Ionis Pharmaceuticals, Inc. (IONS) Earnings Call Transcript & Summary

Hi, everybody, welcome. Sorry for the technical challenge, but I think we're good now. Okay. So welcome, everyone. Thank you for joining this webcast. I am Frank Rigo, the Vice President of Functional Genomics and Drug Discovery at Ionis Pharmaceuticals, and I'm going to be the moderator today. I'm really excited to have a virtual discussion on some of the key science that was showcased in the documentary that was released recently by PBS called The Gene: An Intimate History. The Gene is actually a 2-part documentary which is a beautiful journey of the history of the gene, intertwined with the stories of patients and families that are afflicted by terrible genetic diseases. The documentary also highlights in a very touching way the hope that is brought to patients in the form of new transformative medicines that come from understanding the very thing that unites us across the globe, which is our genes. So many of you are probably not aware that 3 of the stories of hope, the spinal muscular atrophy story, the Huntington's disease story and the KIF1A story that were featured in the documentary came straight from Ionis. And when the narrator refers to the biotechnology company that created the drug that is delivering the hope and treatments for those individuals who desperately need them, he's talking about us, Ionis. So today's intimate discussion will center around Ionis' antisense technology as well as the experiences of the researchers and scientists who pioneered the RNA space and who are successfully translating genomic medicines into transformative antisense medicine. So I'm very pleased today that we have an outstanding panel, and with us is Dr. Brett Monia, who is the Chief Executive Officer of Ionis Pharmaceuticals. We have Dr. Frank Bennett, who's the Chief Scientific Officer and Head of the Neurology franchise. We have Dr. Eugene Schneider, who's the Senior Vice President and Head of Clinical Development; and last but not least, Dr. Holly Kordasiewicz, who is Vice President of Neurology. So we will first start to discuss the documentary with our panel, and then at the end, we're going to open it up for questions of everyone who's online. So let me start off with Brett first, get some of his opinions on the documentary. So Brett, where do you think -- where does Ionis and antisense technology fit in the history of the gene?

Thanks, Frank, and I hope everybody can hear me well. So it was a great documentary and one that we're very proud to be -- to have been part of. Ionis was founded in 1989, over 30 years ago now, with 1 goal, 1 mission, and that was to create a new platform for drug discovery, a new way of bringing forward, delivering new medicines to patients in -- with great need, great unmet medical need. Patients that weren't being treated adequately with existing modalities, old-fashioned approaches, if you will, and it was a platform called antisense that we conceived and pursued. It was a big dream but it was a dream that we knew if we were successful in achieving that dream, we would be able to not only be more efficient -- develop a more efficient way to discover drugs, bring more drugs to patients faster, but we would be able to tackle diseases that were unapproachable with traditional drug platforms, diseases with large unmet medical needs and as well as rare genetic diseases as were highlighted in the documentary. And we plugged away at that for many years. Virtually, the same year that Ionis was founded, the Human Genome Project was launched, and it was highlighted in the PBS documentary in fine detail and I remember that. I remember being in the laboratory, trying to make antisense work with my colleagues and reading articles, scientific articles on the progress that was being made, on press articles that highlighted the controversy, whether they should do the Human Genome Project or not and in the controversy that came about with shotgun sequencing and the competition to be first and all that. What I also remember is the remarkable discoveries that were being made along the way, that were uncovering new causes, new genetic causes of human diseases one after another as we were making progress in developing a new drug platform to do something about those diseases. And it really -- these 2 work streams were going on in parallel. And both were challenging, both -- and their controversies. Ultimately both were wildly successful, antisense and the completion of the Human Genome Project. And that was incredibly important because really, at the end of the day, it was a perfect marriage, a marriage in which we have the Human Genome Project discovering new aspects of human biology and more importantly, new causes of human diseases, genetic causes. And then you have a platform that we invented, created that can do something about it. We were able to basically bridge the gap between understanding human disease at a new molecular level and be able to provide medicines to patients with -- who are in great need. Sometimes, I think back on that and I ask myself, what if there was no antisense. I mean, we would have all these great discoveries. We'd understand what causes various genetic forms of human diseases and not be able to do anything about it. But that never happened, luckily, thankfully. So it's a perfect marriage that really the results of which are providing tremendous benefit to patients and will do so for many years to come.

