Investor Update

Sep 9, 2021

Slides

Good day and thank you for standing by. Welcome to ProQR TeraTropics, the Axiomir Opportunity Conference Call. At this time, all participants are in a listen only mode. After the speaker presentation, there will be a question and answer Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Sarah Kiley. Please go ahead. Thank you, operator, and good day, everyone. I am Sarah Kiley, Vice President of Investor Relations and Corporate Communications at ProQR. We are very pleased to share with you today an update on our Axioma RNA Editing Platform Technology following the recent partnership announcement with Eli Lilly and Company. Briefly, some logistics. This webcast can be accessed under the Events section of our website at www.proqr.com and will be available for replay later today. The slides for the webcast can be downloaded from the webcast player or directly from our website. I would also like to bring your attention to the live captions that are available for this event. We will first go through our presentation and will then open the call for In order to include your question on today's call, we request that you call into the telephone numbers provided in the press release announcing this call. During the call today, we will make forward looking statements. There are risks and uncertainties associated with an investment in ProQR, which are described in detail in our SEC filings. On Slide 3, you will find the agenda and today's speakers. Daniel DeBoer, our Founder and CEO, will open the call with some brief remarks, providing an overview of the Axiomer opportunity. Then, Gerard Plattenberg, our Chief Innovation Officer, will review the Axiomer platform in more detail, with Bart Klein, our Senior Vice President, Innovation, providing an overview of our IP portfolio around Axiomer. Following our prepared remarks, Nidil Shah, our Chief Business and Financial Officer, will join Daniel and Harrod for the Q and A, after which we will conclude the webcast. I will now hand the call over to Daniel. Thanks, Vera, and good day, everyone. We're pleased to share with you an update today on our axiomer RNA Editing Platform technology. Since the inception of our company, ProCure has been focused on RNA technologies that allow us to develop potentially life changing medicines for patients with high unmet need. And today, we have a pipeline of several clinical stage programs for genetic eye diseases. At the basis of our development pipeline lies a robust scientific organization that in addition to discovering new programs for genetic eye diseases is also exploring new ways to use allaconucleotides to target otherwise untreatable conditions. We've made significant scientific advancements, including the discovery of several RNA editing technology platforms, of which today we will elaborate on the Axiomer platform technology. In 2014, we started to work on Axiomer at the Proteo Labs and filed our first patents on the 1st generation of Axiomer. Since then, we have advanced the science, built out an extensive IP portfolio and generated the scientific expertise and know how around this exciting platform to create medicines for patients in need. The Axiomer opportunity is significant as it can be applied to more than 20,000 G2A mutations. Proteus' core strategy is to develop medicines for genetic eye diseases. And for therapeutic applications of this platform outside of the eye, our strategy is to selectively enter into partnerships like the one we announced with Lilly yesterday that helped to advance and capture the full potential value of the platform. Beyond Axiomer, we have another RNA editing technology platform called Trident. With this technology, we can make similar but different edits to the RNA, editing use into pseudo use, which allows for the selective suppression of nonsense mutations or premature stop codons. This group of mutations account for approximately 11% of all disease causing mutations that are known today and Trident can potentially result in medicines for those mutations. At a later time, we will share more about the Trident technology, and today, we will focus on Axiomer. ProCare has a deep pipeline with 4 clinical stage programs based on a variety of different mechanisms of action, of which 2 are currently in pivotal stage. Our most advanced program, cepofarsen for CEP290 associated LCA is on track for its Phase IIIII pivotal readout in the first half of next year. Beyond our 4 clinical stage programs, we have a deep pipeline of dozens of earlier stage preclinical programs for other genetic eye diseases, of which a few are depicted on this pipeline slide. Our partnered programs are depicted at the bottom of this slide. Earlier this year, we announced a partnership with Djaro Biotechnology, a company incubated by RTW on an undisclosed non ophthalmology target. And we have now announced our first partnership, Erlander Axiomer platform technology, with the exclusive license of up to 5 targets to Lilly. Lilly has a powerful development organization and has significant