Dicerna Pharmaceuticals, Inc.
Q2 2020 Earnings Call Transcript

Published: 10 Aug 2020

Operator:

Good morning, everyone and welcome to Dicerna 2020 Virtual R&D Day. As you know we also issued a press release this morning detailing our Financial Results for the Second Quarter ended June 30 2020, which can be found under the Investors and Media tab on our website at dicerna.com. During this morning's presentation, we will be reviewing data results from our ongoing studies of RG6346 in collaborative development with Roche for hepatitis B, and nedosiran for the treatment of primary hyperoxaluria. We are also excited to share with you the initial preclinical data from our RNAi technology and extrahepatic tissue including the CNS, muscle and adipose tissues. I'd like to remind listeners as noted in today's presentation that management may be making forward-looking statements on today's call, including, for example, the clinical development, therapeutic or potential of nedosiran or RG6346 and the development programs, research and development plans and timelines, the potential for Dicerna to continue to add programs and extend the reach of our technology to additional tissues in our internal discovery research and in collaborative programs. Expectations related to our collaborations with Novo Nordisk, Roche, Lilly, Alexion, Boehringer Ingelheim and Alnylam and the potential for future collaborations. We may make forward-looking statements regarding Dicerna's financial position, expectations about current or future clinical data and timelines for collaboration funding, expenses or cash usage. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the risk factors and section of Dicerna's latest Forms 10-Q and 10-K filed with the SEC. We may elect to update these forward-looking statements on the future. We specifically disclaim any obligation to do so if our views change. I'd like to take a moment now to introduce you to our speakers for today. We have with us Dicerna's President and Chief Executive Officer, Doug Fambrough, who will introduce our corporate vision and strategy; and our Chief Scientific Officer, Bob Brown, who will discuss both our novel S-antigen targeting approach in HBV and review hepatic data. Our guest speaker for today, Dr. Yuen, who will present our Phase 1 data for RG6346. We also have Dr. Bernd Hoppe, Dicerna's Vice President of Global Medical Affairs with us to discuss the current treatment paradigm and unmet need for PH and Ralph Rosskamp, our Chief Medical Officer who will present interim data for our ongoing PHYOX 3 open label extension study of nedosiran. Additionally, we have with us Rob Ciappenelli, our Chief Commercial, who will discuss ongoing preparations related to the potential approval and launch of nedosiran. Now, I'd like to turn the call over to Douglas M. Fambrough. Doug?
Doug Fambrough:

Thank you, Lauren. Next slide, please. Dicerna's vision is to maximize the impact of RNAi on medicine. This is a broad vision and it's justified both by Dicerna's success to-date and by the successes in the RNAi field in general. To us, what maximize the impact of RNAi on medicine means, is to capitalize on as many as possible of the opportunities to meet unmet medical need, that we can address with RNAi. And that includes, taking RNAi technology beyond the liver where we've had great success and enabling its delivery throughout the body to maximize the number of opportunities to which we can apply it. Very broad vision and being a smaller company, we're not going to be able to capitalize on all these opportunities on our own. And so we have developed a strategy we're executing against, where we very carefully consider which programs we will take forward as Dicerna. There must be high probability of success programs meeting unmet medical need. And for each program we choose as a core, high probability of success internal program, it is our intent and strategy to gain commercial rights in the United States, and which may be in collaboration with a partner depending on the magnitude of the opportunity. There are, of course, far more opportunities that we will not be able to take forward on our own. So, to complement our internal core pipeline, we are collaborating with therapeutic area experts in an attempt to enable as many as possible of the new opportunities enabled by RNAi to be pursued by people who can take those programs through commercial realization. I should add then in doing so, it has been an extremely lucrative business opportunity for Dicerna. Next slide, please. This vision for RNAi is possible, because RNAi has come of age. It is no longer coming of age, it is come of age, there are multiple approved products. There are multiple candidates and registration and pivotal development, including from those nedosiran program for the treatment of all forms of primary hyperoxaluria. There are large established population studies showing the potential safety and tolerability of RNAi and showing an acceptable profile, and there are at this point, many multiple committed pharmaceutical companies and I'm very pleased that many of them are Dicerna's partners in RNAi. This success rests on a foundation of success in the liver. But today, RNAi technologies are exploring the vast opportunities outside the liver. Next slide, please. We believe that Dicerna is uniquely positioned to succeed in bringing RNAi beyond the liver. And we believe that's due to our proprietary structure which differs in detail from other structures that companies in the RNAi field are pursuing. You'll see this generic representation of our GalXC platform or RNAi platform here, two strands of RNA, one we've denoted in orange that's so called, guide strand. It is complementary to the mRNA were seeking to silence and it is retained by the silencing complex within the cells. The blue strand, so called passenger strand can be thought of like a carrier, and uniquely for Dicerna's platform, you can see that that blue strand extends well beyond the orange strand, folds back on itself, creating a drug molecule area where Dicerna can pursue medicinal chemistry to optimize the delivery and pharmaceutical properties of our molecules. Medicinal chemistry is constrained in the region around the guide strand due to the need to interact with the silencing complex. But in this extended region, Dicerna has a free hand to alter chemistry in multiple and diverse ways without impacting RNAi activity, and thus more freedom to change the molecules to drive delivery. We have been working on this technology for outside the liver for some time and observers will note that our collaboration with Lilly, which we signed in Q4 of 2018, involved our delivery technology for the Central Nervous System. Today, we'll be presenting subcutaneous delivery to muscle and adipose tissue, and also liver all at the same time. This does not represent the full spread of our extrahepatic activity. We have multiple additional tissues under development as well. Importantly, in delivering to muscle and adipose and liver tissue, we are going beyond cell type specificity, using our medicinal chemistry flexibility to create more general solutions to RNAi delivery to expand the opportunities that RNAi can apply to. Now, let me shift to our core pipeline, next slide. This pipeline, as I mentioned, carefully selected as high probability of success programs for Dicerna covers nedosiran for all types of primary hyperoxaluria currently in pivotal studies and we will present data from our multidose PHYOX 3 open-label study today. It includes RG6346 for the treatment of chronic hepatitis B virus and today we will present Phase 1 data associated program that program is partnered with Roche, although Dicerna retains the right to opt into co-fund pivotal development and with that gain certain US co-promotion rights. We will not be talking about the third program, DCR-A1AT or ALN-AAT02 today, that is for the treatment of AAT liver disease and involves a collaboration between Dicerna and Alnylam to choose the best candidate to take forward, where Dicerna's 100% US commercial rights nor will we be talking about the fourth program which will enter clinical development next year and which is fully owned by Dicerna. Next slide, please. Across our core pipeline, we believe we have created best-in-class opportunities. This is the result of very careful work within Dicerna's lab, exploring both disease mechanisms and thinking about clinical development strategies and primary hyperoxaluria, believe we have the potential for a best-in-class product with the most comprehensive target profile seeking to address all forms of PH, and we believe, potentially be the best therapeutic for PH type 1 and I believe the data will be presenting today bears that out. And hepatitis B virus, Dicerna's, again, fundamental disease research identified an X-sparing approach that predicts that we should have an extended duration of action that we believe can lead to the best treatment, most convenient and longest duration of effect and potentially more effective than non-X-sparing strategies. And again, the data we will present today, I believe bears this out. For alpha-1 antitrypsin liver disease, let me just note here that the collaboration between Alnylam and Dicerna is designed such that the best program will be taken forward for the treatment of this disease. Then class theme extends to our technology because we believe the extended structures that we use for RNAi and the medicinal chemistry flexibility afforded by the extended structure means we are best-in-class for modifying RNAi molecules for delivery to other tissues to go beyond the cell type specific paradigm. GalXC is just for hepatocytes to the more general solutions that deliver RNAi to multiple tissues. Now, let me turn to our collaboration pipeline. Next slide, please. With our five collaborations with Boehringer Ingelheim, Alexion, Lilly, Roche and Novo Nordisk, we have more than 15 programs at various stages of early development, including four programs for which a clinical candidate has been defined, agreed with the partner and move forward in pre-clinical studies. The most advanced of these programs, one of our Lilly programs, with the intraclinical development in the hands of Lily later this year. Next slide, please. As I mentioned, this has been a very lucrative partnering process for Dicerna. In fact, our strong balance sheet that we enjoy today is largely attributable to the upfront payments that we have received as part of these collaborations and to a lesser extent, the equity that was included in some of these collaborations. I would extend the best-in-class moniker to our operation strategy as well, both our execution and structure for the first two collaborations with Boehringer Ingelheim and Alexion, those involved partner options to bring more targets into the collaboration, under both those options have been fully exercised by our partners. For our two most recent collaborations with Roche and Novo Nordisk, they have an important business feature, where Dicerna can opt in to development of clinical stages. I've mentioned this for Roche already when RG6346 is advanced to pivotal trials, Dicerna has the option to co-fund pivotal development for enhanced economics and certain co-promotion rights in the United States. For Novo Nordisk, where all the programs start at Discovery stage, Dicerna has opt in rights to two programs once they have already produced clinical data to opt into co-development and co-promotion. This is, well, I don't know if it's unique, but it's certainly a rare type of term and I'm not familiar with another deal that has a collaboration that has this potentially high risk targets that we could not define as high probability of clinical success, may astir early clinical data have proof of concept that makes them much higher probability of success and occurs, Dicerna can opt in and begin to deploy our resources and have the co-promotion and enhanced economics associated with those and those programs we had at that point become part of our core pipeline. I think this is a really important term that builds for the future of Dicerna and I look forward to programs from the Novo collaboration going into the clinic. Now with that, let's get to today's main event. Next slide, please. We're going to start by talking about our RG6346 program for the treatment of chronic hepatitis B virus. And we'll start by reviewing our X-sparing hypothesis. Bob D. Brown, our Chief Scientific Officer and EVP of R&D will do this presentation. Next slide, please. But before I switch to Bob, let me just remind people that chronic HBV is an extremely widespread infection. Estimates vary depending on the source, but all agree, a vast number, a quarter of a billion or more people chronically infected with HBV, causing nearly a million deaths per year. Current treatments are rarely effective and Dicerna is collaborating with Roche on the development of RG6346. The picture on the right was taken through an electron microscope and involves the sample from the blood of a patient. Everything you see in this picture is HBV. White dots and white oblong features, however, are so called aviral or decoy particles. The slightly larger and darker concentric circle features are infectious virus. One of the nefarious qualities of HBV is that, these numerous decoy particles prevent the immune system from clearing the infection. And I think this photograph makes the point that if we're going to have an effective therapy for HBV, we need to click these immunotolerizing particles. Since they are made of S-antigen, that's what's establishes S-antigen as the key biological parameter to impact for an HBV treatment by RNAi. We have developed our X-sparing hypothesis to maximize the depth of suppression and duration of suppression of S-antigen. Bob, you take it from here.
Bob Brown:

