Taking Flight: A Look Toward the Current and Future Clinical Trials for Angelman Syndrome
Barb Bailus PhD
Hello everyone, in celebration of International Angelman Syndrome Day last week, we are going to take a glance into the future and review several of the current and upcoming clinical trials for Angelman Syndrome! Let’s also take a moment to realize that the December Gala marked the 10 year anniversary of FAST and we had not one, not two, but FIVE companies who were represented in Chicago discussing their therapeutic strategies for AS.
I want to take a moment to recognize that much of this has been made significantly easier due to the Global Angelman Registry spearheaded by FAST Australia. If you haven’t registered yet, what better time than now. https://angelmanregistry.info/
Ovid Therapeutics have been a constant presence at the gala for the last several years, and this year Dr. Rakhit detailed the results of their Phase 2 STARS clinical trial which focused on the drug OV101 . The Phase 2 trial was done in adults and adolescents, with Phase 2 completed, Ovid met with the FDA to discuss Phase 3 trials. Phase 3 trials are one of the last steps before a drug can be approved for use in patients and prescribed by doctors. In Angelman syndrome, tonic inhibition is diminished Tonic inhibition can be thought of as a way for the neurons to focus and direct their signals in the brain so that the correct thoughts and actions are processed. One way to think of this is that if you were standing in a room and you heard the television, telephone, doorbell and radio all going at once, you wouldn’t be able to focus on one sound; there would be too much confusion and noise. Tonic inhibition makes 
each of those devices play at a separate interval, allowing for you to focus on one distinct input at a time. Ovid proposes OV101 influences tonic inhibition by targeting GABA receptors, which partially control tonic inhibition. The reason that GABA receptors are important in AS is that the lack of UBE3A results in decreased levels of GABA; which means the GABA receptors are not effectively controlling neuronal signals through tonic inhibition so the neuronal signals are not directed or focused. It is Ovid’s aim that OV101 act as a direct substitute for the lowered GABA levels by binding to the GABA receptors, restoring tonic inhibition and refocusing the neuronal signals. The STARS Phase 2 clinical trial had three treatment groups: twice daily, once daily and placebo (sugar pill). Although the trial focused on safety, there were some indications that OV101 might be effective. Caregivers reported improved motor skills, with their child being able to pick-up pennies or walk on a treadmill; also, some children went to sleep faster and stayed asleep longer. The once daily treatment group saw the most improvement, and this will be used for the open label study ELARA planned to take place in 2019. Moving forward, a new study is underway with NEPTUNE, which will test OV101 in children from 4-12 years old . The data from NEPTUNE and the Phase 3 clinical trial, if warranted, will be used to file for an Investigational New Drug FDA application (NDA) with the hope of being the first AS specific drug to market. According to Ovid’s website, “The Phase 2 STARS clinical trial in adults and adolescents met its primary endpoint of safety and tolerability and also showed a statistically significant improvement compared to placebo in the physician-rated clinical global impression of improvement (CGI-I) – an important measure that captures the constellation of clinical symptoms of Angelman syndrome. CGI-I was ranked first in the topline statistical plan. Subsequent topline analyses were conducted on a prespecified subset of scales across the domains of behavior, sleep and gait. While the analysis of these pre-specified subsets did not show a statistically significant difference from placebo, full data analyses on these domains are ongoing and will be communicated in the future.”
