I miss conferences in person a lot. And the type of conference in person that I miss the most is the annual patient conferences organized by the rare epilepsy patient organizations that I collaborate with.
Last weekend, the CDKL5 deficiency disorder (CDD) community gathered in front of their computers for a virtual annual meeting organized by the International CDKL5 Alliance. Did you know that there are about 20 countries in the Alliance? That is how large and connected this community is. The last face-to-face meeting took place two years ago and I strongly encourage you to read the summary from that meeting.
For the 2021 Alliance meeting, the organizing team commissioned a series of pre-recorded videos to a large range of speakers and then published the videos with subtitles so that all CDD families from all around the world could watch them at the same time. You can also access the videos at the CDKL5 Alliance website.
Some parents of children with CDD have asked me to write a summary of the virtual conference, since a written summary is always easier to translate and digest. For all of you here is a personal summary of the 2021 CDKL5 Alliance meeting, sprinkled with some opinions as I often do.
1. THE SCIENCE: HIGHWAYS AND HEADQUARTERS
Prof John Rouse from Dundee reviewed where we are in our understanding of what CDKL5 does. In the recent years we have made large progresses on our understanding of what CDKL5 does in the cell and therefore what goes wrong when CDKL5 is missing.
Today we know that the protein CDKL5 turns other proteins on and off as if they had a light switch, and many of these proteins that are controlled by CDKL5 are associated with the neuronal skeleton (the cytoskeleton). The neuronal skeleton is not like our bones, which are essentially there to give us some structure. In cells, the skeleton is more like highways that are used to transport things to where they need to be, for example making sure that glutamate receptors get to the right spot in the surface of the neuron for the neuron-to-neuron connection to work fine.
And in addition to being important for the highways, it turns out that CDKL5 has a second job at the cell nucleus, which is basically the headquarters or control center in the cell from where all decisions are made. But what could CDK5 be doing there? This is what keeps John awake at night, so he has put together a team of scientists to try to answer this question. It turns out that in the nucleus, where all of the copies of all of our genes are located, the genes (made up of DNA) are constantly suffering small damages that the cell quickly repairs so that all genes work properly. And CDKL5 is a member of that DNA damage surveillance team. It does that by turning on other proteins that are needed to do the repair. And it also helps the cell read some of these genes. So CDKL5 is really important for the nucleus to function properly.
With the very complex (and multiple!) roles of CDKL5 in the cell, it is clear to me that the best way to fix the disease is to put the gene or the protein back, or to fix the mutation. Anything that will produce functional CDKL5 protein again. Trying to bypass a protein that is missing is doable if the function was only one, but for CDKL5 there are too many functions to try to fix, so I would focus on bringing CDKL5 back.
2. CLINICAL TRIALS: WHERE ARE WE TODAY
Before a drug or a gene therapy can be approved to be used to treat patients it has to progress through clinical trials. I think this year with the coronavirus vaccines we are all very familiar with how clinical trials work, so I will only explain that in rare diseases like CDD we have two stages of clinical trials: Phase 2 trials, where a small group of patients get the treatment, and Phase 3 trials, where many more patients from many countries get the treatment and usually half of them get placebo (but are offered the treatment at the end of the study anyways). If the Phase 3 is successful, then the company can apply for marketing authorisation. The entire process for trials and regulatory review for approval ends up taking 4 to 5 years.
We still don’t have gene or protein therapies for CDD, so while we wait for scientists to develop them we are trying to discover medicines that could treat the symptoms of CDD, helping all patients have a better life until we get to the curative treatments. We have had some clinical trials already with symptomatic treatments in CDD.
Last year we had very good news about clinical trials: the first Phase 3 trial in CDD, ganaxolone from Marinus, had been successful.
This year we also have very good news about clinical trials: we are about to start our second ever Phase 3 clinical trial in CDD, this time the drug is fenfluramine from Zogenix.
