Clinical trials in CDKL5 Deficiency Disorder – 2Q 2019

Some rare diseases can go for many years without much research on them. Other rare diseases, however, attract so much attention from scientists and companies that in a couple of years can make the progress that would have otherwise taken decades.

This is the case of CDKL5 Deficiency Disorder (CDD), a monogenetic rare disease that affects brain development and causes a very severe epilepsy with hundreds of seizures a month. I also reviewed all of the news on CDD in my review of the last CDKL5 Forum meeting HERE (October 2018).

This article is a summary of where we are with clinical trials for CDKL5 Deficiency Disorder for families and other interested readers.



There are currently 4 clinical trials ongoing or about to start in CDD. 

If you are coming from the patient side, and not from the medical community, you have probably heard about clinical trials being always divided in three stages:

  • Phase 1 trials: Small trial (study) in healthy adult volunteers, not in patients. The purpose of this phase is to determine the safety of the drug, as well as to explore different doses of the drug and measure the biodistribution (how soon you eliminate it, how it breaks down, does it accumulate… etc)

  • Phase 2 trials: Also known as “pilot” trials. Small trials in real patients with the disease that the drug intents to treat. This phase is mainly intended for determining safety, and also to pick a sign of efficacy. There are usually not enough patients to be sure that the drug works, but it enables companies and regulators to decide to move on to the next phase if the data looks good.

  • Phase 3 trials: Also known as “pivotal” trials. These are large confirmatory studies, in patients, with a placebo-controlled group (to serve as a control of what the normal change in the disease would have been in the absence of the drug, everything else remaining the same). You often need two of these trials for approval. Depending on the disease, it could be over a thousand patients per group. Other times it is many hundreds. Because of the need of finding so many patients it can take years to complete.

This is the default design, but there are exceptions to it. One exception is that when diseases are rare, you often need fewer patients, and might only need one pivotal trial to show efficacy and get a drug approved. This means a company can go from starting clinical trials to approval in 4 years, as GW Pharma recently did with Epidiolex for Dravet and Lennox-Gastaut syndromes, as opposed to 10+ years on non-orphan diseases!

Another exception is when the drug being tested has already gone through a Phase 1 evaluation in the past when being considered for other diseases, so once the company that owns the drug shows an interest in your disease they can move straight into Phase 2 (pilot) trials.  

Both exceptions are true for CDD, so as you will see below our timelines are much faster than the usual length of Phase 1 + Phase 2 + Phase 3 trials that you will find described in most on-line materials. Also, our pilot (Phase 2) trials need less than 20 patients, and the first drug that has reached the pivotal (Phase 3) stage only needs one trial with 70 patients. This makes it all a bit more doable and a lot faster.

One important note about CDD trials is that all of them add the experimental drug or the placebo treatment to the other medications that the patient is already taking for a duration of 12 to 17 weeks. This means that no participant will ever find themselves in a “no treatment” trial group if receiving placebo, they will simply start adding the actual experimental treatment to their usual medications later. Some of the clinical trials do not even include placebo group. 

So let’s jump into the update: which are these four drugs, what do we know about their efficacy, and where can you learn more about these trials or what comes after them.


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From the drug that first started clinical trials in CDD to the one that is about to start, these are the four clinical trials for CDD that you should know about:


Ataluren is a drug approved in Europe for the treatment of a subset of patients with Duchenne Muscular Dystrophy and marketed under the name of Translarna. It is currently completing a placebo-controlled Phase 2 (pilot) study at NYU Langone Medical Center in children with CDKL5 Deficiency Disorder caused by non-sense mutations. 

How does this drug work?

The brand name of ataluren is “Translarna” because it facilitates translationof RNA. I like how clever the name is. What it does is to target specifically a type of mutations known as non-sense mutations, which cause a premature stop in the gene sequence. These mutations appear in many different genes. That is why we can test this drug in diseases other than Duchenne, such as CDD and Dravet syndrome (the second disease evaluated in the same clinical trial). What ataluren does is to make the cell read through that premature stop and complete the protein that is otherwise missing in that disease.

Is there any previous clinical experience with this drug?

