Ultragenyx update, May 2021

[vc_row][vc_column][vc_custom_heading text=”Ultragenyx update, May 2021″ use_theme_fonts=”yes”][/vc_column][/vc_row][vc_row][vc_column][vc_column_text]May 26, 2021

Dear Families Living with CDKL5 Deficiency Disorder,

While some of you may already know our company from previous presentations at scientific meetings, we are now pleased to provide your community with a more formal communication regarding Ultragenyx’s research on CDKL5 deficiency disorder (CDD).

Ultragenyx is currently in the early, pre-clinical stage of development for UX055, our investigational gene therapy program for CDD. Our investigational gene therapy is designed to deliver a fully functioning copy of the human CDKL5 gene to neurons. The goal is for those neurons to read the new gene and produce functional CDKL5 protein. We are using Adeno-Associated Vector Serotype 9 (AAV9) to transport the CDKL5 gene into neurons in the brain.

Click below to read the entire newsletter…..[/vc_column_text][ult_buttons btn_title=”Open Newsletter” btn_link=”url:https%3A%2F%2Fcdkl5alliance.org%2Fwp-content%2Fuploads%2F2021%2F05%2FUltragenyx-update-May-2021.pdf|target:_blank|rel:nofollow” btn_bg_color=”#99003f” btn_bg_color_hover=”#981a4e” btn_title_color_hover=”#ffffff” icon_size=”32″ btn_icon_pos=”ubtn-sep-icon-at-left”][/vc_column][/vc_row]

Twenty “must-read” publications from 2020

#1 to #3:  Gene therapy and X reactivation:

Gene replacement ameliorates deficits in mouse and human models of cyclin-dependent kinase-like 5 disorder.

Gao Y et al., Brain

Proof-of-concept for a gene replacement approach to CDKL5 deficiency disorder.

Benke TA and Kind PC, Brain

  • First published proof of concept for AAV-mediated gene therapy for the treatment of CDKL5 Deficiency Disorder.

Artificial escape from XCI by DNA methylation editing of the CDKL5 gene.

Halmai et al., Nucleic Acids Res

  • Impressively detailed and well-executed study providing strong proof of concept in a human cellular context for specific reactivation of the X-inactivated CDKL5 allele using genome-targeting strategies.

#4:  Molecular function in the nucleus:

Epilepsy kinase CDKL5 is a DNA damage sensor which controls transcriptional activity at DNA breaks.

Khanam et al., BioRxiv (pre-peer review manuscript)

  • Identification of novel CDKL5 kinase substrates in the nucleus of human cells highlights the role of CDKL5 in regulating transcription elongation/processivity, including in response to UV-induced DNA damage.  Important implications for the global role of CDKL5, and primate-specific functions which might not be detectable in other animal models.

#5 to #9:  Molecular function in the periphery:

Cyclin-dependent-like kinase 5 is required for pain signaling in human sensory neurons and mouse models.

La Montanara P, et al., Sci Transl Med

  • Detailed analysis of deficiencies in pain signaling resulting from the loss of CDKL5, including the specific knockout of CDKL5 expression in DRG neurons.

A kinome-wide screen identifies a CDKL5-SOX9 regulatory axis in epithelial cell death and kidney injury.

Kim JY, et al., Nat Commun

CDKL5 controls RTEC fate during AKI.

Carney EF, Nat Rev Nephrol

Involvement of the CDKL5-SOX9 signaling axis in rhabdomyolysis-associated acute kidney injury.

Kim et al., Am J Physiol Renal Physiol

CDKL5: a promising new therapeutic target for acute kidney injury?

de Caestecker MP, Am J Physiol Renal Physiol

  • In this series of two primary research reports from the Pabla lab, and two reviews by experts in the field, the role of CDKL5 in mediating a cell death response in acute kidney injury is nicely demonstrated, including implicating CDKL5-directed degradation of the SOX9 pro-survival factor as being a key step.

#10 to #13:  CNS Function and seizure-like activity in mouse models

Dopaminergic loss of cyclin-dependent kinase-like 5 recapitulates methylphenidate-remediable hyperlocomotion in mouse model of CDKL5 deficiency disorder.

Jhang et al., Hum Mol Genet

  • This is the first detailed demonstration of functional disruptions in dopaminergic signaling due to loss of CDKL5.  Implications for this disruption on striatal signal transduction and functional outputs are discussed.

X-linked cellular mosaicism underlies age-dependent occurrence of seizure-like events in mouse models of CDKL5 deficiency disorder.

