Tag Archives: Preclinical animal models

Especially Valuable Epilepsy Cure Advice

Current Research Advances, ,

Introduction 

Despite an extensive research effort and a wealth of available antiseizure medications, a cure for epilepsy remains elusive.  Riley and Danzer (2024) in a recent review discuss the reasons for this.  The path to a cure begins with preclinical research that focuses on the disease initiation termed epileptogenesis and its associated co-morbidities.  Epileptogenesis and disease-dependent co-morbidities, e.g. cognitive decline are key therapeutic targets for a cure.  Riley and Danzer (2024) provide especially valuable epilepsy cure advice by their critique of current preclinical models and proposed improvements.  The especially valuable epilepsy cure advice provided by these scientists is summarized below in a series of insights.

Preclinical animal model types:  acute, acquired and genetic

Especially valuable epilepsy cure advice – Insight 1 

In the development of antiseizure medications (Assessment 6 – Epilepsy Medication – Need to Know Information), the model of choice is the acutely provoked seizure model.  It is known that “acutely evoked seizures generated by normal brains, however, are mechanistically different from spontaneous seizures generated by epileptic brains” (Riley and Danzer, 2024).  Despite this, there are over 25 approved antiseizure medications. Many more are presently in clinical trials (Novel Anti-seizure Drugs – Ongoing Research). 

It is clear that antiseizure medications do not provide a cure for epilepsy.  Seizures return with drug cessation. As supported by clinical trial results, antiseizure medications have no ameliorating effects on epileptogenesis (origin of the seizure) or associated disease comorbidities e.g. cognitive decline.  Epilepsy cure advice proposes that basic preclinical research investigate ways to slow disease progression and initiate beneficial changes even when therapy is withdrawn (Riley and Danzer, 2024).  Since development of antiseizure medications will not yield a cure, a change in research focus is needed.

Especially valuable epilepsy cure advice – Insight 2 

Some of the preclinical epilepsy models are acquired epilepsy models induced by any number of traumatic brain injuries that go on to change the normal brain to an epileptic one.   These model will play an important role in finding a cure for epilepsy. 

However, in these models, it is important to distinguish between the effect of therapy on injury reduction per se and its effect on prevention of induced epileptogenesis.  Thus, determination of timing between these events is key.  Not surprisingly, early therapeutic interventions are more successful. This is because they reduce the effect of injury per se. Such therapy is obviously impractical in real life where brain injury is unpredictable.  Although the goal is epileptogenic therapy and disease modification, injury reduction in traumatic brain injury, where known, is still very important.

Especially valuable epilepsy cure advice – Insight 3 

Epilepsy is chronic.  Patients endure this disease for years.  Therefore, animal models need to be long term.   However, animal models are rarely chronic due to expense and time/labor commitment.  Yet chronic models would be the best ones to study.  Additional advantages of chronic models are many. They include the ability to obtain a baseline EEG, group animals according to similar seizure types, reduce variability and actually use fewer animals (Riley and Danzer, 2024).  Biomarkers would greatly facilitate investigations in epileptogenesis with chronic models (Engel and Pitkänen, 2020).  Sadly, there markers are still in early stages of development.

Especially valuable epilepsy cure advice – Insight 4 

Genetic models target a subset of epilepsies.  In these models, the time of expression of  abnormal gene(s) needs accurate determination to be relevant to epileptogenesis.  Additionally, long term studies with genetic models would be of considerable value.

Especially valuable epilepsy cure advice – Insight 5 

The epilepsy therapy screening program (ETSP)originated over 40 years ago. It provided essential data for many of the antiseizure medications approved by the FDA.  Historically, the ETSP has focused on identification of antiseizure medications for patients who are drug resistant. Currently, “the ETSP contract site has, for the first time, adopted a strategy to explore the potential of novel compounds to prevent epilepsy or to be disease modifying” (Wilcox et al., 2020).  The Neurological Diseases and Stroke of the National Institute of Health at the University of Utah funds and administers this program.  

Scientists now use several epilepsy models. These are an infection-induced model of temporal lobe epilepsy, genetic models and the validated KA-SE (Kainic Acid-Status Epilepticus) model. The latter produces spontaneous seizures.  The KA-SE model mimics temporal lobe epilepsy in humans both in epileptogenesis and disease progression. 

Analysis of therapies in these models has potential to achieve a cure. However, evaluation of therapies in novel etiologically relevant  models face many challenges.  These include lack of a positive control, need to develop an appropriate study design, determination of time window to treat following the brain insult, the duration of treatment and dose, and how long post treatment to observe animals.  These all remain for future evaluation but are realistically achievable.

Conclusions 

A number of researchers, notably those mentioned above and others, are providing especially valuable epilepsy cure advice.  It is important to move away from discovery of antiseizure medications that only suppress symptoms of epilepsy. These medications do nothing to prevent epileptogenesis or modify disease progression. They have failed to identify a cure for epilepsy.  Therapy testing in relevant animal models in essential to meet this goal.

