Good morning, everyone, and thank you for joining us for today's RNAi Roundtable, in which we'll be discussing several of our liver-directed RNAi therapeutic pipeline programs. I'm Joshua Brodsky, Senior Director of Investor Relations and Corporate Communications at Alnylam. I'm joined today by my colleagues, Eric Green, Senior Vice President of Development Programs, Tanya Fischer, Vice President of Clinical Development, and Joshua Friedman, Senior Director of Clinical Research. Today's RNAi Roundtable is part of a series of roundtable webinars that we're hosting this summer and fall to review progress across our various programs. Today's event is expected to run approximately one hour.
Eric will moderate a Q&A session at the conclusion of the presentations, and if you'd like to submit a question, you can do so at any time during the event by typing your question in the Ask a Question field, which is located to the top right of the slide window. 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. Now, before I hand it over to Eric, I'm excited to announce that Alnylam will be hosting its 2021 R&D Day on the morning of Friday, November 19, where we'll be reviewing progress across our pipeline of investigational RNAi therapeutics. This will be a virtual event.
More details will be provided in the coming weeks, but for now, please save the date for the morning of Friday, November 19th, for Alnylam's 2021 R&D Day. We hope you can join us. And so with that, I'll now hand it over to Eric Green.
Thank you, Josh. Hello, everyone. I am Eric Green, and as Josh mentioned, I'm SVP and Head of Development Programs here at Alnylam. Today, we have the pleasure of providing an overview of several of our liver-directed RNAi therapeutic programs. I'll start with a brief introduction to RNAi therapeutics generally and an overview of our pipeline before handing it over to Dr. Tanya Fischer and Joshua Friedman to present several of our programs. Throughout the presentations, please feel free to submit your questions by clicking the Ask a Question button. RNAi therapeutics are a new class of innovative medicines that have been clinically and now increasingly commercially established as an approach with transformational potential across a variety of different disease states. They are based on Nobel Prize-winning science with the ability to theoretically silence any gene in the genome.
Specifically designed and synthetically produced siRNAs form the basis for RNAi therapeutics, which, when introduced into the body, engage the endogenous RNAi machinery to specifically target and modulate the levels of proteins involved in human disease and do so in a reversible and dose-dependent manner. RNAi is a potent and durable mechanism of action and serves as the product engine for sustainable innovation for Alnylam. As noted a moment ago, RNAi therapeutics are now commercial medicines. Alnylam has achieved marketing authorization for three products in just over two years, starting with ONPATTRO in 2018, followed by GIVLAARI in 2019, and OXLUMO in late 2020. In addition, our partners at Novartis have gained approval in Europe and a few other countries for Leqvio, a product invented by Alnylam. Leqvio remains under review in the U.S. with a PDUFA date of January 1, 2022.
Here you can see a robust, organically built pipeline of commercial and development stage programs. You can see that we have focused in four strategic therapeutic areas: genetic medicines, cardiometabolic diseases, infectious diseases, and most recently added CNS and ocular diseases. Through our roundtable series over the summer and early fall, many of these programs have been discussed in greater detail. I would encourage you to visit the Capella portion of our website to review these prior roundtables if you're interested in learning more. Today, we will focus on several of our clinical programs in our liver-directed portfolio, namely ALN-HBV02, an investigational RNAi therapeutic for the treatment of hepatitis B virus, cemdisiran, an investigational agent for the treatment of complement-mediated diseases, and ALN-HSD, an investigational RNAi therapeutic for the treatment of NASH.
In addition to our robust portfolio of clinical stage development programs, we are also working on over 25 preclinical programs across four different tissues, expanding beyond our historical focus on liver-expressed proteins. We expect our research group will continue to be a source of sustainable innovation that will feed our development pipeline. We plan to deliver two to four INDs per year from our organic product engine over the next several years, with the potential to advance four or more INDs per year by the middle of the decade. As you can see, a large number of programs are part of our collaboration with Regeneron, but we do retain full rights to several liver-directed programs.
