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.

FIRST, A NOTE ABOUT CLINICAL TRIALS

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.

CDKL5 DEFICIENCY DISORDER CLINICAL TRIALS REVIEW

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:

#1 ATALUREN – PTC THERAPEUTICS

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. 

#2 GANAXOLONE – MARINUS PHARMACEUTICALS

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. 

#3 – TAK-935 / OV935 – OVID THERAPEUTICS AND TAKEDA PHARMA

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.

#4 - FENFLURAMINE – ZOGENIX

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.

THE FUTURE - IS THERE ANY MORE RESEARCH ONGOING BEYOND THESE TRIALS?

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

Main Lessons from the World Orphan Drug Congress USA 2019

Many orphan drugs are advanced therapies. Pricing and access are major issues. Epilepsy is catching up with gene therapy. We shouldn’t call them rare diseases, but frequently misdiagnosed diseases. Either we wait 2,000 years for treatments or we start thinking “many diseases at a time”, and online patient communities are now part of the drug development process.

That’s the short summary of the main lessons I took home from attending the World Orphan Drug Congress at the National Harbor April 10-12. The WODC one of the largest meetings dedicated to the development of new medicines for rare diseases and takes place once in the US and once in Europe every year. 

In a bit more detail, here is the expanded list of what I would like to share with you from the conference:

1- A lot of “orphan drugs” use new technologies.

Although the Orphan Drug Act was conceived to stimulate development of therapies for rare diseases in general, and it has often been used in an “opportunistic way” for drugs that could have targeted broader populations, the new technologies that allow us to target specific gene defects are taking over the field. There was an entire day on Next Generation Therapies that highlighted programs in development using antisense, base editing, gene therapy and cell therapy approaches. There was also a great plenary session with multiple of these approaches including companies already in the clinic such as Alnylam, Sangamo Therapeutics and CRISPR Therapeutics. 

I believe that with most rare diseases having a genetic cause, and most genetic diseases being rare diseases, it is only natural that gene-targeting technologies will find their home in the rare disease space.

2- Big challenges: delivery, manufacturing and drug pricing 

In many of the debates the conversation went beyond the medical use of these new technologies and focused on some important challenges that the orphan drug community needs to face and address. One important issue that multiple of the new technologies face is how to get into their target tissue. This is particular complex for neurological diseases, although some companies are making great progresses in this space and Alnylam announced a few days before the WODC a partnership with Regeneron to apply their RNAi therapeutics to ocular and neurological diseases. Manufacturing challenges also limit cell and gene therapy development, making many of these one-time treatments too expensive. And that was indeed one of the main topics of discussion in the meeting: pricing and affordability of these new therapies. Emil Kakkis from Ultragenyx stressed the importance of ensuring access to therapies saying that this is the golden age for rare diseases and yet a therapy means nothing if patients cannot get access to it. While delivery and manufacturing are technical challenges, identifying suitable payment mechanisms that guarantee patients access to treatments is a social challenge that is likely to be the hardest to address. 

3 – Epilepsy meets the future

I regularly participate in orphan drug conferences, where I get to see all these exciting new technologies, yet at the epilepsy conferences (my field) most of what we see is traditional pharmacology that focuses on reducing brain activity without targeting the specific cause of the epilepsy in that patient. I work on neurological syndromes with epilepsy, and a very large number are monogenetic meaning that they would be the ideal target for these new approaches. Barry Ticho from Stoke Therapeutics said it very clearly at the WODC:

“there are more than 100 epilepsy genes but not a single therapy that treats the causes”.

But that is changing.

At the WODC we could see multiple approaches in development to specifically target the causes of several neurodevelopmental syndromes with epilepsy. In addition to Stoke presenting their antisense approach for Dravet syndrome, the small company RogCon presented their antisense approach for SCN2A epilepsies, Roche presented their antisense approach for Angelman syndrome, and as part of a panel, Xenon Pharma highlighted their small molecule approach with a potassium channel opener for KCNQ2 epilepsy. This is a good reminder that for some genetic diseases, small molecules could also offer an excellent disease-targeting approach, as also seen in cystic fibrosis where different CFTR protein alterations are treated by specific molecules designed to address those alterations.

