Main lessons from the European Congress on Epilepsy 2018

Every other year the International League Against Epilepsy organises a major epilepsy medical congress in Europe called the European Congress on Epilepsy (ECE). This year I attended the main three days of the ECE addition in Vienna, looking at the field partly as a drug developer and partly as a patient advocate working on behalf of rare epilepsy patient communities. 

Here is the list of what I found the most interesting at the ECE 2018 meeting:

1. The big players are gone, the orphan players are taking over.

I missed seeing the large stands in the exhibition hall that UCB or GSK would always have. Instead we are now surrounded by (often) smaller companies that are launching molecules to treat orphan forms of epilepsy. It is an evolution that we also see in other disease fields, and that started becoming clear in epilepsy a couple of years ago. As rare diseases become more popular for drug development and we have more approvals, not only we see more orphan drugs at epilepsy conventions but we also see different players. 

If you turned around at the ECE 2018 meeting you could see the stands of GW Pharmaceuticals, fresh from their FDA approval for Epidiolex for treating Dravet and Lennox-Gastaut syndrome (expected EMA decision 1H 2019); Biomarin, which develops Brineura, with a stand focused on CLN2 (one of Batten disease types); Biocodex, with the newly FDA-approved stiripentol for treating Dravet syndrome (approved in EU since 2007); and Novartis with a stand on Tuberous Sclerosis Complex for their also recent approval of Votubia/Afinitor.  

In addition to those, Zogenix, in very late stages of development of fenfluramine for the treatment of Dravet syndrome, didn’t have a stand but sponsored a symposium on Dravet and had multiple posters. I would expect to see Zogenix and potentially Ovid Therapeutics get some more visibility at the next American Epilepsy Society meeting given their active late-stage programs in Dravet and Lennox-Gastaut syndromes. But for now, at the European meeting, we could already see four orphan epilepsy syndromes replacing much of the exhibition floor space formerly dedicated to medicines with a much broader spectrum. Since I focus on rare epilepsy syndromes, seeing that many drugs coming to the market and so much research on rare syndromes with epilepsy makes me very happy. 

2. Epileptologists discussing much more than just epilepsy.

Probably as a combination of paying more attention to rare epilepsies, which often have many serious and disabling comorbidities, and to patient-centricity and patient-empowerment becoming more mainstream, the epilepsy specialists start talking about these epilepsies in a much boarder way which captures much better the patient and caregiver experience. While years ago most presentations would focus on seizures, at the ECE 2018 we also talked about how to explain families a new diagnosis, the impact on caregivers of having a child with a rare epilepsy, the impact on siblings as well, and many aspects related to intellectual disability or psychiatric comorbidities. This large conversation shift was very refreshing for those coming from the patient side, and is likely to lead to much better patient outcomes.

 

3. A lot of exciting new therapies are coming, in particular for genetic forms of epilepsy.

Many presentations on the future of epilepsy treatments highlighted the new trials that are coming, most focused on orphan forms of epilepsy. In addition to Epidiolex and fenfluramine (for Dravet and Lennox-Gastaut syndromes) several presentations highlighted ganaxolone from Marinus for treating CDKL5 deficiency disorder, XEN1101 from Xenon for KCNQ2 encephalopathy, and OV935/TAK935 from Ovid Therapeutics and Takeda for multiple rare epilepsies as well. 

There are also hopes about future genetic therapies able to increase expression from the heathy gene copy, in all of those cases where the disease is caused by a de novomutation in one of the gene copies. In fact, I had the pleasure to meet with one executive of Stoke Therapeutics attending the conference and hear about their program to use an antisense treatment in Dravet syndrome that will increase the missing protein expression. They are still at a preclinical stage, but from my conversation I came out of the meeting convinced that they are doing an excellent work and that they are well-prepared to take into clinical trials, in some years, what could be the first disease-modifying treatment for Dravet syndrome.   

I missed hearing a bit more about gene therapy approaches, which we know are also in development for several of these rare epilepsies where the genetic problem is due to a loss-of-function or a loss-of-expression of a gene. I´m sure it won't be long before these therapies are discussed at epilepsy meetings alongside more classical pharmacological approaches.

