Alnylam Pharmaceuticals, Inc. (ALNY) Earnings Call Transcript & Summary

Okay. We'll go ahead and get started. This -- thanks, everyone, for attending here, the 2020 JPMorgan Healthcare Conference. My name is Anupam Rama. I'm one of the senior biotech analysts here at JPMorgan. I'm joined by Tessa Romero and Matt Bannon from the team. Our next presenting company is Alnylam, and presenting on behalf of the company is CEO, John Maraganore. John?

Great. Well, thanks, Anupam. Joining me on the stage this morning are Pushkal Garg, our CMO; Barry Greene, our President; Yvonne Greenstreet, our COO; Jeff Poulton, our CFO; and Akshay Vaishnaw, our President of R&D. Now 10 years ago on this stage, we suggested that the 2010s might be the RNA decade. Well, if you look at what happened to Alnylam over the last 10 years, we actually might have been right. We started the decade in 2010 as a company that was -- I think most people thought we weren't going to necessarily make it, and we ended just last year as a global commercial company with 2 products on the market, 2 additional products in registration, 11 programs in the clinic, including 6 in late stages and a product engine delivering 2 to 4 new INDs per year. So you might ask what's going to happen in the 2020s? Well, we believe that in this decade, Alnylam will emerge as a top 5 biopharma company. And I can't wait to be here on this stage or maybe in the bigger room stage, in 2030, with all of you here in the audience to check in on that goal. So we're looking forward to that. Now with that, I'd like to remind you that I'll be making forward-looking statements during my presentation. Now as you know, Alnylam is committed to advancing a whole new class of medicines, RNAi therapeutics to treat many diseases for patients. At Alnylam, we have pioneered and advanced the harnessing of the RNAi technology for the purposes of creating new medicines that we can bring to patients around the world. We're very proud of having brought the first RNAi therapeutic to the market with ONPATTRO. ONPATTRO is now approved in the U.S., Europe, Canada, Japan and Switzerland, and we expect additional approvals for ONPATTRO in 2020, including in Brazil. Now ONPATTRO is indicated for the treatment of polyneuropathy associated with hereditary ATTR amyloidosis in adult patients. ATTR amyloidosis is -- more broadly speaking, is a debilitating, progressive and generally fatal disease caused by misfolding of the TTR protein, which accumulates in a wide range of tissues causing disease pathology in the tissues, of note, include the nerves, the gut and the heart. There are about 50,000 patients around the world with hereditary ATTR amyloidosis like Cece shown here on this slide. And then a much larger number of patients with so-called wild-type ATTR amyloidosis, which is an increasingly recognized cause of preserved ejection heart failure. We achieved steady and continued growth for ONPATTRO throughout 2019 with over 20% quarter-on-quarter growth. We expect growth to continue in 2020 driven by new patient finding, geographic expansion as well as evidence-generating activities. Yesterday, we were very pleased to announce our Q4 revenues for 2019 at $56 million, bringing our full year tally to $166 million. We also announced that we have over 750 patients now on commercial ONPATTRO, which when you add patients that are in our expanded access program and also patients that are in our clinical studies, we have now exceeded the 1,000 patient mark for ONPATTRO. So we're very pleased with our commercial execution for 2019, and we expect this to continue in 2020 and beyond. Now very importantly, we believe our ONPATTRO launch really is just the beginning of the value that we can create across the entirety of our ATTR franchise. Starting around the 2021 time frame, assuming clinical studies are positive, we expect to be able to bring ONPATTRO to the broader cardiomyopathy setting, including wild-type ATTR. We believe that the wild-type ATTR amyloidosis opportunity for Alnylam is a multibillion-dollar anchor product for the company, not unlike EYLEA was for Regeneron or Revlimid was for Celgene. Also in that 2021 time frame, we also expect to bring vutrisiran to the market in the polyneuropathy segment to cement our leadership in that space. Thereafter, with outcomes data for vutrisiran in the cardiomyopathy setting, we can anticipate even further growth for Alnylam's efforts. The bottom line here is that we believe that we have a multiyear opportunity across the entirety of our ATTR amyloidosis efforts. We believe that our leadership, our innovation and our commitment to patients can continue to deliver growth, impact for patients and value creation for shareholders. So let's now turn to GIVLAARI. With the earlier-than-expected approval of GIVLAARI late last year, Alnylam became a multiproduct company. GIVLAARI is the second RNAi therapeutic to ever be approved, and it is the first GalNAc conjugate to ever be approved, representing a real milestone for Alnylam innovation. First, a few words on the disease. Acute hepatic porphyria is a family of ultra-rare orphan diseases characterized -- defined by mutations in the heme biosynthesis pathway. This is a disease with enormous burden for patients. These patients suffer from frequent and intractably painful abdominal attacks often accompanied by other symptoms, such as seizures and paralysis. And