Genes vs syndromes at the International Epilepsy Congress in Barcelona

THE DEBATE

Earlier this month, the epilepsy community gathered in Barcelona for the 32nd International Epilepsy Congress. There were three interconnected topics that dominated much of the program: genetics of epilepsy, rare epilepsy syndromes and personalized medicine. The other large topic that dominated the agenda was the new epilepsy and seizure classification by the ILAE, and it felt like two separate conferences.

While most scientists are looking inside the cell, looking for genetic changes, many practicing physicians are looking at what they can see, and creating new nomenclatures to define seizure types. And from the patient side this makes a large difference, because the same child with an SCN2A mutation might be diagnosed by a specialist as having SCN2A encephalopathy, and as having Dravet syndrome by another physician based on clinical symptoms.

There has been a trend in the recent years towards creating new syndromes that group patients by the gene that they have affected when their epilepsy is found to have a genetic cause. Some examples of this are CDKL5 deficiency disorder or STXBP1 encephalopathy, which until recently would have be classified as atypical Rett syndrome and Lennox-Gastaut or Ohtahara syndrome respectively, at least in most cases. And that is the catch, that the same gene mutation can lead to different phenotypes in different patients and actually manifest itself as a complete different syndrome.

We see this mismatch between gene and syndrome every day. For example, the nigh before I few to the congress a mother had contacted asking how it was possible that her daughter with Dravet syndrome had exactly the same gene mutation that another patient diagnosed with Ohtahara syndrome had. Then at the congress, Professor Jackie French from NYU presented the case of a family with an inherited mutation in SCN1A that included individuals with mild forms of epilepsies, for example just febrile seizures, but also one child with the much more severe Dravet syndrome. As a physician, she would adjust their medication to their seizure type and treat more aggressively the individual with Dravet syndrome, because their diseases are indeed different ones.

So what is the best classification approach? Should we talk about syndromes based on the gene that causes them or should we talk about them (and treat them) based on the clinical characteristics that they display?

This debate is not just about semantics, it affects a lot how well we develop new medicines and how many patients will benefit from them. So it is important that we get it right.

What follows is my personal view of which syndrome classification is best, when to use it, and what regulatory changes are needed in order to get more medicines to all patients with rare genetic epilepsy syndromes.

OVERLAP BETWEEN SYNDROMES AND GENES

The way I see the debate between genetic and symptom-base syndrome classification is that they are not exclusive; in fact, they form a matrix where many of the epilepsy genes can produce phenotypes that fit into many of the classical (phenotypic) syndrome boxes.

For illustration purposes, I’ve selected a handful of genes and syndromes and created the matrix below. While not all of these genes are found in all of these syndromes, what we have to remember is that many of the epilepsy genes are present across a large number of epilepsy syndromes.

With this in mind, what would be the correct diagnosis for the child of the previous story that had a diagnosis of Ohtahara syndrome before performing genetic testing but was later found to have an SCN1A mutation (typical of Dravet syndrome)? Should the genetic finding change the diagnosis to Dravet syndrome?

I would argue that both a genetic and a clinical diagnosis are needed, so the best diagnosis for this child, if his clinical symptoms are indeed a better match for Ohtahara than for Dravet syndrome, would be “Ohtahara syndrome caused by SCN1A deficiency”. And the other child in the same story would have “Dravet syndrome caused by SCN1A deficiency”. Except for a few truly monogenic syndromes, most epilepsy syndromes have many possible genetic (and sometimes non-genetic) etiologies, and most epilepsy genes produce multiple phenotypes, so I don’t need we need to prioritize the symptomatic classification over the genetic one or vice versa; both are useful and both are necessary. Instead, we should point to the right box in the matrix when diagnosing a patient, which provides both sets of genetic and clinical data.

My purpose when creating this visual matrix is not to break down already rare syndromes into even smaller diseases. On the contrary, the purpose of this exercise is to make the syndrome classification more flexible, so that we can cluster syndromes, and create more flexible indications for developing new drugs and for treating more patients.

