Ionis Pharmaceuticals, Inc. (NASDAQ:IONS) HALOS Study of ION582 in Angelman Syndrome Conference Call July 22, 2024 8:00 AM ET
Company Participants
Wade Walke - Senior Vice President of Investor Relations
Brett Monia - Chief Executive Officer
Holly Kordasiewicz - Senior Vice President, Neurology
Elizabeth Jalazo - Assistant Professor of Pediatrics, Division of Genetics & Metabolism, University of North Carolina School of Medicine
Becky Crean - Executive Director, Neurology
Lynne Bird - Professor of Clinical Pediatrics, University of California, San Diego, Rady Children's Hospital San Diego
Eugene Schneider - Executive Vice President, Chief Clinical Development and Operations Officer
Conference Call Participants
Debjit Chattopadhyay - Guggenheim Securities
Denis Reznik - Raymond James
David Lebowitz - Citi
Amy Li - Jefferies
Yanan Zhu - Wells Fargo Securities
Jessica Fye - JPMorgan
Jay Olson - Oppenheimer
Gena Wang - Barclays
Paul Matteis - Stifel
Andy Chen - Wolfe Research
Salveen Richter - Goldman Sachs
Yale Jen - Laidlaw & Company
Brendan Smith - Yaron Werber
Kostas Biliouris - BMO Capital Markets
Jason Gerberry - Bank of America
Myles Minter - William Blair
Operator
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.
Wade Walke
Thank you, Drew. Hello and thank you for joining us today to discuss the results from the HALOS Study of ION582 in people with Angelman Syndrome. Before we begin, I encourage everyone to go to the Investors 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 24th. We will post the 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 supported advancing this program into development.
Rebecca Crean, Executive Director of Neurology Clinical Development, will present the design of the Phase 1/2 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 of 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.
Brett Monia
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 two preeminent clinicians and researchers in the field of pediatric neurodevelopmental disorders.
Both are experienced investigators in several clinical trials in Angelman Syndrome, including our HALOS study. Dr. Jalazo, as both clinician and parent of a child living with Angelman Syndrome, brings a unique perspective to our discussion of this disorder, where she will touch on the unmet need, the tools we have to evaluate potential disease-modifying treatments and definitions of clinical meaningful benefits 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 into transformational medicine 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 Angelmann 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 US launch of WAINUA now underway, the first co-branded medicine for Ionis 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 exemplify 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 3 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's 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. Their 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.
Holly Kordasiewicz
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 to the foundational work that led to our Angelman's Program.
Here's a look at our neurology pipeline. With three approved medicines and eleven clinical programs for a range of neurological diseases, this pipeline reflects our experience discovering and developing RNA therapeutics for the CNS.
Our wholly-owned neurology pipeline is focused on four areas, pediatric neurology, dementia, neuromuscular and peripheral neuropathies and movement disorders. We are prioritizing targets that are causal to disease, and by focusing in these areas, we believe we will be able to leverage various synergies across programs. This will be important as we develop our commercial capabilities for this franchise. ION582 aligns with these criteria, making an excellent fit with our strategy.
Here is 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 rare leukodystrophy, Alexander disease. It is in Phase 3 development and has 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 inpatient study. And third, we plan to advance our program for MECP2 Duplication Syndrome, a neurodevelopmental disorder, into the clinic soon.
In our dementia pillar, our Prion disease programs, ION717 is advancing in a first inpatient study in this 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 ten programs in lead 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 variants on the maternal copy of chromosome 15 that disrupts the normal function of UBE3A, an enzyme involved in the ubiquitin-proteasome pathway and critical for neuronal function and synaptic development.
Most cases are caused by a deletion of a region of chromosome 15 that includes the UBE3A gene. The remaining cases are caused by mutations or imprinting deficits that lead to loss of UBE3A protein. Importantly, in all of these cases and in all neurotypical brains, there is a functional paternal UBE3A gene, which is silenced in neurons, as is illustrated on this slide.
Our approach for Angelman Syndrome aims to restore UBE3A protein production in neurons, do this by suppressing the UBE3A antisense transcript with antisense oligonucleotides or 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 silenced paternal UBE3A gene. On the right is an ASO reactivating the paternal UBE3A gene, allowing production of paternal UBE3A protein which is represented by the blue circle.
The idea to target an endogenous UBE3A antisense transcript in the nucleus to activate the paternal UBE3A gene originated at Ionis in collaboration with Dr. Art Beaudet at Baylor College of Medicine, and Dr. Beaudet was part of the team that discovered UBE3A loss is causal for Angelmen. When he first began, it was not known if targeting an endogenous antisense transcript in the nucleus could reactivate a repressed gene, we can, we have demonstrated we can reverse the UBE3A gene repression in animals with ASOs at work via the RNA phage mechanism.
