viagra and I made the decision early on that I would actually work on Viagra. A what an iconic brand, and who wouldn't like to kind of learn and understand how an iconic brand works? And the second piece of it was, unlike most of our medicines in those erectile dysfunction category, doctors tend to abdicate the sort of writing these products to their patients. So I felt like I'm going to work with science and I'm going to work with these very unique therapies throughout my career. But Viagra will probably come once in a lifetime where you actually get to understand how patients think through, and it's obviously in those days especially. It was a stigmatic category and working in a stigmatic category and working in a stigmatic disease area and working with the patients was very intriguing to me and, frankly, I never looked back after the experience. It really allowed me to understand how patients think and how to actually help patients with a condition that is so stigmatic.
Ben Comer:Yeah, absolutely. In the late 90s I was working in a mom and pop pharmacy is actually a compounding pharmacy and I remember the Viagra sales team coming in, which maybe you can answer this question for me before I tell this short story, I promise.
Tolga Tanguler:I want to talk more on biotech, but yes, let's talk about Viagra.
Ben Comer:Yeah, just for a second.
Tolga Tanguler:Bear with me here.
Ben Comer:I was always curious about why the sales detail team came into a pharmacy, given that the pharmacists weren't writing prescriptions. Can you clear that up for me?
Tolga Tanguler:Yes, yes, actually. In fact, when I was a year, when I started my rotation program at Merck, I spent in the field a year and we were asked to go into these pharmacies. It was mainly because you wanted to understand how the pharmacists reacting to the patient needs and also understand if they see any demand, so we would actually just talk. It was always a bit of an optional call in those days. I don't think we do that anymore as an industry and you have, you know, ability to capture a lot of data and insights through third party without going to these pharmacies, but it was actually a bit of an industry standard in the 90s. You're spot on.
Ben Comer:Yeah, well, what I remember from the sales detail folks that came through was a Viagra calculator that you may remember this. It was flat and you pushed a button on it and the top kind of rotated around and then ultimately stood the calculator up a little bit, which we were, you know, as a high school male, I was very, very tickled by.
Tolga Tanguler:But anyway, well, listen, those are some of the practices that I'm so glad that the industry moved away from.
Ben Comer:Well, I was going to use that as a segue to ask you you know how launching and commercializing new therapies has changed since you worked on on Viagra in the early aughts.
Tolga Tanguler:Yeah, I mean listen, like everything, the industry had some growing up to do and I think we did. And obviously the diseases that I'm so keen on commercializing, which is simply a word meaning how do we get this product value back to our companies that continue to innovate for transformative diseases that patients that need the most? So that's been my passion and that's how we've evolved, and what I really like about the space that we're in has a lot to do with the words that I just used, which is high medical needs and transformative therapies, and society right now, in the right way, start valuing and rewarding those actually products that truly make a difference, so that you know you don't get to work on, spend a lot of human and capital to areas where you're just developing a me-too product that is no longer acceptable and that's not where you generate value. And let me tell you also another personal story about why I'm so keen on actually working on those products. It has a lot to do with my son and his journey. Products has a lot to do with my son and his journey In about the middle of my career this is just before I start leading the rare disease unit in North America for Pfizer.
Tolga Tanguler:My son was diagnosed with leukemia childhood leukemia. He was 11 years of age and even though, you know, I was in the middle of my career in the pharmaceutical biotech industry and I always thought I was very patient focused and I always cared about the impact that our medicines, or potential medicines, will make on people. But, boy, when that hits you in your family in a very personal way, you start looking at things very differently. And, frankly, that was one of the reasons why I was attracted to Rare, because you knew that the impact that individual impact you can make is really profound on a single life. And now, obviously, with the therapy areas that we're working on at Alnylam for the future, is what really excites me is you can actually make those profound impact in a much broader population. And what's so great about Alnylam is and I guess we'll get into this is the technology platform that we have that enables us to do, whether it's a single genetic mutation condition or a protein that may actually impact a significant illness like hypertension or hypercholesterolemia.
Ben Comer:Yeah well, thanks for sharing that story. Did your son survive?
Tolga Tanguler:He did I should have said that, yes, he's an annoying 20-year-old college student. He's doing great, and we all recognize that none of those things are for granted.
