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

Good morning, and welcome to the Ionis 2020 Neurology Webcast. As a reminder, this webcast is being recorded. At this time, I would like to turn the conference over to Wade Walke, Vice President, Investor Relations. Wade, please begin.

Thank you, Kate. Before we begin, I encourage everyone who has not launched the webcast to proceed to the Investors section of the Ionis website to find the link to this webcast and the related slides. I would like to draw your attention to Slide 2, which contains our forward-looking language statement. We'll be making forward-looking statements, which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors discussed in our SEC filings for additional detail. With me on today's webcast are Dr. Brett Monia, our Chief Executive Officer, who will open up the webcast; Dr. Frank Bennett, our Chief Scientific Officer and franchise leader for neurology, will provide an overview of the neurological disease franchise and then introduce our ALS program targeting both genetic and sporadic forms of the disease. Dr. Frank Rigo, Vice President of Functional Genomics and Drug Discovery will provide an update on IONIS-C9Rx targeting C9 ALS and 2 new ALS programs, ION363, targeting FUS-ALS, the third most common inherited form of ALS, and ION541 targeting ATXN2 for sporadic ALS. Dr. Holly Kordasiewicz, Vice President of Neurology Research, will discuss our programs targeting Alzheimer's disease and dementia, Parkinson's disease, multiple system atrophy and a brief overview into our growing and advancing pipeline of Ionis own medicines for neurological diseases. And then Brett will wrap up the call and open it up for questions. With that, I'll turn the call over to Brett.

Thanks, Wade. Good morning, and thanks, everyone, for joining us today. Ionis was founded to invent, validate and advance a new and highly efficient drug discovery platform. Our platform technology, antisense is now established and clinically and commercially validated, enabling us to target diseases that were previously considered undruggable using traditional drug discovery platforms. Today, we are the global leader in RNA-targeted drug discovery and development, a leadership position that we believe will continue to grow as our technology advances. We have generated a world-class pipeline of potentially transformative medicines targeting a broad range of diseases. Our strategic partnerships are performing well to advance many of our mid- to late-stage medicines through development and commercialization. In addition, we have 18 Ionis-owned nonpartnered medicines for a broad range of serious diseases. The growth and maturation of the Ionis-owned pipeline is a top priority, and we are investing in this pipeline to further advance our pipeline while optimizing our commercial capabilities. We take a great deal of pride in our accomplishments, but this is just the beginning. We are laser-focused on the future and will further strengthen our leadership position in biotech innovation by continuously advancing our technological reach and by providing transformational benefit to millions of patients living with severe diseases. I realize this vision is a bit bold and aggressive, but I believe we have the right people and the technology in place to achieve these goals and elevate ionis to even greater heights and success. So how do we achieve this vision? By continuing to focus on our core fundamentals of innovation and scientific excellence like we have done from the beginning. By expanding the scope of our antisense technology, growing our Ionis-owned pipeline, optimizing our commercial capabilities and maintaining our focus on developing first and best-in-class medicines with the potential to transform the lives of patients. We have a pipeline of over 40 medicines, targeting a broad range of diseases and are preparing to deliver many of these medicines to the market over the next several years. Some of the expected indications are for rare or ultra-rare diseases, but we also have a rich pipeline of medicines addressing very large patient populations afflicted with common diseases like cardiovascular diseases and Alzheimer's disease affecting millions of people. Our cardiometabolic and neurology franchises are the 2 largest franchises at Ionis today with over 10 medicines in each franchise with more coming. Today's webcast will focus on the neurology franchise. I believe we have the leading neurology drug discovery and development pipeline in the industry with many more medicines including a host of Ionis-owned neurology medicines on the way. As many of you know, there is a tremendous unmet medical need in this space, and yet many pharma companies have been unsuccessful in finding effective therapies to treat neurological diseases and have exited the space. But here at Ionis, neurology remains a key focus. Building off of the success of SPINRAZA, we believe we will deliver a broad range of transformational medicines for neurological diseases to the market because we have a validated platform for neurological diseases that is advancing rapidly across a wide range of neurological diseases. Our medicines target all major regions of the brain and CNS cell types, our medicines target the root cause of neurological diseases. And importantly, our technology continues to advance in this area through scientific innovation, including through medicinal chemistry. These are the current areas of focus. As you can see, our pipeline encompasses a broad range of neurological diseases from the common, like Alzheimer's and Parkinson's to rare diseases like prion and ALS, to name just a few. Looking ahead, we believe our neurology pipeline will continue to grow through drug discovery and advancements in our technology while moving into new areas such as neurodevelopmental diseases and chronic pain. And many of these programs are Ionis owned, which you can see highlighted in red. As I mentioned before, the Ionis-owned pipeline is a key priority, and we are planning on bringing many of these medicines through development and commercialization, thereby maximizing their value to Ionis. And with that, I'll now turn the call over to Frank to discuss our advancing and growing neurological franchise.