Incidentally, as with splice modulation, sRNA have not been effective for this application because they have not been shown to work well in the nucleus. Additionally, we found that by strategically placing ASOs on the UBE3A antisense transcript, we can suppress the transcript and activate the paternal UBE3A gene. And importantly, we can do this without inadvertently down-regulating 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, I'm sharing data for preclinical models demonstrating that UBE3A protein can be upregulated by targeting the UBE3A antisense transcript.
On the left panel is a healthy brain in which UBE3A protein is present in neurons as seen in white. The images in the middle and right-hand panel show brain from an Angelman preclinical model. In the middle image, there has been no active intervention and we can see very little UBE3A protein present in neurons. However, on the right, following treatment with an Ionis ASO targeting the 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, it is performing similar to healthy controls.
These results in preclinical models support our work to advance a program addressing Angleman's into human clinical testing. But to do this, we designed ION582. One of the important things our experience and know-how in developing ASOs for the CMS has given us is our ability to design molecules that have consistently demonstrated favorable safety and potency in clinical settings.
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 ultimately resulted in a potent molecule able to substantially upregulate UBE3A while also demonstrating a favorable preclinical safety profile.
ION582 is a similar chemistry to our already approved CNS delivered ASOs, SPINRAZA and QALSODY. As people with Angelman Syndrome live a normal lifespan and will likely require lifelong treatment. We are pleased that 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 a treating physician and parent of a child living with this disorder, Assistant Professor of Pediatrics at University of North Carolina, Dr. Elizabeth Jalazo.
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 front-row seat 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 this program and Angelman Syndrome is a rare severe genetic neurodevelopmental disorder affecting approximately one 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 two and four after failing to meet key developmental milestones in areas such as speech 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 treatments when they can help the most. Even with improved access to genetic testing, though, and earlier diagnoses, most families still endure a lengthy diagnostic odyssey between when concerns first arise 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 and people living with this disorder have a normal life expectancy and the level of disability remains generally stable throughout life.
Without approved disease-modifying treatments, we manage symptoms through a combination of supportive therapies such as speech, occupational, and physical therapies, and medications for seizures, maladaptive 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 symptoms are wide-ranging, affecting all areas of functional performance, with significant deficits seen in areas of communication, cognition, and motor function.
Communication is always severely impacted. We generally see improved receptive communication with a learned ability to comprehend simple phrases and follow simple commands. However, expressive communication is disproportionately impacted, with most individuals remaining non-verbal for life.
Alternative communication systems such as picture exchange systems and AAC devices can be used to facilitate communication but with variable results, an incredible amount of hard work in individuals with 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 that cognitive abilities plateau around the developmental age of two to four years old, and severe learning, comprehension, and attention deficits make it difficult for individuals to follow directions and engage in school and social settings.
These challenges can exacerbate hyperactivity, aggression, anxiety, and other maladaptive behaviors. Motor function is also severely impaired, slow unsteady gait, ataxia, and poor muscle coordination and tremors are characteristic. Irregular, often jerky, voluntary movements significantly delay and can prevent skills such as walking, grasping, and feeding.
Seizures are also common, generally presenting before the age of three. Anticonvulsant medications can help and are a mainstay of therapy in Angelman Syndrome. However, breakthrough seizures are common, and many families struggle to find the right drug or combination of medications. The tremors and jerky movements we see in these kids can be difficult to distinguish from seizures and can lead to anticonvulsant overmedication.
In my experience, children with Angelman Syndrome can be some of the most loving, social, and hardworking kids. They're stubborn and desire to be more independent to be understood by their family and their peers. But despite this drive and persistence, their limitations caused by Angelman Syndrome create frustration, which is heartbreaking as a parent.
I told you that people with Angelman Syndrome are expected to live a normal lifespan, 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 of people with Angelman Syndrome, symptoms related to impaired communication are reported to be among the most challenging to manage. An improvement in this area would be a priority in considering a disease-modifying treatment for their child or loved one.
Parents and caregivers also report that impaired cognition, disruptive behaviors, mobility issues, and inability to participate in activities of 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 values assigned, the measures shown on this slide are generally accepted as the most robust and comprehensive tools to evaluate people with Angelman Syndrome.
These tools measure functional ability through direct objective assessment or subjective assessment reported by the clinician or caregiver. The Bayley Scales of Infant and Toddler Development Fourth Edition, 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, the Bayley is appropriate given the developmental 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 assesses adaptive skills and independence through measures of communication, motor function, socialization, and daily living skills. The Bailey-4 and Vineland-3 scales are often expressed as gross scale values or GSVs, especially in clinical trial settings. GSVs were developed specifically to track change in performance over time and across repeated treatment administrations. They do not measure change by age group, which is beneficial when measuring a wide range of ages.