Ben Comer:Yeah, yeah. Well, I'm happy to hear that I wanted yeah.
Tolga Tanguler:And, by the way, I mean, let me add this he wouldn't have survived if it wasn't for our industry and science, because only 50 years ago this was a death sentence. Now the prognosis rates are as good as 90%. So that's the progress that we need to continue to make, because there are a lot of kids out there, there are a lot of adults out there whose illnesses are not transformed yet, but we were very lucky that we got into that bucket of diseases that science and medicine have figured out a way to solve it.
Ben Comer:What would you say is different about launching and commercializing an RNAi drug versus other more established drug modalities? And I'm thinking you know we had a short call just to prepare for this podcast Tolga, and you know one of the things that that came up was this kind of you know, I don't know if drug, but also how you bring such a new modality to physicians and overcome, you know, some of those kinds of resistance to change that they might present.
Tolga Tanguler:Right, yeah. So I mean, listen, I find it, to be honest, is an opportunity. I think we talked about Eliquis and, how you know, at the time we had head-to-head data, both on the primary endpoints, like you know stroke prevention and risk reduction, and safety versus Coumadin, which is a 50-year-old product that's been out there for blood thinning, and essentially, even though you had a head-to-head trial that showed superiority versus Coumadin, in both on primary endpoints as well as on safety, doctors were not willing to make the change. They all felt, like you know, they were able to control the patient's bleeding, which was not an easy dosing, and then you had to get liver enzyme tests and everything, and that took us a while. So there is, I guess, an inherent condition in all of us, and also with doctors, to be a little skeptical about new treatment options. What's so great about, I think, what Alnylam provides and allows us to rethink is the fact that you can literally do a subcutaneous injection every three months to, you know, lessen the hypercholesterolemia. One of our products is right now being marketed by Novartis. It's a product named Leqvio. So that is. You know, I see that the numbers are picking up. That is exactly the example where how doctors tend to resist.
Tolga Tanguler:Now I find that also gives us an opportunity to completely rethink how medicine is practiced. We're currently working on a product called Zilebesiran that is subcutaneous in the injection every six months that lowers potentially lowers systolic blood pressure. Now we have several highly effective medicines that are out there that lowers blood pressure and they are inexpensive. Yet, for any account, there is about 20 million Americans that suffer uncontrolled blood pressure that results in stroke and other significant consequences of blood pressure. So why is that? Well, one of the answers is actually probably patients are not taking their medicines every day. Once a day pill or twice a day pill, as sound, as simple as it is. Now I'm that age where I'm taking some of those medicines. I can tell you I miss them and I know what the consequences are.
Tolga Tanguler:So bringing a medicine that is highly effective and safe and with a simple subcutaneous injection that you visit your doctor or a nurse comes in your home and injects you, opens up a whole set of opportunities. That really excites me, because commercializing a new technology in that respect is really, really, I think, advantageous. But it's going to require us to also challenge ourselves to see how we actually bring some of those opportunities in mind. Now, the other plus I think that we have that maybe amazing gene therapies, therapy options are actually struggling is we're not one and done.
Tolga Tanguler:You know, we're not actually required to change how we get reimbursed. Actually, we fit nicely into the reimbursement structure that is currently set for medicines that are taken regularly. We don't need to actually price our disease as one and done, which actually gives us some advantages to actually work within the existing reimbursement system. And those are, I would say, actually it's not going to require us to change. But at the same time, these treatment regimens that are actually infrequent and simple, with a subcutaneous injection, may give us sort of an opportunity to force the health care system to rethink how medicine is practiced.
Ben Comer:You know. That brings to mind for me, you know, a key commercial issue that I wonder if you know I'm sure some of our listeners for the business of biotech will know about this Others may not though which is the gross to net issue. And I noticed in fourth quarter and 2024 earnings report that there were some positive gross to net adjustments made in the US during the fourth quarter, and I wonder, Tolga, would you mind just giving a brief, very high level explanation of what gross to net is?
