A Letter from FAST’s CSO
The GTX-102 results raise important questions about what we learned and where we go from here. The optimism so many of us felt following the Phase 1/2 data was not misplaced or naïve. That data showed changes across a range of measures, from objective, rater-assessed tools like the Bayley Scales, to caregiver-driven measures like the Vineland and ABC-C, versus strong natural history data. We are also aware of the countless personal accounts that parents and investigators shared in interviews and vignettes about the changes they saw in these children. Now, more than two hundred individuals and families lived through a clinical trial experience. Nothing about the Aspire results erases what those families experienced, contributed and sacrificed.
We can believe deeply in what many people saw in their loved ones, and also that the Phase 3 study did not demonstrate wide benefit. Both can be true. None of it makes anyone's experience less real. And none of it makes the Phase 3 data less important. It means we have more to understand.
It is our responsibility at FAST to seek answers on behalf of the AS community at large. This includes each researcher, clinician and pharmaceutical partner working in this space, and, most importantly, the participants in each trial. We have to try to get to the bottom of why the experience of some families and the official trial results appear so vastly different. Topline data does not give us complete answers; we need to deeply investigate the data to inform future studies.
To this end, we are working with Ultragenyx to gain access to their data, and FAST will be spearheading a deep exploration into it. We are working with them to ensure they will present study results to the community at the FAST Global Science Summit, and as we learn more we will share it to help inform future clinical studies.
As this unfolds, we have to resist the temptation to explain the result before we understand it. Aspire could be telling us something about this particular drug, about how we measure change, or about several things at once. Without seeing these data, all of our speculative questions, however smart and potentially insightful, are just jumping to conclusions, any number of which could simply be wrong. Our job is not to defend or destroy a drug, an endpoint, or a prior assumption. Our responsibility is to follow the data wherever they lead, to understand what they are telling us, and to continually learn from them. We must remain open to what the science reveals, challenge our assumptions, and use every lesson to strengthen the programs that come next. This is how we move the field forward: grounded in evidence, guided by rigor, and never by opinion alone.
As we wait, we wanted to give the community a window into some considerations we must keep in mind about clinical trials in general.
Why might a clinical trial fail to show a benefit, even when early data are promising?
This is a question we must think through carefully, honestly, and without rushing to a single explanation. In our experience, with every therapeutic program we support, trial outcomes like this are rarely the product of one issue alone. This is not limited to Angelman syndrome. There are always more failures than successes in drug development, and often the “cause” of failure is several factors combined.
One possibility, true of any drug in any trial, is that the specific dose, frequency it was given, or route of administration used may not have been sufficient to produce or sustain a beneficial effect, even though the underlying mechanism is sound. This may or may not apply to the Aspire trial. This is, after all, the entire purpose of clinical testing: a therapy that behaves one way in an animal model may behave very differently in humans, and that discovery process, while the most meaningful part of drug development, is also the most costly and the most emotionally demanding.
A second possibility is an exaggerated placebo response. When families and participants enter a trial with hope for improvement, that expectation itself can generate real, measurable change in a sham or placebo-controlled arm, change that isn't present in natural history data because there is no “reason to believe” in that setting. This is precisely why open-label data must always be interpreted with caution relative to natural history comparisons, even when the observed effect looks promising. If a true effect exists alongside a strong placebo response, the two should offset each other in the final analysis. Having access to this new sham-controlled dataset will be critical for programs in the future.
A third possibility is that the trial design or endpoints were not able to fully capture a genuine treatment effect. We want to be unambiguous here: It is our assessment that the Aspire trial design was rigorous and thoughtfully constructed. It was built directly from the strength of the Phase 1/2 data, with real intention: to minimize placebo effects and to be as minimally burdensome as possible for families already carrying so much. Those are difficult, and sometimes competing goals, and the trial team worked hard to balance them.
The endpoints themselves, including the Bayley Scales of Infant and Toddler Development, were the same category of measures that showed such clear changes in Phase 1/2. The Bayley is an objective tool, but it is also performance-dependent, and for individuals with Angelman syndrome — who often contend with apraxia, dyspraxia, anxiety, and sleep disruption, on top of the demands of trial participation itself — it is an inherently difficult assessment to complete. And yet, in Phase 1/2, participants performed well on it. It is entirely possible many performed well again in Phase 3, but that signal may simply not have separated clearly from a noisier sham arm. It's also worth noting that the Bayley was never the sole measure in this study; multiple objective, subjective, clinician-rated, and caregiver-rated tools were used together, precisely so that multiple measures could be used to gauge response, even though a primary measure had to be selected. All of the data were methodically collected and evaluated.
