En Español - Fármacos en camino para el síndrome de Dravet

¿Sabíais que hay 14 terapias en desarrollo para tratar el síndrome de Dravet? ¿y que varias de las terapias no buscan solo controlar las crisis epilépticas sino corregir el defecto genético que causa la enfermedad?

Los avances en torno al tratamiento del síndrome de Dravet en los últimos años han seguido pasos agigantados. En los últimos 5 años hemos experimentado una explosión en el número de programas en desarrollo para tratar la enfermedad: de tener solo Diacomit y nada más a tener Diacomit y 14 más en desarrollo.

Por segundo año publicamos una revisión de los fármacos en desarrollo para tratar el síndrome de Dravet (ver entrada).

El texto original va dirigido a empresas interesadas en el sector o que ya están desarrollando fármacos, así como otros profesionales relacionados con la industria farmacéutica. Este año hemos querido ofrecer también un resumen en Español dirigido a familias, con el texto no solo traducido sino también ajustado a los intereses de aquellos que tienen un hijo/a con síndrome de Dravet y su entorno. Hemos incluido texto y una figura adicional dirigido a esta audiencia, y eliminado secciones que no son tan relevantes. 

El texto describe todos los fármacos en desarrollo para tratar el síndrome de Dravet a fecha de julio de 2018 y plantea las direcciones futuras.  

Esta adaptación de cómo están todos los fármacos en desarrollo para el síndrome de Dravet la dedicamos a los guerreros de la Fundación Síndrome de Dravet, que han contribuido de manera directa a muchos de los logros que resumimos en la revisión.

Un sueño... una meta.

DRAVET SYNDROME DRUG DEVELOPMENT PIPELINE REVIEW 2018

It has been a year since we released the 2017 Dravet Syndrome Pipeline and Opportunities Review, a market research publication that provides an overview of the global therapeutic landscape of Dravet syndrome.

There have been many developments in the last year, including the approval by the FDA of Epidiolex (cannabidiol) by GW Pharmaceuticals for the treatment of Dravet syndrome, the announcement of positive data from two Phase III clinical trials with ZX008 from Zogenix, and the arrival of a new company pursuing a disease-modifying antisense-based approach (Stoke Therapeutics). 

The 2018 Dravet Syndrome Pipeline and Opportunities Review provides a review and analysis of 14 drug candidates in development for the treatment of Dravet syndrome, including 9 products that have received orphan drug designations.

The report includes the most recent updates on Epidiolex (cannabidiol) from GW Pharmaceuticals; ZX008 (fenfluramine) from Zogenix; Translarna (ataluren) from PTC Therapeutics; OV935 (TAK-935) from Ovid Therapeutics and Takeda; EPX-100, EPX-200 and EPX-300 from Epygenix Therapeutics; ZYN002 (transdermal cannabidiol) from Zynerba Pharmaceuticals, BIS-001 (huperzine) from Biscayne Neurotherapeutics; PRAX-330 from Praxis Precision Medicines; SAGE-324 from Sage Therapeutics; OPK88001 from OPKO Health; XEN901 from Xenon Pharmaceuticals; and an ASO program from Stoke Therapeutics.

The 2018 Dravet Syndrome Pipeline and Opportunities Review also includes an analysis of the competitive landscape and evaluates current and future opportunities of the Dravet syndrome market. 

The report is now available in this site.

Ana Mingorance PhD

What you should know about patient data after May 2018

When scientists don’t fight over funding they fight over data.

Having large amounts of data that competitors can’t access means having the upper hand when it comes to publishing and getting funding. Corporations operate the same way. Science is, after all, a knowledge economy, where data is knowledge and knowledge is power.

But in a world where data is seen as an asset, patient rights when it comes to accessing their own data and deciding what to do with it can be compromised. And they are, in a regular basis.

I am a vocal advocate for empowering patients (and individuals in general) by giving them access to their personal data files so that they can know what these contain and choose whom to share it with. I also know that not everybody feels the same way. I have had the opportunity to address data scientists twice, first in 2015 and more recently at a personalized medicine meeting in 2017, and both times I managed to divide the audience and offend some data scientists and clinicians. 