Additionally, GSVs are being used as the basis for research supporting development of Angelman-specific MCID 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 was used 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's verbal and non-verbal 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 like 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 developed 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, or CGI, which is widely used to evaluate a variety of conditions in clinical and research settings.
Both assessments are scored on a 7-point Likert 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 in implementing a natural history study over 15 years ago. This rich data set shows us that in contrast to neurotypical children, here we see rapid functional increase through age 3.5 years, where the Bayley scale is cut off for neurotypical children.
For kids with Angelman Syndrome, due to UBE3A deletions, the more severe and more prevalent genotype overall function generally plateaus again at the level of a neurotypical two-year-old. And those with the UBE3A non-deletion mutations generally reach a slightly higher level of function in line with a neurotypical four-year-old.
In all forms of Angelman Syndrome, once these levels are achieved, they remain relatively stable with minimal improvement through adulthood. Again, this is not to say that people with 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 scales. 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 two 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 one 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 national history study data is not yet available for comparison.
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, write, or ace the SAT to profoundly impact the day-to-day function of our loved ones with Angelman Syndrome. Just improving sleep 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 a simple yes-no exchange and two to three turn conversation is profoundly impactful. Being able to communicate basic wants and needs to a caregiver with a communication device is a profound leap in independence for a person with Angelman Syndrome.
Improved balance could mean less falls, less trips to the ER, less stitches, less fear for families, and more functional independence for people with Angelman Syndrome. And gains in areas of functional independence like self-feeding and toileting can improve autonomy and really truly be life-changing for people with Angelman Syndrome and their families and caregivers.
In summary, Angelman Syndrome is a severe disorder that needs disease-modifying treatments. 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.
Becky Crean
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. We designed HALOS to be comprehensive because we wanted to demonstrate safety and meaningful efficacy in a demographic representative of the Angelman syndrome population.
HALOS is a three-part open label Phase 1/2 study designed to test ION582 in a broad range of people with Angelman syndrome. Entry criteria included male and female participants ages two through 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 of benefit in key areas of clinical function relevant in this population. Part one of HALOS is the multiple ascending dose, or MAD portion of the study. Parts two and three comprise the long-term extension or LTE.
The LTE is ongoing, enabling participants to continue treatment for up to four 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-dosed 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 point in the MAD was at six months. All participants received three doses of ION582 over three months at baseline, month one, and month three, which are represented by the blue triangles on this diagram.
All participants were assessed at four months, which is one month after the last MAD dose. Participants in the medium and high-dosed groups were also assessed at six months, which is three months after the last MAD dose. The focus of the data review today will primarily focus on the results from the six-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 3 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 are 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 objective and subjective assessments from multiple vantage points.
Importantly, having data from multiple different assessments allows us to see consistency of response across all domains. There are three domains under Bayley shown on the left-hand column of this table, the daily living skills, socialization, and behavior that we did not evaluate in the HALOS study.
While these are domains within the Bayley, 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 show the data from all these assessments comparing the study results to the natural history where possible and across tests to assess consistency in the 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 support advancing ION582 into Phase 3 development.
And here now to discuss the findings from the MAD portion of the HALOS study, the principal investigator in HALOS and the long-running natural history study Professor of Pediatrics at UC San Diego, Dr. Lynne Bird. Dr. Bird?
Lynne Bird
Thank you, Becky, and good morning everyone. I have some disclosures. I'm a principal investigator on the studies that you see there and I'm also a consultant 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've 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 enrolled in this study. A total of 51 participants were enrolled in the multiple ascending dose or MAD portion of the HALOS study. Ages ranged 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. Participants were generally older in the medium and high dose groups compared with low dose with all adult participants enrolled in high dose groups.
There were a greater number of participants with deletion compared with UBE3A mutation, 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 enroll in the long-term extension.
ION582 demonstrated a favorable safety and tolerability profile in all three 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 three dose groups on the daily floor for four 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 four months. While a comparison to natural history is not shown here, benefit across these measures exceeded the minimal change in functional ability we would expect based on natural history.
The medium and high doses demonstrated similar performance at four 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 six months.
As previously noted, this was the final time point in the MAD and only included participants from the medium and high-dose groups. As participants from the low-dose group were not included in the efficacy assessment at six 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 increased 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 groups as was shown at four 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 its psychometric properties were substantiated. The 39 participants from the core medium and high-dose groups were matched by age and genotype to natural history participants for these data analyses.
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 two-point or greater change is presumed to be clinically meaningful.
The 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 one point or greater out of a maximum of three points on the standard CGIC 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 receptive communication observed for baseline and exceeding natural history. This improvement is seen with both the Bayley and the Vineland assessment tools.