Next to speak at the Gala was Dr. Herber from Disruptive Nutrition, which FAST is funding a clinical trial to evaluate a ketone dietary supplement. Dietary supplements have previously been shown to help control seizures in epilepsy, and preliminary studies by Dr. Ed Weeber have shown promise in AS mouse models. Disruptive Nutrition is currently recruiting for a ketone supplement clinical trial to investigate if a ketone dietary supplement can result in symptomatic improvements. One might ask, “Why not just have the individual on a ketogenic diet?”, but a ketogenic diet lacks 
variety, and in many cases will lack the individual’s favorite food, like bananas. Ketogenic diets are very difficult to maintain, especially in young children. If the ketone supplement is enough to keep the individual in ketosis (this is what a ketogenic diet does for its benefits) then the individual could maintain their normal diet and just add the supplement. Being in ketosis means that the body is using fats and proteins as the main source of energy instead of sugars; and this change in energy source is pivotal for controlling seizures. The clinical trial is designed to test the safety of the ketone supplement and to gather information on potential outcome measures. The patients that are being recruited will be between 4-11 years old, and each individual will receive the treatment over two phases: one phase where the individual is on the ketone supplement, and another where they are on a placebo; caregivers will not be told which phase their AS family member is in. In this way, each individual serves as their own control; which, considering how varied the home diets will be, is important when trying to evaluate both safety and any behavioral improvements. The behavioral improvements will be measured by home sleep monitors and home iPad diaries for caregivers to record observations in. There will also be clinical visits looking at mobility and brain measures (EEG and ERP). For those interested in enrolling, individuals with AS need to be able to walk on a treadmill (for gait analysis). At the conclusion of the study, all information will be added to the global registry in order to help future companies with their clinical trials.
At the 2017 and 2018 FAST Summit, Dr. Jodi Cook from Agilis had spoken to us, this year Dr. Cook shared the news that Agilis Biotherapeutics had been acquired by the global company PTC Therapeutics, which focuses exclusively on rare diseases. This acquisition will be of great benefit for the development of Agilis AS strategy, as there will be an increase in people and resources focusing on the project. One of 
the key individuals involved in the therapy development is Dr. Ed Weeber, whose work on UBE3A gene replacement strategy is being used as the basis for PTCs therapeutic approach. In 2011, Dr. Weeber’s Lab published a study showing that the Ube3a gene, when packaged into an AAV virus and injected into the brains of mice, could help rescue several AS associated symptoms, including the ability of AS mice to learn and remember information . With Dr. Weeber spearheading the current work, PTC is now focusing on creating the most effectives method to deliver the UBE3A gene into the human brain and detect the delivered UBE3A. For delivering the UBE3A, an AAV (adeno-associated virus) is being used as the envelope with a neuronal address to insure the UBE3A gets into neurons, where it is missing in AS. This may sound a bit scary, but think of the virus as a “gift” box with a special shipping label on it; what scientists have done is opened up the box, replaced the original “gift” with the human UBE3A gene, and then resealed the gift box with the shipping label intact. This AAV “gift box” will likely be injected directly into the brain or by spinal tap, and should persist in the neuronal cells for an extended period of time. Dr. Weeber’s team has tested to see if the delivered UBE3A was detectable in the spinal fluid and amazingly it is detectable; this is wonderful news since it offers a biomarker for testing if any of the UBE3A activation/replacement therapies are working. This work has resulted in a very exciting therapeutic strategy, as well as an excellent biomarker that can be used in many different studies.
Dr. Meghan Miller from Roche discussed how Roche is investigating the potential of reactivating of the paternal UBE3A. The paternal UBE3A is silenced by a long UBE3A-antisense transcript (UBE3A-AS) that prevents the paternal UBE3A from being expressed in all of us. An easy way to think of 
this is to imagine that the expression of the UBE3A-AS acts as a red stoplight for paternal UBE3A expression. What Roche is planning to do is find a way to change the stoplight color to green by using a tool called an anti-sense oligonucleotide (ASO), which will allow the paternal copy of the UBE3A gene to be read instead of silenced. Roche is currently screening dozens of potential ASOs to find the very best candidates, by using AS patient cells and looking for an increase in UBE3A expression. The best ASO candidates will then be tested in small monkeys to evaluate deliverability, safety and effectiveness. However, it is important to note these monkeys are not AS monkeys, so they express maternal UBE3A. Looking toward future clinical trials, Roche has identified what they consider clinically meaningfully outcomes: communication, independence, improved sleep, improved motor skills, decrease in seizures and a decrease in maladaptive behaviors. To evaluate these outcomes Roche will be testing some new wearable devices for AS patients in 2019. With the completion of the monkey studies, these ASOs will hopefully move forward to clinical trials.