often, more often than not, these patients suffer from chronic pain in between their attack symptoms. In the U.S. and Europe, there are about 3,000 patients with active and diagnosed disease, like Yeliz shown here on this slide. And we know that this number will increase over time as we improve disease awareness and the rates of patient diagnosis. GIVLAARI, we're very pleased with the label that we received from the approval last year from the FDA for GIVLAARI. The drug is approved for the treatment of acute hepatic porphyria in adults. It's administered as a low-volume, low-dose, once-monthly subcutaneous injection, and the data and the approval was based on the ENVISION Phase III trial, which really was a landmark study in the whole field, where we showed a 74% mean reduction in the annualized porphyria attack rate for GIVLAARI and also a safety profile that's certainly acceptable in this severe patient population. GIVLAARI is now launched, and we're excited about the early patient demand that we're seeing. We're going to be following the ONPATTRO playbook for the GIVLAARI launch. And we're also going to be leveraging significant global capabilities that we've already built for ONPATTRO. Of course, our commercial efforts here start with a strong product profile, which we clearly achieved in the ENVISION Phase III study. We're very focused also on medical education to improve overall disease awareness. We're providing free genetic services -- genetic testing services through a third-party to facilitate patient diagnosis. And very importantly, and even featured a little bit this morning in the Wall Street Journal, Alnylam is being proactive about our engagement with payers, and this includes value-based agreements and a new feature for GIVLAARI, called the prevalence-based adjustment. And the goal of all that is to really ensure that our -- that all incentives are aligned between Alnylam and payers and that we can ensure strong patient access for this medicine. Regarding the commercial opportunity for GIVLAARI, we believe that a transformational therapy in a disease with the unmet need that exists here in porphyria and also disease, unfortunately, with very limited treatment options can lead to an opportunity that over time can generate over $500 million in annualized peak sales. Now very importantly, Alnylam's commercial story goes beyond ONPATTRO and GIVLAARI. We have, over the next 12 to 24 months, the opportunity for 4 additional transformative medicines that can be introduced to the market, either directly by Alnylam or with our partners. This includes lumasiran, our program in primary hyperoxaluria, where we just reported positive Phase III data last month. It also includes vutrisiran, our TTR subcu drug, which will expand the ATTR amyloidosis opportunity beyond what we can achieve with ONPATTRO. And then with partners, we have inclisiran, a very exciting program now partnered with Novartis, where the Phase III results last year were really a feature of a very important highlight of the year, and then together with Sanofi, we're partnered with fitusiran in hemophilia. The bottom line is here. These 6 programs create a rather remarkable commercial story for Alnylam that we believe plays out in the relatively near term, again, the next 12 to 24 months, with 6 potential sources of product revenue. Let's now turn to our R&D activities, where we'll spend most of our time discussing our 6 clinical-stage programs where Alnylam has retained substantial global rights. We're very excited about our opportunity with patisiran and the APOLLO-B study. Patisiran is a nonbranded name for Apollo -- for patisiran -- for ONPATTRO. APOLLO-B is a randomized, double-blind, placebo-controlled study using the 6-minute walk test as the primary endpoint, and this is being done in patients with hereditary and wild-type ATTR amyloidosis. We expect data from this study in the 2021 time frame. There are many reasons to be encouraged by the potential for patisiran in the cardiac amyloid setting. In our APOLLO-B -- in our APOLLO Phase III study, the original Phase III study, we included a number of prospectively defined exploratory endpoints: echocardiographic biomarker as well as functional endpoints, where we showed positive and statistically significant results with patisiran. Moreover, as shown on the left, in a post-hoc analysis, we were able to show a 50% reduction in mortality and hospitalization. So we've included these specific endpoints into our APOLLO-B study to test the hypothesis further. More recently, we've seen some very exciting data out of a study performed out of the National Amyloidosis Centre in the U.K., and these results have actually just been replicated and published by a Dutch group as well. Here in this study, nuclear imaging of cardiac amyloid was done at baseline and then again, after 1 year of treatment, with patisiran. On the left, you can see the very clear accumulation of cardiac amyloid in this patient at baseline. And then I think, at the right, you can see very clearly the rather striking reduction of cardiac amyloid in this patient after 1 year of treatment with patisiran. We're very encouraged by these data. We've included this type of imaging in the APOLLO-B study to strengthen our findings from that evaluation. And I think notably, cardiac amyloid regression has not been observed for TTR stabilizer drugs either diflunisal