Data from the ORCA will be presented separately. The SAS-CGI doesn't measure receptive communication, so that's why you don't see this measurement. A similar level of improvement was observed in the Bayley-4 measure of receptive 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 six-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 four 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 improvements 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 the 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 caregivers are seeing consistent, measurable improvement in this key functional area. On the Angelman-specific ORCA measure of communication treatment with ION582 led to a nearly four-point improvement exceeding the clinically meaningful two-point change or greater in this measurement. ION582 also exceeded natural history in this assessment.
A correlation analysis comparing improvements on the relatively new Angelman Syndrome-focused communication test, the ORCA, to the Bayley, which has more data from its use in the natural history studies, 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 one 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 three of the assessments, the Bayley, the Vineland, and the CGI.
Scores measuring fine motor function show improvement following ION582 treatments for all three assessment tools. For the Bayley and Vineland, the improvements we see with ION582 exceed that of natural history. We again see consistency in the data. ORCA does not affect motor function, so it is not shown.
Here we have gross motor function like the results in fine motor function, we observe similar improvements across the three assessments that exceed expectations from natural history on the Bayley and Vineland and reached clinically meaningful benefit level on the SAS-CGI.
In the SAS-CGI assessment of overall change in Angelman Syndrome symptoms, clinicians reported clinically meaningful improvement in overall symptoms in 97% of participants at six 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 maladaptive behaviors, sleep 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 anticonvulsant medication and it was a requirement for participants to be on stable medication regimens to enter the study.
The consistent benefit across subdomains 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 six 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 skills.
I will also point out improvements seen in a majority of patients in daily living skills and socialization that also outpace natural history gain. Here now is a 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 assessed, we saw improvement in a majority of participants.
The consistency of the improvements 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 functioning in a post-treatment survey at the four months' 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 showed favorable safety and tolerability in this study. As reported at the FAST meeting in November, reductions in delta power were observed in children at four months and those reductions continued at the six month time point.
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 symptoms on the SAS-CGIC and improvements in cognition, communication, and motor function exceeded natural history expectations on the Bayley-4, the Vineland-3, and the ORCA.
And in conclusion, these data, while early, are encouraging and I believe warrant further clinical development of ION582 in a well-controlled Phase 3 trial. And with that, I'll turn the call back over to Brett.
Brett Monia
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 four years. We plan to meet with regulators later this year to gain alignment on our Phase 3 study design, and we expect to start the Phase 3 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 we have a long line of analysts queued up for questions. So I request that each analyst limit themselves to a single question, please, and jump back in the queue if you have more, so we can try, and have time for everybody to ask their questions.
And with that operator over to you.
Question-and-Answer Session
Operator
We will now begin the question and answer session. [Operator Instructions] At this time, we will pause momentarily to assemble our roster. The first question comes from Debjit Chattopadhyay with Guggenheim Securities. Please go ahead.
Debjit Chattopadhyay
Hi. Good morning all. Congrats, Ionis, on the data, and thanks for taking our question. Our representative or the national history data to what would be anticipated in a Phase 3 trial, and given the treatment effect, can ION582 deliver a stat sig outcome on Bayley-4 cognition? Should that be the primary endpoint? Thank you.
Brett Monia
Thanks, Debjit. So as Dr. Jalazo presented very, very nicely and commented on by 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 3 development. Nevertheless, we do believe that a placebo-controlled study in Phase 3 development is important to actually validate the findings 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?
Elizabeth Jalazo
No, I'll just echo, I think this 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, enrolling 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.
Brett Monia
Thank you, Debjit.
Operator
The next question comes from Gary Nachman with Raymond James. Please go ahead.
Denis Reznik
Hey, good morning. This is Denis Reznik on for 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 3, 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 so much.
Brett Monia
Thanks, Dennis. We're putting our final touches on the Phase 3 trial design now and we look forward to sharing the design once we get FDA feedback and we agree to settle on a Phase 3 trial design. You know, broad strokes, we're looking at a couple of 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 3 development as early as possible next year.
Denis Reznik
Thanks so much.
Operator
The next question comes from David Lebowitz with Citi. Please go ahead.
David Lebowitz
Thank you very much for taking my question. When designing the upcoming Phase 3 trial, how do you determine which components of the Bayley-4 are optimal? Should there be similarities between competitor trials or could there be variations? Thanks for taking my question.
Brett Monia
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 demonstrate pretty convincing -- 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 -- we will continue to look at all of these endpoints to ensure that we have an endpoint that we believe will demonstrate true clinical meaningfulness in a placebo-controlled trial, based on the objectivity of the analyses and our confidence that we will actually be able to demonstrate improvements. We will also certainly include additional secondary endpoints that are part of Vineland and Bayley, and those will all, in totality, be critically important to demonstrate -- to really demonstrate convincing and 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.