A fourth possibility is that the trial simply needed more time. Was one year enough to see an effect? It is fair to ask whether a longer duration is needed to see a statistically clear effect against the backdrop of a placebo response, particularly in a neurodevelopmental disorder, where learning takes time for every individual, and especially so for those with learning impairments. The honest complication here is cost, in every sense of the word. Extending a placebo/sham-controlled period is enormously expensive to run, and very hard on families to keep a child on a sham arm for well over a year before gaining access to a potential therapy. This is a real tension we have to sit with as a community: the trial duration that may be scientifically ideal is not always the duration that is easy to ask of families, and we need to think seriously about how to resolve that for neurodevelopmental disorders going forward.
A related and equally important possibility is variability among participants themselves. If a trial is not adequately accounting for and balancing across factors that cause variability (e.g., medications, supportive therapies, etc), the resulting data can become too noisy to clearly detect an effect, even when one is present in some participants.
What comes next?
FAST is actively working with Ultragenyx to gain access to their data in an effort to explore all of the above. This requires some legal and compliance nuances that they are fully engaged in ensuring are completed. In addition, they are working closely with us and the study Investigators as they consider next steps for the program.
We will work diligently through this data in the months ahead—not to assign a single cause, but to understand the full picture. We understand that individual families feel that some participants showed responses that would be very difficult to attribute to placebo alone. It is equally clear that others did not respond in the same way, or at all, and we need to understand why. The honest answer, most likely, is that several of these above factors combined to produce this result. We owe it to this community, and to every family who contributed data, time, and trust, not to draw hasty conclusions before we have done that work.
What needs to be further investigated?
Endpoints and biomarkers
One important question is whether repeated exposure to the assessments may have affected performance over time. In other words, how much of what families observed represented developmental gains, and how much may have been influenced by familiarity with the assessments, repeated testing, or participation in a clinical trial rather than the drug itself?
We also need to continue advancing objective biomarkers, including measures such as EEG and possibly UBE3A protein in CSF, which may provide important complementary and objective evidence of treatment response.
What are the implications for other ASO trials?
This is understandably one of the biggest questions we are hearing from the community. Both Oak Hill Bio and Ionis have issued community letters this week which detail the reasons why their programs are different from Ultragenyx‘s program and why they still remain hopeful and committed to their ongoing studies.
What about individuals whose parents and clinicians feel had a meaningful response?
We are also hearing from many families who experienced meaningful changes during the trial and are asking whether an expanded access or other mechanism could provide continued availability of the drug while future treatment options are developed.
We recognize how important this question is, particularly for individuals and families who feel they experienced a meaningful benefit. We do not yet know what the path forward will be, but we are working closely with Ultragenyx and the study investigators as they evaluate potential next steps. As more information becomes available, we will share what we can with the community.
Lastly, a word about our partners:
For seven years, Ultragenyx has been an extraordinary partner to Angelman families, investing enormous resources, and showing a genuine, sustained commitment to this community that we are deeply grateful for. They, like other companies, carefully chose outcome measures based on a thorough analysis of Phase 1/2 results and natural history study, collection of patient experience data and work by the A-BOM. Throughout this process, they have been generous with their time, transparent in sharing data, and are fully willing to collaborate with us as we work through what these results mean. That work will take time, and we ask for your patience as it unfolds.
We also want to take a moment to recognize the other partners walking this road with us.
We are grateful to be working side by side with ASF on behalf of the entire Angelman syndrome community. Ionis has been a steady and dedicated presence in this space, bringing decades of deep scientific expertise in antisense technology and a genuine, sustained investment in seeing this science through for individuals with Angelman syndrome. And Oak Hill Bio has shown real commitment and thoughtful partnership as well, supporting the work of advancing treatments for this community with the same seriousness and care this moment demands. We are grateful to be working alongside these partners who share our resolve to get this right, and we will continue to lean on all of these relationships as we navigate what comes next, together.
As we learn more, we are committed to keeping this community informed, every step of the way. Every data point, every family's lived experience, every interview and piece of feedback shared over the course of this trial matters, and all of it will help shape better trials and better outcomes for the future of Angelman syndrome drug development.
I know this is hard. I know there is disappointment, uncertainty, and a lot of unanswered questions. As a parent, I deeply feel this too.
But I also know that questions are where progress begins. We will keep asking the hard questions, seeking the answers, learning from what we discover, and using those lessons to make future trials and treatments better.
Most importantly, we will keep moving forward. We will continue to build and strengthen the Angelman syndrome drug development ecosystem so that every lesson brings us closer to treatments that can truly change the lives of our children.
We are in this together, and we will keep moving forward together.
With gratitude and resolve,
Allyson Berent, DVM, DACVIM
Representing: FAST and A-BOM Leadership