2023 CDKL5 Forum
For the past nine 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 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 the past few meetings here: 2018, 2019, 2020, 2021 and 2022.
The 2023 CDKL5 Forum edition took place November 6-7 in London, UK, and will return to Boston next year for the 2024 edition. Each year I say that this was the best Forum so far, but it is true. I wrote 47 pages with notes. There was so much good information and so many important moments! I will try to summarize the main take-home messages from this year’s Forum including the scientific pre-forum meeting. This won’t cover all the presentations, but rather focus on the main themes that we saw and the main progresses – which are many.
1. USEFUL NEW INSIGHTS INTO CDD
The Forum always opens and closes with the words from the patient community. This year, Cristina, from CDKL5 Spain, opened the conference with some powerful words. She explained that when they received their daughter’s diagnosis, they also learnt that their daughter “would live a life somewhere between uncertain and horrible”.
That’s why for her, research means hope.
And every year we keep learning new things about CDD that have important implications to understanding the disease and thinking about treatments. Here are 3 of those, and check out also point #6 in this summary.
Dr Lauren Orefice from MGH and Harvard showed us that food texture aversion in CDD happens because of sensory changes, rather than behavioral reasons. Mice with CDD have sensory neurons that are hyper-reactive to rough texture, so no wonder they don’t like it. This is probably the same for people with CDD who might have difficulties with specific food textures.
Several research projects keep finding functional changes in brains with CDD, rather than structural changes (Dr Tanaka, Dr Higley, Dr Fagiolini and others). This means that neurons are in the right place, and overall the brain is all well shaped and connected, but some neurons are firing together more than they should while others are not firing together as much as they should. To me, this is promising for treatments because normalizing neuronal activity can lead to plastic changes in this type of neuronal functional connectivity. What would be much harder is to try to correct having neurons in the wrong place.
We had a wonderful lecture by Sir Adrian Bird, who became famous after showing that Rett syndrome could be reversible in mice. He explained to us how in Rett syndrome too little or too much MECP2 are both bad options, so the gene therapies in development for Rett syndrome (too little MECP2) all incorporate control mechanisms to prevent running into overexpression MECP2. A big surprise from this Forum was Dr Sharyl Fyffe-Maricich from Ultragenyx confirming with data in mice and primates what we had suspected for several years: the body puts a limit to how much you can express CDKL5 and it will not let you get into overexpression (too much) of CDKL5. The neurons eat all of the excess away, no matter how much gene therapy you give them. This is very encouraging, because it makes gene therapies for CDKL5 easier since we don’t need to add that “break”.
Food texture aversion and learning from the Rett syndrome field
2. SOLVING KEY PROBLEMS TO ADVANCE DIAGNOSIS AND RESEARCH
The 2023 Forum showed even more collaborative reagent and model generation than previous years, and in particular I would like to highlight advances around diagnosis and seizure models.
Genetic testing is not always easy to interpret. For example, if your child has a mutation in the CDKL5 gene that breaks the gene, then it is easy to interpret in a genetic test. But what happens when the mutation changes a letter by another one? This one is hard, and we end up with VUS (variant of unknown significance) and an uncertain diagnosis. A team from the Telethon Institute of Genetics and Medicine (TIGEM) is making in the lab all of the possible letter changes in the CDKL5 kinase domain and will check all of their functions in cells and then put the results in a database. That way, genetic labs will always have an answer for any letter change that they find. No more VUS for CDKL5, what a cool project.
And another big research tool progress from this year was that lots of seizure-relevant models are finally available! We had Dr Liz Buttermore show us a beautiful plate assay with cells from patients with a very nice hyperexcitability signal in patient-derived neurons. As a former pharma scientist, I know this is the type of assay that I would like to use. If you remember from other years, Dr Muotri from UCSD had a great in vitro CDD model using organoids from brain cortex. This year Dr Rebeca Blanch from his lab showed us that they are now making thalamo-cortical organoids, to try to better recreate one the main epilepsy circuits. Very cool! And Prof Peter Kind showed us how his lab has identified an epilepsy hotspot in CDD rat brains and they are able to stimulate it to induce seizures whenever we want. That’s such as great epilepsy model! This year we had incredible progress in this area.