Again, today we will focus on our liver-directed portfolio of preclinical programs with a deep dive on ALN-XDH, an investigational RNAi therapeutic for the treatment of gout that we expect to enter the clinics in early 2022. ALN-KHK, an investigational program for the treatment of type 2 diabetes, and ALN-PNP, another investigational agent for the treatment of NASH, which is currently in the pre-IND stage. Based on the characteristics of our RNAi therapeutics, which include a clamped pharmacology that is generally durable for months, we see the potential to treat a large number of patients across a number of prevalent diseases.
This supports the evolution of our pipeline that starts in rare, genetically defined diseases that typically affect thousands of patients, including the three diseases that our approved products are indicated for, into specialty care diseases that may affect hundreds of thousands of patients, and into prevalent diseases that may affect millions or tens of millions of patients. You'll see that many of the programs we will discuss today fall in this latter category. With that overview as a backdrop, I will now provide a brief overview of ALN-HBV02 program in development for the treatment of chronic hepatitis B virus infection. This program is partnered with Vir and is also known as VIR-2218. I'll use the two product names interchangeably throughout the next few slides.
HBV is a significant global health problem impacting developed and developing countries with an estimated global prevalence of nearly 300 million people, primarily in Asia and Africa. ALN-HBV02 is an investigational, GalNAc-targeting RNAi therapeutic that allows for a single siRNA to suppress hepatitis B surface antigen from both integrated DNA and covalently closed circular DNA. The product utilizes our ESC+ technology that allows for targeted delivery to the liver and prolonged pharmacodynamic effect with a subcutaneous administration. Earlier this summer, Vir and their research partners presented data at EASL showing sustained antiviral activity of VIR-2218, that is ALN-HBV02, after two doses were given at day zero and one month later. The treatments were found to be generally well tolerated with no treatment discontinuations.
Greater than or equal to one log reduction in HB surface antigen were observed in both HBe antigen negative and HBe antigen positive participants across all dose levels and sustained in the higher dose cohorts. The data support continued development in combination regimens targeting a functional cure. Also at EASL this summer, Vir presented preliminary phase II study results with VIR-2218 used in combination with PEG interferon alpha. Administration of VIR-2218 both alone and in combination with the interferon were generally well tolerated. Preliminary antiviral data demonstrate that VIR-2218 alone and in combination with the PEG interferon alpha were associated with clinically meaningful HB surface antigen reductions greater than one log by week 12 of the treatment period. Additionally, they demonstrate that the combination of VIR-2218 and the PEG interferon alpha resulted in a more rapid and substantial surface antigen decline compared to VIR-2218 alone.
Vir and its partners, Gilead and Brii Biosciences, have built a robust clinical development plan that is exploring multiple combinations on what is potentially the best-in-class siRNA backbone VIR-2218. Importantly for Alnylam, we have a free 50/50 opt-in right prior to the start of the phase III studies, which potentially allows us to participate in this exciting program more directly. I'm now going to hand over to Tanya and Josh, both physicians at Alnylam, to discuss several of our clinical and preclinical liver-directed programs. First, Tanya will present on cemdisiran. Tanya.
Thank you, Eric. Hi, everyone. I'm Tanya Fischer, Vice President of Clinical Development. I'll start by describing our efforts advancing cemdisiran as an investigational therapeutic for the treatment of complement-mediated diseases. The complement system plays a major role in targeting the innate immune defense system and is primarily involved in antimicrobial defense, clearance of apoptotic cells and immune complexes, and finally, immune regulation. Insufficient control of complement activation is associated with excessive inflammation, tissue damage, and autoimmunity and underlies the pathophysiology of a variety of diseases. Inactivation of complement component 5, otherwise known as C5, and thus the generation of C5a and membrane attack complexes has shown great therapeutic benefit in complement-driven inflammatory diseases such as atypical hemolytic uremic syndrome, or aHUS, and paroxysmal nocturnal hemoglobinuria, or PNH. C5, which is predominantly expressed in liver cells, is a genetically and clinically validated target.
A subcutaneously administered RNAi therapeutic that silences C5 represents a novel approach to the treatment of complement-mediated diseases. Cemdisiran has been designed to reduce the level of C5 mRNA in the liver, thereby reducing levels of circulating C5 protein, inhibiting terminal complement activity, and preventing formation and deposition of the membrane attack complex on endothelial cells in the kidney. Furthermore, cemdisiran utilizes Alnylam's GalNAc conjugate technology, which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index. Cemdisiran has shown rapid and robust C5 suppression, up to 99%, maintained up to 13 months followed by a single dose in a healthy volunteer study, which indicates long residence times of cemdisiran within hepatocytes.
