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

Good morning, and welcome to day 2 of our Virtual Alnylam R&D Day event. I'm Christine Lindenboom, Senior Vice President of investor relations and Corporate Communications at Alnylam. With me today are Dr. Arun Sanyal, Virginia Commonwealth University School of Medicine; and Josh Friedman, Senior Director of Clinical Research at Alnylam, who will discuss succeeding in NASH with genetically validated targets. Pushkal Garg, Chief Medical Officer at Alnylam, will cover progress from our earlier-stage clinical pipeline. Kevin Fitzgerald, Chief Scientific Officer at Alnylam, will discuss opportunities beyond the liver with RNAi therapeutics and we will close with an update on our path to a self-sustainable financial profile with Alnylam's CFO, Jeff Poulton. Before I hand it over to Josh Freeman, I'd like to start with a few brief comments. Today's event is expected to run until approximately noon eastern standard time. Akshay will moderate a Q&A session at the conclusion of the presentations. [Operator Instructions] Finally, a replay of this event will be available on the Investors page of our website in the Capella section later today. As a reminder, we will be making forward-looking statements during this webinar, and we encourage you to read our most recent SEC filings for a more complete discussion of risk factors. And with that, I'd like to turn the session over to Josh.

Thank you, Christine. I'm Josh Friedman, Senior Director of Clinical Research at Alnylam. I'll be speaking a little later about our activities in NASH. But first, it is my pleasure to introduce our guest speaker, Arun Sanyal, Professor of Medicine at Virginia Commonwealth University. Dr. Sanyal's interest include all aspects of NAFLD and NASH as well as complications of cirrhosis and end-stage liver disease. He has served in several leadership roles nationally and globally. Including Chair of the hepatobiliary study section of the NIH and President of the American Association for the Study of Liver Disease. He's currently engaged in numerous clinical trials and leads several Phase IIb and III trials for NASH as well as complications of end-stage liver disease. His many contributions have been recognized through awards, including the distinguished mentorship award from the American Gastroenterological Association, and the distinguished scientific achievement award from the American Liver Foundation and the distinguished achievement award from the American Association for the Study of Liver disease in 2018. I'm delighted to pass the podium to Dr. Sanyal.