VUS databases and CDD rat seizure model
3. “THE APPROVED 4”, AND TREATMENT PIPELINE TODAY
CDD had the first drug approved in the US (2022) and Europe (2023).
To show you just how special and how hard it is to have a drug approved for a rare epilepsy syndrome, I will repeat here what I said in my talk during the treatment pipeline session: there are more than 300 epileptic syndromes, and there are only 4 epilepsy syndromes that have any drug approved. These are Tuberous Sclerosis Complex (TSC), Lennox-Gastaut Syndrome (LGS), Dravet syndrome, and CDD. That’s it, just 4.
A pharma company recently started referring to these as “the approved 4” because it is so exceptional for an epilepsy syndrome to have a drug that has made it all the way to the finish line. For companies looking to develop treatments, these approved 4 are going to be easier and therefore more attractive than the others, because there is already a precedent and therefore many answers to how to get a drug to approval for them. So the value of ganaxolone goes beyond the value of the medicine.
We have gone from zero to 8 clinical trials in 8 years and have become part of the approved 4. This is a very strong beginning.
Now the question that remains is “what’s next”. At the Forum we had several presentations for the therapies that come next and many of the efforts to support them, which I summarize here and in the next three sections.
Marinus Therapeutics announced at the Forum that they have now signed a Global Access Program to help get ganaxolone to people with CDD in countries where it is not commercially available (or in process of becoming available, like is the case for Europe). Their website has a contact email for doctors to reach out to learn more about access. They also showed nice data of sustained seizure efficacy with ganaxolone over 2 full years.
UCB Pharma was represented by two speakers, including their CMO, who explained that UCB spends 30% of their revenue in R&D – this is a lot for the industry. And as you know some of that went to acquire Zogenix and their drug fenfluramine, which is now in Phase 3 trials for CDD. The trial has a website with an easy to remember name: cddstudy.com and you can see there all the countries where the trial is available in Asia, Europe and North America.
We also reviewed several drugs in development for other epilepsies or other neurodevelopmental disorders and that could potentially join the CDD pipeline in the coming years. These included other GABA drugs, KCC2 activators, Cav2.3 inhibitors (which we review in section 6) and some treatments that target the gut microbiome and that I find very interesting.
The conclusion for the session on the current CDD pipeline was that ganaxolone is just the beginning and that are multiple options coming behind it.
CDD therapeutic pipeline presentations
4. CLINICAL TRIAL READINESS: HOW THE PATIENT COMMUNITY IS MAKING THE FUTURE THERAPIES POSSIBLE
After the Forum we got emails from pharma and biotech industry professionals that attended the Forum and they all mentioned this session as very impactful. As one literally wrote, “this will attract more industry participation”.
This session was about biomarkers and outcome measures, which is “what to measure in trials that will look at more than seizures”. This is particularly critical for the future gene therapy trials, and the last 12 months have seen tremendous progress.
Biomarkers are way to see changes in the brain without directly taking a biopsy. One type of biomarkers are the ones we can measure in blood (glucose levels are a biomarker for diabetes), and Dr Massi Bianchi from Ulysses showed us very promising early data for measuring neuronal plasticity in a blood test by looking at two key markers. Another type of biomarker is using brain imaging, and Dr Eric Marsh from CHOP showed us data from a large collaboration where they can correlate EEG signals with disease severity in CDD patients. Both of these types of biomarker are very likely to be used in future clinical trials.
Dr Marsh also updated us on the development of novel clinical scales to measure CDD symptoms beyond seizures run by the ICCRN network. They have completed a first part and they are now tweaking and confirming the new scales, which are looking really promising. And one important bit to highlight: this is a study with over 100 patients, and 100 patients is the size of a Phase 3 trial in CDD so kudos to the patient community for mobilizing to make this work and the biomarker studies possible.
And then Dr Xavier Liogier, from the Loulou Foundation, updated us on the progress around the CANDID study which is run in collaboration with a consortium of companies developing CDD treatments. This study evaluates well-known clinical scales that have already been used in clinical trials but for other diseases, to see how they may apply to CDD. Last year Xavier told us about the first patient having been enrolled. Twelve months later he told us that we will get more than 100 participants by the end of this year and showed us a lot of data for how these scales are able to capture different CDD symptoms. The recruitment graph looked exponential, again showing the tremendous mobilization of the patient community to make the CANDID study possible.
