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

Good morning, and welcome to Ionis' conference call to discuss Ionis' HALOS study results. As a reminder, this call is being recorded. [Operator Instructions] At this time, I would like to turn the call over to Wade Walke, Senior Vice President of Investor Relations, to lead off the call. Please begin.

Thank you, Drew. Hello, and thank you for joining us today to discuss the results from the HALOS study of ION 582 on people of Angelman Syndrome. Before we begin, I encourage everyone to go to the investor section of the Ionis website to view the press release we issued this morning and to see the slides accompanying today's webcast. These data will also be presented at the Angelman Syndrome Foundation Family Conference, or ASF, this Wednesday, July 24. We will post ASF slides on the Ionis website following the presentation on Wednesday. I would like to first draw your attention to Slide 2 which contains our forward looking statement. Our discussion today will contain forward-looking statements based on our current expectations and beliefs. Such statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors contained in our SEC filings for additional detail. Joining me on today's webcast, we have Brett Monia, our Chief Executive Officer, who will provide opening remarks; Holly Kordasiewicz, our Senior Vice President of Neurology Research, who will discuss ION582 in the context of Ionis' wholly owned neurology pipeline and strategy and review some of the preclinical data that support advancing this program into development. Rebecca Crean, Executive Director of Neurology, Clinical Development, will define the design of the Phase I/II HALOS study. Eugene Schneider, our Chief Clinical Development Officer, will join us for the Q&A portion of the call and we are pleased to be joined today by Dr. Elizabeth Jalazo, Assistant Professor in Pediatrics at the University of North Carolina School of Medicine, who will talk about the unmet need associated with Angelman Syndrome and Dr. Lynne Bird, Professor of Clinical Pediatrics at the University of California in San Diego, who will present the HALOS study results. And with that, I'll turn the call over to Brett.

Thanks, Wade and thank you, everyone for joining us to discuss our Angelman syndrome program and the positive results from our HALOS study of ION582. We are pleased to be joined this morning by 2 pre-eminence clinicians and researchers in the field of pediatric neuro developmental disorders. Both are experienced investigators and several clinical trials in Angelman syndrome, including our HALOS study. Dr. Jalazo is both clinician and parent of a child living with Angelman syndrome, brings a unique perspective to our discussion of this disorder, which she will touch on the unmet needed tools we have to evaluate potential disease-modifying treatments and definitions of clinical meaningful benefit in Angelman syndrome. And Dr. Bird will bring an equally unique and important perspective during her presentation of the HALOS study results. As one of the lead investigators in the long-running Angelman syndrome natural history study, she has contributed greatly to our understanding of this disorder. Her experience also qualifies her to provide her expert perspective on the results that she presents today. Ionis was founded on the principle of turning groundbreaking science and technology to transformational medicines for diseases with significant unmet need. Today, we are building upon that foundation by advancing a broad pipeline of innovative wholly-owned medicines through clinical development and now directly to patients. Our wholly owned Angelman syndrome program is a perfect example of our strategy in action with the positive HALOS study results we're presenting to you today, we believe ION582 has the potential to deliver significant value to the tens of thousands of people living with this severe disease. Today, we are on the cusp of achieving our goal to deliver a continuous, steady stream of new transformational medicines to patients. With the U.S. launch of WAINUA now underway, the first co-branded medicine for Ionis is followed by our upcoming anticipated independent commercial launches of olezarsen and donidalorsen, we are right on track. We are also looking further ahead, advancing our next wave of wholly-owned commercial medicines focused initially in neurology, while in parallel, rapidly advancing early programs across a number of existing and emerging therapeutic areas. SPINRAZA, QALSODY and WAINUA exemplified the transformational potential of Ionis medicines for neurological diseases. With over 15,000 patients treated to date, with Ionis discovered and developed medicines for neurological diseases and our fast advancing wholly owned neurology pipeline. Ionis is extremely well positioned to reach an increasing number of patients in need well into the future. Turning now to Angelman syndrome. Angelman syndrome is a severe, rare neurodevelopmental disorder characterized by profound developmental disabilities in many key functional areas, including communication, cognition and motor function. And with no approved treatments available today, Angelman syndrome represents a very significant unmet medical need. We are highly encouraged by the positive early results from the HALOS study of ION582 in people with Angelman syndrome. First, we have produced evidence of consistent improvement in many areas of clinical function, including communication, cognition and motor function. Second, we observed consistent improvements across ages and genotypes. And third, ION582 demonstrated a consistent favorable safety and tolerability profile in our studies. While early, we believe the consistency of results observed across assessments strongly support advancing ION582 into Phase III development as soon as possible. Furthermore, based on the emerging profile of ION582 and its potential to provide meaningful benefit to this sizable population, we believe our Angelman program is positioned to become the cornerstone of our wholly-owned neurology pipeline. Now before I turn the call over to Holly, our Neurology Franchise Leader and Head of Neurology Research, I'd like to thank everyone in the Angelman syndrome community, who have participated and continue to participate in the HALOS study. The contributions have allowed us to both advance a potentially disease-modifying treatment and to broaden our understanding of this severe disorder. We look forward to continuing to work with and learn from this dedicated community well into the future. And with that, I'll pass the call over to Holly.