Thank you, Josh. I will now talk to you about the mechanisms by which NASH develops and how this information is being translated into therapeutics. Just so we start at the same place, it's good to start this discussion by first defining some key elements of what actually NASH is. So steatohepatitis is part of a spectrum of disorders where you get excess fat in the liver. It is not simply fat and inflammation. But involves 3 specific lesions called steatosis, hepatocellular ballooning, where individual cells swell up and can contain these ropy eosinophilic inclusions called Mallory-Denk bodies and scattered inflammation in the lobules of the liver. Together, these constitute what we call disease activity. Now the consequence of steatohepatitis is scarring of the liver. And that typically starts in the sinusoids in between the liver cells, providing the liver this blue chicken wire appearance that you see on this slide. And the degree of fibrosis is referred to as the fibrosis stage. As fibrosis progresses, you lose more and more liver cells, and you transform the liver into a sea of scar tissue with little islands of liver tissue as seen over here, and this is known as cirrhosis. So fatty liver disease is part of a spectrum of disorders, where you can either get fat with a little bit of inflammation, which is also known as a nonalcoholic fatty liver or you can have steatohepatitis. And as the name nonalcoholic implies, this is not attributable to the consumption of alcohol. So it is important in this to remember the 2 key concepts, which are that disease activity is represented by the fat, which is the primary driver which causes tissue injury, which is represented by ballooning, which then leads to an inflammatory response. And together, these lead to a scarring response in the liver. So the disease activity and the disease stage are not independent of each other, but are tightly interrelated. So with that background, next, let's talk about why are we even having a conversation about NASH. NASH is a very common cause of chronic liver disease and tends to progress to cirrhosis with some regularity. Now the more scarred up your liver is, the closer you are to cirrhosis. So as shown on the left is the time to progression to cirrhosis based on the longitudinal cohort study that we performed in the NASH clinical research network than published last year. And as you can see, patients with stage 3 disease, they have more than 50% to 60% progression to cirrhosis within about 10 years. So 2 messages. First, that yes, progression to cirrhosis does occur, mostly in stage 2s and 3s but the numbers are quite modest. If you look at the number of people progressing annually. And when you look at the burden of outcomes, that, however, continues to increase and particularly, if you look at the burden of people who are living with liver-related endpoints, which is variceal bleeding, ascites, encephalopathy and who actually experienced a liver-related death or who have decompensated cirrhosis. So together, considering that fatty liver disease involves a large segment of the population and the burden of outcomes is progressively increasing, it indicates that there is a substantial ongoing as well as yet to come burden of disease due to end-stage liver disease, which is really when the patients require the greatest health care resources for their health needs. So without approved therapeutics, this is going to really create a big public health problem. So how do we tackle this? Now we have learned over the last 20 years that the cause of the disease can really be thought of in terms of 4 interrelated gears. Starting with a metabolic gear, which is the primary root cause, where you get excess lipids and carbohydrates pouring into the liver, within a systemic milieu, which is pro inflammatory, where the gut microbiome is already altered and is sending additional inflammatory cues to the liver. In that setting, this metabolic overload of the liver leads to stress within the hepatocytes, which if severe enough leads to apoptosis and this triggers an inflammatory response. Now normally, if you have a small injury, you get some inflammation. It cleans out the dead cells, you restore normal liver tissue. But if the injury continues because you're continuously pouring toxic lipids and fats and sugars into the liver, then the cell stress and inflammation continues and leads to the fibrogenic remodeling, which we recognize as the disease stage, which ultimately leads to cirrhosis. And this, of course, has given us the current approaches towards treatment of the disease. Now you notice that disease activity is referred by steatosis, inflammation and ballooning. Now if your target of therapeutics, is actually going to affect disease activity, you should expect to see changes in disease activity, which should then, in the long term, translate into decreased fibrosis. But if you use a primary antifibrotic or a drug at the interface of inflammation and fibrosis, then most of the disease activities upstream of your target, you really should not expect to see changes in disease activity. So as you think about drugs and the evidence that is needed to show that they are working, you need to think about the mechanism of action. And based on that, think about what evidence actually you need to see. Now let me very quickly review for you some of the frontline drugs, thinking also about not only where they sit in terms of the data. But also in terms of where I think their strengths lie as well as some of their weaknesses. So first, I would talk about some of the PPARs and up within the PPAR categories, there's some recent very exciting data from a pan-PPAR agonist, lanifibranor from Inventiva. These are data that were presented at ASLD. And as you can see, this is 1 of the first compounds, certainly the first compound within the PPAR categories that not only met the criteria of resolution of NASH without worsening of fibrosis, but also improvement on fibrosis by 1 stage or more without worsening of NASH. So it met both endpoints. And that really is -- is really a powerful statement when in a well powered Phase II study with 247 patients, they can show this. In addition to this, the HDL increased, although there was no change in LDL, but there was also a decrease in triglycerides and hemoglobin A1c, all of which is actually good news for a NASH drug because you want NASH drugs not only to help the liver, you wanted to help the extrahepatic cardiometabolic milieu because cardiac deaths are an important part of adverse outcomes within this patient population. Downside, well, there was some amount of diarrhea. There's weight gain and edema, and I think this is something that will need to be derisked by appropriate patient selection and ongoing approaches to minimize weight gain while patients are on therapy. Now this year, obeticholic acid, which is an FXR agonist, completely different mechanism of action. It's a bile acid agonist that already is in Phase III and its Subpart H results were published. And it actually met a prespecified primary endpoint of decreased fibrosis, yet they received a complete response letter from the FDA. Now what we learned from this process is that it's not only important to meet your primary endpoint. But in the end, drug approval is based on assessment of benefit versus risk. So on the benefit side, OCA decreased activity, decreased fibrosis, making it reasonably likely that you will decrease cirrhosis in the long term, decrease liver outcomes and in the end, improve mortality. So this is really the basis for Subpart H approval. But on the other side, there's some pruritus, which is manageable in the majority of patients. There's an LDL-cholesterol signal. Of course, there's no outcomes data that suggest there is a problem. But any time in a fatty liver disease patient with condition where you have increased cardiovascular risk an increase in LDL-cholesterol is not considered a good thing. So although this is manageable with statins, there's the LDL signal. And then recently, there have been some reports of potential hepatotoxicity in rare instances. When taken together, this, again, switch the FDA's benefit to risk assessment, and that's why they got a complete response letter. And of course, the study is -- a REGENERATE trial is still ongoing, and there have been no additional adverse events. And I think showing the safety element is going to be critical for this drug to get approved. And I would not write-off OCA, I would say, OCA now just has to show that all of these other issues are manageable so that the benefits of fibrosis improvement and particularly progressive fibrosis improvement over time, even beyond Subpart H, actually does start translating into decreased progression to cirrhosis. Now another part of the bile acid access, of which the FXR is such an important part is the FGF19. And over here, we actually see that the FGF19 data looked very, very promising. Where FGF19, this is cohort 4 with aldafermin showing not only an improvement in fibrosis stage. But again, once again, improvement in the resolution of steatohepatitis as well. Although patients who did not have end of treatment biopsies over here were imputed as nonresponders which is the general thing you do when you do an intention to treat principal. So some of the issues with the FGF19. It does increase LDL cholesterol. But again, they were actually quite savvy. And in the context of this cohort 4, they had a very rigorous LDL-cholesterol management program integrated into the trial. And at the end of the study, the majority of patients had lower LDL-cholesterol than when they came in. So that's been more successful in mitigating that by showing not only that it can be brought down, but showing that at least in the context of the trial, that their risk mitigation plan works. There's also some concern in the long term, whether FGF19 exposure can lead to cancers. The drug itself has been designed in a way not to be oncogenic. But I think over time, particularly when you turn on the FGF19 access over a long period of time, the safety of this is something that everybody will be keeping a close eye out on. FGF21 is another such molecule. It's a FGF, but it does not impact the bile acid pathway. So it works through adipose tissue and on the liver tissue directly. And essentially, FGF21 improves the metabolic state and FGF21 here, these are data from Akero, showing that it improved NASH resolution without worsening of fibrosis, particularly in the higher doses. And at the same time, in the -- particularly in those who had improvement in steatosis, it improved actually fibrosis stage as well. FGF21 improved A1c, it improved HDL cholesterol and improved triglycerides. But on the downside, up to 50% of patients receiving this particular compound had some diarrhea and about 25% reported abdominal pain. Now these are very small numbers. It's very encouraging, but small numbers. And what I would caution is that we need to see more data. And I think the Bristol Myers FGF21 program, which is very, very rigorous, and it's a Phase IIb trial, a proper Phase IIb trial. Those data will read out very soon in the next few months, I think, I guess. I think that's about right. And that should really tell us how the FGF21s really do. Semaglutide is GLP-1 agonist, very exciting because semaglutide also improves cardiometabolic and renal outcomes in high-risk diabetic patients. And over here, you see 58.9% of patients getting semaglutide, 0.4 milligrams actually had resolution of steatohepatitis. It also improved HDL, improved triglycerides and caused weight loss. Interestingly, they were numerically more neoplasms. I don't want to over-interpret this. Because there's lots of data within the diabetes population where this is not an issue. But simply because there was a numerical imbalance, it's something that I think in stage 3, we will be watching very closely. Now the other thing with semaglutide is that it did not produce a significant fibrosis improvement. But if you look at this slide, what you see over here is compared to placebo, if you look at the proportion of patients, who had worsening of fibrosis, you actually see that it's slightly less in semaglutide 0.4 milligrams. But if you look at the -- sorry, if you look at those who had no change, that's about the same. But if you look at worsening, it's 18.8% in the placebo arm and it's 4.9% at semaglutide 0.4 milligrams, 7.7 at 0.2 milligrams and 10% at 0.1 milligrams. So there are 2 things. One is the pattern of fibrosis, the improvement, even though it didn't hit significance. The second is this dose dependency. So to me, it suggests that given time, this will translate into less fibrosis as well. So this is basically where we stand with the current regulatory pathway, where for precirrhotic patients, the Subpart H requires the resolution of steatohepatitis without worsening of fibrosis or improvement in fibrosis without worsening of activity. And then post Subpart H, demonstration that this translates into less progression to cirrhosis and clinical outcomes, whereas in the cirrhotic population, you have to show improvement in fibrosis or reduction in MELD progression from less than 12 to MELD of 15 or higher and then ultimately show improved outcomes. So where do we go from here? Well, I think what we've learned from all of these different studies and a lot of the studies that have failed that we don't -- didn't have time to go into in detail is that the successful development depends on following some core principles which is finding the right target in the right population, defining the safety and then the efficacy. And the common elements of some of the leading programs in NASH is that most of them are anchored on an upstream metabolic target or have pleiotropic mechanisms of action where they are affecting multiple steps along the pathophysiologic cascade that I showed you earlier. Also, well-designed and properly powered Phase II programs with robust findings, derisk development of -- derisk your Phase III development and the likelihood of failure in Phase III. Meeting end points particularly that are agreed upon by regulatory agencies in Phase IIb really should give you the confidence to make it in Phase III. If there's a common weakness, I would say, maybe not enough attention to safety in many of these. And I think a big lesson to be learned here through the OCA experience that instituting your risk mitigation strategies within your Phase III trial and demonstrating that they actually work can really be very, very helpful. And I think you're already seeing the FGF19 program incorporate that into their approach. So if you think about the various targets and how the metabolic anchor of disease treatment is now being translated for therapeutics, we start with dietary fat that can go through adipose tissue and from adipose tissue due to insulin resistance, have fatty acid leak that contributes to the fatty acid pool in the liver. And these are being targeted through PPAR gammas, mTOTs, GLP-1s, FGF21s or the excess sugars can be converted in the liver into fat through de novo lipogenesis. And these are being targeted through SGLT2 inhibitors, KHK inhibitors and then a variety of targets within the siEBP cascade. The free fatty assets can then be burned off or utilized or converted into triglyceride, and that's where some very interesting and novel targets are now emerging, particularly leveraging the knowledge in genetics of NASH and what we find now are that there's a growing number of generic targets that are linked to the development and progression of NASH. Of these, of course, PNPLA3 is the best-known and as shown on the left, you can see over here that if you have basically the PNPLA3 allele, also the other target that really has come into play is theHSD17B13. Having the TA allele mitigate some of the risks with PNPLA3. PNPLA3 can be present in as high as almost 50% of Hispanics, as shown in the middle panel, and there's now growing amount of data that the variance in steatosis does actually correlate with variances in fibrosis over time. So how do these actually work? So recently, we have been able to connect the dots between PNPLA3 and NASH progression, where if you look on starting from the left, we see in a mouse model where we put a human PNPLA3 wild-type and mutant into the mouse and we're able to accelerate the disease and then by silencing the PNPLA3, we're able to rescue the phenotype. When you do a combined metabolomic transcriptomic analysis, it gives us a number of targets that are listed on this slide. And we focused in on sphingolipid and ceramides and actually confirmed that when you look at the middle panel and the top, you see that there are basically 2 diet conditions, Chow diet, CD or Western diet, WD, and there are 3 types of PNPLA3 conditions. So luc empty vector or luciferase LUC wild-type or mutant WT or MT. And you can see that when you have Western diet, and you have either -- and you have the mutant PNPLA3, you have a significant increase in total ceramides. This total ceramide increase is further linked to increase in Stat 3, and Stat 3 is a major pro oncogenic signaling pathway, and it has a number of downstream factors that it affects. And these are all impacted by mutant PNPLA3. At the same time, these ceramides working through the sphingosine receptors and particularly the S1P2 receptor, can affect other pathways such as Ras and MAP kinase, et cetera, causing progression of the inflammatory response. And we further show that condition media from hepatocytes from these animals can actually activate stellate cells. And this can be inhibited by inhibiting stat 3 within the hepatocytes. So we're now beginning to understand not just how PNPLA3 leads to fat accumulation but actually leads to tissue inflammation, injury and fibrosis. The other very, very interesting variant is the HSD17B13, which was published a couple of years ago now. And this is really a tour de force paper from just absolute fantastic population genetics. And looking at the large number of cohorts across multiple etiologies of liver disease, it was found that HSD17B13 has a splice variant, the TA variant which is associated with lower transaminases, reduced risk of alcoholic and non-alcoholic liver disease and cirrhosis and protection from NASH in patients with fatty liver. And this is the allele, which remember, also actually abrogate some of the risks from PNPLA3. Now what we don't know is exactly how this how this allele -- how this variant actually leads to this protection, and that's an area of intense investigation. What we do know from the PNPLA3 story, on the other hand, is that not only is it important, whether you have the mutant PNPLA3, but the degree of gene expression is extremely important. Because when you increase the gene expression, particularly in the context of a high fat diet, you lead to profound acceleration of the disease. But then if you silence the PNPLA3, you can rescue the phenotype. So whether the HSDB17 (sic) [HSD17B13], how the HSDB17 (sic) [HSD17B13] actually translates into disease is something that is actively being investigated as well. And whether by increasing the expression of this variant, or by silencing the wild-type would actually benefit the patient is really a very fascinating concept. And it's going to be important to establish sort of as a first step, precision therapeutics in the context of NASH. How do we evaluate if these are even going to work? So there's been a lot of recent talk about actually looking at changes in fat fraction. And it's been reported that up to 30% or more change in fat fraction translates into resolution of NASH. And these are the data presented by Rohit Loomba at the European meeting, showing that 41.5% was sort of the sweet spot. However, I would caution that I think you have to take the mechanism of action of individual drug. And even for drugs working on the metabolic end, a thyroxine beta receptor may not work exactly the same way as the GLP-1 or a FGF21. So I think for each of these thresholds will need to be established. Probably the biggest moving target in more advanced NASH trials right now is how we assess efficacy, which we all know is done by assessment of histology. A good histological marker should be specific, measurable, attainable, relevant and time bound. Unfortunately, when you look at the kappas between pathologists of the individual histological findings, and these are data from Beth Davison's paper from J. Hep summarized from the Cirius trials, the kappas are rather suboptimal. And so this has led to great interest in actually looking at machine learned approaches to identify changes in histology with greater precision. And different companies are approaching this in different ways. So PathAI is focused primarily on increasing the reproducibility of the findings. So by improving the kappas so that if there is improved ballooning, it really tries to capture the improvement it reduces the noise in the reading. Now what PharmaNest and HistoIndex are trying to do is actually convert the ordinal scale, which has errors at the boundaries of these stages, simply because fibrosis is a continuous scale, is a continuous process. And when you develop an ordinal scale for a continuous process you introduce error. So they are trying to introduce a continuous scale for fibrosis. In addition, HistoIndex, which actually uses second harmonic generated images also is looking at the dynamic nature of fibrosis evolution and regression, taking into account both the cellular the fibrotic elements. And we presented this as part of the FXR -- FLIGHT-FXR et cetera at ASLD recently. So in the end, where are we? We're still looking for the ideal agent that improves the activity and fibrosis, improves cardiometabolic status and reduces cancer. And these are the big risks in our population. Why? Because NASH does not occur in a vacuum. It occurs in the context of metabolic stress systemic inflammation and fibrosis, which is reflected in increased arterial risks, increased cardiovascular risk, increased diabetes and increased chronic kidney disease. And in the end, remember that approval of agents will require a high benefit to risk ratio. So with that, I will conclude and turn this back over to Josh. Thank you.