The good news is that this debate is becoming obsolete in May 25th 2018, when a new regulation protecting patients right to access their data will enter in force.

The surprising news is that the solution didn’t come from a medical organization but from the EU Parliament, in the form of a General Data Protection Regulation. The key word here is “general”, because the new regulation was not written with patients or even with medical data in mind. It applies to anyone who collects other people’s data. From Google storing your preferences, to Facebook knowing your friends, to your aunt having a mailing list for her cooking blog. And patients are, surprisingly, a key collateral beneficiary of this regulation.

Let me review the current problems that patients face to access their own data and why the General Data Protection Regulation is so important.

CURRENT PROBLEMS AROUND PATIENT DATA

Before 1973 your doctor didn’t need to tell you what he thought was your diagnose, or to ask you to consent to the treatment he was prescribing. This would be unthinkable in today’s world, but it was grounded on the observation that the doctor, and not the patient, is the most knowledgeable person in the room when it comes to medicine. While this is generally true, it is also paternalistic and condescending, and in 1973 the American Hospital Association adopted the Patient’s Bill of Rights to put an end to this practice. After the Bill, patients were entitled to receive information about their disease and to make decisions about treatments (except in emergencies), among other important rights. Similar regulations were then adopted worldwide.

When I give presentations on this topic I like to use the slide below to illustrate the problem of scientists and healthcare providers not supporting the transfer of patient data from a study to another. It shows the example of a patient having to repeatedly give the same personal and medical information over and over to their hospital, a patient registry for their disease, to a couple of academic studies, and probably also to a clinical trial where the patient participates and that is also generating a separate patient registry. The burden on that individual patient is ridiculous, and this is not a made up example. I know multiple cases of patients with rare diseases where they end up interacting with such a large number of data holders in an attempt to get the best medical care and to help advance the scientific understanding of their disease. 

There are two separate problems here:

1- Data holders refuse to share the patient data with other data holders.

The main argument is often that the informed consent didn’t consider sharing data with third parties, but in my experience even if the patient (or caregiver) offers to sign a new informed consent to support that transfer the original data holder refuses. As I see it they are not thinking on the patient’s best interest but looking at the data instead as an asset that they own.

2- They also often refuse to share the patient data with the patient himself.

If patients had access to their entire medical history and relevant studies in a way that can be easily transferred to other data holders, such as new registries and studies, the patient would choose who has it and who doesn’t. But they don’t have that choice when they don’t have their data files. The expressed reasons to not grant the patient access to his or her own data files fall often into two categories. One is the technical one, like in the real example: “we never designed our registry with a output format that could be useful to you”.  The second is the same one that led to the 1973 Patient’s Bill of Rights, as in another real example: “no we can’t give you your whole exome sequence because you don’t understand genetics, interpreting sequences is hard and confusing, and you might make the wrong decisions based on uninterpretable data”.

The cry of patients for accessing their own genetic sequence data files is so loud that in 2015 the European Society of Human Genetics issued a press release with the following headline: “People want access to their own genomic data, even when uninterpretable”.

It wasn’t about patients having the knowledge to read a raw whole exome sequence file, but about being entitled to get a copy of such file.

I personally thought it would have to be an organization like the European Society of Human Genetics or the American Hospital Association who would issue a new recommendation (or hopefully something more enforceable) to protect patients right to access their own medical data files. Surprisingly the regulation that would come to protect these patients rights was simply a new general regulation for personal data protection that was never developed thinking specifically of patients.

WHAT THE GDPR ACHIEVES

The General Data Protection Regulation (GDPR) was approved by the EU Parliament in 2016 and will enter in force in May this year. It doesn’t matter where the organization that collects personal data of data subjects (including medical data) is located. What matters is that if the data subject resides in the EU, the organization needs to be compliant or face heavy fines. Unless organizations are planning to follow separate Standard Operating Procedures for EU and non-EU residents, most will simply have to be compliant with the GDPR and the new regulation will also protect non-EU patients.