or tafamidis. Now while we work to expand the ONPATTRO opportunity in the cardiac setting, we're also advancing vutrisiran, our subcu TTR silencer drug, which supports -- with durability that supports a once quarterly subcutaneous dosing regimen. We're encouraged by this product and have -- certainly believe that this will be a great option for patients going forward. We're currently focused on bringing this market to -- this product to market as quickly as we can, and we're doing that in the HELIOS-A Phase III trial. HELIOS-A is a randomized, open-label Phase III study in patients with hereditary ATTR polyneuropathy. The primary endpoint is the mNIS+7 neuropathy score, and we'll be comparing the results at 9 months for vutrisiran-treated patients to the results obtained in the original APOLLO study in the placebo arm. So it's a very innovative design to bring this medicine to market. We're pleased to announce today that we are now over 85% enrolled in the HELIOS-A study. So we're very much on track to have results from this study in early 2021. The second step for vutrisiran is to bring it to market in the broader cardiomyopathy setting with outcomes-based data. This allows us to have an outcomes label that is optimal for competitive positioning of the product. This is being done at the HELIOS-B study, which we launched last year, a randomized, double-blind, placebo-controlled study in both hereditary and wild-type ATTR cardiomyopathy patients. Now another effort at Alnylam is our program, lumasiran, in primary hyperoxaluria Type 1, or PH1. PH1 is an ultra-rare orphan disease caused by mutations in the hydroxyproline biosynthesis pathway that leads to excessive oxalate production as well as recurrent kidney stones, end-stage renal disease and other systemic complications. There are about 3,000 to 5,000 patients with this disease, like Benson shown here on this slide. Current treatment options are very limited for patients. They ultimately go on to dialysis and ultimately require a dual liver kidney transplant. Now we're exploring the safety and efficacy of lumasiran in the ILLUMINATE program. This is a comprehensive set of studies across the entire spectrum of PH1 disease. It includes ILLUMINATE-A, our pivotal study in adult and adolescent patients with mild-to-moderate renal impairment. It includes our ILLUMINATE-B study in pediatric patients and then ILLUMINATE-C being conducted in patients with severe renal impairment. Altogether, the ILLUMINATE program is the most comprehensive set of studies in PH1 in the industry today. Just last month, before the holidays, we reported positive Phase III results from our ILLUMINATE-A Phase III trial, showing a highly significant effect on the primary endpoint, which is reduction in urinary oxalate, and also showing that we hit on all of our secondary endpoints in the study, including a near normalization of urinary oxalate and even a normalization of urinary oxalate. On the safety side, we're very encouraged by the results. There were no serious or severe adverse events. The safety profile was very much in line with what we've reported previously for lumasiran, including no LFT elevations. The full study results will be presented in March at a medical meeting. We just started our rolling NDA submission on Friday, and we plan to complete our NDA submission in early 2020. And assuming positive regulatory review, we should have this drug approved in the U.S. by the end of the year. Now looking at the market opportunity for PH1 and lumasiran, we believe that a disease-modifying therapy in PH1 would be a game changer for patients and do believe that we can achieve over $500 million in sales with this product over time. Now finally, we have 2 additional late-stage programs that are in development with partners. This includes inclisiran in hypercholesterolemia partnered now with Novartis and then fitusiran in hemophilia A or B with or without inhibitors partnered with Sanofi. We're very excited about the prospects for both of these products. In both cases, they have highly differentiated profiles compared to agents that are either in the market or in development. And for each of these markets, they are, on their own rights, multibillion-dollar markets. Of course, for Alnylam, the key point here is that we've retained substantial economics with up to 20% royalties on inclisiran and 15% to 30% royalties on fitusiran. These royalties not only represent near-term opportunity for revenue generation for the company, but they also represent potential balance sheet opportunities for Alnylam outside of the equity markets. Now in the interest of time, I'll just touch on some of our earlier-stage clinical programs. We have 5 programs in Phase I or Phase II development on top of our late-stage pipeline. This includes cemdisiran, our anti-C5 RNAi therapeutic in Phase II study in IgA nephropathy. We're also exploring cemdisiran together with Regeneron and their anti-C5 antibody for a broader range of complement-mediated diseases. We're very excited about our ALN-AGT opportunity, where we aim to reimagine the treatment of hypertension, a disease where there's been no innovation for decades. We also have a program in alpha-1 antitrypsin deficiency and a program partnered with Vir for the treatment of HPV infection. Now in addition to these clinical programs, we have our product engine delivering 2 to 4 INDs per year. And in 