experience with innovative RNA science, making them a great first partner for our Axiomer technology. Under the partnership, we will work with Lilly on up to 5 targets to potentially benefit patients with genetic disorders in the liver and nervous system. Where ProPure will drive the discovery phase and Lilly takes the lead on the development and commercialization. This partnership provides significant value to Proteur, where Proteur will receive US50 $1,000,000 upfront, including an equity investment of US30 $1,000,000 Proteus is also eligible to receive discovery, development, regulatory and commercial milestones, totaling up to $1,250,000,000 plus royalties on potential product sales. This transaction is a significant milestone for Proteller, providing a valuable endorsement of our technology, platform and capabilities as well as substantial funding. We're excited about this partnership and look forward to working with Lilly to create medicines for patients. It's now my pleasure to turn the call over to Gerard Plattenberg, Realtor's Chief Innovation Officer and my Co Founder. Javier Kazak has some experience in RNA science and is a widely acknowledged leader in the field, having been involved with several important advancements in the field, including putting the 1st axon skipping drug in clinical trials. Beyond being responsible for all discovery efforts that underlie our clinical pipeline, Gerard was also instrumental in the discovery of the Axioma and Triadent platforms. I will now hand the call over to Gerard to walk you through our Axioma platform. Thank you, Daniel. I am very proud to be able to spend some time today shining a spotlight on our Axiomer platform, which was invented in house at ProQR. Axiomer, as you will see, allows the use of synthetic editing oligometritis or EONs to change selected adenosine very specifically into immunosine in RNA. This has tremendous potential for application in therapeutic development for genetic diseases for currently there is still no treatment. The scientific field has been exploring the potential of oligonucleotides for several decades now. And back in the 80s, it all started with ASO or GAPMIR mediated knockdown of targeted messenger RNAs. With this technology, it is possible to degenerate entire strands of RNA that may cause disease. The next step in the evolution of RNA technology going in the 1990s with axon skipping or splice modulation. With this technology, it became possible to cleave out the axon from the RNA that contains the disease causing mutation, creating a shorter, but often functional messenger RNA. With RNA based editing, we are now taking it even a more precise level. Our axiomer and trident based editing technologies have very broad applications. We will focus mostly on axiomer today and touch on Trident layer. Axiomer is a very powerful RNA editing platform, enabling us to use the same modality of synthetic oligonucleotides to specifically make changes at the base level in the RNA, the rare mutations or even to change properties of proteins. And we do this using the machinery that is already present in human cells called ADAR. At immunosin, the mRNA is acting on RNA and its genes were first discovered in 87. ADARs induce adenosine into adenosine RNA editing, which is one of the most common forms of RNA editing. ADAIR is able to both modify and regulate the output of messenger RNA as inuzine is interpreted by the cell as guanosine. ADER has also been determined to change the functionality of small RNA molecule. Recently, ADERs have been discovered to act as splicing regulator with their editing capability or RNA binding function. The post transcriptional modification of mammalian transcripts in the central nervous system by adenosine to using RNA editing is an important mechanism for the generation of molecular diversity and serves to regulate protein function through messenger RNA recoding. A2 RNA editing of the glutamate gated ion channels is the most extensively studied. In fact, the first target of AtoI RNA editing discovered in the mammalian system was the AMPA GLUTRDSubunitrescent RNA in which a genomically encoded glutamine codon, a CAG, was changed to an arginine codon, or the IG. This edited QR side determines the iron permeability of the glutamate channel. Channels that contain the edited R form are less permeable to calcium. So essentially the body uses ADAR in this context to create different isoforms of the glutamate channel to regulate calcium transport. And there are numerous other examples of RNA editing taking place in our bodies. RNA editing is a very frequently occurring natural process. Our abcyomer or oligonucleotide directed RNA A2I edible platform was evolved on the mechanism from what nature was developed. Certain dose standard RNA targets are engaged by ADA, as you can see on the left side. And the specific adenosine is deaminated resulting in an inozine. On the right side, you see that ProTR created synthetic editing oligonucleotides based on what we saw in nature. This mimics the double stranded RNA target