Thank you, Brett. Over the past 10 years, we've built a remarkable and exciting pipeline of drugs to treat neurological diseases. In 2010, we just started a clinical trial for our first SOD1-targeting antisense drug. We had a couple of drugs in preclinical development and a handful of drugs in drug discovery. We learned a great deal from these early programs, which we have enabled us to grow our neurology franchise to one of the largest neurological disease pipelines in the industry over the past 10 years. Within our neurology franchise, we now have 2 commercial drugs, 3 drugs currently in Phase III clinical trials, 4 drugs in Phase I/II studies, and by the end of the year, we expect to have a total of 7 drugs in Phase I/II clinical trials. We are by no means done as we expect at least 3 additional drugs to enter the clinic next year and more than 5 medicine on the market over the next 5 years, and we have a large pipeline behind these drugs. This pipeline is a result of investments we've made in developing a solid foundation in antisense technology and applying it to the CNS. Antisense technology is well suited for treating neurological diseases, the technology is applicable to a broad range of therapeutic targets and antisense technology is very efficient as evidenced by the robust pipeline being created by a relatively small research team. Importantly, antisense drugs target the root cause of neurological diseases, resulting in disease-modifying therapies such as SPINRAZA and TEGSEDI. Finally, we've demonstrated that we can safely deliver antisense drugs throughout the central nervous system. Many neurological diseases are caused by toxic gain of function changes that occur in a variety of proteins and in a few cases, RNAs. This includes genetic diseases, such as Huntington's disease as well as sporadic diseases such as Alzheimer's and Parkinson's. Each disease has a unique protein or gene product implicated as the cause defector and these specific proteins are expressed in different brain regions. In almost all cases, the proteins implicated as cause for each of these diseases is not readily approachable by traditional small molecule drugs. Because antisense drugs target the RNA that produce these proteins, they are readily targeted with antisense technology. As mentioned, these toxic proteins are expressed in different brain regions, and we've demonstrated that we can broadly target these brain regions with antisense drugs. We started off focusing on the spinal cord, SPINRAZA for spinal muscular atrophy and our SOD1 antisense drug for familial forms of ALS are examples of programs we initiated to explore the effects of antisense drugs and diseases of the spinal cord. We have clearly established our antisense drugs work very efficiently on spinal cord diseases in numerous preclinical and clinical studies as well as in the commercial setting with nearly 11,000 patients treated with SPINRAZA. As our confidence grew that we could efficiently and safely target multiple cell types in spinal cord and treat spinal cord diseases, we started to explore whether antisense drugs could target additional regions of the central nervous system. We generated data first in rodents, then in larger species, including nonhuman primates, documenting that we could target regions of the brain affected by many neurological diseases, such as Huntington's disease. Today, we have demonstrated broad effects of antisense drugs throughout the brain in multiple preclinical species and in humans. This work was the foundation for our robust neurological disease pipeline in which we take advantage of the broad distribution of antisense drugs in the CNS and target diseases that cause pathology in these different brain regions. In addition to different brain regions, we've also investigated what cell types within the brain we can target with antisense drugs. In contrast to other modalities, like gene therapy, we effectively target all the major cell types in the CNS, such as neurons, microglial cells, astrocytes and oligodendrocytes. And it is also important to note that antisense drugs can target RNA in the nucleus and the cytosol, which means that we can target toxic RNAs that build up in the nucleus. At any time, we were exploring the effects of antisense drugs in the central nervous system, we also demonstrated that antisense drugs can be used to treat diseases of the peripheral nerves stem in muscle. TEGSEDI is an example of the former. These results are why we have the ability to create a broad pipeline in neurological and neuromuscular disease drugs. Today, Ionis has one of the most robust neuro pipelines in the industry. We are developing therapies for rare neurological diseases as well as common neurological diseases, such as Alzheimer's. We have 3 drugs currently in Phase III clinical trials. We have 4 drugs in Phase I/II studies and expect to have a total of 7 drugs in Phase I/II studies by the end of the year and at least 3 additional drugs entering the clinic next year. These medicines in development represent potential treatments for millions of patients who today have no effective treatments for their disease. We are excited to share updates for the highlighted programs with you today. So I'll start with SPINRAZA. SPINRAZA is a blockbuster drug that has transformed the lives of SMA patients. Sales of the drug continue to grow, and we and our partner, Biogen, believe there are continued growth opportunities for SPINRAZA. We and Biogen are committed to advancing new generation antisense drugs for patients with SMA with potential increased potency that should support less frequent dosing, possibly every 9 months to yearly. The NURTURE study is a presymptomatic study in which infants who are genetically diagnosed as being at risk for developing SMA were started on SPINRAZA before they developed any disease symptoms. NURTURE demonstrated for the first time that treating before symptom onset either prevents disease or markedly changes the disease course for these children. In the NURTURE study, 100% of the children treated with SPINRAZA can sit without support, 92% have achieved the milestone of walking with assistance, and 88% can now walk without assistance. Before SPINRAZA, most of these patients with SMA never achieved the ability to sit, and unfortunately, were not expected to live beyond the first 2 years of life. Today, 100% of the children started the study several years ago were still on therapy, some for almost 5 years. This is truly unprecedented. This is a milestone not only for patients with SMA, but also has important implications for patients with other inherited neurodegenerative diseases, such as Huntington's disease. That is prophylactically treating patients before they develop disease symptoms may prevent them from getting the disease. SPINRAZA is not only effective in children with SMA, but recent published studies from independent research groups provide evidence that SPINRAZA provides benefit in adult patients. Results from these studies demonstrate meaningful improvements in motor function in patients who have been living with SMA for many decades, such as no longer needing a cane to help them walk. In summary, SPINRAZA is the foundation of care for all SMA patients. Nearly 11,000 patients are being treated with SPINRAZA throughout the world. The drug is effective in all types of SMA patients and continues to show good safety profile. Our partner Biogen is exploring higher doses of SPINRAZA in the DEVOTE study to determine if greater efficacy is possible, and we are working closely with Biogen to advance new generation antisense drug into the clinic that supports less frequent dosing. Next, I'll discuss Huntington's disease. Huntington disease is a monogenic disease caused by CAG expansion in the huntingtin gene. This mutation leads to production of a toxic mutant protein that inflects destruction throughout the brain. Huntington's disease patients experience movement, cognitive and psychiatric dysfunction and ultimately succumb to their disease after about 15 to 20 years after symptom onset. Tominersen, our antisense drug for Huntington's disease is the first potential disease-modifying therapy targeting the root cause of the disease. Tominersen is the only Huntington-lowering therapy in Phase III clinical study. The study was fully enrolled earlier this year. Our partner, Roche, has developed a comprehensive development program from tominersen. This includes the pivotal Phase III study, Generation HD1, which has enrolled 790 patients. It's important to realize that this is one of the largest clinical studies for Huntington's disease. In addition to the Phase III study, Roche is conducting a natural history study in which patients who completed this study are eligible to enroll in an open-label study. Patients who enrolled in the Phase I/II study and completed the open-label extension study are also able to continue to receive the drug in a long-term extension study. Finally, Roche is generating additional pharmacokinetic data with the GEN-PEAK study. When completed, these studies will provide a robust set of data that should facilitate a quick regulatory review. Tominersen is a potential breakthrough therapy for Huntington's disease. The Phase III study is on track to read out in 2022. We've demonstrated robust and sustained reduction in mutant huntingtin protein in patients, which is well documented to be the cause of the disease and is the direct target of our drug. Tominersen continues to have a favorable safety profile. The drug has a long duration of action, which supports bimonthly or potentially triannual dosing. Now I'd like to turn to our ALS program. ALS is a severe motor neuron disease with no effective treatments. Current therapies extend survival by only a few months. ALS is caused by loss of motor neurons in the spinal cord and motor cortex, resulting in weakening and eventual paralysis and respiratory failure. The average survival time for ALS patients is 3 to 5 years from disease onset. However, some patients have a much more aggressive disease with survival less than 18 months. And the majority of ALS patients have sporadic disease. However, approximately 10% to 15% of ALS patients have a genetic cause, which has devastating consequences to those families who harbor such mutations. We started our ALS drug discovery program focusing on inherited forms of the ALS as the targets and how they contribute to disease were well validated. As our understanding of the pathways that contribute to ALS increases, we and our partner, Biogen, are also developing drugs to treat sporadic forms of the disease. Our most advanced ALS medicine is tofersen, which is currently being tested in a Phase III study called VALOR. The study should complete next year. As you will see in the next slides, patients treated with tofersen in the Phase I/II study demonstrated a slowing of progression of clinical decline compared to placebo-treated patients. The results of the Phase I study have recently been published in the New England Journal of Medicine. To help put this study in context, it is worth noting that there is a good genotype to phenotype correlation in SOD1 ALS patients. That is some SOD1 mutations result in a rapid progressing form of the disease, while some mutations have disease progression that is in line with the majority of sporadic ALS patients. Therefore, based on the specific SOD1 mutation, it's possible to predict how rapid a patient's disease progresses. This study evaluated multiple doses of tofersen up to a dose of 100 milligrams. Patients treated with 100 milligrams of tofersen showed a slower rate of disease progression as measured by the ALS Functional Rating Scale, which is shown on the 2 panels on the left. And the effect of tofersen on pulmonary function is shown on the 2 panels on the right. This slowing of disease progression was particularly evident in patients with mutations predicted to result in their rapid progressing form of the disease. Based on the ALS Functional Rating Scale and pulmonary function, there appears to be a clear beneficial effect on the disease progression in tofersen-treated patients compared to placebo. This does not mean that the drug only works in patients with rapidly progressing mutations. It's just that, unfortunately, the disease progressed efficiently in this 3-month study in the fast progressing patients to clearly see the drug effect. Tofersen has the potential to be the first disease-modifying therapy for ALS, demonstrating for the first time that ALS may be a treatable disease. VALOR is the placebo-controlled Phase III study of tofersen in ALS patients with SOD1 mutations. Patients will either be treated with tofersen or placebo for 24 weeks, and then have the option to enter into an open-label extension study. We expect to see data from this pivotal study in 2021. Tofersen is the first investigational medicine to demonstrate clinical benefit in SOD1 ALS patients. We demonstrated robust reduction in SOD1 and CSF, which is tofersen's target. In patients with rapid progressing mutations, tofersen demonstrated apparent slowing, a progression to clinical decline after only 3 months of treatment as measured using both the Functional Rating Scale and respiratory function. This is unheard of in this patient population. In fact, we were concerned that the disease course in these patients was so rapidly progressing, they would -- we'd not see a benefit. The drug is well tolerated and based on these data, Biogen initiated the Phase III clinical study, which is reported out next year. On that note, I'll now turn the call over to Frank Regal to discuss our other medicines to treat other forms of ALS.