REGULATORY IMPLICATIONS

For as long as we didn’t have a good understanding of the genetics behind epilepsy, we have been perfectly OK with symptomatic epilepsy classifications. But the progresses in genetics in the recent decade, and the appearance of many new “genetic epilepsy syndromes”, has opened the door to the development of new drugs that specifically target those genetic defects, creating a new regulatory landscape where our former classification of syndromes based on symptomatology falls short.

The patient groups are already confortable using the genetic syndrome classification, the conference rooms talk more and more about personalized medicine and genetic syndrome classification, and companies pipelines start getting populated with programs that specifically target those abnormal genes and proteins that cause these epilepsies. The next step is to start using the genetic syndrome classification as a suitable drug indication in the drug development process as well.

Let’s go back again to the genes versus (phenotypic) syndromes matrix and see the different therapeutic implications of using one classification versus another.

The first example (scenario A) corresponds to the current preferred way of selecting drug indications.  There are 8 different products that have received the Orphan Drug Designation to treat Dravet syndrome. This makes sense because Dravet syndrome has been recognized as a separate clinical syndrome since 1978, way before the genetic mutations that give rise to this phenotype were uncovered. It also makes sense because all of the drugs approved or in clinical trial for Dravet syndrome are symptomatic, meaning that they are not treating any genetic problem.

In short: if the drug treats a particular cluster of symptoms that corresponds to a syndrome, then the best indication for that drug is indeed the classical (phenotypic) syndrome.

But things change when a drug in development specifically targets a disease gene, and this is what is happening right now with a program by OPKO Health designed to increase SCN1A gene expression levels. This product has received the Orphan Drug Designation by the FDA to treat “Dravet syndrome”, because about 80% of patients with Dravet syndrome have mutations or deletions in SCN1A, but would have been more appropriate to match the gene-targeting therapeutic with a genetic patient classification, and target “SCN1A deficiency” as the product indication, like in the scenario B.

If we stick to the classical (phenotypic) syndrome classification for the programs in development that target the gene or protein that are defective in patients, we will be unnecessarily limiting the number of patients that will benefit from that drug. It is clear that in the case of the OPKO program, the indication cannot be simply “Dravet syndrome”, but a subset of patients with Dravet syndrome caused by SCN1A deficiency. But how about the people that having the same SCN1A deficiency have received a different clinical diagnosis based on their symptoms? With the current indication, those people will not have access to such treatment because it will be off-label.

The specific program that OPKO is developing is oligonucleotide-based and therefore very invasive, requiring intrathecal administration, so it is not likely to be used in people with SCN1A mutations and milder phenotypes. But there are small molecule approaches also in development for SCN1A deficiency, and these should not have an indication restricted to a subset of patients with Dravet syndrome. The same will happen with drugs that modulate SCN2A, a related channel that produces multiple phenotypes when mutated and leads to multiple diagnosis. Asking the drug developer to seek approval for only a subset of patients in a rare disease would artificially restrict the number of patients that would benefit from that drug.

This is why we need to get confortable with drugs being developed for a genetic indication that overlaps but doesn’t match the classical (phenotypic) syndrome classification. At the other side of the approval line, physicians must also get confortable with patients having both a genetic and a symptomatic diagnosis so that they can receive both types of medications.

I do believe that indications based on a gene defect (gain-of-function or loss-of-function), when the drug treats the gene or protein that is altered in those patients, will be acceptable and soon become common. What I am more worried about is the need of a scenario C (see next) and the mismatch between the clinical practice and the regulatory pathway.

ADDING COMPLEXITY – SCENARIO C AND MULTI-SYNDROME INDICATIONS

There are drugs that don’t treat the disease (gene or protein) but the symptoms, in the case of epilepsy they treat the seizures, yet they get approved for treating a particular syndrome only. Staying on the example of Dravet syndrome, this would be the case of stiripentol (Diacomit), which is only approved for treating Dravet syndrome but it is simply a GABA-ergic modulator that has no biological reason to work only – or even preferentially – in this syndrome. It is basically a strategic corporate decision to focus on a given orphan indication. Another example is ganaxolone, also a GABA-ergic modulator, that has received Orphan Drug Designations for PCDH19 epilepsy and CDKL5 disorder and is in development for these indications, while there is no obvious biological reason to target those syndromes and no others.