References https://pubmed.ncbi.nlm.nih.gov/

1.  Riley VA, Danzer SC. Preclinical Testing Strategies for Epilepsy Therapy Development.Epilepsy Curr. 2024 Oct 25;25(1):51-57. doi: 10.1177/15357597241292197

2.  Engel J, Jr, Pitkänen A. Biomarkers for epileptogenesis and its treatment. Neuropharmacology. 2020;167:107735 doi: 10.1016/j.neuropharm.2019.107735

3.  Wilcox KS, West PJ, Metcalf CS. The current approach of the Epilepsy Therapy Screening Program contract site for identifying improved therapies for the treatment of pharmacoresistant seizures in epilepsy. Neuropharmacology. 2020;166:107811 doi: 10.1016/j.neuropharm.2019.107811

Anti-Seizure Drugs of the Future

Future Anti-seizure Drugs, ,

Introduction

There are now more than 30 anti-seizure drugs available to treat seizures, the manifestation of epilepsy.  Despite the ongoing effort to develop novel drugs over the past century, none of the drugs in use today cure epilepsy.  Additionally, approximately 30% of patients with epilepsy are not helped with these drugs and many patients taking anti-seizure medications experience adverse reactions.  Thus, there is a need for future anti-seizure drugs with specificity, with no adverse side effects, with greater tolerability and with a potential to cure epilepsy.  This blog will briefly review the development of present day anti-seizure drugs and describe the pipeline of future anti-seizure drugs.

History of Anti-seizure Drugs

A detailed history of the development of anti-seizure drugs has been reviewed by Loscher and Klein (2021).   Potassium bromide  (1850s) and phenobarbital (1910) were the first two drugs to treat epilepsy.  Modification of the barbital structure gave rise to the first generation of anti-seizure drugs (e.g. phenytoin, acetazolamide, ethosuximide of the 13 available by 1958).

Second generation anti-seizure drugs appeared from 1960 to 1975 with structures different from first generation anti-seizure drugs and included (valproate, carbamazepine and the benzodiazepines).  Subsequently, third generation anti-seizure drugs were developed with the objective of “targeting” a specific molecular component of excessive neuronal activity e.g. sodium channel or a neurotransmitter.  Third generation drugs of which there are 20 or more include for example, lamotrigine (lamictal), vigabatrin (sabril), levetiracetam (Kappra), and cenobamate (xcopri).

The specific CNS targets on which the third generation of drugs exert their anti-seizure effects have been reviewed in Assessment 6 – Epilepsy Medication – Need to Know Information.  Some of the third generation anti-seizure drugs exhibit fewer side effects such as reduced potential for teratogenicity (harm to fetal formation), reduced skin sensitivities (allergies), less interference with other drugs and hence greater tolerability.  However, “most novel (third-generation) anti-seizure medications are not more effective than older drugs” Losher and Klein, (2021).  Consequently, the number of patients failing to experience seizure suppression has not changed despite considerable drug discovery effort. 

Experimental Identification of Anti-seizure drugs

The majority, if not all, of the anti-seizure drugs on the market were identified in select rodent models of seizures.  The main ones are 1) MES or maximal electroshock useful in identification of drugs effective against generalized tonic-clonic seizure e.g. grand mal seizure, 2) 6-Hz seizure test and chronic kindling models important in the identification of  drugs suppressing focal-onset seizures and 3) genetic rat models for identification of drugs affecting generalized absence seizures (Loscher and Klein, 2021).  Significant drug discovery assistance has been provided by the Epilepsy Therapy Screening Program supported by National Institute of Neurological Disorders and Stroke (Kehne et al., 2017). 

Why third generation drugs are not more efficacious than older drug?

The main answer relates to preclinical drug discovery.  The standard rodent models of epilepsy have been undeniably important in anti-seizure drug development.  But as emphasized by Loscher and Schmidt (2011) there is now a clear need for additional animal models and new innovative models that can identify more efficacious anti-seizure drugs in general and anti-seizure drugs effective in patients resistant to current drugs.  More importantly, newer more relevant models, although more complex and time-consuming are needed to identify drugs capable of the prevention and cure of epilepsy.   

Another reason for the failure of third generation anti-seizure drugs to achieve greater efficacy relates to the clinical trial protocols.  For drug approval, new drugs are compared to either placebo or a low dose of an approved drug.  This lowers the bar to development of  greatly improved drugs.  The result is that comparison of efficacy head-to-head of a new drug and an approved drug remains unknown, stalling progress.   Ideally, the best clinical trial compares an approved drug with a new drug at several doses.  Expense and large number of required recruits limit this trial type.  Sadly, several  large pharmaceutical firms, which could handle large clinical trials, have discontinued their epilepsy programs; remaining smaller companies are focusing on rare genetic epilepsies.

Future Drugs in the Pipeline

There are over 20 drugs currently in Phase I, II and a few in Phase III trials.  There are 8 promising compounds still in preclinical studies but nearing a phase I clinical trial.  Many of these novel compounds have mechanisms of action different from approved drugs on the market.  The following mechanisms are of interest.

