For the past eight 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 and 2021.
The 2022 CDKL5 Forum edition took place November 7-8 in Boston, returning to a face-to-face format after two on-line editions during the pandemic. Being back in person made this year’s meeting even more special. It was also, in my opinion, the best CDKL5 Forum meeting so far. Our understanding of CDKL5 deficiency biology and the pace of therapy development have advanced significantly in the last few years, so I will summarize my main take-home messages from this year’s Forum below and contrast them to where we were the last time we saw each other in Boston in 2019.
1. THE YEAR CDD BECAME PART OF THE 5 PERCENT
We always hear the same line: “there are more than 7,000 rare diseases, and only 5% have a treatment approved”. That is a special club of rare diseases that have received so much attention and investment that a medicine was specifically tested and approved for that rare disease.
In 2022, CDD joined that club.
In 2022, ganaxolone received approval from the FDA for treating seizures in CDD, and we are expecting the EMA decision soon. When we met last time at the 2019 Forum, we announced that Marinus was on track to complete recruitment for their ongoing Phase 3 trial with ganaxolone in CDD. Since we met last time, Marinus completed a first-ever global clinical trial for CDD in the middle of a global pandemic, and ganaxolone is now available for patients in the US and hopefully soon in other countries. I’m amazed at the courage of the Marinus team to bet on this un-tested rare disease, and to fight thought the pandemic to bring the first therapy to the market for people living with CDD. They have made the path easier for everyone else to follow.
And yet the first drug approval for CDD is only one of the two biggest news of the year…
2. CDD GENE THERAPY IS COMING TO CLINICAL TRIALS
One of the biggest hopes of the CDD patient families is the arrival of gene therapies to clinical trials. In CDD, half of the neurons (in girls) or all of the neurons (in boys) don’t produce the protein CDKL5, which is a very important protein for brain functioning. Gene therapies aim to use a virus to carry a new copy of the CDKL5 gene to neurons, so that they can start producing the protein [see also the next section in this update].
At the 2022 CDKL5 Forum, Emil Kakkis, CEO of Ultragenyx, said the words that CDD families were waiting for: “Gene therapy for CDD is coming to the clinic, we believe next year”.
Later in the conference, Sharyl Fyffe-Maricich (who has been leading the CDD gene therapy program at Ultragenyx) explained all of the steps they have taken to optimize their gene therapy to that it could get to as many neurons as possible before sitting down with regulators to talk about starting a clinical trial. The quality of their science is impressive, and Emil explained that clinical development is hard but we will all be in this together.
When we met in person last time at the 2019 CDKL5 Forum we were starting to have some data of experimental gene therapies in mice. Major questions back then were whether these therapies would work well enough in animals to progress to clinical trials, and when that might happen. We now finally have an answer and a timeframe: if everything goes well, clinical trials with the first gene therapy for CDD could start as early as in 2023.
This was the second big news of the year, and the highlight of the 2022 CDKL5 Forum.
3. TACKLING CDKL5 DEFICIENCY FROM ALL ANGLES
During the Forum Dinner, Phil Reilly (a very experienced developer of medicines for rare diseases) shared with us some stories about diseases that used to be considered untreatable until patient families intervened and played a key role to developing a cure. His message was: “there is no intractable disease”.
The next day, Emil Kakkis would remind us that “CDD has reversible components, and that is not true for many other neurological diseases”. He was referring to what we know from mice with CDD, where multiple aspects of the disease are reversible in older animals if CDKL5 is re-expressed. We also know that CDD is not a degenerative disease or even a strict neurodevelopmental disease where CDKL5 is needed only during a limited time in development. It is actually a neuromaintenance disorder, as we saw in the 2020 Forum, so there is much clinical hope around the possibility of restoring CDKL5 expression in CDD patients.
