For the past seven 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 advances in the field. You can find written summaries from the past three meetings here: 2018, 2019 and 2020.
The 2021 CDKL5 Forum edition took place November 1-2, and for the second year, due to the ongoing pandemic, it was held fully on-line. The Loulou Foundation turned this into an opportunity to also host a series of workshops prior to the 2-day conference, turning the Forum into a giant Think Tank. This made this year’s Forum quite unique, and I hope the pre-conference workshops are here to stay.
I know that many in the CDD patient community are waiting for this written summary, so I will try to extract the main conclusions from the Forum with this audience in mind. But I want to start with a warning: if you are reading this summary mainly looking for an answer to “when are the gene therapy trials for CDD starting?”, the best answer that we have today is “we don’t know yet”. I understand this might feel disappointing to some, as if we are not progressing fast enough, and potentially make you feel a bit hopeless. That’s only human, so I want to acknowledge that upfront.
In the next paragraphs I will walk you through the magnitude of the effort and the tangible progress that has taken place around research and treatments for CDD, and that was presented at the Forum. I invite you to read it in the spirit of celebrating each step and each progress and small victory along the way, because we have come a very long way, and this year the progress in biology understanding and therapy development has been particularly significant.
It is remarkable how far we’ve come in the last few years, and the size and commitment of the community of scientists and companies that has grown around CDD.
Because of that, I have structured the summary of this year’s Forum around the following themes: hope, tangible progresses, strategy and partnerships.
1. HOPE
The 2021 Forum started with the voice of the patient. This year it was IFCR’s President Karen Utley, who shared with the audience the life of her daughter Samantha, and the impact that CDD has on Samantha and her entire family. Samantha sees 14 different specialists a year and takes 15 different medications, which gives us some quantitative data for the complexity of this disorder. From the many great messages from Karen, I keep two: (i) small improvements can be life changing for patients and families, so please don’t focus only on cures and keep working to make more smiles and happy days, and to (ii) please keep hope alive for those who are feeling too overwhelmed to stay hopeful.
Her plead to keep hope alive was adopted as a motto by many of the conference speakers in the two days that followed.
There were several moments during the conference where science showed us there are many reasons for hope. These are some of those reasons:
Hope because mice show us that CDD is a good candidate for genetic rescue
Just two weeks before the Forum we celebrated the publication of a landmark study showing that CDD is reversible in mice (article link). Zaolan (Joe) Zhou, from the University of Pennsylvania, also presented the results of his study at the Forum, which show that CDKL5 is needed throughout life to keep proper neuronal functioning and that, in mice, turning “on” the CDKL5 gene in near-adult mice that grew up with CDKL5 Deficiency leads to large reversal of most symptoms. This is very valuable because it helps us learn what is biologically possible, and that CDD is not just a disease of neurodevelopment but also of neuronal maintenance.
In layman terms, it appears that in CDKL5 Deficiency, the brain developed fine and the problem is that neurons are not talking to each other correctly. So once we put the protein (or the gene) back they can start talking to each other correctly, because nothing was really lost: there was no neuronal death or failure to form those neurons, and they are not in the wrong location, which are all things that happen in other neurodevelopmental diseases. This study is a big reason for hope, and Joe received the CDKL5 Forum Award for Lab of the Year for this contribution to the field.
Hope because other diseases are already seeing great results
As part of the gene therapy session, Krystof Bankiewicz, from Ohio State University, showed us videos of children with AADC Deficiency who participated in a clinical trial for a gene therapy to deliver to their brains the AADC enzyme that they are missing. If you saw the videos you probably had chills. Patients with AADC Deficiency have very strong hypotonia, intellectual disability, dysautonomia and other complications due to missing an important enzyme necessary for producing dopamine and serotonin. Prior to treatment, the mobility of these patients is so impaired that they reminded me to several of the boys with CDD, unable to even hold their heads up. In the videos, we saw children go from that extreme hypotonia state to seeing changes 1 month after gene therapy, sitting after 6 months, walking with assistance of DAFOs after a year, and totally unrecognizable walking by themselves after 18 months. Krystof explained that many of the patients also became verbal, which was highly unexpected. While we don’t know yet how fast and how much people with CDD will improve once we have a gene therapy for them, seeing the results in this other enzyme deficiency help us learn what is biologically possible, and it is a big reason for hope.