Thank you, Brett. I'm very pleased to share with you the progress we're making in advancing our neurology pipeline and to introduce you through the foundational work that led to our Angelman program. Here is a look at our neurology pipeline, with 3 approved medicines and a level clinical program for range of neurological diseases. This pipeline with backpack trend discovering and developing our new therapeutics for the CNS. Our wholly-owned neurology pipeline is focused on 4 areas: pediatric neurology, dementia, neuromuscular and peripheral neuropathy and movement disorders. We are prioritizing targets that are causal to disease. And by focusing in these areas, we believe we'll be able to leverage various synergies across programs. This will be important as we develop our commercial capabilities for this franchise. ION582 align with these criteria and will be an excellent fit with our strategy. Here's an update on the progress of our wholly-owned neurology pipeline, beginning with pediatric neurology. First, in addition to ION582 is Zilganersen, our investigational medicine for a rare leukodystrophy Alexander disease. It is in Phase III development, and we just announced the study is fully enrolled with data expected next year. Second, we recently advanced our program for Pelizaeus-Merzbacher disease, another rare leukodystrophy into a first in-patient study. And third, we plan to advance our program for MECP2 duplication syndrome, a neurodevelopmental disorder into the clinic scene. In our dementia pillar, our Prion Disease program, ION717, is advancing the first inpatient study that is rapidly progressing dementia. And we expect to advance our second dementia program into the clinic this year. We also plan to expand our neurology pipeline focused on neuromuscular diseases, peripheral neuropathies and movement disorders and with more than 10 programs in neuro identification and preclinical testing today, we're making great progress, towards further expanding our neurology pipeline. Now turning to Angelman Syndrome. This disorder is caused by genetic variance on the maternal copy of chromosome 15 that disrupt the normal function of UBE3A, an enzyme involved in the ubiquitin proteasome pathway, in critical for neuronal function and synaptic development. Most cases are caused by a dilution of a region of chromosome 15 that includes the UBE3A gene. The remaining cases are caused by mutations in printing deficits that lead to loss of UBE3A protein. Importantly, in all of these cases and in all neurotypical brain, there is a functional paternal UBE3A gene which is silenced in neurons, as is illustrated on this slide. Our approach for Angelman Syndrome is to restore UBE3A protein production in neurons. To do this by suppressing the UBE3A antisense transcript with antisense oligonucleotides for ASOs, thereby enabling the paternal copy of the UBE3A gene to be reactivated. In other words, the maternal protein is gone and our approach is to activate production of the paternal protein which is functionally identical to the maternal. But to visualize this, on the left side of this slide is an Angelman syndrome neuron with genetic disruption in maternal UBE3A and the naturally followed paternal UBE3A gene. On the right is an ASO reactivating the paternal UBE3A gene, allowing production of paternal UBE3A proceeds, which is represented by the blue circle. The idea to target an endogenous UBE3A antisense transcript in the nucleus to activate the paternal UBE3A originated at Ionis in collaboration with Dr. Arthur Beaudet at Baylor College of Medicine. And Dr. Beaudet was part of the team that discovered UBE3A loss is causal for Angelman. When we first began, it was not known that targeting an endogenous antisense transcript in the nucleus could reactivate a repressed gene. Which can. We have demonstrated we can reverse the UBE3A gene repression in animal with ASOs that work via the RNA phage mechanism. Incidentally, as with fake modulation, sRNA have not been effective for this application because they have not been showing the work [indiscernible]. Additionally, we found that by strategically placing ASOs on UBE3A antisense transcript, we can suppress the transcript and activate a paternal UBE3A gene. And importantly, we can do this without inadvertently downloading any of the other genes on the transcript. Using this approach, we were able to demonstrate clear benefit in preclinical models of Angelman syndrome. Our seminal paper describing this invention was published in nature, and I'll walk you through some highlights. On this slide, on sharing data from preclinical models and ensuring that UBE3A protein can be upregulated by targeting the UBE3A antisense transcript. On the left panel is a healthy brain and a UBE3A protein is present in neuron, has been in white. The images in the middle and right-hand panels show brain from Angelman preclinical model. In the middle image, there has been no active intervention. And you can see very little UBE3A protein present in neuron. However, on the right, following treatment with an Ionis ASOs targeting UBE3A antisense transcript, there's clear restoration of UBE3A protein. The restoration of UBE3A protein production results in a functional benefit in the model. The bar graph on the far right highlights the significant improvements observed in learning and memory. Here in the Angelman syndrome model treated with an Ionis ASO is performing similar to healthy controls. These results in preclinical models support our work through the [indiscernible] program addressing Angelman into human clinical testing. Since we do this, we designed ION582, one of the important things are experience and know-how in developing ASOs for the CNS has given us, is our ability to design molecules that have consistently demonstrated available safety and potency in critical setting. In designing ION582, we evaluated about 2,600 ASOs in vitro and about 550 in vivo. We applied an iterative process to optimize the design which also resulted in a potent molecule, able to substantially up-regulate UBE3A, while also demonstrating a favorable preclinical safety profile. ION582 is a similar chemistry to our already approved CNS delivered ASO, SPINRAZA and QALSODY as people with Angelman syndrome with a normal life span and will likely require lifelong treatment, we are pleased with our first investigational medicine for this disorder, uses our well-established and proven CNS chemistry, where we have extensive experience with long-term treatment of neurological diseases. Our Angelman syndrome program is fully aligned with our vision to expand our wholly-owned neurology pipeline. We are well positioned to deliver a steady stream of development milestones for patients with severe neurological diseases. And here now to discuss Angelman syndrome from her perspective as the treating physician and parent of a child living with this disorder, Assistant Professor of Pediatrics at University of North Carolina, Dr. Elizabeth Jalazo.