2020, we expect to have our HSD program in NASH, which is a common disease, and then our ALECT program in ALECT2 amyloidosis, a rare disease. Now beyond 2020, we're very excited about the many RNAi therapeutic opportunities beyond the liver. In particular, we're advancing nearly a dozen investigational programs today for the treatment of CNS and ocular diseases. Our most advanced programs here include ALN-APP targeting amyloid precursor protein for the treatment of cerebral amyloid angiopathy and potentially other diseases. And then ALN-HTT targeting the Huntington gene for the treatment of Huntington's disease. In this space, we're partnered with Regeneron in a 50-50 partnership that we formed last year with the goal of building the industry-leading pipeline of transformational medicines for the treatment of CNS and ocular diseases. One of the reasons we're so excited about our CNS and ocular pipeline relates to the potency and durability of RNAi therapeutics. Just like we've seen in the liver, we're seeing similar types of effects in the CNS and ocular space. These are brand-new data from nonhuman primates out of our ALN-APP program, showing highly durable knockdown of the APP protein in cerebrospinal fluid of primates for up to 6 months after a single dose administration. So we think these results support a biannual, if not less frequent, dosing regimen for RNAi therapeutics in the CNS and this would be a major advance in the field. Let's now turn to a brief discussion of our guidance and goals. And I'd like to also say a few words about our path forward here as a company. Since 2015, Alnylam has been focusing on our Alnylam 2020 goals that we set forth at that time. We announced this past November that we're going to actually exceed our original guidance and end 2020 in 4 strategic therapeutic areas, or stars, with 4 marketed products, 14 programs in clinical development, of which 6 will be in late-stage development, and if you add to this our product engine delivering sustainable innovation, we are aiming to exit 2020 with a profile that's been rarely achieved in biotech history, which is very exciting. 2020 itself is going to be a very catalyst-rich year for the company. We have -- at a high level, we have a number of important goals. This includes commercial execution on ONPATTRO and GIVLAARI. We're aiming for 2 additional regulatory approvals by the end of the year for lumasiran and inclisiran. We are expecting 1 Phase III data readout for lumasiran in the ILLUMINATE-B study. We're executing on 6 late-stage programs in 9 distinct clinical trials and again, aim to deliver 2 to 4 new IND filings in 2020 from our product engine. Now I'd like to share just a few thoughts on Alnylam future prospects before wrapping up. First, I think it's really important to look now historically, since we have enough data, at our track record of success from the Alnylam platform. And if you look at the cumulative probability of success from start of clinical studies through the end of Phase III and you look at the Alnylam success rate, it exceeds 50%. Comparing very favorably to the industry norms of 10% or less. This is not luck. It is driven by the power of a reproducible and modular platform, combined with a focus on genetically validated targets. And going forward, we plan to continue to leverage our reproducible and modular platform with a steadfast commitment on human genetics to make sure that we can continue to deliver outsized returns from our R&D investments. The second point I'd like to make is that Alnylam is now very much focused on achieving a self-sustainable financial profile as a company, and this is a top priority for us. The key elements of this transition include top line revenue growth currently from 2 marketed products, but soon 6 marketed products, in addition to more moderated growth in our R&D investments. We've committed that 2019 was our peak loss year as a company, and as we get better visibility on our top line growth, we'll be able to provide specific granularity on our profitability horizon, so don't take this slide too literally. But to be clear, and I want to be very clear here, Alnylam's achieving a self-sustainable financial profile is not a question of if, but it's a question of optimizing the when and the how to deliver the greatest impact for patients and deliver the greatest value for shareholders. So as we look at Alnylam today, illustrated on the left, and where we're going over the next 5 to 6 years, described in the middle, we really see the opportunity of building a top 5 biopharma company, bringing transformative medicines in rare diseases and common diseases to patients around the world and growing with excellence, innovation as well as responsibility. We're committed to this future for the company, and we believe that we're very well positioned to achieve it. So in closing, I want to comment on the patients you saw during the presentation, Cece with hATTR amyloidosis, you saw Yeliz with acute hepatic porphyria and Benson with PH1. These are some of the patients that we've been inspired by during our journey. We won't stop until we help as many of these patients as we can. And we're convinced, and in this decade you should be too, that we can treat a lot of patients and a lot of diseases with RNAi. So with that, I'll stop by thanking all of you and wishing all of you a happy new decade. Thank you very much.