In the last year a new company arrived on the scene funded by FAST, GeneTx, with Paula Evans, Allyson Berent and Dr. Scott Dindot comprising the core leadership of the company . FAST holds the majority ownership of the GeneTx, helping insure that the therapy being developed there is moving forward as quickly and safely as possible. The therapy builds upon Dr. Dindot’s research of the UBE3A-AS locus and the development of ASOs that target the UBE3A-AS. Dr. Dindot’s early research on UBE3A-AS was one of the first robust studies FAST funded back in 2012. Although Roche is focusing on this strategy as well, the approach is very promising and each company is 
using a slightly different platform. Dr. Dindot has already identified a set of ASOs that increase paternal UBE3A exrensively. By establishing GeneTx as a company it allowed for investors to be brought on, which helps with the expense of initiating and implementing the clinical trials. These ASOs have been tested in human neuronal cells, and they are now being optimized for both delivery and for sustained expression. They have taken the most promising of these candidates forward into non-human primates and have injected them by intrathecal injection (base of the spinal cord). The results indicate that there is widespread reduction of the UBE3A-AS in multiple regions of the non-human primate brain. Jennifer Panagoulias described the next exciting steps toward an Investigational New Drug application. GeneTx has already had a face to face pre-IND meeting with the FDA that will allow the ASOs from GeneTx to move forward as quickly as possible toward Phase 1 human clinical trials.
One of the best attributes of FAST is how much the organization encourages collaboration between all parties, meaning that companies will share and have access to each other’s methods, providing a larger set of measures that can be used to evaluate all the potential therapeutics. This is one of the reasons that progress toward a successful therapeutic has been so rapid, the amount of shared information and collaboration between all parties. I hope you are as excited as I am after reading about all of the fantastic progress being made toward a vast array of different therapies. The last ten years have been amazing for FAST and for progress on treating AS, and I expect the near future to be truly phenomenal.
I want to take a moment to recognize that much of this has been made significantly easier due to the Global Angelman Registry spearheaded by FAST Australia. If you haven’t registered yet, what better time than now. https://angelmanregistry.info/
Ovid Therapeutics have been a constant presence at the gala for the last several years, and this year Dr. Rakhit detailed the results of their Phase 2 STARS clinical trial which focused on the drug OV101 . The Phase 2 trial was done in adults and adolescents, with Phase 2 completed, Ovid met with the FDA to discuss Phase 3 trials. Phase 3 trials are one of the last steps before a drug can be approved for use in patients and prescribed by doctors. In Angelman syndrome, tonic inhibition is diminished Tonic inhibition can be thought of as a way for the neurons to focus and direct their signals in the brain so that the correct thoughts and actions are processed. One way to think of this is that if you were standing in a room and you heard the television, telephone, doorbell and radio all going at once, you wouldn’t be able to focus on one sound; there would be too much confusion and noise. Tonic inhibition makes each of those devices play at a separate interval, allowing for you to focus on one distinct input at a time. Ovid proposes OV101 influences tonic inhibition by targeting GABA receptors, which partially control tonic inhibition. The reason that GABA receptors are important in AS is that the lack of UBE3A results in decreased levels of GABA; which means the GABA receptors are not effectively controlling neuronal signals through tonic inhibition so the neuronal signals are not directed or focused. It is Ovid’s aim that OV101 act as a direct substitute for the lowered GABA levels by binding to the GABA receptors, restoring tonic inhibition and refocusing the neuronal signals. The STARS Phase 2 clinical trial had three treatment groups: twice daily, once daily and placebo (sugar pill). Although the trial focused on safety, there were some indications that OV101 might be effective. Caregivers reported improved motor skills, with their child being able to pick-up pennies or walk on a treadmill; also, some children went to sleep faster and stayed asleep longer. The once daily treatment group saw the most improvement, and this will be used for the open label study ELARA planned to take place in 2019. Moving forward, a new study is underway with NEPTUNE, which will test OV101 in children from 4-12 years old . The data from NEPTUNE and the Phase 3 clinical trial, if warranted, will be used to file for an Investigational New Drug FDA application (NDA) with the hope of being the first AS specific drug to market. According to Ovid’s website, “The Phase 2 STARS clinical trial in adults and adolescents met its primary endpoint of safety and tolerability and also showed a statistically significant improvement compared to placebo in the physician-rated clinical global impression of improvement (CGI-I) – an important measure that captures the constellation of clinical symptoms of Angelman syndrome. CGI-I was ranked first in the topline statistical plan. Subsequent topline analyses were conducted on a prespecified subset of scales across the domains of behavior, sleep and gait. While the analysis of these pre-specified subsets did not show a statistically significant difference from placebo, full data analyses on these domains are ongoing and will be communicated in the future.”