At the Alliance conference, Marinus reviewed their good data with ganaxolone in CDD. They are offering ganaxolone to all of the trial participants that want to keep taking it, and in the USA they are also offering it to other families who want to try ganaxolone before it gets approved. This is done through an Expanded Access Program. Ganaxolone works by acting on GABA, the inhibitory signal in the brain. If everything goes well ganaxolone will be the first drug to be approved for CDD.
Last year there were two Phase 2 studies in CDD. One was with the drug soticlestat, from Ovid and Takeda. This drug works by acting on the glutamate system, which is the excitatory signal in the brain. The companies were testing the drug in four different epilepsy syndromes, and after reviewing their data Takeda has announced that they will run Phase 3 studies in Dravet syndrome and Lennox-Gastaut syndrome. They still have not announced what they will do with CDD, and they did not present at the conference so we will have to keep an eye on any news about this program.
The second Phase 2 study from last year was with fenfluramine, which works by acting on the serotonin system, a modulatory signal in the brain. Fenfluramine has already been approved in the US and Europe for the treatment of Dravet syndrome, where it has impressive efficacy to reduce seizure frequency. Zogenix presented an overall introduction to the company at the Alliance meeting and didn’t talk much about their plans for CDD, but they have already announced that they are starting a Phase 3 trial in CDD with fenfluramine starting this year. Phase 3 trials are international, happening in many countries, so I look forward to the announcement of which countries will be included in this study. And if the Phase 3 results look like the small Phase 2 study results, we could have potentially a second drug approved for the symptomatic management of CDD.
This progression of clinical trials for CDD is exceptional! Only 5% of rare diseases have any drug approved, which means that 95% have nothing. And we are having these two Phase 3 trials back to back in CDD, so we are on track to join that 5%!
But these symptomatic treatments are only the tip of the iceberg. Right below we have a growing pipeline of therapies in development that will correct the lack of CDKL5.
3. THE FUTURE: FROM SYMPTOMS TO CURES
If you have a child with CDD the main answer that you probably wanted to get from this conference is WHEN are gene therapies starting clinical trials.
And I am sorry to say that the answer is “we don’t know yet”. Because we cannot know yet, nobody does. There were four different groups that presented data at the Alliance meeting showing their progresses towards developing a gene therapy for CDD. That is four different shots on goal, four independent efforts like when many companies all started developing vaccines for COVID without knowing how many would succeed and how fast it would happen. And we are following the same approach in CDD: many efforts all at the same time going as fast as they can.
The university of Bologna is developing a mix between an enzyme replacement therapy and a gene therapy. An enzyme replacement therapy is “protein therapy”, a type of treatment where you add the brain the protein that is missing, in our case the protein CDKL5 already made. For a gene therapy scientists use a virus to bring to cells a copy of the CDKL5. It is similar to the AstraZeneca or the Janssen vaccine but instead of using a virus to carry to the body the sequence of the coronavirus spike we use them to carry the sequence for the CDKL5 gene. The university of Bologna is using a virus to deliver to neurons the sequence for the CDKL5 gene, but it has been tweaked so that the protein CDKL5 will then be secreted by those neurons to all the surrounding ones, doing “local enzyme replacement therapy” on top of gene therapy. This is also called “cross-correction”. It is a cool idea. Amicus is doing something very very similar, in addition to classical enzyme replacement therapy with the purified protein. And then Ultragenyx and the University of Pennsylvania are doing the classical gene therapy using a virus to carry the sequence for the CDKL5 gene to the neurons in CDD. That means that we got to hear about FIVE different gene therapy or enzyme replacement approaches at the patient conference, by four groups since Amicus has two different programs. That is a lot.
The university of Bologna showed data using their cross-correction therapy in laboratory cells and mice. This is still early work at a university so it is too early to know how much work the experimental treatment still needs before it could move to trials.
Amicus presented some data about their cross-correction therapy program and their classical enzyme replacement therapy program. It was not an in-depth project review, but more of an overview of all the work that Amicus is doing in CDD which includes not only these two programs but also helping understand better how CDKL5 works and developing biomarkers (detection of special signals using EEG) that will help check if therapies are working in CDD mice and patients much faster. CDD is clearly important to Amicus. They are doing many experiments in mice with both treatments to see how well they could prevent or reverse the symptom of the disease in mice with CDKL5 deficiency.