Okay. We'll go ahead and get started. This is the Alnylam breakout session. John, if you want to introduce who's on stage here with you, we can get started.

Yes, absolutely. Let me do it alphabetically. We got Pushkal Garg, who is our Chief Medical Officer; Barry Greene, our President. We've got Yvonne Greenstreet, who's our Chief Operating Officer; Jeff Poulton, who is our CFO, and let's see whom I'm missing, oh, yes, Akshay Vaishnaw, Our President of R&D.

I'll just kick off. The physician mix for the ONPATTRO launch between cardiologists, neurologists and other. It's been shifting quarter-to-quarter. Maybe you could talk us through that dynamic on what you're seeing out there? And what's causing this sort of shift in quarters?

Yes, I'll give it to Barry in just a second. I think in general, the shifts that we're seeing are, I think, are relatively small shifts. Over the course of the whole year in 2019, we reported just yesterday that we've seen scripts from 44. And this, by the way, is only the U.S. market. That's where we have these type of data. Scripts from 44% of the scripts are cardiology driven, 38% was neurology driven. The other balance is just a whole range of different specialties. Barry, do you want to add some more to that?

I think you covered it up. We're really gratified by the awareness in the physician community, in general, by TTR amyloidosis. We've said this for quite a while. There's multiple players in the field. Every neurology and cardiology meeting you attend, medical meeting has a track on TTR amyloidosis. Of course, a lot of that's driven by how many wild-type patients are out there and the awareness growing. The dynamic we're seeing is, as John described, both neurology and cardiology are heavily invested in understanding TTR amyloidosis. And in our case, our -- the big job we're doing is to make sure that genetic testing is done in patients and physicians are looking for the polyneuropathy in these mixed phenotype patients. So we'll continue to see up and down. But I think some people were nervous about is that given other drugs, maybe the cardiology interest would dry up, but that's not what we've seen. There's a lot of interesting cardiology for hereditary patients and finding the polyneuropathy of these patients.

In the presentation, John, you mentioned that there may be a potential approval in Brazil this year. Maybe you could talk about sort of the size of that opportunity? And what are the sort of gating factors to getting approval?

Yes, absolutely. We -- we're very committed to the geographic expansion of ONPATTRO. Overall, Brazil is certainly a large country that we do expect approval in 2020. Barry, do you want to talk a little bit about the market?

Yes. So Brazil is a market where the first step, obviously, is to get the drug approved and then we'll work with the Brazil government on price and access. We're going to take the same value-based approach we've taken in the United States and other countries to Brazil, and it will take a little bit of time to work through getting access for patients. There are a lot of patients in Brazil. Brazil is a country that has both a very heavy V30M mutation, given the Portuguese descent and the V122I given the number of West African folks that made it to Brazil. So it should be a very robust patient population. Too early to talk about the size until we have a few more back and forth with the government.

Questions from the audience? All right. Good.

Can you speak into the microphone?

The press release last week, you mentioned the rolling submission for Lumasiran was started. Maybe you could walk us through the steps of completing that filing.

Yes, let me turn it over to Pushkal, actually.

Yes. So as John mentioned, as you saw, late last year, we announced the top line results from our ILLUMINATE-A study for lumasiran for PH1 and which was positive at the primary endpoint and all the secondary. So we've initiated the submission for lumasiran with the nonclinical sections that just went in on Friday, and we'll follow that up with the CMC and the clinical sections later in the first quarter early this year. And so we're optimistic that assuming a positive regulatory review that we may see approval later this year in the United States and soon thereafter in Europe.

John, I think it was you on the third quarter call, who kind of alluded to potentially providing ONPATTRO guidance for 2020, still an internal discussion. So just wondering if that's still a discussion or should we stay tuned?

Well, we can definitely update you on that. Jeff, do you want to do it?

Yes. We do plan to give ONPATTRO guidance on our year-end call in February. So stay tuned for that.