Terzic B, et al., Neurobiol Dis

Aged heterozygous Cdkl5 mutant mice exhibit spontaneous epileptic spasms.

Mulcahey PJ, et al., Exp Neurol

  • These two papers, from a collaboration between the Zhou and Coulter labs, demonstrate the EEG and behavioral characteristics of epileptic spasms or “seizure-like” events in female heterozygous CDKL5 ko mice when aged out to several months.

Seizures in Mouse Models of Rare Neurodevelopmental Disorders.

Fallah MS and Eubanks JH, Neuroscience

  • Published early in 2020, this is a nice review from the Eubanks lab on spontaneous or induced seizure/seizure-like behavior in animal models of different neurodevelopmental disorders, including CDKL5 Deficiency Disorder, before the publication of the studies above.

#14 to #16:  QOL, genotype/phenotype, and seizure-free CDD patient:

Exploring quality of life in individuals with a severe developmental and epileptic encephalopathy, CDKL5 Deficiency Disorder.

Leonard H, et al., Epilepsy Res

Expanding the phenotype of the CDKL5 deficiency disorder: Are seizures mandatory?

MacKay CI, et al., Am J Med Genet A

Exploring genotype-phenotype relationships in the CDKL5 deficiency disorder using an international dataset.

MacKay CI, et al., Clin Genet

  • A series of important papers from Helen Leonard and Jenny Downs on epidemiology and genotype-phenotype relationships in CDD, as well as a provocative finding of mutations in the CDKL5 gene of a patient who presents with many of the symptoms associated with CDD – but not seizures.

#17 to #18:  Clinical studies, including NIH natural history study on Rett and Rett-related disorders (including CDD)

Comparison of core features in four Developmental Encephalopathies in the Rett Natural History Study.

Cutri-French C, et al., Ann Neurol

  • First report on data from CDD patients within the NIH-funded Developmental Encephalopathy natural history study.

Evoked Potentials and EEG Analysis in Rett Syndrome and Related Developmental Encephalopathies: Towards a Biomarker for Translational Research.

Saby et al., Front Integr Neurosci

  • A nice review on the pre-clinical and clinical data around the use of evoked potentials and EEG in Developmental Encephalopathies, including CDD, as functional biomarkers to aid therapeutic development.

#19:  The Voice of the Patient Report

CDKL5 Deficiency Disorder:  Voice of the Patient Report

  • This report, prepared by the Loulou Foundation and the patient advocacy group IFCR following the externally-led Patient-Focused Drug Development (PFDD) meeting with the FDA on November 1, 2019, summarizes the patient and caregiver perspective of living with CDKL5 Deficiency Disorder, including the symptoms of CDD that matter most to patients and families in their daily life, current treatment/therapy options, and the impact that meaningful therapeutics would have on their quality of life. 

#20:  The videos of presentations from the CDKL5 Forum 2020

CDKL5 Forum 2020

  • Registration in the CDKL5 Forum portal is required to view the videos; if you are not already registered in the portal, you can apply for membership by clicking here.

Marinus Launches Expanded Access Program for Ganaxolone Treatment in CDKL5 Deficiency Disorder ​

Marinus Launches Expanded Access Program for
Ganaxolone Treatment in CDKL5 Deficiency Disorder

RADNOR, Pa.–(BUSINESS WIRE)– Marinus Pharmaceuticals, Inc. (Nasdaq: MRNS), a pharmaceutical company dedicated to the development of innovative therapeutics to treat rare seizure disorders, today announced the launch of an expanded access program (EAP) that will allow the company to offer ganaxolone to patients with CDKL5 Deficiency Disorder (CDD) who were unable to participate in the company’s Marigold Study Phase 3 clinical trial.

“With the positive results in our clinical trial, we felt it was an important measure to make ganaxolone available to patients with CDD as we prepare to submit a new drug application to the FDA,” said Scott Braunstein, M.D., Chief Executive Officer of Marinus. “There are currently no approved treatments specifically for patients with CDD, creating a strong need to provide early, compassionate use access to investigational ganaxolone therapy for these children.”

Candidates for the EAP must be at least two years of age, with a confirmed diagnosis of CDD, and experiencing uncontrolled seizures. The investigational treatment will initially be available in sites in the United States. It is important to remember that investigational drugs have not yet received regulatory approval; therefore, their potential risks and benefits are not yet established. Doctors and patients should consider all possible benefits and risks when seeking expanded access to an investigational drug.