Thank you for sharing your insights on NASH, Dr. Sanyal. I'm Josh Friedman, Senior Director of Clinical Research, and I'm delighted to share our work at Alnylam, leveraging the power of genomics to identify and develop novel therapeutic targets for this widespread disease. As Dr. Sanyal explained, NAFLD is the hepatic manifestation of over nutrition, often occurring in parallel with cardiovascular and metabolic disease. It's highly prevalent in developed countries, as illustrated by the values in the bottom figure, with almost 100 million Americans having NAFLD. 1/4 of these will have NASH. NASH is defined microscopically with fat accumulation and lipid droplets, the wide areas in the image at the top left, signs of hepatocyte injury and infiltration with inflammatory cells. In response to this injury, scar formation occurs in the form of fibrosis, as shown by the blue staining in the top right image. The progression of fibrosis is the aspect of NASH, most strongly linked to morbidity and mortality as caused by complications of portal hypertension, liver failure and hepatocellular carcinoma. NASH is expected to be the #1 reason for liver transplantation within the next 10 years. In the face of this pressing need, there are no approved medical therapies. We've learned from individuals who succeed in losing weight, that NASH can be stopped and even reversed. But in practice, weight loss is hard to achieve and sustain. The progression of NAFLD to cirrhosis suggests that intervention is possible at multiple stages. That is steatosis, inflammation and injury, and fibrosis. In the rest of this presentation, I'll share 2 targets identified through genomics. The first is HSD17B13 or just HSD for short; and the second is PNPLA3, which I am excited to introduce as a new target within our partnership with Regeneron. The suppression of which may interrupt NASH at the first stages of disease progression. The 2 targets were identified in an unbiased manner that is not based on any prior knowledge of what cells they are expressed in and what their functions are within the cell. It's therefore noteworthy that both are predominantly expressed in liver cells, and within those cells, their protein products are localized to lipid droplets. In the case of PNPLA3, the genetics point to a variant that increases the risk of NAFLD. In contrast, for HSD, the genetics have revealed a loss of function bearing whose beneficial effects we propose to mimic with an RNAi therapeutic. Let's look more closely at HSD as a therapeutic target to interrupt NASH at the inflammation and injury stage. The first indication of a role for HSD in liver disease came from genome wide studies such as this one, looking for variants associated with the serum markers of liver injury, ALT and ASD in 46,000 participants. A variant in HSD associated with lower ALT and AST was detected. In the figure, the red line indicates the cutoff for genome wide significance. While these lab tests are not specific to a particular liver disease, phenotyping in this cohort allowed a more focused analysis. As shown on this table, the variant is associated with reduced risk of both alcoholic and non-alcoholic liver disease and cirrhosis providing the first indication that HSD could be a viable target for NASH. The ultimate measure of a disease association is mortality. As shown in this study, in a separate Danish cohort, the HSD variant is associated with reductions in liver-related mortality in both the general population and in those with cirrhosis. So having confirmed the association with NASH and outcomes, a key question is, what's the mechanism of this protective effect? The HSD protein is a member of the hydroxysteroid dehydrogenase enzyme family, and it's localized to lipid droplets, as shown in the figure on the left. However, its endogenous substrates are unknown. Turning to the protective variant. The change disrupts a splice site resulting in premature termination of translation. The normal protein isoform A is lost as shown in the figure on the right. And instead, low levels of the variant isoform D are produced. This isoform has reduced enzymatic activity, so the net result is a severe loss of function. While the full biochemical effects of this loss of function are unknown, a metabolomic study of individuals with or without the variant, reveals increases in several phospholipid species in the liver. This provides both a clue to the potential mechanism of protection from liver disease and also provides candidate biomarkers of therapeutic HSD suppression. The same study revealed decreased measures of hepatic inflammation as expected and showed that several other pathways are not affected by the variant. In interpreting this protective variant, it's theoretically possible that it causes a gain of function through some activity of isoform D. This is eliminated by the discovery of a second variant that changes a single conservative amino acid in HSD, with the resulting loss of enzymatic activity in vitro, as shown in the bottom left for two substrates. The authors tested the association between this variant, not only with NASH, but with histologic features within NASH, confirming protection from inflammation and hepatocyte injury. Putting together what we've learned from HSD genetics leads to our therapeutic hypothesis. The siRNA mediated knockdown of HSD will mimic the genetic loss of function, reducing hepatic inflammation, injury and fibrosis in NASH patients. In the next few slides, I'll review the path from this hypothesis through preclinical and most recently, clinical development of the therapeutic RNAi named ALN-HSD. ALN-HSD is the result of a process that began with over 750 siRNA candidates that were narrowed to 55 based on in vitro assays, then 5 based on mouse studies; and finally, 1 based on nonhuman primate, NHP screens. Along the way, we took advantage of next-generation sequencing to confirm specific knockdown of the target with minimal off-target effects across the transcriptome, as shown in the middle panels on the right, in human hepatocytes and NHP liver. NHP studies of ALN-HSD also confirm potent and durable knockdown of HSD mRNA and protein after a single dose and preclinical toxicology studies did not show any toxicity of concern and established high safety margins, consistent with our platform. Based on this preclinical data and scientific foundation, ALN-HSD has entered clinical trials with CTA approval earlier this year. I'm excited to share that the first Phase I cohort was dosed earlier this quarter, and the study is ongoing. We anticipate the start of POC in 2022. Let's take a closer look at the Phase I study design. The Phase I study is designed to assess the safety and tolerability of ALN-HSD. It comprises single ascending doses in healthy volunteer cohorts, followed by multiple dose cohorts of NASH patients to enable PK and PD assessments in the context of disease. Each NASH cohort includes baseline and posttreatment liver biopsies to measure mRNA and protein knockdown as well as several exploratory liver and circulating biomarker assays. We look forward to sharing results in future presentations. I hope we've conveyed the scale of medical need for NASH treatments and the path we've taken from genetic discovery to ALN-HSD and into a human clinical trial with our partner Regeneron, with whom we have filed strong patent protection for the target the ALN-HSD molecule and the program. I would now like to return to PNPLA3, which also came to attention through genomic association and which provides an opportunity to intervene at the first stage of NASH steatosis. A PNPLA3 variant was associated with hepatic steatosis 12 years ago, as shown on the left and bottom right. The variant is a missense mutation, changing the conserved isoleucine to methionine. Since that discovery, the same variant has been associated with a range of liver diseases, including alcoholic liver injury, NASH steatosis, fibrosis and hepatocellular carcinoma. The PNPLA3 I148M substitution causes hepatic steatosis, as shown in the transgenic mice in the top left. How does this happen? The substitution results in resistance to proteasomal degradation, as shown on the bottom left, so the variant protein accumulates on hepatocyte lipid droplets. On the lipid droplets, the excess PNPLA3 binds to the protein CGI-58, a co factor for adipose triglyceride lipase. The net result is inhibition of triglyceride degradation in lipid droplets. These findings suggest that suppression of PNPLA3 in hepatocytes will reduce steatosis and its downstream consequences. This was tested in a mouse model of NASH. And as shown in the published figure on the left, suppression of PNPLA3 reduces steatosis, inflammation and fibrosis in mice expressing the human I148M variant and even had a similar but weaker effect in wild-type mice. Based on these genetic and mechanistic findings, we've screened siRNAs targeting PNPLA3, several of which effectively suppressed the target in I148M knock-in mice, as shown in the top right figure, and a non-human primate liver, as shown in the bottom right. We have seen that the PNPLA3 I148M protein is associated with steatosis and NASH that knockdown is effective in mouse NASH models and that candidate siRNAs can effectively suppress PNPLA3 in mice and NHP. Looking ahead, we anticipate development candidate selection for PNPLA3 RNAi therapeutic in early 2021, and we'd like to note that IP for the PNPLA3 targeting family was filed in 2015. Many thanks for your attention, and now I'm pleased to pass the podium to Pushkal Garg.

