Epilepsy Pipeline Update 2010

Joyce Cramer, President, Epilepsy Therapy Project

The world was watching the Winter Olympics in Vancouver during February, but the focus of people interested in epilepsy was on the special event taking place in San Francisco February 25 – 26, 2010. The Epilepsy Pipeline Update – 2010 was the “NeurOlympics” featuring entrepreneurs who had already won preliminary events and achieved success by forming a company and securing patent rights to bear novel approach to epilepsy treatment. The program allowed these entrepreneurs to display (rather than compete) their prowess in demonstrating efficacy toward helping advancing seizure control or other factors related to epilepsy. The sheer number all startup companies interested in epilepsy was astounding, with presentations by:

• 11 companies working on devices and hybrids to detect or prevent seizures, some by brain stimulation and others by direct drug delivery into the brain.
• 4 groups described new animal models or genetic approaches to understanding epilepsy treatment period.
• 11 companies described drugs (new molecular entities) or biologics (gene-based treatments)
• 4 companies described early clinical studies with drugs already evaluated for basic safety in humans.
• 7 companies described late stage clinical studies of drugs ready to be submitted to the food and drug administration for regulatory review.
• 6 companies provide updates all of already marketed drugs, including new information about mechanisms of action and potential new indications.

We know that despite the dozen or more currently approved epilepsy treatments there is an enormous unmet need for better or seizure control with fewer adverse effects for the 50 million people worldwide who have epilepsy, including 3 million in the USA. Estimating that one third of people have poor seizure control despite use of multiple different drugs, these companies could see the potential for a new approach.

Who would have guessed that so many groups would be willing to embark on the long, arduous, expensive route toward developing yet another epilepsy treatment? I was astounded that so many companies responded to my invitation to be a presenter at the conference. This was particularly surprising because of the devastating effect the economic turn-down had caused on capital investments in startup companies. That’s why I say we saw the best of the best, the ones who survived the capital crunch in 2009 and stayed afloat, continuing their work.

This conference was particularly important in the 2010 environment because most major pharmaceutical companies have greatly reduced or eliminated their basic research programs. Instead, they are relying on venture funds to support start-ups with new ideas. This risk is shifted to investors who win on less than 1 in 10 of their investments. Large companies then pick the winners for something already de-risked. This new model puts all the risk for new therapy development on the entrepreneurs, early angel investors, and venture capital funds to support the 9 of 10 companies that will not succeed. ETP plays a valuable role by providing guidance as well as non-dilutive funding to start-up groups who need extra funds from our grants and small investments, as well as the public recognition that ETP business and scientific experts consider the concept likely to succeed.

PROGRAM

The agenda for the full program may be seen at http://www.epilepsy.com/etp/pipeline2010_program and webcasts of presentations are available at http://www.epilepsy.com/etp/pipeline2010_webcasts.

The concept of "open innovation" described by the keynote speaker Henry Chesborough PhD (Haas Business School, UC Berkeley), explained much of the current approach to developing new ideas both in the business and medical research areas. He explained the need for big companies to look outside their own resources for new ideas, comparing costs of missing the next big idea with the cost of openness. The program progressed through the Science of Epilepsy with overviews on seizure detection/devices, and mechanisms of action of drugs and biologics, screening models, and novel formulations. Robert Fisher MD, PhD (Stanford University, and Editor-in-Chief of www.epilepsy.com) reviewed a dozen approaches to extra cranial and intracranial seizure detection and modulation , as well as watch like devices. Ivan Osorio MD provided some pros and cons to temper the discussion on devices, noting the hurdles to be overcome in these invasive approaches. Michael Rogawski M.D. Ph.D. first lamented the dearth of large pharmaceutical companies investing in research to develop drugs for epilepsy but then described the limitations of therapy with small molecules. He highlighted the promise of alternative approaches and direct delivery of drug into the brain to minimize the toxicity of orally administered drugs. Roger Porter MD questioned whether knowing a specific mechanism was as important as a other features of drug discovery, particularly efficacy in clinical practice. Steven White PhD commented on the usefulness of currently available screening models for preclinical testing of compounds. Although the NIH Anticonvulsant Screening Project provides free testing of any new compound, the limited number of all assays probably misses many potentially effective drugs because they are not efficacious in these traditional models. Stephen Collins MD PhD noted that new models are being developed, but have not yet been incorporated into the NIH testing program, thereby leaving the gap in our ability to evaluate drugs that work by novel mechanisms. James Cloyd PhD reviewed the commercial unmet need for drugs that treat sometimes very rare specific syndromes. Such drugs can be developed as an orphan indication. He also described approaches to novel formulations for existing drugs that could be more convenient for patients as well as extend patent protection. The need for treatment that could be administered rapidly and have immediate efficacy in acute situations would be quite be achieved with a nasal spray despite the many limitations inherent in this route of administration. An intramuscular administration (currently in testing) also may be effective. These alternative routes would be more acceptable to many patients than is the currently available rectal administration route, the only currently approved treatment of acute repetitive seizures. Jacqueline French MD noted the pros and cons of novel formulations the difficulty in testing them in order to achieve regulatory approval.