I understand the appeal of orphan indications with limited competition, and how the incentives that the orphan designation brings make these drugs possible so that patients ultimately benefit from them. It is possible that without these incentives these drug developers would have never had the resources to bring forward their drugs to a broader (non-orphan) market. But things start changing when the same developer goes after many orphan epilepsies with a broad symptomatic drug, and we are seeing this right now with Epidiolex (cannabidiol, by GW Pharmaceuticals).

Let me first set one thing straight, I don’t think that GW Pharma is abusing the orphan regulatory route with Epidiolex, they simply have no choice. If they want to develop their product for a large number of patients with orphan refractory epilepsy syndromes, which happen to be separate indications under the traditional classification, they must develop a separate clinical development program for each syndrome. And because they have a broad-spectrum drug with the potential to treat many types of refractory epilepsy syndromes they are running clinical trials for Lennox-Gastaut syndrome, Dravet syndrome, Tuberous Sclerosis Complex and West syndrome. That’s four separate indications.

I wonder how many syndromes should a drug be approved for before it becomes clear that it should have a broader indication and label. In this case, the most appropriate indication would have been “epileptic encephalopathies” or “developmental encephalopathies” or similar, given that the drug appears to behave similarly in all of them. This is what the scenario C is about, drugs that treat a general symptom and should therefore have an indication that is broader than a single individual syndrome (or four).

Recently Takeda started a Phase 2 trial in collaboration with Ovid Therapeutics that is recruiting patients diagnosed with any type of epileptic encephalopathy for treatment with their drug TAK-935. This is what is known as a “basket trial”, where multiple indications are combined. Basket trials started in oncology but this is the first time that we see it run with a mix of epilepsy syndromes. The Takeda trial is not a pivotal trial so it won’t lead to an approval, but it gives me hope that we will one day see this mix of refractory epilepsy syndromes considered as a single indications for drugs that, like the Takeda drug, have mechanisms of action that don’t make them specific for one particular syndrome. As I see it, the basket trial approach should be the future trial design for such drugs, and the broad-label indication should also be the preferred indication unless the product has reasons to only work in a particular syndrome or seizure type.

An interesting consequence of broadening the indication towards this “umbrella” indication might be that it is not longer considered orphan, and therefore the product is no longer eligible for the orphan development pathway and incentives. The answer to this question has important regulatory and commercial implications.

Last, one of the most important aspects of this broad-label scenario C is not the benefit it might bring to drug developers, but the impact it will have towards making sure that all patients with rare epilepsies get access to new medications. Some of the syndromes have patients that can be counted in the low hundreds or even less. The best way to facilitate the development of new medicines for these ultra-rare syndromes is making it possible for them to go together with the other syndromes that share common phenotypes when it comes to evaluating and approving symptomatic drugs. This approach makes medical sense because it is also the same way that physicians work with these syndromes in their regular practice, and it will enable them to stop relying on off-label use of medications.

THE FUTURE

In conclusion, we have a few things to work on when it comes to the debate between genetic and symptom-base syndrome classification:

– First, we need to understand that both classifications are needed because they address different aspects of the disease: the cause and the clinical manifestation.

– Second, as drugs that treat the genes/proteins and not just the symptoms get into clinical trials, we need to be willing to switch from indications that follow the classical (phenotypic) syndrome classification to indications that reflect the drug mechanism so that it can be used across multiple classical syndromes.

– And last, we need to identify better regulatory pathways to make sure that the ultra-rare syndromes can get drugs approved for them as well. In the case of epilepsy this means considering the umbrella indication of epileptic encephalopathies or similar as opposed to artificially slicing indications unless the drug has a syndrome or seizure type-specific mechanism of action.

I hope all of these points will also create a new debate and have an important position in the agenda of the next the International Epilepsy Congress. Until then, I would appreciate your comments and thoughts.