4. It is never too late to improve the life of a patient living with a severe epilepsy.

As we talk about those potentially disease-modifying treatments, and at the very least disease-targeting treatments, one hope and one fear emerge. The hope is that they will help us treat not only the epilepsy but also the cognitive, psychiatric, motor and other problems that the patient experiences, since they will target the root of the disease. The fear is that beyond certain age, they might do little for the patient.

I have to thank Prof Sanjay Sisodiya from UCL who works with adults with difficult-to-treat epilepsies for his beautiful and inspiring presentation on diagnosing genetic epilepsies in adult patients. He showed us the image of the medical records of a patient with drug-refractory epilepsy and intellectual disability in his late 50s that was the size of an encyclopaedia collection. Going through that much medical history to try to diagnose the patient would represent an enormous challenge to any physician. The patient’s disease was so severe that he had even stopped talking, so one might think that knowing the specific cause wouldn’t make much of a difference to this patient condition. It turns out the patient had Dravet syndrome, which could be identified in a genetic test, and this finding enabled his doctors to remove the contraindicated medication that he was taking and prescribe instead the standard of care for this particular syndrome. The patient condition improved to the point that Prof Sisodiya showed us a video of the patient, now 66, having a conversation with him. 

“It is never too late” was the message to the audience. 

It is never too late to diagnose a condition, and it is never too late to offer the patient the best medication that is currently available for their disease. This will be particularly important once we have actual disease-targeting therapies in the market, and only then will we be able to know how much improvement is achieved at each age.

SUMMARY

Overall, an evolution of epilepsy therapy discovery from treating symptoms to treating causes is clear. Much of this is driven by improved understanding of the genetic causes of many types of epilepsy, which points to potential new targets for therapies, and much is driven by the progresses in technologies such as the development of more specific ion channel modulators or antisense strategies that now enable us to tackle those targets.

The second major evolution, linked to the previous one, is a greater focus on rare (orphan) epilepsies over the large symptomatic market. This evolution, as is other disease fields, follows a combination of business advantages and better therapeutic fit, given that many of the rare epilepsies have a genetic cause. For example, as one of the most common genetic forms of epilepsy, Dravet syndrome is likely to be the first --or one of the first-- syndromes to get a disease-modifying treatment using these new approaches. 

And last, I have seen another evolution in the way that epileptologists talk about the epilepsies at their major conferences, which has become more holistic and patient-centric. When I started working in the epilepsy therapeutics field 9 years ago, the view of epilepsy by the epilepsy specialists and the pharmaceutical companies was much more focused on the seizures and less on the overall patient experience. Now, as a result of much patient advocacy, physicians look at the disease the same way the patient and their families do. Companies and regulators have also changed the way they used to operate, now including much more directly the patient perspective as part of their work, which has expanded the way they see the disease and think about treatments. And in a medical conference like the ECE 2018, this change was very visible. 

I personally missed hearing more about CDKL5 deficiency disorder and other “less popular” rare epilepsies, and about some of the non-pharmacological therapeutics in development, such as antisense therapies and gene therapy approaches. Next stop for the epilepsy community is the American Epilepsy Society meeting starting November 30thin New Orleans where I hope to hear more about those topics, and report back. 

Ana Mingorance, PhD

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

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

2016 numbers: CNS orphan drugs growing

With 2016 numbers now available, the number of orphan drugs in development for neurological indications is looking quite positive. I have reviewed the numbers of orphan drug designations and approvals by FDA in 2016 to see how popular are neurological orphan drugs today and what the trend is for the near future.

The FDA approved only 22 new drugs last year, a big fall from the 45 approvals it granted in 2015. But not all approvals are for new molecules, there are also many approvals that are new indications of previously approved drugs, also known as “drug repurposing”, so the total number of approvals is actually higher than what news outlets otherwise suggest (see here and here).

We see many cases of drug repurposing in rare diseases, so I have looked at the total number of orphan drug approvals and the total number of orphan drug designations in 2016, including new molecules as well as new indications (or designations) for already approved drugs.