Tolga Tanguler:Yeah, essentially it's the the your products revenue minus, you know, minus essentially your royalties and rebates and cost of goods. So that's how you know gross net is adjusted. And look, I mean, I think it's a it's a question of for a company that is destined to to change how medicine is practiced. We need to continue to force ourselves and our organization, how our cost of goods is actually continuing to be brought down. And this is an area where obviously we're not a biologic, we're also not a small molecule. Our manufacturing is complex and it's not cheap, but we certainly believe, unlike a gene therapy cost or even a biologic cost, we have an opportunity to actually to continue to further reduce cost.
Tolga Tanguler:Our CEO to continue to further reduce costs. Our CEO, Yvonne Greenstreet, has this vision of democratizing RNAi, meaning try to manufacture it as inexpensively as possible so we can actually make it available not just in the US but in other markets where cost is even a more bigger sensitivity. We're trying to obviously make that happen. Now, specific to the Q4 results there's always going to be ins and outs how those rebates are actualized. There's some also timing of some of those rebates, how they're actually being recognized. So I wouldn't necessarily pay too much attention to quarterly changes. What's really helpful is to look at the annual metrics, and those obviously metrics will also continue to evolve.
Ben Comer:Right and just for the benefit of our listeners gross to net. Gross obviously meaning what the product is sold for. Net is what you're actually making on the product and a lot of times the criticism of this so-called gross to net bubble has to do with rebates. Now, Tolga, you're reducing the cost of goods, so that's an excellent way to improve gross to net and, similarly, fixing the compliance issue, which I've been a journalist covering biopharmaceuticals for close to 15 years and for a while there it seemed like once a year I'd write the adherence and compliance article and somebody had a new idea about how to improve it. It never improved. You know we still. It's an ongoing challenge, but you know, when you have a shot that you can give over a course of months, you're, you're taking yourself out of that compliance quandary. Similarly, with lowering the cost of goods, you're setting yourself up for success in gross to net, at least in terms of things you can manage.
Tolga Tanguler:No, you're spot on, Ben, because I mean, look, just like you. Over the years when I worked on especially on tablets, both the industry as well as like pharmacists I've seen pharmacists actually have these devices that every time you open the pill tab it would actually send a message whether you're compliant or not. So the whole industry has been working around this issue, around tablets, and we haven't found anything, because I think inherently, taking a pill every day or twice a day is not a normal human condition. Now again, there are people who are incredibly adherent.
Tolga Tanguler:But even in oncology we see adherence rates as low as 70 percent I mean this is cancer. Rates as low as 70% I mean this is cancer In more you know, sort of metabolic diseases we see rates at 60%, 70%. So if we can actually solve this by simply how patients take their medicine every three months, every six months in physician office or a nurse practitioner visiting your home, I think we will go a long way. And I don't think we actually we can't overestimate the human health impact that's going to be made on the patients. And if you look at our current products, our adherence rates are 90, 95% every category that we work on. So there's something obviously to be said about how our medicines are administered.
Ben Comer:Yeah, I mean. The other thing about a daily tablet and compliance to me is, you know, particularly maybe in disease areas like cholesterol or even diabetes. I think one of the major challenges is that if you miss a dose, nothing really happens. There's no consequence right away from missing a dose. It's taking it over a period of time and missing doses, and so when you're not automatically feeling better because you took your cholesterol medicine on a given day, it makes it difficult to really incentivize.
Tolga Tanguler:You're spot on, and as an industry, I think we face two major hurdles. One is the physician complacency, because if you can do this yourself, or those colleagues that are watching this, should do that. If you ask any doctor in any therapy area whether their patients are actually adherent or compliant, they'll say yes.
Ben Comer:Of course right.
Tolga Tanguler:So there is that, I think, issue. And then, to your point, patients, yeah, if I miss my statin or hypertension, but again I'm giving you some numbers, even in cancer, where patients actually don't take their medicine, or maybe they need a caregiver that needs to do that and they don't have the socioeconomic, you know, setup to be able to do that. And we see it mostly on pediatric patients. And if the caregiver is, you know, less educated or a single parent that's working, those compliance rates tend to go down. So this is an area where I think we need to continue to work as an industry, and one solution is obviously come up with better medicines that are taken less frequently.
Ben Comer:I mentioned in the intro Tolga about Alnylam's global expansion. Almost half of the company's revenues now are coming from ex-US markets. What can you say about the strategy that Alnylam followed to accomplish this and what are some of the biggest challenges in building a large and growing global footprint?