To prepare the field of epilepsy for these new personalized approaches, early genetic diagnostic is paramount. Invitae has now extended the Beyond the Seizure epilepsy program to offer free genetic testing to all US children under 60 months of age with epilepsy. This program is sponsored by BioMarin, Stoke and Xenon, and I hope it will get more sponsorship to be opened to patients currently older than 5 years old and from other countries. Having a genetic diagnosis (early or not) is still one of the big challenges for rare disease patients around the world. 

4- Don’t call them rare – the importance of the words we use

Carol-Anne Partridgeis the Founder of a patient charity, and the mother of a beautiful girl with CDKL5 Deficiency Disorder. In her presentations, Carol-Anne always stresses that we need to change the narrative around rare diseases. Her experience resonates with that of many other people with rare diseases and their families, tired of a focus on what they cannot do (instead of what they can do, or the future cures they will have), and physicians talking in front of their kids in a way that doesn’t respect them. We need to change the narrative to one of hope and positivity and respect for people with rare diseases.

Arndt Rolfs, CEO of Centogene, made a similar plead to the WODC audience about the need to change the narrative. If we call them rare diseases, he explained, physicians will think that they will never across one, so they will not watch out for rare diseases. We should call them frequently misdiagnosed diseases instead, so that physicians are particularly alert to not miss them. This makes so much sense, and has such important consequences to patient diagnosis, that we should all start using the “frequently misdiagnosed diseases” term a lot more often.

With his presentation, Dr Rolds echoes Carol-Anne’s message: we need to change the narrative around rare diseases if we want to diagnose, treat and respect people with rare diseases.

5 – Reshaping “Rare” by thinking “many diseases at a time”

Chris Austin, Director of NCATS, gave one of my favorite presentations at the WODC about reshaping “rare”. At the current rate of orphan drug approval it will take 2,000 years before we have treatments for all rare diseases (assuming each new drug is approved for a different rare disease, which is not the case). A radical change in the way we discover and develop these therapies is needed. Chris’ proposal is to move from working on “one disease at a time” to working on “many diseases at a time”, exploiting commonalities among rare diseases and platform technologies to diagnose them and treat them. NCATS has multiple initiatives around this “many diseases at a time” approach, from empowering patient communities to get active in research to providing guidance on interoperable registries and partnering in drug development, including developing a gene therapy platform. 

While Chris advocated for these multiplexing approaches to diagnosis and therapy development, I think that we will need some regulatory innovation to address the challenge that in some fields companies are forced to run pivotal trials in a rare disease at a time, making it not viable for companies to run trials in ultra-rare diseases and condemning these patients to off-label drug use (more thoughts on this regulatory challenge here). 

6 – The place for social media and on-line patient platforms in orphan drug development

An interesting topic that also was present in different tracks at the WODC was the importance of social media and digital platforms in research and development. Luke Rosen, Head of Patient Engagement at Ovid Therapeutics, explained how Ovid believes that listening to the patient community voice is crucial for companies to understand what truly matters to families affected by rare diseases, and how Ovid is supporting the conversation by helping create community sites. A patient community that comes together becomes a stronger community, and an essential part of the drug development process. And Luke understands this well because he is also the Founder of the KIF1A.org Foundation to develop therapies for his daughter and other children with KIF1A associated neurological disorder. 

We also had a workshop during the first day of the WODC, where I participated, where we reviewed how on-line communities are able to capture the patient voice in a way that is directly usable for drug development. 

DuchenneXchange, for example, was created to help connect, educate and inform the Duchenne muscular dystrophy community, and James Valentine explained how regulators appreciate the use of on-line platforms to collect patient experience and preference data that will be useful for regulatory purposes. In fact in the FDA guidelines for Patient Focused Drug Development meetings, one of the methodologies for collecting patient experience data are precisely “Social Media and Identifiable Patient Communities”.

