MAIN LESSONS FROM THE 2025 CDKL5 FORUM
For the past eleven years, the Loulou Foundation has hosted an annual meeting, the CDKL5 Forum, where scientists and drug developers working on CDKL5 Deficiency Disorder (CDD), together with clinicians and representatives from patient organizations, meet to discuss the latest developments in the field and to advance towards treatments and cures. You can find summaries from some of the last meetings here: 2018, 2019, 2020, 2021, 2022, 2023 and 2024.
The 2025 CDKL5 Forum edition took place October 27-28 in Boston, and will return to London next year for the 2026 edition. This was again the largest Forum to-date, with over 200 participants including representatives from 27 companies and 22 national patient groups.
I will try to summarize the main take-home messages from this year’s Forum. This won’t cover all the presentations, so I apologize in advance to all the scientists and doctors whose work I won’t cover. My focus will be on the main themes that we saw and the main progresses towards treatments.
1. Expanding our (useful) knowledge of CDKL5
Image: Forum Director Dr Dan Lavery (Loulou Foundation); Dr Enya Paschen (Ulysses Neuroscience); Prof Peter Kind (University of Edinburgh); summary of some CDKL5 direct targets; Ulysses Neuroscience seizure platform.
Before this 2025 Forum, I thought that maybe we have uncovered most of what we need to know about how the CDKL5 kinase works, and therefore any new discovery would barely move the needle. And boy was I wrong! At this Forum, we learnt about multiple discoveries for how CDKL5 plays roles far beyond what we thought. And many of these, are useful for treatment design.
For example, we learnt about a discovery made at the same time in two countries that CDKL5 controls a protein that binds to RNA, which means that when CDKL5 is active it not only turns on and off other proteins (as kinases do), but it also controls how much of other proteins gets made. CDKL5 is also involved in autophagy, which is how cells get rid of protein aggregates. So that is another way to control how much or how little of other proteins stays in the cell. And another lab discovered how CDKL5 controls several synaptic proteins because it has a Velcro-like domain that sticks to synaptic proteins (a PDZ-binding domain). And these new functions are added to all what we knew already! like CDKL5’s control of the ion channel Cav2.3, or its modulation of microtubule dynamics and plasticity.
What this means for scientists like me who work in therapy development is an expanding map with more new targets, and therefore more therapeutic directions that we can try to pursue. So it might look like more complexity is bad, but it is actually good news. We also had a presentation from Ulysses Neurosciences showing their mouse testing platform for CDD, including behavioral readouts in male and female mice and also seizures and EEG readouts, which will make it easier to evaluate all those therapeutic options.
Bottomline: scientists are still mapping the “dark matter” of CDKL5 biology, and each of these new discoveries is a potential clue into how to develop therapies for CDD. The 2025 Forum was exceptionally fruitful on this front, with many new biology discoveries.
2. More options to access new medicines than ever before
Image: CDD pipeline listing most programs in development; moderator Prof Orrin Devinsky (NYU Langone); Angel Neurotherapeutics program; fenfluramine activity (UCB Pharma); Bexicaserin trial recruitment sites (Lundbeck); Praxis CSO Prof Steve Petrou.
During his introductory remarks, Dr Dan Lavery from the Loulou Foundation showed a slide of the CDD pipeline, showing multiple generations of small molecule drugs and gene therapies all in trials or advancing towards trials for CDD.
And the most important thing: in 2025 we have one drug approved, a second one having successfully completed Phase 3 trials, and two global Phase 3 trials actively recruiting patients with CDD. There was never a year before like this 2025.
This is the first year that we had Immedica at the Forum, after their acquisition of Marinus. The Immedica team presented their learnings about a slower titration with ganaxolone to reduce side effects. Ganaxolone is already commercialized in the US, and Immedica is working on market access for other countries.
This summer, UCB Pharma announced that their Phase 3 trial with fenfluramine in CDD had been positive, and at the Forum they shared the complex mechanism of action of fenfluramine, which includes more than the serotonin receptor 5HT2C. They will announce the exact results from the CDD trial at the American Epilepsy Society meeting in December, so we will watch for those. UCB will file for expanding the label of fenfluramine to also include treatment of seizures in CDD.