So Brett, so what does it mean to you to see that our treatments are being held as the examples of success in the documentary?

Oh, it's great. It's heartwarming. I mean, to have 3 of 5 of the disease areas highlighted in such an elegant documentary, in such a well-received documentary, 3 of 5 disease areas that we conceived, we came up with, we pursued, we identified medicines against and we're providing strong evidence of patient benefit, at least some of those drugs in clinical trials showing encouraging results. And then, of course, nusinersen, which has proven to have transformed the lives of so many patients over the years. SMA and Huntington's disease and KIF1A that were highlighted in that program. It's very heartwarming. It's very encouraging. It's very motivating to be recognized in that documentary for our contributions. And it's also motivating not just to be recognized, but it's also motivating by the fact that it's a small sampling, those 3 disease areas, of what we have underway, the drugs that we're bringing forward to treat patients with tremendous unmet needs. And although the highlight of this webcast is neurological diseases, which was the highlight in the PBS documentary, it's -- we have many neurological diseases like the ones I just mentioned, but there are others, cardio -- genetic causes of cardiovascular disease, genetic causes of respiratory diseases, non-neuro rare diseases in cancer. So it's very motivating to be recognized like that and very encouraging to continue the fight to bring all these medicines forward to patients.

So Brett, given sort of the breadth that Ionis covers, in your opinion, what do you think Ionis' contribution to the history of developing targeted therapeutics has been?

Well, Frank, as I mentioned in the beginning, our mission in the very beginning when we created Ionis was to build a new platform for drug discovery based on antisense therapeutics by targeting RNA, a very novel, innovative approach, which has obviously been very successful. What we essentially did was create a new sector in the biotech industry, in the pharmaceutical industry, called -- it started with antisense and now has a broader name called RNA-targeted therapeutics, an approach that offers precision medicines for patients, precision -- drugs that work in a precise manner to only affect the gene product that's causing the disease, which avoids, of course, nonspecific safety issues and toxicity issues and so on. So it's very gratifying that we've created this whole new sector called RNA therapeutics and led the way in doing that and continue to lead the way in doing that. And it's also very gratifying to see so many others join in, join in right behind us and follow our lead. I mean -- and they're providing medicines to patients as well in great need. And after all, at the end of the day, we're proud to be the leaders of that. We're proud to have others join in because the winners in all of this are the patients, more drugs for more patients who desperately need them. So it's very heartwarming, it's very gratifying.

Thank you, Brett. I -- now I want to turn it over to Frank, and I want -- Frank, maybe you can tell us about your journey from when you first started using antisense technology in the central nervous system until today.