sequence that is recognized by endogenous ADAR, which is then able to deaminate a specific targeted adenosine. This corrects the mutation or can be used to diversify the function of the targeted mesony RNA. This allows us to recruit endogenous ADAR and make edits in the RNA where we want. Turning now to ProQR's axiomer RNA editing platform. On the left, the axiomer RNA platform technology enables single A to I editing in RNA using an editing oligonucleotide for E. ON to attract endogenous machinery to a targeted adenosine. Invented at ProPr, we have focused to establish the ground rules for the on design and develop strong IP protection with our current portfolio of 11 patent families. Combined with a very strong KOL base in this field, positions us well for further development of this promising technology into the clinic. T3 mutations make up how SNPs that are associated with human disease. Therefore, this platform has a huge potential to treat currently untreatable diseases. The high potential of the Axiomer platform for therapeutic development is based on 2 key pillars. Firstly, Axiomer uses synthetic oligonucleotides, which builds on the tremendous wealth of knowledge generated over the last 4 decades. Because the platform uses oligonucleotide manufacturing, chemistries are readily available. Much is known about targeted delivery of all the nucleotides to the organs such as liver, kidney, CNS and eye, facilitating development strategies in those organs. Secondly, using endogenous AR machinery allows that the axiomer RNA editing technology to avoid the use of complex delivery vectors has a reversible mode of action and acts only where the target is expressed. So with this technology, we combine innovative technology with a modality experience of the last 4 decades. The Xeolone technology can induce AI editing in all RNA and therefore can be used in a wide range of applications. Firstly, Axiomer can potentially treat genetic diseases by reversing the intera mutation. This way it's possible to repair the genetic effect of both the RNA and protein level. Examples of such applications can be found in riparian splicing defects or correcting premature cell codons or snips causing defects in certain proteins. Over 20,000 G2A mutations are known to cause human disease. So the value of this approach is tremendous. Secondly, by making compensatory and de novo A2I or GE changes, Axiomer has the potential to make subtle changes in RNA and our drug just in protein expression or function. This is just the tip of the iceberg of this very promising technology. The genetic medicines field has made great strides in recent years. We believe Axiomer has a unique and attractive proposition in the field of genetic diseases. With Axiomer, we are using our body's own systems such as ADAR to correct mutations only in infected cells where the messenger RNA is expressed. As the machinery for editing is already in the cell, the editing oligonucleotides that include AR don't have to be complex molecules that need to be packaged or that are essentially the same as other single stranded oligonucleotides. This makes delivery possible to a wide variety of organs. Using synthetic oligonucleotides, we ensure the therapeutic effect is seen as long as we will be dosing. No long term effect potential off target editing is expected. Moreover, we don't have to over express the editing machinery or genes in cells. Axiore based editing can be applied across a wide variety of target teams and here you have a taste of what that looks like. During our technology development, we were focused on understanding the groundhose to harness and darogenous aid our use in EONSS and have explored this in many genes of which a few are displayed in this slide. As you can see, E. ONS can induce A to I editing at high efficiencies in various system, resulting in therapeutic levels of editing. And now the time has come to take this synthetic platform into therapy development. Axoma has the advantage of using a proven modality. That means the oligonucleotide would establish functionality in different organs of the body. Axioma has with a vast number of disease dosing mutations, the possibility to create medicines in all important disease areas. As an example, select number of disease targets that could be amenable to axiomy various organs are listed on this slide. Indeed, in addition to the rare monogenic diseases, also non genetic diseases that affect large populations can be served using our Axioma platform. With our announced Lilly collaboration, we are proud to share we will be starting to develop up to 5 targets in the liver and NERFASTANT system, Combining our pioneering RNA editing platform with the development power of our partner will propel our Axioneer platform forward. Aligned with our corporate strategy, Axiomer allows ProQR to fully exploit this RNA editing technology in the development of medicines for genetic eye disease, and there are many. We anticipate that there are more than we have on the targets in the genetic eye disease that are amenable to