Thanks, Josh, and hello, everybody. I'm Pushkal Garg, Chief Medical Officer at Alnylam, and I'm delighted to be here with you today to speak about several additional opportunities we are pursuing for liver-directed RNAi therapeutics. As I hope you'll see what is incredibly exciting is that the unique profile of Alnylam's RNAi therapeutics with potent and specific target knockdown, durable silencing that permits convenient, infrequent dosing, and a rapidly growing patient experience and well understood safety profile affords us the opportunity to bring forward meaningful therapies that may be able to help patients coping with a number of highly prevalent diseases. Specifically today, I want to speak to you about some of our earlier liver-directed programs. You've already heard from others about ALN-AGT for hypertension and ALN-HSD for NASH. I'm going to discuss several exciting clinical and preclinical programs we're pursuing to address recurrent renal stones, complement-mediated disorders, hepatitis B, gout and metabolic syndrome and diabetes. Let me start first by talking about a new program that I'm excited to announce today, investigating the potential for lumasiran to treat recurrent renal stones. As you know, lumasiran was approved just a few weeks ago to treat PH1 patients of all ages in the European Union and the U.S. Now the pivotal data supporting that approval came from the ILLUMINATE-A study. Importantly, that study demonstrated that silencing of hepatic glycolate oxidase by lumasiran reduced oxalate production and led to a 53% reduction in urinary oxalate. Reduction in urinary oxalate was the critical endpoint for approval in PH1 since elevated oxalate leads to renal stones and the many other manifestations of pH1. But oxalate stones are not only found in PH1. Renal stones, in fact, are very common, affecting 10% of men and 7% of women and 35% of affected individuals have recurrent events. Having kidney stones also nearly doubles one's risk of developing chronic kidney disease. But unfortunately, there are limited treatment options for these patients and all have limited efficacy. It's important to note, however, that 85% of renal stones are composed of calcium oxalate. And moreover, epidemiologic data from 3 patient cohorts show a graded relationship between levels of urinary oxalate and the incidence of renal stones, that's shown in the graph on the lower right of this slide. So these data raise the intriguing possibility that lumasiran by reducing urinary oxalate may be able to reduce the risk of stone recurrence in patients suffering from oxalate stones. We plan to initiate a Phase II study to investigate this important question in late 2021. One of the important reasons we're excited about this study is that, if successful, it presents an opportunity to take an already approved therapy for a rare indication and expand its use and impact to a much larger population of patients with a prevalent disease. Let me turn now to cemdisiran, which is in development for complement-mediated disorders. We now know that there are multiple debilitating diseases that are complement-mediated and which may be addressable by cemdisiran. As a reminder, cemdisiran targets production of complement component 5 in the liver, potently inhibiting the terminal complement pathway. We're pursuing a dual strategy for cemdisiran development in collaboration with our partners at Regeneron. First, we're evaluating cemdisiran as a monotherapy for IgA nephropathy and other inflammatory renal disorders. In these diseases, submaximal complement inhibition may be effective, and I'll describe this more in a moment. And second, we're also developing cemdisiran in combination with a potent anti-C5 antibody. Here, our colleagues at Regeneron are taking the lead as we work to develop a best-in-class, highly potent C5 inhibitor regimen for paroxysmal nocturnal hemoglobinuria or PNH, myasthenia gravis and other diseases. As a reminder, cemdisiran as a monotherapy is a very potent and durable inhibitor of C5. As shown in our Phase I/II study, single doses of 600 milligrams led to mean inhibition of 97% at 3 months, with potent inhibition lasting for over a year. That level of complement inhibition may be appropriate for IgA nephropathy. IgA nephropathy is the most common glomerular disease in the world and is caused by immune complex deposition and complement activation at the glomerulus. And importantly, 30% to 40% of patients with this disease end up in chronic renal failure, and there are no definitive therapies other than renal transplantation. We have a Phase II study of cemdisiran in IgA nephropathy that's underway. The study includes 30 patients with IgA nephropathy or being randomized 2:1 to cemdisiran versus placebo with an endpoint of proteinuria reduction at 32 weeks. This study is ongoing, and we expect initial data in 2021. Now for other diseases, we're developing cemdisiran in combination with an anti-C5 monoclonal antibody developed by Regeneron, which offers an even more potent level of complement inhibition. Importantly, we already have human data for such a combination from the Phase I/II study of cemdisiran with eculizumab in PNH. There, we saw that the combination led to a multi log increase in potency, relative to the antibody alone with lower peak to trough fluctuations or variability. And in addition, the regimen prolonged the functional half-life of the antibody, resulting in a convenient, less frequent dosing regimen. Our partners at Regeneron are currently evaluating the combination of Phase I study and then will be moving into studies in patients with disease. The next program I'd like to talk to you about is HBV02 or VIR-2218, which is in development by our colleagues at Vir for hepatitis B infection. Now HBV, as you may know, is 1 of the most prevalent diseases in the world. It affects an estimated 290 million people worldwide, of whom only 27 million are currently diagnosed. HBV02 is an siRNA that targets a conserved region in the X gene of the virus. HBV02 can silence all 4 major viral transcripts, which overlap this region and can suppress HB surface antigen from both integrated and covalently closed circular DNA. And as Akshay mentioned earlier, HBV02 is an ESC+ molecule that's been optimized for both potency and specificity. HBV02 is being evaluated currently in a Phase II study in patients where we have already seen some exciting results. In that study, HBV02 exhibited dose-dependent knockdown of HB surface antigen with a 1.5 log reduction seen with just 2 doses of 200 milligrams. And importantly, the regimen was well tolerated as well. Based on these encouraging data, Vir is now expanding the development program in developing HBV02 as a foundational therapy for hepatitis B infection. They expect to report longer term data, indicating the durability of effect in 2021. And they are initiating combination studies to evaluate several HBV02 based regimens to achieve functional cure. One is with PEG interferon alpha and the other is with their anti HBV monoclonal antibody. They're also initiating studies in China, which has a very high prevalence of HBV infection. We, of course, are working closely with our colleagues at Vir to support the development program and are enthusiastically awaiting the results as we at Alnylam have opt-in rights to this program prior to Phase III. Now let's turn to a new preclinical program that I'm excited to announce today, ALN-XDH for gout. Gout is the most common inflammatory arthritis, globally affecting 14 million to 18 million people in the United States, EU5 countries and Japan. It's caused by an accumulation of uric acid crystals in the joints, leading to pain, edema, buildup of tophi and joint destruction. And in some patients the elevated urate level contribute to chronic urate nephropathy as well. Importantly, we know that urate lowering therapy is essential to control this disease. And it's in that context that we believe an sRNA targeting xanthene dehydrogenase or may offer potent and durable urate lowering, and thereby improve disease control. XDH represents a clinically validated target, as it's a target for 2 approved therapies for gout, allopurinol and febuxostat. An important question is whether hepatic silencing alone, using a liver directed sRNA will be effective? And in fact, the preclinical data on the right from a liver-specific XDH knockout mouse model show that hepatic silencing has the potential to be quite effective. In these published data, use of a liver-specific knockout of XDH reduced the transcript by 95% and reduced plasma uric acid by 50%. Thus, these data are quite encouraging about the potential for a liver-directed RNAi therapeutic, targeting XDH to reduce uric acid levels and gout flares. Now you may be asking yourself, why develop a new treatment for gout? While, in fact, there remains a tremendous amount of unmet need in this disease because current therapies have substantial limitations primarily due to safety and tolerability concerns. And as a result, the majority of patients cannot adhere to prescribed therapy and do not reach target uric acid levels. For instance, it's been reported that fewer than 50% of patients reach uric acid goals on allopurinol. And this ALN-XDH may address key unmet need for gout patients with proteinuric lowering, infrequent dose -- dosing with tonic control, acceptable safety and tolerability and a reduction in gout flares. Finally, I'd like to turn to ALN-KHK, which I'm pleased to announce today, we are developing for metabolic syndrome and type 2 diabetes. Now you may be well aware that the high fructose in our diet is a major cause of a number of chronic diseases, commonly referred to as metabolic syndrome. These include high blood pressure, diabetes, obesity and hyperlipidemia. KHK is a key upstream enzyme in the liver that metabolizes fructose. And as I'll show you in a moment, KHK knockout mice are protected for some of the downstream impacts of dietary fructose, including insulin resistance and liver steatosis. Moreover, knockdown of KHK is expected to be well tolerated and safe. There's a rare disease called essential fructosuria that is caused by mutations in the KHK gene and individuals with KHK loss of function mutations have high fructose in the urine, but are otherwise healthy. This next slide summarizes data from a series of experiments conducted by Alnylam scientists and academic collaborators that support the potential for liver-directed silencing of KHK to have a beneficial effect. The bright red bars in this graph show the impact of an anti KHK siRNA directed to the liver in mice who are fed a high-fat diet and fructose. Animals treated with the siRNA experienced less weight gain, lower liver weights and lower triglycerides than control mice. And importantly, targeting KHK led to improved liver histology with less steatosis of liver. Thus, these are very encouraging data about the potential of ALN KHK to favorably impact metabolic syndrome and type 2 diabetes. And while there are some small molecule KHK inhibitors in development, we believe that a liver-specific silencing approach as well as the potential for durable and tonic control of KHK activity with infrequent administration offer the potential for a highly differentiated therapy. So in summary, we see multiple opportunities to advance meaningful RNAi therapeutics against liver targets to address diseases of high unmet need, such as the ones I've shown here. Importantly, we continue to focus on genetically validated targets, which increases the probability of success. And as I hope you've also noted, we have an increasing focus on specialty and large market opportunities which is enabled by the emerging safety profile of our platform and the pharmacologic profile of our molecules, which offer the potential for durable tonic control of disease-causing genes. Thanks very much for your attention, and I look forward to updating you on these programs in the months to come. And now I'll turn it over to Kevin Fitzgerald, our Chief Scientific Officer.