Hope because science (and scientists!) keep coming up with great genetic tricks very quickly
While we are today very focused on gene therapies to bring an extra copy of CDKL5 to each neuron in the brain, we got to see at the Forum some of the science that is coming afterwards, and that will allow us to fix the mutated gene in patients with genetic diseases. David Liu, from the Broad Institute, showed us how he is using an advanced version of the CRISPR system to correct mutations where one letter is missing, and showed us how they can do it already in cultured cells from a girl with CDD (this is still all very early and being optimized). And Feng Zhang, also from the Broad Institute, showed us another advanced version of the CRISPR system that instead of correcting one letter in the DNA can swap large sections of a gene or an entire gene. So we can imagine one day getting a single gene therapy that gets to the brain and swaps the entire CDKL5 gene for a good copy, and that could potentially be used for kids with all types of mutations.
But before we get to see these gene editing approaches turned into actual treatments, we have many other therapies coming our away. I review those in our next section: tangible progress.
2. TANGIBLE PROGRESS
Progress in three gene therapies
Last year at the 2020 Forum we talked about the two gene therapies for CDD that had shown to have efficacy in mice deficient in CDKL5, or as we call it in science had “preclinical Proof-of-Concept”. We also talked about how gene therapies need to go through three stages: first prove that you can treat a mouse, then prove that you can use it in larger brains (non-human primates) since it is much more difficult than in small mouse brains, and then finally start the first trials in a very small group of patients to determine safety before exposing more patients.
This year we saw not two, but three gene therapies, and how the most advanced ones are now working on that second stage that goes between showing that you can treat mice and being able to start clinical trials.
The gene therapy that we saw presented for the first time is the program between the University of Pennsylvania (Penn) and the company Amicus, and it is a very interesting hybrid between gene therapy and protein (enzyme replacement) therapy. They call the approach cross-correction, because the therapy uses a virus to bring to neurons a copy of the CDKL5 gene (this is a gene therapy), with a special version of CDKL5 that will produce a secreted protein. The idea is that the neurons that are successfully corrected will act as local sources of enzyme to supply to neighboring cells. This was the first time that we saw mouse data from this project at the Forum, and the researchers are trying to see how much more efficacy they can get by using this special version of CDKL5 as opposed to plain CDKL5.
For the other two gene therapies, from Penn (in collaboration with Elaaj Bio) and Ultragenyx, we got to see some of the work that goes into getting the therapies ready for patients now that we know both of them work in mice.
The gene therapy program from Penn/Elaaj came with new EEG data, showing that it is not only the symptoms but also the EEG abnormalities in mice with CDKL5 deficiency that get corrected with the gene therapy. And more importantly, they showed two newer versions of the gene therapy, more advanced than the one we saw last year, and how with each iteration they are getting better and better distribution in the non-human primate brains. They are making these upgrades trying to get as much expression of CDKL5 and as broad as possible, and as the presenter said, “we are getting closer to the target of robust expression in the brain” that they want to see before moving into clinical trials.
The team from Ultragenyx also dedicated most of their presentation to talk about those next steps after seeing efficacy in mice with CDD (which we saw last year). They told us about the need to fully evaluate safety and toxicology in animals before entering the clinic, and also about all of the additional work that they are doing to prepare for clinical trials involving natural history and biomarker data. This was very impressive, and showed how Ultragenyx has many people in the clinical and regulatory teams and many other teams in addition to their preclinical researchers all working on the CDKL5 program.
So we don’t know yet when trials might start, but we know that these three programs keep getting closer and closer to the clinic, and that we have some of the best people in medicine working on solving all of the difficult barriers that need to be overcome to take these treatments into clinical trials (like better brain distribution, and development of biomarkers, and clarity on clinical scales to use). You will see more of this in the last section about strategy and partnerships.
Progress with ganaxolone
If everything goes well, ganaxolone will become the first drug to be approved for the treatment of CDD. The FDA plans to make a decision in March 2022, and the EMA some months later. In the meantime, Marinus has an Expanded Access Program ongoing which is now also open to Europe.
What I found really exciting from the Marinus presentation was data from their open-label studies, where they showed how patients from the Phase 3 trials are doing as they rolled over into the open-label extension. Since it is also openly available in their website and not confidential, I am going to copy their slide here because the data looks really good and it is better seen in the graph:
In the solid green bars, you see the patients that received ganaxolone during the Phase 3 study, and then continued taking it in the open-label extension. Remember that the study is blind, so no one knows if they are taking placebo or ganaxolone during the 17-week study. These patients had a seizure reduction of 30% at the end of the trial, and for the following 12 months their seizure control got better, staying more around 40-45% seizure reduction. This is not trivial, because it is common for patients with CDD to respond to a new medication for 3 or 4 months and then lose efficacy, while ganaxolone doesn’t show signs of losing any efficacy after a year, all the contrary.