Thank you, Holly, and good morning, everyone. I'm thrilled to be here this morning to provide a unique perspective on this disorder, both from the parent and clinician perspective. I've had the privilege of serving in my most relevant role as parent in this community for nearly 10 years, which has given me a progress feed for the incredible progress that's been seen in this community over the last decade. It really is an incredibly hopeful time to have a loved one with Angelman syndrome. All right. I am a paid consultant for the development of the program. Angelman syndrome is a rare, severe genetic neurodevelopmental disorder, affecting approximately 1 in 15,000 to 20,000 people worldwide. While the earliest manifestations of Angelman syndrome often occur early in infancy. Historically, kids were diagnosed between ages 2 and 4 after failing to meet key developmental milestones in areas such as reach and mobility, or with the onset of seizures. Fortunately, better access to genetic testing and greater awareness among physicians is now leading to earlier diagnosis and intervention with supportive treatment when they can help [indiscernible]. Even with improved access to genetic testing though in earlier diagnosis, most families still endure a lengthy diagnostic odyssey between when concerns first arrived and when diagnosis is made. There are ongoing efforts in the community to develop diagnostic assays suitable for newborn screening, and we're hopeful that with newborn screening in the future, we can start treatment even earlier in more children with this disorder. Angelman syndrome is characterized by profound developmental disabilities and a distinct set of clinical features. However, it's important to recognize that this is not a progressive disorder, as people living with this disorder, have a normal life expectancy and the level of disability remains generally stable throughout life. Without approved disease-modifying treatment, we manage symptoms through a combination of supportive therapies such as speech, occupational and physical therapy and medication procedures, now adaptive behaviors and the like. While these therapies are beneficial to a point, they're unable to meaningfully change the overall trajectory of this disorder. The associated concerns are wide-ranging affecting all areas of functional performance with significant deficit seen in areas of communication, cognitions and motor function. Communication is always severely impacted. We generally see improved receptive communication with learnability, comprehend simple phrases and follow simple commands. However, expressive communication is disproportionately impacted with most individuals remaining nonverbal for life. Alternative communication systems such as picture, exchange systems and AEC devices can be used to facilitate communication, but with variable results, an incredible amount of hard work for the individual with the Angelman syndrome. Intellectual disability is another prominent feature. While people with Angelman syndrome continue to gain incremental developmental skills across the lifespan, 15-plus years of natural history studies have shown us the cognitive ability to plateau around the developmental age of 2 to 4 years old and severe learning, comprehension and attention deficits make it difficult for individuals to follow directions, engage in school and social settings. These challenges can exacerbate hyperactivity, aggression, anxiety and other maladaptive behaviors. Motor function is also severely impaired. Flow on study date ataxia and core muscle coordination in terms of the characteristics. The regular often jerky, involuntary movement significantly delay and can prevent skills such as walking, grasping and feeding. Seizures are also common, generally presenting before the age of 3. Anticonvulsant medications can help and our main stay of therapy in the Angelman syndrome. However, breakthrough seizures are common and many families struggle to find the right drug or combination of medication. The tremor and jerky movements we see in these kids can be difficult to distinguish from seizures and can lead to anticonvulsant over medication. In my experience, children with Angelman syndrome can be some of the most loving social and hard-working kids. They're severn in desire to be more independent to be understood by their family and their peers. But despite this drive and persistence, there are limitations caused by Angelman syndrome great frustration, which is heartbreaking as a parent. I told you that people with Angelman syndrome are expected to live a normal life span, but I want to highlight that at the current time that requires full-time care and supervision throughout their lives, with caregiving often falling to a parent or a close family member. In recent years, there have been efforts to quantify the challenges faced by parents and caregivers with people of Angelman syndrome. Symptoms related to impaired communication are reported among the most challenging manage, an improvement in this area would be a priority considering a disease-modifying treatment for their child or loved one. Parents and caregivers also reported impaired cognition, disruptive behaviors, mobility issues and inability to participate in activities at daily living are similarly challenging to manage. There are a number of tools we can use to measure symptoms in people with Angelman syndrome. While none are validated endpoints and most do not have established minimal clinically important differences or MCID value defined, the measures shown on the slide are generally accepted as the most robust and comprehensive tools to evaluate people with Angelman Syndrome. These tools measure functional ability to direct objective assessment or subjective assessment reported by the clinician or caregiver. The daily scales of [indiscernible] for physician or the Bayley-4 is a standardized direct objective clinician-administered tool used to diagnose and quantify developmental delay in young children. Through direct observation and interaction during structured activities, the clinician assesses strengths and deficits in communication, cognition and motor function to determine a level of delay. And while designed for young children, it really is appropriate given the development level of people with Angelman syndrome. The Vineland Adaptive Behavior Scale-Third Edition or Vineland-3 is another standardized tool developed to diagnose intellectual and developmental disabilities. In Angelman syndrome, the subjective parent and caregiver reported tool of adaptive skills, independence through measures of communication, motor function, socialization and daily living skills. The Bayley-4 and Vineland-3 scales are often expressed as growth scale value or GSVs, especially in clinical trial settings. GSVs were developed specifically to track change in performance over time and across repeated treatment administration. They do not measure change by age group, which is beneficial when measuring a wide range of ages. Additionally, GSV are being used as the basis of research supporting development of Angelman's specific MCIT values. Unlike Bayley-4 and Vineland-3, the recently developed observational rating of communication abilities assessment or ORCA was specifically developed for Angelman syndrome and indeed exclusively to evaluate communication abilities across various settings applicable to daily living in this population. This subjective caregiver reported assessment was designed to capture individual verbal and nonverbal communication skills in their daily lives. Change on the ORCA is expressed as a total T-score derived using item response theory incorporating responses for the 22 communication concepts evaluated. This is a commonly used scoring method, in fact, college entrance exams at the SAT and ACT use this method. Like the ORCA, the symptoms of Angelman Syndrome Clinician Global Impression of Change or SAS-CGI-C is a subjective clinician-reported assessment to evaluate change across key functional areas in this population. The SAS-CGI was adapted for Angelman syndrome from the standard clinical global impression of change of CGI, which is widely used to evaluate a variety of conditions in clinical and research setting. Both assessments are scored on a 7-point micro scale and generate a score reflecting overall impression of change. The Angelman specific SAS-CGI also generates scores within each individual domain. The Angelman syndrome community has benefited immensely from the forethought of the clinician and research community and implementing an actual history study over 15 years ago. This rich data set shows us that in contrast in neurotypical children where we see rapid functional increase through a 3.5 years where the daily skills cut off for neurotypical children. For particularly, Angelman Syndrome due to UBE3A deletion, the more severe and more prevalent genotype overall function generally plateaus again, as the level of a typical neurotypical 2-year old. And those with the UBE3A nondilution mutations generally reach a slightly higher level of function in line with an neurotypical 4-year old. In all forms of Angelman syndrome, once these levels are achieved, they remain relatively stable with minimal improvement through adulthood. And then this is not to say that people with the Angelman syndrome don't continue to develop meaningful skills across the lifespan, that rate of gain just slows dramatically and the change is incremental. So what is clinically meaningful? In the context of clinical trials, it's important to understand what is clinically meaningful on these scale. Clinical meaningfulness is not yet defined for the Bayley or the Vineland, although efforts to establish these levels are ongoing. Fortunately, we have a wealth of natural history data like the data set I just shared with you that we can use as a comparator to show treatment effect with an intervention in a clinical setting. Based on research supporting the ORCA an improvement of 2 or more points is considered clinically meaningful. Despite this being a new assessment only recently included as a measure in the ongoing natural history study, there are sufficient data available to serve as a comparator to the natural history. And clinically, meaningful benefit on the standard CGI is equal to or more than 1 point change, while clinically meaningful change has not been validated on the Angelman specific SAS-CGI, given the similarities in the scale and the approach, it's reasonable to use the same criteria to measure benefit in this setting. As the Angelman-specific SAS-CGI is a newer scale longitudinal natural history [indiscernible] data is not yet available for comparisons. But what does this mean for a person with Angelman syndrome or a family impacted by Angelman syndrome in day-to-day life. Perhaps this isn't what you'd expect. We don't need our kids to necessarily learn to read and write at the age to SAT to profoundly impact the day-to-day function of our loved ones with Angelman syndrome. Just improving feed could profoundly impact the functioning of a person with Angelman syndrome and their family, I can tell you. Going from having no functional expressive language to even developing a handful of functional gestures, modified signs or word approximations that allow us simple, yes, no exchange, 2 to 3 turn conversation is profoundly impactful. Being able to communicate basic wants and needs to a caregiver with the communication device is a profound leap and independence for a person with Angelman syndrome. Improved balance could mean less falls, less trips to the ER and less stitches, less fear for family and more functional independence for people with Angelman syndrome. And gains in areas of functional independent like self-feeding and toileting can improve autonomy and really truly be life-changing for people with Angelman syndrome and their families and care-givers. In summary, Angelman syndrome is a severe disorder that needs disease-modifying treatment. Fortunately, we have a very proactive community, robust natural history data and a combination of measures that together positions us well for this endeavor. And with that, I'll hand the call to Becky.