Axioma RNA. In the coming 12 months, we plan to announce more details on the next targets OQR will pursue with Axioma. With the alliance with Lilly and a wealth of ophthalmology targets, this is an exciting time for our Axioma platform. The growth application and a large number of unencumbered targets create a significant opportunity for further value creation through additional partnerships in therapeutic areas that are non core to ProTR's strategy. I will now turn over the call to Bart Klein, our Senior VP Innovation. Bart has played an instrumental role in the discovery of our Axiomer technology and with his background as an IP lawyer for over 25 years, he ensured a robust IP position we have built around Axiomer, which he will now provide an overview of. Marc? Thank you, Gerard. I'm pleased to share an overview of ProQR's IP estate around axiomer and ADAR mediated RNA editing. ProQR filed a total of 11 pack families covering the key features of the Agiomer technology. There are 2 general categories of patents with some overlap. First is covering the concept of recruiting endogenous ADRs with guides that possess a separate ADAR recruitment part, which can be a stem loop structure or any other structure, such as an aptamir, the facility for ADARs. The second category is patents covering guide designs with the lens that bring desired pharmacological properties such as metabolic stability, target based specificity, metallosis by ADARs and a variety of chemical modifications in the oligonucleotide backbone and or base. In summary, the Axiomer IP estate protects all the foundational elements of the platform using endogenous ADAR for therapeutic purposes beyond 2014. The design rules for editing oligodendrocytes in terms of the chemical modifications that are preferred and or tolerated in each position in the ELN have been established. These modifications and modification patterns are portable from one sequence to another and are therefore target independent. We have patented these features independently of target specific IP and we refer to these patents as the platform patent. Mentioned earlier, there are 11 patent families covering these platform features. The colored circles represent the nucleobase sequence, which is determined by the sequence of the target RNA. The pentagons represent Rybox, which can be modified to break zyto properties, such as metabolic stability and editing specificity. Finally, the linkages between the nucleopases are represented by sticks with different color coding, indicating that different linkages have been tested for performance and subsequently patented. These linkage modifications are important for pharmacological properties such as metabolic stability and cellular uptake. These are properties independent of the neutral base sequence. Table lists the modifications that we patented found to be preferred and or tolerated. As you can see, we defined and patented the use of and the design rules, including all standard background chemistries used with the oligonucleotide field. Beyond chemistries, we also covered the stereo pure forms for the linkages, where modifications would introduce a cryo center, such as a PS and PM language. These are the 11 patent families that cover the foundational features of the Axioma technology, the platform patents. As stated before, the features covered by these patents are target independent. A special case is family with target number 32. This covers a base modification of the acetylenes fitting opposite the target adenosine in the target RNA when in double strength RNA formation. This base modification, when applied in leading to a 3 to 4 fold increase in editing efficiency compared to guides comprising a non market volume base. All filings have been published, except the youngest with Doctor. 39. The earliest filed patents have already been granted in major jurisdictions such as the U. S. And EU, as indicated in the left column. The others are in various stages of examination and are expected to proceed to brand due course. In summary, ProQR's Axiomer IP portfolio is strong. It is broad and provides coverage for the foundational features of the technology beyond 2040. I will now hand the call back over to Shurad. Thanks, Bart. As we have developed the technology platform, we have benefited from our relationships with several renowned scientific advisers, including those on our Scientific Advisory Board. Here we have combined decades, volume nucleotide chemistry, delivery and development knowledge with top science in RNA editing space. Art Levin has been helping us since day 1 and has 4 decades of RNA therapy development experience. Bill Zaimor was one of the inventors of siRNA and a co founder of Alnylam and has been an important advisor on our RNA editing efforts and broader RNA science. Martin Meijer spent considerable time both at Ionis and Alnylam and is a valued member of our SAB with significant translational science expertise. Peter Pio is a world renowned expert in AIGA and we work with him and his lab on optimization, understanding