Epilepsy drugs have 'little effect' on patients becoming seizure-free: paper

Central Clinical School researchers have been investigating the efficacy, toxicity and tolerability of newer generation anti-epileptic drugs – an area that has been under-researched. We present some of their findings in this series of stories.  

by Anne Crawford

From 1989 on, 18 new antiseizure medications were developed around the world to address the shortcomings of older, first-generation drugs. Thirty years later none of these ‘second-generation’ drugs appear to be substantially more effective than their predecessors, a review co-written by a Department of Neuroscience researcher has found.

Professor Patrick Kwan was part of an international group of clinician-researchers who reviewed the overall impact of second-generation anti-seizure medications on epilepsy management in a paper published recently in Lancet Neurology.

“The four of us have been directly involved in developing, evaluating and using the second-generation ASMs in one way or the other over the past three decades. Naturally, we thought it would be timely to ‘stock-take’ on what we have learnt and how the field should move forward in epilepsy therapy development,” Professor Kwan said.

While the review finds that some second-generation drugs have shown advantages in tolerability and safety – particularly in the treatment of older patients and women of childbearing potential – it reported they have had little effect on the proportion of patients who become free of seizures.

The review stresses the need for novel strategies in epilepsy drug development to counter their shortcomings.

Second-generation drugs were developed to overcome the problems of older existing drugs including barbiturates, benzodiazepines and valproic acid, such as their ineffectiveness in controlling the seizures in a third of patients, propensity to induce many adverse effects including pregnancy outcomes, undesirable interactions with other drugs and unfavourable pharmacokinetics (the movement of the drug into, through, and out of the body).

Some have conferred advantages. The advent of second-generation drugs has widened treatment options, expanding opportunities for clinicians to tailor treatment choices based on individual patient characteristics – a key principle in the management of this heterogeneous disease.

Another benefit is that they have a low propensity to cause metabolic drug interactions, which is particularly advantageous for patients receiving other medications. Some have been shown to be safer for women to take during pregnancy and have benefits for older people and patients with comorbid conditions, such as migraine, anxiety, bipolar depression and neuropathic pain.

Certain second-generation medications, such as levetiracetam, also offer safety advantages in patients with a history of hypersensitivity reactions to certain other anti-seizure drugs.

For many of them, the introduction of generic options has improved their accessibility, but overall these drugs remain more expensive than first-generation agents, the review finds.

One of the reasons why little progress has been made in reducing the burden of drug resistance is the use of traditional preclinical models, and by targeting seizures rather than the underlying disease; a change in the approaches used for drug discovery is needed, the paper urges.

“Our review is not meant to be nihilistic, but to show why we need ever-more effort from the scientific community, and investment from the government and pharmaceutical industry to develop more efficacious and safer treatments for epilepsy,” Professor Kwan said.

Future treatments are likely to become increasingly personalised and target the molecular mechanisms responsible for the manifestations, or the development, of epilepsy. Areas in which important progress is being made include the targeting of molecular defects due to epilepsy gene mutations, autoimmune mechanisms, neuroinflammation, and dysfunction in the brain-gut-microbiome axis.

Ongoing projects focus not only on discovery of new chemical entities, but also on the repurposing of medications used for other indications and non-pharmacological interventions such as gene therapies and stem cell therapies, the review finds.

Chen Z, Brodie MJ, Liew D, Kwan P. Treatment Outcomes in Patients With Newly Diagnosed Epilepsy Treated With Established and New Antiepileptic Drugs: A 30-Year Longitudinal Cohort Study. JAMA Neurol. 2018 Mar 1;75(3):279-286. doi: 10.1001/jamaneurol.2017.3949.