Thank you, Dr. Jalazo, and thank you for that impactful presentation about the unmet need associated with Angelman syndrome. Good morning, everyone. I'm Becky Crean, and I lead the project team for Ionis' Angelman syndrome program. I'm especially pleased to be here today to present the design of a HALOS study of ION582. And we designed HALOS to be comprehensive because we wanted to demonstrate safety and meaningful efficacy in the demographic representative of the Angelman syndrome population. HALOS is a 3-part, open-label Phase I/II study designed to test ION582 in a broad range of people with Angelman syndrome. Entry criteria included male and female participants, ages 2 to 50 with confirmed diagnosis of Angelman syndrome caused by UBE3A deletions or mutations. The primary endpoint in HALOS is safety and tolerability. Exploratory measures are focused on generating evidence to benefit in key areas of clinical functions relevant in this population. Part 1 in HALOS is the multiple-ascending dose or MAD portion of the study. Part 2 and 3 comprised of long-term extension or LTE. The LTE is ongoing, enabling participants to continue treatment for up to 4 additional years. We tested low, medium and high dose levels of ION582 in the MAD. The medium and high doses were selected for continued evaluation in the ongoing LTE being dosed quarterly. Participants from the MAD low dose group who enrolled into the ongoing LTE are now receiving the medium dose of ION582. Today, we'll be reporting on safety and efficacy data from the completed MAD. The final time plan in the MAD was at 6 months, all participants received 3 doses of ION582 over 3 months, at baseline, month 1 and month 3, which are represented by the blue triangles on this diagram. All participants were assessed at 4 months, which is 1 month after the last MAD dose. Participants in the medium and high dose groups were also assessed at 6 months, which is 3 months after the last MAD dose. The focus of the data review today will primarily focus on the results from the 6-month time point. This table shows the domains we measured in the key functional areas Dr. Jalazo just described. We believe this comprehensive array of assessment tools positions us to generate a robust data set in this study. Additionally, the standardized Bayley-4 and Vineland-3 assessments are widely recognized and have been widely used across numerous Angelman natural history studies and interventional studies. And importantly, we believe Bayley-4 and Vineland-3 are likely to be recognized as valuable measures for our upcoming Phase III study. In the table on this slide, the green boxes represent the functional domains included in the HALOS study. Domains either not included in the assessment or not analyzed in the HALOS study or in the boxes shown in white. And as you can see, many of these domains were evaluated within more than one assessment. Our goal was to develop a holistic view of the participant with the data from objectives and subject assessments from multiple vantage points. Importantly, having data from multiple different assessments allows us to see consistency of response across all domains. There are 3 domains under Bayley shown on the left-hand column at this table, the daily living skills, socialization and behavior that we did not evaluate on the HALOS study. While these are domains within the daily, we did not include them in HALOS because they are nearly identical in content and assessment type to the Vineland where we did assess those domains. Today, Dr. Bird will share the data from all these assessments comparing the study results to the natural history where possible and a cross test to assess consistency in a response. We are so pleased with the progress we made with our Angelman syndrome program and with the results from the HALOS study, Dr. Bird will present next. And importantly, we believe the emergent profile and positive data from the HALOS study supports advancing ION582 into Phase III development. And here now to discuss the findings from the live portion of the HALOS study, principal investigator in HALOS and in the long-running natural history study, Professor of Pediatrics at UC San Diego, Dr. Lynne Bird. Dr. Bird?