Thank you. So thank you, Pushkal, and good morning. I'm Kevin Fitzgerald, the Chief Scientific Officer. I've been with Alnylam for over 15 years, and I'm very excited to talk to you today about going beyond the liver into extrahepatic tissue. Both Akshay and Pushkal have discussed our continued progress as innovators of GalNAc conjugated oligonucleotide delivery in the liver. It is now clear that we have a safe modular, robust and durable platform, capable of specifically silencing any gene in the liver genome. Today, I'm very excited to update you on our progress in 3 additional tissues, the central nervous system, the eye, and the lung. As you can see here, we are developing a very extensive pipeline outside of the liver with more than 15 programs underway, including 11 in the CNS area, 5 in the eye and 3 or more in the lung. Let's start with our CNS programs. We've taken a keen interest in delivery to CNS as there remains a tremendous unmet medical need across many difficult-to-treat diseases. To date, the lessons we have learned about making potent, durable and safe molecules in the liver have directly translated to extrahepatic tissues such as the CNS. This opens up diseases such as Alzheimer's disease, ALS, frontotemporal dementia, Huntington's and Parkinson's, which represent a variety of important orphan and large market indications with tremendously high unmet medical need. We believe that using our conjugate platform and its tremendous efficacy and importantly, it's durability, resulting in very infrequent dosing can be applied to many CNS diseases in which there are genetically well-validated targets. We designed our initial CNS RNAi conjugates for broad CNS distribution hitting a wide variety of cell types in the CNS, as we believe this will be required as we look to target many of the most important inherited diseases. We also, however, continue working on more cell type specific ligand receptor pairs where that may be beneficial. As an example of broad distribution of our CNS conjugate platform, here, you can see CNS distribution of a labeled radiotracer siRNA conjugate after a single intrathecal dose in a rodent. To orient you from right -- from left to right, we are looking at time course of a single dose, the top being the head where the brain is with the bottom being the lower part of the spine. Note the very quick and broad distribution of the drug represented white across the entire spine and throughout the brain, including deeper regions. Eventually, you can see a fraction of the drug is cleared from the CNS into the periphery indicated in pink by the liver starting to light up. With single intrathecal doses, we have seen robust pharmacological effects across all animal species from rodents to non-human primates including in deep brain region such as the striatum. This silencing lasts for 6 months to a year, allowing for biannual to annual dosing, which I'll show you in a couple of upcoming slides. As previously announced, our first program for clinical development targets APP or amyloid precursor protein for the treatment of early onset Alzheimer's disease. It's very clear that APP is the genetic driver of diseases in early onset disease, also known as ADD (sic) [ADAD] or autosomal dominant Alzheimer's disease. There are about 50,000 patients in the U.S. with the mean onset of Alzheimer's dementia at the tragic age of 44. Subsequently, the disease rapidly progresses over the next 6 to 9 years. This genetic disease is caused by mutations in where that impact the level of APP or Abeta production, both intracellularly and extracellularly. This disease is unfortunately 100% penetrate, meaning if you carry 1 of these mutations that impact APP, you will get the disease. Having positive proof-of-concept in ADAD would, of course, open the possibility of treating the more general AD population where app is also known to play a very important role. So what differentiates our strategy from the antibodies and small molecules that have come before? I don't have time to review each of the programs that have come before in detail, and they all have unique characteristics. There are several profound ways, however, in which RNAi therapeutics approach to APP is very differentiated. First of all, we believe there are certain parallels in approaching the treatment of this disease to another disease we are all quite familiar with, where misfolded proteins accumulate and cause damage, that of TTR amyloidosis. As in the case of TTR, we believe that the key is to stop the production of the offending protein instead of trying to mop it up once it's already been produced and deposited. Moreover, in the case of targeting APP the siRNA approach will remove not just secreted extracellular Abeta proteins that travel to and are deposited throughout the brain, but also the intracellular production and accumulation in the cells that are actually making APP to begin with. There is a large and growing literature, as you can see on this slide, around the role of Abeta peptide buildup in the cells in which they are made, the so-called cell autonomous effect. These depositions of APP protein fragments have never really been effectively targeted in the disease. To put it in another way, accumulating data suggests that the mutant forms of APP kill or just regulate the neurons in which they are made, just as readily as they kill the neurons next door. An RNAi therapeutic targeting APP itself will prevent both. Moreover this approach will remove all fragment forms of APP. You will note that I said all fragment forms of APP. If one looks at the pathological mechanism of APP, 1 will see that intracellular Abeta accumulation is responsible for dysregulation of many levels -- at many levels, including markers of pathology like tau hyperphosphorylation and [indiscernible] optic dysfunction. In addition, Abeta can exist in many assembled states such as monomers, oligomers, protofibrils, fibrils and plaques. It's never been exactly clear which of these forms actually drives the pathology of disease. And the latest thinking is that several forms are very important for the disease. The attempted antibody treatments to date, for instance, have bound just won or a few confirmations. Where an RNAi strategy will eliminate all of them. We believe that targeting all assemble forms of Abeta as well as the intracellular and extracellular fragments of APP is critical for disease mitigation, just like turning off the tap is for TTR. As an example of APP lowering here, we've used an siRNA mechanism to silence APP and a mouse over-expression model, the so-called CVN model. This model over expresses human mutant human APP proteins that as you can see on the left-hand side. Here, we've observed marked behavioral changes in disease mice, the dark blue bars, for instance, on the bottom left versus the light blue bars. What we observed after a single IT dose of siRNA targeting APP, the green bars is that abnormal behaviors such as distance traveled, their rearing frequency are normalized in the treated mice. In addition to AD or ADAD, there's another inherited disease caused by a specific subset of mutations in the APP protein. These cause increases in production of a fragment called Abeta 40. The disease is called cerebral amyloid angiopathy or HCAA. This is also a disease that unfortunately is 100% penetrated. That is individuals with mutations that accumulate Abeta 40 and form plaques, will get the disease. These plaques specifically deposit in small blood vessels of the brain. This accumulation causes microbleeds that eventually lead to much more significant brain infarct, stroke and can lead to death. Lowering of mutant APP in these patients is predicted to prevent or reverse the accumulation of APP protein fragments, Abeta 40 in the blood vessels and clear out existing plaque. In addition to inherited CAA, there is a much larger population of individuals who have something called sporadic CAA, that's where without features of general Alzheimer's disease. While these individuals do not have mutations specifically in APP, they accumulate fragments in blood vessels as they age, developing brain bleeds similar to the inherited forms. You can think of it a little bit like mutant HT inherited TTR versus wild-type TTR. Here, I'm showing an animal model of HCAA disease. Here, this model contains overexpression of several mutations, the Swedish, Dutch and [IO] mutations that are responsible for the human forms of CAA. On the top left in green, you can see an increased production of human APP buildup as we over express those mutations in these animals. On the right-hand side in green, you can see that over time, as in the human disease, Abeta 40 fragment stained in green accumulate in the microvasculature of the brain. What this leads to on the bottom left is microhemorrhages as shown in the blue staining on the bottom left. In the next slide, we can see after a single intrathecal dose of an siRNA conjugate targeting APP, all mutant forms of APP that the deposition in the brains here as stained in green, are completely abolished on the bottom, that's a representative of 2 different individual animals that have received siRNA targeting APP. With our development candidate, we've been able to measure a lowering of all fragments of APP. Here, we're showing an alpha and a beta form in cerebral spinal fluid or CSF after a single intrathecal dose in nonhuman primates. What's remarkable here is that we see effects that are essentially clamped out past 6 months, indicating that our platform is capable of very infrequent biannual to annual dosing. We believe that this could offer a significant advantage over molecules that need to be dosed more frequently given the treatment limitations of intrathecal dosing. We've selected our development candidate for APP and are excited to be on a track for a CTA IND filing in mid-2021, with proof-of-concept data expected in 2022. In addition, our partners at Regeneron have opted into this exciting program. While APP is exciting, it is only the beginning of our rapidly emerging CNS portfolio. A second target of high interest is ALN-HTT for the treatment of Huntington's disease. As you all know, Huntington's disease is a dominantly genetically inherited disease with devastating consequences to patients and their families. There are an estimated 30,000 patients in the U.S. with this terrible disease. As with the above diseases, it's 100% penetrate. If you have the mutation, you will get the disease. It involves a trinucleotide expansion of exon 1. Recent advances in the disease understanding have led to ideas about how to best target HATT (sic) [HTT] at the molecular level. HTT has a complex locus, and initially, it was thought that processing of the full-length transcript and subsequent proteolysis led to the mutant aggregating HTT protein, as you can see in this figure. More recent data, however, has shown that there's a different way that these fragments can be produced. In fact, and that's the so-called exon 1 transcript, it's a distinct transcript that actually comes off of a separate messenger RNA. In fact, as the disease progresses, 1 finds more and more of the exon 1 fragment being produced. Here, we are looking towards a differentiated strategy that lowers the very important exon 1 fragment. We continue our progress in this program towards a development candidate, along with many other targets for important diseases of the CNS. Turning next to the eye. We continue to make clear progress in the delivery of the ocular space in collaboration with our colleagues at Regeneron. Shown here is data in nonhuman primates that demonstrates similar to the liver and CNS, very effective and durable lowering in this example of the TTR protein at doses as low as 3 micrograms to 10 micrograms per injection. Note that this is micrograms and not milligrams. Moreover, as shown here on the left graph, these doses are durable with silencing out to 6 months and much more potent than siRNA is lacking in our ocular ligand as shown on the right. We are excited about the potential of ocular RNAi therapeutics to help patients with many different forms of eye disease and continue to work diligently with our Regeneron partners, clear leaders in the ocular commercial space to build out the ocular pipeline. Pivoting now to yet another organ, the lung, where we have again demonstrated robust efficacy with our ESC+ RNAi conjugate platform, focusing initially on SARS CoV-19 and host factors given the current ongoing pandemic. Building our experience targeting viruses such as HBV with our partners at Vir, early in the year, we launched an effort to attack SARS CoV-19 with RNAi therapeutics. As you all know, the RNAi mechanism is a natural 1 involved in responses to viral infections. Direct delivery of RNAi therapeutics in the lung enables knockdown of targets. In this case, the SARS CoV-19 genome at the very side of viral application in the nose and the lung. On this slide, you can see the top left, staining and distribution of an RNAi lung conjugate delivered intranasally in the pink, you can clearly see we get broad distribution throughout the loan. On the bottom left, you can see that this broad distribution translate into robust silencing in this case, of a ubiquitously expressed gene, SOD1. Moreover, the silencing is durable out to a month or more. And on the right, you can see silencing of a SARS CoV-19 known host factor a gene called ACE2, which is involved in viral entry, a second potential strategy for the prevention of COVID-19 infection. We've been working hard on development candidates for SARS CoV-19. On the top left of this slide, you can see an example of lead molecules that lower SARS CoV-19 genomes, a dose-dependent matter in vitro. On the right-hand side, you can see an example where 1 of these molecules can suppress viral infection. The first panel shows infected shells with viral nucleocapsids stained in red. And on the right, RNAi treated cells where viral replication has clearly been suppressed as in the indication -- indicated by the absence in the -- of red. To prevent viral breakthrough, we are using 2 different siRNAs targeting separate conserved portions of the virus. These lead molecules are currently being tested in hamster COVID-19 infection models. Building on our COVID-19 work and our demonstrated effective conjugate delivery to the lung, we turn to human genetics using the UK Biobank resource that Akshay discussed yesterday, and we've identified several genetically validated targets in the lung for different diseases. In fact, as you look in here, we've identified targets spanning diseases from asthma to IPF and COPD, and we look forward to bringing potential therapies to bear to meet these high unmet medical need areas. In summary, the knowledge we've gained about how to make safe and effective liver-directed RNAi therapeutics excitingly, translates very well across multiple tissues, including the CNS, the eye and the lung. This includes the basic safety properties of the molecules in preclinical species, the extended duration of action leading to infrequent dosing and the basic concepts of using ligand receptor pairs for delivery. We continue very significant efforts in this area to identify pairs that are capable of opening up yet additional tissues of high interest. Combining our ESC+ siRNA designs, with our delivery capabilities and the power of human genetics, we look forward to continuing our track record of building and executing on what we think is 1 of the most exciting pipelines in the industry. With that, I'm happy to hand it over to Jeff Poulton, our Chief Financial Officer.