Ana Mingorance PhD

Dravet Syndrome Drug Development Pipeline Review 2017

June 23 is a special day for families of people with Dravet syndrome. It is the International Dravet Syndrome Awareness Day, that in 2017 celebrates its 4th edition.

That's why today we announce the publication of the 2017 Dravet Syndrome Pipeline and Opportunities Review, a market research publication that provides an overview of the global therapeutic landscape of Dravet syndrome.

Dravet syndrome is an orphan epilepsy disorder with multiple non-seizure comorbidities and high unmet medical need. The disease has recently gained significant attention as an orphan indication within epilepsy, and as of June 2017, the drug drug development pipeline for Dravet syndrome comprises at least 13 drug candidates, of which 3 are in late-stage, placebo-controlled Phase II or III studies. Two of the products in development are potentially disease-modifying treatments, and 8 different products 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; BIS-001 (huperzine) from Biscayne Neurotherapeutics; OPK88001 (CUR-1916) from OPKO Health; OV935 (TAK-935) from Ovid Therapeutics and Takeda; EPX-100, EPX-200 and EPX-300 from Epygenix Therapeutics; cannabidiol from INSYS Therapeutics; a Nav1.6 inhibitor program from Xenon Pharmaceuticals; and SAGE-324 from Sage Therapeutics. 

The 2017 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

7 Lessons from the World Orphan Drug Congress

Gene therapy is here, VCs want to invest in orphan drugs, Rettsyndrome.org foundation is doing a great work, the line between patients and drug developers is blurring, we should start talking about industry (not patient) engagement, networking is not always easy, and Fulcrum Therapeutics should be in your list of companies to watch.  

That’s my 17 seconds version of the main lessons I got from attending the World Orphan Drug Congress in DC April 20-21. 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 than 17 seconds, here is the expanded list of what I would like to share with you from the conference:

1- Gene therapy is not a thing of the future, it is already here. I particularly enjoyed the presentations from Bluebird Bio and Spark Therapeutics. Nick Leschly from Bluebird Bio gave us excellent advice for building a rare disease company. My favorite: (1) if you have seen one company do it, you have seen one company do it (=every case is unique); (2) the power of n=1; (3) if you see great improvement for one patient you have to fight for that drug; (4) getting pricing reimbursement and adoption are the real end goal, regulatory approval is just the start; and (5) keep constructive paranoia, don’t get in the comfort zone, do something that has a lasting effect in a human being. Bonus lesson: videos of patients before and after gene therapy are always amazing. No graph with 200 patients has the power of showing a video of a child that was previously blind navigate a circuit with obstacles one year later.

2- Developing drugs is an expensive business and investors need to be part of the game…and the conferences. Listening to Venture Capital partners at the Pitch and Partner track was extremely interesting. A panel shared their views on what they look for in the orphan space, the concept of orphan vs ultra-orphan, how they work with academic founders and partner with patients, and best advice when pitching to them. It is a great decision to give a voice to VCs in orphan drug conferences. Also, Philip Ross from JP Morgan should be the moderator for all conference panels, or at least be in charge of the questions.

3- Anavex’s CEO Christopher Missling talked about partnering with patient organizations and explained that a year ago they didn’t even know what Rett syndrome was. He credits Rettsyndrome.org CSO Steven Kaminsky for making it very easy for them to test their most advanced drug in a Rett mouse model and for mobilizing resources to help them start a clinical trial when those results where very positive. They plan to start a Phase 2 trial this year. Rettsyndrome.org is a great example of how patient organizations can attract companies to their disease by proactively engaging the industry and understanding how to remove drug development bottlenecks, such as offering access to good animal models. 

4- Times are changing. I met several parents of children with rare diseases that attended the WODC that have created their own companies or that are considering starting one. The line between patients and drug developers is blurring. There are more and more patients and parents that have turned drug developers, from the more senior John Crowley from Amicus to companies that are just starting. This trend is likely to make the biggest impact for ultra rare diseases.