Tolga Tanguler:Yeah, I mean, first and foremost, I don't think I can take the full credit of the online expansion strategy, because those actually who founded the company always had this really bold vision and, frankly, since I've arrived in four or five years ago, what I've been able to do is to actually embolden that strategy even further. Now to your point. We do generate about 40% 45% of our revenue. We continue to grow in terms of volume about the same rate that you would see in the US and, frankly, it's mainly driven by how I believe we're approaching our expansion. And for a small biotech, I think we're punching way above our weight and I don't think we ever look back about having that international presence. But we do it very thoughtfully and very carefully because actually it can put a strain on your resources. Having that geographic footprint, put a strain on your resources having that geographic footprint, but the potential benefit of investing a little bit on your ex-US markets actually happens, that you actually balance your revenue flow. So that's actually a big plus. You start finding opportunities where there might be some endemic regions that are less in the US. We certainly see that in our ultra-rare disease area and as you grow you don't need to leave a lot of value on the table for a third party or distributor that actually ends up actually really commercializing your product, where you get to keep that value again to transfer it into your research and development. You get to keep that value again to transfer it into your research and development.
Tolga Tanguler:So, with that outlook, what we did is we started looking at the globe not just geographically, but actually we looked at it from an archetype market, archetype perspective. And what do I mean by that is, if I look at geographies like Europe, there are actually many, many archetypes within that European geographies like Europe. There are actually many, many archetypes within that European geographies. You have developed markets like UK, Germany, Spain, Italy, where there's value that's being generated by good reimbursement system, good healthcare system, where you have access to new, innovative therapies. But you also have markets where I don't know Turkey, Greece. You know Eastern European markets where access to medicine is less likely and where you don't want to probably spend a lot of time and energy in commercializing and have someone else do it, because the juice is not simply enough, the squeeze. Now, when I look at Southeast Asia, I see more similar markets like the ones that I just described with you, like the distributor markets like Vietnam and Korea and Singapore, where you actually, again, you may want to go to a distributor and not have your own direct footprint. But then you have Japan, that actually very similar markets, like Germany and UK and Spain.
Tolga Tanguler:So what we did is we said let's look at the market archetypes, let's combine those markets that are similar under one roof and that's our international market that actually spans through Canada all the way to Japan, including all major European markets. And then, when it comes to those distributor markets and we call them affectionately our partner in emerging markets let's consolidate with few. So, instead of having work with like 10, 12 different distributors, let's keep them a few, two or three of them, so we can actually expand through them. That actually helps us to actually minimize disruption, deepens our relationships and, by the way, it allows us to make them more compliant. We actually have these partner emerging markets that we work with a few of them and we expand through them, and then we obviously treat our US as our single most important market. And then the rest of the world we call them partner and emerging markets.
Tolga Tanguler:Now, the other category we have is our global rare business units. So, unlike our TTR franchise, where we really focus on market-by-market opportunity, our ultra-rare market, we actually consolidate our expense basis in a very small footprint and our global rare franchise operates as an end-to-end business unit and that actually gives us a lot of efficiencies and also allows us to focus on. Not all markets in ultra-rare are equal. So our global rarity maybe focus more on Middle East markets where we see endemic on hyperoxaluria, but then we don't go and maybe work too deeply on France for instance, because the opportunity may not be as big as some of the markets in the Middle East.
Ben Comer:Yeah, that makes a lot of sense. I'm curious about what factors you consider when you're deciding whether or not to partner with a distributor or go as Alnylam. How do you make that call?
Tolga Tanguler:That's a great question. First of all, it's a very nuanced call and there's no one single playbook. But what we look at, of course the longevity and the growth trajectory of the particular category For any particular time point. We say, look, do we have the resources right now Because we're just about to become profitable this year? Right, that's what we declared. So we still need to look at our sales and administrative costs. We look at, then, the complexity of the market Are we going to be able to actually build the regulatory muscles that we need to have? And again, if the longevity, the sustainability of that growth, is worthwhile, then we go after it.