Great. And then can you walk us through some of the gross margin dynamics, I think, for ONPATTRO specifically?

Yes. So for most of 2019, the cost of goods sold as a percentage of revenue ONPATTRO has been sort of in the low double digits. And during the course of the year, we've been selling fully expensed inventory that will transition in the first quarter of 2020, and we would then expect to see COGS on ONPATTRO, more in the sort of mid- to high teens as that transition occurs.

Turnaround 11% or so?

Yes. I think it's been 11% or 12% across 2019. And again, that will step up a bit in the first quarter.

Got you. And then for GIVLAARI, you mentioned its 13 new start forms in the first 6 weeks post approval? So for ONPATTRO, you also give the start form metric, and you noted that it's not perfect. Is there any reason to think that this may be more or less like better of an indicator for sales here?

No. I would say the following, and Jeff, you can comment as -- and Barry, you can comment as well. I -- we like using at the beginning of a launch, start forms as a sort of a leading indicator of demand. And we did that with ONPATTRO and as we got into like a couple of quarters worth of ONPATTRO, it no longer was a relevant number. We had global sales as well and so forth, and we're giving patient numbers out and revenues, of course. So we'll probably do the same playbook, if you will, with GIVLAARI, give a couple of quarters worth of start form data in addition to revenues, of course, enough patients on commercial drug. And then over time, just transition to revenues and patients on commercial drug because that's what really matters at the end, especially as you're doing a global launch. Do you want to add to that, Barry or Jeff?

Yes. The only comment I'll make to your point is, we do expect some number of sales to come from outside Alnylam Assist or the start forms. We really encourage physician patients to use the start forms because we can bring all of the services we offer in marshalling that patient through the process and ensuring they get on drug and stay on drug. However, as you know, we've really cleared the access hurdle for ONPATTRO. We intend on doing the same for GIVLAARI. So what happens is that institutes are not afraid to buy and bill because they understand that Alnylam will, in fact, get the drug reimbursed. And that's a great dynamic to have, but it causes some institutions to order outside the start form process.

John, I think you mentioned on stage that the ILLUMINATE-A results would be presented at a medical meeting in March. So maybe -- was that disclosed on the slide, which medical meeting? And what additional analysis could we learn beyond what the top line showed, which had a lot of detail?

Yes, absolutely. Well, the plan is to present at the OxalEurope meeting, which is in March, the end of March. I believe it's March 31, and we did note that when we announced the top line, just a small note. It wasn't -- you didn't miss anything, but we did note that. And so we look forward to doing that. Maybe Akshay, you can comment a little bit on what we would expect to present.

Yes. We'll give the full data set on ILLUMINATE-A. And as you know, in December, we released the top line, which basically focused around the primary and all the secondary being hit with statistical significance, but obviously, there's interest to know the full data and the extent of treatment effect. We're confident that the drug has performed extremely well. And I think the data sets much anticipate from a safety perspective. We've said that we're very encouraged by the data overall, and we continue to feel that way about the program. So really, it's the full data set.

Questions from the audience?

You just mentioned geography expansion strategy and mentioned about Brazil, but what about Asia, for example Japan, Korea, China and all other Eastern kind of countries? So -- and also, what kind of strategy are you thinking, just organic, to grow the footprint there? Or you may think there's some kind of licensing, joint venture, partnership, et cetera?

Yes. Great question. I'm going to hand it over to Barry in just a second, but I'll start by saying that we're already direct in Japan. We're approved in Japan. We're launched in Japan. We're selling in Japan. Japan -- we expect Japan to be our second largest market by the end of 2020. If there's -- as you may know, there is endemic disease in Japan. So it's a big opportunity. And we retain very good pricing in Japan. So Barry, do you want to talk about the rest of Asia?

Yes, I'll back up a step. So we -- it's incredible to be in the position we're in where we have so many organic RNAi therapeutics that we own globally. And we intend on being a fully integrated global company. As you know, where it makes sense for Alnylam to have Alnylam headquarters or Alnylam people to go direct. We've done that, U.S., Western Europe. We talked about Brazil then Japan. We also used a mixed model where we have somebody doing the back end, where we represent the front-end selling medical information. And then we also have distributorship model set up. So we're going to canvass the globe. In terms of where we have direct presence, as John mentioned, Japan was our launching pad for Asia. We do pan -- plan on getting into South Korea, Taiwan and others. And then Brazil is our launching pad for Latin America. China is definitely an interesting market, but one that we will probably wait a few years before moving into.