Thanks, Kevin, and hello, everyone. I'm Jeff Poulton, Alnylam's CFO, and I'm happy to have the opportunity to close out the formal presentation portion of our 2020 R&D Day. After the last 2 days, I hope you concur with our view that for 2021 and beyond, we've got key business drivers, which enable long-term value creation, including commercial platform currently focused on near-term opportunities and rare indications, but longer term, with emerging opportunities to expand into larger, more prevalent diseases. And we've got a robust R&D pipeline that is enabled by a platform that generates sustainable innovation and value creation through organic means. And the final driver that I'd like to now spend some time on is how we combine our commercial capabilities and R&D platform and achieve profitability and financial self-sustainability. The framework I'll walk through on this topic is the same as what I highlighted last year at R&D Day. So this represents a good progress report. As I indicated last year at R&D Day, we've committed to becoming a profitable, self-sustainable company and that there are 2 primary operational levers that we focus on that support that path. The first being top line growth and the most important lever in determining time line to profitability, which is currently being fueled by 3 product approvals in just over 2 years as well as collaboration revenue from strategic partnerships, and most recently an approval for Leqvio adding a new royalty stream. Second lever is disciplined investment in our operations, which for R&D means investment in a proven organic platform, now including an increasing number of common disease opportunities, underpinned by confidence in the efficacy and safety of our platform. We also continue to leverage partnerships when appropriate to support innovation while sharing cost and risk, most notably with our Regeneron partnership. Which Kevin just updated you on earlier today. And for SG&A, discipline takes the form of operating leverage following the initial commercial infrastructure build to support ONPATTRO, more details on this in a few slides. As we've committed to 2019 was our peak non-GAAP operating loss year, which I remain confident is the case and that we'll see sequential year-over-year improvement going forward. Since the last time I spoke with you 12 months ago, we have continued to make great progress in solidifying our commercial foundation. You heard from Yvonne yesterday who shared her perspective on a number of initiatives and key success factors that have supported the build-out of our commercial capability over the last several years. We're really pleased with our commercial performance in 2020 in the face of a global pandemic. Both ONPATTRO and GIVLAARI have had strong years as our commercial and medical teams quickly adapted to challenging market conditions to ensure continuity of care for existing patients as well as the identification of new patients appropriate for care. Last year at R&D Day, I referenced the possibility of 6 new sources of potential revenue by 2025, which included the potential for 2 new products, 2 label expansions and 2 royalty streams. So we're very pleased with the progress we've made over the last 12 months with the recent approval of OXLUMO, an ultra-orphan RNAi therapeutic for the treatment of PH1 which we believe represents a $500 million plus peak revenue opportunity and a new royalty stream with the initial approval of inclisiran or Leqvio in the EU, which will be marketed by Novartis. And upon whose sales we'll be entitled to royalties up to 20% or 50% shared with Blackstone. Breadth and depth of the commercial opportunity at Alnylam is really quite impressive, and I continue to believe somewhat underappreciated. And I'll reiterate that launching these drugs well and growing our top line is the most important thing we must do effectively to achieve profitability and self-sustainability. And so far, so good on this imperative. Now an update on the second lever, aiding our path to sustainability and 1 over which we have complete control, that being disciplined investment in our operations. Starting with our progress in R&D. We continue to build on a remarkable track record of success in programs we have brought into the clinic that have successfully progressed through Phase III as can be seen by the statistics on this slide with the cumulative probability of success greater than 50%, which is multiples higher than industry benchmarks. I expect that we will continue to see greater than 50% of our R&D spend on late stage, high ROI programs as we enter 2021, with the ramp-up in spend expected in our Phase III TTR cardiomyopathy programs, APOLLO-B and HELIOS-B as we enroll substantially more patients in these studies. It's also worth noting that the diversity in our pipeline continues to expand, both in terms of a mixture of programs across different indications and size of disease populations, both rare and prevalent, as well as expanding beyond the liver into different tissue types, including ocular, CNS and the lung. Now a few comments on our investment in SG&A, where we've built a solid global foundation over the last several years, first to support ONPATTRO, but with an eye towards supporting multiple product launches in a compressed time frame. We're now starting to generate operating leverage from that initial investment, and I anticipate that we'll continue to increase that leverage as we enter 2021. There are some interesting data points in the chart on the upper left-hand side of the slide, that reflect this increasing operating leverage we're beginning to deliver. In the chart, the columns represent annual revenue back to 2015, both collaboration revenue in purple and product sales in blue, with 2020 representing current sell side consensus or just under $500 million. And then the line in the chart represents the year-over-year percentage growth in combined non-GAAP R&D and SG&A expense. You'll see that back to 2015, it has been consistently north of 25% year-on-year growth, but we see a break in that trend in 2020 with growth at 10% projected versus 2019 and based on the current analyst consensus. Robust top line growth, combined with moderating growth in operating expenses, leads to the trend that we see in the upper right-hand chart in the slide which reflects our non-GAAP operating loss by quarter over the last 4 quarters. As you can see, we're on a trajectory of delivering smaller losses each successive quarter. This slide brings it all together and hopefully, is a picture that you're all familiar with as it is 1 that we've been using consistently over the last year to represent our expectation of the path that we're on towards achieving profitability. It's worth repeating that we believe 2019 represents our peak non-GAAP operating loss year, with improvement expected on an annual basis as depicted by this chart, ultimately culminating and achieving profitability. We'll get there via strong commercial execution and discipline in our approach to investing in R&D and SG&A to ensure we're creating long-term sustainable value. Another key point of progress over the last 12 months worth highlighting relates to the strength of our balance sheet. You may recall that back in the spring, just at the onset of the pandemic, we announced a strategic financing collaboration with Blackstone worth $2 billion, anchored by monetization of 50% of future inclisiran royalties for $1 billion that we believe secures our bridge towards self-sustainability about the need for additional equity financing. And again, a reminder on inclisiran, in addition to shoring up the balance sheet with this deal, we retained 50% of the inclisiran royalty going forward. So the deal not only allows us to capture significant upfront value but also retains upside by participating in the future commercial success of inclisiran. Just a quick comment on corporate responsibility. In addition to focusing on driving financial value for our shareholders as a firm we also prioritize other stakeholders as highlighted in the pie chart on the right. We're convinced this is the right thing to do. We've recently developed a corporate social responsibility or CSR framework, that we'll be using to establish goals and track our progress. The tagline for the framework is accepting challenges that improve the health of humanity. We anticipate sharing our initial CSR summary report in early 2021 and plan that we'll then be doing an update on our progress annually going forward. And lastly, as John shared yesterday, our aspiration is to build a top 5 biotech over the next 5 years. And we're confident that we've got all the ingredients necessary to enable that. And this slide depicts how we believe the profile of Alnylam will evolve to achieve that top 5 status. And that concludes my prepared remarks. We'll now transition to a Q&A session, and I'll be handing it over to Akshay to moderate that session. Akshay?

Well, hello, everybody. Thanks for calling in again to day 2 of R&D Day here at Alnylam, and hope you've been in joining the presentations. We're now going to go into a Q&A session. I've been joined by the presenters during the morning panel. And with that, let's kick off. Our very first question actually relates to the NASH space and the question Dr. Sanyal is what can you say about the importance of safety in evaluating NASH drug particularly at longer time points what are you looking for and what are your thoughts on safety of drugs RNAi therapeutics targeting HSD. Maybe you can kickoff and Josh, you might want to talk about HSD and safety endpoints as well. So Dr. Sanyal.

So thank you. At a very high level, we know that NASH is associated with a number of comorbidities such as hypertension, coronary artery disease, CKD, et cetera. So particularly drugs that impact lipid metabolism, it would be very important to document that there are no unexpected adverse effects on the atherogenic profile or there's no signal for increased rates of hypertension, CKD or some unexpected vascular event that is unexpected. The second issue is one of cancer. Because we know that excess -- all cause cancer mortality in NASH. And certainly, I think a lot of drug companies do not spend a lot of time thinking about it, but we know, for example, there's increased colorectal cancer, et cetera. It's got to be sort of neutral. If a signal emergence in the context of a trial, then that becomes a problem that you have to deal with. So the more you know and the more you can derisk it from that perspective, from HSD from RNAi therapeutic perspective, particularly liver-targeted therapeutics, we're really talking about all of these safety issues in the context of liver disease, but with 1 additional add on which is to make sure that you don't get an unusual form of delay. You know the classic DALYs have all been described with the traditional drugs, not with RNAi based therapeutics. But what we learned from immunotherapeutics is that now there's a whole new class of DALY, which is based on immunotherapeutics, where you get immune reconstitution and immune-mediated liver injury. So it just make sure we don't get surprised by something like that. So paying attention to markers of DALY in the early development is really, really important.

Yes. So, Josh, before you jump...

I'll turn it Over to Josh.

Yes, before you jump in, Josh, on that DALY issue, I would comment that we've really focused on the safety of the platform, especially with the advanced amount of data from inclisiran, well over 10,000 patients now. So the platform where it all looks very encouraging, but your comment, obviously, is very fair. And liver safety is always going to be very, very important, Dr. Sanyal will agree. So far, we don't have a signal of DALY with the platform, which is very encouraging. Josh, what about follow-up on HSD and safety? What are your thoughts?

Yes. All of those points that are just made are well taken by me, and of course, safety is paramount in the study. I'd say that in terms of monitoring, the observation period for the patient part of the study is 12 months, which is already pretty generous for a Phase I program. And has been said, we're encouraged by the overall safety of the platform, but there's another piece, which is that we're also encouraged by the safety implied by the genetics. The variant that I discussed is fairly common, about 20% of the population. It's a loss of function. And so that provides a whole another aspect of assessing the safety of knocking down HSD. And as mentioned, the preclinical animal toxicity had no safety findings of concern whatsoever.

Great. Thank you, Dr. Sanyal. Thanks, Josh. Next question is what Alnylam's IP position on the 2 NASH targets, HSD and PNP? I'll kick off, and Kevin, you may want to jump in as well. So in general, we have, as I think most people know, industry-leading estate around RNAi therapeutics. So the targets, the technology that we use for the treatment, et cetera. So there are multiple ring fences. There's the composition of matter IP that we have, obviously, against RNAi therapy, the sRNAs themselves, then the IP related to the delivery technologies that we use, and then finally, with respect to targets, we have target-related IP. And in the case of these 2 targets, we have very strong IP. The HSD story began with Regeneron. They discovered the target. They came very rapidly to us. And we and Regeneron had comprehensive IP in place, both for RNAi and ASO-based approaches against HSD, which is our habit now with all targets to try and do that. Our PNPLA3, we're also first mover. And maybe, Kevin, you can speak to the target level coverage we have for PNPLA3 and when we're starting the work on that.

Yes. So I mean we've been working on PNPLA3, again, based on human genetics out of UT Southwestern many years ago. And so we have filed extensively on it, both from an sRNA as well as an antisense oligo typical kind of a walk that we would do down the gene for activity to identify molecules.