PIPELINE REVIEWS

Interspersed among these plenary discussions on a science of epilepsy were intensive reviews of dozens of pipeline companies (see listing below). Each group was allowed “five slides in five minutes” to describe how they are device or drug worked, its patent status, development challenges, timelines/milestones and financial needs, as well as expectations of what it would bring to the marketplace. Rigorously brief presentations gave the audience rapid-fire overviews of the 43 companies and their programs. Although it felt like speed-dating, there were numerous opportunities for networking among investors and entrepreneurs, when they could exchange information and make plans for follow-up.

PANELS

Highlights of the program included panels in which investors and corporate executives discussed their views on the current milieu for medical research and marketing success. Investors addressed the impact of changes in financing and how to get started and keep glowing in the new venture capital model. The five panelists all had experience in the biotechnology space when times were good, but have revised views about how their world will function for the next few years. Basically, large companies do not recognize the continuing unmet need for an effective treatment, thinking that the dozen currently available drugs fill the market. Yet, epilepsy is an attractive portal into other central nervous system (CNS) indications (e.g., pain, migraine, bipolar disorder) because of predictive animal models, standardized clinical trials with established endpoints, and opportunity to gather long-term safety data. Although the “old” model for investors included late partnering with major companies ending with a public offering of stock or acquisition by another company, the “new” model is to partner early to improve cash flow and assure acquisition when the product is mature. The potential to become an independent company is considered highly unlikely for the near future. In addition, investing will be more milestone-driven than in the past. This risk-reward model requires less investment cash up-front, but is less lucrative for investors for successes.

The view from the entrepreneurial side revolved around market dynamics and the value of developing a product for epilepsy before or simultaneously with another indication. On the positive side, although the market has been consistent for decades, “blockbuster” drugs still can’t succeed. Both drugs and devices focused solely on epilepsy, with no other indications, can be highly successful. These companies gain expertise in the epilepsy domain that is invaluable in achieving and maintaining market share. Nonetheless, new treatments can emerge given novel approaches, what management teams, and focused approaches toward establishing efficacy and tolerability. I spoke about the usefulness of non-dilutive funding and overall support from a non-profit organization like Epilepsy Therapy Project was a positive note for entrepreneurs who need both the grants and investments made by ETP, but also the imprimatur of our recognition that the company is likely to succeed.

REIMBURSEMENT

After spending 5-6 years in clinical trials (and $30-$60million) to achieve FDA approval, the next hurdle is to obtain reimbursement from various commercial health insurers, pharmacy benefit management, and federal agencies (Medicare Part D, Medicaid, VA and military formularies etc.). This is a difficult time for new products for any medical disorder because of the numerous drugs that are now available in generic formulations. The requirement is to be listed on a drug formulary but also to have a low co-payment. A requirement for prior authorization is another step that can limit prescribing any new drug. Devices have different , but equally difficult, hurdles establish reimbursement. All of these steps are needed to reach patients. A potential future limitation on epilepsy treatments may be the greater use of comparative effectiveness studies. This approach may require head-to-head studies to demonstrate the superiority of a product (efficacy and tolerability) with the winner taking all by excluding losers from formularies. Thus far, epilepsy treatments had not been given the scrutiny of other types of therapies (e.g., antihypertensives) because they are considered high need for a relatively small population.

BIOMARKERS

With the expanding number of available therapies, the next question is how can we predict which treatment (particularly drug) will be appropriate for an individual patient? Although the electroencephalogram is a physiological biomarker, its use has been limited to differentiating between primary and partial onset epilepsies. The new era of genomics should be leading us toward a match between drugs that work on specific ion channels and patients who have genetic abnormalities for that channel. This new technology allows sophisticated research comparing large numbers of genes, proteins and protein fragments to learn what differentiates affected and non-affected people, as well as responders and nonresponders to treatments. An example of a poorly understood problem is sudden unexplained death in epilepsy (SUDEP) for which neither is a predictor known nor is the mechanism for death understood. Ongoing research in animal studies suggest that potassium and sodium channels occurring in both heart and brain tissue might be at fault. Defects in these channels may be the link between cardiac arrhythmia and SUDEP. Studies in humans are needed to confirm this hypothesis for a rationale for preventing the tragedy of SUDEP. Variance in other ion channels may alter cellular excitability that leads to seizures and epilepsy. Avenues for prediction all seizure susceptibility may come from better understanding of genetic mutations in individuals predispose them to seizures. These markers may be the “path to the pot of gold” that improves epilepsy treatment for millions around the world.

SUMMARY

The good news is that although we already have more than 15 approved therapies for epilepsy, so many scientists are continuing to search for new approaches. Today we must ask whether the start-up companies (listed below) will be able to bring their ideas to fruition, and deliver new therapies to people with epilepsy. Venture capital funds have reduced their investments in early-stage ideas that traditionally move ideas forward. More and more entrepreneurs come to Epilepsy Therapy Project for a grant or seed investment so they can continue developing their idea.

Joyce Cramer
President, Epilepsy therapy Project

The agenda for the full program  may be seen at http://www.epilepsy.com/etp/pipeline2010_program and webcasts of individual presentations may be seen at http://www.epilepsy.com/etp/pipeline2010_webcasts.

A review of the epilepsy pipeline

Please contact Joyce Cramer for additional information (joyce@epilepsytherapyproject.org)

The agenda for the full program may be seen at http://www.epilepsy.com/etp/pipeline2010_program and webcasts of individual presentations may be seen at http://www.epilepsy.com/etp/pipeline2010_webcasts.