Thank you. Thank you, Frank. This morning, I will provide you with an update on additional ALS drugs, including Ionis IONIS-C9Rx targeting C9ORF72 ALS and 2 new ALS programs. ION363 targeting FUS-ALS, the third most common inherited form of ALS and ION541 targeting ATXN2 for sporadic ALS. So let's start off with our C9ORF72 program. Our C9 medicine is a novel approach for the treatment of patients with ALS who have a mutation in the C9ORF72 gene for whom there is no effective treatment. Our C9 medicine is a highly potent and selective inhibitor of mutant C9 transcripts. In addition, we have obtained proof-of-concept in an animal model of C9 ALS. For this program, intrathecal administration allows for direct access to key effective regions in the central nervous system. Our partner, Biogen, is evaluating the safety, tolerability and pharmacokinetic profile of our C9 drug in adults with C9 ALS in a Phase I/II clinical study, and we expect the data from the Phase I/II clinical study in 2021. Now I want to tell you about the C9 molecular pathology. In mutation, in the C9 gene, is the most common inherited form of ALS and frontotemporal degeneration or FTD. This mutation is present in approximately 10% of all ALS and FTD patients. In normal subjects, a few copies of the 6 nucleotide sequence GGGGCC is present in the first intron of the C9 gene. However, in ALS or FTD, this 6 nucleotide sequence is repeated thousands of times, and the repeat sequence is referred to as a repeat expansion. There are 3 proposed mechanisms that have been put forward to explain how the C9 repeat expansion causes ALS and FTD. First, it has been shown that the repeat expansion causes reduced transcription of the C9 gene. And therefore, reduced production of the C9 protein. Secondly, the transcript, which is made that contains the repeat expansion is a toxic RNA. This toxic RNA sequesters a number of RNA binding proteins and this sequestration prevents the RNA binding protein from performing their normal RNA function in neurons. And thirdly, small peptides are translated from the RNAs that have the repeat expansion, and these peptides are toxic to neurons. So 2 out of the 3 proposed mechanisms that cause C9 ALS are gain of function toxicity mechanisms, and we -- and that are well suited to mitigate with our antisense technology. Our antisense drug for C9 ALS is designed to specifically target the mutant C9 transcripts. By selectively targeting the mutant transcripts, we demonstrate that we block the production of toxic RNA and the production of the toxic peptides. Importantly, this is accomplished without significantly affecting the production of C9 protein. Here's the proof-of-concept data that we have generated in a mouse model of C9 ALS. As you can see from the data to the left, when we deliver a C9 antisense drug to the CNS of mice, this results in a very robust reduction of the toxic transcripts with the repeat expansion. Importantly, there is no reduction of the normal C9ORF72 transcripts that do not have the repeat expansion. As you can see from the data in the center, our antisense drug results in a robust reduction of the toxic RNA with the repeat expansion that sequesters the RNA binding proteins. And the data to the right shows that our antisense drug also causes a dramatic reduction of the toxic peptides. In conclusion, our C9 antisense drug robustly neutralizes the pathogenic molecular mechanisms that result in toxicity to neurons. Biogen has already initiated a Phase I/II study for ALS patients with a C9 mutation. The primary endpoints in the study are safety and tolerability of intrathecally administered Ionis C9Rx compared to placebo. The secondary endpoints are measures of motor function. And after the pertinent follow-up, the patients are eligible for the open-label expansion. Now let's talk about ION363, an Ionis-owned medicine targeting FUS for FUS-ALS. FUS-ALS occurs to new mutations in the fused in sarcoma, or FUS, gene and this form of ALS, like all other forms, has no effective treatment. FUS-ALS is the third most common inherited form of ALS with an incidence that is approximately 25% of the incidents found in SOD1 ALS. FUS-ALS is generally a predictably fast progressing disease with a good genotype-phenotype correlation like Frank described for SOD1 ALS. FUS mutations cause motor neuron degeneration through a toxic gain of function mechanism. FUS, an RNA binding protein and -- FUS is an RNA binding protein, and the toxicity of the FUS protein is associated with its aggregation in the cytoplasm of neurons. We have demonstrated that our FUS antisense drug, which reduces mutant FUS protein in a FUS-ALS mouse model, also prevents motor neuron loss. We have identified a clinical candidate, ION363, which is designed to selectively reduce the expression of human FUS. And our FUS medicine has already been used by a clinical investigator to treat several ALS patients with FUS mutations under a compassionate use IND. Initiation of the Phase I/II study in FUS-ALS patients is on track for late 2020 or early next year, and we are excited that our FUS medicine has the potential for a rapid path to the market. Until now, we have been talking about our medicines for genetic forms of ALS. ION541 is our first medicine targeting sporadic ALS. Approximately 90% of all ALS is sporadic with no apparent familial history. However, a prominent pathological hallmark found in the neurons of people with sporadic ALS is the aggregation of the RNA binding protein called TDP43. In the picture, you can see the aggregation of TDP43 in the cytoplasm of spinal cord motor neurons. The aggregation of TDP43 induces toxicity to motor neurons. Importantly, preventing the aggregation of TDP43 has been an intense area of investigation in the ALS field. ATXN2 has been shown to play a role in modulating TDP43 toxicity. And human genetic data validates it as a therapeutic target for sporadic ALS. ION541, a highly potent inhibitor of ATXN2 mRNA is the first gene-targeted medicine designed to diminish the toxicity of TDP43. We have tested an antisense drug in a mouse model of sporadic ALS, which is driven by TDP43 toxicity. As you can see from the data at the bottom, administration of the ATXN2 antisense drug to the CNS of disease mice results in a substantial increase in survival and in motor function. These are very exciting time for ALS patients. We are using antisense technology to discover and develop potential disease-modifying medicines for patients with all forms of ALS, both familial and sporadic. We have demonstrated significant reductions of the SOD1 protein in the CSF of SOD1 ALS patients and have demonstrated a clinical benefit in a short-term study in SOD1 ALS patients with the most rapidly progressing form of the disease. And we are excited that our Phase III VALOR study is underway. We are currently in an ongoing Phase I/II study in ALS patients with mutations in the C9ORF72 gene, which is the most common cause of genetic ALS and FTD. We are advancing our wholly owned program for FUS, which is our third genetically validated ALS target. We plan to start a Phase I/II study in FUS-ALS patients by late this year or early next year. We are very excited of our ATXN2 medicine that is our first medicine for sporadic ALS, and ION541 is on track to initiate a Phase I/II study in the second half of this year. Finally, we and our colleagues at Biogen who we are collaborating with are by no means done. We are continuing to work hard on identifying other genes that could be targeted with our antisense medicines to treat sporadic forms of ALS. It is still early but we are optimistic that we will advance several additional antisense medicines into clinical trials over the next few years to treat sporadic ALS. And with that, I will now turn over the call to Holly.

