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The 5th edition of the CDKL5 Forum recently took place in Boston, in November 4 and 5. The Forum is an annual meeting hosted by the Loulou Foundation where scientists and drug developers working on CDKL5 deficiency, together with representatives from patient organizations, meet to discuss the latest advances. This was the third Forum I attended, and the second since joining the Loulou Foundation.
Because of the 5th anniversary, the CDKL5 Forum Director (and my dear friend) Dan Lavery offered an update of how much the entire CDKL5 deficiency field has changed since the first Forum edition. And it has changed so much that it seems we are looking at two different diseases!
So I will borrow Dan’s review of then versus now to share with you an update about the recent CDKL5 Forum and highlight how far along we have come in the CDKL5 Deficiency Disorder field.
1. FROM ULTRA-RARE DISEASE, TO BEING ONE OF THE MOST COMMON GENETIC CAUSES OF EPILEPSY
When the first Forum took place in 2015, CDKL5 Deficiency Disorder (CDD) was thought to affect maybe around 200 children worldwide. It would soon become clear that there were many more cases, but having a specific number has remained a challenge.
This year we obtained the first well-documented incidence estimate for CDD, with mutations in CDKL5 being found in 1 out of every 42,400 live births. The study followed a cohort of all children born in Scotland over 3 years (over 150,000 births), and genotyped all those having epilepsy during the first 3 years of their life. This methodology makes the study very solid, and indicates that CDKL5 would be one of the most common genetic causes of epilepsy in children. Now we know that the real numbers are not 200 cases, but well over 20,000 cases. Definitely not an ultra-rare disease!
The real number of patients diagnosed (prevalence) is still unclear. This is because of two reasons. One, because genetic testing is only regularly done in the recent years, so most adult patients remain undiagnosed even though they exist out there. And two, because we don’t have a good way to track the number of patient diagnosed.
To address this, the Loulou Foundation and IFCR applied this year for CDD to have a unique ICD-10 code, which will allow clinicians to use this diagnostic code with their patients and support the epidemiological studies that are needed. In the meantime, one thing is clear: we are looking for tens of thousands of patients out there, not hundreds.
2. FROM ORPHAN KINASE TO MASTER REGULATOR
If there is one area where the field has evolved dramatically since 2015 is the understanding of what CDKL5 does in the brain. It was clear that it was a kinase, those proteins that turn other proteins on and off as if they had a light switch, but the specific proteins that get turn on or off by CDKL5, and what these do in the neurons, was unknown.
Now scientists have identified many of the target proteins of CDKL5, and produced lab tools (antibodies) that allow us to see when and where CDKL5 is active in the brain. Scientists have also identified that CDKL5 controls a number of proteins associated with the neuronal skeleton (the cytoskeleton) and it is likely through this process that it regulates the presence at the membrane of different proteins including receptors. As a result of this, in the absence of CDKL5 , the formation of synapses (neuronal connections) will remain in more immature stages and the presence of receptors will also resemble the most immature brain state, leading to neuronal hyperexcitability.
There are two important implications for therapies in these results. The first one is that with CDKL5 controlling so many processes it will be hard to “bypass it” or achieve a full compensatory benefit with treatments that target other pathways. We really should try to replace the protein or the gene to achieve the full recovery. The good news is that these treatments are all in development.
And the second important implication is that we have not found large changes in neuronal wiring, or in brain anatomy, and we have certainly not seen neuronal loss or any sign of neurodegeneration. So it would appear that CDKL5 is constantly needed for the very dynamic process of synaptic plasticity and formation. This means that bringing CDKL5 expression back is likely to provide a benefit even in the more mature brains, while in diseases that affect neuronal migration, or that lead to neuronal death, you only have a narrow time window to replace the protein and see any improvement. Based on the biology that we know, I believe CDD will be a good disease for gene therapy or enzyme replacement therapy even in adult patients.
3. FROM ZERO TO FOUR CLINICAL TRIALS AND A GROWING PIPELINE
Another area that has changed dramatically since 2015 is the corporate interest in CDD for the development of treatments. The company who first took the lead was Marinus, and they announced during the Forum that they are on track to soon close their target recruitment for the ongoing Phase 3 trial in CDD, which is 100 patients.
Think about it, we have gone from thinking that there were only 200 patients in the world to being able to run 100-patient trials in parallel to other trials in just a few years.