Last year, the regulatory agencies started allowing companies to run clinical trials combining different epilepsy syndromes and not just one at a time. This has resulted in new clinical trial options for CDD. And because these trials ask for only 4 countable seizures a month and include children as well as adults, they have given us more options than ever to try new epilepsy medicines as part of clinical trials. At the Forum we saw two large Phase 3 trials that are currently recruiting across many countries:
Lundbeck is running the DEEp OCEAN Phase 3 trial with their drug bexicaserin. Bexicaserin uses one of the receptors for fenfluramine, 5HT2C, and had very good efficacy in the Phase 2 trial also in a mix of syndromes. They have about 100 trial sites in the US, Australia, Europe and Asia. Here is the link to the study: https://deepdeestudy.com/
Praxis is running the EMERALD Phase 3 trial with their drug relutrigine. Relutrigine is a next-generation sodium channel blocker with many convenient attributes: no titration needed, once a day dosing, liquid formulation, and the trial can be done from home – they send a doctor and a nurse to your place. The trial is also in many countries, and the website is in 12 languages. Here is the link to the study: https://www.resiliencestudies.com/emerald
In addition to this first generation of treatments, all design to reduce seizure frequency, we got a glimpse for what we might have in a few years: the precision medicines for CDD. These are drugs that can correct some of the key aspects of the CDD biology. This year, we got a presentation from Dr Massimiliano Bianchi from Angel Neurotherapeutics showing their preclinical work with a drug called PME and related analogues. These drugs bind to cytoskeleton-binding proteins to compensate for the loss of CDKL5, and the most advanced drug could reach trials in CDD by 2027. This is one of multiple shots on goal to have precision medicines for CDD reach clinical trials in about two years, and because they target key aspects of the CDD biology, they are expected to also improve non-seizure symptoms as shown for the Angel lead program.
Bottomline: CDD families currently have more access to new experimental therapies than ever before. And this also includes adult patients that had not been eligible for trials until now.
3. Gene therapy progress, and a lesson in safety
Image: Keynote speaker and moderator Prof Jim Wilson (Gemma Bio); Elaaj gene therapy program (Loulou Foundation); Dr Russ Addis (Loulou Foundation); Dr Kyle Fink (UC Davis); UC Davis X reactivation project; Andrew Steinsapir (Apertura Gene Therapy)
Gene therapy remains one of the major topics at the CDKL5 Forum, and this year we received messages of excitement and also caution. Some of the Alliance members at the conference told me how “it felt like real talk”, and how that made them feel that progress in gene therapies for CDD was more tangible and real than ever before.
We learnt about progress in THREE gene therapies for CDD that are in development:
1. Dr Sharyl Fyffe-Maricich from Ultragenyx spoke about their gene therapy program, addressing “the elephant in the room” which is that they can’t give us any timelines yet for when this program might progress into trials. But she gave us a valuable scientific gift, sharing with us their research in monkeys that shows that neurons that already make CDKL5 have room to make some more CDKL5 from the gene therapy. This is important for the many CDD patients with missense mutations, who make CDKL5 but it is not functional because it carries one wrong aminoacid. Sharyl’s research indicates that they are likely to end up having a mix of CDKL5 proteins, some coming from their mutated gene and some from the gene therapy, so this is very positive. I was very relieved and grateful to learn about Ultragenyx’s findings.
2. Dr Russ Addis from the Loulou Foundation presented an update on the gene therapy that the Foundation is advancing. This gene therapy has been made in collaboration with Prof Jim Wilson, using a virus very similar to AAV9 that is now being used in 4 other clinical trials. Inside, the virus carries a copy of the CDKL5 gene and it is administered by injection into the brain CSF. Russ showed us the dose-finding studies in mice with CDD to identify the best clinical dose, and told us that the toxicology studies in monkeys have already been completed. The Loulou Foundation is now starting manufacturing, which is the large production of the gene therapy so that it can go to trials, and is already designing the clinical trial. Russ explained that manufacturing will take “the better part of a year” so we are looking into a clinical trial authorization around the end of 2026 to start trials in 2027. The Loulou Foundation announced a partnership with Gemma Bio, Jim Wilson’s company, to share data from the other gene therapies that use this same design and that are now in clinical trials. And to advance this and other types of gene therapy programs, the Loulou Foundation has created a subsidiary called Elaaj Bio, that as Russ said has a “vision for families and patients have more than one option, and to have more chances to access these therapeutics”.
3. Dr Kyle Fink from UC Davis and his lab are developing a very cool gene therapy for CDD: the X reactivation therapy. It works by using a virus to deliver to each neuron the instructions to read the second CDKL5 gene in the second X chromosome that all girls have. These instructions are a type of CRISPR. He reminded us of how nice his gene therapy works in CDD mice, and all their new progress to turn this mouse science into a human medicine. The new progress included figuring out the best doses to use, and checking that it can work in human neurons (using patient-derived organoids). They have started manufacturing and will soon start the toxicology studies in monkeys to progress into trials. This version of the gene therapy uses a combination of two virus that are administered into the CSF, but Julian Halmai (another UC Davis Professor) is working with Kyle to make a miniature CRISPR version that will enable in the future to do this with only one virus.