Thank you, Frank. I'm excited to talk to you today about another class of neurodegenerative diseases, and these are tauopathies. Tauopathies are a group of diseases characterized by an accumulation and dysfunction in the protein tau. In these diseases, intracellular tau tangle is formed and result in a gain of toxic function, which causes synaptic and neuronal loss. This class of diseases includes, but is not limited to, Alzheimer's disease, frontotemporal degeneration, progressive supranuclear palsy and chronic traumatic encephalopathy. As you may have heard about it in the news, CTE. These are all forms of diseases that collectively affect millions of patients worldwide with no approved therapies to address the underlying cause of disease. As tau is the unifying toxic pathology in tauopathies, preventing the production of tau, stopping it from ever being produced, should provide significant benefit to patients suffering from tauopathy. Two of the tauopathies are diseases most people are familiar with, as they affect 44 million people worldwide. And that's Alzheimer's disease and frontotemporal degeneration or AD and FTD. AD and FTD are dementia that leads to a progressive and dramatic loss of memory and cognitive abilities. There's huge unmet medical need with clear similarities in the underlying pathology where the primary underlying pathophysiology in AD and many forms of FTD can be linked to a gain of toxic function in tau. Mutations in MAPT gene, the gene that encodes tau, are directly caused in some dominantly inherited forms of FTD. In AD, pathological tau spreads throughout the brain. And this increase in tau pathology correlates with cognitive decline. This is in direct contrast with another popular AD target, amyloid beta, where amyloid beta does not have the same strong correlation with disease progression as tau. Because tau is a clear driver of disease, we have designed our MAPT antisense medicine to prevent the production of tau. We're currently testing our MAPT tau medicine in AD patients. Our MAPT drugs binds to the MAPT transcript, which is a transcript that encodes tau protein. This results in a decrease in tau protein production. And it's important to note that in direct contrast to other therapeutic modalities targeting toxic protein, antisense drugs prevent the production of the toxic protein, rather than promote the degradation of extracellular subset. In the case of tau, our medicine is able to target all the known toxic forms of tau, including toxic tau inside of neurons rather than only extracellular fractions. This is important because the vast majority of pathological tau is intracellular. Because we target all toxic forms of tau, in preclinical models of disease, antisense-mediated suppression of tau production, reversed pathology, ameliorated disease and was well tolerated. Indeed, as you can see here, we are able to reverse existing disease pathology, bringing the pathological burden down to almost nothing in an aged model of disease. Our Phase I/II study in AD patients is currently ongoing, and I'd like to take a moment to talk about the design. This is a placebo-controlled multiple ascending dose study. Patients will receive treatment over a 13-week period. In the first 3 cohorts, we're testing the safety and pharmacodynamic effects of our antisense medicine following monthly dose. Then cohort forward work is interested. Similar to what Frank discussed with the HD program, given the promising clinical data from our IT-delivered antisense medicine, we are testing a quarterly dosing interval in our final cohort. This means patients will receive a dose on week 1 and their next dose on week 12. Spreading out the dose interval is supported by our preclinical model and possible because of the potency and long duration of action of our IT-delivered drug. If successful, patients will only need to receive 4 doses a year. The study is fully enrolled, and we expect data next year. Everything taken together, tau is another directly on-mechanism target. And IONIS-MAPTRx has a clear potential to be a transformative disease-modifying therapy for all tauopathies. We've licensed this program to our partner, Biogen. Synucleinopathies are another class of diseases that are caused by a toxic accumulation of intracellular protein. Synucleinopathies are directly linked to the accumulation of alpha-synuclein or aSyn. The most common of these diseases is Parkinson's disease, but this class also includes multiple systems atrophy and dementia with Lewy bodies. Like tau, alpha-syn pathology spreads throughout the brain along neural networks, and the pathology correlates with disease symptomology and severity. Preventing the production of alpha-synuclein is expected to [ suppress ] pathology and disease. Parkinson's disease, or PD, is a devastating disease, largely affecting the motor system, but can also affect other systems, including cortical regions leading to cognitive decline. It affects about 1% of the population over 60. Multiple systems atrophy is a fatal, rapidly progressing disease. It has some symptomology similar to Parkinson's disease with the key difference being the rapid progression. With MSA patients typically succumbing to their disease within 5 to 10 years after the disease onset, those on palliative care exist for these indications, this is a massive unmet clinical need and there is no approved therapy that targets the underlying synuclein pathology. ION464 is our alpha-synuclein antisense medicine designed to decrease SNCA mRNA, the gene that encodes alpha-synuclean and prevent the production of alpha-synuclean protein. Suppression of alpha-synuclean protein, which forms pathological aggregates and synucleinopathies, is another directly on-mechanism approach, that's expected to prevent pathology in this disease. The Phase I/II study, evaluating the safety and pharmacodynamic of ION464 has been initiated in a randomized, placebo-controlled multiple dose escalation study in patients with multiple systems atrophy by our partner, Biogen. There's another promising medicine in this space, and that is ION859, targeting LRRK2. LRRK2 is an interesting target for Parkinson's disease. Mutations of the LRRK2 are the most common dominantly inherited genetic mutations in PD. Increases in LRRK2 protein have a link to sporadic PD. Antisense-mediated reduction of LRRK2 is hypothesized to be beneficial in both patients with gain of function LRRK2 mutations and those with sporadic PD. The biology supporting LRRK2 with a target for PD is fascinating. LRRK2 is a protein with multiple functional domains, including a GTPase, kinase and multiple protein-protein interaction domain. Mutations throughout the protein have been linked to dominantly inherited PD. So it's not entirely clear all the protein functions that are contributing to disease. What is clear, is that it's a toxic gain of function. And this is supported by the genetics and the LRRK2 with increase in sporadic PD. Also that suppression of endogenous LRRK2 is beneficial in the mouse models of sporadic PD. Here on the right, we have some data in an alpha-synuclean model of PD, where antisense-mediated suppression of endogenous LRRK2 decreased alpha-syn