Yes! Ataluren is already approved for Duchenne, so the active dose and the safety profile are known. There is still no efficacy data in patients with neurodevelopmental diseases or epilepsy because these CDD and Dravet syndrome trials are still ongoing. One important difference with Duchenne is that CDD and Dravet are diseases of the brain, not the muscles, so it is possible that the drug doesn’t get well-enough into the neurons to work in these neurodevelopmental diseases. We will have to wait for the trial results to know that.

How is the clinical trial in CDD?

The trial is a pilot study, involving 9 patients with CDD that all go through some months in treatment and some months in placebo. This is called a “crossover” design, where some patients start in the drug and are then crossed over to placebo, and others start in placebo and are then crossed over to drug. This way, none of the patients in the study has to be only in placebo, and it also means that each patient is their own control.

The trial measures epilepsy as the main symptom for improvement. They also track cognitive function and quality of life as additional potential areas of improvement.

What would be the next steps for approval?

This trial is only taking place at one hospital, NYU Langone Medical Center, because it is what is known as an “investigator-initiated study”. Investigator-initiated means that the company that owns ataluren was not who decided to start this trial, but the investigator (the clinician) from NYU approached the company and asked them to let them run this clinical trial at their hospital.

Because it is a small pilot trial, the resulting data will not be sufficient for requesting approval of ataluren for treating CDD. So first the drug results need to be published, it has now completed recruitment but the data collection and publication are not yet completed. And after that, if the data is positive, PTC would need to run a Phase 3 pivotal trial. So the next step to this clinical trial is another (larger) clinical trial if the results are positive.

Where can I find more information about the trial?

The clinical trial and contact information are here



Ganaxolone is a drug currently in Phase 3 (pivotal) trials in CDD. It is also in clinical trials for other neurological diseases. It has not yet been approved for any disease, and if everything goes well it is likely to become the first drug to be ever approved for the treatment of CDD since it is the most advanced one.

How does this drug work?

You might be familiar with medications like Valium and Xanax. They belong to a class of drugs, benzodiazepines, that are used for anxiety, insomnia and muscle relaxation among other uses. Some drugs in this class, like clobazam (Onfi) are even used for treating epilepsy. These drugs all enhance the activity of a type of brain receptors called GABA receptors and the result is “brain relaxation”. The brain of people with CDD has an excess of neuronal activity, so drugs that enhance or facilitate GABA receptor function can help reduce excessive activity and minimize some of the symptoms.

Ganaxolone binds to the GABA receptor and enhances their activity in a different way to how benzodiazepines work, so it is thought to achieve the “brain relaxation” with slightly different properties. It is also known that in some epilepsy syndromes, patients have low blood levels of a ganaxolone-like endogenous body hormone, so part of the efficacy of ganaxolone could be due to it helping correct this deficiency.  

Is there any previous clinical experience with this drug?

Yes. Ganaxolone has been in clinical trials for other neurological diseases, like Fragile X syndrome and partial onset (focal) seizures in adults. More importantly, there has been a Phase 2 (pilot) trial in people with PCDH19 epilepsy and CDD that sowed it had efficacy on both patient populations when looking at their epilepsy. Because ganaxolone was also safe, it has now been progressed to the final Phase 3 (pivotal) studies in PCDH19 epilepsy and in CDD, now in two separate studies.

How is the clinical trial in CDD?

The Phase 3 clinical trial of ganaxolone in CDD is called the Marigold Study and takes place at numerous centers internationally. The trial is currently recruiting for patients. You can find more information about trial sites in the website of the Marigold study.

To enroll in the trial the patient needs to have a mutation in CDKL5, be 2-21 years old, and have at least 16 “major seizures” per month, which includes tonic-clonic seizures and atonic (drop) seizures. They are looking for at least 70 trial participants.

During the trial some of the patients are given ganaxolone while some receive placebo. Neither the families nor the physicians know which group the patient is in. After 17 weeks all patients are offered a chance to take ganaxolone, so if your child is placed in the placebo group it just means they will be starting the actual treatment about 4 months later.

The trial will measure epilepsy as the main symptom for improvement, and will also track improvement in other areas such as attention and behavior.

What would be the next steps for approval?

The Marigold study is a pivotal trial, meaning that it is a final trial. Once the study is completed, Marinus will submit all the documentation to the different regulatory agencies and request the marketing authorization for the treatment of CDD.

Where can I find more information about the trial? 