Because the Marinus trial is not alone, there are three additional clinical trials in CDD going on right now, all in Phase 2 (pilot) stages. PTC recently completed a trial with ataluren for CDD patients with non-sense mutations in CDKL5 and are analyzing the data. Ovid and Takeda have a clinical trial ongoing where they are enrolling around 15 patients with CDD for treatment with their drug TAK-935. And a 10-patient investigator-initiated study with fenfluramine, developed by Zogenix, is starting in New York. During the Forum, Zogenix received the CDKL5 Forum Award of Excellence for “Company Making a Difference” in the clinical space for supporting the latest clinical study in CDD.
So we have gone from having a disease that was thought to be ultra-rare, and that was not recognized as a stand-alone disease by regulators because even the medical community confused it with Rett syndrome, to having a clearly independent unique disease with orphan drug designations and having four clinical trials by five pharmaceutical companies (TAK-935 is developed by Ovid and Takeda together).
And these five companies are not alone. Many companies in the room such as Amicus and Ultragenyx are developing treatment for putting back CDKL5 into the brain, and we were able to see several potential additional therapies presented during the Forum:
A collaboration between the Trinity College Dublin and Insubria University showed that a drug that acts on the neuronal skeleton (which does not work well in the absence of CDKL5) can correct memory problems in mice with CDD.
A group from the University of Pennsylvania showed that another drug, which acts only in immature neuronal receptors that happen to remain present for too long in brains with CDD, also corrects some of the neurological problems in mice with CDD.
The same group also showed that cannabidiol addresses some of the neurological problems in mice with CDD, supporting the data by GW Pharma that Epidiolex could have efficacy in this disease as well.
And even the company Takeda showed a second drug that they are developing (not the one already in CDD trials) and that can also correct some of the neurological problems in mice with CDD by acting on another signaling pathway. They even obtained the Orphan Drug Designation by the FDA for their drug earlier this year.
In total these were four mouse trials showing that there are many more therapies that could move into clinical trials and help reduce not only epilepsy but also other neurological problems associated with CDD. There were some extra treatments presented, but I will cover them in the next section.
What is important to know is that all of these promising findings have been possible because of so much new understanding that we have of how CDKL5 functions in the cell in normal situations, what happens when it is missing, and how CDD presents in mice when their CDKL5 is removed – since it is a bit different than in people. All the investments in research by several patient groups and the Loulou Foundation have made this work possible, and more recently the labs have started being successful at obtaining R01 funding from the NIH. This is one of the areas where the patient community can make a big difference, by supporting the early research and the generation of animal models for the disease that will later allow those groups to be self-sufficient at obtaining the highly-competitive public grants. De-risk early so that a research field can then take off on its own.
4. FROM SYMPTOMS TO CURES
All of the treatments that I listed above in mouse experiments, as well as the current drugs in clinical trials (except for ataluren), help the brain but do not correct the mutation in the CDKL5 gene or the lack of CDKL5 protein in the brain. They help the brain function better with CDKL5.
I have a slide that I use at patient conferences to explain the different types of therapies that could be developed for CDD. That slide is perfect to explain this. Essentially, we know that in CDD the brain does not function well, because it does not have CDKL5 protein, because the CDKL5 gene is mutated. And knowing this we can think of different levels of treatment. We can think of treatments of help the brain function better despite not having CDKL5. Or we could put back the protein. Or we could add a copy of the gene. Or we could go into more difficult approaches and try to correct the mutated copy, or perhaps reactivate the second copy of CDKL5 gene that all females have in their second X chromosome but that is not being used.
In the previous sections I described all the progresses to develop better therapies able to make the brain function better despite not having CDKL5, but where we have seen an explosion of science is in the next approaches: correcting the cause of the disease.
There was a session during the Forum when we had a dream team on stage: Kyle Fink from UC Davis, James Wilson from the University of Philadelphia, and David Liu from the Broad Institute. One by one, they showed us three ways to try to get neurons to produce functional CDKL5, and it was like seeing a conference from the future, when we will be able to correct genetic mutations in a way that we are just beginning to see.