The long pharmacodynamic duration of action in liver and low immunogenicity and acceptable safety profile enables low, infrequent subcutaneous dosing and support further evaluation of cemdisiran in complement-mediated diseases utilizing a dual strategy, both as a monotherapy or in combination with a C5 inhibitor antibody. Alnylam is currently evaluating cemdisiran monotherapy for the potential treatment of IgA nephropathy, or IgAN for short, where it is thought that submaximal levels of complement inhibition may be sufficient to allow for clinical benefit to be seen. Furthermore, there is a potential opportunity to expand to other renal diseases involving complement. IgAN is the most common primary glomerulonephritis in the world. It affects younger adults, and approximately 30% of patients with IgAN develop end-stage kidney disease 20 years after renal biopsy. It is a glomerulonephritis with a very broad clinical presentation, making it difficult to stratify and treat.
IgAN is characterized by dysregulation of the immune system, which causes an abnormal synthesis of IgA1 that is deeply phosphorylated, causing its mesangial deposition and ultimately inflammation. Interestingly, it's estimated that approximately 6% of cases, there may be a family history or genetic predisposition for the disease. The spectrum of clinical manifestations in IgAN is wide, from incidental asymptomatic microscopic hematuria to kidney failure. However, the most common presentation in clinical settings is microhematuria and moderate proteinuria with relatively preserved kidney function. IgAN may have different clinical courses ranging from spontaneous remissions in a low number of individuals, which is rare, to rapid deterioration of renal function, also rare, to the slowly progressive deterioration of renal function over prolonged follow-up, probably the most frequent form of clinical presentation.
Macroscopic hematuria and proteinuria following an upper respiratory tract infection may be one of the typical forms of presentation, especially in children and early stages of diseases in adults. Currently, with the exception of RAS inhibitors in the U.S. and in Europe, no other disease-specific therapies are available in clinical settings for the treatment of IgAN, although the range of new drugs under investigation is extensive. An individualized approach is often used to balance the risk-benefit of the different therapeutic options, including the use of steroids and immunosuppressive drugs, which have variable results. We are currently conducting a phase II trial of cemdisiran in IgA nephropathy. This is a multi-center, double-blind, placebo-controlled study in approximately 30 patients. Following a run-in period during which patients' blood pressure, kidney function, degree of hematuria, and proteinuria are measured, patients receive either 600 milligrams of cemdisiran or placebo given subcutaneously every four weeks.
The primary endpoint is the change in proteinuria, which is assessed at 32 weeks, along with several other important secondary endpoints that are highlighted on this slide. Patients are then eligible to enroll into a three-year open-label extension period to further evaluate the long-term safety and clinical activity of cemdisiran. We are very pleased to announce that enrollment for this important trial has been completed, and we expect to have initial data readout in late 2021. We are also interested in evaluating cemdisiran in combination with an anti-C5 monoclonal antibody. We believe that for certain diseases, complete inhibition of C5 is necessary to achieve the desired level of efficacy. In collaboration with Regeneron, we are exploring cemdisiran in combination with investigational pozelimab for the potential treatment of two different complement-mediated diseases, myasthenia gravis and PNH. Alnylam has conducted a study with cemdisiran in healthy volunteers and in patients with PNH.
This phase I/II study was designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic properties of this investigational therapeutic. Three PNH patients were eculizumab treatment naive and received cemdisiran as a monotherapy during the treatment phase, and three were receiving eculizumab at study entry and continued to receive concomitant eculizumab with cemdisiran during the treatment phase. These data have enabled us to model what complement inhibition may look like with an antibody alone versus an antibody plus cemdisiran. As you can see here, the combination of an antibody plus cemdisiran lowers free C5 levels better than an antibody alone. This provides us with confidence that the combination of cemdisiran with an anti-C5 antibody will offer the potential for highly potent C5 inhibition, resulting in a convenient, less frequent dosing regimen. One of the diseases for which we are interested in utilizing a combination approach is PNH.