Next to speak at the Gala was Dr. Herber from Disruptive Nutrition, which FAST is funding a clinical trial to evaluate a ketone dietary supplement. Dietary supplements have previously been shown to help control seizures in epilepsy, and preliminary studies by Dr. Ed Weeber have shown promise in AS mouse models. Disruptive Nutrition is currently recruiting for a ketone supplement clinical trial to investigate if a ketone dietary supplement can result in symptomatic improvements. One might ask, “Why not just have the individual on a ketogenic diet?”, but a ketogenic diet lacks variety, and in many cases will lack the individual’s favorite food, like bananas. Ketogenic diets are very difficult to maintain, especially in young children. If the ketone supplement is enough to keep the individual in ketosis (this is what a ketogenic diet does for its benefits) then the individual could maintain their normal diet and just add the supplement. Being in ketosis means that the body is using fats and proteins as the main source of energy instead of sugars; and this change in energy source is pivotal for controlling seizures. The clinical trial is designed to test the safety of the ketone supplement and to gather information on potential outcome measures. The patients that are being recruited will be between 4-11 years old, and each individual will receive the treatment over two phases: one phase where the individual is on the ketone supplement, and another where they are on a placebo; caregivers will not be told which phase their AS family member is in. In this way, each individual serves as their own control; which, considering how varied the home diets will be, is important when trying to evaluate both safety and any behavioral improvements. The behavioral improvements will be measured by home sleep monitors and home iPad diaries for caregivers to record observations in. There will also be clinical visits looking at mobility and brain measures (EEG and ERP). For those interested in enrolling, individuals with AS need to be able to walk on a treadmill (for gait analysis). At the conclusion of the study, all information will be added to the global registry in order to help future companies with their clinical trials.
At the 2017 and 2018 FAST Summit, Dr. Jodi Cook from Agilis had spoken to us, this year Dr. Cook shared the news that Agilis Biotherapeutics had been acquired by the global company PTC Therapeutics, which focuses exclusively on rare diseases. This acquisition will be of great benefit for the development of Agilis AS strategy, as there will be an increase in people and resources focusing on the project. One of the key individuals involved in the therapy development is Dr. Ed Weeber, whose work on UBE3A gene replacement strategy is being used as the basis for PTCs therapeutic approach. In 2011, Dr. Weeber’s Lab published a study showing that the Ube3a gene, when packaged into an AAV virus and injected into the brains of mice, could help rescue several AS associated symptoms, including the ability of AS mice to learn and remember information . With Dr. Weeber spearheading the current work, PTC is now focusing on creating the most effectives method to deliver the UBE3A gene into the human brain and detect the delivered UBE3A. For delivering the UBE3A, an AAV (adeno-associated virus) is being used as the envelope with a neuronal address to insure the UBE3A gets into neurons, where it is missing in AS. This may sound a bit scary, but think of the virus as a “gift” box with a special shipping label on it; what scientists have done is opened up the box, replaced the original “gift” with the human UBE3A gene, and then resealed the gift box with the shipping label intact. This AAV “gift box” will likely be injected directly into the brain or by spinal tap, and should persist in the neuronal cells for an extended period of time. Dr. Weeber’s team has tested to see if the delivered UBE3A was detectable in the spinal fluid and amazingly it is detectable; this is wonderful news since it offers a biomarker for testing if any of the UBE3A activation/replacement therapies are working. This work has resulted in a very exciting therapeutic strategy, as well as an excellent biomarker that can be used in many different studies.