pathology and improved motor function in the animal. Given all this, many groups are interested in LRRK2 as a target. Since one of its functions is a kinase, small molecule kinase inhibitors are being tested. One key consideration for small molecule inhibitors is that they suppress the LRRK2 kinase function throughout the body. And it is shown that this can lead to side effects, including backflows in the lungs. A key advantage of essentially driven antisense medicine is that we can selectively suppressLRRK2 in the brain or molding supression of LRRK2 in the lungs. Another benefit of owing overall LRRK2 protein is it's expected to target all the functions of LRRK2 that is implicated in PD, like the GTPAse function and not just the kinase function. Our LRRK2 antisense medicine, ION859, is currently in a Phase I/II study of PD patients and is being conducted by Biogen. This study will include both sporadic patients and patients with LRRK2 mutations. Now I'd like to discuss another group of diseases, the spinocerebellar ataxias. Like the other diseases discussed today, spinocerebellar ataxia is a class of devastating neurological diseases, affecting about 200,000 patients worldwide. The spinocerebellar ataxias are caused by diseases characterized by cerebellar dysfunction, which leads to a balance and movement disorder. Many of the SCAs also involve other brain [ majors ], and patients experience a myriad of neurological symptoms, most of which are fatal. Interestingly, many of the SCAs are monogenic disease caused by repeat expansion, similar to the CAG expansion in huntingtin gene in HD. These repeat expansions are found in different genes, depending on the SCA [ stock ] subject and are largely dominantly inherited. An example, SCA1 is caused by dominantly inherited expansion in the ATXN1 gene and SCA7 is caused by an apparent expansion in ATXN7 gene. As you may recall, Frank Rigo discussed ATXN2 earlier as a target for ALS. ATXN2 is also a target for SCA2 as dominantly inherited mutations in ATXN2 cause SCA2. These expansion mutations lead to the production of toxic mutant protein that wreak havoc throughout the brain. We're currently in development advancing programs into development for 4 of the SCAs, which cover about half the patients that suffer from spinocerebellar ataxia, and we're working on more preclinically. With many of the diseases we have discussed today, antisense medicines are uniquely suited to target the underlying primary disease mechanism in the SCAs. And we have the potential to be transformative therapies for patients with these diseases. This is supported by the preclinical work where rodent models of the disease have been treated with antisense drugs, suppressing the mutant gene product and had remarkable effects, dramatically improving the function of disease in these animals. We are developing 3 of these programs in partnership with Biogen, and that is SCA1, 2 and 3 and SCA7 is an Ionis own neurology program. As Frank mentioned earlier, we have a rapidly growing neurology pipeline. Given the tremendous unmet clinical need, coupled with the success of our platform in treating neurological diseases, we have acted quickly to expand our portfolio. I'd like to take a moment to discuss 3 very exciting Ionis own neurology programs. In addition to SCAs and ATXN7 discussed earlier today, these are prion disease, Alexander's disease and Lafora disease. One of our Ionis own programs I'm particularly excited about is our program for Alexander's disease. Alexander's disease is a severe childhood onset disease. It's hugely fetal. It's a devastating disease. The patients experience, among other things, seizures and developmental issues. It's caused by a toxic gain of function in protein called GFAP. Antisense drugs targeting GFAP mRNA have been shown to lower protein threat and importantly, reverse pathology in models of disease. Alexander's disease is largely a demyelinating disease, meaning the sheath that surrounds neurons aiding electrical conduction is lost. In preclinical models, preventing the production of GFAP is the primary driver of disease and has allowed myelination to repair itself leading to a reversal in disease phenotype. Shown here is the functional score in animals carrying the Alexander's disease mutation. A healthy animal with no [ over ] neurological phenotype will have a score 0. The animals with disease are already sick at the time of treatment. Following treatment with the GFAP-targeting antisense drug, the sick animals get better. They score similar to normal animals, and it's truly remarkable. We've identified ION373 as a potential medicine to treat Alexander's disease and plan to initiate clinical studies this year. Another exciting Ionis own program is our prion disease program. Prion disease is a rare, rapidly progressing and fatal disease. It's caused by a pigment, which is a misfolded variant of the protein that propagates the toxic form throughout the brain. Prion disease can be inherited, acquired or sporadic. All prion diseases are caused by misfolding of the prion protein. In model of the disease, it's not possible to get prion disease without prion protein. ION716 is designed to suppress the PRNP gene, which encodes the prion protein. Without the prion protein, disease can't propagate and exert toxicity. Since ION716 prevents the protein production rather than targeting a full specific fold or form, we can treat all forms of prion disease. The data in preclinical model is really remarkable. A piece of that is shown here. In rodent models of disease, infection with misfolded prion leads to death about 150 days after infection. Suppression of endogenous prion protein production can extend life to more than 400 days. It's truly incredible, the benefits we're seeing in preclinical models. Finally, here's another wonderful program, and that's our Lafora disease program. Lafora disease is an absolutely terrible childhood epilepsy. Children with mutations in genes involved in processing of brain glycogen have an accumulation of misformed glycogen throughout their brain. This leads to a progressive deterioration with progressive epilepsy and dementia. ION283 is designed to target glycogen synthase. Glycogen synthase, as the name implied, is involved in synthesizing glycogen. The mutations that cause the Lafora disease are loss of function mutations and protein involved in processing of glycogen, leading to a toxic accumulation. By lowering the synthesis of glycogen in kids whose brain have improper accumulation of glycogen, we're rebalancing the scales for them. In preclinical models, decreasing glycogen synthesis, as expected, can abolish the misaccumulation of glycogen caused by the loss of the processing enzyme. By lowering glycogen synthase, we have the potential to dramatically restore the balance in these children's brains. As you can see, we're very excited about all these programs that have the potential to help a lot of people suffering from truly horrible diseases. And we're not done yet. We're continuing to take on these and other terrible neurodegenerative diseases and are working to bring treatment to patients in need. With that, I'd like to hand the call back to Brett.