Yes. So it's been sort of a life-changing journey. And -- good morning, I should have said that at the beginning. But the project really started as a small feasibility study like most of the projects at Ionis, where we're really exploring the application of antisense technology for various applications. And this particular project started as a collaboration between Ionis and 2 investigators, 1 at University of California, San Diego, that is Don Cleveland, and a second physician investigator who was working at Center for Neurological Studies in La Jolla. And we got together and decided that we wanted to determine whether antisense technology could be a viable technology for modulating expression of genes in the central nervous system. And so the first question we wanted to address is if you administer the drugs into the cerebrospinal fluid, which is the fluid that surrounds the brain and spinal cord, whether the drug would distribute from that fluid base into the tissues and bind and modulate the target RNA that was of interest. And so after a little bit of discussion, we decided to start working on a gene called superoxide dismutase or SOD1. And one of the reasons for picking that gene as a test case was that at the time we started this project, it was a well-recognized genetic cause of ALS, and it was known that it was a dominant gain of function that is the mutations in SOD1 that cause disease are causing the protein to become toxic. And therefore, we rationalized that if you remove this toxic protein from the brain tissue that it may be beneficial as a treatment for ALS. And so we had a path forward into the clinic if the feasibility study worked. And so like most projects, you have your ups and downs. You have good days and bad days, but overall, the project was showing some promise. And after a couple of years, we were all convinced that the technology had legs. That is that we were able to modulate the expression of SOD1 in CNS tissues, and that modulation was having a benefit in models of ALS. And so based on that, we decided to push that drug forward and, at the same time, expand our program. So one of the projects that we expanded into was the Huntington's disease project that was featured in the film. And in fact, that was a project that Holly first was recruited to Dr. Cleveland's lab as a postdoctoral fellow to work on Huntington's disease. It was the first interaction with Holly. And in addition, we started working with Dr. Adrian Krainer at Cold Spring Harbor Lab on spinal muscular atrophy. And again, that was really the poster child for how successful the technology could be when we applied it into the CNS. So again, a lot of years passed where we're really optimizing the technology and learning how to use it in the CNS. And today, it's really gratifying to reflect back that we have one approved drug, which is SPINRAZA. Two drugs that are in Phase III clinical trials, the Huntington's drug that was featured in the film and the SOD1 drug that we started working together on is in Phase III trials, is showing very encouraging data. And 11 additional drugs that are in our pipeline, either preclinical development or in clinical trials ranging from diseases like Alzheimer's, Parkinson's, spinocerebellar ataxias or SCAs and even some ultra-rare diseases like Alexander's disease or prion disease. And we have a pipeline behind that of over 30 targets that we're trying to find drugs for to treat an additional greater than 30 different diseases. So it's been really gratifying from sort of that humble beginning to see how important the technology has been for treating these neurological diseases. And these are all diseases that have no therapeutic options. And so we really do view that antisense technology can be a technology that is going to have a dramatic impact on inherited neurological diseases.

Thank you, Frank. So let's maybe talk a little bit more about Huntington's disease. And you have known Nancy for many years. Can you tell us about how you met and how you became involved in Huntington's disease? And maybe perhaps you can tell us about what inspires you about Nancy.

Yes. So I've known Nancy Wexler's name for a long time before I met her. I met her about 10 years ago at an international conference on Huntington's disease. And I was in the conference and I knew Nancy was there but I didn't know who she was. And after sort of scanning the audience and seeing how people were very reverent to this lady that was in the audience, you kind of connect the dots and recognize that that's Nancy Wexler. And so I was introduced to Nancy at the meeting, and Nancy's a person that is really larger than life. Some of her personality came out in the meeting. I would encourage those in the audience to view a short clip on Nancy where -- that's associated with the film. It wasn't included in the film, but in the clip, Nancy finally gets tested to see if she's at risk for Huntington's disease. And in the clip, I think it really reflects her personality. Nancy is a person who you can't say no to. She's the godmother of Huntington's disease and had such a big impact on the disease. And the researchers who worked in the program are really -- Nancy's been able to galvanize a lot of disparate personalities to work on this disease. So to me, Nancy's an example of why we come to work every day, to help patients like Nancy. And the program again started in humble beginnings and ultimately with our partner, Roche, is now in Phase III trials, and it's showing a lot of promise for patients with Huntington's disease. We still have to prove that it works, but it -- from what we've seen so far, we're on track for doing that.

So Holly, obviously, Huntington's disease is very near and dear to your heart. So can you tell us about what inspired you the most about the documentary as it pertains to Huntington's disease? And then your journey in developing a therapy.