And “community” is perhaps the main value of the World Orphan Drug Congress. As much as I enjoy the workshops and presentations and roundtables, the main value I get from attending the WODC is the network. I get to catch up face to face with people I already knew, and I get to meet new people from promising companies or related patient communities.

See you all next year!

Ana Mingorance PhD 

Dravet syndrome gene therapy

See gene therapy update in September 2020

One of the top google searches that brings people to my website is “Dravet syndrome gene therapy”.

I often review the Dravet syndrome pipeline (recently HERE and HERE, notably HERE), but so far we haven’t had yet any clinical trials with gene therapy in Dravet syndrome so those treatments are largely not in the reviews. Nevertheless, it is understandable that gene therapy is the most attractive therapy for people with Dravet syndrome. 

Here is a review of the gene therapies in development for treating Dravet syndrome, how each of them works, and when they are expected to start clinical trials.

CURRENT GENE THERAPIES IN DEVELOPMENT FOR DRAVEY SYNDROME

In diseases like Dravet syndrome where the problem is that a copy of the gene is missing or not functional due to mutations, the desired therapy is one that can restore normal gene expression and therefore normal protein production. In other words, we need more protein.

In the case of Dravet syndrome, the gene is SCN1A, and the protein that is needed is the neuronal sodium channel Nav1.1. As a result of mutations in the gene, the number of Nav1.1 channels at the neuronal surface is not sufficient, there is less sodium crossing the membrane, and the neuron cannot fire properly. The result is Dravet syndrome. 

One particularity of Dravet syndrome is that only one of the two copies of the SCN1A gene is affected, the second one is perfectly fine, so that second copy can serve as the supply for extra protein production. As you will see, the most advanced programs are exploiting this possibility.

Broadly speaking, there are two approaches to restore protein expression in Dravet syndrome: you either supply the cell with an extra healthy copy the gene, which will lead to more protein being produced, or you try to boost the expression of the healthy gene. 

(1) Supply a new copy of SCN1A 

When people think about “gene therapy”, the type of therapy they are thinking about is the one where the DNA of a virus gets replaced by the gene that the person needs, and that modified virus is used as a Trojan horse to infect cells and deliver them the therapeutic gene. 

If the SCN1A wasn’t so large that it cannot fit the most commonly used virus for gene therapy, the Adeno-Associated Virus (AAV), we would probably have clinical trials right now using AAV-based gene therapy for Dravet syndrome. A year ago I reviewed this problem in the article “big gene, small virus”.

However the large size of the gene has so far kept all gene therapy companies away from working with viral vectors for Dravet syndrome, and only academic groups are trying to push the current comfort zone of AAV gene therapy into a new era where we can use virus to deliver large genes. The good news is that there are multiple labs working on this, so there are multiple shots on goal:

||   Dravet Canada and the US Dravet Syndrome Foundation are supporting a gene therapy project at Toronto University that is developing a gene therapy for Dravet syndrome although not details are available on the approach used (virus or gene).

||  The Spain-France-Israel consortium CureDravet started a year ago to develop a gene therapy for Dravet syndrome using Adenovirus, a type of high-capacity virus that is large enough to contain the entire SCN1A gene (Strategy 1 in the figure). They are collaborating with Dravet Syndrome Foundation Spain and the Dravet Syndrome European Federation, and have also developed a close relationship with patient groups.

||  At UCL, the team of Rajvinder Karda is working on two approaches. One is to use another type of large-capacity virus, Lentivirus, to carry the SCN1A gene (Strategy 1 in the figure). The second approach uses two AAV virus, each containing half of the SCN1A gene, which are able to recreate the full channel once they co-infect the same cells (Strategy 3 in the figure). They have received the support from Dravet Syndrome UK and share updates with other interested patient groups.