My favorite “data subject rights” are the following:

1- Right to Access. 

Under the GDPR the data holder will have to provide patients with a copy of their personal data, free of charge and in a machine-readable format. It won’t be ok to argue that the database wasn’t built for export functions or to be passive-aggressive and give the patient only a small summary in a PDF. The patients, and all data subjects in general, are now empowered to have a copy of their data files, to know how much data the data holder has collected from them, and to know what they are using it for.

2- Right to be Forgotten.

Under the GDPR the data holder can withdraw consent and request their data to be removed from the data holder files and to not be user or disseminated. If you are a patient that gave data to a registry on the understanding that they would use it to further research in your disease, and you later become aware that they are refusing to share data with other research groups, you can now approach the registry and request your data to be removed.

3- Data Portability.

Under the GDPR the patient can request the data holder to provide them with a copy of their files in a machine-readable and usable format not only for their own records, but also to transfer them to another data holder. In my real example of a rare disease patient that has his data in multiple registries and studies, the patient can now get usable files from his hospital including proper gene sequencing files and then share this file with the other registries and studies. They won’t have to give the same data, and be subject to the same procedures, over and over as it happens nowadays.

AFTER MAY 2018

After May 2018 I will have to change my PowerPoint presentations. Patients will have the right to request access to their data files. They will have the right to withdraw their data from a database that is not being used in the way that the patient through it would operate. And the patient has the right to obtain these files generated by a particular data holder, for example a gene testing lab, and get the usable file and share it with as many studies and registries as the patient wants.

In 2015 I offended some data scientists at a big data meeting with the following message:

“Health data must be shared
In particular with the patient (even if they don’t understand it)
Because it is their data
And because they will share it”

I wanted to shift the conversation on giving patients’ access to their own data from “the patients don’t understand the data” to “they need to have access so that they are able to share their data”. I guess we don’t need to debate this anymore. After May 2018 we just need to say that it is the new law!

Ana Mingorance PhD

Big gene, small virus

We wrapped up 2017 with the news of the first gene therapy approved in the US to treat a genetic disease. It was Luxturna, approved for treating vision loss in patients carrying mutations in a particular gene that causes retinal dystrophy. The videos of vision improvement in patients treated with Luxturna that Spark Therapeutics has shown are breathtaking, and I trust gene therapy will one day be the go-to treatment for most genetic diseases.

There are in fact many genetic diseases! From the estimated 6000 to 8000 rare diseases, the large majority is thought to be also caused by gene mutations. And the most common consequence of those mutations is loss of function of the gene, so the approach that Luxturna used to deliver a backup healthy copy of the gene to the affected cells would be the ideal one.

But here is the catch: Luxturna uses a small virus, called Adeno-Associated Virus or AAV, to deliver the therapeutic gene to the affected cells. AAV is the gold-standard when it comes to gene therapies in development, with many advantages over other virus that are less infective (don’t get into as many cells) or might trigger an immune response. But AAV can only transport small genes, and not all diseases have mutations in small genes.

In a recent Dravet syndrome families meeting, a gene therapy expert explained to the parents that that scientists have been very good at developing cars able to transport a healthy gene copy to the patient, but that their particular disease will need a bus. I like the metaphor very much.

Many diseases will need virus larger than AAV to be able to have a gene therapy. We need a bus.

CAN WE MAKE GENES SHORTER?

In some diseases that have “big genes” it might be possible to develop shorter versions of the gene that could fit into an AAV and retain sufficient functionality to have therapeutic benefit. The main example that comes to mind is the mini-dystrophin gene, which is currently in clinical trials (here and here). This approach is only possible because dystrophin is a large scaffold protein that needs to attach to multiple partners and can be reduced to only those main protein domains retaining functionality.