5- I’m thinking we should start the hashtag #IndustryEngagement. I spent the last 5 years working with patient organizations trying to get the industry interested in our diseases. Our research strategy was to make it so easy for anyone to work on Dravet syndrome that we would have 300 labs and companies working on it tomorrow. That’s why Dr Kaminsky from Rettsyndrome.org is one of my heroes. And when I sit down with other patient organizations, as I did during the WODC, our conversation is always about best practices to engage the industry. We hear so much about patient engagement from industry speakers that I am not sure they know that the reverse conversation is also taking place under the same roof. I pretty much wrote an entire book about it. I’m thinking we might need to come up with a proper name for that reverse patient engagement. Let me know if you have other ideas about how to call it.

6- The WODC is multiple conferences in one. The conference places a big emphasis in networking, but there are so many vendors in attendance (CROs and similar) that the speed networking sessions and most networking opportunities where not useful for somebody like me. I’m not useful for them either, since I don’t use their services. All of my useful contacts but one happen by going through the attendees list and pre-programing meetings ahead of the conference. So here is my recommendation: maybe we could use different color badges for the different sectors. That way I will go straight to drug developers and patient groups and not struggle to find them in a sea of service providers.

7- Somehow I hadn’t noticed Fulcrum Therapeutics before. Or at least I hadn’t noticed how cool what they are doing is. Co-founder Walter Kowtoniuk gave an amazing presentation at the WODC that not only got me to fall in love with their approach but also with his passion. Fulcrum is doing small molecule regulation of protein levels through gene regulation. So many diseases are caused by having one defective gene copy and therefore another one to upregulate (or a copy to reduce, in case of gain of function or toxic function) that the sky is the limit. And they clearly know it, seeing their aggressive expansion and approach. I need to get them to talk with me about rare epilepsy syndromes!

 And these are my main lessons from the WODC. I hope you also found them interesting.

This is the first time I attended the USA congress after having attended some of the European ones, and Terrapin always does a great work at putting together such a large and varied congress (see lesson #7). I look forward to the one in Barcelona in November.

If you attended the WODC and have more lessons to share leave a comment or reach out in Twitter.

Ana Mingorance PhD

Everolimus, and how rare diseases are reviving the field of epilepsy

In January of 2017, the European Medicines Agency approved everolimus (Votubia) for the treatment of seizures in tuberous sclerosis complex, becoming the first anti-epileptic medication ever approved. But there are more than 25 different molecular entities approved as anti-epileptic medications, so let me explain you why this case is different and why it represents a big milestone for the epilepsy field.

Epilepsy is a rather common disease, affecting up to 1% of the world population. As a target indication for new medicines it has been extremely successful, with a very extensive list of approved anti-epileptic medications.

The secret to this success lies in the availability of very good animal models and the robustness of seizure counting as primary endpoints. Other neurological diseases with complex cognitive outcomes, for example, have been much more difficult to translate preclinically and to test clinically. Clinical trials in epilepsy are also relatively short, requiring only three months of treatment in general, making the indication particularly attractive for CNS-acting drugs.

But this incredible success reached two walls, and eight years ago, when I started working in epilepsy, I would often hear my colleagues say that the field was dying and that only very few companies were interested in epilepsy anymore.

The first wall is competition. It is hard to add to a field where there are so many treatments available and where many are generic. Most portfolio decisions will therefore favor indications where the return is expected to be superior to the one we can expect in epilepsy, even if the risks are also higher.

The second is drug resistant forms of epilepsy. Since the initial discovery of bromides to treat epilepsy in 1850, about a third of the patients have remained pharmacoresistant. This means that these patients continue to have seizures, despite having tried all of the anti-epileptic medications available and receiving combinations of four or more of these drugs to at least partly reduce their seizure frequency. Newer generation of anti-epileptic drugs improved the tolerability and drug-drug interaction profile of the earlier drugs, but the wall of the pharmacoresistant patients remained.

And ironically, this second wall became the opportunity that would revive the field.