Of course. So one of the most powerful moments for me was to hear Pete and his family's story. So Pete is a patient with HD that is in our clinical trial. And obviously, we don't get to know individual patients in a trial. And to see someone who has received our drug feeling better in that scene where he was writing, it was just really impactful. And even more than that, it was lovely to hear the personal story of one of the individuals and their families who have made the sacrifices to be in the trial. We could not do our job if there were not people willing to participate in clinical trials, to show up for all the appointments, to do all the tests. So they are the real heroes in the research and to see one of our own heroes, our own participants, I don't really get to do that. So that was -- it meant a lot to me. And then you also asked about my personal journey. So for my personal journey with HD, it actually started with Nancy Wexler. I mean, I have to echo what Frank said, she's a force of nature. It's a great way to put it. She's one of the very first people I met after I decided to take a postdoctoral fellowship in a laboratory to study antisense oligonucleotides. And I was introduced to her at her Hereditary Disease Foundation meeting, and I was a student fresh out of grad school, just nobody and she gives me this huge hug and that's it. From that day on, you're just part of her fight. And in my postdoc lab at UCSC in collaboration with Ionis, when I met Frank, I was able to do the preclinical work in the mouse models to test the Huntington oligonucleotide and it worked. I mean, it worked so well I couldn't let it go, so I followed it to lab test to see it through. And now it's in Phase III trial. And it's actually that small vial of hope that Ed Wild held up in the film. And to see that in that moment, it was just -- makes you very proud and humbled to be a part of that.

So Holly, I mean, obviously, our goal is to have many, many more vials of hope. And so what would you say is unique about Ionis' approach to finding medicines for devastating diseases?

Yes. So I think this comes across in the film that every bit of science is built upon something that came before it. And it takes real dedication to follow that science and steadfastly day after day. And Ionis has been dedicated to perfecting all of those for 30 years. And that culture of asking hard questions and following the science, I think, is really essential. This stuff is not easy. But if we stick to it, we can make these transformative therapies and things like SMA and -- can happen. And the second thing that I love about what we do and I think is so important is how open and collaborative we are. So science is not done in a box, and Nancy's story in the film highlights that. It takes a village. Our culture allows us to be incredibly collaborative with research community, patient advocacy groups, patients, physicians, other companies. And this collaborative environment allows us to find the very best that a drug needs to succeed. Plus it's really fun that we get to work with a lot of brilliant and inspirational individuals.

Yes. I totally agree. And so one of the projects that was highlighted in the documentary extensively, and I think we've all cried about it at the company, is the spinal muscular atrophy project. And so maybe Frank, who is leading that project, can tell us about how we first started working on finding an antisense medicine for SMA.

Sure. As I mentioned, it was a derivative of the work that we started with Don Cleveland and Richard Smith that once we saw some promise for CNS-delivered antisense oligos, we -- I was interested in trying to identify additional applications for the technology. And our collaborator, Adrian Krainer, had published a paper many years ago that outlined a mechanism that we could use antisense oligos to treat spinal muscular atrophy. So I contacted Adrian and wanted -- and inquired whether he'd be interested in collaborating to really translate these basic science findings to a therapy. And he readily agreed, and so it's really that initial contact that started the collaboration. The technology that he first published on didn't work out. That is part of the process. We identified SPINRAZA and very quickly, as we were doing work, SPINRAZA was working in cells, it worked in the animal models. And it worked so well that we made a decision that the only way we're really going to know if this drug works is to take it into clinical trials. And it's sort of the magic story within biotech that we started treating patients with SPINRAZA, and we're getting very encouraging anecdotes from the clinic about how patients were responding. And it was sort of a once in a lifetime project to work on. And it's not just myself but I really have to recognize that it does take a village. And to a person, everybody at Ionis and then ultimately our partner at Biogen who came on the project a little bit later, to a person, every single person dedicated and put whatever it took to make this drug successful, everybody saw the promise what the drug could do. And I think it really reflects the spirit of the community that they all came together and spent many long nights or even sleepless nights working on the project to make it successful.

Great. And so maybe, Eugene, you can give us some perspective from the clinical development front. And so I was just wondering as a pediatrician, what do you feel when you see the stories of children being treated with SPINRAZA?