Thank you, Becky, and good morning, everyone. I have some disclosures. I'm comfortable investigator on the studies that you see there and I'm also in consult with Ionis in the development of their Angelman program. So I've been involved in Angelman Syndrome Research since I was drafted by a family in 2001, and I continuously enrolled patients in a natural history study since 2006. And I estimate that over the years, I've personally evaluated more than 175 individuals with Angelman syndrome. And I'm very pleased to be here today to present these results. I'll start by describing the participants involved in this study. A total of 51 participants were enrolled in the multiple ascending dose or MAD portion of the HALOS study, ages range from 2 to 34 years and included both mutation and deletion genotypes. As expected in a relatively small first-in-human study, age and genotype are not evenly distributed between the dose groups. Participant were generally over in the medium and high dose groups compared with low dose, with all adult participants enrolled in high dose group. There were a greater number of participants with deletion compared with UBE3A mutations, which is consistent with the genotype distribution in the general Angelman population. 50 of 51 participants completed the MAD portion of the study with all 50 study completers opting to a enroll in the long-term extension. ION582 demonstrated a favorable safety and tolerability profile in all 3 doses evaluated in the MAD portion of the HALOS study. There were no discontinuations or adverse events that were considered related to study drug. The majority of adverse events were consistent with participant medical histories, Angelman syndrome symptoms or related to the lumbar puncture. Additionally, there were no reports of lower limb weakness, ataxia or radiculopathy. Turning now to data across functional measures. Performance from all 3 dose groups on the Bayley-4 for 4 months the last time point when participants in the low dose were assessed for efficacy are shown here. Improvements in GSV scores versus baseline values were observed across all key functional areas on the Bayley at 4 months. While in comparison to natural history is not shown here, benefit across these measures exceeded the minimal change in functional abilities we would expect based on natural history. The meeting with high doses demonstrated similar performance at 4 months as well as improvements that were consistently greater than the low dose in all domains. The remaining data we will be presenting today are from the final efficacy assessment of the MAD portion of the study at 6 months. As previously noted, this was the final time point in the MAD and only included participants from the medium and high dose group, as participants from the low dose group were not included in the efficacy assessment at 6 months, they are not included in the further analyses to be shown today. The medium and high dose groups were pooled for purposes of this evaluation. Pooling these groups increase the ability to detect treatment effects and to homogenize age and genotypes for comparison to natural history data. This was appropriate based on the small size of the study, the imbalances in age and genotype between dose groups and the similar efficacy observed with the medium and high dose group as was shown at 4 months. Data from the Bayley, the Vineland-3 and the ORCA will be compared to natural history in these assessments. As I mentioned before, the natural history study has been continuously enrolling patients since 2006, and we have more than 550 participants now. However, the natural history study has undergone some changes along the way. For example, we initially evaluated participants using the Bayley-3, but when the fourth edition became available, we switched to this version. So the number of patients evaluated are smaller than the total enrolled. Similarly, the ORCA did not exist when the natural history study began, but we introduced it once the cytometric properties were substantiated. The 39 participants for the score of medium and high dose groups were matched by age and genotype to natural history participants for these data analysis. As Dr. Jalazo discussed, since we have no established clinically meaningful change for Bayley-4 and Vineland-3, we use the natural history data for comparison. On ORCA, the Angelman specific assessment of communication, a 2-point or greater change is presumed to be clinically meaningful. This SAS-CGI-C, the Angelman specific clinical global impression of change does not have a natural history comparator, we instead measure benefit against the established level of clinically meaningful change of 1 point or greater out of a maximum of 3 points on the standard CGI-C scale. Deficits in communication are seen in 100% of individuals living with Angelman syndrome and are generally one of the most challenging symptoms to manage for people with this disorder. Communication is consistently rated by caregivers as the most important area for improvement. Inability to communicate needs or participate in daily activities often leads to frustration and maladaptive behavior common with this condition. Following treatment with ION582, there is an increase in respective communication for baseline and exceeding natural history. This improvement is seen with both the Bayley and the Vineland assessment tool. Data from the ORCA will be presented separately. The SaS-CGI does not measure receptive communication. So that's why you don't see this measurement. A similar level of improvement was observed in Bayley-4 measure of effective communication in deletion and mutation subjects. As you can see in this table, HALOS participants with deletion were considerably more impaired at baseline than those with mutations as expected from natural history. If you then compare change from baseline in GSV scores to the 6-month time point following treatment with ION582, the magnitude of improvement was the same regardless of genotype. On the next few slides, you will see improvements observed in expressive communication across all 4 assessments. Here, we see the change from baseline for the expressive communication domain on the Bayley, Vineland and CGI, both by direct measurement and subjective reporting from caregivers