Emerging drugs for partial onset seizures

Importance of the field: Patients with epilepsy have recurrent unproved seizures. Epilepsy is common, with a prevalence range that centers at around 1%. Patients with epilepsy can have a poor quality of life and suffer significant social stigma. Despite the availability of a large number of antiepileptic drugs (AEDs) including standard and newer ones, a significant percentage of patients with epilepsy remain poorly controlled.

Areas covered in this review: In this review, we briefly summarize data on the available AEDs, then present current information on the emerging AEDs, including their chemical structure, pharmacology, mechanism of action, and efficacy and adverse event profile in clinical trials. The AEDs included are rufinamide, lacosamide, eslicarbazepine, retigabine, brivaracetam, ganaxolone, stiripentol and carisbamate. Most of the literature related to these AEDs was published in the past 5 years.

What the reader will gain: The reader will become familiar with the pharmacology of emerging AEDs and the results of clinical trials with these AEDs. The reader will also be able to assess the advantages of AEDs and their potential respective places in the treatment of epilepsy.

Take home message: The emerging AEDs offer predominantly improved pharmacokinetics and tolerability and occasionally new mechanisms of action. They will probably have a modest impact on drug-resistant epilepsy.     

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Introduction: Neuropathic pain and chronic inflammatory pain are large unmet medical needs. Over the past two decades, numerous ’pain targets’ have been identified for analgesic drug discovery. Despite promising results in rodent pain models, many compounds modulating such targets lacked efficacy in clinical trials. An exception is oral EMA401, a small-molecule angiotensin II type 2 receptor (AT₂R) antagonist.

Areas covered: Herein, angiotensin II/AT₂R signaling-induced hyperexcitability and abnormal sprouting of cultured dorsal root ganglion neurons, together with radioligand binding, pharmacokinetics, analgesic efficacy and mode of action of small-molecule AT₂R antagonists in rodent models of peripheral neuropathic and chronic inflammatory pain, are reviewed. The findings of a successful Phase IIa clinical trial of EMA401 in patients with neuropathic pain are presented in brief.

Expert opinion: The functional importance of angiotensin II/AT₂R signaling has remained enigmatic for decades, and there are no clinically available medications that target the AT₂R. However, on the basis of preclinical findings and recent clinical trial data showing that the peripherally restricted, small-molecule AT₂R antagonist, EMA401, successfully alleviated neuropathic pain in a Phase II clinical trial, the AT₂R is receiving considerable attention as a new therapeutic target with human validation for the relief of peripheral neuropathic and chronic inflammatory pain conditions.     

Emerging drugs for neuropathic pain

Introduction: Neuropathic pain is a costly and disabling condition, which affects up to 8% of the population. Available therapies often provide incomplete pain relief and treatment-related side effects are common. Preclinical neuropathic pain models have facilitated identification of several promising targets, which have progressed to human clinical phases of evaluation.

Areas covered: A systematic database search yielded 25 new molecular entities with specified pharmacological mechanisms that have reached Phase II or III clinical trials. These include calcium channel antagonists, vanilloid receptor antagonists, potassium channel agonists, NMDA antagonists, novel opioid receptor agonists, histamine H3 receptor antagonists, a novel sodium channel antagonist, serotonin modulators, a novel acetylcholine receptor agonist, α-2b adrenoreceptor agonist, cannabinoid CB2 receptor agonist, nitric oxide synthase inhibitor, orexin receptor antagonist, angiotensin II 2 antagonist, imidazoline I2 receptor agonist, apoptosis inhibitor and fatty acid amide hydrolase inhibitor.

Expert opinion: Although the diversity of pharmacological mechanisms of interest emphasise the complexity of neuropathic pain transmission, the considerable number of agents under development reflect a continued enthusiasm in drug development for neuropathic pain. Ongoing enhancements in methodology of both preclinical and clinical research and closer translation in both directions are expected to more efficiently identify new agents, which will improve the management of neuropathic pain.     