THE NUMBERS

In 2016 the FDA approved 37 orphan drugs, out of which only two were for neurological indications: Spinraza (nusinersen) from Biogen for spinal muscular atrophy, and Carnexiv (carbamazepine injection) from Lundbeck for epilepsy as an alternative to oral carbamazepine. The rest of the approvals, as usual, were dominated by oncology.

This means that only 5% of all orphan drug approvals during 2016 were for neurological indications.

However when we look at the drugs that received an orphan drug designation last year the picture is much better for neurology.

The FDA granted 333 orphan drug designations last year. This number includes some diagnostic reagents so I have only included in my analysis 325 orphan drug designations for the treatment of rare indications. Out of these, 48 orphan drug designations were for neurological indications  (see full list at the end of the article) and again oncology dominated in the remaining cases.

With 48 designations in 2016, neurology accounted for 15% of the cases, indicating that the percentage of orphan drugs approvals for neurological indications could triple in the near future.

THE BREAKDOWN

Among the 48 designations, the largest area was neurodegeneration, followed by epilepsy. This reflects two important trends in CNS drug development.

One trend is to target orphan indications when the large indications become too crowded. This is the case of epilepsy, where many of the orphan designations are for drugs that could have efficacy in broader epilepsies -and in many cases are already approved for broader forms of epilepsy- but choose to seek approval for a specific syndrome or type of seizures (such as acute repetitive seizures) to reduce competition.

The other trend is to use rare diseases to obtain the initial clinical proof-of-concept for a compound that is eventually aimed at targeting the large indications. This has became very common in the neurodegeneration field where a Phase 3 failure can cost many hundreds of millions, so de-risking the program in a smaller and more uniform patient population is an excellent development strategy. Amyotrophic lateral sclerosis (ALS) was traditionally the rare disease model for neurodegenerative compounds and had 6 orphan drug designations in 2016, and frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP) have emerged more recently as attractive rare diseases to re-risk molecules in development for Parkinson’s disease or Alzheimer’s disease.

What I classified as neurodevelopmental diseases includes the syndromes of Rett, Angelman, Fragile X and tuberous sclerosis complex. I could have classified some of these as epilepsy based on the trial endpoint, like is the case of the orphan drug designation for treating tuberous sclerosis complex with cannabidiol. Likewise, I could classify some of the epilepsy syndromes as neurodevelopmental diseases given the clinical presentation but kept them under epilepsies for this analysis purposes because of the seizure-focused trial endpoints. Collectively, all of these neurological syndromes characterized by seizures, cognitive, behavioral and motor problems are very popular within the orphan drug space.

Among the remaining designations I found interesting 4 treatments for ataxias (Friedreich's ataxia and spinocerebellar ataxia), and two for narcolepsy.

THE FUTURE

Looking at the 2016 orphan drug designations in neurology (see the full list at the end of the article) I can see how rare diseases are facilitating a revival of a field that has suffered from some areas being overcrowded and others being extremely difficult to pursue (think of Alzheimer’s disease). By providing smaller and more homogenous populations rare diseases offer the possibility of shorter and cheaper development programs, opening the field to smaller companies that could now have developed a clinical asset without partnering with a large company. And the genetic nature of many of the rare diseases has also offered us targets that increase the likelihood of succeeding in those trials versus symptomatic approaches in heterogeneous populations.

But not all is opportunistic strategies to reduce competition or de-risk programs. We are also seeing a growing number of gene therapy or antisense approaches in development that target the cause of these rare diseases, including 2016 designations for Sanfilippo syndrome, Friedreich's ataxia and Batten disease and antisense oligonucleotides for ALS and Huntington's disease.

Based on these numbers the future looks promising for neurological orphan drugs, with numbers that could triple and the development of disease-modifying treatments.

Ana Mingorance PhD

FULL LIST ORPHAN DRUG DESIGNATIONS FOR NEUROLOGY - FDA 2016

What marihuana teaches us about drug discovery

There was one clear star at the American Epilepsy Society Annual meeting last week, and that was Epidiolex. Epidiolex is the brand name of cannabidiol, a drug isolated from medicinal cannabis that GW Pharmaceuticals (Greenwich Biosciences in the US) is developing for the treatment of a number of orphan refractory epilepsies.