First Jim Wilson presented data from a gene therapy program that he is running at Penn where he has developed a virus that contains the entire CDKL5 gene instead of the virus DNA. When he then injects these virus into the brain of mice with CDD, he can see that the CDKL5 protein is being produced and that this gene therapy corrects some of the neurological problems in mice with CDD. Jim explained that there are still some steps to do before starting clinical trials, like knowing how much CDKL5 is needed, and in which cells, and how safe the entire approach is before it can move into the clinic. But as I see it looks like we are just talking about a couple of years for CDKL5 gene therapy to be ready for trials, and this for medicine is essentially just around the corner.
It is important to know that two companies, Amicus and Ultragenix, are also working very hard for developing gene therapies for CDD (even though they did not present data at the Forum) and that in fact Ultragenyx received the CDKL5 Forum Award of Excellence for “Company Making a Difference” in the preclinical space for their gene therapy program. With so many options ongoing, I trust that one or more of these programs will reach clinical trials.
Then Kyle Fink showed us some data of a project that they are running to rescue the second CDKL5 gene copy that all females have. Because male cells only have one X chromosome (XY), female cells (XX) inactivate one X chromosome so that we don’t produce twice the levels of proteins located in those genes as males do. So all of our cells randomly inactive the X chromosome that we got from dad, and others the one that we got from mum. What happens when one of these chromosomes carries a mutation in the CDKL5 gene is that half of our cells will be fine (they inactivated the “bad” chromosome!) but the other half has deficiency in CDKL5 because they happened to inactivate the “good chromosome” and are left with a mutated CDKL5 gene copy. What the Fink lab is doing is to develop tools based on the famous CRISPR to find the inactive CDKL5 gene in the inactive X chromosome and “release it”, without messing up with any of the other genes in the chromosome. This is very cool, and appeared to be impossible to do until recently. They are doing this right now in cells in culture (not yet in mice with CDD), and the result is that all cells will read both copies of CDKL5, one good and one that is not functioning, and that is perfect because that means that they will all have exactly what they need: one copy that works. Next step is to develop a good technique to get those CRISPR-like tools into the brain (likely into a virus as well) and test it in mice.
Last, David Liu presented what we could call the next frontier of gene editing: prime editing. Gene editing is when you can fix the mutated gene. Not add a new one coming in a virus. Not activating the other copy in the inactive chromosome. But get to the mutated one and fix it.
This approach was recently published in Nature and attractive massive media attention across the globe. What the Liu lab can do with this approach and his latest variations is to correct mutations that until now appeared impossible to correct: those where your child has one or two extra letters in their DNA, or is missing one or two letters in the gene (these are called frame-shift mutations). While we knew that CRISPR would replace one letter, swap the mutated letter by the correct one, we could not insert or delete. Now David Liu can do that, and he told us they are starting to apply it to some mutations in CDKL5. Just like with the Fink approach, the next step after being able to fix the gene in cells in culture is to develop a good technique to get the prime editing tools into the brain (likely into a virus as well) and test it in mice.
Because they are more immature, these last two approaches are likely to take several more years to get to the point when they can be tried in clinical trials. But to know that it is biologically feasible to do these things, and that they are applying it to CDD, is already amazing and tremendously encouraging.
And then there is a man who has been challenging all these timelines, and he too gave a presentation at the Forum and invited us to think about this differently. And that was Tim Yu, from Boston Children’s Hospital and Harvard Medical School. In the rare disease space we all know of Mila, the girl with Batten disease that got a personalized drug developed for her in a record time to try to stop the progression of her terrible disease. The drug is not a traditional type of drug, it looks more like a little piece of DNA (called and oligonucleotide), and got the name of Milasen. And the scientist who developed it and was able to treat Mila just 12 months after her diagnosis was Tim Yu. Just like David Liu with prime editing, this has also been all over the news. We learnt from Tim that not all types of mutations can be targeted with these personalized pieces of DNA, it is mainly the ones that cause “splicing” defects in the gene (not most missense, not the nonsense, not the frameshift, not the ones where a piece of the gene is missing). But for those cases where the mutation would be a candidate, his lab is now pushing the traditional steps of developing a drug for a disease at a time and seeing how to develop the drug for one child at a time. This is a complete revolution, and we are lucky to be living this time where all of these discoveries are changing the way we do medicine.
By the way, I know that many patients and parents get lost with so many genetic approaches and which one would help all patients versus which one is patient-specific, so I have made a separate text box to address this question for CDD.
In short: we have gone from saying “how could get one of the many epilepsy companies to try their drugs in CDD” to saying “how can we have enzyme replacement AND gene therapy AND X-chromosome reactivation AND gene editing all developed for CDD”. All in under 5 years.