All of these projects are in early preclinical stages, and they have not yet published a proof of concept in a Dravet syndromemouse model, which is an initial stage prior to advancing the treatments towards clinical trials. These programs are therefore all years away from clinical trial initiation, with no guarantee of succeeding.

(2) Boost expression of SCN1A

Another strategy that has been used successfully in other diseases is to use small fragments of RNA (oligonucleotides) to boost the expression of a gene either without needing to add an external gene copy with a virus. This one is the strategy most advanced for Dravet syndrome.

||  The first program to be developed was OPK88001(previously CUR-1916) by OPKO Health. The therapy is a piece of oligonucleotide that binds to the DNA and removes an endogenous repressor of SCN1A (Strategy 3 in the figure). As a result, the good copy of SCN1A experiences much more transcription, leading to more mRNA and more Nav1.1 protein levels. The company expected to initiate clinical trials as early as in 2017, later announced to be in 2019, and as of February 2019 there are no news of when the program will be able to move into the clinic. 

||  2018 brought the good news that Stoke Therapeutics was developing an antisense oligonucleotide treatment to boost expression of SCN1A as well. This oligonucleotide binds to a form of mRNA and leads to an increase in the levels of mature mRNA and Nav1.1 protein (Strategy 4 in the figure). The company has shared preliminary data with efficacy in a mouse model and is planning to initiate clinical trials in 2020.  

||  Last, an academic group in Italy, with funding from CURE and the Dravet Syndrome European Federation,  is researching an alternative approach to boost production of Nav1.1 protein from the existing mRNA through another oligonucleotide approach (Strategy 4 in the figure).

REMAINING NEEDS FOR GENE THERAPY IN DRAVEY SYNDROME

(1) Questions to answer

Is overexpression of SCN1A bad? This is one important question that the field needs to answer so that we know if an excess of sodium channel as a result of the gene therapy could have negative consequences. This has been seen in some diseases where there are patients with duplication of the gene, for example in Rett syndrome where patients with Rett syndrome have a bad copy of MECP2 but there is also another disease caused by duplication of MECP2. In that case, increasing MECP2 levels too much with gene therapy would convert neurons from MECP2-deficient (Rett syndrome) into MECP2 duplication! 

There appears to be no negative consequences of mild overexpression of SCN1A but there has been no clear study how much increase is enough and how much is too much. This is one science gap important for gene therapy.

Other questions impact how to design a clinical trial with a gene therapy in Dravet syndrome. So far clinical trials measuring seizure frequency have been very successful, but a gene therapy is expected to improve the syndrome beyond just seizure frequency. Unfortunately, the field of Dravet syndrome is still immature when it comes to clinical outcome measure development and validation for non-seizure outcomes (for non-scientists in the audience: we don’t know how to quantify improvements of the disease in a clinical trial beyond seizures).

Also, all of these approaches are increasing the levels of Nav1.1, yet we don’t have any biomarker that could help us see what are the levels of functional or total Nav1.1 in patients. Imagine a clinical trial where a dose of the treatment is ineffective. If we don’t know if the dose had succeeded at restoring Nav1.1 levels, how would we interpret that trial? 

(2) New players needed

While it is exciting to see so many academic groups testing new forms of gene therapy for Dravet syndrome, I would like to see more companies in this space, in particular in the viral-mediated therapies. Beyond achieving the initial mouse proof of concept, the development of these therapies will face important challenges such as safety testing, scale up and manufacturing, clinical trial design able to measure non-seizure outcomes and biomarkers, and the massive cost of clinical trials. These challenges require the involvement of companies with the expertise and funding that can take these discoveries into the clinic and into the market, so the involvement of more companies in the gene therapy space for Dravet syndrome will be a necessary step as the pipeline progresses.