structural biology in relation to our Axioma platform. And Professor Yita Yu is our collaborator on the other orange editing technology called Trident that Daniel briefly touched upon earlier. At Professor Hughes' lab, pseudo urulation is a focus and we are pleased to collaborate with him on this approach. In summary, we are extremely pleased with the validation of our exomer technology in partnership with Lilly and look forward to a productive relationship. ProQR will focus the platform to develop exosomere based therapies in the genetic eye disease field, for which we will announce our development projects in the next 12 months. Our axiomer platform with tremendous applications will form the basis for additional value creating partnerships. I thank you all for your interest in today's call. I will now hand over the call to the operator questions. Operator? Thank you. And your first question comes from the line of Taegan from Stifel Josh Schimmer from Evercore. Please ask a question. Hey, I think that's me. Thanks so much for taking the question and congrats on this partnership. Hoping maybe you can discuss the advantages or disadvantages of targeting RNA over DNA? Yes. Hi, Jos. Thanks. So yes, obviously, there's a lot happening in the field of base editing and genetic medicines. I think DNA and genetic editing in general is really coming of age and it's getting to the point that it's ready for development. The RNA technology that we are developing, Axioma, has some unique features that allow us to target very specific individual bases that we can change out for other bases that allow for essentially reprogramming of the messenger RNA, which is done in a non permanent measure. So we can do that without having to touch the DNA, which obviously has some advantages from a safety and practical perspective. So we think that for a large number of these applications, there's a very interesting case to be made for RNA. Editing. Okay. Thanks very much. Thanks Josh. Thank you. And your next question comes from the line of Dae Gon from Stifel. Please ask the question. Great. Good morning. Thanks for taking my questions and congrats on this deal as well from me. So two questions, maybe for Daniel, Oriva and Harard. In terms of the proof of concept data, I was just going back to some of your earlier deck and saw that proof of concept data had been presented for the IDUA, the Harler syndrome mouse model and in vitro. Can you maybe elaborate on what other proof of concept data that you have generated to date that may have culminated in this deal? And then secondly, kind of related to Josh's question, I guess looking specifically at the Acxiomar versus some of the other ADAR technologies that are available today, maybe for Gerard, can you maybe explain a little bit about ADAR? Perhaps it's just based on the EONs and the technology there, but if you can elaborate on that, that would be great. Thanks and congrats again. Thanks. Yes, Shneur, can you address this question, please? Yes, thank you very much. I think the proof of concept data that we are addressing in, I believe, Slide number 18 shows you that we have we have made quite an extensive editing in several systems. We've progressed from there on as well. So as you can see for alpha-one antitrypsin on the SERPINA-one, we also got some very nice editing going on. And we also have which we have not disclosed yet, but we have certain editing in, let's say, IRD, inherited retinol disease targets. And that's something that we will build upon going forward to the future. So we have progressed from there, and we will be focusing now together with our partner on certain liver, which are not disclosed and also nervous system targets, so to speak. Yes, so as to your second question, I think there's several technologies out there that are going after ADAR editing. And we can say that there's certain schools out there which express, let's say, hybrid proteins that are hybrid between ADR and other proteins that target the editing activity using also a guide sequence and those are expressed from A and B. So let's say that's where it is for B. For Wave and the other schools that are using, let's say, oligonucleotides to recruit endogenous ADRs is quite similar to our approach, as well as for as far as we know for Coro. And I believe that some of the other companies where they face this shape, they are using an approach where they are going for endogenous ADOS, which then would be recruited by expressed and more structured RNA guys. So there's different schools out there that go after the RNA editing as dictated by ADAS. So I hope that answers your question. Thank you. And your next question comes from the line of Joel Welen from GMP Securities. Please ask your question. Hey, good morning and congrats from me as well on the partnership. Just one on logistics. Can you discuss your responsibilities under the deal with Lilly and whatever you're responsible for in either the early work or handing off the technology? And then one on the technology, can you discuss delivery in a little bit