Epilepsy meets rare diseases

A large percentage of patients with pharmacoresistant epilepsy have much more going on than just epilepsy. Many have neurological syndromes where seizures are just one of the symptoms. And these syndromes are orphan diseases, also known as rare diseases, which are those that affect less than 5 in 10,000 people in Europe and less than 200,000 Americans, and that are therefore covered by the Orphan Drug Act and equivalent incentive programs in the large markets.

These incentives have been key to rescue the highly competitive field of anti-epileptic drug development, and in the recent years we have seen a boom in the number of anti-epileptic drugs in development for rare epilepsy syndromes.  

Interestingly it first started slowly, with some of the anti-epileptic drugs that were being developed for common epilepsy also being tested and approved for some of the better-known epilepsy syndromes. Two good examples are topiramate and lamotrigine, approved for Lennox-Gastaut syndrome in addition to partial onset seizures and generalized seizures (the two indication approvals for common epilepsy based on main seizure type), or vigabatrin, for infantile spams/West syndrome as well as partial onset seizures.

But more recently we are seeing a growing number of medications being developed for the treatment of seizures only in some rare epilepsy syndromes. And what I find very interesting is that many of these players are not the traditional big pharma companies, but smaller companies that could not go after very large markets due to the demands of large trials and that are now able to afford pursuing these epilepsies because they are orphan size.

This doesn't mean that there were no medications previously available for rare epilepsy patients. These patients are already being treated with regular anti-epileptic drugs, often failing to achieve complete seizure control despite polymedication. In fact, because many of these epilepsy syndromes are so tough to treat, it is not rare to come across a patient that has gone through most if not all of the drugs in the catalogue of anti-epileptic drugs.

What we didn't have are drugs that could be effective in these populations.

And this leads me to my next point…

What the orphan epilepsies need is disease-targeting drugs

There are many medical conditions that will make a person have spontaneous recurrent seizures, which is the definition of epilepsy. Some are consequence of brain damage or malformation, some are genetic, and in many cases the cause in unknown. What they all have in common are seizures, produced by hyperactivity and hypersynchrony of neurons.

Because of the heterogeneity and incomplete pathogenic understanding, epilepsy has traditionally been treated by simply reducing brain hyperactivity. Increasing brain inhibition by acting on the GABAergic system, or reducing excitation with glutamate receptor inhibitors or ion channel modulators, are the main mechanisms behind most of the approved anti-epileptic medications. For a few of the medications, the specific mechanism remains unknown. And collectively they do just that: reduce brain hyperactivity to prevent seizures.

But most rare diseases are genetic, and for many we now know the genetic cause. So these rare epilepsies tell us not only about the problem but also about the potential solution.

A big message every year at the American Epilepsy Society meeting is that we need to develop disease-targeting medications, not just symptomatic ones. Because when we think about what they do, the so-called “anti-epileptic medications” are not such thing. They truly are “anti-seizure” or “anti-convulsant medications”, that treat the symptom that is the seizure. They don’t treat the disease, the epilepsy.

And many orphan epilepsy syndromes, by having a clear genetic cause, open the door to develop the first truly anti-epileptic medications.

Everolimus did just that. And for as much as the whole anti-convulsant vs anti-epileptic debate fills the rooms at the major medical conferences, I have been very surprised to read very little about it after the approval of everolimus for threating epilepsy in tuberous sclerosis complex.

Everolimus is the first anti-epileptic drug approved, and the significance of this approval needs to be acknowledged and placed in the right historical context.

Everolimus is the first of hopefully many anti-epileptic medications

In January of 2017, the European Medicines Agency approved everolimus for the treatment of seizures in tuberous sclerosis complex, becoming the first anti-epileptic medication ever approved.

Tuberous sclerosis complex is a genetic rare disease that affects many organs but that particularly affects the brain. Like other neurological syndromes, it presents with epilepsy in approximately 85-90% of the patients, intellectual disability and behavioral problems. There is a broad spectrum of disease severity, and receives its name from the formation of tubers (non-cancerous tumors) in different organs.

Tuberous sclerosis complex is the result of hyperactivity of the “mammalian target of rapamycin” (mTOR) pathway due to inactivating mutations in genes that encode the upstream proteins TSC1 and TSC2 in patients. And knowing that cause, hyperactivation of the mTor pathway, also tells us the solution: inhibition of the mTor pathway.