With Stoke now leading the development of oligonucleotide therapies for Dravet syndrome, it feels safe to think that the probabilities that we will have the first disease-modifying clinical trial for Dravet syndrome in 2020 is very high, and that an antisense therapy will reach the clinical trial stage. It is much less clear whether any of the current viral strategies will reach clinical trials since there is no corporate involvement. Antisense therapies and therapies with viral vectors have different advantages and disadvantages in the clinic. Because of that, I hope to see the antisense oligonucleotide approach from Stoke followed into the clinic by some company with a viral-mediated gene therapy approach, as it has happened in other fields such as SMA.

IN SUMMARY

• There are multiple gene therapy programs in development for Dravet syndrome including those that supply and extra copy of the SCN1A gene and those that boost expression from the healthy SCN1A gene copy.

• Clinical trials are around the corner, with Stoke Therapeutics expecting to initiate clinical trials in 2020.

• Just Stoke is not enough. New corporate players, and ideally some precompetitive collaboration around the common challenges of validating clinical outcome measures and biomarkers, are needed to maximize the success of gene therapies for Dravet syndrome.  

Do you know of any other gene therapy project that I missed? Let me know in the comments.

Ana Mingorance PhD

Expected Dravet syndrome news during 2019

2018 saw many progresses in the Dravet syndrome drug pipeline, including major milestones such as the approval and launch of Epidiolex in the US, the completion of a second very successful pivotal trial with fenfluramine, the initiation of clinical trials in Dravet syndrome by Ovid and Takeda and the appearance out of the blue of Stoke Therapeutics, with an antisense approach for restoring Nav1.1 expression in Dravet syndrome.  

Some of these news were already anticipated by the companies at the beginning of the year (reviewed here), so we knew when to expect them. But other took us by surprise, mainly around the programs that were less advanced at the beginning of the year. 

Keeping that in mind, here is what we can expect in 2019 from the Dravet syndrome programs from GW Pharmaceuticals, Zogenix, Ovid Therapeutics and Takeda, PTC Pharma and NYU, OPKO Health, and Stoke Therapeutics, based on what these companies have communicated.

Epidiolex (cannabidiol) – GW Pharmaceuticals 

The decision from the EMA to approve or not Epidiolex for the treatment of Dravet and Lennox-Gastaut syndrome is due within the first quarter of 2019, and if the decision is positive, GW hopes to start the first national launches of Epidiolex starting as early as Q2 2019. 

Fintepla (fenfluramine) – Zogenix

Zogenix also expected to deliver good news during the first quarter of 2019, when it planned to complete the submissions of the marketing authorizations for the two largest markets (called NDA in the US and MAA in Europe). This was one of the first news that we had in 2019, since the successful double-submission was announced at the beginning of February.  

We should have the news about the FDA decision on Fintepla in Q3 2019, followed by a launch in the US market before the end of the year. For the approval and launch in Europe we will have to wait until 2020.

Translarna (ataluren) – PTC Therapeutics / NYU

Last year we anticipated to get the results of the Phase 2 clinical trial with ataluren in children with Dravet syndrome caused by nonsense mutations during the second quarter of 2018. However the clinical trial has not yet been completed (according to clinicaltrials.gov it is active but not recruiting and is still ongoing in the last PTC pipeline review). In the absence of any public estimates on trial completion, all we can estimate is that if the trial has completed enrollment, and based on the trial protocol duration, we might expect to hear news by the end of Q2 2019.  

TAK-935 (OV935) – Ovid Therapeutics / Takeda

Even before completing the Phase2a basket trial in adult patients with different developmental and epileptic encephalopathies, Ovid and Takeda announced the initiation of a Phase 2 clinical trial in pediatric patients with Dravet syndrome and Lennox-Gastaut syndrome. The trial, called ELEKTRA, is currently recruiting and based on the company last estimates it will continue to enroll during 2019. This means that we might or might not get the news of the next milestone for this program for Dravet syndrome during 2019, which would be the completion of trial enrollment.