Emerging drugs for focal epilepsy

ABSTRACT

Introduction: Epilepsy is one of the most serious neurological conditions, affecting almost 50 million people around the world. Despite more than 20 antiepileptic drugs (AEDs) available, seizures are still uncontrolled in one third of patients.

Areas covered: The present paper reviews current compounds in preclinical and clinical development for the treatment of focal epilepsies and new potential molecular targets recently identified.

Expert opinion: 1OP-2198, Cannabidavirin, Everolimus, FV-082, Ganaxolone, Minocycline, NAX 810–2, Padsevonil and Selurampanel seem to be particularly promising in focal epilepsy. Some of them, Everolimus and Ganaxolone, are already completing Phase III development while others are still at a preclinical stage. Everolimus represents the first example of precision-medicine in epilepsy and the first generation of disease-modifying agents but data on long-term safety are needed. Among AEDs in Phase II development, Cannabidavirin, Padsevonil and Selurampanel may represent a promising fourth generation of compounds for focal epilepsies if they successfully proceed to subsequent stages. Data on general tolerability, effects of cognition and behavior as well as the potential for interactions in polytherapy will be key element for the success or decline of these drugs.     

Pharmacotherapy for children and adolescents with epilepsy

Introduction: Childhood epilepsies are the most frequent neurological problems that occur in children. Despite the introduction of new antiepileptic drugs (AEDs) 25 – 30% of children with epilepsy remain refractory to medical therapy.

Areas covered: This review aims to highlight the main published data on the treatment of childhood epilepsy. The electronic database, PubMed, and abstract proceedings were used to identify studies. The aim of antiepileptic therapy should be to provide complete seizure control, if possible without the burden of any side effect. Since 1993, new agents have been approved for use as an antiepileptic. Although there are few published data (especially in pediatric populations) to establish that the second-generation AEDs are more efficacious than the older AEDs, they appear to have better tolerability.

Expert opinion: Old AEDs are efficacious agents that continue to play a major role in the current treatment of epilepsy. These agents actually remain the first-line treatment for many specific seizure types or epileptic syndromes. The new AEDs were initially approved as adjunct agents and – subsequently – as monotherapy for various seizure types in the adult and children. Despite these improvements, few AEDs are now considered to be a first-choice for the treatment of epilspsy in children.     

Pharmacological management of epilepsy: recent advances and future prospects

There is still a need for new antiepileptic drugs (AEDs) as the clinical efficacy, tolerability, toxicity or pharmacokinetic properties of existing AEDs may not be satisfactory. One new AED has recently been approved (rufinamide in 2007) and six others are in late-stage development (phase III and onwards) [brivaracetam, carisbamate, eslicarbazepine, lacosamide, retigabine and stiripentol]. The purpose of this review is to provide updated data on proposed mechanisms of action, efficacy and tolerability on these new AEDs, and to discuss the rationale for their development and possible advantages compared with existing treatment, based on recent publications and MEDLINE searches.Rufinamide, brivaracetam and stiripentol have been given the status of orphan drugs. Rufinamide was approved in Europe in 2007 for the use in Lennox-Gastaut syndrome. Brivaracetam has gained orphan status for development in progressive and symptomatic myoclonic seizures in Europe and the US, respectively. Stiripentol has gained orphan status in children with Dravet's syndrome and pharmaco-resistant epilepsy. All of these drugs demonstrate efficacy as adjunctive therapy in partial seizures. Three of the drugs are derivatives of existing AEDs: brivaracetam is a derivative of levetiracetam with improved affinity for the target molecule; carisbamate is a derivative of felbamate with improved tolerability; and eslicarbazepine is a derivative of carbamazepine with less interaction potential and no auto-induction. Lacosamide, retigabine, rufinamide and stiripentol are new compounds, unrelated to other AEDs.Further investigation and development of new broad-spectrum drugs is important for improved treatment of patients with epilepsy and other neurological and psychiatric disorders.     