In the Marigold Study, patients given oral ganaxolone showed a significant 32.2% median reduction in 28-day major motor seizure frequency, compared to a 4.0% reduction for those receiving placebo. In this trial, ganaxolone was generally well tolerated with a safety profile consistent with previous clinical trials, with the most frequent adverse event being somnolence. Marinus is preparing to meet with the U.S. Food and Drug Administration (FDA) in Q1 2021 regarding its planned mid-2021 NDA submission, as well as a 1H 2021 pre-marketing authorization application (MAA) meeting with the European Medicines Agency (EMA).

For more information on the Marinus Expanded Access Treatment Protocol for ganaxolone, please visit https://marinuspharma.com/expanded-access-program/

About CDKL5 Deficiency Disorder

CDKL5 deficiency disorder (CDD) is a serious and rare genetic disorder that is caused by a mutation of the cyclin-dependent kinase-like 5 (CDKL5) gene, located on the X chromosome. CDD is characterized by early-onset, difficult-to-control seizures and severe neuro-developmental impairment. Most children affected by CDD cannot walk, talk, or feed themselves. Currently, there are no therapies approved specifically for CDD.

About Ganaxolone

Ganaxolone, a positive allosteric modulator of GABAA receptors, is being developed in intravenous and oral formulations intended to maximize therapeutic reach to adult and pediatric patient populations in both acute and chronic care settings. Unlike benzodiazepines, ganaxolone exhibits antiseizure, antidepressant and anti-anxiety activity via its effects on synaptic and extrasynaptic GABAA receptors. More than 1,600 study participants, both adults and children, have received ganaxolone at therapeutically relevant dose levels and treatment regimens for up to four years.

About Marinus Pharmaceuticals

Marinus Pharmaceuticals, Inc. is a pharmaceutical company dedicated to the development of innovative therapeutics to treat rare seizure disorders. Ganaxolone is a positive allosteric modulator of GABAA receptors that acts on a well-characterized target in the brain known to have anti-seizure, anti-depressant and anti-anxiety effects. Ganaxolone is being developed in IV and oral dose formulations intended to maximize therapeutic reach to adult and pediatric patient populations in both acute and chronic care settings. Marinus recently completed the first ever Phase 3 pivotal trial in children with CDKL5 deficiency disorder and is conducting a Phase 2 trial in tuberous sclerosis complex, as well as a Phase 2 biomarker-driven proof-of-concept trial in PCDH19-related epilepsy. The company has also initiated a Phase 3 trial in status epilepticus. For more information visit www.marinuspharma.com.

Forward-Looking Statements

To the extent that statements contained in this press release are not descriptions of historical facts regarding Marinus, they are forward-looking statements reflecting the current beliefs and expectations of management made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Words such as “may,” “will,” “expect,” “anticipate,” “estimate,” “intend,” “believe,” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements. Examples of forward-looking statements contained in this press release include, among others, statements regarding our plans to meet with the U.S. Food and Drug Administration (FDA) in Q1 2021; our plans to submit a new drug application to the FDA in mid- 2021; our plans to meet with the European Medicines Agency (EMA) in first half of 2021 regarding a pre-marketing authorization application (MAA). Forward-looking statements in this release involve substantial risks and uncertainties that could cause our clinical development programs, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, uncertainties and delays relating to the design, enrollment, completion, and results of clinical trials; unanticipated costs and expenses; clinical trial results may not support further development in a specified indication or at all; actions or advice of the U.S. Food and Drug Administration may affect the design, initiation, timing, continuation and/or progress of clinical trials or result in the need for additional clinical trials; our ability to obtain and maintain regulatory approval for our product candidate; delays, interruptions or failures in the manufacture and supply of our product candidate; our ability to raise additional capital; the effect of the COVID-19 pandemic on our business, the medical community and the global economy; and the availability or potential availability of alternative products or treatments for conditions targeted by us that could affect the availability or commercial potential of our product candidate. Marinus undertakes no obligation to update or revise any forward-looking statements. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to the business of the Company in general, see filings Marinus has made with the Securities and Exchange Commission.

View source version on businesswire.com: https://www.businesswire.com/news/home/20201207005216/en/


Sasha Damouni Ellis

Vice President, Investor Relations & Corporate Communications

Marinus Pharmaceuticals, Inc.



Copyright © 2020 Marinus Pharma, All rights reserved.


2020 is the year when the world discovered the urgency that the rare disease community feels to develop effective medications and cures.

