1. Intro: Back in Rome
The first CDKL5 conference that I attended happened to be the patient meeting in Rome in 2017, where the CDKL5 Alliance was started. I am a neuroscientist and I was already working with patient foundations for related disorders, so I wanted to learn about CDD. I remember meeting some Spanish families (my country) who quickly explained me the disease. Also seeing Marinus on stage talking about a very small trial that they were running in CDD with their experimental drug ganaxolone. And I remember Antonino Caridi, a CDD grandpa, who took the initial leadership of the patient Alliance and welcomed us from stage.
I ended up joining the Loulou Foundation in 2018, so having the CDKL5 Alliance meeting return to Rome in 2025 felt very special. We were back in the same place, but everything about CDD is now immensely larger: the size of the community, the treatment pipeline, and the number of people working on it. And Antonino still looks the same.
The ALL IN(VOLVED) conference started Friday June 27th, with families catching up with each other, and meetings of the national patient group leaders and also with the pharma representatives. To give you some numbers, we had over 300 participants, with 41 people with CDD and many siblings who made the conference very enjoyable. In total we had participants from 24 countries or territories! in alphabetic order: Albania, Australia, Austria, Belgium, Brazil, Bulgaria, France, Germany, India, Ireland, Italy, Japan, MENA, Netherlands, Philippines, Poland, Romania, Slovakia, Spain, Sweden, Switzerland, the UK, Ukraine and the USA. That’s why we call it the Global Alliance. And we had 9 pharmaceutical and biotech companies supporting the meeting. Just hearing these numbers would have blown the minds of the 2017 participants.
Then on Saturday 28th we started with a series of science talks for all attendees, where we reviewed the disease, the natural history studies, the pipeline, and learnt about different therapeutic modalities and where they are. We called these the ALL IN(FORMED) sessions.
We also had a presentation from the team at the Pediatric Therapy Center High Hopes, in Dubai, because the non-pharmacological therapies are so far the best therapies that we have for kids and adults with CDD. They showed us best practices to improve strength and mobility and promote neuroplasticity in these kids, and talked about a “multidisciplinary team with a family-centric approach” with parents as co-therapists.
For the afternoon we split into two tracks. I stayed with the scientists and the pharma companies in a partnering session where we learnt about specific programs on new therapies and model systems for the disease. I will mention these in my summaries below but without much detail, given that this track was designed to be only for scientists and not open to families. The parallel track for families included biomarker sampling and pet therapy with a dozen of beautiful dogs, which made us, scientists, very jealous.
And we closed the conference on Sunday June 29th with the ALL IN 1 COMMUNITY session where the families took the stage and we all listened.
I will summarize below the main news from the scientific sessions, and some of the main messages from the families that I found particularly impactful. Please keep in mind that I am looking at the therapeutic progress as a scientist, not as a parent. And this is not the entire summary of the ALL IN(VOLVED) CDKL5 Alliance conference, so apologies in advance for the parts that I might be missing.
2. Science: small molecule drugs
The first generation of treatments developed for CDD are anti-seizure drugs. That’s because CDD is one of the genetic syndromes that comes with the highest seizure frequency, and there is no good drug to control those seizures, so we really need something better.
In 2017 in Rome, Marinus presented data on 4 patients with CDD taking ganaxolone, FOUR. Three out of four had improved, the fourth one didn’t, but it looked promising. Their plan was to recruit more patients.
By the time we met back in Rome for the ALL IN(VOLVED) 2025 conference, we know that the Phase 2 trial included 7 patients and was successful, that it would be followed by a global Phase 3 trial with more than 100 patients also successful, that then Marinus succeeded at getting ganaxolone approved for treating seizures in CDD in the US and Europe, and that Marinus was later acquired by a larger company called Immedica Pharma who was now with us in Rome at the conference. Change and progress can seem slow looking forward, but quite fast when you look backwards.