Dravet syndrome is caused by mutations in the SCN1A gene, which produces an ion channel that needs to cross the plasma membrane 24 times. Such a large protein needs to go in an out the membrane the right number of times and to have the right loops inside and outside to be able to form the correct channel structure and functionality. There is no spare protein bit that we could chop out of the gene to reduce it to a size where it could fit into an AAV. We need a bus.

LOOKING FOR A BUS

Dravet syndrome is not the only disease caused by mutations in a gene too large to exploit the great advances in using AAV as therapeutic vehicles for gene therapy. The entire field of gene therapy needs to find the best solution for the next-generation therapies that go beyond what AAV can give us.

Within Dravet syndrome, these next-generation therapies are being led not by companies but by academic groups with the support of patient organizations:

||   Dravet Canada and the US Dravet Syndrome Foundation are supporting a gene therapy project at Toronto University that will use AAV to deliver compensatory genes (not SCN1A) for the treatment of Dravet syndrome. Because the AAV technology is the most advanced one this approach offers the fastest gene therapy path to the clinic, but it doesn’t represent the ultimate ideal treatment that would involve the delivery of a healthy copy of the SCN1A gene to the affected neurons.

||   One of the projects aiming to develop that ideal treatment is led by Simon Waddington and Rajvinder Karda from UCL. This team is working on one type of “bus”, Lentivirus, that has enough capacity to carry the SCN1A gene and become a treatment for Dravet syndrome. They have received the support from Dravet Syndrome UK and share updates with other interested patient groups.

||   And a larger collaboration was recently awarded a European grant to also look for a different type of bus. This time scientists from Spain, France and Israel are trying to develop a gene therapy for Dravet syndrome using Adenovirus, another type of high-capacity virus. They are collaborating with Dravet Syndrome Foundation Spain and the Dravet Syndrome European Federation, and have also developed a close relationship with patient groups.

If everything goes well, one or more of these programs will "cure" a mouse with Dravet syndrome using one of these virus within the next 2 to 3 years. The next step are clinical trials. This all used to look like a very distant future, but with the approval of Luxturna it has now become a reality. Soon someone will get a gene therapy using a big virus approved, and that day Dravet and many other syndromes caused by mutated large genes will have found a bus.

Ana Mingorance PhD

Looking ahead: Dravet syndrome news during 2018

I was talking yesterday with some friends that have children with Dravet syndrome, and they asked me about what news we can expect in 2018 from those programs that are in clinical trials for Dravet syndrome. 

For them, and for anyone interested, here is what we can expect in 2018 from the clinical programs from GW Pharmaceuticals, Zogenix, Ovid Therapeutics and Takeda, PTC Pharma and NYU, and OPKO Health, based on what these companies have communicated.

First quarter 2018

No big news expected this quarter around Dravet syndrome unless OPKO Health announces the initiation of the clinical trials with their antisense oligonucleotide OPK88001 [4]. This product was expected to start pilot trials in the second half of 2017 or first half of 2018. OPK88001 is the first disease-modifying treatment to be developed for Dravet syndrome and a potential game-changer.

 

Second quarter 2018

This is a very exciting quarter for Dravet syndrome. FDA has June 27 as the deadline to make a decision on the approval for GW Pharma Epidiolex to treat Dravet and Lennox-Gastaut syndromes [1]. Around the same time, Zogenix will announce the results of the second large Phase 3 clinical trial in Dravet syndrome with fenfluramine [2]. If the data are as strong as the first clinical trial the Dravet community will have fantastic news for their International Dravet Syndrome Awareness day (June 23rd).

Around the same time we expect also the results of the pilot study of ataluren in Dravet syndrome and CDKL5 deficiency disorder that is taking place at NYU [3]. This is an investigator-initiated trial, not a pivotal trial, but the placebo-controlled double-blind design makes it a very important trial to evaluate the potential efficacy of ataluren in children with nonsense mutations in SCN1A (Dravet syndrome) and CDKL5.

 

Third and fourth quarter 2018

The third quarter arrives with the required DEA rescheduling of cannabidiol (90 days after the FDA approval), followed by a potential launch in the last quarter. The epilepsy community meets every year during the first week for December for the American Epilepsy Society meeting and if there are no bad surprises Epidiolex should be the star of the 2018 meeting with an imminent launch. 