Emerging drugs for endometriosis

Background: Endometriosis is a benign, common gynecological disorder affecting mostly women of reproductive age. It is associated with dysmenorrhea, pelvic pain, and subfertility. The current non-surgical medical treatment is not satisfactory and there is a pressing need for novel therapeutics with better efficacy, tolerability and safety profiles. Objective: To investigate the development of new therapies for endometriosis. Methods: The PubMed database has been extensively searched for all compounds tested preclinically and clinically. Results/conclusion: Besides the three main classes of drugs, i.e., GnRH agonists, progestins, and androgenic agents, there are several classes of compounds that have been tested preclinically and clinically. Surprisingly, a considerable proportion of officially registered Phase II/III clinical trials are listed as completed yet no information on their outcomes is available. Three completed and published Phase II trials found the tested compound disappointing. Another two Phase II clinical trials have been suspended. This apparent gap between the generally promising preclinical findings and the clinical trial outcomes reflects our current woefully inadequate understanding of the mechanisms underlying endometriosis-associated pain and subferitility and recurrence of endometriosis; questions the adequacy and value of animal models of endometriosis that are still in use; highlights the difficulty in developing new therapeutics for endometriosis; and calls for more research in the mechanisms underlying endometriosis-associated pain and subferitility and recurrence of endometriosis.     

Brivaracetam for the treatment of epilepsy

Introduction: Approximately one third of patients with epilepsy fail to respond to existing medications. Levetiracetam is an effective antiepileptic drug (AED) postulated to act by binding to synaptic vesicle protein 2A. Brivaracetam is a novel high affinity SV2A ligand with approximately 20-fold higher affinity for SV2A protein than levetiracetam. It is at an advanced stage of clinical development for treatment of epilepsy.

Areas covered: This article reviews animal data, pharmacokinetics, and phase 1-3 data of Brivaracetam treatment of epilepsy. Brivaracetam has broad-spectrum anticonvulsant activity in animal models.

Expert Opinion: Phase 1 studies indicated that single oral doses of 5-800 mg and repeated oral doses of up to 600 mg were well tolerated and showed favorable pharmacokinetic profile. Phase 2 studies indicated good safety and tolerability of brivaracetam in the dose range of 5-150 mg/day and provided proof of concept for efficacy in treating refractory partial onset seizures. Efficacy and safety have been evaluated in 4 phase 3 studies with dose range of 5-200 mg which have demonstrated efficacy in the range of 100-200 mg/day dose and, in most studies, also with 50 mg/day dose, and good safety and tolerability profile across 5-200 mg doses in adjunctive treatment of refractory partial onset seizures.     

Eslicarbazepine acetate: a new option for the treatment of focal epilepsy

Background: Epilepsy is a neurological condition with an increased probability of seizure occurrence through time. Although many anti-epileptic drugs (AEDs) exist, they fail to treat seizures in 30% of patients with epilepsy. For these patients, new AEDs potentially more efficacious and safe are developed. Objective: To evaluate the effectiveness of eslicarbazepine acetate (ESL) in the treatment of patients with refractory epilepsy. Methods: A review of the literature was carried out using PubMed central. A direct contact with the drug manufacturer and developer was made. Results/conclusion: ESL is an AED that acts by inhibiting voltage-gated sodium channels. It has proved efficacious in the treatment of patients with refractory focal-onset epilepsy with a good safety profile. Evaluation of its use for treating other epileptic syndromes and its role as an initial treatment option for patients with epilepsy is warranted.     

New antiepileptic drugs that are second generation to existing antiepileptic drugs