Thanks, Holly, and thanks to the rest of the team as well. Today, we provided you with a brief look into our neurology franchise, one of the largest therapeutic franchises at Ionis today. We believe that our neurology franchise is the leading therapeutic franchise for neurological diseases in the industry, which we expect to deliver a large number and broad range of potentially transformative medicines for many years to come. Neurology, as we all know, is an area of tremendous unmet medical need and a space where you have seen many companies exit due to failure to redirect their attention to other therapeutic areas. Here at Ionis, we remain committed to the patients in need suffering from neurological diseases and are focused on delivering transformational medicines for a broad range of severe neurological diseases with 7 drugs in clinical development and many more expected to enter development over the next several months and for years to come. As the leader in targeting neurological diseases, our antisense platform is demonstrating its effectiveness in all major brain regions, all CNS cell types, the peripheral nervous system, and now we believe we're on the brink of effectively delivering our medicines to muscle, further expanding our platform by reaching new types of neuromuscular and cardiovascular diseases. This chart illustrates the growth in our neurology pipeline over the past 10 years and the growth expected through 2025. Over the next 5 years, we are on track to deliver up to 8 NDAs for severe neurological diseases and add 10 or more programs to the neurology pipeline. As you can clearly see, our neurology franchise is firing on all cylinders and on track to be one of the key pillars of our growth for years to come. Of the 10 or more NDAs expected through 2025, approximately half are projected to come from our neurology franchise. Before we open the call for questions, I would like to take this opportunity to make you aware that later this year, we plan to host another investor webcast, this one focused on our other major franchise, our cardiometabolic franchise. So stay tuned for the details. And with that, operator, Kate, we're ready for questions now.