PNH is a rare acquired disorder, primarily in adults, in which hematopoietic stem cells and their cellular progeny have reduced or absent GPI-anchored proteins on the cell surface. Loss of the GPI-linked complement inhibitors CD55 and CD59 on red blood cells leads to chronic and/or paroxysmal intravascular hemolysis and a propensity for thrombosis, organ dysfunction, and hypocellular or dysplastic bone marrow. Typically, most patients fall in the age range of 30 to 40 years. Children can be affected by PNH as well, but it is uncommon. Most patients present with nonspecific and variable symptoms that include fatigue, general malaise, dyspnea, and renal insufficiency. But patients can also experience dysphagia, abdominal and back pain, and erectile dysfunction. Because signs and symptoms are so variable, it's often difficult to diagnose this condition, and hence diagnosis is often delayed.
Common complications of PNH include venous and arterial thrombosis, acute or chronic renal disease, and pulmonary hypertension. There remains an unmet medical need with respect to treatment. Patients on eculizumab can experience fatigue and breakthrough hemolysis on approved treatment doses due to insufficient complement inhibition. Moreover, the short half-life makes having a therapeutic with infrequent dosing desirable. Another disease in which we're interested in utilizing this combination approach is myasthenia gravis. Myasthenia gravis is the most common disorder of neuromuscular transmission. The hallmark of the disorder is weakness in ocular, bulbar, limb, and/or respiratory muscles due to immunologic attack directed at proteins in the postsynaptic membrane of the neuromuscular junction. Complement plays a role in the pathophysiology of the disease, as the recruitment of the membrane attack complex is a key mechanism of damage to the postsynaptic membrane.
Myasthenia gravis is a relatively uncommon disorder with a worldwide prevalence of 50-300 per million people. Treatment for myasthenia gravis can be placed into four main buckets: symptomatic therapy with cholinesterase inhibitors, immunosuppression, including monoclonal antibodies like eculizumab, plasmapheresis or IVIG, and lastly, surgical treatment, specifically thymectomy. Regeneron is currently leading development of the cemdisiran-pozelimab combination approach. This slide highlights the ongoing and the planned clinical trials evaluating this approach. You can see that there is a phase I study in normal healthy volunteers that's currently underway. There are two phase II studies in paroxysmal nocturnal hemoglobinuria or PNH. Lastly, there is a planned myasthenia phase III study with initiation planned for late 2021. I'd like to now hand things over to my colleague, Dr. Joshua Friedman. Josh?
Thank you, Tanya. Tanya mentioned I'm Josh Friedman.
I'm 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 non-alcoholic steatohepatitis, or NASH. NASH is the progressive form of non-alcoholic fatty liver disease, or NAFLD, and NAFLD is the hepatic manifestation of overnutrition, 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 for the United States, with almost 100 million Americans having NAFLD. One quarter of these will have NASH. NASH is defined microscopically with fat accumulation and lipid droplets. Those are the white areas in the images at the top left. Findings 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 on the left. 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 number one reason for liver transplantation within the next several 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 of the process, that is, at steatosis, inflammation and injury, and fibrosis.
In the rest of this presentation, I'll share two targets identified through genomics. The first is HSD17B13, or just HSD for short, and the second is PNPLA3, a second NASH target within our partnership with Regeneron, the suppression of which may interrupt NASH at the first stages of disease. The two targets were identified in an unbiased manner through genetic association. That is, not based on any prior knowledge of what cells they're expressed in and what their functions are within the cell. It's therefore remarkable 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, NASH, and liver fibrosis.
In contrast, for HSD, the genetics have revealed a loss-of-function variant with beneficial effects on NASH and fibrosis, which we propose to mimic with an RNAi therapeutic. The HSD protein is a member of the hydroxysteroid dehydrogenase enzyme family. Its endogenous substrates are unknown, but the levels of several phospholipids are changed in individuals lacking functional HSD. This may provide a clue to the mechanisms of protection from liver disease, and we expect to learn more from our clinical trials. Our therapeutic hypothesis is that siRNA-mediated knockdown of HSD will mimic the genetic loss of function, reducing hepatic inflammation, injury, and fibrosis in NASH patients. The molecule ALN-HSD is the result of a process that began with over 750 siRNA candidates that were winnowed down to ALN-HSD based on in vitro assays, mouse studies, and non-human primate assays.