It is also the year that prevented us from hosting large conferences, so the 6th edition of the CDKL5 Forum, which would have taken place in London, UK, instead took place October 12-14 in a virtual conference center. The Forum is the annual meeting hosted by the Loulou Foundation where scientists and drug developers working on CDKL5 Deficiency Disorder (CDD), together with representatives from patient organizations, meet to discuss the latest advances. This was the fourth Forum I attended, and the third since joining the Loulou Foundation.

Screen Shot 2020-10-12 at 14.53.54.png

Every year, the CDKL5 Forum allows us to look back in time to how the field was just a couple of years ago, review all the progresses made in the last year, and anticipate how the next year of research into CDD and drug development is likely to look like. And if we are to learn from our predictions from the past years, we will probably underestimate how much everything will move in just 12 months.

Dr Orrin Devinsky, Chairman of the Loulou Foundation Advisory Committee, summarized the 2020 Forum stating how “what we have seen these 3 days is breathtaking”. For those of you who were not in the room, these are my main conclusions from the CDKL5 Forum and how far along we have come in the CDD field.


The Forum always starts by updating our growing understanding of what the CDKL5 protein does and why mutations in the CDKL5 gene lead to such a dramatic neurodevelopmental condition.

I am a cell biologist and I am used to thinking about genetic conditions by knowing what the missing (or mutated) protein does. For example, “this is an ion channel so when it is missing neurons are hyperexcitable”, or “this protein is essential for protein degradation so when it is mutated there is abnormal buildup of toxic proteins”. But CDKL5 deficiency is challenging all those simple schemes. The CDKL5 protein is a kinase involved in so many cellular processes that learning about what happens when CDKL5 is missing is not only teaching us about how the deficiency disorder works, it is also teaching us new biology previously unknown to science.

In the words of Dr Victor Faundez from Emory University, which capture very well this take-home message:

““One mutant opened the door to wonderful biology”

We saw much of this during a pre-meeting with the Loulou Foundation awardees as well as during the first day of the Forum. Scientist from all around the globe shared their findings about how CDKL5 modulates microtubule dynamics (like the skeleton within cells), and how this is so critical for neuronal plasticity and formation of new synapses (neuronal connections). And CDKL5 also seems to have important functions at the cellular headquarter where DNA is located: the nucleus. They also told us how CDKL5 also regulates motile cilia, like in the epithelial cells that surround the brain ventricles and move CSF around, and about functions outside of the brain. And CDKL5 starts looking like a kinase that probably controls many other kinases, like a critical node in a network, so it takes us in many directions. From some of these pathways we start identifying “actionable” targets, which suggest possible drugs that might be used to at last ameliorate some of these consequences of missing CDKL5.

That said, it is clear that with CDKL5 controlling so many processes it will be hard to “bypass it” or achieve a full rescue with treatments that target individual pathways. We really should try to replace the protein or the gene to achieve the full recovery. The good news is that these treatments are all in development.

Some of the consequences of missing CDKL5 remind me to what goes wrong in other neurodevelopmental disorders. For example, all of the microtubule dynamic discussions make me think of KIF1A associated neurological disorder, and a recent publication showing that CDKL5 could be flagging proteins for ubiquitination in the kidney reminds me to Angelman syndrome, where a missing ubiquitin ligase is the culprit. So these all make sense as individual pathways that once de-regulated by the lack of CDKL5 might lead to the neurodevelopmental disorder, and they happen to all be engaged at the same time in CDD.

All because of the one mutant that opened the door to wonderful biology.


One of the reasons why so many scientists have come to work on CDKL5 is the biology that it uncovers. Another reason is research tools.


Scientist cannot research a protein or a disease if they don’t have the tools to produce that protein, or to see its activity, or to model the disease in cells or animals. A big focus of the Loulou Foundation and our partner organizations has been to build “the translational toolbox” so that we have all we need to take a therapy all the way from understanding what happens in the cell to completing clinical trials. Last year the Forum dedicated the parallel breakout sessions to map out the needs for tools and to focus our efforts to create them. A year later, those efforts have paid off.

I will only highlight three of those tools, there were more presented:

Dan Lavery, CSO of the Loulou Foundation and our Forum host, announced that Coriell (a biomedical tool repository) will soon start offering iPSCs from CDD patients. This is the result of years of work in collaboration with the Boston Children’s Hospital that led to the creation of several lines of iPSCs together with isogenic controls. For the non-scientists: iPSCs are inducible pluripotent stem cells, a sort of stem cell that is obtained by taking some cells from the blood or the skin of a person (in this case CDD patients) and “reverting” them to stem cell state. They are very useful because scientists can then make them go forward in development, this time to neurons, and be able to have CDD neurons in a dish. And because they will be available from this repository, getting them will soon be as easy for scientists as placing an order on Amazon.