Dr. Meghan Miller from Roche discussed how Roche is investigating the potential of reactivating of the paternal UBE3A. The paternal UBE3A is silenced by a long UBE3A-antisense transcript (UBE3A-AS) that prevents the paternal UBE3A from being expressed in all of us. An easy way to think of this is to imagine that the expression of the UBE3A-AS acts as a red stoplight for paternal UBE3A expression. What Roche is planning to do is find a way to change the stoplight color to green by using a tool called an anti-sense oligonucleotide (ASO), which will allow the paternal copy of the UBE3A gene to be read instead of silenced. Roche is currently screening dozens of potential ASOs to find the very best candidates, by using AS patient cells and looking for an increase in UBE3A expression. The best ASO candidates will then be tested in small monkeys to evaluate deliverability, safety and effectiveness. However, it is important to note these monkeys are not AS monkeys, so they express maternal UBE3A. Looking toward future clinical trials, Roche has identified what they consider clinically meaningfully outcomes: communication, independence, improved sleep, improved motor skills, decrease in seizures and a decrease in maladaptive behaviors. To evaluate these outcomes Roche will be testing some new wearable devices for AS patients in 2019. With the completion of the monkey studies, these ASOs will hopefully move forward to clinical trials.
In the last year a new company arrived on the scene funded by FAST, GeneTx, with Paula Evans, Allyson Berent and Dr. Scott Dindot comprising the core leadership of the company . FAST holds the majority ownership of the GeneTx, helping insure that the therapy being developed there is moving forward as quickly and safely as possible. The therapy builds upon Dr. Dindot’s research of the UBE3A-AS locus and the development of ASOs that target the UBE3A-AS. Dr. Dindot’s early research on UBE3A-AS was one of the first robust studies FAST funded back in 2012. Although Roche is focusing on this strategy as well, the approach is very promising and each company is using a slightly different platform. Dr. Dindot has already identified a set of ASOs that increase paternal UBE3A exrensively. By establishing GeneTx as a company it allowed for investors to be brought on, which helps with the expense of initiating and implementing the clinical trials. These ASOs have been tested in human neuronal cells, and they are now being optimized for both delivery and for sustained expression. They have taken the most promising of these candidates forward into non-human primates and have injected them by intrathecal injection (base of the spinal cord). The results indicate that there is widespread reduction of the UBE3A-AS in multiple regions of the non-human primate brain. Jennifer Panagoulias described the next exciting steps toward an Investigational New Drug application. GeneTx has already had a face to face pre-IND meeting with the FDA that will allow the ASOs from GeneTx to move forward as quickly as possible toward Phase 1 human clinical trials.
One of the best attributes of FAST is how much the organization encourages collaboration between all parties, meaning that companies will share and have access to each other’s methods, providing a larger set of measures that can be used to evaluate all the potential therapeutics. This is one of the reasons that progress toward a successful therapeutic has been so rapid, the amount of shared information and collaboration between all parties. I hope you are as excited as I am after reading about all of the fantastic progress being made toward a vast array of different therapies. The last ten years have been amazing for FAST and for progress on treating AS, and I expect the near future to be truly phenomenal.