At the 2022 Forum we saw many updates about different approaches to tackle CDKL5 deficiency from all angles. Here are some quick notes on the different approaches:
Treat the disease symptoms: there is a Phase 3 clinical trial ongoing in CDD with the drug fenfluramine. This drug has beautiful efficacy in Dravet syndrome, and the company that developed it (Zogenix) was recently acquired by UCB Pharma, one of the leading epilepsy companies. The clinical trial is already enrolling in the US and expanding to Europe and Japan.
Treat the disease symptoms: Takeda had evaluated the efficacy and safety of soticlestat in a small study in CDD and updated us about the patients that continued taking the drug after the study. From the 12 patients that participated in the small trial, 8 are still taking the drug and all have experienced seizure reduction during the time they’ve been taking soticlestat. And it is not just about seizures, parents reported overall improvements including in communication and engagement. I hope to see this drug considered for treating patients with CDD.
Correct the CDKL5 pathway: there is a new discovery that opens the door to designing new treatments to correct some of the direct consequences of CDKL5 being missing. I dedicate to it the entire section 4 of this update.
Add more CDKL5 protein: the development of an enzyme replacement therapy for CDD (make the protein in the lab and give it to patients) has proven to be very challenging. Maria Luisa Tutino presented at the Forum her work towards producing full-length functional CDKL5 to be used for enzyme replacement and all of the challenges that they are solving one by one. There is need for more labs and companies to join the efforts to develop an enzyme replacement therapy for CDD because it remains an important therapeutic approach and it is very hard.
Correct the mutated RNA: the CDKL5 gene gets copied into messenger RNA, which then is used to produce the CDKL5 protein. If a gene has a mutation, then that mutation is still copied into the RNA. There are a variety of strategies to try to make functional protein from a mutated RNA without needing to fix the gene. For example there is a project ongoing to develop antisense oligonucleotides (ASOs) that could help with mutations in CDKL5 that cause splicing problems (like spinraza for SMA) or also that could potentially skip exons that might contain a mutation (skip part of the RNA sequence, like some treatments for Duchenne). And we know that there are also companies developing approaches to help cells read past non-sense mutations, which is sometimes also the problem for some people with CDD, so I hope to hear more news about these approaches and see them tested for CDD.
Reactivate the second CDKL5 gene copy: we had two presentations at the 2022 Forum about gene therapies that use a version of CRISPR to find the inactive CDKL5 copy and reactivate it. Kyle Fink has been leading the development of one of these gene therapies for CDD for the last couple of years, and recently was awarded a $1,4M grant to further develop the gene therapy for CDD. He also received the Lab of the Year award at the Forum.
Fix the mutated gene: there are several new approaches in development for correcting letters in a gene, or inserting letters. Majid Jafar, co-founder of the Loulou Foundation, explained that Loulou is missing one letter in her CDKL5 gene, and that her mum had asked “why can’t they just put that letter back?” when learning about the diagnosis. David Liu has been advancing a modified CRISPR-like approach called prime editing to do precisely that: put one letter back. He showed us how he can already fix the CDKL5 of kids like Loulou in cells in culture, and he is now working at getting it to work in living mice. Some of these gene editing approaches are starting to make it to clinical trials barely 5 years after the technology was discovered. His ultimate goal is not just to be able to add or replace one letter, but to replace the entire mutated CDKL5 gene by a healthy copy. It is always inspiring and a window into the future to hear David give a talk.
Add another copy of the CDKL5 gene: this is the classical gene therapy approach where scientists use a virus (usually AAV) to carry a gene to neurons. The virus cannot multiply, it just delivers the gene to neurons and from then on, neurons can produce the missing protein, in this case CDKL5. At the 2022 Forum we had a wonderful update about the Ultragenyx gene therapy program, and the news that it is progressing to clinical trials.
4. A BREAKTHROUGH IN UNDERSTANDING CDKL5
There were many presentations at the Forum about new understanding for how the CDKL5 protein works and some of the consequences to the brain when CDKL5 is missing. But I will only highlight one in this update, because I consider it a major breakthrough in our understanding of the protein and the disease. It also opens an important door to new treatments.