Another important tool to research CDKL5 is CDKL5 itself. Brian Ranes from Amicus Therapeutics offered to share purified CDKL5 protein with the research community, opening the door to exciting science that was until now very difficult to do because producing and purifying CDKL5 is remarkably complicated. But Amicus has developed considerable expertise around protein production, and showed once again their commitment to advancing research in CDD beyond just working on their own therapeutic programs.

One critical challenge in the development of therapies is reproducibility, in particular reproducibility of the preclinical (mouse) drug studies. A year ago, the Loulou Foundation signed a joint collaboration with Baylor College of Medicine and the Texas Children’s Hospital to establish a pipeline of CDD mouse models and behavioral assays to be able to evaluate (and confirm) potential therapeutics for CDD in a rigorous and unbiased way. The work is led by Dr Rodney Samaco, who was the recipient of the Lab of the Year 2020 award by the Loulou Foundation for the transformational value that this mouse behavioral assay platform will have for the development of therapeutics in CDD. This platform has already been instrumental for the preclinical proof-of-concept for the gene therapy from Ultragenyx that was also presented at the Forum (more information below).

Building the research toolbox takes many years, many scientists, much funding and much collaboration. The CDD translational toolbox is a reflection of the maturity of the CDD field.


This provocative statement is one of the major conclusions that I take from the 2020 CDKL5 Forum.

Coming into this Forum we already knew that there are no large changes in neuronal wiring in CDD, or in brain anatomy, and we have not seen signs of it being a neurodegenerative disease. So it would appear that CDKL5 is constantly needed for the very dynamic process of synaptic plasticity and formation. This means that bringing CDKL5 expression back is likely to provide a benefit even in the more mature brains, while in diseases that affect neuronal migration, or that lead to neuronal death, we only have a narrow time window to replace the protein and see any improvement. But we really had no evidence for this yet.

During this Forum we learned from mouse studies that the CDKL5 protein remains highly expressed throughout life (so it is not only there during early development). We also learnt that if we remove it from the brain of an adult mouse that has otherwise developed completely normal, as if CDD could be started in an adult individual by flipping a switch, this results in all of the same problems that mice have if they are born with CDD. Joe Zhou from the University of Pennsylvania showed us how removal of CDKL5 expression in adult mice resulted in hyperactivity, reduced sociability and other autism-spectrum behaviors, memory problems and poor motor coordination (this is how CDD looks in mice, remember that it is very hard and rare to see seizures in CDD mice). Because removal of CDKL5 at a later stage is enough to produce the disease, Joe’s conclusion was that “CDKL5 is indispensable for life”.

But what about the reverse? What is the consequence of bringing CDKL5 expression back to a brain that has developed without it? Joe told us how he plans to do the reverse mouse, one where the animals are born without CDKL5 and then he can start the gene at different ages, and we all look forward to seeing those results. In the meantime, the first partial answers to these questions came from the gene therapy programs. Sharyl Fyffe-Maricich from Ultragenyx showed how administering AAV carrying a copy of CDKL5 to mice with CDD aged 3 to 5 weeks, which is the equivalent of children 4 to 11 years old, was able to improve several of the phenotypes of these mice, including motor function and cognition. While she made it clear that they were only able to restore CDKL5 expression to 35% of its usual levels, which is just a partial rescue, these experiments showed that at least in mice even partial rescue of CDKL5 expression is sufficient to reduce the disease symptoms, and this is the first time that we have been able to measure this directly.

What this tells us is that CDD is not strictly a neurodevelopmental disorder, where the CDKL5 protein is needed for brain development and no longer needed afterwards. Instead, CDD is a neuromaintenance disorder, where CDKL5 protein expression is needed throughout life to ensure proper neuronal functioning. We don’t appear to be fighting against a transient neurodevelopmental window when CDKL5 is needed and where the damage is already done if we come too late. And this is much more hopeful for treatments, because all of these experiments tell us that CDD is a good candidate for gene therapy or enzyme replacement therapy even in adult patients.

“CDD is not a neurodevelopmental disorder, but a neuromaintenance disorder, and this is much more hopeful for treatments.