Tolga Tanguler:I'll give you one example. Actually, it's interestingly originally Australia was a market where we said it's part of this sort of archetype where it needs to be under our international market, because you have socialized medicine, you have access to patients and it's reimbursed. So we said let's go and work and have our footprint. Then, actually, our partner in the emerging markets, lider, gave us a challenge. He said I can actually make this product available faster and I can actually do it with a lower cost base. So both teams got together and actually we ran a business simulation and we ended up actually saying you know what? For now, let's actually go and distribute this market with a trusted partner that we already knew, and you know what? They beat those timelines and we actually made one of our products available already in Australia much faster than we would ever imagine if we were to go there faster. So, as I'm explaining, there is no real one single playbook. There are principles that we look into and then we make the decision accordingly.
Ben Comer:That's really interesting. Who is the partner in Australia?
Tolga Tanguler:It's a company called Medison which we actually partner with multiple markets.
Ben Comer:Great. What role, Tolga, does pricing play in mapping out market entrance strategy globally? I mean, do you think about country sequencing and price? How do you think about that?
Tolga Tanguler:Yeah, first of all, I mean, of course, to your point, it's a bit of an industry standard to make sure that we actually really understand and appreciate cross-border impact of how it's priced and also if we were to sort of be dealing with reference price impact and so forth. But I think what's really exciting about Alnylam and again this is an area where I like to think that we've been punching above our weight is, before we even commercialized our first product, we came up with a patient access philosophy and that patient access philosophy has been actually sort of the guiding light for us. We're never going to increase our price above inflation and if you look at our pricing over the years now we have been commercializing products for the last five, six years we made very few price increases, if that ever, and that's always been under inflation. So that's been number one. Number two is we play to our strength of our science and our platform technology. We only promote and make our products available that are transformative as medicines. So we're, essence we always keen on what's the value to the society.
Tolga Tanguler:How am I going to actually interpret that for the payer? Then, the last but not least, what's the patient affordability is going to be? It's one thing to put your list price and to your point. In the US we also have this rebates that we need to work with. It's an imperfect system. We don't like it, but that's the system that we're currently working on.
Tolga Tanguler:And then it becomes this question about what's the impact on the patient. Is the patient going to actually have to pay the copay? Are there programs that we can make that happen? Are there things that we can work with the payers? We have been pioneering value-based agreements.
Tolga Tanguler:Now those value-based agreements are essentially about really putting your money where your mouth is. So if I'm negotiating with a payer and saying, look, we believe the patients will stay on therapy and they're not going to have to deal with the consequences of the disease, albeit maybe organ transplant or patient, if they stay on therapy, they're not going to be hospitalized. Depending on the label, depending on the agreements, I can't disclose a lot of those, but what I can tell you is we're now covering about 60 percent of those patients that are covered under commercial or Medicare advantage through these value-based agreements roughly about 55% of those. So those really actually help us. So it's not just the cost or the price, it's how do you actually build the ecosystem around that that enables us to actually go in and provide the value narrative around the payers.
Ben Comer:Yeah, I want to get into this value-based contracts topic a little bit. It's something I probably first wrote about, this idea of value-based contracts, I don't know 10 or 12 years ago and it's kind of gone up and down in terms of interest and popularity and value-based contracts. I think, like so many things, there was great excitement at the beginning and then some kind of reality seeped in where people found out it's. You know it's not so easy always to manage these kinds of contracts, assess them. You know across sort of agreed upon points and you know the the lifestyle, life cycle of the medicine or even in the patient's health. Could you, would it be possible, tolga, to give us an example or two of a value-based contract that Alnylam is involved with, sort of from soup to nuts. Explain you know what products involved, how it works. Soup to nuts. Explain you know what products involved, how it works, how you assess it, how it's managed.
Tolga Tanguler:Right. So just up front, you know I'll be able to give you some flavor, but not all the all the specifics, but I'm sure it's going to be helpful for your audience. But look, I mean, let's, let's also take the first point you just made. Um, you have to stick with it, right? So one of the great, I think, skills, or the values that we have as Alnylam, is being very resilient. So when RNAi was in favor, we were there and RNAi wasn't in favor, a lot of these big pharma companies pulled out we were still there. And value-based agreement is a bit like that too. If you believe in the theory and if you believe in the practice, working with some partners, in the long term it actually gives you credibility. You also learn from each other and you start building this as a real capability. So you can't just treat this as a flavor of the month, and because of that, I think I can kind of safely talk to you about some of the programs we have. So you want me to be a little specific.