Dr Billy Dunn, former Director of the Office of Neuroscience at FDA and current Senior Advisor to the Loulou Foundation, moderated this session and praised all presenters for the spirit of collaboration in sharing all these data while still in progress, and highlighted the value of building all these biomarkers and scales as a “menu to choose from” to enable complex trials in CDD.
Ulysses biomarker project and exponential CANDID recruitment curve
5. MAKING A GENE THERAPY IS LIKE BUILDING A HOUSE
One year ago, at the 2022 Forum, we through that by the end of 2023 we would have the announcement that one of the gene therapies for CDD had received green light for a trial. We didn’t get this news.
And discussing with some parents at the Forum about the best way to explain to non-scientists the implications of delays in very complex process projects, we came up with the idea of how this is very much like building a house from scratch. You approve the initial design, and the constructor gives you a timeline for when you will get the keys. Then it rarely ever happens as planned. And that is because there are too many steps that can end up taking a bit longer, but this is not a sign that there is a fundamental problem with the house or that you will never get the keys. It may be that pouring the foundation is delayed due to a long winter, the insulation had to be redone, building the skeleton of the house can also unlock some surprise… add to that installations, exterior finishes, then all of the interior work… there are just many steps that impact timeline predictions.
Making a gene therapy is not unlike building a house. The biotech experts know how to make gene therapies, but they still have to adjust each step to our particular gene therapies and there are so many complex steps including regulatory reviews (like the different house inspections!) that timelines end up shifting but that is just a normal part of making a gene therapy.
What we know today is that the gene therapy from Ultragenyx and the one that the Loulou Foundation is developing with UPenn have indeed both already been presented to regulators in 2023, and are both now hoping to get clinical trial approval in 2024. So the progress has been good, just not as fast as we all hoped for. And Sharyl from Ultragenyx was very clear in her presentation this year: they have not found any adverse safety signals with the CDD gene therapy to date in any of their studies in animals including primates. This is a case of having to complete some more extra work to pass the house inspection.
Bottomline: at the end of last year we were told “I think I can give you the keys to the house by the end of next year” and that didn’t happen yet, but there is no problem with the house. It is just really hard to predict the exact timelines in very complex projects.
At the 2023 Forum we also reviewed the progress using new gene therapy modalities that haven’t been yet approved for any human disease so there are no precedents. In particular we had an update from Dr Kyle Fink from UC Davis who has been developing a CRISPR-like approach to reactivate the second copy of CDKL5 gene in each cell in females (from the second X chromosome), and also from Kelcee Everette from David Liu’s lab who is also developing a CRISPR-like approach called prime editing to correct the wrong letter or inset a missing letter in CDKL5 mutated genes. In both cases, much of the work focuses on improving efficiency (more copies of the gene fixed), specificity (not mess up with other genes) and figuring out how to make the CRISPR tools smaller so that they can fit the viruses used in gene therapies. These projects are like building new houses with completely new materials that had never been used before, and that so far are too large to fit well into the house. So timelines are unknown, but progress is very tangible. And it is quite amazing to see that one of the first diseases that these new technologies are being applied to is precisely CDD.
Multiple gene therapies in development
6. TWO SUPRISES THAT HAVE OPENED TWO IMPORTANT NEW DOORS
Not everything is taking longer than we thought. Some things are happening faster than we thought. We saw two great examples of this at the Forum.
Learning from evolution
Dr Ibo Galindo from the CIPF presented a fascinating evolutionary analysis of CDKL5 from the first single cell that existed and throughout the entire tree of life. It turns out that plants had CDKL genes but lost them (they have CDD!), and the original CDKL gene was CDKL5 but then it got duplicated twice leading to 5 forms. And it turns out that while all CDKL1-5 forms appear to be important to control cell skeleton, CDKL5 seems to have acquired new functions in vertebrates. There were two important conclusions: (1) there is probably functional redundancy among CDKL proteins, and (2) CDKL5 has a unique tail in vertebrates that suggest a new function not related to cytoskeleton.