Any additional questions from the audience?

What -- maybe you could talk us a little bit through kind of on sort of what you're seeing in terms of disease awareness, not just in FAP, but the spectrum of ATTR with the multiple of products approved?

Yes. Well, let me start, and then Barry, again, you can continue. I think this is a really remarkable period for ATTR amyloidosis, more broadly speaking, again, across the entirety -- entire segments, hereditary, wild-type and within hereditary and wild-type, the neuropathy and cardiomyopathy. There is absolutely a palpably different level of understanding of this disease that you would expect when you have new medicines that come forward. And of course, new companies that are very actively engaged in medical education. That's a very helpful thing, but the other dynamic that's happening here, which is really quite interesting that it's all happening at the same time, is the availability of a noninvasive diagnostic method for identifying patients that have cardiomyopathy, which oftentimes leads to patients that are being found that have neuropathy along with that cardiomyopathy. So this convergence of a new diagnostic method, namely PYP scans, combined with medical education coming from new medicines that are out there is palpably changing the understanding and the recognition of the disease overall. Barry, what do you -- want to add something to that?

I'm -- I think you covered it. I mentioned it earlier, a decade ago, TTR amyloidosis was not talked about at medical conferences. Every neurology conference, every cardiology conference is made to track. And you see the world leaders of this disease, as John described, presenting the diagnostic pathway and having people look for this disease. Of course, a lot of this is driven by wild type. We may find a decade from now that wild type, in fact, isn't an orphan disease. It's a very prevalent disease. But right now, the underdiagnosed is so significant, it's still in the orphan category. That's going to change over the next decade, significantly, given the tools that exist, the PYP and genetic testing.

Yes. Question?

A follow-up on your comment about over the next decade, where do you see a wild versus new forms of clinical cardiac side takedown between newer technology versus the stabilizers. You also had an antibody that has [ a consolidated ] platform. I'm not -- first of all, it's always difficult. But cardiology seems to be something that's [indiscernible] you do to market [indiscernible].

Yes. So just for the purpose of the webcast, let me reproduce -- let me repeat the question. This is a really excellent question around where do we think it goes over the next -- what do we think ATTR amyloidosis goes over the next decade with the stabilizer drugs that are out there, and also, with antibody therapies as well as the silencer drugs and so forth? And so I'm going to start, but I'm actually going to ask Yvonne to also make some comments on this because she leads up our program -- broader program activities, and maybe Barry would also like to add. My view of where this is going, and we're now all crystal ball gazing, is that this is going to become very much like the MS disease was in the '90s, where when Betaseron got started and then Avonex came to market, I happen to come out of Biogen. So I saw this happening live. And then before you know it, there were multiple different modalities and over a dozen products that are on the market and multibillion-dollar franchises that were built in the MS space and improved disease awareness and improved patient diagnosis. To me, that's what this might become and I do think that there will be multiple modalities that are used out there for patients to achieve the best results. We are perhaps biased, but we believe strongly that the silencer category, TTR knockdown as a mechanism of action, we believe, will be a major part of that story in the future. We think it will be the predominant one, but we can arm wrestle with others on that debate. But we think it's going to be an important part of it. So maybe I'll turn it over to Yvonne and your comments?

Yes. And I'll just refer and I think I do agree with John. I think it really is going to be a market growth story, not a market share story. And there's going to be, given the very large numbers of patients that we anticipate, particularly with the wild-type disease, I think there will be a number of products that will be successful. I do think the really quite unique regimen, particularly a vutrisiran with infrequent subcutaneous injections will be something that will be very appreciated by the community. And I see that. And again, it's crystal ball gazing. But I see that being really the dominant therapy if we look over the long term.

Last question.

What is your conviction that this cardiac part of the story is going to involve [indiscernible] neuropathy?

So I'm going to turn that over to Akshay to start on some reasons that we have conviction around cardiac disease with fitusiran. Of course, we have to do clinical studies to prove that, but Akshay?