As illustrated in the figure, NHP studies of ALN-HSD confirmed potent and durable knockdown of HSD mRNA and protein after a single dose. In addition, preclinical toxicology studies did not show any toxicology 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 in the start of phase I in 2020. We expect initial safety data from healthy volunteers later this year and anticipate the start of proof-of-concept trials in 2022. Let's take a closer look at the phase I study design and current status. 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 post-treatment liver biopsies to measure liver and mRNA protein knockdown, as well as several exploratory liver and circulating biomarker assays. I'm pleased to share that part A dosing is complete with no safety concerns limiting ascending dose progression or initiation of dosing of NASH patients in part B, which is now ongoing. We look forward to sharing results in future presentations. To summarize, we've reviewed non-alcoholic steatohepatitis, a subset of NAFLD that can lead to progressive fibrosis, cirrhosis, and hepatocellular carcinoma. There's a significant unmet need with no medical therapies currently approved. HSD is a novel target for the treatment of NASH, discovered on the basis of loss-of-function genetic variants in the human population. We've initiated a phase I trial of ALN-HSD in healthy volunteers and in NASH patients, with safety results expected late 2021 and the initiation of POC in 2022.
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, ALN-HSD molecule, and the program. I would like now to turn to PNPLA3, which also came to our 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 13 years ago, as shown on the left, and as shown on the right, the variant of the missense mutation changing a conserved isoleucine to methionine, and it leads to increased liver fat without affecting BMI or circulating triglycerides.
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 at the top left. How does this happen? The substitution results in resistance to proteasomal degradation, as shown in the bottom left. So the variant protein accumulates on hepatocyte lipid droplets. On the lipid droplets, the excess PNPLA3 competes for binding to the protein CGI58, a required cofactor 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 is tested in a mouse model of NASH, and as shown in the figure on the left, suppression of PNPLA3 reduces steatosis, inflammation, and fibrosis in mice expressing the human I148M variant.
It even has 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 in non-human primate liver, as shown in the bottom right. A development candidate has been selected, and the CTA/IND is expected to be filed in 2022. In summary, we've seen that the PNPLA3 I148 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. Development candidate selection for a PNPLA3 RNAi therapeutic is complete, 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 back to Tanya.
Thanks, Josh.
I'm now very excited to talk about ALN-XDH, a preclinical RNAi therapeutic we're developing for the treatment of gout, which we plan to advance toward the clinic later this year. Gout is the most common inflammatory arthritis globally, affecting 14-18 million people in the United States, EU-5, and Japan. It is caused by the deposition of monosodium urate crystals in patients with hyperuricemia and characterized by very painful recurrent acute attacks of arthritis. Typically, gout attacks cause painful and swollen joints. Recurrent gout attacks can lead to permanent joint damage and tophi deposition. The gold standard for diagnosing gout is the identification of MSU crystals in synovial fluid by polarized light microscopy. Standard treatment consists of anti-inflammatory drugs for gout attacks, sometimes followed by long-term preventative urate-lowering therapy.
We know that lowering urate is essential to controlling this disease, and it's in that context that we believe that an siRNA targeting hepatic xanthine dehydrogenase, or XDH for short, may offer potent urate-lowering and disease control. XDH represents a clinically validated target, as it's the target for two approved therapies for gout, allopurinol and febuxostat. But since these drugs may be associated with hypersensitivity reactions, there's great interest in the development of novel XDH inhibitors for long-term use with fewer or no adverse side effects. An important question is whether hepatic silencing alone using a liver-directed siRNA will be effective. The preclinical data on the right side of this slide 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%. These data are therefore quite encouraging about the potential for a liver-directed RNAi therapeutic targeting XDH to reduce uric acid levels and potentially gout flares. Recent NHP data with ALN-XDH, shown here for the very first time, have demonstrated promising results, supporting the potential for a new gout treatment that would have infrequent dosing. Single doses of ALN-XDH were administered at three different dose levels in monkeys. More than 90% of liver XDH protein silencing was achieved, with a maximum average of approximately 85% silencing at day 29. Encouragingly, suppression was maintained up to day 56. Based on allometric principles, we believe we may see extended XDH suppression in humans greater than 90 days. Hence, this non-clinical pharmacodynamic profile supports quarterly and potentially biannual dosing in humans.