OPK88001 – OPKO Health

Over the years OPKO has provided very limited information on their program targeting Dravet syndrome with an antisense therapy. 2017 materials had indicated that the therapy, OPK88001, would be ready to start clinical trials in late 2017, which was later to moved to be planned to start somewhere during the first half of 2018. The latest corporate update, from June of 2018, still lists the program as active and indicates the Phase 2 trial will start during the second half of 2018. There were no news about the trial initiation and there are no more news about this program. The program is still listed as active in the last company presentation of September 2018 but no timelines were provided. We are therefore not able to predict if we will hear any news from this program during 2019.

Antisense Oligonucleotide - Stoke Therapeutics

One of the big news of 2018 was Stoke Therapeuticscoming out of stealth mode with an antisense oligonucleotide approach to restoring expression of the protein missing in Dravet syndrome, and  plans to bring the antisense therapy into the clinic by 2020. Although the company has not communicated any expected release of news to take place during 2019, it is predictable that during 2019 Stoke will announce the clinical trial plans, and communicate/publish more complete preclinical proof-of-concept data that supports their clinical trial plans. 

Other surprises

During the American Epilepsy Society meeting in December of 2018, the company Encoded Genomics, still in stealth mode, appeared as a new company developing a gene therapy approach for the treatment of Dravet syndrome. The company sponsored the Dravet Syndrome Roundtable and were open about the fact that they are developing such therapeutic approach, although no more details were given. If Encoded or any other new company confirms that they are working on a gene therapy for Dravet syndrome, and releases some news during 2019, it will solidify the transition of Dravet syndrome from a disease that we manage with symptomatic anticonvulsant medications to a disease that we can start targeting with a variety of gene therapy approaches. 

SUMMARY

2019 will be the year when we might have the European launch of Epidiolex, the US approval and launch of Fintepla, an ongoing clinical trial with TAK-935, hopefully some news about the ability of Translarna to improve Dravet syndrome by rescuing some of the nonsense mutations, and a year to prepare for the clinical trials that starting in 2020 will dominate the field: gene therapy approaches for Dravet syndrome that will treat more than just seizures.

Ana Mingorance, PhD

Sources:

 [1] GW Pharma company presentation January 2019

[2] Zogenix investor update December 2018 and press release 6 February 2019

[3] ClinicalTrials.gov information for NCT02758626

[4] Ovid Therapeutics Press Release 4 January 2019

[5] OPKO Health company presentation September 2018

[6] Stoke Therapeutics press release December 2018

Announcements within the same quarter ordered by drug name (alphabetic).

Orphan drug approvals: 2018 set new record for the EMA, but some red flags

In 2018, the European Medicine Agency (EMA) issued 84 positive opinions on new medicines. While the total number is lower than the year before, when 94 programs received approvals, the number of drugs being approved for the first time in Europe was higher than in 2017 (42 versus 35), meaning that there was more innovation reaching the market. 

In this month of February, when we celebrate and promote awareness on rare diseases, I would like to review how 2018 looked when it comes to orphan drug approvals, and orphan drug designations (data from the EMA).

The first observation that stands out when looking at the graph of orphan drug designations in Europe is a notable drop in the last two years when compared to the previous trend (Aqua). 

The second observation is the progressive increase in orphan drug approvals (yellow), although quite far from the number of orphan drug designations being issued.

Let’s discuss those two trends and what they might mean about the future of orphan drugs in more detail.

2018 Orphan Drug Designations

While we often refer to them as orphan drugdesignations and orphan drugapprovals, these are the notations used by the FDA. In fact, the EMA and the European Commission (which is the ultimate organism authorizing a drug approval) prefer to talk about “orphan medicinal products” instead. 

The number of orphan medicinal product designations has grown much since the process was started in 2000, and reached a peak during the years 2014-2016 with designation numbers of around 200 per years. While the drop in 2017 to numbers just shy of 150 could have been a fluke, 2018 has confirmed the decrease in the number of drugs obtaining the orphan status, indicating there might be some difference in the trend.