Terrific. Thanks, Kevin. I think here's one for you, Pushkal. How quickly can Alnylam get into Phase III for new luma indication? And here, I think the question is referring to the recurrent renal stone's indication.

Yes. Thanks, Akshay. So this is, as I mentioned in the presentation, a really exciting opportunity to take a now approved therapy for a small-sized population and extend it into a very much more prevalent indication. What we'll be focusing on really is first going into a Phase II study in this population, where the endpoint will not be stones, but really looking at oxalate lowering. And we showed in the PH1 population with lumasiran that, that can be shown in a modest number of patients within a matter of weeks. So our expectation is to start next year with a modestly sized Phase II study, show oxalate lowering and then move into Phase III soon thereafter. So we think we can move fairly rapidly.

Great. Thank you, Pushkal. Back to the NASH landscape. And I think you are best to address this one, Dr. Sanyal. Where does the THR beta approach fit in? And here, the question is referring to the drug resmetirom. How does it fit in mechanisms? Can you help us with that?

Sure. Absolutely. So I did not have time to go through each and every drug and mechanism of action in my presentation. That, of course, does not imply that those mechanisms, all those other mechanisms that I didn't mention are irrelevant. I just wanted to cover some of the newer data that have come out this year in my presentation. So thyroxine beta receptors are turning out to be a very interesting and important mechanism of action in the NASH space. Because they're relatively liver specific, and they have not only very rapidly defected the liver but have good resolution of NASH. Now where the issue with these class of drugs lies is that we, at least in the Phase II trials, there was not a big signal for improvement in fibrosis. And increasingly, the fleet not only wants to see improvement in disease activity, but wants to see it translate into reduced fibrosis. Remember that fibrosis is a consequence of activity. And so it will be very important in the Phase III trial to see whether the THR betas actually not only improve disease activity, but whether this translates into less fibrosis. In the absence of that, I think they would face a high bar to try and convince everyone that it's a viable player in the space. So the good news is very good lipid profile lowering and relatively safe, well-tolerated, orally available, and rapidly defects the liver and improves NASH, but at least they have not been able to show a big signal on fibrosis, and that's where I think -- that's what everybody is sort of waiting to see.

Yes. Thank you for that, Dr. Sanyal. And I mean that comment just gets us be more excited about our choice of HSD and PNPLA3, where we're getting very proximal in the disease. And the hope would be that, that would impact the whole cascade of downstream events up to, and including, not just the information, but also the fibrosis. And certainly, in all the other programs with multiple drugs where we go approximately, we see very good broad downstream beneficial effects for patients.

Yes.

So that's exciting.

I think one caveat is the timing of the study because depending on the mechanism of action, how long it would take to improve fibrosis can be quite variable. After bariatric surgery, it takes 2 years plus to see the fibrosis needle move. So for each mechanism of action, yet we know with FGF19, they were able to show improvement in fibrosis in a relatively short-term study. FX are required 72 weeks. So I think for each mechanism of action, it may be different. And the more upstream you are, like with the GLP-1, it may take longer.

Yes, indeed. Thank you for that. So the next question is where are we? Here we are. So when allocating capital to pipeline, do you use industry standard probability of success? Or do you use the much higher probability of success that you have recently realized? Would you say that your IRR hurdles for R&D investments are higher or lower than peers? I mean I can kick this off, and then Jeff Poulton, our CFO, sure wants to comment as well. We generally use our internal metrics and our internal assessment of the probabilty of success in the sense that, as we were just discussing the situation with NASH, we believe in the importance of selected genetically validated targets and the higher rates of success like [indiscernible]. So do you understand that the biology of the target, the mix of action, pharmacology, and those are principal drivers for us in terms of selecting programs and choosing to invest. And I think the data shows that we deliver better IRR using that approach. Now I'll stop there, but Jeff, I'm sure you want to comment as well.

Yes. I agree with what you just said, Akshay. I think this is why when we talk about getting the profitability, we're not talking about getting there as fast as we can. We think we've got a lot of great opportunities to continue to invest in R&D programs that will position us for long-term growth, and we intend to take advantage of those opportunities.

Great. Thank you, Jeff. Next question. Nice comment from somebody. Great day. So much going on at Alnylam. The question is with multiple targets in various diseases, such as liver disease and at other areas, do you see the potential for multiplexes RNAs to deliver combinatorial effects in a single therapy? It's a really interesting question and one that Kevin Fitzgerald, our CSO, obviously, leads our thinking on. Kevin, why don't you start and focus with that?

Yes. So I think one of the beauties of having a safe and durable platform is that there is the opportunity to combine multiple targets, either as of this molecule, which is a single molecular entity or potentially also just as a simple mixture of the 2. And I think it has broad applications potentially for people who have -- we've mentioned HSD and PNPLA3. There is potential they could work better together. Certainly, in the central nervous system, there are multiple targets where we believe a combination will be an effective therapy. So I think we're just starting to dip into where the potential there to have multiple targets within either a single construct or a mixture.

Yes. I agree, Kevin. I think in the liver space as well, there are many opportunities beyond NASH. And if we look at the lipid -- lipidology and combining various drugs for LDL and triglycerides -- sorry, Kevin?

If you think about -- no, I was going to say, if you think about metabolic syndrome, right, it is. And as you get into broader diseases that are a little bit more polygenic.

Exactly, exactly. So I think it's a very exciting area. Thanks for the question whoever sent that in. Next question, Pushkal, I think. Is there an advantage, Pushkal, of targeting GO for recurrent renal stones versus LDHA?

Yes. So we've looked at -- when we were starting our lumasiran program or targeting PH1, we looked at actually targeting LDHA versus GO. And we made the decision really to go after glycolate lycolide oxidase in the liver, really -- primarily because of the potential downstream safety effects of targeting LDHA. So it's obviously involved in very fundamental aspects of cellular metabolism, the Krebs cycle, et cetera. And so -- and we've been very excited about the safety profile that's now been established for lumasiran, which has now been approved. So I think that's really the primary reason. So I think we're encouraged by that. We also know, for example, that patients with AGXT mutations, loss of function to have an increased risk of stones. That's common to PH1. And so we expect in any population that we study with recurrent renal stones there will be patients like that. So I think there's a number of reasons to feel good about taking lumasiran forward into that patient population.

So Pushkal, that's helpful. Thank you. Whilst we're with you, here's another one for you. What are Alnylam's thoughts about opting into the HBV program, the timing of that?

Yes. So the rights that we have at Alnylam, and obviously, we're working closely with our colleagues at Vir, who are leading the program at this point are to be able to opt-in prior to Phase III. And as I mentioned earlier, Vir is taking a very ambitious program forward in terms of developing HBV02, [ V122I A ] as a foundational therapy, looking at as a monotherapy but also in combination with an anti-HBV monoclonal antibody with other existing therapies to really develop a functional cure regimen for this really prevalent disease. So we'll be able to look at those data as they're emerging and opt-in prior to Phase III.

Excellent. Jumping about a little bit and going back to NASH here, Josh, this questioner wants to know, where are we with dosing in the Phase I study for ALN-HSD? And are we targeting data release next year? Can you give some updates on that, Josh?

Yes. Thank you. Well, we've been making steady progress through the healthy volunteer single ascending dose cohort phase of the study. And we anticipate having data to share in late 2021.

Super. And I presume there will be a medical meeting that will be appropriate for that, that we'll find, Josh, so. And going back to Pushkal. So in the case of gout and the XDH target, do we see our RNAi therapeutic being used as a monotherapy or on top of allopurinol? And what's the epidemiology around the number of patients that are on control, so to speak?

Yes. So I think as maybe a couple of things here. One is that while allopurinol is widely available, unfortunately, it's very challenging for physicians to prescribe and patients to tolerate it because it can cause GI disturbances, other problems for patients. And as a result, we know from epidemiologic data that even on patients who are prescribed allopurinol, fewer than 50% actually get to their uric acid targets, which we know to get under 6 mg per deciliter, which is necessary to control subsequent gout flares. So their at risk for ongoing gout flares, tophi, destruction of joints, et cetera. And so the opportunity with ALN-XDH is actually to target that same enzyme, but actually now use a very infrequently administered sRNA that's hepatic specific in terms of its signaling. So we expect it will be better tolerated, but also have variable and potent knockdown of that enzyme, and so that we can prevent gout flares and keep uric acid levels tonically lower and in the target range that's necessary to prevent gout flares. So initially, we will be bringing it forward as a monotherapy. But certainly, we expect that we will be looking at combinations during the development program, if that provides an advantage. We know from preclinical data that have already been published that hepatic-specific targeting of XDH should have sort of equivalent efficacy as systemic use of allopurinol or [indiscernible] or other enzymes targeting XDH systemically.

Great. Thank you, Pushkal. This questioner asked about KHK. So there are small molecules in development for KHK and the question is, how will RNI compete? Pushkal, Kevin, you guys want to tackle that? Pushkal?

Yes. I can start a little bit and then turn it over to Kevin. I think there have been -- there are small molecule inhibitors in development. I think, one, they've shown some initial proof-of-concept in terms of impacts on liver fat and insulin resistance, which is encouraging and gives us reason to believe. I think that said, I think we're very encouraged about the opportunity, one, to develop the molecule that targets KHK with our pharmacology. Again, this is -- these are going to be chronic diseases that need to be treated. And so using an sRNA that can be administered in an infrequent manner to provide durable control, potentially with a Q3 or 6 months or maybe even annual dosing would be something that would be a dramatic advantage and adherence in this complex metabolic disease. But there also may be some benefits to liver-specific silencing that maybe Kevin wants to speak about.

Yes. So I agree with everything you said, Pushkal. And we have been studying KHK with our collaborators at the Dassel diabetes and other centers. And there, we've -- KHK is expressed in the liver, but also in the kidney and the intestines. And we do know from earlier work that targeting some of those other tissues is not desirable. And we've done some head-to-head studies with compounds as a comparator of preclinical models and have seen a benefit of hitting just KHK in the liver alone. So we think that liver targeting with infrequent dosing in this type of a setting will be highly beneficial.