And those conclusions provide a beautiful context to two projects coming from the lab of Dr Sila Ultanir at the Crick Institute that I summarize below. Sila’s lab was awarded the Lab of the Year Award by the Loulou Foundation in this last Forum, but I like to call them the “Lab of the Decade” because of their major ongoing contribution to the CDD field.
(1) Functional redundancy. Found the right paralog. Found a new therapeutic avenue.
A paralog is a gene that was born from a duplication of another gene, so now the two copies are so similar that they might have overlapping functions. This is what happened in SMA, the neuromuscular disease that is lethal in babies born without any functional SMN1 gene, that is now treatable because scientists found a way to use SMN2 (a paralog!) to compensate for the loss of SMN1.
Sila’s lab found that the most famous cytoskeleton target that we know for CDKL5, called EB2, wasn’t only controlled by CDKL5 in neurons, there seemed to be another kinase that could do the same job. And it turned out to be CDKL2! So now she is looking into the possibility of upregulating CDKL2 to compensate for the loss of CDKL5. And there is a potential to achieve this using an ASO approach. At the Forum we had a wonderful lecture by Dr Stanley Crooke, who founded and led Ionis (the company that made the first ASO treatment for SMA) and later created a non-profit organization called N-Lorem to make ASOs specifically for people with nano-rare diseases. And he explained that “CDKL2 has nice architectural features to make it suitable for overexpression” using ASOs. And he knows about this!
It has been quite unexpected to find out that we might get to follow the steps of SMA by finding a second gene that could do much of the work of the first gene (at least in neurons, because looks like in other organs it could be another CDKL). And this happened super-fast.
(2) Predicted to have targets beyond cytoskeleton. Found the right target. Found a new therapeutic avenue.
Dr Marisol Sampedro, working in Sila’s lab, had made the discovery last year that CDD could be partly a channelopathy because she found a new target for CDKL5 that is an ion channel. The channel is called Cav2.3, and when it is not phosphorylated by CDKL5 (as would happen in the deficiency) the channel stays too open, and the neurons stay too active. So what we would need is inhibitors. You can read about this in last year’s Forum recap (point 4, where I called this discovery a breakthrough).
One year later we had a new company standing on stage, called Lario Therapeutics, telling us that they are developing Cav2.3 inhibitors for CDD and for a disease caused by gain-of-function mutations in that gene (so they also have too much activity). Lario’s chief scientist explained that they are close to finishing the chemistry optimization and to start running safety experiments to advance their new drug towards clinical trials. This is a precision medicine approach to treat CDD and this seriously happened super-fast.
SUMMARY: MOMENTUM
We learnt this year that the first gene therapy is taking a bit longer that we thought, but many other things are happening faster than we thought, including having new therapeutic avenues (CDKL2 and Cav2.3) that were unimaginable for us barely 2 years ago. We also had several multi-year-long efforts all give us tangible results finally this year, like the two observational studies that have recruited as many patients as Phase 3 trials, or finally having beautiful in vitro and in vivo epilepsy CDD models of the type that pharma companies need. It feels to me that the pace of progress is accelerating, almost like that recruitment timeline for the CANDID study, and we have reached a powerful momentum.
That is exactly the same word that Stan Crooke chose when he stood on stage, and told us how “you can feel the momentum behind the science” in the CDD space. And I think that is a good word to capture what we saw this year.
And this momentum builds on two pillars that were also mentioned often during the 2023 Forum: determination and the spirit of collaboration.
Voice of the patient at the 2023 CDKL5 Forum
So I will leave you with quotes from three of the parents that spoke at the meeting that capture some these messages:
Cristina, from CDKL5 Spain, reminding us that “People with CDD are amazing and they deserve the best”.
Majid, from the Loulou Foundation, acknowledging the road to come with “We have moved faster and further than I expected thanks to all of you. And at the same time, that’s never as fast or as far as hoped for by the families”. He then called upon the audience to recommit with even more passion, more drive and more determination.
And Heike, representing the CDKL5 Alliance, who told us about his daughter and her personality, the efforts that all countries in the alliance and doing at the local and international level, and how “together we are stronger”.
I know I say this every year, but this was the best CDKL5 Forum so far.
I hope you enjoyed this summary. Please let me know your thoughts in the comments.
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.