The topic of gene therapies was a major one in day 2 in the 2020 Forum. Jim Wilson, a veteran from the gene therapy field, explained us how gene therapies have to progress roughly through 3 stages before they can be used to treat large groups of patients in clinical trials. I will give them a name based on my own words:

–       Stage 1 – Prove that you can treat a mouse: the first treatment studies are often done in mice that carry the same genetic deficit that the patients have, to test the ability to correct the disorder in these animals with the experimental therapy and get an early feeling of potential toxicity issues. In gene therapy scientists use a virus that they have emptied from virus DNA and replaced by the therapeutic gene that is needed for the patient, so that when the virus infects the patient it is actually bringing the gene to the cells. So the biggest challenge of this stage is to produce that “transgenic therapeutic virus” which involves several pieces, and to treat the CDD mice with it.

–       Stage 2 – Prove that you can treat larger brains: these are the toxicology studies which are done in large animals, often non-human primates, looking for safety and ability to bring the virus to large parts of the brain. This is often the biggest challenge, the “biodistribution” of the virus, in particular for diseases that need to treat large areas of the brain (or other organs) as opposed to very focal diseases.

–       Stage 3 First in Human studies: this is when the therapy reaches clinic for the first time, and the first studies focus on safety and toxicology before risking exposing too many patients to the new experimental gene therapy.

Jim reviewed how the challenge for many gene therapies is step 2, and figuring out how to scale up from very small mice to large animals. For example, figuring out the route of administration. In the case of CDD, could we use intravenous administration or should we deliver the virus directly into the brain? Earlier in the program we had learned from Amicus that they are working on a project to boost the number of neurons that can benefit from gene therapy by using a virus to deliver not the plain CDKL5 gene but a gene encoding for a secretable CDKL5, so that the neurons that receive the virus and can express CDKL5 will also act as local factories to secrete CDKL5 that can then get into neighboring cells, an approach that they called “cross-correction”.

And then we got to one of the most exciting moments in the Forum, when we got to see two proof-of-concept in mice from two companies developing gene therapies for CDD.

The first one was from Jim Wilson’s group, who is running a gene therapy for CDD program for a company called Elaaj Bio. Ralf Smichd presented a very large collection of experiments optimizing the gene therapy for CDD. He showed us how much work went into creating the “transgenic therapeutic virus”, from seeing which of the different isoforms of CDKL5 is needed (there are 4!) to checking what happens if you overexpress CDKL5 in the brain (to know if we face an overexpression risk) to confirming activity in both males and females. And to run the proof-of-concept, this group chose to go for the best-case scenario, which is to treat CDD mice at birth. This ensures the greatest brain coverage for the virus as well as treating as early as possible. The best-case scenario in CDD mice was amazing. Ralf showed complete rescue of CDKL5 protein expression AND activity, because we can monitor the kinase activity looking at a reporter phospho-target called EB2. He showed us beautiful brain expression of CDKL5, and rescue of all the symptoms in these mice when examined months after the virus administration into their CSF. He even showed some preliminary EEG improvement, and had reproduced these data in a separate lab with two additional CDD mouse strains. You can hardly get more solid science than here.

This gene therapy is now being optimized for the stage 2 that Jim explained to us before, which is to tweak it until it has good biodistribution in the non-human primate (large) brain so that they can confirm toxicity and safety and best dosing in these large animals before thinking about trials.

And as I commented before, Ultragenyx also presented a mouse proof-of-concept with their own gene therapy, which earned them the 2020 CDKL5 Forum Award for the “Company making a difference” in the preclinical space. And I found very interesting that Ultragenix had chosen a different approach for designing their mouse proof-of-concept. Instead of going for the best-case scenario, as in the previous therapy, Ultragenyx chose to go for the real-life-scenario, which was to treat older mice with a partial rescue of gene expression. And Sharyl showed us how even partial rescue with the virus administered directly into the CSF of CDD mice at the equivalent human age of roughly 4 to 11 years old resulted in partial efficacy across different symptoms. The results were therefore tremendously encouraging because we are likely to achieve only partial rescue in the clinic and we will be treating patients that are not newborns anymore. So the question of “is this sufficient” is indeed very relevant, and the answer – at least in mice – is “yes”.

So in 2020 we have proof by two companies that we can rescue CDD in mice, with improvements even in older mice, and the discussion has now moved to how to scale this up to work in larger brains. We have made it past stage 1.

