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:
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.
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.
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.
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.
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.
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.
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.
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.
Please contact Joyce Cramer for additional information (firstname.lastname@example.org)
($ -supported by ETP)
|Advanced Neurometrics||Ambulatory EEG Cap||EEG recording without the nuisance of needles attached to the scalp with glue; can be used for long-term recording while the person walks around or sleeps. In development.|
|BioLert||Seizure alert system||A motion detector that senses seizures; can send signal to alert family. In clinical testing.|
|Cyberonics||Vagus Nerve Stimulation||Seizure detector that can activate the VNS signal; also could record seizures as an electronic diary. In development.|
|IntelliVision||$-SmartWatch Alert||A motion detector that senses seizures; can send signal to alert family. In clinical testing.|
|Medtronic||Deep brain stimulation||Electrodes implanted in the brain can stimulate the thalamus to abort seizures. Successful studies led to FDA review in March 2010.|
|Neuropace||$-Responsive Neurostimulation System||A small box implanted under the skull bone with electrodes into the brain delivers a stimulus when seizures are detected. Successful testing completed in 2009; preparing for FDA review.|
|NeuroVista||$-Seizure Advisory System||A small box to be implanted in the brain to detect seizures at onset and abort with a stimulus. Undergoing animal testing.|
|New York University||$-Hybrid Drug/Seizure Detection||A mini-pump implanted inside the brain will deliver small amounts of drugs directly into the brain to reduce side effects of oral drugs. Undergoing animal testing.|
|Univ Kansas||Brain cooling device||A device implanted in the brain that can cool the brain when a seizure is detected, to stop the event. Undergoing animal testing.|
|Visualase||MRI-Guided laser surgery||Lasers (guided by MRI images) destroy only identified epileptogenic tissue, making this approach more selective than open surgical removal. Clinical testing starting in 2010.|
|CanCog||Canine epilepsy model||A network of Dog Epilepsy Clinics can be used to test new treatments; dogs have seizures similar to humans. Available for commercial use.|
|Epinano||$-Magnetonanoparticles for MRI||Magnetic particles linked to chemicals allow standard MRI machines to visualize brain more clearly. In clinical testing for use as an imaging agent.|
|NeuroInDx||Peripheral biomarkers||Evaluation of genes to predict who might develop epilepsy after head trauma. In clinical testing to develop a diagnostic test.|
|SynapCell||Mouse models||New rodent model of epilepsy to evaluate potential drugs for efficacy against treatment-resistant epilepsy, and other genetically-linked syndromes. Commercially available from vendor.|
|Texas Institute for Genomic Medicine||Gene clones & knockout mice||Maintains a library of 10,000 mouse cell clones available for pre-clinical testing of potential genetic associations with specific drugs or seizure types.|
|Asklepios Biopharmaceuticals||Galanin gene transfer||Evaluating the use of a neutral virus to bring galanin into the brain. The neuropeptide is effective against seizures in animals; human testing is planned.|
|Catalyst||CPP-115||A GABA-aminotransferase inhibitor, similar to vigabatrin, expected not to have retinal toxicity. May be useful for decreasing cocaine addiction as well as seizures.|
|Legacy Research||$-Adenosine Releasing Implants||Adenosine embedded into nanospheres, and placed into the brain on silk-based scaffolds, is expected to release the active compound slowly . Animal studies show reduction in seizures; human testing is planned.|
|MedGenesis Therapeutix||$-Convection-enhanced toxin delivery||Toxins known to reduce seizures can be administered safely by direct injection into the brain. The convection-enhanced delivery system disperses the drug into fluid surrounding the brain for chronic seizure suppression. Animal studies are ongoing.|
|MediPro Pharma||MPP-021||A drug with multiple mechanism of action, previously tested in patients in Russia, is being evaluated for cognitive enhancement with seizure control. Animal studies are ongoing.|