The discovery came from the lab of Sila Ultanir, at the Crick Institute. The protein CDKL5 is a “kinase”, which are proteins that can change the function of many other types of protein. This means that when the kinase is missing the problem multiplies because now you have all those other proteins not working well. The Ultanir lab has discovered a very important protein that needs CDKL5 to work properly, and it turns out to be a calcium channel (Cav2.3). When CDKL5 is missing, the calcium channel opens well but then closes too slowly, leading to too much calcium going through.
This is very important because many developmental and epileptic encephalopathies are caused by problems with ion channels, we call them “channelopathies” as a group. For example Dravet syndrome is caused by a sodium channel working less, KCNQ2 epilepsy is caused by a potassium channel working too much, and there is even a very rare syndrome caused by the Cav2.3 calcium channel working too much. The discovery that deficiency in CDKL5 makes that same calcium channel also work too much is unexpected and helps explain a lot.
I call this discovery a breakthrough for two main reasons:
1) We often wondered… if CDD is caused by a kinase missing, why does it look so similar to the channelopathies? Now we have the answer: CDD could be partly a channelopathy!
2) This discovery opens the door to designing new treatments to correct some of the direct consequences of CDKL5 being missing. Now we know that we want companies to develop Cav2.3 blockers.
5. MUCH PROGRESS EXPANDING THE RESEARCH TOOLBOX
For scientists to understand what CDKL5 does in cells, and to test treatments years before they are ready to go into trials, they need to model the disease in animals or cell cultures in the lab. There has been a giant effort by scientists across many countries to find animals or cells where we could remove CDKL5 and see a strong symptom (which scientists call “a phenotype”).
The most used animals in medical research are mice and rats. This year we had several great presentations that expand the CDKL5 research toolbox to fish and flies, and potentially frogs (tadpoles) and even pigs.
We had presentations from two groups showing that a tiny fish called zebrafish might help us research some of the symptoms of CDD. A group from Portugal has seen that zebrafish missing CDKL5 have bone problems (which also happens in patients!) and interesting motor symptoms that could be monitored to test experimental medicines in those fish. And a group from Boston is changing the fish genetics so that they can miss CDKL5 in only half of their neurons, which is what happens in girls with CDD.
My favorite presentations about new CDD models were two:
The lab of Ibo Galindo, in Spain, has made fruit flies that lack the CDKL5 gene and they have very strong epilepsy and their disease is so severe that they even die sooner than normal flies with CDKL5. In fact flies only have one gene for CDKL1/2/3/4 and 5, so these flies are missing all of the CDKL genes! And they look like other good fly models of genetic epilepsies. The flies also have interesting behaviors, and could be a powerful genetic system to understand the function of the 5 human CDKL proteins by making the flies express each of the human genes and see which ones can make them healthy.
The company Vyant is using stem cells taken from skin or blood samples from children with CDD to grow organoids in the lab. Organoids are like a ball of neurons and other brain cells all produced from the child stem cells and look like a mini-brain in a petri dish (they are to the right of the rat in the pictures that accompany this text). It turns out that organoids from kids with CDD have the in vitro equivalent of epilepsy. Vyant is using these organoids as a platform for drug screening directly in human cells, and they are already finding some promising compounds. I really liked their platform.
I was very impressed with the tenacity of so many scientists making a giant effort to leave no stone unturned, and to check every animal and every cell and tweak them and optimize them. This means that today we have a variety of different models that can be used to answer different questions about biology and treatments, and this type of work takes a big community effort, it cannot be done by only a few labs. I’ll come back to this in the next section.
6. “WE ARE IN THIS TOGETHER”
A theme that emerged as the 2022 CDKL5 Forum motto was “we are in this together”. We heard it in words, and we saw it in action. These are only some of the examples that we saw during the Forum:
No patient left behind. There are patients with CDD in all countries, and that also means they come in all languages. Sadly language barriers are a major limitation to reach the international community. To bring together the data of as many patients as possible, and to be able to reach out to them about news such as clinical trials, the CDKL5 Registry is recently available in many of the common languages and will be expanding to more. Current languages are English, French, German, Italian, Spanish, Arabic, Chinese (traditional and simplified), Japanese and Russian! This was a lot of work, but we are in this together.