David Lebowitz
Thanks for taking my question.
Operator
The next question comes from Akash Tewari with Jefferies. Please go ahead.
Amy Li
Hey, everyone, this is Amy on for Akash. Thanks so much for taking our question and congrats on the data. So we've seen that maternal deletion patients generally have worse prognosis than other genotypes. Outside 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 these cohorts weren't age-matched? Thanks so much.
Brett Monia
Yeah, 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 you in receptive, we showed similar magnitude of benefit in both populations. And I can tell you that we've also seen consistent benefit in deletions and mutations, although there's far fewer mutations in our study than deletions benefit across other measures of benefit as well. And as I mentioned earlier, we expect to include a broad patient population in our Phase 3 trial design. Indeed, we did have imbalances in certain -- in demographics, in certain treatment groups, in particular the age groups. We had all of our adults in the high-dose group, and that was actually out of design. We felt most comfortable to share or to expose, since this is a first inpatient, 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. 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. So thank you for the question. And next question?
Operator
The next question comes from Yanan Zhu with Wells Fargo Securities. Please go ahead.
Yanan Zhu
Great. Thanks for taking our questions and congrats on the data. So I wanted to ask about the dose response between medium and high dose and it was noted that there's imbalance in age and genotypes. Could you -- could 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. Thank you.
Brett Monia
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 an interventional treatment like ION582. So first of all, in the dose response, we did show evidence of a dose response, the low-dose group at four months clearly was not showing evidence of efficacy comparable to the medium and the high-dose groups. 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 of 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 both of those dose groups and 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 day one, one month, and then two months later. So it was a loading regimen. As we move into a long-term extension, will be dosing quarterly. So we may see separation of the median and the high-dose groups. We have not decided on our dose yet for Phase 3 development, so this data will be very informative. As far as age, we're 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 interventional treatment related to different age groups?
Lynne Bird
Well, sort of intuitively, one would think that the earlier you start in a neuro-developmental 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. Those data will come, but at the moment, it appears that every age group can benefit.
Brett Monia
And I'll ask Dr. Jalazo for her thoughts on newborn screening and the importance of that, but as you know, Yanan, in our spinal muscular atrophy trials with nusinersen, we showed that if you can actually treat babies early on after genetically diagnosed at birth, many of those babies live a normal life. So getting in early is certainly better, but maybe, Dr. Jalazo, a little on newborn screening and where we are with that.
Elizabeth Jalazo
Sure. This is 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 dry blood spot 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 to the Angelman Syndrome community. I think, as Dr. Bird mentioned, logically we think it's a 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 is, as Dr. Bird mentioned, that we might expect to see a response at whatever age we intervene, which is amazing.
Brett Monia
Thanks for the question, Yanan. Next.
Operator
The next question comes from Jessica Fye with JPMorgan. Please go ahead.
Jessica Fye
Hey, guys, good morning. Thanks for taking the question. 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?
Brett Monia
Yeah, thanks, Jess, for the question. As I mentioned earlier, we're seeing consistent benefit 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 3.
Jessica Fye
Thanks.
Brett Monia
Thanks for the question, Jess and next.
Operator
The next question comes from Jay Olson with Oppenheimer. Please go ahead.
Jay Olson
Hey, thanks for providing this update and congratulations on these results. What do you see as the ideal outcome or target goal for Angelman in 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 ION582, even beyond the impressive results you've presented here today? Thank you.
Brett Monia
Well, I would like to ask Dr. Jalazo to take the first part of your question from her perspective as both a parent and a lead investigator for 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 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.
Elizabeth Jalazo
Gosh. I mean, first and foremost, I love this conversation about optimizing future delivery methods. And I think this is, I'm so excited to hear us talking about this. I think even with the current delivery method, 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 to 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 Angelman Syndrome, whether they are 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 a handful of expressive communication tools could be really profoundly impactful for a family and an individual to both increase functional independence but also ease of day-to-day living with this devastating disorder.
Brett Monia
Thank you for the question, Jay. Next question.
Operator
The next question comes from Gena Wang with Barclays. Please go ahead.
Gena Wang
Thank you for taking my questions. 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 the impact or the patient stratification regarding the Phase 3 trial design?
Brett Monia
Yeah. 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 that it's an early time point. It's very possible that with longer-term treatment and spacing out the dosing interval, we'll see a separation of the dose-response for the medium dose and the high-dose long-term extension. And we're 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 four months, and that supports our preclinical modeling. That's 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 -- dose-response results we've seen so far. But thank you. Next question.
Operator
The next question comes from Michael Ulz with Morgan Stanley. Please go ahead.