One possibility is that the decrease in orphan designations is due to a decrease in the number of applications. However the number of designations (successful applications) in 2017-2018 is comparable to 2012-2013, yet the number of applications was 25% higher in 2017-2018 meaning that the success rate was lower.   

A breakdown of these numbers indicates indeed that the success rate as decreased, and in the recent years the percentage of successful orphan applications has gone down from about 70-76% to a recent low of 59% in 2017. However 2018 has returned to the rate of previous year with 67% of the applications receiving a favorable opinion. Therefore, a reduced success rate due to the EMA becoming stricter or applications becoming weaker cannot fully explain why for the last two years we are seeing a substantial decrease in the number of orphan medicinal product designations in Europe. 

2018 Orphan Drug Approvals

The number of orphan drug approvals in Europe continues to experience a progressive increase over the years. In the last 5 years, for example, we had an average of 18 approvals of orphan drugs year, up from 7-8 during the previous ten years.

The actual number of orphan medicinal products is a bit smaller. For example, in 2018, a total of 21 orphan medicinal products were approved for a total of 26 orphan therapeutic indications, meaning that some drugs had approvals for multiple rare diseases.

Both of these numbers, 21 orphan medicinal products approved for 26 orphan therapeutic indications, are a record, exceeding any previous year and making 2018 the best year for orphan drug approvals in Europe.

The upward trend in the number of new orphan drug approvals does not reflect the regression in the number of designations experienced during 2017 and 2018. This is possibly due to the fact that most products receive the orphan drug designation years before they get approved, and raises the question of whether we could expect to see a decrease in the number of orphan drug approvals as soon as the smaller generation of “2017 and 2018 designations” reaches the finish line. 

Therefore, although 2018 was a record year in orphan drug approvals in Europe, it is expectable that we will see some reduction in the next few years.

2018 – US FDA vs EMA

2018 was the best year for orphan drugs in Europe, with 21 different drugs obtaining marketing authorization for 26 orphan indications. Yet when we compared these numbers with the orphan marketing authorizations issued by the FDA during the same time period the European numbers are dwarfed. Year after year, the number of orphan drug approvals in Europe is only one fifth to one third of the number of drug approvals in the US. 

It is also clear form the graph that the lengthier approval process in Europe is not responsible for these lower numbers, since the dips and peaks of both graphs are identical and do not suggest a simple delay in Europe. 

As an advocate for the rare disease patient community in Europe, these numbers worry me and trigger more questions than they address. For example, what does this mean for patients with rare diseases in Europe? Are they accessing the US-approved drugs through some medication import mechanisms or are we looking at a massive drug access problem in Europe? We need to also take into consideration that these graphs represent only central approvals, and that each country in the EU has to give the manufacturer green light to launch in that country, which due to price negotiations or poor market outlook is limited to only a fraction of the countries in the EU.

In summary:

• 2018 was a record year of orphan drug approvals in Europe

• The trend matches the US trend, also with a record of approvals in 2018

• However the number of orphan drugs approved in Europe is much smaller than in the US, meaning less options for patients

• The number of orphan drug designations (before approval) in Europe has fallen in the last two years

• If orphan designations represent an early marker of the orphan drug development trend, then we might expect a decrease in the number of approvals in the immediate future

 Ana Mingorance, PhD

2018 in review: Dravet syndrome milestones

With 2018 now behind us, it is time to review how well companies working on Dravet syndrome delivered based on the timelines that they had announced at the beginning of the year. This was the summary figure that I published a year ago outlining what to expect in 2018:

So how did it go?

While it is hard to predict exactly when many milestones are going to happen, in particular those still over half a year away or more, the class of 2018 did quite well overall, and many of the news that we were expecting took place on schedule – with some exceptions.