In the last decade, 10 new antiepileptic drugs (AEDs) have been introduced that offer appreciable advantages in terms of their favourable pharmacokinetics, improved tolerability and lower potential for drug interactions. However, despite the large therapeutic range of old and new AEDs, ～ 30% of the patients with epilepsy are still not seizure free and, consequently, there is a substantial need to develop new AEDs. The new AEDs currently in development can be divided into two categories: drugs with completely new chemical structures such as lacosamide (formally harkoseride), retigabine, rufinamide and talampanel; and drugs that are derivatives or analogues of existing AEDs that can be regarded as second-generation or follow-up compounds of established AEDs. This article focuses on the second category and thus critically reviews the following second-generation compounds: eslicarbazepine acetate or BIA-2-093 and 10-hydroxy carbazepine (carbamazepine derivatives); valrocemide and NPS 1776 (isovaleramide; valproic acid derivatives); pregabalin and XP13512 (gabapentin derivatives); brivaracetam (ucb 34714) and seletracetam (ucb 44212; levetiracetam derivatives); and fluorofelbamate (a felbamate derivative). In addition, a series of valproic acid derivatives that are currently in preclinical stage has also been evaluated because some lead compounds of this series have a promising potential to become new antiepileptics and CNS drugs. For any of these follow-up compounds to become a successful second generation to an existing AED, it has to be more potent, safer and possess favourable pharmacokinetics, including low potential for pharmacokinetic and pharmacodynamic drug interactions.     

New antiepileptic drugs that are second generation to existing antiepileptic drugs

In the last decade, 10 new antiepileptic drugs (AEDs) have been introduced that offer appreciable advantages in terms of their favourable pharmacokinetics, improved tolerability and lower potential for drug interactions. However, despite the large therapeutic range of old and new AEDs, approximately 30% of the patients with epilepsy are still not seizure free and, consequently, there is a substantial need to develop new AEDs. The new AEDs currently in development can be divided into two categories: drugs with completely new chemical structures such as lacosamide (formally harkoseride), retigabine, rufinamide and talampanel; and drugs that are derivatives or analogues of existing AEDs that can be regarded as second-generation or follow-up compounds of established AEDs. This article focuses on the second category and thus critically reviews the following second-generation compounds: eslicarbazepine acetate or BIA-2-093 and 10-hydroxy carbazepine (carbamazepine derivatives); valrocemide and NPS 1776 (isovaleramide; valproic acid derivatives); pregabalin and XP13512 (gabapentin derivatives); brivaracetam (ucb 34714) and seletracetam (ucb 44212; levetiracetam derivatives); and fluorofelbamate (a felbamate derivative). In addition, a series of valproic acid derivatives that are currently in preclinical stage has also been evaluated because some lead compounds of this series have a promising potential to become new antiepileptics and CNS drugs. For any of these follow-up compounds to become a successful second generation to an existing AED, it has to be more potent, safer and possess favourable pharmacokinetics, including low potential for pharmacokinetic and pharmacodynamic drug interactions.     

Utilization of zonisamide inpatients with chronic pain orepilepsy refractory to othertreatments: a retrospective,open label,uncontrolled studyin a VA hospital

SUMMARY

Objectives: Zonisamide (1,2-benzisoxazole-3-methanesulfonamide) is a novel antiseizure medication approved for use in the United States as adjunct therapy in the treatment of partial seizures in adults with epilepsy. It has also been used to treat other conditions including intractable pain. The aim of this study was to determine the usefulness of zonisamide in patients whose seizures were not controlled after having been treated with at least three other currently available anticonvulsant medications or in patients whose pain control was suboptimal despite the use of commonly used drug regimens.

Methods: This was a retrospective study documenting the efficacy of zonisamide in 48 consecutive patients who presented at an outpatient neurology clinic at a Veterans Administration hospital. The patients were diagnosed with refractory partial seizures (n?=?21) or a variety of intractable neuropathic pain syndromes (n?=?27).

Results: Sixteen out of 21 seizure patients (76%) experienced a 50% or greater reduction in seizure frequency when zonisamide (100–200?mg daily) was added to their existing anticonvulsant medication regimen. Of 27 patients with neuropathic pain, 17 (59%) responded to zonisamide, reporting subjective reduction in pain by at least 50%. The most common adverse events were gastrointestinal upset, somnolence, and one case of skin rash.

Conclusions: In this study, zonisamide appeared to be an effective adjunct therapy in the treatment of partial seizures in adults who continued to experience frequent episodes while taking other anticonvulsant medications, and in adults whose neuropathic pain was not well controlled with analgesics. These promising results must be tempered by the fact that this investigation included a small patient population in an uncontrolled study design. Further research into the efficacy and tolerability of zonisamide in these areas is warranted.     