Tolga Tanguler:So let me give you a few examples, one of which is in ultra-rare, ultra-rare. So in ultra-rare, what you usually see is, especially in the United States, per treatment cost tends to be higher than your other treatments and therefore payers avoid sort of end up with these patients. But if you're around there and if you're covering many lives, you're going to end up with some patients. Unfortunately, frankly, not all these rare conditions, a very small percentage of these rare conditions, are actually now diagnosed and treated. But when you get them, what you worry is how am I going to manage this cost inflation and is this going to be impacting my level of predictability? And, as you know, insurers care about the cost but they care more about predictability. So one of the things we did with the value-based agreements is we said look, according to everything that we see and the prevalence numbers that we see in ultra-rare, we're going to cap some of the costs if a number goes way above what that prevalence ratio should show, based on all the population and epidemiology data that we have.
Ben Comer:So that provides yeah, you're giving them some predictability, exactly.
Tolga Tanguler:So that's one angle. Another angle that we do with our TTR franchise is we look at clinical outcomes. We say, look, according to this, here's how the patient should behave, and if you don't, then we're actually willing to provide you a certain rebate or a discount or refund based on the given, the value-based agreement. So by doing this again, we A provide. Frankly, it also shows our confidence about look, our medicines are based on genetic information, based on the biology, human biology, so it gives us a lot of predictability and confidence that our product's going to work. And now we're just about to finalize our CV outcomes study on our cardiomyopathy, the labeling I should say we just published the Heliospeed. So we know these products work, we know that actually it provides a real benefit to the patient.
Tolga Tanguler:So why not actually tell the payer that we stand behind those data points? And that again gives us an enough. Is every payer willing to do it? No, because, to your point, not everybody is equipped to do the administration of how to follow up these patients. They say, ah, by the time it takes me to actually follow up the patient and administer this, it's going to get more costly. But in some cases we simplify the administration and in most cases we do, so that actually works really well. And then some payers believe in this and they like what they see and they stick with us. Some payers don't prefer it, and that's OK.
Ben Comer:So you're working directly with the insurers to help set up this, this whole program of how they can manage results. Do you find? I mean, does it work better with insurers?
Tolga Tanguler:Some governments, by the way, sort of interrupt you, but in some cases we do work ex-US with some governments.
Ben Comer:With governments as well, right? Do you look for health insurers or governments who have some experience in these kinds of deals, or are you also building some of you know forging these for the first time with some health insurers?
Tolga Tanguler:It's a little bit both. Frankly, those who have started the journey five, six years ago with us, they like what they see, so they stick with us and in some cases we publish and show them hey look, this is what your competitor is doing. Wouldn't you like to be part of this? And especially those plans that look at the totality of the patients, that are well integrated networks. They really like this. So they not only have the insurance system, but they also they cover the patient at the payer side and also provider side, so they actually fund the you know, the hospitals, those systems. They really like that those, those systems.
Ben Comer:They really like that, right? Yeah, um, I wanted to um move on to alnylam, you know, kind of crossing back over into into larger therapeutic indications. But before we leave rare disease, I wanted to ask you about diagnosis, which is a critical aspect of rare disease. Getting the right diagnosis critical. I'm wondering, uh, what alnylam does, what kind of work Alnylam does in terms of helping patients get diagnosed? What can you tell me about that?
Tolga Tanguler:So that's your spot on. The ultimate test is once you make the product available. We immediately see, first of all, a pool of patients that were already diagnosed and they are desperately looking for an option and we go and make sure that you treat that. But then you need to actually continue the pool of patients, the flow of patients that are coming in down the pike, and get them treated early. So making the product available is actually a big leap forward in itself because it increases awareness. The second point is we also work with you know diagnostic companies. If it's a hereditary disorder, we work with you know genetic counselors, actually genetic diagnostic companies that provide genetic testing and assays available for the providers. So it's essentially really becomes a question of where is the problem? Is it really about sort of genetic testing? Genetic testing Is it really about awareness or is it actually really?