Companies collaborating in clinical studies. When we met last time in Boston in 2019, we talked about the need for an observational study to validate outcome measures for CDD (to check that we know how to track CDD symptoms in a way that is useful for clinical trials). The catch is that we wanted only one study, with the different pharma and biotech companies coming together to co-design it and run it, so that we would not overburden the patient community. At the 2022 Forum, Xavier Liogier from the Loulou Foundation stood in that same stage to announce that the first patient has been enrolled in that study, called the CANDID study, which will have the size of a Phase 3 trial in CDD. The years in between came with much work (including getting the study reviewed by the FDA!) and also with a giant step from seven companies that came together in a study that is a first-of-a-kind precompetitive collaboration. We are in this together.
Preclinical collaborations. The CDKL5 research community has always been exceptionally collaborative, and the Forum has a series of parallel workshops (the last two editions also added pre-meeting workshops) where we get organized. At the 2022 Forum we saw a proposal to get the companies developing treatments for CDD more actively involved in this preclinical collaboration network, because it is easy for pharma and biotech scientists to share advice, but hard to share actual research data! The goal is to have academics and companies compare their CDD mouse data to validate what are the best and most reliable endpoints (the best mouse symptoms). The academic groups are already doing this, and I hope that by next year’s Forum we can announce that companies are also joining this very needed effort. We are in this together.
The patient alliance helps accelerate clinical studies. A big challenge for companies to run trials in rare diseases is to know how to find the right hospitals. The CDKL5 Alliance has put together a list of hospitals in the different Alliance countries where they have trusted clinicians. We learnt at the Forum that this resource has already helped accelerate the initiation of the observational CANDID study, and I hope that it will also help accelerate treatment trials. We are in this together.
The leadership of patient families. The CDKL5 Forum is a scientific and medical conference, where we review the news from the previous year and get organized to help progress the field further. But it is also a meeting led by a patient family, where patient families feature prominently in the agenda and the discussions. We opened the meeting with the words from Natalie Ladly from CDKL5 Canada, sharing with the audience the toll of CDD on her family (#brynnstrong!). Simon and Fiona Walsh from CDKL5 Ireland also invited us to look into their family’s life during the Forum Dinner, and Rick Upp, from the IFCR, closed the meeting with an update from the CDKL5 patient community. The Champion of Progress CDKL5 Forum Award of this year went to Antonino Caridi, from CDKL5 Italy, one of the most loved and respected leaders from the patient community in the fight for a cure for CDD. And representatives from 14 different countries (the Alliance includes more than 30 countries!) were also in attendance, mixing with researchers and actively participating in the discussions, in particular during the interactive breakout sessions. That’s how the words and actions from the patient families during the Forum also spelled out how we are in this together.
SUMMARY
If we had to boil down the 2022 Forum to a few sentences, it would look like this:
There is no intractable disease.
CDD is now part of the 5% of rare diseases that has a treatment approved.
CDD gene therapy is coming to clinical trials.
And clinical development is hard, but we are in this together.
The Loulou Foundation started in 2015 with the mission to have “treatments for CDD (in clinical trials) by 2020, and cures by 2025”. Back then there were not therapeutic programs at all being developed for CDD, but there was faith in science and in the power of a large community. With the news shared at the 2022 Forum, it now seems realistic to believe that even before 2025 there will be people living with CDD who will have received a gene therapy as part of a clinical trial. This was a great year for CDKL5 research.
I hope you enjoyed this summary. Please let me know your thoughts in the comments.
Ana Mingorance, PhD
Disclaimer: These are my own impressions from the presentations and topics that I was most interested in as a scientist and supporter of the patient community, 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.