And in the striped green bars you see the patients that received placebo during the Phase 3 study, but then started taking it in the open-label extension. Because the study is blind no one knew during the 17-week study if they were getting the drug and not responding to it or if they were in placebo. On average this group had seizure reduction of only 6,9% during the trial (since they were not on the drug), and as they rolled over into the open-label extension their seizure control got better and better until they caught up with the ones that we already taking ganaxolone in the trial.
This is a beautiful graph, that shows that ganaxolone has better efficacy in CDD than what is seen only during the double-blind phase, and that you have to give it enough time to show its full potential. It is also quite encouraging to see how stable the efficacy of ganaxolone remains over time.
Progress with fenfluramine
Fenfluramine is an anti-seizure drug that is already approved for Dravet syndrome where it has exceptionally high efficacy in reducing seizures. After a successful small pilot study in CDD run at NYU, the company Zogenix has been working on preparing for a Phase 3 trial of fenfluramine in CDD.
And the Zogenix team gave us the great news at the Forum that the Phase 3 trial with fenfluramine in CDD has already started and is already enrolling patients in the US clinical sites! They are enrolling children and adults with CDD as young as 2 years old, and once they have enough safety data they might open it to 1-year-olds and older, and patients need to have active epilepsy since that is what the study is measuring. For the trial, Zogenix is looking for 100 participants.
This is really good news because it means that at least 100 patients with CDD will get to try fenfluramine, and if it has in them even a fraction of the efficacy that we have seen in Dravet syndrome and in the small study in CDD, it will be very meaningful for those patients and their families.
3. STRATEGY AND PARTNERSHIPS
The Forum becomes a Think Tank
During the week prior to the conference, the Loulou Foundation hosted focused workshops that covered four areas of priority for the development of therapies for CDD:
Spontaneous and induced seizure activity in CDKL5 knockout animal models
New technologies for improved therapeutic cargo delivery in the central nervous system
Biobanking of patient samples and fluid biomarker discovery/validation to support CDD therapeutic development
Functional biomarker development/validation and inclusion in clinical development plans
For each workshop, the Foundation invited a group of academic, industry and clinical researchers, and for some also patient representatives, to try to map out (i) where we are, (ii) where we need to be, (iii) what are the technologies or fields that we should be paying attention to, and (iv) how we can get organized to address those challenges including specific proposals for collaborations. This is what turned the 2021 Forum edition into a true Think Tank, and the outcomes from each of the workshops were presented during the main conference to share with the entire community.
To give you an example for how these workshops worked, when talking about new technologies for delivering genes to the brain, we covered all approaches from engineered viruses to synthetic biology, nanoparticles and the possibility to attach CDKL5 to proteins that cross the blood-brain-barrier to use them as shuttles. And we had scientists from companies that are developing all of these approaches sit on the same workshop and share with everyone else their thoughts and proposals. This level of collaboration among traditional competitors is highly unusual, and it is one of the themes that we kept seeing during the conference: the building of a scientific community around CDD that includes many companies joining forces to help us get to better treatments. You will hear more of this later, when I talk about the CANDID study.
The long road to solving the translational puzzle
Translational medicine refers to the bridge between treating mice and treating people. It seeks to answer questions such as: “how will we know that we have increased CDKL5 protein in the brain?”, “how will we know if we are improving synaptic function?” and “how are we going to measure improvements in patients in the trial?”.
To answer these questions, we need to develop ways to see things, which can be biomarkers (like things you can see in a blood test, or brain scan) or clinical scales. Because CDD is a relatively newly-described disease, we still don’t have these biomarkers and scales.
The good news is that there are many collaborative efforts ongoing to address all these questions and develop all these biomarkers and outcome measures. This was a central theme of this year’s Forum and the subject of two of the pre-meeting workshops, with important presentations on these topics:
Need and plans for a biobank of patient samples, with standardization of analytical techniques and data sharing including universities and companies
EEG-based biomarkers, presented by Eric Marsh from CHOP, as a way to measure dysfunction of brain activity in mice and patients with CDD, to detect potential restoration with treatments
Blood-based biomarkers, presented by Max Bianchi, from the Trinity College Dublin, as another way to measure dysfunction of brain activity in mice and patients with CDD, to detect potential restoration with treatments
A US and Australia NIH-funded study coordinated by Tim Benke from the University of Colorado to also test and validate biomarkers as well as new clinical scales for CDD in an observational study
An international observational study coordinated by the Loulou Foundation in partnership with 7 pharma companies to test and validate clinical scales for CDD, called the CANDID study (see also next section)
In addition to helping us solve the translational puzzle, what all of these efforts and studies have in common is that they all require the active participation of the patient community. This could look like organizing the collection of some blood samples at your next national families meeting to then send them to Dublin, or participating in an EEG study in Philadelphia or Boston, or volunteering to participate in the observational studies that will take place in clinics from around the world. You will likely hear of some study near you!