Well, I feel many things, Frank. But I think mostly, I feel privileged to live during these amazing times when scientific discoveries like antisense can lead to breakthroughs like SPINRAZA that ultimately change lives for thousands of patients and their families, when these genetic diagnoses like type 1 SMA no longer mean the death sentence and families affected by these horrible diseases can have hope and promise to live a better future.

Right. And so -- because, I mean, you are very intimately involved. And so what the -- can you just tell us a little bit about your personal contribution to bringing SPINRAZA to patients? And a question that I ask everybody, when did you first realize that SPINRAZA was actually going to work?

Yes. So I embarked on SPINRAZA journey in 2013, initially as a medical lead and later on took additional kind of leadership responsibility for -- as a project team leader at Ionis. This was truly -- as Frank just pointed, this was truly the most amazing journey of my career, a roller-coaster ride that I'll probably never forget, and I shared this ride with the amazing team of people at Ionis and outside. You asked me when I realized that SPINRAZA was going to work. Well, we kind of knew that it was working pretty early on, and although the evidence was light initially. And look, we're trained to be skeptics, right? We were trained to interpret early evidence from clinical studies very carefully, especially when these studies don't have a control group. But it's also impossible to ignore the data, and what I started to see and what we all started to see in early studies with SPINRAZA was really, really encouraging. So I guess for me, the epiphany moment that SPINRAZA was going to not just work but be something truly special was during our first study in babies with the most severe form of SMA, these babies who are destined to slowly get weaker and weaker and be losing the milestones that they've gained before the disease had set in and to generally not survive past their second birthday, were instead getting stronger and gaining new milestones like sitting and rolling over and standing and a few cases even walking. And sometimes I guess, you just don't need statistics to tell you that the drug works, right?

Right. Yes. It's definitely magical. So Frank, you alluded to before that obviously, not everything is easy sailing and there's many challenges. So can you tell us about some of the challenges that you encountered when developing SPINRAZA and really the emotional journey that we all went through with SMA?

Sure. I'm happy to. So like most research projects, you run into a few roadblocks. And unfortunately for SPINRAZA, the roadblocks were just, in many cases, lack of knowledge. And so we had to really optimize how to deliver the antisense drug into the CNS, how to get the best delivery to the target cells that we were working on. That wasn't -- it was a lot of work that went into it from a lot of people, but we worked our way through that and got into the clinical trials. There were some regulatory challenges that we had to deal with, both the European and U.S. FDA. This was really the first antisense drug that was being administered into the CNS, the cerebrospinal fluid, of these patients. And so there was a lot of caution on the part of regulatory agencies. And it was warranted at the time because we didn't know a lot about antisense technology and what effects it would have in the CNS both from a safety as well as an efficacy standpoint. And so it was a little bit slow going in the beginning. And I think a number of us found it a bit frustrating because we had to very carefully do our dose escalations and very carefully extend the duration of treatment. And at the same time, we were hearing from the clinics' encouraging data. I remember at an SMA meeting where we were with some of the investigators and one of the people who were participating in the study as an investigator kind of whispered to me, "These patients seem to be getting stronger." And like Eugene said, we -- you kind of have to put that in context that there is a placebo effect that you have to be careful about, overinterpret these studies. But it was encouraging and we pushed forward. We got the regulatory agencies aligned with us, and they allowed us to go into larger studies in different patient populations. And then ultimately, we have enough data that we and our partners, Biogen, designed a Phase III study that would definitively prove whether the drug was working or not. And to me, that was one of the hardest things that we had to do, was the decision to use a sham-controlled study for these most -- severely affected patients, that is the type 1 SMA patients who, without treatment, their life expectancy is less than 2 years of life. And knowing that some of those patients would not get drug was really a very difficult decision and we grappled with it. Our partners, Biogen grappled with it. And I know the investigators who participated in the study grappled with it as well as the families. And again, I have to really give a lot of credit to the families that participated in these studies, especially knowing that 1/3 of the patients who participated would not receive drug. But ultimately, that's the most scientifically rigorous way to prove that the drug worked. And it actually accelerated the approval of the drug because we had preplanned an interim analysis in the study. And the interim analysis was a blowout. It really did demonstrate that the drug worked, and we immediately switched all the patients that were on control, in this case it was the sham control, onto active drug. But that was a very hard decision and I think for everybody that was participating in the studies. But once we had the interim analysis data in, it went very quickly. Our partners, Biogen, filed the IND within a couple of months after having that data, which was really remarkable that we were able to put all the data together. And the FDA approved the drug 3 months after filing, which is one of the all-time records for drug approvals by the FDA. So it was just such a compelling data set that was there that resulted in a very fast approval of the drug. But there were some dark moments as we were conducting these studies. And again, a real shout-out to the patients who participated. Them and their families were the real heroes in this process.