Antiepileptic drugs in non-epilepsy disorders: relations between mechanisms of action and clinical efficacy

Antiepileptic drugs (AEDs) are used extensively to treat multiple non-epilepsy disorders, both in neurology and psychiatry. This article provides a review of the clinical efficacy of AEDs in non-epilepsy disorders based on recently published preclinical and clinical studies, and attempts to relate this efficacy to the mechanism of action of AEDs and pathophysiological processes associated with the disorders. Some newer indications for AEDs have been established, while others are under investigation. The disorders where AEDs have been demonstrated to be of clinical importance include neurological disorders, such as essential tremor, neuropathic pain and migraine, and psychiatric disorders, including anxiety, schizophrenia and bipolar disorder. Many of the AEDs have various targets of action in the synapse and have several proposed relevant mechanisms of action in epilepsy and in other disorders. Pathophysiological processes disturb neuronal excitability by modulating ion channels, receptors and intracellular signalling pathways, and these are targets for the pharmacological action of various AEDs. Attention is focused on the glutamatergic and GABAergic synapses. In psychiatric conditions such as schizophrenia and bipolar disorder, AEDs such as valproate, carbamazepine and lamotrigine appear to have clear roles based on their effect on intracellular pathways. On the other hand, some AEDs, e.g. topiramate, have efficacy for nonpsychiatric disorders including migraine, possibly by enhancing GABAergic and reducing glutamatergic neurotransmission. AEDs that seem to enhance GABAergic neurotransmission, e.g. tiagabine, valproate, gabapentin and possibly levetiracetam, may have a role in treating neurological disorders such as essential tremor, or anxiety disorders. AEDs with effects on voltage-gated sodium or calcium channels may be advantageous in treating neuropathic pain, e.g. gabapentin, pregabalin, carbamazepine, oxcarbazepine, lamotrigine and valproate. Co-morbid conditions associated with epilepsy, such as mood disorders and migraine, may often respond to treatment with AEDs. Other possible disorders where AEDs may be of clinical importance include cancer, HIV infection, drug and alcohol abuse, and also in neuroprotection. A future challenge is to evaluate the second-generation AEDs in non-epilepsy disorders and to design clinical trials to study their effects in such disorders in paediatric patients. Differentiation between the main mechanisms of action of the AEDs needs more consideration in drug selection for tailored treatment of the various non-epilepsy disorders.     

Lestaurtinib,a multitargeted tyrosinse kinase inhibitor: from bench to bedside

Importance of the field: Internal tandem duplication of the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD) is a common recurring mutation in acute myeloid leukemia (AML) with normal karyotype, and the presence of FLT3-ITD confers a poor prognosis on this large subgroup of AML patients. Since the discovery of lestaurtinib as a potent FLT3 inhibitor, in 1985, there has been considerable interest in the development of this agent (CEP-701, Cephalon, Frazer, PA, USA) for treatment of this population.

Areas covered in this review: An extensive literature search was conducted that included published articles and abstracts on the preclinical and clinical development of this agent spanning the last decade.

What the reader will gain: The review describes the historical development of this agent and reviews the available preclinical and clinical data on lestaurtinib and expands on potential future directions in development of this agent.

Take home message: Lestaurtinib is a multi targeted tyrosine kinase inhibitor which has been shown to potently inhibit FLT3 at nanomolar concentrations in preclinical studies, leading to its rapid development as a potential targeted agent for treatment of AML. Phase I studies have shown lestaturtinib to be an active agent particularly when used in combination with cytotoxic drugs. Currently, Phase II and Phase III studies are underway aiming to establish the future of this agent as a treatment option for patients with FLT3-ITD AML.     

Relative performance of brivaracetam as adjunctive treatment of focal seizures in adults: a network meta-analysis

Objective: To estimate the relative efficacy, safety and tolerability of adjunctive brivaracetam and other antiepileptic drugs (AEDs) using a Bayesian network meta-analysis (NMA) approach.