So if you have a family member with CDD, I encourage you to consider participating in some of the studies as well as enrolling into the CDKL5 Registry (this one only needs data, no samples or visits to a clinic needed).
We cannot answer all of these key translational questions without you.
A first-of-its-kind partnership
Just a week before the Forum, the Loulou Foundation announced the launch of a pre-competitive industry collaboration involving seven biopharmaceutical companies together with the Loulou Foundation. The consortium will run an observational study specifically designed to evaluate the feasibility and suitability of a collection of clinical outcome measures in people with CDD from all ages.
Xavier Liogier, from the Loulou Foundation, explained how this study fits into a larger roadmap for preparing the CDD field for the arrival of better therapies and cures, and that already started with the PFDD meeting in 2019 and getting an ICD-10 code for CDD.
Observational studies are like a clinical trial but instead of testing a drug you are testing the clinical scales to check that they are good for that disease. These studies are very important to be ready for clinical trials that look at several symptoms or disease domains. Usually, when companies run observational studies of this kind, they do it alone, so in diseases where there are many companies developing therapies we might end up seeing several observational studies, each one run by a different company with a slightly different design.
We wanted to avoid this for CDD.
The idea for the CANDID study was born two years ago as a big hairy audacious goal: what if we could get all of the companies working on CDD come together, and co-design a single observational study that would meet everyone’s needs, get also the FDA to review it while we are at it, and then run that single study with all of the companies working together to minimize the number of observational studies that we need in CDD.
It sounded good. And all of the clinical teams at the different companies that we talked to also told us that it would be something they would support. That’s what gave us the conviction that we needed to try to make it happen. The problem was that we had no reference for other collaborations of this type. There was no book that we could read to know how to do this. This was going to be a first-of-its-kind partnership.
So for the past two years we had to figure out a way to co-design a study among so many parties without the study dying of decision paralysis, and we had to figure out the best way to build a consortium to govern the study where all companies would be equal partners. We also had to grow as a Foundation to be able to lead and coordinate these efforts, which brought us new team members like Xavier Liogier, who has the ideal human and professional mix to lead this study, and new strategic partners in clinical operations to help run this observational study with the very same standards as a pharma-run Phase 3 trial.
This is why I am so proud to be part of this story, as part of the Loulou Foundation team that made the CANDID study possible. We knew that all the companies working on CDD would like to see a consortium-run study, and we all understood that we needed to try to avoid having multiple corporate observational studies in CDD. So we figured out how to make this first-of-its-kind partnership happen, and in the process, wrote the first chapter of that book.
The CANDID study is about to start and will look for 100 participants of all ages (with active epilepsy or not), hoping to include study sites in the US, Canada, UK, France, Spain, Italy, Germany and Russia. This will help us make the study accessible to the large majority of patients diagnosed with CDD.
Strategy and partnership also on the advocacy side
Natalie Ladly, secretary for the International CDKL5 Alliance, helped close the conference with a presentation about the Alliance and a call for action.
There are 17 patient organizations under the Alliance (check them out at https://cdkl5alliance.org/) and one of the top priorities is to help the community be trial-ready. Natalie explained that they have 47 clinical trial sites around the world, at least one on each of the countries under the Alliance, and made a call to the industry and the medical community to reach out to the national patient groups and the Alliance and tell them what would help them (industry and clinicians) the most. Essentially, “help us help you”, and “by the way we have solved your problem for finding trial sites”.
I believe every year I write a longer summary. There is just so much going on, and so many news and progresses in many areas, that it is difficult to know what to cut from the summary. My main impressions from the 2021 CDKL5 Forum are that we are seeing solid tangible progresses in many areas, and that we seem to be turning a corner, where the ratio of individual labs working on CDD versus partnerships is changing and now a majority is working on the same agenda to solve the same problems together. This partnership model was started by the academic and clinical centers, and it has now also reached biotech and pharma companies.
This is why I want to commend in particular the professionals from so many biotech and pharma companies (we had 24 companies at the Forum!) that came to the Forum and sat down with their traditional competitors to share their best ideas for CDD and agree on joint efforts to make these happen. And I believe that the industry consortium behind the CANDID study is a testimony to that spirit of breaking previous barriers to industry collaboration, not just by saying nice words, but by working together to make progress actually happen.
And that is why hope, tangible progresses, strategy, and partnerships, where the themes of the 2021 CDKL5 Forum.
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 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.