The University of Pennsylvania presented a lot of data in mice with CDKL5 deficiency using a gene therapy to show that it is possible to prevent most of the symptoms in CDD mice. I say “prevent” because they give the gene therapy to mice when they are babies. I really liked the presentation, because they showed how the gene therapy was effective in many disease symptoms. That is the main different with symptomatic treatments: with gene therapy, you put the gene back and you are treating all of the different symptoms at once by removing the cause of all of them. This group has also run initial experiments in larger animals (macaque monkeys) to check safety and because we need to check that the gene therapy can get to enough neurons in larger brains, which is literally a much larger challenge than delivering the gene therapy to the brain of a mouse which is the size of your thumb nail. They explained that they are currently optimizing the gene therapy so that then they can go to trials.
The last presentation was from Ultragenyx, who are also developing a classical gene therapy similar to the one from the University of Pennsylvania. I also liked this presentation very much because they treated CDD mice at older ages, the equivalent of children 4-11 years of age, so what they showed to us was that it is possible to reverse many of the symptoms in CDD mice. They saw reduction of cognitive, motor and behavioral symptoms in the mice, and even used the gene therapy to correct neuronal connection problems in “human neurons” which were produced from patient skin biopsies and turned into neurons in the lab. Just like for the University of Pennsylvania, they explained that they are currently optimizing the gene therapy to be able to get into many neurons in larger brains (monkey) so that then they can go to trials.
As soon as one of the groups considers that their gene therapy is optimized enough, they will start the process to request a clinical trial permission and at that point we will finally get a date for when clinical trials might start. I hope you all realize how much work all of this is, and how lucky we are to have these five protein and gene therapy programs being all developed at the same time for CDD!
4. DATA, DATA, DATA
There were several presentations about why the international CDKL5 patient registry is so important, the international CDKL5 patient database from Australia, a study to validate several severity and symptom assessment for CDD, and an international observational study that is about to start and that is coordinated by us at the Loulou Foundation.
At the core of all of these efforts is a common theme: we need to understand better the symptoms of CDD and how they change over time (the natural history), we need to identify good scales to measure these symptoms, and this information and scales are absolutely essential to be able to tell if a treatment is working beyond just reducing seizures.
For the registry and the database, you can provide data about your child from your living room, and for the observational study we will try to get as close to your town and living room as possible!
By the way, have you noticed that clinical trials all have names? For example the trial with ganaxolone in CDD is the Marigold study, and the famous trials with spinraza in SMA was called Nurture. The Loulou Foundation is requesting suggestions from the community to name the international observational study so please reach out with your proposed names! (you can get some ideas here)
5. THE COMMUNITY
Although we didn’t get to meet in person, we did get to see many of the visible faces of the CDD patient community at this virtual conference.
Patric Benz from the Swiss CDKL5 patient group was the meeting host on behalf of the German-speaking national patient associations who were the organizers. His greeting in several languages and the fact that the videos were available with multiple language subtitles was a testimony to the reality of rare disease patient communities: at the same time dispersed and united.
During the conference we also saw images of people with CDD kayaking, skiing, ice skating and cycling. If there is something notable about this community it also their fearlessness and determination.
To conclude the conference, Nathalie Ladly from CDKL5 Canada and Antonino Caridi from CDKL5 Italy spoke about some of the big efforts of the Alliance in this last year, like developing the organization manifesto and sourcing a list of all possible clinical trial sites world-wide recommended by the community so that we can accelerate clinical trials. The goal of the Alliance is to expedite treatments and a cure for CDKL5, so of course a global pandemic would not stop them from putting together such a great conference program.
Next stop is the CDKL5 Forum in November, also full of updates about the treatment programs in development for CDD. Hopefully by then we get to meet in person.
I hope you enjoyed this summary! let me know your thoughts in the comments.
Ana Mingorance, PhD
Disclaimer: These are my own impressions from the presentations that I was most interested in, and not an official text about the Alliance meeting by Alliance or 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 ;-)