These programs open the path for follow up therapies based on gene editing, the technology that earned the Nobel Prize for Chemistry in 2020. At the Forum we reviewed several of these programs, including a modified CRISPR approach to try to “unlock” the inactive CDKL5 in the second X chromosome of each cell, as well as “prime editing” which is a field pioneered by David Liu who explained us that CDD is one of the first diseases that they are trying to correct with prime editing. There are so many therapeutic programs in development for CDD that it would be hard to list them all in this type of update. What is important to know is that pretty much every therapeutic technology that we know already has an active program (or more) to apply  it to CDD, so the question is no longer whether we will ever get a curative treatment, but instead it is “which of them” and “when”.


Day 3 of the 2020 CDKL5 Forum came with many great news. Dr Orrin Devinsky summarized the data with Epidiolex in CDD as part of an expanded access program that showed efficacy, and then announced for the first time the results of two small investigator-initiated phase 2 studies (those are “one hospital” clinical trials) that he has led:

1.     Ataluren did not have efficacy in CDD. Orrin showed us the data of a study with 18 patients, some of them with CDD some of them with Dravet syndrome, in which some patients started with ataluren and then continued with placebo and others did it the other way around (a placebo-controlled crossover study). Ataluren is a molecule that helps the cell skip premature stop codons caused by non-sense mutations, so all of these patients had non-sense mutations. Ataluren did not show an effect in reducing seizure frequency or improving cognitive, motor, or behavioral function or quality of life in subjects with either Dravet Syndrome or CDKL5 deficiency due to nonsense mutations. This randomized, placebo-controlled trial was limited by a small sample size and a treatment-phase of 12 weeks, which may be too short to identify a disease-modifying effect. .

2.     But fenfluramine does have efficacy in CDD! Fenfluramine is an anti-epileptic drug that works through the serotonin system and that has been approved in the US and Europe for the treatment of Dravet syndrome, another complex neurological condition. Orrin is running a 10-patient study with fenfluramine in CDD at NYU, and was able to present the results from the first 6 patients. And the results are very good, with a 90% reduction in generalized tonic-clonic seizures that are the strongest seizure type, and also efficacy in other seizure types. He still has 4 slots open for patients with CDD ages 2 to 18, and encouraged the company developing fenfluramine to consider CDD for a phase 3 trial.

And the phase 2 study with fenfluramine was only the first out of THREE positive clinical trials in CDD that were presented that afternoon. Dr Julia Tsai from Ovid Therapeutics presented positive data with soticlestat in CDD, where a large majority of the parents reported positive improvements in different disease symptoms and where seizure improvement (the primary endpoint) continued increasing over time. Soticlestat acts through a completely novel mechanism of action that includes indirect glutamate modulation and other potential therapeutic benefits, so these different therapies are good candidates for being used in combination in the future if they get approved. Ovid also run other phase 2 studies with this drug in other genetic syndromes with epilepsy, and has not yet announced how many will be progressing to phase 3 trials or when.

And taking about phase 3 trials, the next presentation was by Alex Aimetti from Marinus who walked us through the positive results of the phase 3 trial with ganaxolone, the very first pivotal trial ever run in CDD, and that recently announced it had met its primary endpoint. The Marinus team explained how until recently the regulators were not even sure if CDD was a separate disorder, and it was thought that there were so few patients in the world that a phase 3 trial could only have 50 patients, but a couple of years later they have the Orphan Drug Designation by both the EMA and the FDA, the Rare Pediatric Designation by FDA, and a 100-patient positive Phase 3 trial in CDD. Ganaxolone led to a significant reduction in major motor seizure frequency and was well tolerated, so the company will apply for marketing authorization and plans to initiate an Expanded Access Program first in the US, that might potentially will get to additional territories later on. Marinus was awarded the 2020 CDKL5 Forum Award for the Company making a difference in the clinical space, and the company has played a unique role at helping de-risk clinical development in CDD and bringing visibility to the disorder.


I want to stress again what we just saw at the Forum: three positive clinical trials in CDD. One pivotal trial, the first ever, which was positive and will hopefully lead to the first drug approved for treating CDD, and two phase 2 studies each of which looks good enough to lead to a new phase 3 study for CDD. I don’t believe there are many rare diseases that get that type of pipeline progression in one year.


In the last years we have been talking much about getting the field ready for more complex studies, and by that I mean studies that will look at symptoms beyond seizures. This is particularly critical for the gene therapies. A small molecule can get away with measuring seizures and getting approved for “the treatment of seizures in CDD” even if it has efficacy beyond that symptom, but when treatments are more invasive they need to demonstrate that they have broader benefit.