The reason why it has been faster to develop mTor inhibitors for treating tuberous sclerosis complex than similar disease-targeting drugs for other epilepsies is that mTor inhibitors already existed.

Rapamycin is a natural compound first developed as an antifungal agent and later found to be a very effective immunosuppressant. Everolimus is a rapamycin analogue and had already been approved as immunosupresant and for a number of cancers.

In everolimus, Novartis saw not just the possibility of treating one of the tumor types that appear in patients with tuberous sclerosis complex (SEGAs), but also of treating other aspects of the syndrome.

I particularly love how Novartis has run separate trials to measure the efficacy of everolimus in treating seizures, intellectual disability and autism associated with tuberous sclerosis complex.

Some times in epilepsy trials, when cognitive endpoints are included, these are secondary safety endpoints to confirm that the treatment does not negatively affect cognition. Such common trial design ignores the fact that most of the genetic epilepsy syndromes have intellectual disability and behavioral problems, in addition to seizures, as regular manifestation of the syndrome. And many of the patients that participate in these trials (and their caregivers) do so in the hope that they will see improvements in these domains, not just in seizure frequency. Running separate trials designed to generate evidence for each of these domains shows that Novartis understands the reality of these diseases, and it is a great example of patient centricity.

The future of epilepsy through orphan epilepsies

Right now, rare epilepsy syndromes are a favorite choice for companies developing drugs with anti-seizure potential because of the smaller trial size, relatively uniform patient population, and market exclusivity when obtaining an orphan drug designation. In most of the cases today, the drugs in development are still symptomatic treatments, just like the many previously approved medications.

For the most heterogeneous and often cryptogenic syndromes, notably infantile spams/West syndrome and Lennox-Gastaut syndrome, the symptomatic approach that treats seizures without targeting the disease might still be the main approach moving forward. But for the growing number of genetically-defined syndromes where epilepsy is one of the main problems we are likely to see a growing number of treatments developed that target the cause of the disease.

Among these genetically-defined syndromes, the better-known ones and where patient populations are the largest include tuberous sclerosis complex, Dravet syndrome, Rett syndrome and Angelman syndrome. Following the pioneer everolimus, there are already some treatments in development for Dravet syndrome that target the ion channel deficit that causes the syndrome and the seizures (see recent orphan drug designation for OPKO’s antisense therapy).

And behind those, there are multiple monogenic syndromes that also wait for their turn to have an anti-epileptic medication designed for them. For some, like PCDH19, there are already ongoing clinical trials that partly act on the disease biology (see ganaxolone). For others, like CDKL5, there are small investigator-initiated trials to test the potential efficacy of read-through therapies in the subset of patients that carry non-sense mutations.

Other syndromes still wait for the first trial to start. Most have dedicated groups of parents that have created very active patient organizations and that would gladly work with any company that wants to join them in their quest. This includes SCN2A, SCN8A, STXBP1 and so many others, and for some like SCN8A the possibilities to develop disease-targeting medications already looks within reach.

I've provided links to many of the patient organizations for the genetic epilepsy syndromes in case you are a drug developer that wants to get in touch.

As more patients are discovered with these mutations thanks to genetic testing, these syndromes will serve as new orphan indications for companies to get their anti-seizure medications to the market. They are the ones likely to keep the epilepsy field alive, and the patients really need those effective medications – both symptomatic and disease-targeting.

I have had the pleasure of meeting many families of children with many of these syndromes. I’m glad I am meeting them today, and not a decade ago when it seemed that there was little room to develop new drugs for epilepsy. And I’ve met many of these kids and seen very few seizures. What I see the most, and what the families and the physicians deal daily with, are the developmental delays, cognitive disabilities and behavioral problems that are inherent part of all of these epilepsy syndromes.

Because in the end, if a drug really stops all the symptoms there is little difference between a symptomatic treatment and one that targets the disease biology. But in complex syndromes like most of the genetic epilepsy syndromes, there is no such thing as a symptomatic drug that will be able to treat the seizures, the intellectual disability, the motor problems and the behavioral problems. 