Ataluren – Phase 2 clinical trial

Ataluren (Translarna, by PTC Therapeutics) is being tested in a double-blind placebo controlled Phase 2 trial in patients with Dravet syndrome and CDKL5 Deficiency Disorder due to non-sense mutations. Although early last year the trial was expected to have results by Q2 of 2018, the trial is not yet completed and so the results have not been communicated. This is an investigator-indigitated trial involving only one clinical site so any delays in recruitment in that site cannot be buffered by recruitment elsewhere and has therefore a large impact on the trial timelines. 

Epidiolex – FDA approval and US launch

2018 promised to be a very exciting year for GW Pharma (Greenwich Pharmaceuticals in the US) and it did not disappoint. Every expected milestone came successfully and on time.

The first milestone was the FDA marketing authorization that came as planned in Q2 2018, following a very successful FDA advisory committee meeting some months before. After approval, the DEA rescheduled Epidiolex (cannabidiol) in Q3, enabling a successful market launch in Q4 (November). Epidiolex is currently available in all 50 states.

GW also expected the announcement of the results of the second pivotal trial in Dravet syndrome to take place during the second half of 2018. The results were announced in November and matched the previous three positive pivotal trials in Dravet syndrome (one) and Lennox-Gastaut syndrome (two). 

All in all, a very good year for GW, that expects the European marketing authorization in the first quarter of 2019.

Fintepla – Second pivotal trial data and regulatory filing

Zogenix also had a very good 2018, with the expected timelines being only slightly optimistic. The announcement of the results of the second pivotal trial with Fintepla (fenfluramine) in Dravet syndrome planned for Q2 ended up coming in July, and confirmed the first pivotal trial results showing unprecedented efficacy in this very difficult patient population.  

The NDA submission was initiated on schedule in Q4, but is expected to be completed during Q1 of 2019, together with the European MAA, after Zogenix communicated that after pre-NDA discussions with the FDA they had decided to “conduct some additional analyses of our clinical data that could positively impact our product label” which would delay the submission of the final sections of the NDA by just a couple of months.

So, all in all, also a very good year for Zogenix.

OPK88001 – Initiation of first clinical trial

Over the years OPKO has provided very limited information on their program targeting Dravet syndrome with an antisense therapy. 2017 materials had indicated that the therapy, OPK88001, would be ready to start clinical trials in late 2017, which was later to moved to be planned to start somewhere during the first half of 2018. The latest corporate update, from June of 2018, still lists the program as active and indicates the Phase 2 trial will start during the second half of 2018. There are no further news about this program. 

But just as the patient community wondered if the therapy from OPKO will ever move into the clinic, Stoke Therapeuticscame out of stealth mode with another antisense oligonucleotide approach to restoring expression of the protein missing in Dravet syndrome. So while the program from OPKO might not have reached the milestones that it expected to reach this year, a strong contender has appeared and has plans to bring the antisense therapy into the clinic by 2020.

 OV935 / TAK-935– Results from the basket trial

The last clinical trial news that were expected for 2018 were the results of the Phase1b/2a basket trial with patients with mixed epilepsy syndromes that Ovid Therapeutics and Takeda were running with their molecule. The companies had planned to release the top data of this trial in the second half of the year, and just as we were wrapping up the year the trial results were announced, meeting another successful milestone. The trial had very promising efficacy data in a group of patients that included cases of Dravet syndrome, Lennox-Gastaut syndrome and other rare epilepsies. 

Even before the completion of the pilot trial, Ovid and Takeda decided to move forward with additional clinical trials with OV935 (TAK-935) in four rare epilepsies, announcing in September of 2018 the initiation of a placebo-controlled Phase 2 clinical trial in Dravet syndrome and Lennox-Gastaut syndrome, and a smaller open-label Phase 2 trial in CDKL5 Deficiency Disorder and Dup15q syndrome.

So for Ovid and Takeda, 2018 delivered even more for Dravet syndrome 8and for OV935) than they had envisioned at the beginning of the year. 

In the next article I will review the news that we can expect in 2019 from those programs that are in clinical trials for Dravet syndrome. 

 Ana Mingorance PhD