Unidentified Analyst
Hi. Good morning. It's Avi Novick on the line for Mike. Thank you for taking our questions. 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? Thank you.
Brett Monia
Yeah, sure. So as was mentioned, I think earlier of the 51 patients that we enrolled in the Phase1/2 study, 50 enrolled over into the long-term extension, which is, of course, very nice to see. And the vast majority of those patients continue today with a good number of those patients now treated beyond a year in the long-term extension. I forgot the second part of your question, I apologize.
Unidentified Analyst
It's when might you consider disclosing the data on the long-term expansion?
Brett Monia
Yeah, we're 100% laser-focused on getting the Phase 3 trial design completed, get to the FDA and the EMA and other geographic territories to get finalization of the Phase 3 trial design and get that study started. We're also laser-focused on continuing to evaluate the data in the long-term extension and we'll share data from the long-term extension down the road, but right now we don't have a specific time point for that, but we're looking forward to it. Thanks for the question. Next question, please.
Operator
The next question. I'm sorry, that is from Paul Matteis' location at Stifel. Please go ahead.
Paul Matteis
Hey, how you doing? Thanks for taking the question. I was just wondering, as you think about endpoints for Phase 3, what is a credible assumption for the placebo arm and how might that vary by age or genetic population? Thanks.
Brett Monia
I'm looking to Dr. Bird to maybe comment on what he think -- what he might -- thank you for the question, Paul, on a placebo effect would be, in other words, the progression of the placebo group. I mean, what we do know is that patients for all of these domains almost have no progression, like no improvement over time, Paul. So we're not really expecting that in the placebo group that whether we're looking at cognition, expressive communication, receptive communication, that there's going to be a big difference in the clinical trial time span in a control group. But as one of the leaders of the natural history study, maybe Dr. Bird, you should comment.
Lynne Bird
Yeah, thank you. The rate of acquisition of skills in all domains in Angelman Syndrome is incredibly slow. The slope of that curve is pretty flat. And so I would not expect that there's going to be a huge jump in ability in the placebo group that will create a lot of noise and difficulty with comparison to the treatment group. So we have robust natural history data that support that the rate of skill acquisition is very slow, so we wouldn't expect too much change in placebo-treated patients.
Brett Monia
Holly, is there something you want to add?
Holly Kordasiewicz
There's been other trial. So we're getting the data from the other trial to try to then be able to analyze and compare what maybe a placebo should be used to redesign our trials going forward, what that data looks like.
Brett Monia
Thanks for the question. Thanks, Paul. Next, please.
Operator
The next question comes from Andy Chen with Wolfe Research. Please go ahead.
Andy Chen
Hey, thank you for taking the question. The question might be for Dr. Bird. So I see in the disclosure that you're working with all the major players in Angelman, I'm curious if you can compare and contrast the different products, especially Ionis and Ultragenyx, who has also presented their data. Can you comment on the strengths and weaknesses of the products based on what you see, which product you like more, and why? Thank you.
Brett Monia
Okay. Thank you, Andy. So, before I ask Dr. Bird for her perspective, what she's seeing in ION582 trial, let me just say, we'll repeat, Andy, what I said before, our competition is Angelman Syndrome. We're rooting for any and all programs that can deliver a life-changing medicine for this disease population. And we love our program. And we have seen nothing out there that sheds -- that causes us to pause -- cause any pause in advancing our program to Phase 3 development as fast as possible to achieve our goal and to tackle this disease. But Dr. Bird, the question was for you. So you should provide a perspective.
Lynne Bird
Well, I never thought in my professional lifetime that we'd be talking about a treatment for an intellectual disability disorder. So, I would be thrilled if all three of these compounds ended up moving forward into Phase 3 and ultimately getting approval for patients. That's what would be best for patients. It's really impossible to answer your question because these trials were not designed in an identical way. They certainly weren't designed to be able to do any head-to-head comparisons. I think from what we know, they all have probably strengths and probably have some differences in terms of chemical composition, maybe that will influence the side effect profile, maybe it will also change the dosing frequency, but at this point, we really can't say that one is superior to another. I was very pleased to see, though, with the Ionis data that we didn't have a safety signal of radiculopathy.
Brett Monia
Thanks for the question, Andy. Next, please?
Operator
The next question comes from Salveen Richter with Goldman Sachs. Please go ahead.
Salveen Richter
Good Morning. Thanks for taking my question. Could you just comment as to when you plan to start regulatory discussions and what the measures are that will inform not just those discussions, but also the dose, whether it be longer follow-up or need to dose more patients? Thank you.
