The Web Pipeline
In the final self-standing annual report of the Epilepsy Therapy Project (ETP), now merged into the Epilepsy Foundation, we described the creation of the Epilepsy Therapy Pipeline, a listing available on www.epilepsy.com. This list describes potential new therapies for epilepsy and categorizes each by stage of development. Since that report of 2011, the pipeline has expanded to 120 projects. Epilepsy is fortunate to have preclinical models in which to test new therapies, and the fruits of this availability are demonstrated in the robust pipeline. Even more remarkable, the Foundation, including the ETP, has contributed to 60 of these projects, an astonishing 50 percent. Although more resources are needed for translational research, the Foundation is committed to increasing its impact in research in the coming years. For those projects which are beyond the current financial reach of the Foundation, a new award, the Epilepsy Innovation Seal of Excellence launched in the spring to attract the private sector to outstanding opportunities.
The Pipeline Conferences
In addition to keeping tally of potential new epilepsy therapies with the web pipeline, ETP and now the Foundation, have been busy with conferences to highlight the latest advances. Most of you are aware of the Epilepsy Pipeline Update held every other year in San Francisco—the last was in February 2012 and the next is in early June 2014. You may not be aware that we have sponsored a day-long pipeline session held on alternate years at the Antiepileptic Drug and Device Trials (ADDT) meetings in Florida. The most recent of these meetings was in May 2013 and was highly successful.
Highlights of the Most Recent ADDT Meeting
On May 15 through 17, 2013, we collaborated with New York University and the Epilepsy Study Consortium to convene the 12th Antiepileptic Drug and Development conference in Aventura, Florida. The meeting was attended by more than 200 scientists, clinicians, trialists, representatives of pharmaceutical companies and advocates for epilepsy. In addition, there were representatives from government agencies such as the National Institutes of Health and the Food and Drug Administration. The purpose of the meeting was to bring together all of the stakeholders involved in delivering new therapies and devices to the epilepsy community and to discuss advances, roadblocks, and new initiatives. The meeting was followed by a review of many of the new drugs and devices currently in development (“The Pipeline”).
Also, the second “Shark Tank” competition was held. This competition seeks out entrepreneurs working in the Epilepsy therapeutics and device area and offers a $100,000 prize to the person who is deemed the most likely to improve the lives of patients with epilepsy in the near term. The top five finalists presented their ideas live at the conference, and a panel, along with the audience, voted on the winner.
What was on the mind of the conference presenters and participants? One thing was one of the most grievous problems with current therapies, namely adverse effects of the medications used to control seizures. Several scientists discussed new ways to identify how likely new drugs might be to cause side effects, before the drugs are ever used in people. Using new techniques for measuring behavioral abnormalities in animal models may reduce the possibility of advancing drugs to the market with unpleasant adverse effects. Possible measures include a variety of tests under the headings of general behavior, anxiety, depression, mood, and cognition. Just watching animals, and determining how they move in their cages, can indicate sedation and incoordination. In an effort to quantify the current experience with adverse effects, an ILAE (International League Against Epilepsy) working group asked leading expert clinicians to rate (admittedly in subjective manner) current medications with “smiley faces.” If the drug was less harmful than most in a particular area, a white smile was indicated; worse adverse effects were categorized as orange and the very worst as red—see the chart below.
The challenge, of course, is that virtually all anti-seizure drugs have adverse effects at high doses; eliminating otherwise promising drugs from further development on the basis of these behavioral tests will not be risk-free. Nevertheless, the effort to confront this issue is now front and center.
Another hot topic was the increasing partnership with the Food and Drug Administration (FDA) in the design of trials for new therapies. One of the most interesting—and provocative—observations at the meeting was an analysis of the impact of being on the placebo arm of a controlled trial. Specifically, in an analysis of 112 trials, the incidence of SUDEP (Sudden Unexpected Death in Epilepsy) in patients taking placebo was between 5 and 10 times higher than patients taking the active drug under test. To further address this, the FDA has asked for an independent review of SUDEP in placebo arms of most pivotal trials to determine whether being on add-on placebo in a randomized controlled trial is safe. Several alternative trial designs that would limit placebo exposure were discussed. The FDA is also considering eliminating the need for both monotherapy (using the drug alone) and adjunctive therapy (using the drug combined with others) indications for antiepileptic drugs—reflecting not only the difficulty of demonstrating effectiveness of monotherapy in a clinical trial setting but also recognizing the growing expert opinion that drugs proven effective as adjunctive therapy would also be effective when used alone, and this may not require independent proof.
Finally, new seizure detection and alerting devices are coming forward in new and impressive ways. Each new device has its own advantages and shortcomings, but better delineation of seizures seems destined to help not only individual patients but also contribute greatly to the quality of our clinical trials. Some of the notable devices are shown below.
Many other exciting advances were apparent at the ADDT meeting; the few highlighted here give only a brief glimpse into the spectrum of the meeting.
We hope to see you at the next Epilepsy Pipeline Update in San Francisco, California, June 5 to 7, 2014!