Because of this, I celebrate the approval of everolimus and look forward to the development of more disease-targeting medications for these epilepsy syndromes. I also look forward to more clinical trials that look at the different aspects of the disease like Novartis is doing with everolimus. This approval, that somehow hasn’t make much noise, is actually a big milestone for the epilepsy field.

And hopefully the first of many.

Ana Mingorance, PhD

Get your free eBook: #ImpatientRevolution

We are one week away from the Rare Disease Day and the global theme this year is Research. To celebrate this day and honor the theme I am releasing the eBook #ImpatientRevolution, a guide for impatient patient organizations.

You can download the eBook here:

The eBook is free and there is no sign up required. If you want it, it’s yours. All I ask is that if you read it and you like it then help me spread the word so that more patient organizations (or scientists interested) will get to read it too.

For the basic who/why /what questions about the book check out my last entry.

Enjoy!

By Ana Mingorance PhD

Empowering the impatient patient revolution

February 28 is the Rare Disease Day, and the global theme this year is research.

People from all over the world will come together this month to advocate for more research on rare diseases, and to recognize the critical role that patient organizations play in research.

I don’t think the organization could have come up with a better theme. I’m a strong believer in patient-centric research. In working with patient organizations who are changing the world. This is why I am excited to join this year Rare Disease Day and announce the launch of my first eBook: #ImpatientRevolution, a guide for impatient patient organizations.

WHAT IS THE eBOOK ABOUT

This eBook is about the many ways patient organizations can shape the research field around their disease and influence the drug industry to work on their rare disease.

I conceived it as a guide for impatient patient organizations – those wanting to accelerate the development of new medicines for their disease by taking an active role. It explains why and how companies develop drugs for rare diseases, and how patient organizations can use this knowledge to analyze their disease field, to identify the main gaps, and to design strategies to get pharmaceutical companies to develop new treatments for their disease.

My wish is to empower patient organizations that want to play an active role in research, and to invite them to take the plunge and join the #ImpatientRevolution

WHAT IS THE AUDIENCE

As a guide, the eBook is written for patients and patient advocates involved in patient organizations. It will be very useful for those just starting or even considering starting a new patient organization, and it will be a good mental exercise too for those that are already part of patient organizations that are active in research.

As a learning resource, the eBook will be interesting for anyone involved in developing new medicines for rare diseases (orphan drugs), in particular if they interact with patients. I myself am a drug hunter, and this is the guide I would have loved to read when I started!

WHO IS THE AUTHOR

I have been a scientist in academia, a scientist in the pharmaceutical industry, and for the last 5 years I have worked as an in-house scientist and advisor for rare disease patient organizations.

While I looked for new ways to help develop more drugs for Dravet syndrome, I also looked at the industry best practices. From this experience I came up with the framework that is the backbone of the #ImpatientRevolution eBook. I have shared these ideas at rare disease conferences and it was time for me to write them down so that I could share them with all the rare disease community. There was not better time for doing this than joining this year Rare Disease Day.

WHEN IS THE eBOOK LAUNCH

The #ImpatientRevolution eBook will launch on February 21, exactly one week before the Rare Disease Day.

I have chosen this date to celebrate the Rare Disease Day, and, at the same time, give time for people to read the eBook so that they get to February 28 more convinced that ever that patient organizations should be at the center of research.

WHAT IS THE COST

You don’t have to pay anything or sign up to any e-mail list to get the eBook. If you want it, it’s yours. All I will ask you is that if you read it and you like it then help me spread the word so that more patient organizations (or families thinking about starting one) will get to read it too.

WHERE CAN I GET IT

The eBook will be available on-line through this website with no payments or sign up required. I will share the link in social media on February 21 so stay tuned!

In the mean time, help me create awareness and spread the word in social media sharing your support for patient organizations playing a central role in research under the theme #ImpatientRevolution

And if you want early access to a copy, just leave me a note in the comments!

Ana Mingorance, PhD