Brett Monia
Thanks, Salveen. So, we believe we have all the data now. We don't need additional data from the long-term extension or anything else to inform on a very productive conversation or discussion with regulators on a path forward. Our key, and as far as dose goes, we have choices, because both the medium dose and the high dose group in our study were very well tolerated. So we're not -- and the other point I want to emphasize is that we dosed to the top dose that we intended to dose to from the outset. So, we were not capped in our dose. We were able to actually dose through the full dose response that we intended to dose through in our study. So we have choices. We still have not decided on what our dosing strategy will be in the Phase 3 trial design. It's more than likely it will be, we're certain it will be at least quarterly dosing based on the profile of our drugs, ION582 specifically, but the actual dose is to be determined. We're also deciding on the final sample size of our study. As I mentioned in one of the questions earlier, we're thinking it will be somewhere in the 100 to 200 patient dose range. And we're also deciding on, when I say evaluating a broad patient population, what exactly that means. How do we define a broad patient population and how do we ensure that we evaluate ION582 and get as much data as we can from a broad patient population. We're going to get FDA feedback soon. And we're going to -- our plan is to start Phase 3 in the first half of next year, and we're looking forward to sharing our Phase 3 trial design as soon as we settle on it with regulators. So thanks for the question. And next?
Operator
The next question comes from Yale Jen with TD, excuse me, with Laidlaw & Company. Please go ahead.
Yale Jen
Good morning and thanks for taking the questions and congrats on the outcome. Just in terms of the Phase 3 study, given that you have covered a broad age range, would you consider stratify the patient for the Phase 3 study between adult and child or how -- what's your thought at this moment, thanks.
Brett Monia
Yeah. Like, maybe I would turn to Eugene, our Executive Vice President of Clinical Development, to talk a little bit about what we might be thinking about with respect to stratification, age or otherwise in a Phase 3 trial design. Again, it's early -- we haven't finalized, not early, we're putting the final touches on our Phase 3 trial design, but Eugene, would you comment, please?
Eugene Schneider
Sure, Brett, and thanks, Yale. As you said, it's early days and we're putting finishing touches on the Phase 3 design. Of course, the goal will be to as much as possible, balance the key clinical characteristics, including age, genotype and potentially others, across the active and control arms. And certainly, stratification is one way to do it, and we're considering a number of ways to ensure that, again, the study arms are balanced in terms of critical clinical characteristics.
Brett Monia
Thank you, Eugene. Thanks, Yale. Next question, please.
Operator
The next question comes from Yaron Werber with TD Cowen. Please go ahead.
Brendan Smith
Hi. This is Brendan on for Yaron. Congrats on the data. Thanks for taking the question. Maybe just a quick one on safety, because I think we've kind of gone through Phase 3 sufficiently at this point. Can you just maybe give us a sense of the breakdown in some of the AEs between low, medium, high doses? Did you see any dose-dependent effect in any of the reported AEs, or was it fairly balanced between all the dose cohorts? Thanks.
Brett Monia
Eugene, that's a question for you. Please.
Eugene Schneider
Okay, sure. Basically, we did not see the patterns in adverse events that seem to be dose-dependent. So again we already summarized the types of events which are fairly typical in trials in pediatric patients, but there wasn't evidence of any kind of specific event being dose responsive.
Brett Monia
Thanks, Eugene. Thanks, Brendan. Again, Brendan, we're pleased with the safety profile. As Eugene said, there's, there was nothing dose-dependent that we saw, nothing drug-related, and no evidence of lower limb weakness, radiculopathy. So we were really, really pleased. Next question, please.
Operator
The next question comes from Kostas Biliouris with BMO Capital Markets. Please go ahead.
Kostas Biliouris
Good morning, everyone. Thanks for taking our question and congrats on the data. One question on individual patient data. You previously showed literature data showing that the size of delta waves predicts clinical severity in Angelman Syndrome. I am wondering whether you have analyzed your individual patient data in that context and observed a relationship, an evolving relationship, between the delta wave changes and the clinical improvement you see here. Thank you.
Brett Monia
Thanks, Kostas. So, we reported preliminarily data last year at four months showing that in patients treated with ION582, we're seeing a strong shift towards normalization of EEG patterns. And as Dr. Bird presented in our conclusion today, we've seen that continue at the six-month time point. It's most dramatic. What we're also learning is that it's most dramatic in the younger patients, the abnormalities and EEG patterns and the ability to show that we can move those towards normalization. Last year we reported that there was a relationship, a statistically significant relationship, as I recall, between normalization of EEG and improvements in cognition. We're continuing to evaluate all of that data long-term in the long-term extension, so including correlations to functional outputs, and we'll share that data down the road as we learn more, but it's still in process. What we're thrilled about is the fact that we don't need to rely on EEG patterns to inform us on the potential benefit that 582 is offering because the responses we're seeing across the board and all the assessment tools and the domains is happening so rapidly, just after a few months of treatment. So, that's what we're going to be focused on. We're going to be focused on the clinical endpoints that are now well in place. As Dr. Bird and Dr. Jalazo presented today, the Bayley-4, the Vineland, the ORCA and the SAS-CGI, and that's what we're focused on. But we will continue to evaluate EEG as we go through the LTE. Thanks for the question, Kostas. Next.