There remains a tremendous amount of unmet medical need in gout. While existing therapies for gout are effective, they also have limitations primarily due to safety and tolerability concerns. As a result, the majority of patients cannot adhere to prescribed therapies and do not reach target uric acid levels. Therefore, ALN-XDH may address this unmet medical need for gout patients with potent urate-lowering efforts, infrequent dosing with tonic control between doses, acceptable safety and tolerability, which we believe is likely based on our experience with the GalNAc conjugate platform, and reduction in gout flares. Alnylam is planning on filing the CTA for ALN-XDH in late 2021, with a phase I-II trial initiation in early 2022. Thank you. And now I'll turn things back over to Josh.
Thanks again, Tanya. I'd like to talk about ketohexokinase, or KHK, as a target for type 2 diabetes.
Like NASH, type 2 diabetes is linked to overnutrition and the metabolic syndrome. One dietary component specifically linked to metabolic syndrome and its complications is fructose, which is delivered either as a monosaccharide or as half of the disaccharide sucrose. Epidemiologic studies have established that fructose intake is associated with insulin resistance, obesity, and hypertension. The mechanisms of fructose effects are more complex than simply the calories represented by fructose and are mediated by several factors. As shown on the bottom right, fructose metabolites activate the transcription factors ChREBP and SREBP, which in turn activate gene expression pathways promoting glucose production, lipogenesis, adiposity, and insulin resistance. We can understand this even better if we take a closer look at fructose metabolism. Glucose metabolism is shown on the right, fructose on the left.
A key difference between them is that glucose metabolism is subject to negative feedback regulation at early enzymatic steps, and that prevents excess flow through the pathway. In contrast, there's no such control for fructose metabolism, the first step of which is catalyzed by ketohexokinase. In fact, ketohexokinase is induced by fructose in a positive feedback loop. This all means that excess fructose supply is converted to metabolites in an uncontrolled manner, and it is those metabolites that drive the insulin resistance, lipogenesis, and other aspects of metabolic syndrome. This has been demonstrated in mice, in which RNAi-mediated knockdown of KHK on a high-fat, high-fructose, or high-glucose diet reduces total weight, liver weight, and liver fat.
Based on this and other data, we hypothesize that an RNAi therapeutic targeting KHK will address large medical needs among type 2 diabetics, 25% of whom fail to achieve target hemoglobin A1c on current therapies by improving insulin sensitivity and reducing hepatic steatosis. We anticipate acceptable safety based on the overall safety of our platform and on human genetics. There are rare individuals lacking functional KHK, and the only known consequence is fructosuria, or fructose in the urine. Selection of the development candidate is ongoing, with final selection expected in early 2022. I'll now hand it back to Eric to moderate the Q&A session.
Thank you, Josh. Thank you, Tanya.
As you can see from our previous presentations, we feel we have several additional programs in our liver-directed portfolio that could potentially address areas of high unmet need and will allow us to continue to organically build our development pipeline upon the efforts of our internal research group. The selection of diseases exemplifies our strategy to continue to explore the utility of RNAi therapeutics in more prevalent diseases, including NASH, gout, and HBV infection, where potentially millions of patients could be treated. This focus is enabled by the platform's safety demonstrated across four commercial programs and the product profiles that demonstrate the potential for tonic control of target genes with infrequent dosing. The continued reliance on genetically validated targets, we expect, an increased probability of success for our programs compared to general industry benchmarks. So that concludes our presentation, and we'll now be taking questions from the audience.
As a reminder, please submit your questions by clicking on the Ask a Question button located above the slideshow on the webcast player. For that, we'll go for our first question, actually back up to the top of the program almost, Tanya. Questions on cemdisiran. I think you mentioned this a little bit in your presentation, but why do you believe that approximately 97% complement inhibition will be sufficient in IgA, whereas we did not see that being sufficient in PNH?
That's a really good question, Eric. Let me start by saying that preclinical data suggests a strong role for complement in IgA. There have been case reports of efficacy with eculizumab, as well as encouraging data from the small phase II-A trial of avacopan, a C5a receptor blocker.