Yes. No, that's great. Thanks, Kevin. It also takes me back something Dr. Sanyal was talking about liver targeting in NASH and some of the drugs that are being developed in NASH, some of the side effect profiles result from wide by distribution of drugs and things like rashes and other things. Similarly without allopurinol, you get systemic side effects and ALN-XDH hopefully can help by focusing in the liver and substantially reducing urea without posing side effects. So great advantage around delivery technology. Speaking of delivery technology, Kevin, the next question is, can we speak more about our CNS ligands? Are they small molecules? And what's our thinking in trying to develop peripherally administered CNS-targeting products?

Yes. So thanks, Akshay. So we're not disclosing at this current time the ligands that we're using in the CNS for competitive reasons. But they do -- they are conjugates, and they do behave a lot like our GalNAc-conjugates in terms of their properties. In terms of going systemic, obviously, getting across the blood-brain barrier has been out there as sort of a holy grail, and we actively are working on it, along with others in the industry.

Yes. No, that's obviously an exciting frontier, and hopefully, we can crack that. I would also add, Kevin, that we have access to multiple ligands for the CNS and the eye, and we explore those. And we're very happy with the one that we've got, but we can always find newer iterations. So it's an exciting development. And I'm sure there'll be many new technology solutions to [indiscernible].

And I'd also add, Akshay, that given the very long duration that we're seeing in the CNS, while it's an intrathecal delivery, currently, we are anticipating that it will be biannual or potentially even annual, as you could see from our preclinical data in the primary out to 9 months or so.

Great. Thank you. Actually, this one is for you as well, Kevin. How can you show evidence of knockdown for intracellular deposits? I think the question only talk about APP and something...

APP. Yes. So I -- certainly, in preclinical models, right, where we have, including nonhuman primates where we have access to the tissue you use immunohistochemistry, and we can show that the intracellular as well as the extracellular portion is gone. And indeed, what -- if you think about what you're doing, you're turning off the production of the protein added source inside the cell. And so by its mechanism alone, you would anticipate that if you shut off the production of the protein, then both intracellular and extracellular will be gone.

Exactly. Next question is, what is the current status of fitusiran? I touched on it yesterday in my presentation, just to update everybody. As we know, Sanofi had announced a pause in the Phase III for fitusiran, which has been going very well. Two out of the 3 Phase III studies are fully enrolled. And just recently, they've announced that they intend to resume dosing and complete the program and then submit for NDA. So I think we're looking -- we're all looking forward to resumption to what is an exciting program and delivering, hopefully, a once-a-month subcutaneous therapeutic for hemophilia patients, which I think will really serve the space well, both in terms of hemophilia A and B inhibitors and non-inhibitor patients. Okay. So with that, we go back to lumasiran. Pushkal long question here. Can you frame up for us the regulatory hurdles and development path, something about the commercial opportunity and how OXLUMO could transition from rare to common disease? And then there's a second part, which we'll come to. But maybe start with the regulatory hurdles development path and how we transition from rare to common.

Yes. So I think, certainly, as we've talked about, this is renal stones, recurrent renal stones, very prevalent condition. But there's a tremendous unmet need. It's early to speak specifically about the regulatory path in any detail. But I think initially, we're going to be focused really on showing urate lowering or oxalate lowering, sorry, in patients with recurrent stones, which is a very prevalent population. So I think we can get through a Phase II relatively quickly and move into Phase III. In terms of going from rare to common disease, I think that's a well-trodden path for other molecules and in our own pipeline. We're doing that in TTR cardiomyopathy, where we're going from the hereditary population with neuropathy, with ONPATTRO and with somewhat vutrisiran and expanding into the wild-type CM population. So it's something that we will also have internal experience doing as we kind of advance our pipeline.

Indeed, indeed. And I think there are numerous opportunities, as you said. Another one, just as you were talking, came to mind is that, as Kevin was discussing with our APP program, for example, also dominant forms of Alzheimer's disease, which are rare, but still hundreds of thousands of patients around the world. And then, of course, from that, with success there, we could go into broader. There's the more idiopathic forms of Alzheimer's. So yes, lots of opportunities there. And I think there are pricing opportunities there. So with that, to the second part of the question, which we've addressed that in terms of the other opportunities within the pipeline. And Dr. Sanyal, do you think addressing an individual target will be sufficient for NASH? We haven't seen impressive clinical benefit. Will combination of multiple targets be required? So thoughts about going for individual targets versus multiple, Dr. Sanyal, in NASH?

Yes. I think in the end, if you look at the target population of greatest interest, that's the patient who has both active NASH and fairly significant fibrosis. Fibrosis stage 3, in my mind, is really the tipping point where you have enough fibrosis that you're really at risk of moving into cirrhosis and having clinical outcomes, but yet the disease is early enough that you can shift the needle. And in that setting, having something that has more of anti-fibrotic mechanism of action to put the brake on while you have a more upstream targeted therapy to anchor the long-term aspects of treatment would make a lot of sense. I have a feeling that in the end, the monotherapies are going to lead to combination therapeutics, very much like what happened in the HIV space, may not be the best analogy. But given the multitude of targets, it's not a simple disease with 1 linear pathway with 4 targets. There, you can approach the metabolic stress, cell stress, inflammation of fibrosis through old slew of targeting approaches. So I think the short answer is, I do believe that the future probably will be combination therapeutics. But one size will not fit all. I don't think in the end, you will have one1 treatment prescription for all patients with fatty liver disease. Depending on where you are in the course of the disease, you will have monotherapy or you will have combination therapies.

Yes. That's helpful, Dr. Sanyal. As you were discussing analogies, I thought about the limping space actually. And if we think of hypercholesterolemia, for many patients, statin alone is sufficient and serves them well. But then for many others, they need additional combinations on top of that, probably to do with the underlying predispositions and the mechanisms whether they need multiple drugs. But maybe that's an analogy, I don't know, but certainly with these genetically validated targets like HSD and PNP, maybe this hope that we can start as a monotherapy, and hopefully, that will translate. What do you think?

I completely agree. I think the advantage of the HSD and PNPLA3 as a target, is you can identify the population that might benefit very cleanly. And so I think for those populations, to start with monotherapy would make a lot of sense. And particularly if you target people who are not already cirrhotic, you might be able to just completely shut the tap off in that population. And then for people who are very advanced fibrosis, you may need a little -- it would be a very good partner in a combination for something which might have some anti-fibrotic effects as well. But PNPLA3 has direct anti-fibrotic, it's in the stellate cells. So it's not just in the hepatocytes. And at least in our recent work, the fibrosis can also occur from condition media from cells over expressing the mutant PNPLA3 can actually activate stellate cells as well. And so there may be more than one mechanism. But the PNPLA3 -- the nice thing about the PNPLA3 approach is it is hitting both the metabolic end, but may it also have some direct anti-fibrotic benefits as well.

Yes.

So it may have more pleiotropic mechanisms of action.

Thank you. Terrific. Just very quickly, what lung targets are we excited about? I don't think we're revealing the targets currently, Kevin, right? But I think I'd did reiterate that we have multiple targets in asthma, COPD, hepatic family fibrosis and the like. So there's lots of great work we can do that, which then dovetails with actually another question on targets, which someone has asked. Do you think that the number of opportunities is waning? It's a curious question. I don't think so. But Kevin, what are your thoughts about the number of genetically validated targets?

I think that over time as human genetics is only getting better and better, right? As you look at what's going on with the U.K. Biobank and some of the other efforts around the world in genetics, I think the genetically validated targets are the present as obviously evidenced by our pipeline, but also the future. And as we get to open, I think there are additional targets that are left in the liver that will treat disease in an effective manner. And in addition, as we open, I think there's another, what, 60 organs in the human body. And I think the beauty of RNAi is that, that mechanism is conserved throughout all of those organs and those cells. So I have 0 doubt that we'll have a huge number of opportunities. It's really how do you triage those opportunities is where we are now.

You said 0. I just want to confirm. Perhaps they...

They are not concerned.

And this questioner wants an update on ALN-COV, our SARS-CoV-2 program, an update on the time line. Quickly, we are completing additional [indiscernible] and dispose data available early next year. We hope to then accelerate into the clinic. We've been doing the CMC and toxicologic work in the background, but more updates to come early next year. Obviously, important that despite the vaccines, we continue to believe that therapeutics will be needed and will be important. Next question, Pushkal, what are the next steps for the XDH program in gout? And how big a program do you think you've been? What could time lines be like?

Yes. So the XDH program that we just announced today is a preclinical program. So it's a little early to be speaking about any specific time lines. We'll certainly give updates as we advance the program. But as we've talked about, this is a target that's both validated by genetics and validated by clinical proof-of-concept for established molecules. So I think there's a high probability of success there that we're optimistic about and an opportunity to make an impact. The other thing I'll say is that from a regulatory perspective target and the endpoint here is urate lowering at around 6 months based on established precedents. So I think this is actually a program in a very, very prevalent disease, more than 14 million, 15 million patients in the U.S. and EU. So I think we can actually enroll this study relatively quickly. It's a prevalent condition. It's a validated target, and the endpoint will be a 6-month target of urate lowering, we would expect. So we think it can move relatively quickly.

Thanks, Pushkal. Maybe we've got about 60, 90 seconds. Jeff, maybe one last question, then we can say goodbye to everybody. How do you think about pricing RNAi therapeutics from rare to common or RNAi therapeutics from common disease? Any thoughts, Jeff?

Yes. I mean this was a question that came up yesterday as we think about how things might transition as we expand the label and the treated opportunity in TTR. We're not ready to talk specifically about the specifics on pricing, but one framework that I think is worth pointing to is what we've done with our prevalence-based adjustment model in our VBA for GIVLAARI, where we've established a threshold for the number of patients on -- that may go on therapy based on prevalence. And if we exceed that, we start to offer incremental discounts. I think that sort of thinking and that framework as we would move from rare to more common is probably a good guideline.

All right. Great. Thank you for that input, Jeff. Thanks to the whole panel for your participation and to everybody that's called in yesterday and today. Thanks for your interest in Alnylam and our work across R&D. We look forward to speaking to you again soon. Until then, happy holidays. There will be a full video replay available online in Capella later today [indiscernible]. Bye-bye.