Methods: A systematic literature review (SLR) identified randomized controlled trials of AEDs treating focal (partial-onset) seizures for ≥8 weeks and assessed them for inclusion in the NMA. Bayesian random-effects NMA was performed for several outcomes. All interventions within the licensed dose range were included in the network of evidence.

Results: The SLR identified 82 studies; 65 were included in the NMA. These studies had baseline mean age 33.1–38.0 years, mean duration of epilepsy 18.7–23.0 years and median seizure frequency/28 days 8.1–11.8. All AEDs had significantly higher odds than placebo of achieving ≥50% responder rates (odds ratios 1.83–3.58) and all AEDs had a trend of higher odds than placebo of achieving seizure freedom (odds ratios 1.36–5.73), most being statistically significant. Tolerability outcomes were comparable between AEDs; most AEDs had higher odds than placebo of treatment-emergent adverse events leading to discontinuation, serious AEs, nausea, fatigue, dizziness and somnolence.

Conclusions: This NMA would appear to show relative equivalence in efficacy, safety and tolerability outcomes of the included AEDs. However, patient heterogeneity within trials and in clinical practice should be considered when interpreting these results. While NMAs are based on the best available evidence the authors suggest that, due to the inability of NMAs to capture unmeasured confounding factors and population heterogeneity, NMAs must not be the sole basis for comparative treatment recommendations.     

T-type calcium channel blockers: a patent review (2012–2018)

ABSTRACT

Introduction: T-type calcium channels are attractive targets for potential treatment of epilepsy inflammatory or neuropathic pain, insomnia, Parkinson’s disease, and cancer. Three isoforms having different biophysical functions are expressed in peripheral and central nerve. Since the withdrawal of mibefradil, the first compound marketed for selective T-type calcium channel blockade, extensive efforts have been made to identify more selective T-type calcium channel blockers.

Areas covered: This review covers the 43 patents describing ‘organic small molecules as T-type calcium channel blockers’-published since 2012. The most recent similar patent review was published in 2011. Information from a recent review article and relevant research papers has been included, as well as biological data and clinical trial results where available.

Expert opinion: Triazinone derivatives, carbazole compounds, and aryl triazole/imidazole amide derivatives display potent blockade activity α1H, α1G, and pan T-type calcium channel subtypes, respectively, though the specificity of the letter is still unsatisfactory. Nonetheless, improvements seen in the efficacy of compounds targeting α1H T-type calcium channels indicate significant progress. Ongoing clinical trials are for the candidates Z944 (Phase II) and ACT-709478 (Phase II) appear promising. These studies may lead to a new generation of inhibitors with higher selectivity, improved physicochemical properties, and reduced side effects.     

Pharmacotherapy of the third-generation AEDs: lacosamide,retigabine and eslicarbazepine acetate

Introduction: The search for new, more effective antiepileptic drugs (AEDs) continues. The three most recently approved drugs, the so-called third-generation AEDs, include lacosamide, retigabine and eslicarbazepine acetate and are licensed as adjunctive treatment of partial epilepsy in adults.

Areas covered: For the above three AEDs, their mechanisms of action, pharmacokinetic characteristics, drug–drug interactions, pharmacotherapeutics, dose and administration and therapeutic drug monitoring are reviewed in this paper.

Expert opinion: Lacosamide and retigabine act through novel mechanisms, while eslicarbazepine acetate, a pro-drug for eslicarbazepine, acts in a similar manner to several other AEDs. All three AEDs are associated with linear pharmacokinetic and rapid absorption and undergo metabolism. Their drug–drug interaction profile is low (lacosamide and retigabine) to modest (eslicarbazepine) in propensity. At the highest approved doses for the three AEDs, responder rates were similar. The most commonly observed adverse effects compared with placebo were dizziness, headache, diplopia and nausea for lacosamide; dizziness, somnolence and fatigue for retigabine and dizziness and somnolence for eslicarbazepine acetate. The precise role that these new AEDs will have in the treatment of epilepsy and whether they will make a significant impact on the prognosis of intractable epilepsy is not yet known and will have to await further clinical experience.