Epidiolex was featured in multiple talks and posters, the scientific exhibit hosted by GW Pharma was hands down the most popular one during the meeting, and it was also the main conversation topic in the corridors. It was impossible not to hear about it.

Yet four years ago no one would have thought that the cannabis-derived drug would take over the field of epilepsy in such a big way.

The rise of Epidiolex has been spectacular: during 2016 GW Pharma has announced positive results from three different Phase 3 trials with Epidiolex, with ongoing Phase 2 and 3 trials for other rare epilepsies. Analysts predict peak sales of over a billion dollars. Clearly a very useful drug and a successful commercial product.

The reason why I find the success of this drug such an excellent lesson for drug discovery is that it goes against many of the basic requirements to finance a drug development program:

• Cannabidiol is not a new chemical entity, so GW Pharma doesn’t have a patent on the molecule.

• As a major medicinal ingredient in marihuana, it is relatively easy for patients to access the plant or extracts without needing to purchase the branded product.

• Cannabidiol is only expected to have partial efficacy against the main symptom of these orphan refractory epilepsy syndromes, which is seizures. It does not target the disease and is not expected to provide complete symptomatic relief.

• And on top of all that, the mechanism by which cannabidiol is active in epilepsy is still unclear.

If you had tried to approach venture capital firms with a compound that (1) is derived from a medicinal plant, (2) is relatively easy to source as a plant or extract, (3) is likely to provide moderate symptomatic efficacy, and (4) does not have a defined mechanism of action, you would have come out empty-handed.

I know it because I’ve tried this with another molecule having these characteristics.

Investors (and big pharma) want drugs that target the disease biology, with proprietary chemistry and clearly defined mechanisms of action.

What amazes me is that the same investors that would find all those flaws in the investment proposal that I was supporting would turn around and ask me about Epidiolex and its latest results. When confronted with the observation that the very promising Epidiolex happens to have the same profile as our compound the answer was always the same: true, but they have clinical data.

And that’s what this really all boils down to. We create a number of requirements for drugs candidates as a checklist to minimize risks, but once positive clinical data is available that checklist is no longer necessary. We are not short of drugs that target the disease biology, with proprietary chemistry and clearly defined mechanisms of action, that go on to fail in the clinic. We are short of drugs that actually work in the clinic.

Kudos to the GW Pharma team for understanding this and going straight to generating the early clinical evidence that has taken them to where they are today. 

Clearly not every drug can be fast-forwarded with multiple parallel trials and very aggressive timelines as GW Pharma has done with Epidiolex. But drugs isolated from medicinal plants offer the unique opportunity to be fast-forwarded to generate clinical evidence as GW Pharma did.

In the case of cannabidiol the breakthrough was the extensive availability of safety data that enabled the company to sponsor multiple investigator initiated INDs and obtain early clinical data. In other cases, depending on the nature of the medicinal plant, it might even be possible to run food safety clinical studies to obtain that early clinical data prior to an IND.

For drugs isolated from medicinal plants, where the primary screening was pretty much done in human patients, trying to enforce the IP and mechanistic standards that we apply to hypothesis-driven drug candidates might make us throw away the baby with the water bath. The success of Epidiolex has only been possible because GW Pharma was well-funded and had the vision to ask the right questions.

If clinical data is the main deciding factor, then maybe investors should first ask if a compound has a quick path to be tested in patients. For those compounds where the answer is yes, such as in medicinal plant-derived compounds or repurposed drugs, the priority should be in designing a quick clinical study able to generate that early clinical evidence. For those compounds where the answer is no, then we might continue to use checklists to try and minimize risks prior to any clinical study.

When we ask about the possibility to generate quick clinical data, drugs coming from medicinal plants or repurposed assets, where safety has been established, suddenly become exceptional opportunities. 

I don’t know if investors will be able to look at Epidiolex and reconsider what they ask to early candidate drugs. I, for one, will make sure to tell them the story of what marihuana has taught us about drug discovery and about asking one key question: does this compound offer a possibility to generate quick clinical data.

Let me know what you think about it in the comments.

Ana Mingorance PhD

Originally published in LinkedIn on December 16 2016

How close are we to creating transgenic people?