[Operator Instructions] The first question is from Joel Beatty of Citi.

This question is on ALS. I saw in the New England Journal of Medicine article earlier about a week ago, there was an editorial that talked about the potential for your SOD1 agent to be used in the sporadic forms of ALS. Could you share any thoughts on that or the other mutation specific ALS drugs to be used in the sporadic form or would that be better served by your agents that are being developed specifically for sporadic?

Thanks, Joel. I'll pass that over to Frank Bennett to address. As you know, Joel, I'm sure lot of medicines that target a genetic form of a disease often do have the potential to expand into a broader population. And that certainly has the potential in neurological diseases as well. I'll let Frank take on the editorial question and specifically the relationship between genetic forms of ALS and the potential treats sporadic. Frank?

Yes, I'm happy to. So there is a possibility that SOD1 may be useful for sporadic forms of ALS. It's somewhat controversial in the field. And that's one of the reasons why our partner, Biogen, and we wanted to focus on the root cause of the disease, which is the SOD1 patients to really validate that the drug works in that patient population. Having said that, there are data that have been published that identify misfolding a SOD1 in sporadic forms of ALS. And that's detected using an antibody that recognizes the misfolded form of SOD1. And as I said, it's a little bit controversial. Some labs have been able to identify this misfolded form of SOD1, other labs have not been able to identify it. And so I think that's a potential opportunity that once we establish that the drug works in patients with the mutation, there is a potential that our partner, Biogen, will conduct an additional study in patients that have this misfolded SOD1 in their CSF, broadening the application of that program. At this point, though, I think it's a little premature to say that Biogen is definitely going to do that. I think it's -- right now, they're focused on getting the drug approved for the inherited forms of the disease.

Thanks, Frank. And did you want to comment on the potential to expand on -- for C9 and FUS to expand into sporadic ALS or broader indications?

Yes. So C9 is very specific for the C9 protein or RNA. There are, what I referred to as de novo mutations in the C9 gene that occur for the first time in an individual that presents with the case and it wasn't inherited. In total, C9 accounts for about 10% of all ALS cases. Both the inherited forms as well as de novo. For that particular program, I just honestly don't see an opportunity to use that drug beyond patients that have this hexanucleotide expansion that Frank mentioned earlier. For FUS, there is a potential that it could be used more broadly. Right now, I think it's remote, but I wouldn't rule it out entirely. And again, we're focused on patients with the FUS mutation to really document that the drug works. And then we'll revisit whether it's worth exploring in sporadic patients there. We do have other programs like Frank mentioned, on ataxin 2 to target sporadic forms of ALS. And there are a large number of additional targets that have been identified through the excellent research that's going on in ALS right now that have the potential for treating sporadic forms of ALS. And we and our partner, Biogen, are very much focused on exploring those additional targets as well.

The next question is from Tyler Van Buren of Piper Sandler.

Thanks for the very comprehensive and educational webcast. Had a couple of questions on the ALS franchise, which seems to be expanding rapidly. I guess the first one is on tofersen and the VALOR Phase III data next year. Just as we think about the existing data set, can you remind us how you define fast progressors, where you saw the errors bars really start to separate in terms of both the functional and the respiratory endpoints. And then also are -- is the Phase III enrolling a patient population that is consistent with those fast progressors? And maybe you could talk about it in your statistical powering? And then the second one is on FUS ALS, you noted that it's been used by a clinical investigator to treat several ALS patients under compassionate use IND. Can you speak towards that experience? Have they seen any clinical improvements?

Frank, would you like to take that, please?

Sure. So first off with SOD1, as I mentioned, there's a very good genotype to phenotype correlation. There have been several publications that are really documented that if you have a specific mutation, you can predict the clinical course for that patient. And as an example, there's a mutation called A4V, which is alanine for valine substitution at codon 4, that has a very rapid progressing form of the disease. These are patients that will present with some hand weakness and then the year later be dead from their disease. So it's a very rapidly progressing form of the disease as rapid as any cancer is out there. And based on the specific mutation, that's how they categories patients as being fast progressing. And they've also collected clinical data before they went into the study. That further document the rate of the decline that these are, in fact, fast progressing mutations. And so in the study, they define fast progressing mutations as both the specific mutation that occurs that's predicted to be fast progressing and then clinical data that support that they have a very rapidly progressing form of the disease. So hopefully, that answers that question. The second question you asked is about the FUS program. So we were approached roughly 1.5 years ago by a couple of clinical investigators that had just a really heart wrenching story of a young woman who had a mutation in FUS. And at the time, we were exploring FUS as an antisense target for treating ALS and made the decision -- we had done quite a bit of screening to identify a drug candidate, and made the decision to provide them the opportunity to utilize that drug in a capacitate use IND. In total, I think there's been 5 or 6 patients that have been treated. These are uncontrolled studies [indiscernible] studies, so you have to take everything very cautiously. And it's really impossible to determine whether this is the natural history of the disease or if there's a clinical benefit, and this is still very much ongoing. But we're encouraged by what we've seen so far in the data. And that's why we feel that the only way that we're ever going to know whether this drug works is to do a well conducted clinical study to really document that the drug works. And so we've been working with the investigator to set up and start this clinical study. But as I said, it's -- we're encouraged by the data that we've seen, but I don't want to over-interpret it because it's not controlled data at this point.

And if I can -- thanks, Tyler. And if I could just add back to the SOD1 ALS study. So Tyler, the -- it does -- the study does include both the fast progressors and the regular progressors with SOD1 mutations as did the Phase I/II study. Same clinical endpoints that were shown, well, it includes the clinic end points that were shown in the data that we've summarized today, and it's a longer study as well than the Phase I/II study. I think it's about twice -- I think it's twice as long, if I remember correctly, as the Phase I/II study, 6 months, right? So it is very similar to the Phase I/II study, only longer and more patients, of course.

I should say -- I should have pointed out, it isn't enriched in the fast progressing patients. It enroll all of them, but there'll be some enrichment for faster progressing mutations.