Thanks, Frank. And actually, in the chat, I'm seeing a lot of beautiful comments about families with -- that have -- members with other neurological diseases. And so I guess I wanted to ask you, what has the success with SPINRAZA meant for the future of antisense technology for treating other neurological diseases?

Yes. So I think it's multiple. And there are a lot of lessons from SPINRAZA that I think are going to translate broadly across a number of neurological diseases. First off, when we began work on SPINRAZA, there were no effective therapies for neurodegenerative diseases. It was really palliative. You were doing things to support symptoms. But there was really nothing that was impacting the course of the disease. And with SPINRAZA, for the first time, we showed that neurological disease, in particular neurodegenerative diseases like SMA, are treatable that if you have the right target, you can have a dramatic impact on patients. And as an example, we -- the community has long suspected that if you treat patients before symptoms develop, that you could actually prevent the disease from occurring. And Chase in the film is a great example of that, where they started treating Chase before he ever developed symptoms. And I think you'd have a hard time identifying that he's an SMA patient. You saw the videos in the film. And Chase isn't the only example. There are a number of patients that are having a remarkable benefit from treating. So that, again, is the second lesson, is that with these inherited neurological diseases where you know what causes them, if you treat before you develop symptoms, you may be able to prevent the disease from occurring. And then I think from the technology perspective, it really did demonstrate that antisense technology could work in the CNS. And that, as I mentioned earlier, has greatly accelerated the number of projects that we're working on in the CNS, where, as I mentioned, there's over a dozen drugs in development and a large pipeline of drugs in the preclinical space that range from ultra-rare diseases, where there's maybe a couple of hundred patients that have the disease, to very large diseases like Alzheimer's. And we think the technology could be very broadly applicable across those diseases. I see it going beyond just neurodegenerative diseases to neurodevelopmental diseases like our Angelman syndrome project or other neurodevelopmental diseases, things like pain, chronic pain, where you're using non-opioid drugs that would treat chronic pain. And even -- I wouldn't rule out psychiatric diseases. They're very difficult diseases to treat. And as we are learning more and more about the genetic basis for psychiatric diseases, I truly believe that it will give us some opportunities to apply the technology for treatment of those diseases. So it's really been phenomenal and a real pleasure to see from these very humble beginnings to where we are today.

Yes. I mean, there's so much. Clearly, I have to get back in the lab. There's so much -- but another story, which was beautifully featured in the documentary, was the one on KIF1A. And Holly, maybe you can tell us about the work that you're doing on KIF1A.

Yes. Susanna, she's beautiful. She's why I work so hard, her and so many other patients like her that are suffering from these genetic diseases. And I became involved with KIF1A specifically when Luke, her dad, who's also in the film, and Dr. Chung reached out to Ionis to help. And of course, we said yes. The scene in the film where Wendy and Luke were speaking at the conference about our HD work, I think I may have actually presented the Huntington biomarker work at that rare disease meeting. It's part of a session on the importance of biomarkers. And I didn't know Luke and Wendy yet. We became collaborators shortly after that. And the next obvious step was to test ASOs in their mouse model from there. We need a mouse campaign. So that's what we're working on doing now.