Around the same time, Zogenix will file an NDA for the treatment of Dravet syndrome with ZX008, which a potential launch one year behind Epidiolex. Zogenix also has an advanced clinical trial program for Lennox-Gastaut Syndrome, with a Phase 3 trial ongoing based on a positive Phase 2 dose-finding study. 

We also expect to hear before the end of 2018 about the results of the second large Phase 3 clinical trial of Epidiolex in Dravet syndrome and the Phase1b/2a clinical trial of OV935/TAK935 in a basket trial including patients with Dravet syndrome [4].

---

In summary: we expect in 2018 the first approval of a treatment for Dravet syndrome in the US, the results of clinical trials with three new therapeutics (ZX008, ataluren and OV935/TAK935), and the initiation of the first clinical trial ever done with a disease-modifying therapy designed to treat Dravet syndrome (OPK88001).

2018 is going to be a good year.
 

Ana Mingorance PhD

Sources:
[1] GW Investor Presentation, January 2018
[2] Zogenix Investor Presentation, January 2018
[3] Dr Devinsky at CDKL5 Forum, December 2017
[4] OPKO health press release August 8 2017
[5] Ovid Therapeutics Corporate Presentation, January 2018
Announcements within the same quarter ordered by drug name (alphabetic).
 

Top 5 insights from the American Epilepsy Society meeting

Every year the American Epilepsy Society (AES) meeting gets larger. This year, over 5,500 people got together in DC to discuss the latest information about epilepsy care and the development of new treatments for epilepsy.

I’m a scientist looking for a cure for a rare disease called Dravet syndrome. I first attended this conference as a pharma scientist working on new epilepsy therapeutics, later as the head of research of a Dravet syndrome patient organization, and currently as an independent consultant specialized on rare epilepsy syndromes. Because of my background, I look at this conference from the perspective of a drug hunter, a patient advocate and an industry analyst, and I must say that from all of these perspectives the 2017 edition of the AES meeting was an exceptionally interesting one.

Here is the list of what I found the most interesting at the AES meeting:

1- There is a change in epilepsy drug development towards orphan drugs. 

I wrote earlier this year about Everolimus and how orphan drugs are reviving the field of epilepsy. This was very visible at the AES meeting as well. Two of the likely next approvals in epilepsy, based on their positive Phase 3 trial results, are targeting rare forms of epilepsy. These two drugs, cannabidiol (Epidiolex, GW Pharma/Greenwich Biosciences) and fenfluramine (ZX008, Zogenix), were the focus of much excitement and interest during the conference. At the same time, I couldn’t help but miss some of the largest companies that used to have much floor space at the exhibition hall in former AES meetings, like Pfizer and GSK. The pharmaceutical giants are leaving, and smaller companies with orphan drugs are filling in their space. Some loyals like UCB, Eisai and Sunovion are still staying, but times are certainly changing in epilepsy drug development.

 

2- Pharmacoresistant epilepsy is not forever.

We are all used to hearing that despite having many anti-epileptic medications in the market, about 30% of people with epilepsy continue to have uncontrolled seizures. This includes the large majority of the genetic epilepsy syndromes, although it goes well beyond these rare diseases. Breaking into that 30% is the Holy Grail of epilepsy drug development, and the small company Zogenix managed to pull an Indiana Jones move this year with their drug ZX008. In their recent Phase 3 clinical trial in Dravet syndrome, 25% of the patients randomized to the highest dose of fenfluramine (ZX008) had zero or 1 seizure during the 3 months of treatment. That would be 4 or less convulsive seizures in a year, down from a baseline of approximately 40 convulsive seizures per month, or about 500 per year. The median percent of seizure reduction at that dose was an impressive 72.4% versus 17.4% with placebo. The sessions organized by Zogenix during the AES meeting were among the best attended ones, and their results have given us hope in the orphan epilepsy community to dream with seizure freedom, a goal previously though to be unrealistic. Pharmacoresistant epilepsy, now we know, is not forever.

