Written by Dr. Joe D’Orazio, FAST Advisory Council
We all remember the moment we heard those words. For me it was a moment I’ll never forget. I had just finished a very busy shift working in the emergency department. I was in the parking lot when my wife Linda told me our son Gabriel’s neurologist called. I remember hearing the words “Angelman syndrome.” I knew exactly what this meant. I recalled those few little lines in my Genetics course from medical school mentioning the “happy puppet syndrome.” Like most parents, a lot of grieving of what could have been followed. I spent many nights awake thinking about what our future would look like.
My wife and I went to our first FAST Global Science Summit and Gala in 2019, just shy of the year anniversary of Gabe’s diagnosis. I barely knew anything about Angelman research so I was blown away hearing FAST’s Chief Science Officer Dr. Allyson Berent’s scientific recap. I was amazed to hear there was so much activity in the clinical space bringing meaningful treatments to those living with AS. With so many strategies being explored, an approved therapeutic seemed to be imminent.
What I think many people don’t realize is how much work FAST and their incredible supporters have done to drive the progress of this translational research. Angelman syndrome is a promising and unique disorder for scientists to target because it is non-degenerative, genetically unique, and generally affects a single gene, called UBE3A. Unfortunately, few pharmaceutical companies have a financial incentive to invest deeply into rare diseases. Research in this field, as a result, has generally been advanced by foundations like FAST. This has only been possible by the donations of loved ones and supporters who, just like you and me, want to see a treatment that has a transformative impact on their child, as quickly as possible, hence the name ‘FAST’.
FAST has a strategic roadmap to bring meaningful therapeutics to those living with AS, which focuses on 3 pillars. One is to deeply support various different disease-modifying or gene therapy strategies; the next is to support down-stream therapeutics to treat some of the symptoms of AS, and finally the last is to prepare for clinical trials, both future and ongoing. Understanding what is most important and meaningful to families in terms of symptoms, and what degree of improvement would be most impactful and meaningful to a patient or their family, is the necessary groundwork required to design the most robust and appropriate clinical trials. Ensuring that the assessments being performed on patients before a treatment and after a treatment are sensitive enough to capture meaningful change is a tall order in such a complex disorder like Angelman syndrome.
In 2016, through a collaboration of FAST, the ASF, and a small handful of pharmaceutical companies, a pre-competitive alliance was launched called the Angelman Biomarker and Outcome Measure Consortium (ABOM). This was meant to be a pre-competitive space for academic researchers, clinicians, foundation partners, and pharmaceutical companies to meet, brainstorm and agree on the most important disease domains in AS and develop or modify existing endpoints or biomarkers in order to know how to measure change once trials begin. In early 2021, FAST committed $1MM of funding to this initiative to ensure that any endpoint created for AS would be shared across all players in the most transparent and non-competitive way, avoiding the duplication of efforts and delayed data sharing. Many of you may not have been aware of exactly what the ABOM was. Well, I wanted to share with you how exciting this initiative is.
In 2021, I agreed to join the FAST Advisory Council, and with my background in clinical medicine, I was thrilled to take a role as a liaison to participate in the ABOM Consortium and help represent FAST as an advocacy group so the parent and patient voice was always at the table. Prior to my first meeting I thought I was getting into a collegial space of collaboration, mostly made up of academic researchers. What I did not realize was that this was a space for sharing knowledge between 23 highly competitive pharmaceutical companies, all looking for the same thing, an approved treatment for AS. To me that is like Coca-Cola and Pepsi sharing recipes or the Yankees and Red Sox sharing notes. It is quite an amazing endeavor, and has been executed incredible well.
For those of you who are not familiar with the process of getting a medication to FDA approval, it is a complex and cumbersome one. Having the right outcome measures for the disease being studied is so important in order to show that the specific therapy is effective for the disorder and is making a meaningful difference in the progression of the disorder. If you pick the wrong outcome measure(s), even a highly effective therapy may appear to have no benefit statistically. The guidance to establish endpoints that are appropriate for a specific disease are incredibly complicated and can take many years for a single measure. The ABOM Consortium has been tasked to identify the best outcome measures for clinical trials in each area of impact (e.g. communication, cognition, gross motor, fine motor, seizures, sleep, activities of daily living, seizures, etc), which can then be assessed before and after a treatment protocol in order to understand if the treatment impacted the trajectory of the symptoms in AS. If a good measure or biomarker does not exist for a specific focus domain, FAST has committed to develop one. The best two examples of FAST’s impact into the outcome measures field are with the development of the first AS specific endpoint which is known as the ORCA (Observer-Reported Communication Ability in AS) and the piloting of the Actimyo wearable device, which objectively measures dozens of parameters related to a patient’s gait. FAST fully funded the development of the ORCA, with the support of 295 parents and caregivers in our community. This measure has received so much traction that the FDA just awarded a large grant to encourage the development of the ORCA for numerous other neurodevelopmental disorders. This measure beautifully captures the AS population as a measurement of receptive, expressive and pragmatic communication ability through various modalities like sounds, gestures, words and AAC use, just to name a few. This measure is now being used in the AS natural history study as well as numerous active, and soon to be active, clinical trials.
As a new member of the ABOM steering committee, I have been participating in this active group who meets regularly, and I have really enjoyed the incredible collaboration between academic/clinical researchers, pharma and biotech, as well as the foundations, both ASF and FAST. Dr. Allyson Berent is currently serving as the director of this effort, and I must say, KUDOS to Allyson and to FAST for continuing to keep the momentum going, FASTer and stronger than ever, so that each player is keeping their eyes on the prize; a meaningful and transformative treatment for our beautiful children.
Over the past 6 months the ABOM, lead by Dr. Allyson Berent, has made incredible progress through pure collaboration, putting any competition aside, and furthering regulatory science. This effort is so necessary for the execution of the most well organized clinical trials. I hope the community can see how impactful this initiative is, and I hope the team at the ABOM is aware how impressed we all are with your drive and passion to keep this consortium active and robust. As a clinician, I can attest to the fact that this collaborative and productive team is just spectacular.