and clinicians. Consistent improvement in expressive communication were observed across assessment tools. For Bayley and Vineland, where natural history data are available, we see improvements exceeding those observed in the natural history study. For CGI, we see changes exceeding the clinically meaningful one point improvement. Correlations and improvements observed in receptive and expressive communication on the Bayley and Vineland were statistically significant. These findings suggest clinicians and care-givers are seeing consistent, measurable improvement in this key functional areas. On the Angelman specific ORCA, measure of communication, treatment with ION582 led to a nearly 4-point improvement, exceeding the clinically meaningful 2-point change or greater in this measurement. ION582 also exceeded natural history in this assessment. A correlation analysis comparing improvement on the relatively new Angelman syndrome focused communications test the ORCA to the Bayley, which has more data from its use in the natural history study was also conducted. In this analysis, we see a significant correlation with the Bayley on expressive communication domain. We do not, however, see a correlation between the single ORCA T-score and receptive communication on the Bayley. Across measures of communication, meaningful improvements were observed in both receptive and expressive communication with improvements largely correlated between assessments. Moving on to our next functional domain, cognition. Cognition is another key functional area that is profoundly impaired in all individuals with Angelman syndrome. Scores on the Bayley-4 and the SAS-CGI both showed improvement with ION582 treatment. Improvements measured on the Bayley exceeded natural history. And on the SAS-CGI, improvements exceeded the 1 point or greater change that is considered clinically meaningful. The Vineland-3 and ORCA do not measure cognition, which is why they are not shown. Both fine motor and gross motor function domains are measured on 3 of the assessments, the Bayley, the Vineland and the CGI. Scores measuring fine motor function show improvement following ION582 treatment for all 3 assessment tools. For the Bayley and Vineland, the improvements we see with ION582 exceeds that of natural history. We again see consistency in the data. ORCA does not assess motor function, so it is not shown. Here, we have growth motor function, like the results in fine motor function, we observed similar improvements across the 3 assessments that exceed expectations from natural history on the Bayley and Vineland and reach clinically meaningful benefit level on the SAS-CGI. In the SAS-CGI assessment of overall change at Angelman syndrome symptoms, clinicians reported clinically meaningful improvement in overall symptoms in 97% of participants at 6 months. In a responder analysis of all domains assessed in the SAS-CGI, we observed a beneficial response in most participants within each domain. This includes communication domain, cognition and motor function, but also maladapted behaviors, fleet and impairment of activities of daily living. Seizures had the smallest response. This probably reflects the fact that most individuals with Angelman syndrome have excellent seizure control on their anticonvulsive medications, and it was a requirement for participants to be on stable medication regimens to enter the study. The consistent benefit across subdomain further reinforces the meaningfulness of the data seen in this assessment. Similar robust and consistent results are seen when looking at a responder analysis for all domains of the Vineland. Here, response is defined as improvement from baseline to 6 months that exceeds age and genotype matched natural history data at the same time point. Again, in each domain, we see improvement in most participants exceeding natural history. There are clear improvements in measures of communication and motor skill. I will also point out improvements seen in a majority of patients in daily-living skill and socialization that also outpaced natural history gains. Here now of responder analysis covering all domains assessed in the HALOS study. We see consistent response rates across all domains with most participants showing benefit versus the comparators we discussed previously. And in most domains of test, we saw improvement in a majority of participants. The consistency of improvement gives me greater confidence that this is not simply placebo effect. This slide shows responses from caregivers asked to provide their perspective on changes seen in everyday function in a post-treatment survey at the 4-month time point. Responses include improved expressive communication, increased mobility, better sleep and more independence. As a clinician, while these are not placebo-controlled data, these responses support greater confidence and a potential disease-modifying effect for an investigational treatment at this stage of development. And here are some quotes received from families of study participants that I want to leave you with. All are positive and encouraging, but none is as moving as the last quote on the slide. A child in the study developed the ability to say "mama" for the first time in their life. While one can't put a p-value on this, it exemplifies what clinically meaningful benefit looks like in this population. Here are the key takeaways from the HALOS study. ION582 shows favorable safety and tolerability in this study. As reported at the FAST meeting in November, reductions in delta power were observed in children at 4 months and those reductions continued at the 6-month time frame. Reductions were dose dependent with greater reductions in delta observed in children treated with ION582. Evidence of clinical improvement were observed across all key functional domains, with 97% of participants showing clinically meaningful improvement in overall Angelman syndrome symptom on the SAS-CGI-C. And improvements in cognition, communication and motor function exceeded natural history expectations on the Bayley-4, Vineland-3 and the ORCA. And in conclusion, these data, while early, are encouraging, and I believe more further clinical development of ION582 in a well-controlled Phase III trial. And with that, I'll turn the call back over to Brett.