Tolga Tanguler:improving the non-invasive ways to diagnose the patient. In one instance, for instance, in TTR, we've been fortunate enough to have scintigraphy. Essentially, it's an imaging tool that is widely available in the US, but you can actually make it multi-purpose and by taking a different dye you're essentially having the accumulation of amyloidosis in your body light up. It wasn't invented for that. Now one of the institutions that we work very closely figured out that it can be used for that purpose. So how do you actually make that available? How do you actually disseminate that information? So it's really a question of understanding the value chain where they actually you get stuck in patient diagnosis and start identifying that and working with the ecosystem.
Ben Comer:Excellent, that's great. Getting back to larger indications, hypertension, potentially Alzheimer's disease, is where Alnylam is headed and I'm curious, Tolga, how you manage that evolution and scale from more rare disease indications to these very large indications across the commercial organization. How do you scale that up?
Tolga Tanguler:Listen. First of all, it's very humbling because to think that you can actually come up with a potential solution of essentially a public health problem that is inflicting pain to millions of people is incredibly rewarding. So I just want you to know like this is an area where it gets all of us excited every morning. Now obviously it comes with real challenges, because we started in the beginning of our conversation around how complacent we are as humans, how difficult it is to change and how you need to start looking at it and start telling a very different narrative.
Tolga Tanguler:Big part of commercialization actually becomes market readiness and that requires a lot of resources, a lot of experiences and, frankly, as great as we are as Alnylam, we also need to be humble about what we can do now and maybe what we can actually need to build as a capability. So I know we can do a lot in terms of rare and even in specialty conditions. I think we have the right capabilities, right talent, right infrastructure to be able to commercialize these assets. But actually dealing with a more broader public health problem requires a larger organization and a very different mindset. So this time around zilebesiran with , as you know, we actually chose a partner and I was a big advocate of doing that, even though it's going to require us to share some of that value. But I see it as the value that we can actually create even bigger, more if we were to go along. So Roche actually has done a great job in areas like multiple sclerosis, even though that's actually more of a special disease.
Ben Comer:Right CNS conditions yeah.
Tolga Tanguler:Exactly what we liked about them is with Ocrevus, for instance, which is a very different mechanism of action. They completely looked at the ecosystem very differently. So I think that's what you need in a partner with similar values and similar ambitions and a different mindset. That will take us there. So I think that was really important for us. From a capability perspective you talked about scale Capability perspective you want to work with a partner that you can actually start building those muscles. So we are actually doing 50-50 in the US where we are a co-promoter, co-partner, and then we're letting them commercialize entire ex-US.
Tolga Tanguler:But the next opportunity, we want to be able to actually commercialize it by ourselves, Because by the time the next large opportunity comes along, I like to think that we've already had built those capabilities that I just shared with you.
Ben Comer:I've been told that the 50-50 commercial split was pioneered by Regeneron. Can you confirm or deny that?
Tolga Tanguler:I don't know. I mean I don't know if Regeneron did the deal before Pfizer and BMS did on Eliquis. I can tell you.
Ben Comer:Oh on, eliquis right, yeah, yeah, that was a 50-50 split that was a 50-50.
Tolga Tanguler:Sanofi-Synthelabo and BMS. Before Sanofi merged with Aventis, they did a 50-50 for their hypertension program, so I don't know if it was really pioneered. It's a very smart strategy, especially if you're again early innings of your commercialization.
Ben Comer:Great I wanted to ask about. You know, and this may not be important, it doesn't seem like these laws are going anywhere, but I did notice that a few days ago, Montana, you know, had some sort of preliminary vote on a state law that would ban RNA vaccines entirely for human use. Are you? I mean there's been some noise, I think, in in Idaho, maybe in Texas, none of these again, none of these laws are close to coming into effect. But I'm curious, if it's something that Alnylam is following and you know to your point about kind of setting the table for new treatments, education being a, you know, a key component of that, is this something that's on your radar or not? Do you think it's just sort of talk?
Tolga Tanguler:Yeah, well, listen, first of all and first and foremost, we're a very proud American science organization and our science is based on Nobel Prize winning technology and this company was founded in 2002, and we've been the pioneers of introducing an entirely new class of medicine. As you know, there's a lot of noise out there and there's a lot of sort of noise around. You know genetics and you know RNAi, mRNAi and you know, We're neither a vaccine nor actually an mRNAi right. We are actually essentially RNAi interference. That is actually infrequent, but definitely, you know, not a once and done kind of genetic treatment. That fits very nicely into the existing ecosystem of how medicine is being treated.