 

3- There are too many genetic epilepsy syndromes to not use gene panels as soon as possible.

Diagnosing correctly a child that has refractory epilepsy or epilepsy combined with neurodevelopmental problems is not easy, because there are many syndromes that look very similar or overlap substantially when it comes to clinical criteria. It is just too complicated to try to diagnose any of these diseases based uniquely in their clinical characteristics, so epilepsy specialists should consider epilepsy gene panels as a necessary and urgent test for all cases of childhood epilepsy as soon as they first see these patients. Walking around the patient advocacy area at the AES exhibition hall and trying to understand the characteristics of each syndrome was overwhelming: Dravet, Lennox-Gastaut, Tuberous Sclerosis Complex, SCN2A, PCDH19, CDKL5, STXBP1, SYNGAP1, GLUT1, KCNQ2, Batten disease. These are just the tip of the iceberg, represented at the conference by brave parents that know it is important to get their disease name in front of the specialists. And together they send a strong message to epilepsy specialists: there are just too many syndromes to not use gene panels as soon as possible.

 

4- The arrival of basket trials to epilepsy.

Just as it is important to be aware that epilepsy includes many individual rare syndromes, it is also important to figure out how we are going to develop therapies for all of these syndromes. A year ago at the AES meeting no one had publicly heard about the experimental drug TAK-935. It was already 2017 when Takeda and Ovid Therapeutics announced that they were partnering around this program, and that they intended to develop it for a variety of epilepsy indications. This year at AES there were multiple presentations on TAK-935 and for me the most interesting aspect is the clinical trial design: a Phase 2 basket trial combining patients with three different orphan epilepsy syndromes. In the epilepsy field we had already seen this type of basket trial in investigator-initiated studies, such as the first open-label studies with Epidiolex in the US that served as the basis for the single-syndrome placebo-controlled trials that followed, but not in a company-sponsored placebo-controlled trial. I find the basket trial approach a fantastic innovation for the epilepsy field, and I already developed these thoughts it in more detail in a previous article about genes versus syndromes.

 

5- Beginning to understand the dark side of epilepsy: SUDEP.

Sudden death in epilepsy (SUDEP) is a scary topic. Doctors don’t want to talk about it, in particular because we don’t understand it enough to be able to do something about it, and patients and families would also prefer to not have to hear about. Dravet syndrome has a particularly high incidence of SUDEP, so it is a field that I follow closely. Fortunately there is much research and growing awareness on SUDEP, and we could see at the AES meeting very valuable research that gets us closer to understanding how SUDEP happens. Some time ago it was thought to be of cardiac origin, but nowadays we know that SUDEP starts in the brainstem, and that it is essentially a seizure during sleep that originates or spreads to the brainstem area causing a shutdown of the neurons that control breathing, followed by respiratory arrest and cardiac arrest.

This year at AES we saw research using a mouse model of Dravet syndrome that showed that the brainstem circuits that regulate breathing are dysfunctional in this syndrome, and could trigger hypoventilation when the response should be hyperventilation to increase oxygen saturation. We also saw clinical research in patients with Dravet syndrome that showed that there is also an increased parasympathetic tone during sleep leading to very low heart rate. The extraordinary practical value of these findings is that patients could wear sensors that would produce an alert when oxygen saturation and heart rate drop below regular seizure thresholds and alert a caregiver trained in CPR techniques, which are known to be at times efficacious when practiced early in cases of SUDEP. 

Overall, I felt that this year AES meeting was very positive, showing a great progression of the field that now moves towards orphan indications (with new drugs and clinical trial designs), where patient organizations gain relevance (also a characteristic of the orphan drug field), and where we start having new drugs able to break the barrier of pharmacoresistance and the understanding needed to detect, and hopefully prevent, the big problem that is SUDEP.

For those of you that also attended the AES meeting, I would love hearing about those trends or progresses that you felt were the most interesting ones!

Ana Mingorance, PhD