Thank you, Dr. Bird for your excellent and comprehensive review of the HALOS study results. Based on the positive results we've summarized today, we are highly encouraged about the potential benefit that ION582 could bring to people living with Angelman syndrome and for this program to become the cornerstone of the Ionis wholly owned neurology pipeline. Looking ahead, we plan to continue conducting the long-term extension portion of the HALOS study to generate longer-term data in participants treated with ION582 for up to an additional 4 years. We plan to meet with regulators later this year to gain alignment on our Phase III study design, and we expect to start the Phase III study in the first half of next year and to include a broad range of ages and genotypes. And once more, on behalf of Ionis, I'd like to express our sincere appreciation to the Angelman syndrome community for their partnership, their trust and support as we strive to deliver a very much needed potential breakthrough treatment for Angelman syndrome. And with that, I'll now open the call up for questions. However, before starting, I see the long line analysts queued up for questions. [Operator Instructions] And with that, operator, over to you.

[Operator Instructions] The first question comes from Debjit Chattopadhyay with Guggenheim Securities.

Congrats Ionis on the data. Our representative are the natural history data to what would be anticipated in a Phase III trial. And given the treatment effect, can ION582 deliver a stat-sig outcome on Bayley-4 cognition? Should that be the primary endpoint?

Thanks, [ Robert ]. So no we -- as Dr. Jalazo presented very, very nicely and commented on the -- Dr. Bird as well, the natural history data, for this disease is probably one of the best established most robust natural history data sets that exists for a rare neurodevelopmental disorder. So we believe strongly that this data as a comparator is incredibly meaningful and will be very useful and has been very useful in our decision to advance this program rapidly to Phase III development. Nevertheless, we do believe that a placebo-controlled study in Phase III development is important to actually validate the finding that we've reported today to prove that ION582 truly can be a real breakthrough treatment for this disease. Dr. Jalazo, is there anything else you would like to add to that?

No. I'll just echo. I think, which really is -- we are fortunate in this community to have invested in such a robust natural history study that as Dr. Bird mentioned has been recruiting continuously and rolling continuously for almost 20 years now. I don't see any reason why this wouldn't serve as a representative data set for the pivotal study as well.

The next question comes from Gary Nachman with Raymond James.

This is Denis Reznik on Gary Nachman. We appreciate you providing this comprehensive review of data, and congrats on all the progress here. Can you just give any more insight on the Phase III? How many patients will be needed? How long they'll be studied for and your current thinking on what a good primary endpoint you'd want to study?

Thanks, Denis. We're putting our final touches on the Phase III trial design now. And we look forward to sharing the design once we get FDA feedback, and we really settle on a Phase III trial design. Broad strokes, we're looking at a couple of hundred, 100 to 200 patients, broad population. As I mentioned earlier, and we strongly believe that the Bayley-4 and the Vineland are the choices that are recognized by the FDA, as being most important. Most likely a subdomain within Bayley-4, but we haven't made that final decision yet. We will share it soon. And -- but our first objective, our top priority is to gain alignment with the FDA rapidly. And to move ION582 into Phase III development as early as possible next year.

The next question comes from David Lebowitz with Citi.

When designing the upcoming Phase III trial, how do you determine which components of the Bayley-4 are optimal? Should there be similarities between competitor trials or could they be variations?

We are -- thanks, David. We are 100% focused on our program. And as Dr. Bird presented very nicely today, there are many aspects that are important to improve in this disease that we've demonstrated, I'm pretty convinced, very convincing data that we can benefit patients through, whether it be cognition, receptive or expressive communication, motor function and so on. We will look at all of -- we will continue to look at all of these end points to ensure that we have an endpoint that we believe will demonstrate true clinical meaningfulness in the placebo-controlled trial, based on the objectivity of the analysis and our confidence that we will actually be able to demonstrate improvements. We'll also have -- we will also certainly include additional secondary end points that are part of Vineland and Bayley and those will all in totality be critically important to demonstrate -- to really demonstrate convincing end benefit in our trial. Competition, we're focused on Angelman syndrome. This disease is our competitor. This is a disease that's in tremendous need for treatment today. And that's what we're focused on is tackling this disease.

The next question comes from Akash Tewari with Jefferies.

This is Amy on for Akash. Congrats on the data, so we've seen that maternal deletion patients generally have worse prognosis and other genotypes of the Bayley-4 receptive communication component that you broke out? Did you see any difference in efficacy between deletion and mutation patients in the other domains? And then any reason why the cohorts weren't age-matched?

Yes. Thanks. So you're correct. And as Dr. Jalazo said earlier, indeed, the deletion patients generally have a higher disease burden than mutation patients. So you might think that it might be a lower bar to show benefit in mutation versus deletion. But in fact, in our data that we showed in the receptive, we showed a similar magnitude of benefit in both populations. And I could tell you that -- we've also seen consistent benefit in deletions and mutations, although there's far fewer mutations in our study, than deletion benefit across other measures of benefit as well. And we -- as I mentioned earlier, we expect to include a broad patient population in our Phase III trial design. Indeed, we did have imbalances in certain -- in demographics, in certain treatment groups. The in particular, the age groups. We had all of our adults in the high-dose group. And that was -- actually had a design we felt most comfortable to share or to expose and this is a first in patient, first-in-human trial. We wanted to dose the high-dose group into the adult population exclusively to ensure that we had good safety going forward. But -- so that was intentional. There was also some imbalances in mutations and deletions and -- but more so it was in the age groups. But again, that was intentional. Thank you for the question.

The next question comes from Yanan Zhu with Wells Fargo Securities.

Congrats on the data. So I wanted to ask about the dose response between medium and high dose. And it was noted that there is imbalance in age and genotypes that -- could you put the company comment on how age -- obviously, the high dose group had adult patients, whereas medium group has only pediatric patients. How could that have contributed to the Bayley-4 responses? And if the doctor could comment on, just in general, how should we expect adult patients to perform over time under a therapeutic intervention compared to pediatric patients? That would be helpful.

Thanks, Yanan. Let me start, and then I'll ask Dr. Bird to comment on her thoughts on how, say, adult patients may respond compared to children or adolescents with interventional treatment like ION582. So first of all, in the dose response, we did show evidence of the dose response, the low-dose group at 4 months clearly was not showing evidence of efficacy comparable to the medium and the high dose group. So we did see a dose response in that aspect. And you know what, that was exactly as predicted by our preclinical data. The low dose group was predicted to be barely achieving the threshold without drug exposure to achieve benefit or upregulation of UBE3A. So that's kind of what we expected. As far as the medium and the high dose groups, I think time will tell. We're looking forward to longer-term treatment of those -- both of those dose groups in the long-term extension. And with time, they may separate. The medium and the high dose groups. And as a reminder, we did do a load. So treatment with all the doses, we had several load, we had doses that were done at day 1, 1 month and then 2 months later, so it was a loading regimen. As we move into the long-term extension, we'll be dosing quarterly. So we may see separation of the medium and the high dose groups. We have not decided on our dose yet for Phase III development. So this data will be very informative. As far as age, we are pleased with the evidence of efficacy we saw in children adolescents as well as adults. Very pleased with this outcome. Dr. Bird, your thoughts on what you might expect from an influential treatment related to different age groups?