Tolga Tanguler:And I think, once you explain the science and showing the deep, deep, deep, deep safety information we have and thousands of years of patient lives I mean we have now already five products in the market and Novartis is obviously expanding the aperture with a hypercholesterolemia product, Leqvio even to many more thousands of patients we like where we are in terms of our track record, we like where we are in terms of our science and technology and we believe we need to continue to have that dialogue if, if patients are worried about or the, you know, lawmakers are worried about our products.
Tolga Tanguler:We want to be out there and be able to engage the dialogue and and continue to communicate. So, look, look, because we're standing on very firm foundation of our science. We have, I think, 13 or 14 published studies on New England Journal of Medicine and countless other peer-reviewed journals. We stand very firmly on those foundations. Now it's going to be a question of are there going to be people that are misunderstanding the science and we need to explain it? I think that's part of the job, ben, and we're up for it because we believe in what we're here to do and what we're here to provide.
Ben Comer:In our last couple of minutes here. Tolga, why don't you share your top priorities for 2025?
Tolga Tanguler:Yeah, but look, I mean what's obviously very close to everyone I think the whole industry is an upcoming launch on our ambutra with the cardiomyopathy indication, as you may know. Amvuttra with the cardiomyopathy indication as you may know, we have a late March PDUFA date in the US and then subsequently we look forward to launching the same indication in Germany and Japan and the rest of the world after the second half of the year. Now, that's an important launch. Second half of the year Now, that's an important launch, not just for the obvious reasons, but what will enable us, frankly, is to continue to bring on at the forefront of biotech innovation. As you pointed out, our pipeline is a dream for many. As you pointed out, on CNS, we have assets in hypertension as well as in hematologic disorders. What this launch is going to enable us to do is to actually create the cash flow that will enable us to actually fund these, fund these important innovation that we're about to set out to do so.
Tolga Tanguler:Probably, I would say 60, 70% of my time is really focusing on the Amutra launch and, frankly, this is a focus area for us for the last four years. So that is, I just cannot wait to get out there and communicate the benefits of this incredible medicine but at the same time continue to actually focus our organization to make the right bets on the pipeline and get the market also ready for those. Those are my sort of top of mind. In the meantime, we talked about scaling. Look, the way I see it is.
Tolga Tanguler:We're building skyscrapers not just one skyscraper, that's TTR. Another skyscraper is the rare, but the many things can come in neurological disorders and so forth. What I want to make sure is that the foundation that we're building in the commercial organization can apply to each of those skyscrapers. So that's certain foundational capabilities like AI, like how do we actually continue to generate data? How do we actually build those access capabilities like value-based agreements as a consistent capability? As a consistent capability, how do we actually do omni-channel marketing, so that you know the organization. We can focus on real value-based activities and communication on one-on-one, peer-to-peer where it needs to be and surround sound it with omni-channel capabilities.
Tolga Tanguler:These things are no longer pipe dreams. Right, these are actually things that we deal with and I see great practices in our organization across the categories. But I want to actually consolidate that because essentially, we're building a generational biotech. If you want to build a generational biotech, you need to have the right foundations. Some of my priorities also has a lot to do with that, but first and foremost, obviously, winning in TTR is going to be a key priority and a key test for the organization.
Ben Comer:That is Tolga Tangular, executive Vice President and Chief Commercial Officer at Alnylam I'm Ben Comer and you've just listened to the Business of Biotech. Find us and subscribe anywhere you listen to podcasts and be sure to check out new weekly video casts of these conversations every Monday under the Business of Biotech tab at Life Science Leader. We'll see you next week and thanks for listening.
Ben Comer:Avantor is a leading life science tools company and global provider of mission-critical products and services to the life sciences and advanced technology industries. Avantor works side-by-side with customers at every step of the scientific journey to enable breakthroughs in medicine, healthcare and technology. Avantor's portfolio is used in virtually every stage of the most important research, development and production activities at more than 300,000 customer locations in 180 countries. For more information, visit avantorsciences. com or find them on LinkedIn, ex-formerly Twitter and Facebook.