Operator
The next question comes from Jason Gerberry with Bank of America. Please go ahead.
Jason Gerberry
Hey guys, thanks for taking my question. Mine is really just wanted to understand a little bit how the long-term extension data may kind of inform your Phase 3 plan. So it sounds like greater separation from the medium and high dose could obviously inform dosing strategy. When you look at different subdomains, are you really kind of keying in on which subdomain you see the biggest change as where you might narrow the focus from a Phase 3 endpoint strategy? Thanks.
Brett Monia
Yeah, thanks, Jason. So, Eugene, before I toss it to you, I'd love for you to comment on how you think the LTE could influence how the conduct of our Phase 3 study as we go forward. But I do want to open with this that we believe we have all the data we need right now to inform on a very, very productive end to Phase 2 meeting with the FDA and the EMA and to settle on and put the final touches, really, on our Phase 3 trial design and move forward. So we don't need to wait for LTE data, but that data is going to be incredibly valuable, and we will continue to assess it, and it could maybe alter the way we conduct the Phase 3 study, but, Eugene, your comments, please.
Eugene Schneider
Brett, I really don't have much to add. You already pretty much addressed the value of the LTE is really in trying to inform us on durability of responses that we see on clinical outcomes over time, but certainly, that's not rate limiting for us to design a robust Phase 3 trial and start it.
Brett Monia
Thanks, Eugene. Thanks, Jason. Next question, please.
Operator
The next question comes from Eli Merle with UBS. Please go ahead.
Unidentified Analyst
Hey, this is Jasmine on for Eli. Thanks so much for taking our question today. How are you thinking about the potential for deepening effects over longer time with 582 treatment and how could that influence your thoughts on the timing of a Phase 3 endpoint? Thanks.
Brett Monia
Yeah, thank you for the question. I think the answer to that is similar to the answer to the question on dose responses. We're looking forward to seeing if the improvements that we're seeing at six months get even better, deepen long-term treatment. That's certainly a key aspect of the LTE that we'll be looking closely at. And in fact, if you look at the four-month to the six-month data, you can actually see some evidence that there were some improvements in some of the subdomains as well in just a couple of months in the data that Dr. Bird presented. So certainly that's a key aspect of our studying the LTE is to determine whether or not the improvements we're seeing continue to get bigger and better across the domain. So stay tuned for that. That's going to be a key aspect of the disease. Becky, do you want to add that?
Becky Crean
I just wanted to add that it's really important to remember that learning is a process that occurs over time and the development skills occur over the course of extended experience. So even if you think about normal development, you need time and experience to develop skills. So we expect to see that as well. And so I think the long-term extension will give us more focus on how that development will occur over time with treatment.
Brett Monia
Thanks for the question. And I think we have time for one final question.
Operator
That question comes from Myles Minter with William Blair. Please go ahead.
Myles Minter
Hey, thanks for squeezing me in. Congrats on the data. My question is probably for Dr. Jalazo. I think you said that we're working on understanding the minimal clinically important difference on the Bayley-4. I guess do you have any timelines on when that may be communicated? And is there like academic groups working with the FDA to help inform them? Just very cognizant that we obviously just saw a Phase 3 trial design go out with subcomponent of the Bayley-4 as the primary endpoint, but it does appear as if regulators still want to see on a key secondary, a multi-domain responder index and that raises the questions over what is clinically meaningful. So, just wondering if there's timelines on clarity there for the Bayley-4 specifically. Thanks very much.
Elizabeth Jalazo
Thanks for the question. This, again, much like the natural history study, is something that has been a priority for the community and is something that has been heavily invested in by the patient community and the clinician and research community. I don't have a firm date on when we're anticipating those publications, but I do believe it's imminent. And again, something that has been a high priority for the patient community and something that the patient community is continuing to push for timely delivery because we do understand how important it is for these pivotal trials.
Brett Monia
Thank you, Dr. Jalazo. Thanks, Miles. And I'd like to thank everybody who participated on our call today. Also I'd like to thank Dr. Jalazo and Dr. Bird for your excellent input and overview of the Angelman Syndrome landscape and the data that we're seeing from the HALOS study. We're very excited about this program, obviously, and very much looking forward to getting our pivotal study started as soon as possible to hopefully deliver a truly transformational medicine for this disease with a high -- very high unmet medical need. And we look forward to providing further updates down the road. But until that time, thank you again and I hope you all have a very great day.
Operator
The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.