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