Cool. And obviously, we're working on -- you're working on many other things. And so can you also tell us about what you and your team are doing for other genetic neurological diseases?

Yes. So Frank mentioned a bunch and where do I start? There's a lot. So to -- a few to highlight. One is the spinocerebellar ataxias that we're working on. There are others, SCA1, SCA2, SCA3. These are polyglutamine diseases like Huntington's. Each are monogenic diseases with one gene that we need to target. Then one that is really special that I'm very excited about is prion disease. Here, we target the gene for the prion protein, which is the protein that's misfolded in prion disease. And when it's misfolded, it leads to really widespread loss of brain cells. And we're collaborating with that one with Eric and Sonia, 2 scientists at the Broad Institute. And they're such an incredible couple. Their story could be filmed for our documentary. And like Audrey in the film, the disease they're fighting is in their family. And in their family, it's caused by a dominantly inherited mutation in the prion gene, the gene that we're targeting with our oligos. And their mission is to treat disease before any symptoms, like we've been able to do in SMA. And it's possible here because we can test for that genetic mutation. So we're working with them and trying to see that dream through.

Beautiful. So I think now we have time for the Q&A, and there's a decent number of questions that have been submitted.

So maybe I'll start off with Brett, and we have a question from Amy, who's asking how did Ionis' approach to science and research change, evolve as the genome sequencing continued.

Sure. Thanks for the question, Amy. And Holly highlighted some of this already. Our approach to science to the development of new medicines really has never wavered. We've always asked the hard questions, the tough questions, uncover every stone. There are so many setbacks along the way. This is hard stuff, to be able to invent a new platform for human therapeutics like antisense. The technology evolved, of course, but it evolved based on new learnings along the way, hard work, asking the hard questions, building, as Holly mentioned, on our past experiences over and over and over again and never quitting, never giving up. Others gave up and others gave up on us along the way, but we never did. And that has always been our approach. And the Human Genome Project didn't alter that. What it did was create even greater opportunity for us to help patients in great need by uncovering new causes of human diseases. So as I mentioned earlier, it really was an independent parallel path that was happening simultaneously, but it ended up being a perfect marriage that ended up allowing us to take full advantage of what the human genome uncovered.

Great. We have another question from Ann. And maybe this one is for Frank. So Frank, Ann noted that in myotonic dystrophy, not only are there complications obviously in the muscle but there's neurological complications, too. So she's wondering how the work is going for that.

Yes. So myotonic dystrophy is another project that's near and dear to my heart. And Ann's correct that there are both systemic effects of the disease, so effects on muscle as well as other systemic organs as well as central effects. So it's -- myotonic dystrophy is a disease that's caused by a triplet repeat expansion in a gene called DMPK. And I think most of you are aware that we had a clinical study looking at the systemic effects of an antisense drug to treat myotonic dystrophy. And the clinical study was successful in many regards. It taught us a lot about how to design a clinical study and what to measure in a clinical trial for myotonic dystrophy. But unfortunately, what we found is that the amount of drug that we get to muscle wasn't sufficient enough to produce the desired effect that we wanted to achieve. There were a couple of patients in the study that had very clear effects from the drug, but that just wasn't enough to translate to all these patients in the study. So we decided to take a step back and reengineer the drug to enhance its delivery to muscle. And that's a very active program with Ionis. In fact, Frank Rigo, your host, is leading that work. And so we're making good progress, and we're very hopeful that we'll solve that problem and have a drug that comes back into the clinic. But at the same time, what we're doing is leveraging what we've learned about the CNS delivery of antisense drugs and are identifying a drug that would treat the CNS symptoms of myotonic dystrophy, and again making very good progress. Frank, you can comment on it a little bit more. But I think we're on track to having a drug that would be entering clinical trials within the next couple of years for that program as well.

Yes. Well, we're certainly working hard on it. Actually, Holly, John has a question. He's basically asking with our technology, is it just targeting mutant RNA or is it more than just that?