The next question is from Jim Birchenough of Wells Fargo.

Thanks for all the detail and exciting stuff in the neurology pipeline. Maybe just a few questions on the wholly owned rare diseases, Lafora, Alexander & Peyronie disease. Could you maybe talk about the opportunity in terms of patient numbers for each of those indications to start off with? And then I guess the second part is just how well understood is the natural history data? And is that adequate to benchmark against with-a-single-arm study or will you be doing your own natural history studies?

Holly, you want to take that on?

Yes. So for Lafora disease, Peyronie's disease and Alexander's disease, there's a few hundred patients enrolled for Lafora disease and Alexander's disease and more in Peyronie disease. In Peyronie's disease, we'll be looking at both presymptomatic genetic patients in a pre-treatment paradigm as well as symptomatic patients. So that gets you a bit about the numbers. When it comes to natural history, there is some work done in natural history in all of these indications. We are also working on doing some of our own natural history studies potentially using lead-in natural history studies as well as natural history studies that we've already initiated to help inform the clinical trial design.

Yes. And to add to that, Jim, we're in discussions with regulators now. We can't say more about the path forward at this time. But we are hoping -- we are fully expecting as these our rare diseases with huge unmet medical needs to be able to -- we're hoping to have -- I'm reasonably confident that we'll be able to identify rapid paths forward for clinical testing to hopefully get these drugs to market quickly. We are expecting, as mentioned, I think, it was mentioned in the webcast, to start clinical studies for all 3 of these programs in 2021.

And maybe just a follow-up to that, Brett. I'm assuming those studies in 2021 will be in patients with the diseases. Is that right?

Absolutely. Yes. They'll be in patients with the disease. And as Holly mentioned, we're gathering as much natural history data as we possibly can, both from external sources as well as our own studies to match these studies up against.

The next question is from Paul Matteis of Stifel.

This is Alex on for Paul. Just a quick question, sort of a broad question. As you're thinking about expanding into some of these more whole brain diseases, are you confident that, sort of, the standard intrathecal lumbar administration is sufficient to achieve the knockdown sort of the biodistribution that you need?

Frank, you want to talk about -- a little bit about what our experience is, our confidence is in our ability to deliver our medicines to the deeper regions of the brain and throughout the brain?

Yes. So we're -- most of these diseases, as you mentioned, are whole brain diseases. And so it's important to be able to target a broad section of the CNS. And based on all the preclinical data that we've generated, we're confident that we were able to get drug to where it needs to be. There is a gradient that you're well aware of that were exposed areas of the brain to CSF are going to have higher concentrations of a drug and therefore, more efficacy in those regions. But we have documented it in a number of different studies that we do deliver drug to some of the deeper brain structures. And that's why we have the confidence to go forward with the diseases that we're targeting is that we've documented very nicely in large brain -- species with large brains, such as nonhuman primates and dogs that we can target the regions of interest there. So that supports our decisions to go forward with these programs.

And this would be via just, sort of, a lumbar administration? Or would you explore other options?

Yes. So we've explored broadly, but we don't really see a big advantage for going some of the other options versus intrathecal dosing. We get very similar distribution with other routes of administration.

Next question is from Gil Blum of Needham.

Just a quick 1 on SOD 1 results. So we saw a pretty good difference in the rapid progressor. Was there any look as to the FUS new patient status of those rapid progressors? Was there any back looking kind of into that data?

Gil, you mean, of course, you mean SOD1 mutations, were there any relationship of the fast progressors in mutations in SOD1, not FUS, right?

Just to clarify, it was my understanding that there are FUS 1 mutation as a subtype of patients with SOD1. Also I was interest, if there was also kind of a look backwards at these rapid progressors?

Frank, was that work done?

Yes. I'm not aware that, that's true. So SOD1 patients is a unique population of patients. They have a mutation in SOD1 gene. Patients that have mutations in FUS are a separate group of inherited forms of ALS. So it's a different mutation that causes ALS. They both -- clinically, they're indistinguishable. But the disease is due to a mutation in either FUS or SOD1. In fact, there are over 30 different genes in which they've identified mutations that cause ALS with [ CNI North ] being the most common. SOD1, the second most common and FUS the third most common. So I don't think there's an overlap between SOD1 mutations and FUS mutations that I'm aware of.

All right. That definitely answers my question there. A different question about the treatment of Peyronie's disease. Is there a significant importance to the disease progression when you actually treat the patient, would you expect significant differences at different time points with this kind of treatment?

Yes. So that's a great question. So we've actually asked this experimentally in rodent models of disease. If we treat before symptom onset, we can almost abolish the disease, we can really extend the survival in animals. As we get closer and more into that symptomatic and end-stage disease. We still have a significant benefit in disease, extending the lifespan significantly of the animals, but it just decreases the later in disease. So up to, I believe, about 7 days before the animals die, we can still have a benefit, and then we lose the benefit which makes sense because that's about the time it takes for the oligo to go on board and then decrease the protein. But up until that point, we can still have a significant benefit, but you just -- the benefit is greater the further back that you go. And so fortunately, we will have the opportunity to treat presymptomatically because they are genetically inherited for us. And the sporadic forms, the idea will be to catch them as quickly as possible and get them on drug. And those patients, given the promising data in the animals, we're really excited about treating those as well. But as you mentioned, there is going to be that time window.

So maybe a bit of a follow-on. Is it challenging to identify Peyronie's disease in humans?

It is. And that's one of the things that we're working on and giving awareness into the community to try to be able to increase that diagnosis and have it be sooner. But given the times when diagnosis is currently happening and given the data that we're seeing in animal, there still is a window with how it's now, but of course, you want to improve that and always move that number back.

And of course, Gil, this is one of those diseases where there are centers of expertise, excellence that a lot of these patients will sometimes gravitate to. We're working with essentially all these sites. We also -- this is one area also where we're conducting our own natural history work. And working -- building strong relationships with investigators in the patient community as well. So we're trying to tackle finding the patients in parallel getting the study launched.

We look forward to our cardiometabolic disease.