We also learnt about one gene therapy program that has been stopped:
This was an interesting surprise. Ashton Brennecke from Biogen explained how Biogen had been working in secret on a gene therapy for CDD, and now that the company has terminated the program they wanted to share some of their learnings with the scientific community. In their case, their gene therapy was very similar to the ones from Ultragenyx and the Loulou Foundation, and they studied how to use EEG in mice as a measure for efficacy. It was very interesting to hear about how they optimized EEG methods to be able to see the gene therapy efficacy, but it was also sad to hear that Biogen has joined Amicus and PTC Therapeutics as companies that had started gene therapies for CDD but stopped them before getting to trials. This type of attrition is common in therapy development, and the reason why we need so many shots on goal.
And importantly, we heard about what the field has learnt since the first gene therapy was tried in the first patient in the 90s:
Prof Jim Wilson is of the pioneers in gene therapy development, and delivered a spectacular presentation about the history and learnings on this field. Jim is the former Director of the Orphan Disease Center at UPenn and current CEO of Gemma Bio, the gene therapy company working with the Loulou Foundation on the CDD gene therapy. He explained how they discovered early on that to get gene therapies we would have to fight the immune system, even if it took them 17 years to understand exactly some of the key challenges. He discovered AAV9, and has now put several therapies in clinical trials both using AAV9 and his new generations of virus. Jim dedicated the last part of this talk to address a key topic right now in rare diseases: the recent cases of patients death in clinical trials with intravenous administration of high doses or AAV. His lab has studied the toxicity of gene therapies in almost 500 monkeys, and Jim asked for transparency in the field so that when a company has some unfortunate patient death in a trial, they share the data for how it happened exactly. Only that way, Jim and others can develop preclinical (animal) tests to anticipate that safety issue before it happens in a trial.
Andrew Steinsapir, from the company Apertura Gene Therapy, talked about the capsid (virus) that they are developing for neurological diseases and that is delivered by intravenous administration. The virus is engineered to cross from blood to brain by binding to receptors in the brain blood system. There are previous cases of therapies that used large proteins (although not yet virus) that can also cross from blood to brain using that same receptor, so the Apertura team believes that they should not find unexpected problems once their first programs reach clinical trials. If proven safe in trials, this type of virus could be used to create a second-generation of gene therapies for CDD that instead of being administered by a surgeon into the CSF could be simply injected intravenously.
Last, Dr Basel Assaf, an excellent toxicologist working at Attentive Science, seconded Jim Wilson’s message that so far, the field has been able to use monkeys (non-human primates) to anticipate any toxicity problem that can be later found in patients. However, this has not been perfect, and there was recently a patient death in a clinical trial in another neurological rare disease using an intravenous gene therapy that was not predicted in the monkey studies. Basel also had a great way to help us understand what we mean by “high doses”: an intravenous gene therapy can use seven quadrillion viruses, which is more than the number of cells in our body!
As a reminder: the gene therapies that Ultragenyx, the Loulou Foundation and UC Davis are developing, are NOT delivered using high dose intravenous administration. They use smaller doses, and are delivered straight to the CSF in the brain.
Bottomline: The gene therapy field is learning about safety risks, which requires transparency and collaboration. We have multiple shots on goal to have a gene therapy for CDD, with the possibility for a first trial in 2027. My overall message from this gene therapy session was quite positive. As a CDD dad put it in social media, “real change is coming”.
4. We are probably ready to run complex clinical trials
Image: Panel discussion “Where do we stand today with clinical outcome measures for CDD?”. Dr Xavier Liogier (Loulou Foundation); Dr Barry Ticho (Stoke Therapeutics); Dr Heather Olson (BCH); Dr Jenny Downs (Kids Research Institute, Perth); missing in the image Prof Tim Benke (University of Colorado); Dr Billy Dunn (Loulou Foundation, former FDA)
For the past 5 years of so, we have been hearing about developing and validating outcome measures for running clinical trials in CDD that measure symptoms beyond seizures. Looking at the 2025 Forum presentations, it looks like 80% of the work has been done, and if we had to start a clinical trial tomorrow with a gene therapy we would know what measures to include.
Dr Xavier Liogier from the Loulou Foundation presented the latest update on the international CANDID study, validating for CDD scales that have been used to measure cognition, behavior and motor skills in other diseases, and that regulators accept for drug approvals. By December of this year, CANDID will have 100 patients monitored over 2 years with this collection of scales, giving us longitudinal data for how m much change is expected over a 2-year period. Several scales and subscales are suitable for CDD, and a manuscript is under review for publication. One learning from CANDID with important trial implications is that patients with CDD have one to five seizures a day, so most will qualify for the current seizure clinical trials. This is much more than other epilepsy syndromes.