|Medkura||$-Pulmonary propofol||The anesthetic propofol, a potent anti-seizure drug, is being evaluated for delivery by inhalation to abort clusters of seizures. Animal studies are ongoing.|
|Neuroadjuvants||$-NTX 5055||A compound related to galanin is being evaluated for efficacy against seizures in animal models.|
|Neurologix||$-NPY gene transfer||Evaluating the use of a neutral virus to bring the NPY gene into the brain. The neuropeptide is effective against seizures and Parkinson’s Disease. Monkey studies are ongoing to evaluate safety.|
|NeuroTherapeutics||$-NTP-2014||The new molecular entity has demonstrated efficacy in multiple seizure models and several types of pain. Clinical testing is planned to start in 2010.|
|Paloma||P529 Dual TORC1/2 Akt/mTOR inhibitor||The mTOR pathway is an approach to immunosuppression and tumor reduction . This compound has dual effects that may be effective against Tuberous Sclerosis, and the seizures caused by tubers..|
|PHASE 1-2 DRUGS|
|Marinus Pharmaceuticals||$-Ganaxolone neurosteroid||Ganaxolone, a neuro-steroid, showed efficacy in clinical studies of partial seizures and infantile spasms. It also may be useful for psychiatric disorders. Phase 3 studies are planned with a new formulation.|
|NeuroGenomeX||$-2DG Neural Plasticity||(2-deoxy-D-glucose) is a chemical analog of sugar that may act like the ketogenic diet. Small doses that are widely used for clinical imaging demonstrate safety. Clinical studies in epilepsy are starting in 2010.|
|Supernus||Extended-release oxcarbazepine & topiramate||Controlled-release formulations allowing once daily dosing are being tested in 2010.|
|SK Life Science||YKP3089||The new molecular entity has demonstrated efficacy in animal models of seizures, pain, and anxiety. Clinical testing in epilepsy included a proof of concept photosensitivity study that demonstrated brain penetration in humans. Phase 2 trials are planned.|
|PHASE 3 DRUGS|
|Eisai||Perampanel, AMPA||The novel mechanism is being evaluated in epilepsy and pain, but was not effective for Parkinson’s Disease.|
|King Pharma||Intramuscular diazepam||An injectable device containing diazepam is in Phase 3 clinical testing to determine efficacy for acute repetitive seizures. The device is a standard system used by the military for rapid injection; diazepam has high efficacy against seizures.|
|OrthoMcNeil Neurologics/J&J||Carisbamate/Comfyde||Carisbamate completed several Phase 3 clinical trials, enrolling patients around the world. Unfortunately, the studies did not demonstrate statistically significant superiority over placebo when used as add-on treatment. Development for epilepsy is discontinued.|
|Lundbeck||Clonazepam/Klonopin||This drug has been available almost everywhere for many years, except in the USA. Clinical trials are evaluating efficacy in US patients.|
|Sepracor||Stadesa/Eslicarbazepine||As an isomer, this drug is expected to be clear of the main adverse effects of the widely-used carbamazepine. Efficacy and safety were demonstrated in global clinical trials. The drug is approved for use in Europe, and under review by FDA. Additional studies will assess use in monotherapy.|
|UCB||Brivaracetam, SV2-A blocker||An analog of the widely used levetiracetam, this drug did not show adequate efficacy in global clinical trials.|
|Valeant||Retigabine, potassium channel blocker||This drug has completed global clinical trials demonstrating clear efficacy and safety for partial-onset seizures. It is under FDA review.|
|RECENT DRUG INDICATIONS|
|Eisai||Rufinamide/Banzel||This drug is approved for treatment of seizures associated with Lennox-Gastaut Syndrome. It is particularly effective for the devastating "drop attacks" associated with this syndrome.|
|Eisai||Zonisamide/Zonegran||Developed in Japan, this drug is widely used globally against partial-onset seizures. Weight loss is a notable side-effect.|
|Lundbeck||Vigabatrin/Sabril||This drug was approved for restricted use because it can cause visual defects (reduced peripheral vision) with long-term use. However, it is highly effective for some patients who have not responded to multiple other drugs.|
|Pfizer||Pregabalin/Lyrica||Thought to be a related to gabapentin, this drug has different mechanisms of action for seizure control., It is highly effective against pain.|
|UCB||Lacosamide/Vimpat||Recently approved for treatment of partial-onset seizures, the drug has not yet proven efficacy for pain.|
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.