Yes. So that's a great question. So we can actually target any part of the gene. So -- and sometimes, we target genes that aren't mutated at all that we know are involved in the disease and still causing a problem. And then sometimes, we can target not only a gene that's mutated like in Huntington, where we can target any gene, lower Huntington in any patient with Huntington's disease, we can also take approaches where we put an oligo right on top of a mutation. The mutation just lowers the one allele that happens to have mutation. So really, all the different options are open to us. We can target pretty much any RNA that is made from the genome that we think could have a benefit in disease.

Cool. And Eugene, I think this question is good for you. So Andrew is asking, for diseases where the patient population is small to medium, is there an opportunity to increase the speed of the approval process?

That's a million dollar question. We certainly hope so. There's been a lot of conversations, and we certainly approach development of these programs very carefully and weigh the time factor very carefully against sort of the regulatory risk. But there are no -- there is no one-size-fits-all. It really very much depends on how much is known about a particular disease, how well the natural history has been characterized, what is the actual addressable population and what we believe the data demonstrate. I think we certainly hope that there will be more acceptance of our platform in the future, but we need to bring a few more successful programs to regulators. I think that will certainly help with that conversation. But it is a very challenging and very poignant conversation that we're all having every day.

Right. So I think, Frank, this question's for you. And so Michael is wondering what the differences really are between antisense technology and the technology that is very popular right now, the CRISPR technology.

Sure. So I think there's a couple of fundamental differences. One is antisense technology targets RNA, which is the intermediate molecule between the gene, the DNA and protein. So the gene is transcribed into a copy called RNA, and then that RNA is translated into a copy -- or into proteins that do a lot of the function of the cells. And so by targeting this intermediate molecule, we produce transient effects. So the drugs, when we dose, produce the effect. And because RNA turns over, it's not long-lasting in the cell. You continually make new RNA. So if you withdraw the drug, the effects of the drug goes away. So it's really targeting this intermediate molecule. And that gives us a lot of opportunity that we can target any RNA in the body, whether it's protein-coding or noncoding or RNAs of unknown function. In contest -- contrast, CRISPR technology is a relatively new technology -- we're still learning a lot about it, that modifies DNA. So it's a way to -- you deliver cargo to cells that would do permanent modifications of the DNA. And if you can design it properly, it can correct a genetic mutation. And so for genetic diseases, there is a lot of interest in this technology. It's still very new. And it has a lot of optimization that's still in front of it as far as the technology. And I would really look at it as complementary technologies. They're not really necessarily competitive that in some cases, you may want to really do target DNA and correct the single nucleotide change that causes a disease. In other cases, modulating the protein or RNA may be a better approach for treating it. And I think ultimately for the patients, having all these different technologies available to them is really what's going to be important. It's that there is no one size that fits all. And it's important as scientists that we continue to push the envelope. And I predict 20 years from now, there'll be a new technology out there that is very promising and overshadows both CRISPR technology as well as antisense technology.

Great. Well, thank you all for taking the questions from everybody online. And I want to turn it over to Brett for some final thoughts in the couple of last minutes. And I would ask, Brett, what would you say to the patients that depend on us in difficult times?

I'd say that we're here for you. You can count on us. Count on us to find a way to say yes. As Holly mentioned earlier, when she was approached by the KIF1A investigator, her first reaction was yes. If there's any chance that we can do anything to treat a disease, to slow it down, halt it, reverse it, prevent it, you have our word that we'll go after it no matter how small that disease is or how large or how devastating or how complex the disease is. That's what Ionis is all about. That's why we created this platform called antisense, and that's our dedication to patients in need. It's always been and always will be. Our goal, as we've done in the past and we're doing now and we'll do in the future, is to deliver breakthrough medicines over and over and over again. So that's our commitment to the patients.

So I really want to thank Brett, Frank, Eugene and Holly for this very intimate, great discussion and all of you for tuning in today. And with that, we're going to end the webcast. And thank you to everybody for joining us.

Stay safe now. Thanks.