Prof Tim Benke from University of Colorado, and Dr Jenny Downs from the Kids Research Institute in Perth, presented their work to develop novel clinical scales specifically tailored for people with CDD. The clinical study that Tim leads is also close to having 100 patients reach the 2-year follow up, and importantly it also includes EEG studies so it might help identify a biomarker to see what is happening inside the brain with a gene therapy. Meanwhile Jenny is developing a novel scale for communication in CDD, which is often the top priority for families, and was praised by a former FDA Director for the very hard and diligent technical work that they are doing in developing this scale.
At a panel afterwards, presenters, including ex-FDA Director Dr Billy Dunn and Stoke Therapeutics CMO Dr Barry Ticho, highlighted that clinical trials and patient care have different goals. While patient care requires you to look at the entire complexity of the disorder, and to focus on what matters the most to every single individual patient, it is “not necessary to show everything under the sun [in trials] to get one drug approved”. Billy Dunn warned about “creating unintended obstacles” for clinical trials, and advised developers that “you don’t have to put everything in the trial and put it all in the label”. Instead, he recommended using post-approval studies to get a broader picture of the drug potential, and let doctors explore the value for each individual patient once the drug is approved.
Bottomline: There has been much progress to develop and validate clinical scales for trials in CDD beyond seizures. Because of this work, if we had to start a clinical trial tomorrow with a gene therapy we would know what measures to include. This has been possible because of hundreds of CDD families that have been participating for 2 years (some even more!) in these observational studies where they don’t get any direct benefit, only burden. You should all be proud for making this happen!
5. A strong global community and a global alliance of hope
Image: Lili Hass message and picture (CURE5); Dr Maria Luisa Tutino message; Dr Maria Luisa Tutino together with Lynn and Majid Jafar; Dr Katheryn Frame presentation and picture (CDKL5 Alliance)
The international community, and in particular the CDKL5 Patient Alliance, were repeatedly described as “a global alliance of hope”, united around people rather than around data or molecules.
Beyond just the patient groups, the collaboration among scientists, clinicians, companies, and patient advocates was credited for accelerating progress from molecular insights to therapies for CDD. As a reflection to this collaboration, there were CDKL5 Forum Awards of Excellence granted to UCB Pharma as the company making a difference, Dr Kyle Fink from UC Davis for Lab of the Year, and Dr Massimiliano Bianchi for Champion of Progress, as well as several Junior Fellowship Awards.
The Forum opened with the voice of the patient, with Lili Hass, mom of Margot and co-Founder of CURE5 sharing her family story and “seizures are just the side dish; developmental challenges are the main course”. She asks scientists to look for more therapeutic benefits and to also look beyond drugs and into tools that can make life easier for families like hers, such as equipment, feeding innovations, and better ways to track data from home.
Dr Maria Luisa Tutino, in her dual role as mum of Elettra and protein scientist, gave a talk during the gala dinner and explained that science is not just experiments, it is people, connections and persistence. Allyson Berent from the FAST Angelman Foundation echoed these words for urgency and persistence, as another rare disease mum and scientist.
And Dr Katheryn Frame, mum of Kiera, gave the last presentation, as the Chair of the CDKL5 Alliance, talking about “a world of united hope” and highlighting the work being done by so many CDD patient organizations across the globe. Katheryn explained that to her, “united in hope means strength, determination, resilience, compassion and connection”.
Majid Jafar, dad of Alia and co-Founder of the Loulou Foundation, closed the meeting reminding us that the growth of the CDKL5 Alliance is a huge part to the strength of this collaboration. As in other editions of the Forum, he reflected on how we have progressed farther and faster than we ever thought, but never as far or as fast as families would want to. Majid asked the attendees to renew our dedication to developing cures for CDD, and invited us to meet in one year for the 2026 CDKL5 Forum in London, UK.
And that’s it for the 2025 CDKL5 Forum! where we learnt about unexpected CDKL5 biology that opens new doors for treatment, saw more families eligible for clinical trials than ever before, and where the progress in gene therapies for CDD felt more tangible and real than it has ever been. This was a great Forum.
I hope you enjoyed this summary, and I’ll see you in London.
Ana Mingorance, PhD
Disclaimer: This is my own summary and key learnings, and not an official text about the Forum by the Loulou Foundation. I write these texts with the parents of people with CDD in mind, so excuse also my lack of technical accuracy in parts.