Carol-Anne Partridge is a CDD mum (and leader of the UK patient group) and she presented a study designed to convey better to governments and payers the severity of CDD. This is very important because ganaxolone is the first drug approved for CDD, so when authorities evaluate their reimbursement decision on ganaxolone they are learning about the drug AND the disease at the same time. And because of this learning curve, ganaxolone is still only commercially available in the US. The study surveyed 132 families, and showed that 96.7% of patients are taking anti-seizure drugs, and that if you measure the health-related quality of life of the CDD patients as reported by their parents from 0 (a state comparable to being dead) to 1 (representing full health), the average is 0.18. The survey used the methodology that payers want to see, and was designed to “speak” to them. I think the message is loud and clear about the need for new medications.
The biggest news of this conference came from our second Phase 3 trial in CDD: UCB Pharma issued a press released the first day of the conference announcing that the Phase 3 trial with fenfluramine for treating seizures in CDD was successful, both in efficacy and safety, and that they will be moving forward to request an approval for CDD now (fenfluramine is already approved for two other syndromes). If everything goes well, this will become the second drug approved for CDD. And thank you UCB for the perfect timing with the announcement, we all got to celebrate together.
And what comes after two global Phase 3 trials? another global Phase 3 trial. The company Longboard (part of Lundbeck after an acquisition) is developing a second-generation fenfluramine, called bexicaserin, that is already in Phase 3 trials in the US and is adding many more countries world-wide progressively this year. Interestingly this drug is bringing together into the same trial all of the rare epilepsy syndromes, that are often called “DEEs”, and because people with CDD often have many seizures it means that many will qualify for this trial. It asks for a minimum of 4 countable seizures a month, and ages 2 to 65. In Rome, we had Dr Marina Trivisano present an update on this program and show us the map with all the countries in the trial. You can see more information online if you look for the “DEEp OCEAN” trial, and I encourage you to ask your neurologist about it if you are interested.
These first three large trials were for seizure medications, but I also explained in my presentation about the CDD pipeline that after these trials we are moving into therapies that treat the disease, not the symptom. And this includes not only the gene therapies (more about this in a minute) but also small molecule drugs that act on the most important targets of CDKL5. What we call “small molecule drugs” are the regular medicines that are taken orally like a pill or a syrup and that are made of a chemical compound – not something big like a virus or a protein. And because the work of the CDKL5 protein in the cell is to turn on or off other proteins, acting like a switch (that’s what kinases do), it is possible for scientists to design small molecule drugs that can bind to those proteins now, and turn them on or off as they needed.
In the morning session I introduced that concept, and I called it precision medicine because those drugs are designed to correct some of the key targets of CDKL5. And later in the afternoon during the partnering session we had a presentation from Prof. Massimiliano Bianchi who is developing one of those precision medicine approaches, with drugs that target the cytoskeleton (more of why that’s important for CDKL5 HERE in section 1).
3. Science: gene therapies
There are several gene therapies in development to treat CDD, and we hope that they will get to clinical trials in the near future. A gene therapy uses a virus to deliver a copy of the CDKL5 gene to the brain, so it is made of the outside of a virus (to help it get into brain cells) but inside it doesn’t have virus DNA, it has the CDKL5 gene.
Dr. Stuart Cobb is one of the inventors of a gene therapy for Rett syndrome (with the gene MECP2) and gave us a beautiful lecture on how gene therapies work. In his words: “it is an easy concept, but with complicated execution”. It essentially follows four steps: make the virus, cure a mouse, check for toxicity in monkeys, and then go to clinical trials. He explained how in Rett syndrome they are already in clinical trials, and they are seeing clinical improvements. And two days after his talk, the company developing his gene therapy announced that they are progressing to Phase 3 trials with their gene therapy in Rett syndrome.
Some years ago ,we thought that gene therapies for CDD would be in clinical trials by now. Ultragenyx had said at the 2022 CDKL5 Forum that they hoped to be in trials in the following year. But that hasn’t happened yet, two and a half years later, so I know that has disappointed many families who have been counting how old their kids will be by the time the gene therapies arrive to trials. And that premature announcement has probably also made the other gene therapy developers refrain from speaking too soon about their timelines, to not risk disappointing the community once again. As a result, we are still a bit in the dark about how many gene therapies are being developed for CDD and how far along they are.