Yes. The dominance of the cardiac aspect comes from 2 advantage points for me. One is the epidemiology. So if you look at the mutation-based disease, hATTR amyloidosis, it's now recognized that almost all those patients have both cardiac and neurological facets to their disease. The issue is that the cardiac disease generally ends up being faster in severity and in worsening disease and often ends up being the primary cause of death. So there's an urgency to recognize the disease hATTR, to recognize its different manifestations and to treat the aspects that put the patients at greatest danger and generally cardiac is right up there. That's not to belittle the neuropathy, but that's a major finding. The second aspect is that numerically, wild-type ATTR dominates the landscape increasingly now as Barry was mentioning, and I think many people think that in the decade to come, it may well be well beyond just an orphan disease and that actually speaks well to John's analogy with MS, where back in the '90s, MS was thought to be a relatively small orphan disease. We now know it is not with improved diagnostic modalities, people looking, awareness, et cetera. And -- so that's one aspect of why cardiac story is going to be dominant, and why we pay so much attention to it. And the second is we believe our drugs have great potential in the cardiac space. If you look at the APOLLO data themselves as the Phase III data set for ONPATTRO, we've already published in circulation last year, demonstrating the impact of ONPATTRO in the cardiac subset within the APOLLO cohort on biomarkers of disease and functional aspects of disease. Now we have to further validate that in ongoing studies. We're doing that with APOLLO-B, in the case ONPATTRO with the HELIOS-B, in the case of vutrisiran, subcutaneous therapeutic and the most recent data, which were in John's presentation, showing regression of cardiac amyloid deposition in TTR patients, both at the site in London as well as the recent publication from Holland are very encouraging indeed and speak to the potency of silencers in this disease, TTR amyloidosis. And so for all these reasons, I think the treating community is going to pay more and more attention to cardiac aspects of the disease, and we believe we're very well placed to help these patients.

Yes. Question over there.

You recently shared some very exciting positive data from ESC platform. Could you comment on how that continues to evolve [indiscernible].

Yes. So the question really relates to some of the platform advances that we made with our ESC+ specifically. Yes, so we're excited about how we continue as we advance the company and advance products commercially and more and more programs into late-stage development. At the same time, we're still focusing and investing in our research platform activity so that we can continue to improve all these medicines and make them better and better. And one of the real highlights of 2019 was achieving human proof-of-concept with our ESC+ platform, which removed -- there was in the original ESC molecules, there was a low incidence of LFT elevation, specifically. And we figured out how to remove that. It's driven by off-target events. We figured out how to optimize the on-target versus the off-target. And so all the medicines that we're advancing now going forward are this ESC+ variety, which even provide even better and better overall benefit risk and therapeutic window compared to earlier generations of molecules. So it's something which we're really proud about. It usually doesn't get so much attention in these type of audiences, unfortunately, but it's something which we're happy about. So I'm happy you asked the question.

Yes. A question over here.

I'm here representing my son who has a rare disease called [indiscernible] needs a minimal to RNA-type therapy. Can you talk a little bit more about the hope and where you see this industry going in 5 years? And how many more diseases can be treated by your technology?

Yes. I mean, first of all, thank you for coming to this meeting, and thank you for asking a question. We believe there's a new world very broadly across the industry of new modalities that can help patients with rare disease. And I would even argue even N is equal to 1 diseases. And there's been some...

Can you repeat the question.

Oh, the question really was from a mother of a patient who has a genetic disease, who was asking about where we think this -- where we think these technologies can go and can RNA type approaches help? And so we are very committed to helping as many patients as we can. And even in very small numbers of patients we would like to find ways in which we can help, whether it's directly or through third-party contributions of what we can give and so forth. There are opportunities to help patients. I mean, thank you for asking that question. And I don't know if RNA interference would in your specific case, help your son. I don't know. I have to learn more about the disease. But if it could, I mean, we obviously would want to help. Akshay, do you want to add anything to that?

Yes. I -- obviously, I reinforce all the comments you made. And again, thanks for the question. The only other thing I would add is that this whole area obviously offers hope in these very difficult diseases, but it's going to have to be a partnership with regulatory authorities. And I think we and others have to engage more and more with regulatory authorities. These therapy shows such promise at a platform level to look for more rapid approaches and to look for approaches where drug packages don't conform necessarily to the kinds of packages we create for larger diseases of the type that John discussed in this presentation. And so some creativity has to be engaged in there as well. And so I think we're genuinely hopeful that we can help in situations like yours. Again, we don't know the specifics of your son's case, but it's going to have to be an industry regulatory partnership, and I'm sure nonprofits and patient advocacy groups will also have to be a big part of that discussion.

Keep doing what you're doing.

Okay.

Oh, is that it?

I think we are up.

Oh, good. All right.

Thank you.

Thank you.

Thanks everybody.