Thank you, Doug. Before Dr. Yuen discusses our current clinical results, I'd like to remind everyone of the molecular biology underpinnings of our X-Sparing hypothesis generated by Dicerna Researchers as we developed RG6346 targeting HBV. On this slide, you see four colored arrows and named on the far left, for the major protein products encoded in HBV genome. The light grey outer circle and arcs represent the messenger RNAs transcribed from the virus and you can see how some of them are polycistron overlapping. These overlapping mRNA regions represent an opportunity to target more than one transcript at the same time if appropriate sequences are selected. We focused our sequence search of the most highly conserved regions among all HBV clinical isolates, shown here by the outermost red lines marked Conserved S and Conserved X regions. You can see the target site of RG6346 in the Conserved S-antigen region on the right. As the researchers characterize various preclinical mouse models of chronic HBV and began comparing the in vivo efficacy of different GalXC compounds, they noted a surprising result, targeting S-antigen alone at the monotherapy resulted in a deeper and longer reduction of circulating S-antigen in the mice than either combination therapy targeting S and X together or monotherapy against X alone. One example of this in vivo result is shown in the following slide. This slide shows the greater absolute reduction and longer duration of reduction of circulating S-antigen in an HBV plasmid Hydrodynamic Injection model of chronic HBV. We believe the molecular mechanisms of long-term HBV gene expression in this model are more representative of chronic HBV than other preclinical models currently available, because the viral gene expression itself is dependent on the function of the viral proteins themselves, and is limited only terms. You can see the log scale of circulating S-antigen on the Y axis in three-weekly doses of GalXC test article on the X axis, targeting the S Region alone yielded a deeper and far longer reduction of circulating S-antigen in mice than when S and X are targeted together in a combination therapy approach. S-antigen reduction was too long, it's greater at week 11 for S monotherapy than for the S and X combo therapy. This is reproducible with both different sequences targeting the S and X regions and when X region is targeted alone. A molecular explanation for the faster S-antigen expression rebound observe whenever the X region is targeted which is shown on the next slide. HBV X protein has been described as a rheostat, controlling the balance between infectious viral particle replication and high level production of S-antigen to make decoys as shown in the left panel. The effects of X on HBV gene expression are mediated via the X protein modifications of core protein function. When X is present, this is, when it is not targeted by RNAi, the polymerization of core and viral particle formation in hepatocytes cytoplasm on the far left are favored when X protein is absent, such as when it is targeted with RNA, core protein enters the nucleus of the hepatocytes and interacts with HBV C DNA to drive a high level of S-antigen expression and a viral decoy particle production as shown on the right. It's the high level of S-antigen decoy particles in blood it gives rise to the immune exhaustion observed in chronic HBV patients in which we're trying to overcome. Direct detection of the intracellular location of core protein in HDI mouse liver sections as shown on the right, when the mice are treated with vehicle alone, you can see the light brown staining in the top micrograph shows the core protein in both cytoplasm and nuclei. When S and X are targeted simultaneously, the core protein and nuclei was increased, and thus it was available to drive high levels of S-antigen production. The opposite most desirable result is shown in the bottom panel, where S was targeted alone and core protein was observed only in the cytoplasm. We hypothesized that targeting the S region with RG6346 might lead to a deeper and longer lasting reduction in S-antigen production because of the combined effects of direct RNAi destruction of S encoding RNAs and reduced transcription of S encoding RNA because of a lack of core protein in cell nuclei. We're proud to have partnered late-stage clinical development of RG6346 with Roche. Now, I would like to welcome Dr. Yuen for his presentation of Phase 1 data obtained with RG6346.
Man-Fung Yuen:

Hello, greetings from Hong Kong. I'm going to talk about the preliminary datas of the study of our RG6346 for hepatitis B infection. I'm Man-Fung Yuen from the University of Hong Kong, my main research area is on natural history and treatment of hepatitis B disease. Over the recent year, I have been deeply involved in running trials of novel agents for chronic hepatitis B infection. Next slide, please. This is my disclosure. Next slide, please. Before going into the details of the study of RG6346, let me emphasize again, the importance of treating chronic hepatitis B infection. While we are now seeing decline in mortality due to other chronic infections, including tuberculosis, HIV and malaria, the mortality of hepatitis B is still rising. Putting it in a more recent context, mortality from HBV related disease each year is in fact higher than the worldwide mortality from COVID-19. Next slide, please. Although nucleotide analogue therapy is able to induce virologic biochemical and histological responses and even reduce the risk of cirrhosis and liver cancer, development through long-term treatment or the regional guidelines are now advancing our goal further to loss of surface antigen that is functional cure, which is seldomly achievable by the nucleotide analogue therapy. Achieving functional cure is associated with a further reduction of risk of cirrhosis and liver cancer. Furthermore, patients may take off the therapy which is otherwise supposed to be a lifelong therapy. Next slide, please. Now, let me introduce this as our RNA program by Dicerna. There are three groups in this study, Group One, Group A, which was a single-ascending-dose in 30 healthy volunteers and it has been completed. Group B, again, single-dose, but in naïve treatment, chronic Hepatitis B patients given at a fixed dose, as those dosage are 3 milligram per kilo. They all have been dosed, but the study is still ongoing because of the follow-up period has not been reached. Please note that this was a very special, because as our RNA trials seldomly got a treatment naive patients and this may allow us to see whether there is any special thing happening in this type of patients. Group C is a multiple-dose cohort with ascending-dosage from 1.5 to 6 milligram per kilo given for weekly for four doses. Enrolment was completed in the last cohort and dosing are still ongoing. After completion of period, study subjects with greater than one log reduction of surface antigen are followed in a conditional follow-up period. Next slide, please. The demographics are well balanced between different subgroups. As expected, majority of patients recruited are Asian. We also have a good ratio of E positive versus E negative patients. Main surface antigen levels around 3 to 4 logs IU per ml and cohort B patients who will treat - treatment naïve have higher DNA levels and ALT levels as expected. In my subsequent talk, I will mainly concentrate to report the findings of cohort C, that is multiple-dose cohort. Next slide, please. We find that RG6346 had a profound global reduction of surface antigen across 3 dosing groups. At day 112, that is around four weeks after the last dose, there was 1.4 log reduction of surface antigen in 1.5 milligram group, 1.8 log reduction for both 3 and 6 milligram groups. More importantly, this profound suppression on surface antigen maintained up to day 336, that is about 8 months our last dose in 1.5 milligram groups - dosing group, while we are eagerly expecting an even better result would happen in the 3 milligram and 6 milligram dose cohorts. We had a longest treated patients which receiving a lower dose 1.5 milligram per kilo, who had a very satisfactory reduction of surface antigen by 2.2 log, even up to day 392 - that is around more than 10 months after the last dose. Six out of 10 groups C patients had the surface antigen level below 100 IU per ml at the last reported visit. Next slide, please. This waterfall plots show through the maximum reduction of surface antigen in individual patients treated with different doses denoted with different colors. Placebo denoted with orange color. For patients receiving RG6346 80% had more than 1.5 log reduction and this potent efficacious effect occurs in both E positive and E negative patients. Next slide, please. This graph shows you the HBV-DNA profile of individuals in the cohort C, that is patients who's on NUC therapy before joining the trial. All except one patient has very low level of or undetectable HBV-DNA at baseline. This E positive patients was on entecavir for few years, but still had HBV-DNA level of around 600 IU per ml and he was a very compliant patient. After started with the RG6346 HBV-DNA dropped very nicely, indicating the potent HBV-DNA suppressive effect of this agent on patients who still have residual HBV-DNA levels on nucleoside analogue therapy. Next slide, please. The graph on the left shows the gradual reduction of Covid antigen across the three multiple dosing groups, while the white shows the same pattern for antigen. More data will extrapolate the lines upon subsequent follow-up during the study. Next slide, please. We have three treatment naive patients in Group B, receiving single-dose RG6346 had early on treatment transient serum ALT elevation possibly related to the enhanced host immune response. To show you one example, the graph on the left showed dramatic reductions of all HBV markers, starting from day 29 after the single-dose. In particular, the surface antigen and the DNA reductions were more than 2.5 logs. ALT levels started to rise from day 29 and peaked at day 55 as shown on the right graph, while the liver synthetic function including [INO] [ph] was overall normal. Next slide, please. So this ALT elevation following the dramatic reduction of surface antigen and DNA suggest host with immune restoration. Next slide, please. The phenomenon of ALT flares following surface antigen reduction was also seen NUC suppressed patients in cohort C. This patient had more than 2 logs reduction of surface antigen as illustrated in the left upper graph. At the same time, we saw a small blip of ALT as denoted by the red lines in the right graph. Again, no changes in albumin and bilirubin were observed. It seems that ALT responses may be more blunted in NUC's suppressed patients [indiscernible] were already suppressed. Next slide, please. RG6346 was fine to be safe and well tolerated at all doses either evaluated. There were no serious adverse events associated with RG6346 observed as of June 25th, one healthy volunteer on placebo experienced SAE, which was obviously not related to study medication. There were no dose-limiting toxicity nor safety-related discontinuations. There were also no dose dependent increase in frequency or severity of other parameters, including AEs, laboratory tests, ECG and vital signs. In all patients with ALT flares, liver synthetic and excretory functions were preserved. No cases of simultaneous elevation of ALT within greater than 3 times of level of normal and bilirubin greater than 2 times upper level of normal were observed. The most commonly reported AEs were injection site reaction in which, although mild, except one patient had two moderate reactions. Next slide, please. You can see the injection site reactions were not related to the dosage levels and most of these reactions were mild and self-resolving. Next slide, please. So, patients treated with RG6346 and concomitant nucleoside analogue therapy at meaningful and sustained reductions in surface antigen for all dose levels at the end of treatment period. 80% of subjects on active treatment greater than 1.5 log reduction in surface antigen. In the 3 milligram per kilogram and 6 milligram per kilogram cohorts, the mean surface antigen reduction was greater than 1.4 [sic - 1.8] log reductions at day 112. The greatest maximum reduction we saw was around a 2.7 log IU per ml. First dosed patients in the ongoing study has reached day 392 with 2.2 log in surface antigen. Several patients treated with RG6346 exhibit self-resolving ALT elevations with overall preserved liver function suggesting ALT flares potentially as a result of the treatment-induced enhanced immune responses. No differences in surface antigen reductions were noted between E positive and E negative patients. RG6346 was well tolerated and the study is still ongoing. We have two out of four patients treated with the high dose. 6 milligram per kilogram have not reached to day 112. So with that, I would like to thank for your kind attention.
Doug Fambrough:

Thank you, Dr. Yuen and thank you for agreeing to stay on the line and take questions which we'll get to in just a moment. We're very encouraged at Dicerna at the Phase 1 data so far, believe this data confirms our X-sparing hypothesis and its potential for a best-in-class therapy. Our innovative and thoughtful development strategy including Group B, we believe has shown additional insights into the activity of RG6346. And particularly, our extended follow-up has been able to show the long duration of effect as predicted from the X-sparing hypothesis. As Yuen indicated, this trial is ongoing. There are two patients in the 6 milligram per kilogram cohort that are still receiving doses, and the data will continue to evolve, we will present full data through the treatment period in the fall. We are optimistic based on the initial trajectory of the remaining two patients that we may see a further decline in the mean reduction at day 112 in the 6 milligram per kilogram cohort, but of course, we await the actual data which we'll present in the fall. We're also encouraged that we saw ALT elevations consistent with the induction of an enhanced immune response, so called flares. And as I mentioned at the outset, the goal of therapy and the reduction of S-antigen is to enable the immune system to recover and start responding to the virus. And so it was a great interest to us to see potential evidence of a respiration of immune function in patients treated even with a single-dose of RG6346, particularly naive patients who of course represent the vast majority of a chronic lean infected individuals worldwide. I remind people that under - that Dicerna will not be initiating the Phase 2 that will be done by our partner, Roche. And we look forward to giving updates as Roche proceeds with development. Next slide. Before taking questions, I want to thank our investigators and site teams and our partners, in particular, thanks to the participants in the trial and their family and caregivers. I also want to thank the many members of the Dicerna team who directly contributed to the work associated with RG6346. And with that, let's enter the Q-and-A session which we will conduct for 10 minutes before moving on to nedosiran multidose data. Before moving to that data, we have a presentation on the unmet medical need and the treatment paradigm for primary hyperoxaluria from Dr. Bernd Hoppe. Those who follow the PH field will of course know that Dr. Bernd Hoppe has for many years been a global key opinion leader in the primary hyperoxaluria field. And we were very pleased some time ago when Dr. Hoppe joined the Dicerna team as a Vice President and Global Head Medical Affairs to be part of driving to potentially curative therapy in terms of oxalate levels for primary hyperoxaluria. Dr. Hoppe retains his roles as Head of the German Hyperoxaluria Center and as a Professor of Pediatrics at the University of Cologne in addition to his role at Dicerna. Dr. Hoppe?
Bernd Hoppe:

Yeah, thank you, Doug. Next slide, please. The primary hyperoxaluria are a family of ultra rare, hepatic oxalate all leading to endogenous oxalate overproduction, which may finally lead way to a high morbidity and a high mortality. Specific deficiencies of mostly liver specific enzymes are found in all three types of PH leading way to the glyoxylate accumulation, and the overproduction of oxalate via hepatic LDH. Oxalate an end product of human metabolism then eliminate the kidneys then induces severe hyperoxaluria and based on that recurrent kidney stone and or progressive nephrocalcinosis. This on the chronic inflammatory process induced by the oxalate [indiscernible] will lead to chronic kidney damage over time. Next slide, please. The current prevalence numbers for all types are extremely low, with PH 1 being the most prevalent currently so this is depicted in our registered data. Looking at genomic data, however, they are actually prevalence for all types that dramatically higher which is especially true for type 3 PH. That means, in the US, roughly 80% of patients are not yet diagnosed. Next slide, please. Kidney stones are a hallmark of all types of PH. Nearly every patient has experienced stone in most of them massively recurrent kidney stones over time. This is especially the case for PH 2 patients in essence in early childhood. Before installment of treatment stones look like whitish, light whitish stone or pale yellow microscopically we find loose aggregations of different-sized crystals. Stones are very frequently big in size. Next slide, please. A single stone in the child or recurrent stones in adult should be going through diagnostic evaluation. However, they are the warning signs like a positive family history, recurrent urinary tract infections, chronic kidney disease with unknown etiology or an infantile patient failure to thrive early end-stage renal disease or systemic oxalosis like retinal deposits. This is in a special finding in the infantile of primary hyperoxaluria type 1, but also sudden end-stage renal disease or systemic oxalosis are to mention here. When kidney function and therefore urinary oxalate excretion declined, plasma mean blood oxylate levels are increasing. This leads to difficult saturation of the blocks and to systemic oxalosis deposition, which I will show you on the later slide. Next slide, please. PH often has an early onset of the disease, but the disease is very heterogeneous even within families and therefore symptoms can vary in time and kidney function may be different. As you can see here, there's a huge gap between early onset of disease in median age of diagnosis. Only in PH 3 may be triggered by the fact that the primary symptoms developed early in life, the non-patient are typically diagnosed, but as mentioned earlier, there's in the diagnosis. Kidney function may decline early, especially in PH 1 and more than half of the patients are already an end-stage renal disease at age 40 years. Since new report became available on PH type 2, we now know at about 25% of patients are experienced end-stage renal disease in the course of this disease. Numbers of PH Type 3 patients in registry just small and only one patient so far reported with end-stage here. Next slide, please. Coming back to systemic oxalate deposition in patients with declining kidney function. As said, chronic oxalate in youth inflammation leads to chronic kidney disease in PH patients. With elevated blood oxalate levels, this will be deposited in all other organs, especially in bone, where it leads to bone pain, continuous fractures or treatment resistant anemia or the eyes, the skin, the heart and in any other you will find oxalate deposition also in the Central Nervous System. Next slide, please. Multiple studies show that the earlier the diagnosis is made, the better the outcome, but numbers show a different reality. 42% of patients with PH experience a significant delay in diagnosis. 27% of patients are only diagnosed in end-stage renal disease and about 5% of patients on after isolated kidney transplantation have failed. Current treatment options do not really stop those progression and put some burden on the patient. Next slide, please. Aggressive hyperhydration is mandatory for all PH patients. 2 to 3 liters or more than one meter square body surface area per day is necessary, which is a huge amount of the glasses per day. And those patients being unable to get along a gastrostomy tube is placed. Vitamin B6, which is a cofactor of the defected hepatic enzyme in PH 1 helps to reduce endogenous oxalate production in a subgroup of patients. However, a lot of pills need to be swallowed per day. This is also the case in simpler medication, which inhibits calcium oxalate crystallization. Here medication has been administered three to five or four times daily. Dietary records have to be observed also, which can be problematic in childhood. Recurrent kidney stone excreting stone removing procedures necessary, which is especially problematic in infancy and childhood and may roughly way to decline in kidney function. And interstitial disease no renal replacement therapy is capable of eliminating an equal amount of oxalate where plasma oxalate is rising over time and systemic oxalosis gets worse. Next, slide please. PH then to another systemic disorder. So, early transportation is therefore necessary for which combined or sequential liver kidney transplantation is the recommended procedure in PH 1, but isolated kidney transplantation in PH Type 2, some PH Type 2 patients may however, also needed combined transplantation. So let me conclude. The primary hyperoxaluria presented high mortality morbidity. Current treatment option of scars and new treatment measures are clearly needed as adequate and early diagnosis. In this regard I may now hand over to my colleague, Ralf Rosskamp, the Chief Medical Officer of Dicerna, who will present information about nedosiran treatment and the primary hyperoxaluria. Ralf?
Ralph Rosskamp:

Thank you very much, Bernd. Can I have the first slide, please? As thought of applying the hallmark of the family of the HBV is the overproduction of urinary oxalate. And the common final step in the production of oxalate is the conversion of glyoxalate to oxalate through the LDHA enzyme. A reduction of glyoxalate in PH can also be achieved by blocking the GO enzyme, which of course will only be simple in PH 1. Dicerna shows the best-in-class approach by blocking LDHA and thus in theory can address not only type one, but the whole family of PH diseases. Next slide, please. After choosing a knockout target, one of the first thing our scientists do is to see whether there is a human equivalent with a knockout of that target. This is of course, the worst case scenario as we predominantly knock down the target in the liver. And indeed, there were 14 cases in the literature where congenital knockdown of LDHA have been described. The pathophysiological consequences of this total knockout are limited to the muscle and skin with missioning of liver abnormalities or clinical pictures thereof. Exertional myopathy after strenuous exercise has been described as the dominant symptoms in some patients. And that's why is part of our clinical monitoring plan we are measuring the muscle enzyme CPK. There have been some assumptions made that this type, this clear human biology experiment, ever since in the lactate pyruvate metabolism might be involved with an LDHA knockdown in the liver. We started this very carefully in preclinical studies, where we put the mice on track now, and we measure plasma lactate and pyruvate concentration and we did not see any differences. Also in our Phase 1 PHYOX1 study in healthy volunteers, where patients receive single-doses up to 12 milligram per kilogram of nedosiran, we did not show any changes in plasma lactate and pyruvate concentrations over placebo. We therefore continue to monitor for any skeletal muscular symptoms with our approach. But don't think there's any reason to believe that other organs like the liver might be involved. Switching to our PHYOX1 data. Next slide, please. You most likely have seen some of these data already from our single-dose proof of concept study in 15 patients with PH 1 and 3 patients with PH 2. After the single-dose, patients were followed up initially after they reach 80% of their baseline value, and only then could enroll into the long-term PHYOX3 study. As is many months for patients to reach to that point, this criterion was later dropped. Substantial reduction starting after six weeks and remaining in the low range for urinary oxalate were seen in this study and as you can see on this figure, until then slowly going up. There was a dose dependent effect on the percentage of patients reaching normally near normalization which we defined for normalization as the upper limit of normal of our SA, which is 0.46, and for near normal of 1.3 times upper limit of normal a value of 0.6. This is a more stringent definition than other responders use. And the two highest - those groups, we saw in PH 1, nearly everybody reach a near normalization, whereas in the PH 2 patients, we saw 2 out of 3 reaching this level. Based on these data, we have chosen the quarterly regimen. But as you can see on the next slide, we chose a more simple and convenient monthly regimen, which protects patients from sudden oxalate spikes once they are off their supportive therapy. We use the PK, PD data from our PHYOX1 study to stimulate what would happen with different dose regimens in a multidose study. And our modeling showed that the highest percentage of patients reaching normal urinary oxalate levels occurred with monthly dosing. We also compare this dosing regimen to a regimen with nedosiran using a loading dose and these results were not as good as the results of the monthly dosing regimen. We believe that a monthly dosing of patients at home with prefilled syringes for adults and adolescents is a simple and convenient regimen. It's easy to remember, it may lead to better adherence and it facilitates an establishment of a routine and provides consistent protection. And last but not least, very important, a missed dose is unlikely to lead to sudden spike in urinary oxalate. When patients in our protocols and we believe also, once the drug is available, commercially, reach normal urinary oxalate concentrations there isn't the need any of the support of therapy of hyperhydration and potassium citrate, and they can be weaned off these therapies. At that time, they are really vulnerable to a sudden increase in urinary oxalate which may lead to renal failure within days. You can see in this urine sample on the left, a concentrated urine in a patient with primary hyperoxaluria which can occur to a patient of calcium oxalate crystals within hours and days when the appropriate hyperhydration therapy is not continued. Now, moving on to the PHYOX3 design and the results. PHYOX3 is a three-year open-label extension study for all patients from single-dose and multidose studies with PH 1, PH 2 and PH 3. The primary endpoint of this study is the effect on the estimated glomerular filtration rate. We're also measuring effects on new stone formation and nephrocalcinosis, safety and tolerability, and, of course, we continue to measure the Uox level. In this study, we use a once monthly dosing regimen, which is a fixed-dose regimen in patients 12 years and older. For those weighing less than 50 kilogram, they receive a dose of 170 milligram, which would be 1 mL injection and if patients weighing less than 50 kilogram, the dose will be 136 milligram which is an 0.8 milliliter injection. We will have a weight-based dosing in patients 11 years and younger. Moving on to the demographics of the PHYOX3 study. And the data we want to show today with respect to the urinary oxalate concentrations are data from 11 patients who rolled over from the PHYOX1 study and have reached day 120. So they have received five doses of nedosiran. These were mostly young adults with mildly impaired renal function, although two patients had an eGFR between 30 and 45, which is CKD PH 3 B moderately to severely impaired. 8 patients with PH 1 and 3 PH 2. The average time from diagnosis was 18 years. The baseline, the urinary oxalate baseline in different participants was 0.93 millimolar per 24 hour, baseline corrected with the body surface area corrected, which was 30% lower than their PHYOX1 baseline of 1.32. As already mentioned, one could get into the 301 study when you had at least 20% of the 101 baseline, but this criterion was later removed to which was enrolled into 301. These participants were patiently waiting and collecting urines on two occasions a month. And the reason why they joined the PHYOX1 study was to get a multidose regimen. So therefore, we let them into the PHYOX3 study earlier than what the initial protocol allowed. We therefore believe that the true baseline of these patients is indeed their value of 101 which was the mean of 2 screening 24 hour urine. The next slide show the absolute reduction of urinary oxalate in this group of participants. Substantial reductions after the first dose were observed with reaching normalization levels of normalization near normalization at months two already. At day 120, the baseline, the body surface area corrected, mean value for all patients was 0.524 millimolar for 24 hour. Next slide shows the percentage reductions. This is a similar picture as before, highest reduction occurring after the first dose, but further reductions with subsequent doses. At day 120, the mean reduction value for all patients was 54.3% at day 120. The next slide shows the levels of normalization and near normalization of urinary oxalate reached in the study. I think I already explained that our normalization and near normalization levels are more stringent than from other sponsors. And when you look at the overall number of patients reaching normalization or near normalization, it's 9 out of 11. So, overall 82% reached the clinically important levels of normalization and near normalization already at day 120. The results for the 3 PH 2 patients were not impressive as for PH 1, but we have only 3 patients and we look forward for further data points in the study and from the PHYOX2 study as well. We always say PHYOX3 can serve as a proxy what we think will happen in PHYOX2, but there are differences between this two study as explained on the next slide. I think I mentioned most of the characteristics of PHYOX3 already and I won't spend a lot of time here. Want to just point out the Uox completeness criteria were initially in 3. We only had guidance to the patients and could not repeat the 24 hour urines which we could do in the PHYOX2 trial. This now has changed and it has been more consistent with the PHYOX2 data. The next slide shows you the safety assessments. Overall, we believe that we have demonstrated a favorable risk benefit profile, of nedosiran in the study. The observed adverse events were mostly related to subcutaneous injection. Drug related injection-site reactions were seen in 3 out of 16 patients. There were 2 patients it is for ALT elevations less than 2.5 upper limit normal, which the investigator assessed as possibly related. Both at baseline had already an elevation of 1.7 upper limit in normal and in one case was associated with Gilbert's syndrome, a liver disease known with transient ALT and bilirubin increases. The other patients' ALT has been normalized despite ongoing drug treatment. We had one CS event of nephrolithiasis and we have seen no other clinically significant laboratory abnormalities, ECG findings and vital signs. Next slide shows you an overview of our clinical program. We talked already about our PHYOX3 study, 2 is our double-blind, placebo-controlled, randomized trial, which is currently enrolling in PH 1 and PH 2 patients. We are expecting this quarter to start enrolling in our PHYOX4 study in PH 3 patients in support for our label claim for PH 3. We expect to start enrolling in the fourth quarter a multidose trial missions, first to adults with PH 1 and PH 2 with end-stage renal disease and our patients on dialysis. And by the beginning of next year, we plan to enroll in our early pediatric study in patient zero to five with relatively intact renal function. Following discussion with the FDA on PH 3 to support the label claim of PH 3 indication, we will initiate this month a natural history study in PH 3 patients to evaluate the association between urinary oxalate and stone formation rate. This piece of information is currently missing and we want to provide with this, including patients from two years onwards to show that the degree of hyperoxaluria is actually associated with the number of new stone events. My next slide summarizes. PHYOX3 day 121 results have been in line with expectations from single-dose PHYOX1 study. Already a high percentage of patients reach normalization near normalization at day 120. High Uox percentage reduction despite low baseline. The average Uox for PH 1 participant at day 120 was already in the normal range, 0.404 with an upper limit of normal of 0.46. 5 patients of the total 16, which have been treated as PHYOX1 rollovers have reached normal urinary oxalate concentrations on at least three consecutive visits, and are therefore eligible for gradual fluid reduction, which has started in some of those patients already. Monthly nedosiran administration appears safe and well tolerated. Low rate of injection-site reductions and in the healthy volunteers, we haven't seen any evidence of changes to blood lactate and pyruvate levels. We expect in a comprehensive label, including all ages in patients with relatively intact renal function at the time of launch. The nedosiran fixed dose monthly dosing regimen for 12 years and above is simple and we'll avoid oxalate spikes. Actually, the states we received our modeling and simulation report, and we will use in the children aged 6 to 11 years old, a monthly dosing regimen of 3.5 milligram per kilogram. We have agreement with the FDA on a path of full approval for PH 1 and PH 2 and we hope that same data set of showing a link between hyperoxaluria a new stone formation will be provided by our natural history study to satisfy the FDA requirements. Safety data from patients with severe renal impairment will be included with the NDA. And we currently have 6 compassionate-use cases in young patients undergoing hemodialysis. Last but not least, I want to thank, next slide, all our investigators and site teams for screening, enrolling patients. I want to thank the patient groups, the patients, especially Oxalosis and Hyperoxaluria Foundation and OxalEurope for their invaluable support. And of course, I want to thank team for making this data possible. Thanks, everybody. And, with this, I'll hand over to our Chief Commercial Officer, Rob Ciappenelli.
Rob Ciappenelli:

Thank you, Ralph. Next, I'll be highlighting the key milestones to launch a new strategy to support nedosiran's potential best-in-class profile. Next slide, please. Dr. Hoppe reviewed the burden of PH in the protracted patient diagnosis. Similar to other ultra rare diseases, PH is under recognized and under diagnosed. Estimated diagnosis rates are highly variable by subtype and our current estimates are as follows. Around 40% to 50% for PH 1 patients less than 10%, though on the other hand for PH 2 and PH 3 patients. In many ways, the PH marker reminds me of other rare diseases, with no viable treatments, with no available treatments. This creates a paradox where there's typically less resources available to support healthcare professionals and patients. To change this, the PH marker will require more education, support to patients and care providers and testing, both urinary oxalate testing and genetic testing, plus the potential of available therapies like nedosiran, which is of course the PH disease, allowing PH patients the opportunity to find a little more normal life. Nedosiran with its comprehensive target profile will be the first PH drug for all PH patients with convenient monthly dosing that many patients will choose to self-administer. With appropriate resources deployed and nedosiran's target profile to support known PH types. Globally, Dicerna is estimating peak sales of over $500 million. To support the development and commercialization of nedosiran, Dicerna is building in a measured fashion, the talent and infrastructure to become a fully integrated biopharma company. Now let's look at some of those key milestones. Next slide, please. As we look at the next couple of years, and some of the nedosiran's key milestones. The upper half of this slide summarizes the extensive PHYOX development program that Ralph just described. And each trials estimated report of trial results. Based on the pacing of our PHYOX studies Dicerna is targeting filing in a phased approach with the US Q3 '21 NDA submission. These - then filing in Europe, and then Japan with subsequent potential approvals in 2022. Additionally, our teams are transforming Dicerna into a fully integrated biopharma company as they build out again in a measured manner, the talent and departments to support the nedosiran's commission plan. Ralph has established an extraordinary medical team. My team is coming together nicely. And our leadership team is building the related infrastructure in an integrated manner for a launch readiness. Now let's look at some of the highlights to our business strategy in a little more detail. Next slide, please. Our commercialization plan has two primary aspects, the US and outside the US. In the US, we're building a comprehensive strategy to drive nedosiran's potential best-in-class profile. Outside the US, we have been in active discussions with multinational and regional biopharma organizations, who have the local market expertise to launch a compelling drug like nedosiran into those rare disease markets. As you can appreciate with a likely competitive marketplace, we are generating propriety insights that drive our strategy. That said, our organization has built a world class team with extensive rare disease product launch experience. And all the components of our strategic product plan are in place. They are being challenged. We're refining them under the premise of launching a potential best-in-class, fast follower product into the PH marketplace. And our plans, it all comes a patient, their journey, and the interactions with healthcare professionals. Those insights continue to deepen. Two important meetings that I'd like to highlight are on the left side of the slide, the FDA Voice of the Patient, which will be led by the OHF on October 5th. Voice of the Patient meetings are very important and critical opportunities to really understand what is going on with the patient, but with the care providers who are supporting those patients. Additionally, we'll be able to understand how they're dealing with the burden of disease, and the high level of oxalate. That meeting will cover not only PH 1 patient, the PH 2 and PH 3 patients, and we look forward to seeing the report from that program in fourth quarter. Additionally, another important patient meeting that we're again listening to the Voice of all PH Patients, PH 1, 2 and 3 patients will be the European Primary Hyperoxaluria Patient Advocacy Meeting on September 19th. Those insights drive our strategies. Those insights will help us take nedosiran and its potential profile into the marketplace. To summarize, through the potential best-in-class profile of nedosiran, Dicerna is driven to maximize the impact of this RNA medicine to alter the course of PH disease. Beyond PH, we will leverage our scalable commercialization engine to drive the growing Dicerna portfolio. Now, I'll pass it back to Doug.
Doug Fambrough:

Thank you, Rob. I think we are indeed setting the stage for commercial success with nedosiran and I'm extremely pleased with the data today from the PHYOX3 multidose trial. That data is driven by our mechanism, silencing LDHA, the ultimate step in oxalate production and our comprehensive development plan should we hope allow for a label for all patients with PH type 1, type 2 and type 3, all states of renal health and all ages. We're using format, as Ralph described, that is simple, once monthly with self-administration available for patients 12 and older, that we believe is the most convenient and potentially the most effective treatment regimen, particularly in the context of a missed dose, which frankly is not unlikely in lifetime chronic therapy. And I'm extremely pleased with our data in PH 1, the oxalate levels we've achieved in PH 1 patients on average more than 10% below the upper level of normal. I'm pleased with our performance in PH 2, a disease for which there is no other therapy using RNAi in development, and the type of data we are achieving including normalization and one of our PH 2 patients, we believe will provide a tremendous advance over current disease treatment. We look forward to presenting data in PH 3 from additional PHYOX studies later in the year. As I just went over the data, I believe we have an extremely competitive product profile, both in PH 1 and for the other forms of PH. And importantly, as Dr. Hoppe described, the goal is normalization, normalization allows patients to wean off the burdensome hyperhydration and based on other aspects of disease management. We've had 5 patients in PHYOX3 achieved normalization in three consecutive visits, which allows them to begin the process of weaning off hyperhydration and disease management. That's 5 of the 17, the 16 rollovers from PHYOX1 plus one sibling, who was not included in the interim analysis. Commercial preparations as Rob described, underway. It is a fit to purpose rare disease commercial organization that we're building under Rob's experienced rare disease leadership. We are targeting an NDA filing in third quarter of next year and we expect to complete enrollment of the PHYOX2 pivotal trial in the fourth quarter this year. And with that, I'd like to switch to the third section of today's presentation. Going beyond GalXC, our liberal targeted approach to try and extend RNAi delivery to extrahepatic tissues and to cover that I'd like to invite back to the podium, Bob D. Brown, our Chief Scientific Officer, and Executive Vice President and the Leader of our technology development efforts in RNAi. Bob?
Bob Brown:

Thanks again, Doug. The GalXC RNAi platform shown on the next slide, that forms the basis of our hepatocyte programs is shown as a flattened nucleic acid duplex, formed by an antisense strand in orange, and a sense strand in purple. The GalNAc sugars interact with a solid glycoprotein receptor on the surface of hepatocytes are shown as four diamonds on the right. This fundamental nucleic acid structure provides a robust foundation to expand our applications of RNAi beyond the liver, and to enable mechanisms of action beyond RNAi, both are opening up new targets and clinical indications for Dicerna's future development programs. We're using our R&D experience and knowledge of medicinal chemistry of the fundamental building blocks of nucleic acids and higher order structures of nucleic acids to modify our basic GalXC platform to enhance the intrinsic drug like properties of the nucleic acids themselves, and to create new platforms. We're optimizing the nucleic acid to reduce the intrinsic dose to biodistribution, tissue penetration and intracellular delivery and other important therapeutic properties. By enhancing these characteristics of nucleic acids, we've identified extrahepatic applications we're targeting more of these are not an absolute requirement for effective knockdown of therapeutic target mRNAs. Some of the in vivo data obtained today with these new platforms suggests that they have the potential to enhance function of chemically simple and low molecular weight targeting and delivery moieties when they're needed to achieve maximum therapeutic utility. We're identifying high potency sequences and generating hits against therapeutic gene targets, using new platforms in non-liver tissues, such as the Central Nervous System, muscle, fat and other tissues we can't disclose today. Some of the results obtained with our new proprietary platforms are shown in the slides, starting with the CNS on the next slide. For many RNAi applications deliver can be considered as a monolithic block of blood perfused hepatocytes, where GalNAc is an extremely efficient targeting solution for all target cells present in the organ. Extrahepatic delivery is a more complex challenged than delivery to the liver, at the compartment, organ and cellular levels. Slide shows one facet of our strategy to optimize new platforms for therapy against targets in the Central Nervous System. We've used genes expressed exclusively in the major cell types of the CNS including neurons, astrocytes and oligodendrocytes. To identify nucleic acid features that enhance delivery to each of these individual cell types, versus those that enhance delivery to 2 or all 3 simultaneously. The graph shows a dose response of Target mRNA platform targets expressed in these three cell types after a single intrathecal administration of test article. An example of the data obtained in the structure activity relationship survey in the CNS mice that shown in the next slide. These busy graphs show different nucleic acid constructs from C to M across the X axis. And the Y axis shows the target messenger RNA knockdown at 1 week and 4 weeks after a single 300 microgram dose administered IT in mice. Note the first bullet point. Each of these modified RNA payloads contained the same constant antisense strand, while the sense strand was varied by chemistry, secondary structure or both. This is an example of a structure activity relationship study that took advantage of the intrinsic property of our established GalXC to treat the sense strand as a carrier or delivery vehicle for the active RNA guide strand. On the left, you can see the relatively constant degree of target knockdown that this SAR series yielded across different constructs, again, C through M. Where the different passenger modifications yielded significant improvements in target knockdown as shown on the right or changes to the passenger strand alone reveals significant changes in the duration of action. Some compounds in the series such as H, L and M showed no loss of RNAi activity of one month after the single-dose, demonstrating a long duration of action in the CNS and the ability to differentiate passenger function. Our SAR studies are conducted with an eye towards future applications. So initial markers of tolerability such as CD68 and other inflammatory markers are often measured. Another variable to be addressed in the CNS applications is the route of administration as shown in the next slide. In this study a 1 milligram dose of test article was administered to rats in either a lumbar intrathecal injection or an intracisternal magnet injection. The injection locations are shown in blue and orange next to the rat silhouette on the right. So this is a direct comparison of a single test article administered either at the bottom of the spinal column versus the spinal column. In the graph on the left, you can see remarkably consistent target mRNA reduction was obtained throughout the brain from the frontal cortex to the brain stem by both rats of administration. Target knockdown only began to separate when measured lower in the Central Nervous System and the Peripheral Nervous System as shown in the lumbar spinal cord in the lower dorsal root ganglia at the far right of the graph. This is where our lumbar administration did yield increase target. These results show efficient knockdown of a therapeutic target messenger RNA from the front to the back of the brain that was independent of the route of the administration, even when the doses administered as a site as distal as a lumbar region. The test article exposure versus route administration in this study is visualized and quantitative in the next slide. At the top of the ICM injections, results are shown in the middle, in the brain and on the bottom and the spinal cord and the IT injections in the brain and spinal cord are shown on the far right. The pink color visible in those whole tissue sections of brain and spinal cord relative to the artificial cerebrospinal fluid control injections on the far left is a direct detection by in situ hybridization of the RNAi payloads. We saw the target knockdown in this region and indeed we can simply visually detect the test article present in it. It's quantitated on the right, where from the frontal cortex to the brain stem and the lower spinal cord and the dorsal root ganglia, you can see that again by each route administration is detected by PCR, there's a relatively constant degree of tissue exposure through the brain by either route of administration. Next slide, please. A novel payloads can also achieve a remarkably same association of action in vivo as shown in this rat study. A single 1 milligram per kilogram dose was administered on day zero, and you can see the depth of target mRNA knockdown measured on day 28. The key takeaways from this data set are the duration of target knockdown can be, one, independent of the initial magnitude of target knockdown and sustained with little to no target messenger RNA recovery out to at least day 160. Now we'll see small amount of data obtained in non-human primates. This study shows therapeutic target reductions in non-human primates from the pre-frontal cortex to the brain stem on the left, and from the top to the bottom of the spinal cord after a single modest ICM dose of 45 milligrams per animal and tissue samples taken 4 weeks after dosing. You can see deep and almost uniform activity brain with target mRNA reduction ranging from 65% to almost 90% except in the midbrain on the left. And target mRNA reduction from approximately 60% to greater than 95% from the cervical to the lumbar spinal cord on the right. Direct visualization of the RNA payload in this study in non-human primate CNS tissues is shown in the next slide. Again, the pink color detected here is in situ hybridization detection of the RNAi test article itself. On the right hand side of each pair of panels compared to control injections on the left. And you can see from the labels vertically to the left of each of the boxes from the frontal cortex to the lumbar spinal cord, we can detect the test article present as it relatively uniformly distributed within the tissue being sampled. But also you can see the high degree of intracellular accumulation shown by the dark spots. This confirms productive delivery to the CNS when confirmed by measurements of target messenger RNA knockdown as shown on the previous slide. I'll now switch gears and present extrahepatic delivery and target knockdown results outside of the CNS. Next slide, please. As I described in the introduction, we're working on modifying fundamental nucleic acid properties to enhance extrahepatic delivery by improving both critical properties and nucleic acids. Results from two of our tissues of interests, skeletal muscle and fat are shown here in comparison to delivery to the liver. This study was conducted in two different strands of mice to tease out new mechanisms of extrahepatic delivery. Some of you might be familiar with liver delivery strategies involving liquid nanoparticles and or conjugation strategies that engage lipoprotein and lipoprotein receptor function to achieve liver delivery in the absence of a GalNAc conjugate. As you can see in the far right graph, the nucleic acid payload used in this study does engage the apolipoprotein E uptake system to achieve part of its delivery function in the liver. Target knockdown was less than 50% in Apo E knockout mice were missing a key lipoprotein, but it was over 75% in the wild type mice. In strong contrast to the world though liver delivery shown on the right target knockdown in skeletal muscle and fat tissue was independent of the presence or absence of Apo E protein in these animals. This result suggests that we've engaged an extrahepatic delivery mechanism in muscle and fat tissue that is not dependent on Apo E. We're using these novel payloads to address important therapeutic targets outside the liver. This slide shows the utility of dosing regimens. Next slide, please. And the potential for fractionated subcutaneous dosing to achieve significant extrahepatic target knockdown. Note the uniform degree of extrahepatic target mRNA reduction in muscle and fat that is independent of the dosing regimen in this study, from 5 times 3 milligram per kilogram dosing, daily to a single-dose of 15 milligrams per kilogram. These are obtained in the absence of a high molecular weight or complex chemistry conjugate. Next slide, please. The data on this slide demonstrate the translatability of productive new nucleic acid delivery motifs between rodents and non-human primates. This translatability enables us to rapidly screen and advance promising SAR results from mice into monkeys. Because of this translatability we're already defining extrahepatic therapeutic targets of interest in studying them in non-human primates. And you can see from left to right in skeletal muscle, that knock down of the target messenger RNA in mice is roughly equivalent to knock down at four weeks in monkeys and the same for adipose tissue in the 2 right-hand panels. Next slide, please. We've extended our systemic extrahepatic tissue delivery results into non-human primates as CNS. In this slide, you can see a single-dose comparison of 10 versus 30 milligram per kilogram doses and target gene knockdown in multiple skeletal muscle groups and fat tissue locations. We've observed 75% to 85% target knockdown in these monkeys that is uniformly distributed throughout these important target tissues. In summary, next slide. We're nucleic acid technologies independent of the traditional hepatic GalNAc/ASGPR system. Chemical and structural modifications to our clinical stage GalXC platform have enabled us to increase drug like properties of both RNAi and non-RNAi nucleic acid platforms. We've observed lower barriers to intracellular delivery beyond hepatocytes, including systemic and CNS applications. And again, we're using different structures of nucleic acid payloads to engage additional nucleic acid mechanisms of action. We're applying these advances to a range of indications beyond the liver and the CNS, Peripheral Nervous System, muscle, fat and other important tissues. And we're taking the opportunity to evaluate indications that require simultaneous delivery to 2 or more of these compartments, such as a combination of liver fat tissue together. This may have the utility in cardiometabolic diseases in particular. Thank you.
Doug Fambrough:

Thank you, Bob. I'm extremely pleased with the data that Dicerna has presented today and HBV in primary hyperoxaluria and in delivery of our RNAi molecules to tissues outside the liver. It's a really exciting time. I believe Dicerna is extremely well positioned for both near-term, long-term success. Our core pipeline of carefully selected high probability of success programs is moving forward, meeting the high expectations I have for our work. For nedosiran, we are on track, I believe for a best-in-class therapy, showing activity in PH 2 and in PH 1 which is a competitive indication, I believe the initial indications are that we have the potential for best-in-class with an average level in our PH 1 patients more than 10% below the upper level of normal. For our HBV program RG6346, I also believe we have a potential best-in-class therapeutic, both with the extremely long duration of effect without rebound that we are seeing and which is ongoing. Led of course, by the longest dose cohort, the 1.5 milligram per kilogram cohort out at day 336 with no average rebound in HBV S-antigen levels and with the apparent observation of productive immune flares, where an ALT signal is a positive signal of immune system engagement, which we believe is a critical part of achieving a therapeutic cure for HBV and we'd look forward to future development in the hands of our partner, Roche. With A1AT, I look forward to giving an update next year, but I believe with our collaborator Alnylam on track for a best-in-class therapeutic. That Alnylam collaboration is part of a suite of collaborations with leading global pharmaceutical companies that is on track to yield multiple clinical programs in the coming years. And it has and we believe will continue to have substantial financial upside for Dicerna. As Bob Brown has just walked through, we are using our proprietary extended RNA structures to break out of the cell type specific paradigm RNAi delivery and create more general solutions with multiple extrahepatic tissue delivery capability to provide better and more broad therapeutic options in the RNAi field. This should allow us to continue our business model of carefully selecting high probability of success programs for Dicerna to develop retaining important commercial rights, including in the United States and provide collaboration opportunities that will broadly enable and for our vision maximize the impact on RNAi, as well as continued to be an important source of financing, non-dilutive for Dicerna, while creating additional clinical opportunities in their associated milestones and ultimately, we hope royalties. We have a balance sheet with cash into 2023, which covers our commercial launch timeframe. I look forward to updating you all as we progress in coming months. And for now, we will shift to Q&A across any of the topics we've addressed today and we'll run the Q&A until noon. Thank you.
Operator:

Thank you. We will now begin our question-and-answer session. [Operator Instructions] Thank you. And we have our first question from Mani Foroohar with SVB Leerink.
Mani Foroohar:

Hey, thanks for taking my question. A quick one around timelines. Let's look at the data and more around progress in the program as a whole. Given this data in hand, how should we think about time horizon to get more clarity on potential decisions on the partner Roche's side regarding combo therapy and what is the earliest point at which we would get clarity on whether or not Dicerna is considering their opt-in right around this asset? And how would you think about disclosing that decision?
Doug Fambrough:

Hi, Mani, thanks for your question. Unfortunately, we can't provide much information on Roche's conduct to Phase 2 trials. I know that Roche is very excited about the Phase 1 data that meets or exceeds their expectations that they had when they entered the collaboration. And so they're very eager to move forward in combination studies, but we will only provide information on what those combos are and their timing, when Roche initiates those studies. As far as Dicerna's opt-in, I think the assumption is that we will exercise our opt-in. If the data that comes out of the Phase 2 trials that Roche will conduct supports entering into the pivotal development in the eyes of Roche, I think it's highly likely it'll support entering pivotal development into the eyes of Dicerna, obviously, that would have a commitment of Dicerna. However, the initiation into pivotal trials also is a milestone for Dicerna. And so funding to participate and co-funding global development can be provided by the milestone for pivotal entry. So I think the base case assumption is that, Dicerna will co-fund pivotal development when that comes to pass. Thanks, Mani.
Mani Foroohar:

Great and congrats [indiscernible].
Operator:

And we have our next question from Jonathan Miller with Evercore.
Jonathan Miller:

Great, guys. Thanks so much for taking my question. I guess my question is going to be on those transient ALT spikes that we saw. I understand the theory that they indicate immune activation and therefore sort of the TB mark around this. But is it potentially a safety issue as well as we go to larger trials, a trail that include patients that have already issues with their liver function or is that something that we should be worried about as we start seeing larger and in more new naïve patients?
Man-Fung Yuen:

Okay, thank you for asking this question. In fact, the data showed us that this is really suggestive of immune related flare, because of this drop of surface antigen, and if they actually subside spontaneously and you're very correct in saying that, I mean, is there any concern of patients who are not, I mean, who may having advanced liver disease and that flares may actually decompensate the patients, and that may occur. But remind you that I'll also show you the second patients those - that patients were on - was on nucleoside analogue therapy and you can see the ALT flare is actually relatively low compared to treatment naïve group. So in the future, when we are planning to do all this trial to treat the patients, we are hoping to get correction therapy, most likely the nucleoside analogue therapy will be at the backbone. In this combination therapy, and the nucleoside analogue therapy is on board and even patients who had flares, then, it will be relatively safer for the patients, because they are already on NUCs and we expect the flare will not be as severe as those who are treatment naive. So this is the thing that we may consider.
Doug Fambrough:

Thanks, Dr. Yuen and Jon.
Operator:

And we have our next question from Stephen Willey with Stifel. Stephen, your line is open. Perhaps you're muted on your end.
Stephen Willey:

Yeah, sorry about that. Thanks for taking the questions and congrats on the update. For Dr. Yuen, maybe just give us some commentary around the incidence rate of injection site reactions I know that they were characterized as being mild, but I guess the frequency would be of interest to us just given some of the other competitive products. And then I guess also in the context of competition, how would you contextualize this data relative to some of the other RNAi knockdown data that we've seen from other competitors who are not excluding the X gene? And other compares well just given the small number of patients and different baselines et cetera, but any color you could provide would be helpful. Thank you.
Man-Fung Yuen:

Thank you. Thank you so much. In fact concerning the injection site reaction, if you will look at the table that I presented to you, in each group, there will be around 1 to 2 patients, in fact, most of the groups that we have 1 patient of injections site reaction and they were mild. So I don't think the depends on this, I mean, injection site reaction is high. We defined injection reaction when they proceed for, I mean, after the four hours of injection, so most of them they actually tolerate very well, and we don't quite see except one patient who have moderate reaction or the reactions were very mild. So the percentage may be I mean, 1 out of, I mean, according to this study 1 out of 4 to 6. But concerning the efficacy or the potency of thus, I mean, single trigger, sparing the X compared to other agents with two triggers including the X gene. Obviously, we don't have direct comparative studies. But at least, I can see from this data, we don't see any difference in terms of the suppression of the surface antigen and one thing that we are very encouraged to see is that by prolonged reaction - sorry, prolonged suppression of the surface antigen, and this is one of the data that we are lacking of, in most of the clinical trials. So, and that is all I can say. And I think at least Dicerna this one RG6346 is actually very potent with a very sustained suppression of surface antigen.
Doug Fambrough:

Thanks, Steve and Dr. Yuen.
Operator:

We have our next question from Yigal Nochomovitz with Citigroup.
Samantha Semenkow:

Hi, this is Samantha on for Yigal. Thanks for taking the questions. Maybe a follow-up on the last one trying to put this into context and is fine definition for what up here for HBV would look like in terms of, you know, a reduction of S-antigen and a period after the suppression?
Man-Fung Yuen:

Sorry, I can't hear clearly. Can you repeat again, sorry?
Samantha Semenkow:

Yes, I apologize. Just wanted to see is there a standard definition for what appear for HBV would look like in terms of the degree of S-antigen reduction? And is there clarity before a patient would be considered effectively cured? Or is that still something evolving in the landscape?
Man-Fung Yuen:

Oh, think the consensus now is to achieve the loss of surface antigen. So I mean, we are really targeting the absence of undetectable surface antigen in the plot, and this is I mean primary goal. So obviously, when I presented the data, I actually deliberately showed a data on our patients, how many patients who achieved the surface antigen less than 100? Because we know that for patients who had sustained a response with the absolute level of less than 100, these patients, they have a very high chance of losing surface antigen in subsequent follow-ups. So we don't have a very, I mean, definite cut off for the surface antigen, but what we really want to see is at least we are talking about 1 log reduction of surface antigen and for absolute level, I will consider at least less than 100 IU per ml. And finally, obviously, we really want to have this complete loss of surface antigen in the blood.
Samantha Semenkow:

Got it? And then just one additional follow-up. What's the rationale for the patients that were naive, new, experiencing, you know, more frequently greater magnitude availability, not just the degree of potential HBV-DNA that they are?
Man-Fung Yuen:

We don't have too much data to explain this, but the only differences is, one, I mean, these patients, they don't have nucleoside analogues beforehand, and it's just a monotherapy using the srRNA. So, we will - I mean this logically to think that these conversations when they have players because DNA is high at the baseline with this nucleoside analogue therapy on board, then we will expect the flare will be more and that is also shown in other study using the antisense oligonucleotides. And we saw patients with flare treatment naïve, they have higher flares in terms of ALT level compared to patients who are on nucleoside analogue therapy.
Samantha Semenkow:

Okay, thank you -
Man-Fung Yuen:

Thank you, Samantha.
Samantha Semenkow:

Great, thank you having -
Doug Fambrough:

And thank you Dr. Yuen. We are going to proceed to nedosiran section of the presentation. Thank you for your participation from Hong Kong, where I know it's rather late. For additional questions on HBV, Dr. Rosskamp from Dicerna and, of course, the rest of the Dicerna management team can field questions at the end of the R&D Day as a whole. So at this point, let's move forward. Thank you.
Man-Fung Yuen:

Thank you.
Doug Fambrough:

Thank you, Dr. Yuen. Nedosiran is Dicerna's potential therapy which we believe may have a comprehensive target profile in treating all forms of primary hyperoxaluria and we will present today multidose data from Dicerna's PHYOX 3 open-label study for patients with all forms of primary hyperoxaluria.
Operator:

Thank you. [Operator Instructions] Thank you. We have our next question from Luca Issi with RBC.
Luca Issi:

Oh, terrific. Thanks for taking my question and congrats on all the progress here. Two very quick one here. First one, PH 2, again, the end itself so small so it's very difficult to be definitive. But was there anything out of the ordinary in the baseline characteristics on those three patients? Or do you think that maybe there is any biological reason to believe that nedosiran maybe worthlessly in PH 2. And then the second question is could you just talk about how challenging will be to execute on PHYOX2, if Alnylam gets approved in the early fall? Thank you.
Ralph Rosskamp:

Yes, and I'll take this question. With respect to the PH 2 patients in this study, there wasn't really anything at baseline which was different, these patients had been already in the PHYOX1 study and we have reported they're already in the average reduction of accurate single-dose of 50%. The same patients are now in the 301 study. The only thing we observed there was some variability and the Uox values which we actually contributed partially to not having the urinary collection completeness criteria initially in 301. And as we saw the ability, we, as I said already, we now have the opportunity when we think that is on complete urinary collections to have the patients repeating this, but nothing out of the ordinary there. And with respect to the recruitment of PHYOX2 as you know the PDUFA date is of Alnylam is in December of this year. We are well on our way to recruit patients. So the COVID, the first patients, we have some kind of hold, because the sites were hunkering down, but we are now continue to enroll patients into the study, and I'm pretty confident that in a timeframe, we will have all patients included into the study.
Luca Issi:

Terrific, congrats again.
Operator:

Thank you. We have our next question from Yaron Werber with Cowen.
Brendan Smith:

Hi, guys. This is Brendan on for Yaron. Thanks very much for taking the question and congrats on a busy exciting day for everyone. Just a couple of quick ones from us. I actually wanted to touch this kind of applies to both PH and HBV. But when you kind of look at these course over time after treatment, can you kind of just give us a sense of your thinking, would you expect the reductions in Uox and, you know, respectively, S-antigen to kind of continue to decrease over time with continued treatment? Or do you kind of anticipate a pretty rapid bottoming out there? You know, I'm just thinking ahead would we necessarily expect, you know, that number to go up at a later time point or is that kind of unreasonable thing and then I have a follow-up.
Doug Fambrough:

Thanks for your question, Yaron. I think the answer for what we expect on the continuous dosing is a little different between PH and with HBV. With PH, we do believe by day 120 most or all patients will have achieved their idea and that that should be maintained stably over time. Of course, there's always some barrier for measurement, but you're probably seeing a full treatment effect that can be maintained indefinitely with continued monthly dosing. It's important to note that the normal level of oxalate comes from different sources, not the pathway that creates oxalate and disease. And so, the goal is to bring oxalate down to normal levels and we do not expect suppression of oxalate normal levels. So, what we are achieving, particularly in PH 1 shows I think we're achieving that goal and it's meeting our high expectations for what should occur and that should be maintained. In HBV, I think it's a little bit different, because what we're seeking to do is change the biology of what's going on in the patient through S-antigen suppression to enable a productive immune response. And to the extent that is successful, we made that levels of S-antigen and other viral markers continue to go down beyond the period when RNAi would be driving the suppression. So we'll be looking for that in our long-term follow-up from patients in this study, as well as in future studies conducted by Roche. But I'm pleased that the apparent, if you will, reset of HBV gene expression that's predicted by the X-sparing hypothesis, the data that we have generated to-date is consistent with that occurring in patients. Next question, please.
Operator:

And we have our next question from Robyn Karnauskas with Truist Securities [sic - SunTrust Robinson Humphrey].
Nicole Germino:

Hi, this is Nicole on for Robyn, congrats on the results you've presented today. Just going back to PHYOX3, will there be any enrollment near-term for someone with PH type 3? And then can you give us a little bit more color on the progress for PHYOX2 enrollment or you less 75% of the way to completing enrollment? Can you give us just a little bit more granularity around that?
Ralph Rosskamp:

I couldn't hear the later part of your question. With respect to three patients in PHYOX3, we will first initiate this quarter our single-dose study in PHYOX3 patients. And after we have demonstrated substantial reductions in urinary oxalate in PH three, as we have done in PHYOX1 study for PH 1 and PH 2 patients, these patients will then roll over into the PHYOX3 study. So that would be occurring somewhere in the beginning of next year. So multidose data in PH 3 patients is something we would expect only to have in the second half of next year. And I'm sorry I couldn't fully understand your second part of your question.
Nicole Germino:

Oh, sure. Sorry about that. So for the progress on PHYOX2 can you give us a little bit more color on the progress of enrollment? Are you nearly completed with enrollment? And if so, do you have a more specific timing around that and I know that COVID had some impact on enrollment?
Ralph Rosskamp:

I don't think we had given any specific guidance with respect when the study would be completed. We continue enrolling so we have many sites access again the first site that actually after COVID which started to enroll patients were our Japanese sites where we're pleased with that. But as you heard from Rob's presentation, we are now targeting in the Q3. The Q3 of next year so you can do the math when we would expect the enrollment of PHYOX2 to be completed, because that's the weight limiting study. So once we have the database lock off of PHYOX2, we're able to put our package together.
Doug Fambrough:

We're on track -
Nicole Germino:

Great, thank you.
Doug Fambrough:

Next question, please.
Operator:

Our next question is from Ed Arce with H.C. Wainwright.
Ed Arce:

Hi, everyone. Thanks for taking my questions and congrats on all the data today. My question is around the prolonged duration of your compound for HBV, noting that this first dose in the 1.5 mg a dose out to day 392 which is over 300 days past the final dose, had a 2.2 log reduction and is importantly below the 100 international units threshold. So given that I'm wondering how does this inform your analysis ongoing forward and how many doses ultimately will be enough? And then I have a follow-up.
Doug Fambrough:

Thank you, Ed. That's an astute observation that the level that the most advanced patient has achieved is fair amount below the day 336 number we reported for 2 patients. I am hesitant to get into n equals one analyses since we're talking about an individual of day 396 but it is in fact the case that individual has seen a fairly significant drop in S-antigen levels between day 36 and day 392 after being fairly stable prior to day 336, because it's n of 1 I'm not going to read anything into that in particular, but that is where that number comes from. How that informs future dosing is a fascinating that and unfortunately, I'm not going to get into and I know it's something that is an active discussion in our team and Roche's team and we'll have to wait and see how the Phase 2 trials are presented when Roche is ready to do that.
Ed Arce:

Okay, fair enough. Then the follow-up is sort of juxtaposed to this you know durable, prolonged suppression. How you think about the averages that you saw 1.8 logs on the 3 mg dose and the 1.84 log on the six milligram dose. Does that to you and I recognize again, these are very small numbers. But does that to you suggest any sort of plateau at all in terms of the effect? And how do you think of that in terms of somewhat low reductions competitively? Thanks.
Doug Fambrough:

Yeah, and so that's an n of two and we have two additional patients who are in the dosing period for the 6 MPK. I did mention that the initial trajectory of the initial 2 patients is well, it's like the stronger of the 2 patients who've reached day 112. And so we think there's some likelihood that we will see that the average overall 4 patients and they went while those larger than 1.84. But of course, we will have to wait for that data. But given that initial trajectory, I think there's some likelihood we'll see initial dose response and that there is not a plateau of 1.8, but rather more intensive dosing leads to more S-antigen reduction.
Ed Arce:

That's great. Okay.
Operator:

Our next question is from Madhu Kumar with Baird.
Madhu Kumar:

Yeah, thanks for taking my question. So kind of stepping back and thinking big picture about commercialization for y'all. Is it kind of the long-term goal to say, focused commercialization efforts in the US and kind of partner regionally or with one big partner ex-US or is there a notion there PH you want to start US only, but in the long-term, you would like to build your international sales?
Doug Fambrough:

Hi, Madhu. I'm not sure I caught every word there at the end. But our strategy at this point is to commercialize in the United States for PH, for A1AT and likely co-commercialize, co-promote and HBV in the United States. A move to broader global commercialization, we will take when we believe that the risk profile is favorable, the sources are there and the program is right. But the initial core pipeline Dicerna is targeting commercialization in the US with ex-US commercialization partners. And in fact, we are in discussions with potential ex-US commercialization partners in the PH field.
Madhu Kumar:

Okay, and then kind of following from that thinking about the pipeline kind of take three years from now, how much of the Dicerna trend line three years from now, internal candidates versus in-commercial partnerships currently. Like how do you kind of think about what is left for y'all to do internally versus going to be swathes of collaboration you'll have ongoing?
Doug Fambrough:

So I would note that all of our collaboration programs are ones where our partner Boehringer, Alexion, Lilly, Roche for the Phase 2 and for discovery programs and up until our opt-in, clinical development is conducted by the partners, we have very high bar for programs that we're taking to the clinic on our own. And we will be announcing additional programs in coming quarters that are Dicerna core programs that we will advance and that will include programs outside of the liver based on the technologies that Bob has described. I think we can take one more question.
Operator:

Our question comes from Jonathan Miller with Evercore.
Jonathan Miller:

Great, thanks so much for taking on my question guys. I guess on the PH 2, I'd like to return to the PH 2 the non-responders, can you characterize the sort of Uox reductions are getting I mean, obviously, they're not getting to normalization, but are you seeing robust deductions in Uox from whatever their baseline was? And secondly, will the PH 3 alpha study, when do you anticipate that data being available and that's all going to be part of the NDA package at the same time?
Doug Fambrough:

Let me address PH 2 and then I'll pass to my colleague, Ralph for PH 3. I would not characterize the other two patients as non-responders. We have focused our discussion on the day 120 reading and would note that there are PH 2 patients we did see normalization or near normalization at other time points for other patients. So the fact that it's just one, I believe is a function of variability that Ralph mentioned, and the focus just on the single data point. I'm quite optimistic that we have an effective therapy for PH 2, that we will achieve PH 2 on label and that nedosiran is a tremendous advance over disease management in the standard of care too. Ralph?
Ralph Rosskamp:

Yes, I want to add mechanistically, there is nothing to believe that nedosiran shouldn't work in PH 2. So we have the appropriate knockout model in the mouse where it works and that is one case of liver kidney transplantation in PH 2. And in this case, the urinary oxalate levels were normalized to the liver transplantation. So that also speaks to that the sole source of the oxalate is coming from the liver and not from other organs. So, and as I mentioned already, the same patient had an over 50% response in the PHYOX1 study. So we just have to wait for more days coming up. With respect to the natural history study, we plan to quickly roll this out so we will have a webinar with the OHF coming up soon. We'll post the trial soon that's the natural history study patients activity like just some basic ultra safe at the beginning at urinary oxalate and then the next measurement is at six month, and by including younger patients from three years and onwards where we know especially in the very young patient, they are recurrent stone formers, so they have continuous stones that even with six months data, we will have enough data been able to demonstrate that in those are forming more stones in those six months that they are the ones with the higher oxalate, which seems to be logical that this is the case. So we therefore expect that this at least the six month data, the study will continue, the study will continue for two years, but we hope that with a six month data, we will have enough support to show the link toward that urinary oxalate isn't adequate you to get endpoint for PH 3 as well. And then we have 104 study, hopefully showing substantial reductions and those patients in 301 then with a multidose data showing the durability of effect.
Doug Fambrough:

Thank you Ralph. And with that we're going to draw Dicerna's R&D Day to a close. I want to thank everyone who's tuned in today to hear this varying data on nedosiran, RG6346 and our platform. Thank you.

Dicerna Pharmaceuticals, Inc. Q2 2020 Earnings Call Transcript

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Dicerna Pharmaceuticals, Inc.
Q2 2020 Earnings Call Transcript