Now, cemdisiran was effective in a rat model of membranous nephropathy, another related inflammatory renal disorder. So that gives us confidence that the complement system is important in the IgA disease pathology. Now, RBCs in PNH are particularly vulnerable to even small amounts of complement, as the RBCs are anucleated, and they lack complement regulatory proteins such as CD55 and CD59. In contrast, the podocytes and the mesangial cells that are the targets of complement in IgA are nucleated, and they have intact complement regulatory protein. So as such, submaximal complement inhibition may be sufficient in IgA, where it's not sufficient in other diseases.
That's great. Very helpful. Thank you, Tanya. Josh, maybe moving down to the NASH programs. Exciting to see two different targets being identified. Focusing on ALN-HSD for a moment on the phase I trial. What are you looking for to get out of that study?
The phase I trial, the primary objective is safety and tolerability assessment, with PD measures as secondary objectives. The HSD protein doesn't circulate in the blood, so we don't have direct target engagement data in the healthy volunteers. But in the patient portion, we're obtaining liver biopsy, which will enable us to measure HSD mRNA and protein knockdown and confirm that those occur on ALN-HSD. We'll share more on that as the program progresses. Ultimately, what happens in the liver in the NASH patients in phase I will be of great importance, both biochemically as well as histologically.
Okay. That's helpful to remind. Obviously, the phase I's the first in humans, so we're just learning a little bit here as we go.
On the slide you had presented a few minutes ago, though, you did have a box that said that we'd have some safety data in the healthy volunteers portion of the study by year-end. Can you give us a little bit more color about that?
We expect to have the full safety data on the healthy volunteers and some partial safety data in the NASH patients by the end of the year, with ongoing data going forward.
Okay. And then, obviously, people, I'm sure, will be interested in any potential efficacy signals or data that we'll be generating in that phase I data. And again, on the slide, I think it mentioned some of that potential efficacy data in 2022. Again, a little bit of color on that and what we're looking for, that would be very helpful.
Yeah, that's a great question.
In the ongoing phase I, NASH patients are being enrolled into multiple cohorts in part B, receiving different doses of ALN-HSD. Those patients will have liver biopsy at baseline and after treatment to assess knockdown of the mRNA and the protein, as well as NASH histology scoring. Depending on the baseline LFT characteristics, we may be able to look for changes in liver transaminases following treatment with ALN-HSD. Those data are expected in 2022.
Okay. That's great. Thank you, Josh. Bouncing back to cemdisiran. Tanya, obviously, extremely impressive knockdown. Pharmacodynamic effect with cemdisiran is seen as a monotherapy. So there's a question that come in. Why do we think the combination with a mAb may be appropriate?
Well, like I was saying in the presentation and in my earlier comments, I think for certain diseases, monotherapy may be the way to go because we don't need complete complement inhibition. However, there are certain diseases, PNH and potentially myasthenia being another one of them, where complete complement suppression is necessary. And this is where we think that combining an siRNA with a monoclonal antibody will allow for better success in those diseases.
Yeah. Excellent. We of course look forward to seeing the data, but there's definitely some great potential there. Okay. Question came in on XDH and gout. So from that presentation, Tanya, you mentioned that those NHP data are new. Maybe you can refresh us again. What are we concluding from that study?
The data is super, super exciting.
These data demonstrated that more than 90% XDH silencing was seen following a single subcutaneous dose, which was maintained through eight weeks. Again, based on allometric principles and our extensive prior body of evidence going from NHPs into humans, we do expect extended XDH silencing in humans that would potentially support quarterly or even biannual dosing in humans.
With that type of a profile, how do you think you would position ALN-XDH versus the existing therapies that are out there? Is that more of a refractory setting, or would you plan to capture those patients who are already on allopurinol but not responding well, for instance?
The current standard of care for urate-lowering therapies are xanthine oxidase inhibitors, like allopurinol and febuxostat. But they're associated with a number of shortcomings, such as poor medication adherence, tolerability, and renal impairment and cardiovascular safety risks.
So we anticipate that ALN-XDH will provide benefits over the current standard of care oral agents on these aspects. And it may also offer add-on efficacy on top of the oral xanthine oxidase inhibitor agents.