Positive Allosteric Modulators

There are 8 compounds in this group.  Five of the eight new compounds act on the GABA-A receptor.  This receptor exerts inhibitory effects on neuronal activity.  Many available drugs already target the GABA-A receptor, either through augmentation of this receptor, prevention of the GABA-A neurotransmitter degradation or reuptake.  In contrast, future compounds in development seek to stimulate a regulatory site on the receptor so as to modulate its effects on nerve transmission.  Other compounds in this group target the excitatory glutamate receptors (mGlu2 or AMPA) via positive allosteric modulation.  In this case, modulation serves to suppress nerve activity.

Potassium Channel Openers

Despite the withdrawal of the first generation potassium channel opener, retigabine, due to limited use and toxicities, there are two second generation potassium channel openers in phase II trials and one in preclinical studies.  The expectation is that enhancing the opening of potassium channels will hyperpolarize the nerve membrane and dampen excessive nerve activity.

Calcium Channel Inhibitors/Sodium Channel Modulators

Two novel compounds are in phase I and II that block T-type calcium channels and one in preclinical studies that is considered broad spectrum in blocking both calcium channels and sodium channels.  There are already several approved calcium channel blockers such as ethosuximide (zarontin), methsuximide (celontin), eslicarbazepine (aptiom) and possibly valproate (Loscher and Klein, 2021).

One novel inhibitor of the sodium channel (NaV 1.6) is in phase I trial and another compound which acts as an modulator of sodium channel activity is in preclinical studies.  There are also several sodium channel inhibitors already on the market.

Anti-inflammatory Mechanisms

Compounds in development are focused on different inflammatory mechanisms.  These include general anti-inflammatory activity, inhibition of specific inflammatory enzymes, inhibition of leukocyte migration into the brain, and antagonism of an inflammatory receptor e.g. Il-1 or its production.  Unfortunately,  inhibition of leukocyte migration has already failed in a Phase IIa  trial and data from others are considered mediocre.

Multiple Mechanisms

Compounds in this group modulate multiple targets.  For example, one compound will modulate specific proteins that carry the neurotransmitter to the nerve terminal.  The same compound will also exert benzodiazepine-like effects.  Another compound stimulates serotonin receptors and inhibits sigma-1 receptors involved in protein synthesis in nerves.  Others block sodium and calcium channels plus modulating other receptors.  Thus far this approach has not been successful with generally poor efficacy or poor reproducibility in different trials.

Other Mechanisms

Several compounds will treat rare but devastating infancy and early childhood-onset epilepsies such as Dravet and Lennox-Gastaut syndromes.  Two of these compounds seek to reduce brain metabolism, with either inhibition of the breakdown of glucose or the formation of cholesterol.  Others act by stimulating protein formation or inhibiting formation of acetylcholine, a neurotransmitter involved in memory.

Fate of Future Drugs

Future anti-seizure drugs include compounds with novel mechanisms of action (positive allosteric modulation) and known mechanisms of action (T-type calcium channel inhibitors).  Dampening inflammation or combining multiple mechanisms in one compound does not seem of value.  Whether these unique compounds will succeed in becoming an antiseizure drug to help those currently without drug therapy or become fourth generation drugs no better than previous drugs, remains to be determined.

As emphasized in several reviews, the major problem of understanding epilepsy remains unresolved.  That is, there are a wide variety of epilepsies, most with unknown causes.  It is, therefore, impossible to match a specific drug with a known mechanism of action to a person with epilepsy for which this  is only a general description of the seizure.  Drug selection by the physician is and remains empirical.  Rational drug selection even from a large assortment does not exist for the patient with epilepsy. 

Better Efficacy and Tolerability?

Will these future drugs exhibit a better efficacy and safety profile than the third generation drugs?  There is an awareness for improved safety and tolerability.  This was true for third generation drugs.  Some of the third generation drugs exhibit different pharmacokinetics and interact less if at all with other drugs. 

The fact remains that all these drugs, current and future are developed to suppress seizures. This dampens CNS activity.  And they all were screened in standard preclinical seizure models.  As a result, all will influence numerous other pathways in the brain to cause minor to major unwanted changes.  Specificity in anti-seizure drug discovery is needed but this is impossible since epilepsy itself remains a black box.  Perhaps better drugs will come with more relevant animal models.  At present correcting genetic defects responsible for some epilepsies is the most promising approach and will benefit a few that desperately need it.

References

Loscher W. Kleins P. The Pharmacology and Clinical Efficacy of Antiseizure Medications:

From Bromide Salts to Cenobamate and Beyond. CNS Drugs (2021) 35:935–963

Kehne JH, Klein BD, Raeissi S, Sharma S. The National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (ETSP) Neurochem Res (2017) 42:1894–1903

Loscher W Schmidt D. Modern antiepileptic drug development has failed to deliver: Ways out of the current dilemma Epilepsia, 52(4):657–678, 2011