Majid Jafar and I (both from the Loulou Foundation) mentioned in our presentations that there are multiple gene therapies in development for CDD, but it would have been much better to get some of the companies present an update. Even without stating timelines, seeing the progress that they are making would have been and influx of air for the 300+ family members in the room.
We did have two presentations dedicated to a special type of gene therapy for CDD: a gene therapy designed to open up the second CDKL5 gene copy. For background: because males only have one X chromosome, female cells only use one of our X chromosomes and turn the second one into a tiny little ball that is not read. That way, both males and females have one functional X chromosome. Which X chromosome gets inactivated is totally random and is different for each cell. What this gene therapy does is to carry inside of a virus the instructions to read the second copy of CDKL5, the one in the inactive X chromosome. And because girls with CDD have always one good CDKL5 gene copy (the other one is mutated) this gene therapy can help each of their cells read the two copies, one of which is good, and that’s all we always needed! Dr. Kyle Fink is leading this program and told us that they are now making “clinical grade gene therapy” to start the safety experiments in monkeys that come prior to trials.
4. Science: Enzyme Replacement Therapies
We also had a lecture on how enzyme replacement therapies work. Prof. Elisabetta Ciani explained very nicely how an enzyme replacement therapy consists of making “lab-made CDKL5 protein” to then give it to neurons. This is a good idea because CDKL5 is an enzyme, and other brain enzymes have been successfully adapted to enzyme replacement therapies. But as Stuart had said earlier that morning, this is also “an easy concept, but with complicated execution”. Elisabetta had succeeded at making a modified CDKL5 (so that it enters cells) in her lab and using it to treat CDD mice, but the same methods that worked for mice don’t work as a medicine for people, and here is where the challenge has been.
Prof Maria Luisa Tutino, who is both a CDD mum and a protein scientist, has been trying to make as many changes as needed to the CDKL5 protein to make it suitable as a lab-made protein therapy. The first-generation lab-made CDKL5 only goes to the “stomach” of neurons, so they eat it instead of using it, and she is currently working on a second-generation approach for which she has received a 1 million Euro grant. This one is clearly a very complicated therapeutic approach, but one worth fighting for.
5. Making it easier to develop treatments and to run trials
Before getting to trials, we need to believe that the treatment is going to work. How do we check that it could work? by testing it first in animals with the disease. And once we get to trials, we need to confirm that the treatment works, this time in patients. And how do we see if it worked in patients? by measuring clinical changes.
At the 2025 patient conference we got updates on animal models and on clinical change measures.
We reviewed the animal models in the partnering session, with Prof. Leonor Cancela showing us the zebrafish model of CDD (and small molecule screenings that she is running), María del Carmen Martín showing us the drosophila model of CDD (which has lots of seizures) and the Ulysses Neuroscience team showing us their CDD mouse model testing service. That means we have the entire toolbox to run preclinical trials in CDD animals.
And we got updates on the studies to measure clinical changes during the big morning session with all families in the audience, because all CDD families are critical players in these clinical programs.
Prof. Tim Benke gave us an update about the disease, and also updated us about the ICCRN natural history study in the US where they are developing a single scale to measure the global severity of CDD for each patient. And Dr. Xavier Liogier told us about the international CANDID study that is managed by the Loulou Foundation, where we have been able to see that there are many seizures at all ages, that most of the developmental improvements are seen in children under the age of 6, and that there are several scales to measure different disease domains (like cognition, communication, behavior or motor skills) that could be already used in trials. These two studies have enrolled more than 200 patients together, and participating in these studies means several hospitals visits over several years, so it is a big effort by the patients and their families and it would be impossible to design complex clinical trials (like for gene therapies) without all of you.