In preparation for that, we had launched a series of programs including obtaining a new ICD-10-CM diagnostic code for CDD and co-hosting a PFDD meeting with FDA together with IFCR, to help identify the main symptoms that impact patients with CDD. The next step is to translate those symptoms into “clinical outcome measures” which are clinical scales that assess either one main symptom or a collection of symptoms, and that are used in trials to quantify the efficacy of treatments.

IFCR recently announced the award of an NIH U01 grant to a network of CDKL5 Clinical Centers of Excellencefor the characterization over the next 5 years of a collection of clinical outcome measures that they are developing specifically for CDD by running observational studies through their network.

And the Loulou Foundation announced at the CDKL5 Forum the immediate launch of a large international observational study, in the US and Europe, in collaboration with several bio-pharma companies, to determine the feasibility of using in CDD trials a collection of clinical outcome measures that haves already been used successfully in advanced clinical trials for related disorders. The industry partners hope to be able to apply the learnings from this study to their clinical trials in the near future.

This means that the CDD community, both clinicians and patients, will soon start hearing more about the concept of observational studies and the central role that they play in getting the field ready for more complex studies.


Before concluding, I would like to highlight a couple of additional observations beyond these scientific presentations.

One is how much the idea of how rare CDD is has changed. Not so long ago it was through that we only had a couple of hundreds of patients in the world, and now we know it is one of the most common genetic causes of epilepsy. In their latest corporate presentation, Marinus now estimates about 12,500 children in the US and EU, and the actual numbers could be higher with an estimated incidence of 1 in 42,000 births.

This change in how we see CDD became particularly clear when during the Forum, the speaker from Ultragenyx, a company that was started to treat ultra-rare diseases, spoke about “serving this large patient population” in reference to CDD. And the International CDKL5 Alliance already includes 20 members, also showing the growth of the patient community and their willingness to work closer together.

And the second one is the wonderful keynote speakers that we had in the Forum. On day 1, Antonino Caridi, Ariadna’s grandfather and one of the pillars of the CDD patient community, told us about how life some time takes a turn and places you at war against a monster, and how he found in the CDKL5 Alliance a real alliance beyond just words. He spoke about how we all play a role in the movie about CDD, including the families, and encouraged all “actors” to make the best in the roles they are playing.

On day 2, Yann Le Cam, Founder of EURORDIS, told us about his own journey as a father of a now adult child with a rare disease, and the need to think global and be strategic. In his words: “think about the ecosystem, and not just your organization”. Antonino and Yann both echoed the need to respect the challenge (the monster) ahead, while creating the focus and determination to bring forward a change which requires thinking and acting globally.

And on day 3, Jeremy Levin, CEO of Ovid Therapeutics and Chairman of the Board at the Biotechnology Innovation Organization (BIO), provided us with his unique view, from his global pharma position, of what is happening in biomedical research in 2020 and how the CDD field is doing. He acknowledged the strangeness and difficulties of 2020 for everyone due to COVID-19, and the enormous challenge and disruption that it has brought to the pharma industry. Although we have seen an immediate slowdown of clinical trials, he envisions that many of the changes in trial design and regulatory policies that have been put in place to speed up the development of COVID-19 therapeutic and vaccines will also speed rare disease therapies from now on, including adopting telemedicine. These great changes are not going away, he said, they are here for the future. Jeremy also praised the CDD community for helping Marinus and Ovid deliver late-stage trial results in the middle of the pandemic.

To close, I like to end the Forum updates by reviewing the goals that the Loulou Foundation set when it started, which are to get treatments (to reach trials) by 2020 and cures by 2025. Now we know that by 2020 we’ve had not one trial, but several trials leading to three positive clinical trials including a 100-patient pivotal trial. And based on what we are seeing in the preclinical space, I believe that by 2025, we will have multiple cures (gene therapies and similar) in advanced clinical trials. As Orrin said referring to the progresses during the last year, “what we have seen these 3 days is breathtaking”. We just need five more years like this one.

I hope you enjoyed this summary! let me know your thoughts in the comments. Here are my articles on the 2018 and 2019 Forum meetings.

Ana Mingorance, PhD

Disclaimer: These are my own impressions from the presentations that I was most interested in as a scientist and patient advocate, and not an official text about the Forum by the Loulou Foundation.  I write these texts with the parents of individuals with CDD in mind, so excuse also my lack of technical accuracy in parts 😉