The journal Nature just released one of the most anticipated breaking news of the last few years: CRISPR gene editing has been tested in a person for the first time.

In my day-to-day work I interact with families that have a child with a genetic disease. These are diseases where the mutation is produced “de novo”, which means that it happened during the production of the baby. The family didn’t carry any mutation and most likely that child is the only one with that exact mutation, or one of a handful world-wide. 

As you can imagine, ever since scientists announced they had found a way to do copy-and-paste in DNA to introduce or to correct mutations I get one question a lot: how close are we to turn that discovery into a therapy for people with genetic diseases?

And despite the breaking news from Nature the answer is still “not that close”.

Let me elaborate on that.

Before being available as a treatment for people born with genetic mutations the CRISPR technology needs to go through roughly four steps:

1. Show that CRISPR can correct mutations in human cells in a test tube. This was the groundbreaking discovery that got us started in an amazing medical development explosion.

2. Show that these genetically-modified cells can be delivered to patients. This is more cell therapy than gene therapy and it is very useful on its own. Likely to be the first path forward for the CRISPR approach.

3. Show that we can actually correct mutation in patients using CRISP. Now we are talking about gene therapy, and for years this will have to be done in clinical trials under controlled conditions.

4. Finally, get approval for gene therapy using CRISPR technology so that we can fix patient’s mutations, effectively creating transgenic people.

What Nature announces is that scientists at Sichuan University have treated a patient with lung cancer with cells that had been reprogrammed using CRISPR before being delivered into the patient. This is step 2.

It had also been done before using other technologies that enable gene-editing, also in diseases where scientists first modify those cells outside the body and then deliver them to the patient, such as in cases of leukaemia or HIV. CRISPR is predicted to be the most powerful (and easy!) of these methods and is likely to be the one that will become a real treatment so reaching step 2 is great news.

At this second stage, these are all “ex vivo” approaches where the gene editing technology is applied to the cells that will be used to treat the patient, instead of using the technology directly in the patient.

The move towards step 3, editing the patient DNA, opens serious safety concerns:could the gene-editing enzymes cut and paste more letters in the DNA that they were intended to? Could they cause unwanted mutations? Because of that, it is likely to happen first in very localized indications such as tumours or retinal disease.

Moving from those localized diseases to more widespread ones will have the same challenges to reach the target organs that “traditional gene therapy” currently has. For the non-initiated, “traditional gene therapy” doesn’t change the patient DNA, instead it uses virus that have been stripped of the virus DNA to infect the patient and deliver a healthy version of the gene that the patients have mutated. At the end the patient has his own genes plus this new therapeutic gene. And that is not easy to do in hard-to-reach organs such as the brain!

Because delivering the CRISPR enzymes will also rely on viral vectors, even if CRISPR was proven today to be totally safe we wouldn’t know how to apply it to the brain tomorrow, since we still haven’t mastered that delivery aspect yet.

For any patient with a neurological condition caused by de novo mutations (so mutations unique to him/her) this is how the things to do list looks like before we can treat him:

1. CRISPR needs to be proven safe in small regions (step 3)

2. We need to find good viral vectors to deliver genes to the brain, which is larger than the eye or blood cells and happens to come inside of a hard box.

3. Those viral vectors also need to be safe.

4. CRISPR will be first used for genetic neurological diseases that are inherited, which means where the same mutation is found in many people.

5. And only after all that has happened we can think of using CRISPR therapy when the target mutation is unique for each patient, which introduces additional questions: can we get approval for the disease and just change the target sequence that the CRISPR uses? Will companies ever manufacture separate ones for individual patients?  etc

So for the patients I work with, who carry de novo mutations that cause neurological diseases, the answer to how close we are to use CRISPR as a therapy for people like them can only be “not that close”. These are probably the last diseases to benefit from the gene editing technology.

In the mean time we celebrate that we have reached step 2 with CRISPR, delivering edited cells to a patient, and keep our eyes on that next frontier: the in vivo experiment, the first patient that has his own DNA corrected using CRISPR in a clinical trial, the first transgenic people.

Let me know what you think about it in the comments.

Ana Mingorance PhD

Originally published in LinkedIn on November 16, 2016