more detail on how that might change depending on the target condition? Yes, John, thanks and happy to address those. So in the partnership with Lilly, Proteus will take responsibility of all the RNA science discovery and the design of the molecules. We'll then work with Lilly in the early development and hand it over for clinical development to Lilly where they take full responsibility in execution of all the clinical developments and the commercialization. And with respect to delivery, I think a major advantage of the Axioma platform technology is that we, as Gerard mentioned in his slides, are building on 4 decades of RNA science. And these oligonucleotides are essentially the same modality as all the other oligonucleotides that we have seen over the 4 decades being developed in terms of chemistry, in terms of size, in terms of manufacturing and therefore also in terms of delivery. So that means that the editing allagonylutide we are developing for axiomer can be delivered to all the same organs as other oligonucleotides are applied. And obviously, there's quite some experience out there with getting into some of these key organs that we're targeting here. That's helpful. Thanks again for taking the questions and congrats. Thanks, John. Thank you. And your next question comes from the line of Emma Millen from Cantor Fitzgerald. Please ask your question. Hi. Thank you for taking the question. So in a disease like Crohler syndrome that also has CNS involvement, I guess just curious what the advantages are over a gene therapy approach and the ability of the axiom or to cross the blood brain barrier more broadly in nervous system disorders? Yes. Terence, please go ahead. Yes. So I'm afraid I didn't get the first part of your question. But if you say that the capability of Axiom were to cross the blood brain barrier, I would say that like Daniel just alluded to the fact that our oligo eons or adding oligonucleotides follow kind of the similar path as for other autoimmuneucleotide based modalities. So for the, let's say, CNS components, we will be looking at specific delivery to the brain, for instance, like by using IT delivery or even direct ICD delivery. So I hope that answers your question. Great. That's helpful. And then just one follow-up. Has the 5 targets covered by the collaboration been preselected by Lilly? And just curious if there's any other restrictions around future partnerships in liver and nervous system disorders? Yes. Emma, let me address that. So the targets have not been fully identified yet. We've agreed a certain period for us to work through that. And there beyond that, there's no major restrictions for future partnerships. So we think there's significant opportunity to do other similar partnerships on other targets. Thank you. Thanks, Emma. Thank you. Thank you. Kei Nakae, please ask a question from Chardan. Thank you. Yes, just want to go back to delivery. So for the liver, are you intending to use Galmak? I think Okay. Yes. Sorry, go ahead. So for the liver targets, we intend to explore several routes, but among which there will be a Galak approach, yes. Okay. And then I know you kind of answered this question for the CNS, but so intrathecal would be at least for now maybe the preferred method of delivery? I would I'd totally agree with that, yes. Okay, great. Congrats. Thank you. Thank you, Craig. Thank you. And your next question comes from the line of Rene Wouthers from Kempen. Please ask your question. Yes, thanks for the presentation and congrats on the collaboration from our side as well. First question is, what kind of news flow can we expect from the Lilly Corporation going forward? I mean, do you think that they will or you will announce when targets have been selected, preclinical progress? Any color on that would be helpful. Yes. Thanks, Rene. So obviously, the information that comes out of the partnership and what we disclosed from that is at the discretion of Lilly. So we can't provide specific guidance on that at this moment in time. However, the Axioma platform as a whole will progress for the year and the years to come. And in the next 12 months from now, we plan to announce additional targets that we intend to develop ourselves in the genetic eye space. So that is probably a next milestone for the platform to watch out for. Got it. And a follow-up, can you provide a rough split for the development, regulatory and commercial milestones that you indicated? And with what kind of event do you expect to receive the 1st milestone? Yes, good question. So we can't go into detail there. We haven't disclosed that. But in more broader terms, I think it's well distributed throughout early discovery, early development, later development, regulatory and then some in commercial with royalties on top of that. So there is near term milestones to be expected in the early phase of the partnership. Okay. Thank you very much. Thank you. There is no more questions. So this concludes today's conference call. Thank you for participating. You may now disconnect. Speakers, please stand by.