Well, sort of intuitively, one would think that the earlier you start kind of neurodevelopmental disorder, while the brain is still being wired, the better off you might be. But we certainly saw a benefit across all ages. So I don't think we really know if there's a ceiling at which you can no longer expect any benefit. That -- those data will come. But at the moment, it appears that every age group can benefit.

And I'll ask Dr. Jalazo for her thoughts on newborn screening and the importance of that. But as you know, in our spinal muscular atrophy trials with nusinersen, we showed that if you can actually treat babies early on after or genetically diagnosed at birth. Many of those cases will have normal life. So getting in early is certainly better. But maybe Dr. Jalazo will give little on newborn screening and where we are with that?

Sure. This has been an area of a lot of ongoing effort in the Angelman community both again, to develop an assay that is suitable for newborn screening. We have to be able to detect the disorder in a bloodspot and do that in a cost-effective way. And we're really still in kind of early days of exploring what that might look like on a public health level. But this is certainly something that is of great interest in the Angelman syndrome community. I think as Dr. Bird mentioned, logically, we think it's in neurodevelopmental disorder. The earlier we intervene, the more robust of a response we may see. But again, I think what's really incredibly encouraging about this data, as Dr. Bird mentioned, that we might expect to see a response at whatever age we intervene, just amazing.

The next question comes from Jessica Fye with JPMorgan.

I think you called out during the presentation that there was little to no difference in the magnitude of benefit observed on receptive communication across the deletion and mutation genotypes. What about what you saw on cognition across genotypes?

Yes. Thanks, Jess, for the question. As I mentioned earlier, we're seeing consistent benefit in across mutations in all of the major subdomains in Bayley. So, we're pleased with the fact that whether we're dealing with mutations or deletions or age groups, we're seeing evidence of benefit. So it's very exciting to actually see that data and this supports our plans to pursue a broad patient population in Phase III.

The next question comes from Jay Olson with Oppenheimer.

Congratulations on these results. What do you see as the ideal outcome or target goal for Angelman patients on long-term treatment with 582? And is there eventually a development plan for a brain-penetrant version of 582? What's the potential for your brain penetration technology to improve clinical outcomes for 582, even beyond the impressive results you've presented here today?

Well, I would like to ask Dr. Jalazo to take the first part of your question as -- from her perspective as both a parent and a lead investigator for an Angelman disease, what she would like to see from an investigational medicine to demonstrate benefit. But before I toss it to her. We're really excited about the advancements we're making, the progress we're making, in coming forward with new molecules that cross the blood-brain barrier that allow us to administer subcutaneously, infrequently or even for possibly intravenously. We have several candidate programs that are advancing rapidly to development. And certainly, you can make the case that this is a program that would benefit a great deal from a parenteral systemic administration profile. So stay tuned for that, Jay. We're looking forward to providing updates on our blood-brain barrier penetrant platform down the road. Dr. Jalazo, clinical meaningfulness from your perspective.

Yes. I mean, first and almost, I love this conversation about optimizing future delivery methods. And I think this is -- I'm so excited that you're talking about this. I think even with the current delivery methods the data that we're seeing is really encouraging. As I mentioned before, I think clinical meaningfulness, changes family by family, individual by individual. What is meaningful families really can depend on what a child or an individual is struggling with at that time, and this can be highly variable. But again, I think this is why it's so encouraging to see these results across different genetic subtypes, across different age groups, it just goes to show us that wherever an individual is on their journey with the Angelman syndrome, whether they're more profoundly affected or maybe have more mild symptoms, they stand to benefit. This change could be quite modest in the eyes of an external onlooker. But again, like I was saying, even handful of expressive communication tools could be really profoundly impactful for a family and an individual to have both increased functional independence but also the use of day-to-day living with this devastating disorder.

The next question comes from Gena Wang with Barclays.

So I think you mentioned that the lack of dose response partially due to also the deletion, mutation genotype and also the age. Wondering how would you consider that the impact or the patient stratification regarding the Phase III trial design?

Yes. Thanks, Gena. So I don't think I said that the dose response that we saw in the study was related to genotype. What I said was that we think it probably has to do with the fact that we had a loading dose upfront, and it's an early time point. It's very possible that with longer-term treatment and spacing at the dosing interval, we'll see a separation of the dose response for the medium dose and the high dose long-term extension. And in the long-term extension, we're evaluating all that data as ongoing. We did see a dose response in the low dose group compared to the higher dose groups at 4 months and that supports our preclinical modeling. That is kind of exactly what we expected to see. With that said, the data at the medium dose and the high dose group are showing consistent evidence of benefit regardless of genotype and regardless of age. So we don't think that has any impact genotype or age on the dose response data, those response results we've seen so far.

The next question comes from Mike Ulz with Morgan Stanley.

It's Avi Novick on in for Mike. Can you discuss the enrollment rate into the long-term extension and perhaps when and how you would plan to disclose some of the data from it?

Yes, sure. So the -- as we've mentioned, I think, earlier, of the 51 patients that we enrolled in the Phase I/II study 50, enrolled over into the long-term extension, which is, of course, very, very nice to see. And the vast majority of those patients continue today with a good number of those patients now treated beyond the year, in the long-term extension. I forgot the second part of your question, I apologize.

When might you consider disclosing the data on the long-term extension?