And I think that's where the benefits of our platform generally, infrequent dose, subcutaneous with a long effect that's quite durable up to months. Exactly. Potentially could be a nice complement. That'd be exciting to watch.
No pun intended.
Never. Josh, back to you, actually, on the PNP program. So now we've identified this second target for the potential treatment of NASH. What do you think about pursuing a combination of both of our products, ALN-HSD and ALN-PNP?
Yeah, that is an appealing option, particularly in light of the fact that genetically we know that there's greater risk reduction from the protective HSD variant in patients who also have the PNPLA3 risk variant.
We definitely plan to consider this further as the PNPLA3 therapeutic RNAi program moves forward.
Related to that, moving forward, what are the next steps for ALN-PNP that we're able to share?
We expect to file an IND CTA for ALN-PNP in 2022.
Okay. Great. Tanya, back on complement-mediated diseases more broadly, it was noted that on one of our preclinical pipeline slides, we do have a program named ALN-CC3. Are we still developing a product targeting C3?
Yes, we are. This is a program in our preclinical pipeline. We're evaluating the opportunity in a broad range of inflammatory disorders in which complement C3 is involved, things like autoimmune anemias, kidney disease, autoimmune skin blistering disorders, autoimmune myopathies, autoimmune neuropathies, etc.
What we're going to do is we're going to determine the appropriate manner in which to advance this asset relative to other programs in our portfolio.
Okay. Very helpful. Josh, actually, a question on KHK for you. Would your approach be different from small molecule KHK inhibitors that are also in development right now? Josh, we can't hear you. Maybe you went on mute?
Yeah, here I am. We do think our program is different. For one thing, it's liver-specific silencing. And of course, as with our platform, it has the potential for durable and tonic control of KHK over time with infrequent administration. So altogether, we think that offers a potential for a highly differentiated therapy.
That'll be interesting to watch, and we'll definitely see. One question came in on the HBV program. We had mentioned that you have the opt-in right prior to phase III.
So what are you going to be looking for to make that decision?
The key unmet need in HBV really is for a functional cure. And that really is the development objective for the program that VIR is leading. So we've been very encouraged by the data to date, and we're encouraged that VIR is evaluating a variety of regimens, almost all of them with VIR-2218 or ALN-HBV02 as that foundational therapy with the aim of achieving a functional cure.
So as the data continue to emerge from the various clinical studies, and you notice there are a number of them, both led by Vir as well as by Vir's partners, Gilead and Brii Biosciences, we'll be taking a look at that efficacy data as well as all the emerging safety and tolerability and have the great opportunity to make a decision to potentially participate in that very exciting global health program.
Looking online. Okay. Looks like there's maybe one more question coming in. Josh, this might be for you. Yep. For our HSD program, how would you compare that to ARO-HSD program? And do you feel that we have or they have freedom to operate, given our IP position?
Yeah. Well, ALN-HSD, it's based on our most advanced siRNA design, known as ESC+ GalNAc siRNA technology.
We've shown that it provides better specificity and an improved therapeutic index relative to our ESC chemistry. The favorable translation in humans has been demonstrated for ALN-AAT02 and ALN-HBV02. While we don't know the sequences of the ARO-HSD siRNA, their phase I study is also similar to ours, and that includes NASH patients and liver biopsy to measure target suppression. I would add that Alnylam and Regeneron have filed IP that provides strong patent protection for the HSD target, the ALN-HSD molecule, and the program going forward.
Thank you, Josh. It looks like that is the last questions coming in from the audience. I think with that, I'll turn it back over to Josh Brodsky.
All right. Thank you, Eric. Thank you, Tanya and Josh. That does it for today's RNAi Roundtable.
As always, you can access the replay of the webinar and download the slides on the Capella section of Alnylam's website. And once it's available, we'll plan to post the transcript there as well. We do have one more remaining roundtable in the series, and that will be on Friday, October 1st at 1:30 P.M. Eastern Time. And it will focus on our CNS and extrahepatic delivery efforts. And just another reminder that we'll be hosting a virtual R&D Day on the morning of Friday, November 19th. We hope you can join us for both of these events. All right. Thanks, everyone, and have a great day.