Marinus has created a website specifically for this trial: the Marigold study. You can also find more information as well and some CDD materials for patients at the company website



TAK-935, also known as OV935 since it is co-developed by Takeda and Ovid, is a drug currently in Phase 2 trials in CDD and other neurodevelopmental syndromes with epilepsy. It is an experimental drug and it is not yet approved for any other disease.

How does this drug work?

As you will remember from some paragraphs before, GABA is an inhibitory substance in the brain, which is why some drugs like ganaxolone enhance the activity of the GABA receptors to reduce brain excessive activity. They enhance brain inhibition. The excitatory substance in the brain is glutamate, and we know that the brains of people with CDD have an excess of neuronal activity in part due to too much glutamate signaling. What TAK-935 does is to reduce this excessive activity by reducing glutamate signaling, therefore bringing brain activity down to healthier levels. It reduces brain excitation.

Is there any previous clinical experience with this drug?

TAK-935 had already been in clinical trials for other neurological diseases although it was never taken all the way to the market. Because of that, the Phase 1 trials were already done. When Ovid and Takeda decided to test TAK-935 in drug-refractory epilepsies they run a Phase 2 (pilot) trial with 18 patients with a variety of rare epilepsy syndromes. Because the safety was good, and the patients experienced a reduction in seizures, the companies decided to progress the drug to further testing, and it is now being studied in four different Phase 2 (pilot) trials: one for Lennox-Gastaut syndrome, one for Dravet syndrome, one for Dup15q syndrome, and one for CDD.

How is the clinical trial in CDD?

The CDD and Dup15q studies are combined under a trial called the ARCADE study. The trial is currently recruiting patients, and is looking for 15 people with CDD ages 2 to 35 with at least 3 motor seizures per month. 

Because it is a pilot study, there is no placebo group. All 15 participants will receive the experimental drug on top of their regular baseline medication. Participants will take TAK-935 for 20 weeks (8 weeks bringing up the dose slowly followed by 12 weeks at maintenance levels), and the total trial duration beginning to end is 30 weeks. At the end of this period all participants will be offered to keep taking the drug if they found it to be effective.

The trial will measure epilepsy as the main symptom for improvement, and will also track general improvement.

What would be the next steps for approval?

Because the clinical trial is a Phase 2 (pilot) trial, and not a final pivotal trial, the results of the trial will not be sufficient for the companies to request a marketing authorization. If the trial results are good, then they will have to run one or two Phase 3 (pivotal) clinical trials like the one currently ongoing with ganaxolone, involving many more patients and most likely a placebo group. So the next step to this clinical trial is another (larger) clinical trial if the results are positive.

Where can I find more information about the trial? 

You can find more information about this trial in the ARCADE study website.



Fenfluramine is a drug that was approved many years ago for treating obesity as part of a combination pill. It was later discovered to have efficacy in treating drug-refractory epilepsy in an epilepsy syndrome called Dravet syndrome, and it has now completed all of the clinical trials for Dravet syndrome and is awaiting regulatory review to obtain the marketing authorization. Pilot studies have shown that fenfluramine has efficacy in other syndromes as well, so a pivotal trial is ongoing for Lennox-Gastaut syndrome and the company is interested in evaluating the efficacy of their drug in other syndromes with epilepsy to identify potential new diseases that could benefit from it. One of those, is CDD. 

How does this drug work?

While GABA and glutamate are respectively the main inhibitory and excitatory substances in the brain, there are several other substances that are known as “modulatory” because they tweak brain activity in many different ways. One of these is serotonin, and you might be familiar with antidepressants increasing serotonin signaling to stabilize people mood. This is also what fenfluramine does. Fenfluramine enhances serotonin signaling through some of the serotonin receptors, of which they are in total 15 different ones each playing different roles in the brain. It is not clearly known why these serotonin receptors are involved in epilepsy, but the clinical data so far has shown that fenfluramine is a very good anti-epileptic drug, at least in children with Dravet syndrome. Fenfluramine might also bind to other receptors in the brain, this is all still being studied.

Is there any previous clinical experience with this drug?