While the natural history studies help us know how to measure EXTERNALLY how a medicine might be helping, we use biomarkers to measure the INTERNAL changes. At the Rome conference we saw an update on the ELPIS global biomarker study by Prof. Massimiliano Bianchi, where they track changes in proteins in blood that tell us what is happening in the brain. And we also had a presentation by Vita Cardinale, who won the conference poster competition and was invited to give a talk on her project where they look at biomarkers in saliva from patients. These biomarker studies are made possible by more than 100 volunteer patients and their families who are helping these scientists identify the internal measures of change.
By the way you might wonder how blood or saliva can tell us what is happening in the brain. The answer is that neurons talk to each other by sending out little bits of neuron that contain proteins and RNAs almost like sending a letter by post to each other. The inside of those little bits tells the recipient how that original neuron was feeling. Sometimes the recipient is a neighbor neuron, but sometimes those letters travel so far that the recipient is a scientist that can pick it up in liquids like blood or saliva and read that letter. Science can be very cool.
6. Voice of the community
Patient conferences can be very emotional, with many highs and lows. In Rome we shared three days with families in very different situations, from those who had their little kids with CDD taking their first steps, to parents who have lost their children. So it was only fair that after the main conference day families took the stage.
During this final session we listed to #1minuteofhope videos where parents from all over the world told us what hope meant for them, and asked the audience “what does hope mean for you?”. We had videos from Italy, Peru, USA, Canada, Japan, Ukraine, MENA, and France.
Mais Kanan from CDKL5 MENA started the day, and Majid Jafar from the Loulou Foundation gave us a recap for how much progress has happened since his first daughter Alia got diagnosed with CDD in 2014. His was a message of hope, hard collective work that got us to where we are, and perseverance to get where we need to be.
We then got to hear from two siblings, starting with Iman Jafar who told us about how much she loves having Alia as her older sister, and how the first word that she ever spoke was “up” after hearing so often everyone tell “up!” to Alia to help her with her motor skills. And later we heard from Alessandro Caridi, who had a harder story as a sibling to a sister with CDD, but who also reminds us that the experience of every family and every person is unique, and to not underestimate the impact of this severe disorder on everyone around.
Dr Michela Fagiolini spoke about the possible future and dreams, from her experience working as a scientist in CDD and related diseases. She had some really good messages for families, like “drugs tailored for CDD and gene therapy are coming. These are not just abstract hopes, they are real and moving forward”. And how “it cannot be one person or one lab or one family, everyone is needed, and you are not alone”.
Then CDKL5 Spain shared two voices, one from a founder parent, and one from a more recently diagnosed family. Sandra Pérez spoke about being one of the “5 families and 5 stories” who created the Spanish association in 2014, and how one of the main missions of the group is and was to welcome new families, because they know how it feels to receive a diagnosis that changes everything, and how important to know that you are not alone. Then Manuel Vigara spoke about how thankful he was to those first 5 families who were “a light in the middle of dark, and whose steps opened our path”. He explained that the word “rare” often means no resources and no answers, and asked for the science community to keep dreaming and progressing, because “each hour in the lab is a thread of hope for millions of families” and “each small progress is a miracle in the making”.
We heard from the Fondazione Telethon in Italy about their support to rare genetic patient groups, and how “tenacity” is the identity of the Italian association and host of this meeting, CDKL5 Insieme Verso la Cura.
Last Barbara Verdirame, president of CDKL5 Insieme Verso la Cura, took the stage to thank everybody, from the families to the volunteers to the scientists and the doctors and the industry representatives in the room and everyone who supported the conference. Because in the end it is only through that massive collaborative effort that we get to advance medicine.
And I want to close this summary by capturing some words from Antonino Caridi, who opened the conference by reminding us of how far the International CDKL5 Alliance has come since it was founded in Rome in 2017, how “hope” is not a passive word, but one that gives us the courage to transform the injustice of CDD, and that “the best is yet to come”.
Ciao a tutti!
Ana Mingorance, PhD
Disclaimer: I write these texts with the parents of people with rare epilepsy syndromes in mind, so excuse also my lack of technical accuracy in parts. And credit for the beautiful pictures goes to Massimiliano Marcoccia and the great team from CDHL5 Insieme verso la cura.