Pretty unbelievable.
5. FROM PRECLINICAL TO CLINICAL
A clear consequence of the explosion in research around CDD and the growth of the treatment pipeline is that we have gone from focusing on funding preclinical work (understanding the biology of CDKL5, developing animal models) to having to quickly start working hard on getting the clinical work ready. This means getting ready for clinical trials.
At the Loulou Foundation we have been busy requesting the disease registration in different medical classifications, supporting companies with information as they go through the regulatory process, generating a disease concept model (something that is needed for trials), running studies on clinical outcome assessments (those are the things you measure in clinical trials), discussing with pharmaceutical companies the possibility of working all together to solve the clinical trial challenges as opposed to competing, running meetings with the patient community to understand what they value the most in treatments, and we even hosted a meeting with the FDA together with IFCR (see the next section).
We have not stopped working on the biology and preclinical space! Instead we have expanded what we work on. At the Forum we run 8 separate breakout sessions to have small focused groups of scientists, clinicians and patients go through 8 blocks of what we call “the translational toolbox”, each one focusing on a single topic that combined allowed us to see if we have all we need to take a drug all the way from understanding what happens in the cell to completing clinical trials. We have achieved much in all of these steps but there is still much work to do, so those breakout sessions allowed us to map the needs and focus our efforts in the year until the next Forum.
The greater focus and number of efforts on the clinical space in CDD are a reflection of the maturity of the field. We grew up very fast, in a record time.
6. THE VOICE OF THE PATIENT IS LOUD AND CLEAR
Last but not least, if we are to talk about growth, I must commend on the growth of the CDD patient community. We have gone from having few initial families, organized in the US, UK and Italy, to now have a CDKL5 International Alliance, around 18 national patient organizations, and a world-wide spread that includes countries like Brazil, South Asia, Japan and most recently, China.
The Alliance held a meeting in June, hosted by CDKL5 UK, that I wrote about here and I strongly recommend you reading it if you hadn’t. I have seen many patient communities and this one is exceptional in how well it runs and works together.
During the 2019 CDKL5 Forum, members of the Alliance co-chaired each of the 8 parallel breakout sessions working hand in hand with a clinician, industry professional or scientist chair. This is not something I had ever seen in any other research field, a congress where the patient community is integrated into all discussions along the translational chain, from cells to animals to biomarkers to trials to partnerships. I have no doubt that the strength of this patient community is one of the secret weapons of the CDKL5 field.
And that strength was particularly clear in November 1st, when the US patient community met with the FDA and held an externally-led Patient-Focused Drug Discovery (PFDD) meeting co-hosted between the US patient group (IFCR) and us at the Loulou Foundation. These are meetings where the patient community meets with the FDA to discuss one disease, and where patients speak and the regulators listen. This was a major milestone for the entire field, and I encourage you to watch the video and see the amazing 10 patient (and grandparent!) panelists and the discussions in the room, as the caregiver community explains the regulators how it is to live with CDD, how it impacts the entire family, and the treatment of treatments that they would value the most.
I will dedicate an entire new entry to the PFDD. I just want to highlight here that from all diseases known to mankind, and there are over 7,000 rare diseases alone plus all the non-rare ones, we were the #32 disease-focused PFDD meeting that the FDA had. And that is a reflection of both the fast-growing efforts of the industry to develop treatments for CDD, and the strength of the CDD patient community.
When the Loulou Foundation was born, Loulou’s parents set the goal of treatments (to reach trials) by 2020 and cures by 2025. Now we know that by end of 2020 Marinus will have finished their trial, we will have had at least 4 trials and collectively they will have treated at least 150 kids with CDD that will be able to benefit from these treatments. And I personally believe that by 2025, we will have multiple cures (gene therapies and similar) in advanced clinical trials, possibly even some approved.
If you can imagine it, you can achieve it.
I hope you enjoyed this summary! let me know your thoughts in the comments. Here is my article on the 2018 Forum meeting.
Ana Mingorance, PhD
Disclaimer: These are my own impressions from the presentations that I was most interested in as a scientist and patient advocate, and not an official text about the Forum by the Loulou Foundation. I write these texts with the parents of individuals with CDD in mind, so excuse also my lack of technical accuracy in parts ;-)