Yes! The reason why fenfluramine will be studied in CDD is because of the results they have seen with Dravet syndrome. Dravet syndrome is another neurodevelopmental syndrome with epilepsy, and unlike CDD where some of the patients ultimately outgrow their seizures, in Dravet syndrome this doesn’t happen. Two Phase 3 (pivotal) trials with fenfluramine in these children showed that fenfluramine could reduce seizure frequency by more than 70%, and about one in four participants was seizure free or “near seizure free” (about 4 seizures a year). The side effect profile of fenfluramine is similar to other anti-epileptic drugs and it requires extra cardiac monitoring. 

How is the clinical trial in CDD?

The trial is a pilot study, involving 10 patients with CDD that all receive the drug because there is no placebo group. The trial has not yet started recruiting, it will take place at NYU Langone Medical Center, and is looking for children with CDD ages 2 to 18  with more than 4 convulsive seizures a month that will receive the drug added to their baseline medication during 14 weeks.

The trial measures epilepsy as the main symptom for improvement. They also track quality of life and general improvement.

What would be the next steps for approval?

This trial is only taking place at one hospital, NYU Langone Medical Center, because it is again an “investigator-initiated study” as explained above for ataluren.

Because it is a small pilot trial, the resulting data will not be sufficient for requesting approval of fenfluramine for treating CDD. So the next step to this clinical trial is another (larger) clinical trial if the results are positive.

Where can I find more information about the trial?

You can find more clinical trial and contact information HERE, and additional information about previous results with fenfluramine in Dravet and Lennox-Gastaut syndromes HERE.



Oh yes! These four are all therapies that were already developed for treating other diseases (most for epilepsy, ataluren for addressing one specific mutation type). This means that they could move really fast into CDD, and start clinical trials right away without needing more research or improvements on them. 

But there are other very exciting programs that have been started specifically to address the genetic cause of CDD. These ones will still take a couple of years before they can start clinical trials because they have been started from scratch to be designed for CDD, and that takes time that we didn’t have to wait with the “ready for clinical trials” drugs. 

As a reminder of how CDD happens, CDKL5 is both the name of a gene and the protein that it produces. Each protein in the body has a specific function. The CDKL5 protein function is to put a phosphate onto other proteins which is like an on/off switch for those other proteins. This allows CDKL5 to turn on and off many functions of the neurons. Proteins that do this are called enzymes.

We are all born with mutations that were not present in our parents, that is how evolution works, but in most cases these mutations are in non-important regions, or at least are not too damaging. When one of these mutations, however, happens in the CDKL5 gene sequence and either breaks the sequence or gives it the wrong instructions, then that person cannot produce the CDKL5 protein or produces a non-functional version. Without good CDKL5 protein, all of those functions in neurons that needed CDKL5 to put all of the on/off switches in the right configuration are now not functioning properly. This is why the deficiency in CDKL5 is so bad for the brain.

There are two main efforts to fix these problems in patients with CDD. Not to treat their symptoms, but to correct the faulty biology that is causing the symptoms. These are the type of approaches that in the patient community we often call cures, although you will not hear this word from pharmaceutical companies. They prefer to call them disease-modifyingtreatments because they change the disease.

The first approach is gene therapy. If you could give each neuron a new copy of the CDKL5 gene then they will be able to produce the protein and function as a normal cell. There are multiple efforts going on in this area, but I will highlight the program from the company Ultragenyx, who announced last October that they will develop a virus carrying the CDKL5 gene as a gene therapy for CDD

The second approach is to simply add to the brain the CDKL5 protein. This has been done in the past in other diseases caused by enzyme deficiencies, and are known as Enzyme Replacement Therapies. I would highlight here that the company Amicus has been working on this approach for the last couple of years, trying different approaches to deliver the CDKl5 protein to the brain.

This means that in the next couple of years we will have several clinical trials for CDD that target disease symptoms, and then we will start having clinical trials with therapies that target the cause of the disease. The first group of drugs will reduce the symptoms of the disease and give the patients a chance to acquire more skills faster while they have less seizure burden. The second group of therapies, in particular when used in very young kids, will lead us to a future where children born with mutations in CDKL5 will pretty much be able to grow as if their gene was not mutated. As usual in medicine some trials will fail, but other trials will get started. The important message is that there are so many programs ongoing that the question is not IF we are going to make it to effective therapies, but WHEN


Let me know if you have some questions on these trials that I didn’t cover in the article!

Ana Mingorance, PhD