The epilepsy field offers a telling look at some of the larger trends in pharmaceutical research and development in the post-blockbuster era: specialty companies have emerged to dominate as big pharma has retreated from the difficult therapeutic space, but most discovery is coming from small companies that need to find partners to bring their innovations forward.

The early-stage and discovery section of the pipeline in epilepsy is active, but filled with small firms that lack the expertise, resources, and financial resilience to carry out a pivotal trial program – or withstand a major failure.

The advance of specialty pharmaceutical companies toward dominance in epilepsy R&D continued with the June 13 announcement of Upsher-Smith Laboratories Inc.’s purchase of research boutique Proximagen Neuroscience PLC. The acquisition could position Upsher-Smith to join H. Lundbeck AS and UCB SA in the top tier of epilepsy companies – a list that looks very different from the heavy pharmaceutical hitters that used to reign over the epilepsy space.

Just eight years ago, five big pharma companies accounted for 75% of global antiepileptic drug sales, according to IMS Global. Today, their drugs have largely gone generic and none of the five – Pfizer Inc., Johnson & Johnson, Abbott Laboratories Inc., GlaxoSmithKline PLC and Novartis AG – are involved in novel epilepsy R&D.

The epilepsy pullback is part of a general retreat from central nervous system therapies on the part of big pharma. Even GSK, the only big pharma with a recent NME approval in epilepsy on its books, thanks to last year’s Potiga (retigabine) approval (in partnership with Valeant Pharmaceuticals International Inc.), has exited neuroscience discovery Also see "GSK Argues Its Strategy Is Delivering As Still More Cuts Are Made, Including in R&D" - Pink Sheet, 4 February, 2010..

Specialty firms have filled the vacuum, attracted by a sizeable market still hungering for better therapies and served by a relatively limited number of specialized providers. Lundbeck highlights the 16% share of the worldwide pharmaceutical market held by central nervous system agents in 2011, noting that anti-epileptics accounted for 11% of the world CNS market, based on the IMS World Review Preview 2012. That segment reflects 12% growth from 2010 to 2011, above the overall CNS growth rate of 5%.

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The story of epilepsy drug development is one of incremental advances. Many drugs have been approved for symptomatic intervention, across multiple generations of therapy, but there is still significant unmet medical need. Nothing so far has attacked the underlying disease and 30%-40% of patients are considered refractory, not controlled on one or more medications.

The category encompasses multiple disease classifications, by some counts as many as 25 disease subtypes. Drug development has followed a predictable path. Most manufacturers start with refractory adult patients with partial onset seizures (POS) for initial regulatory approval, before expanding into pediatric populations, monotherapy, rare epilepsies like Lennox Gastaut Syndrome and more extensive seizure types, such as primary generalized tonic clonic seizures.

Many specialty companies, however, tend to be focused on the late clinical stages and marketing aspects of the business. The early-stage and discovery section of the pipeline in epilepsy is active, but filled with small firms that lack the expertise, resources, and financial resilience to carry out a pivotal trial program – or withstand a major failure.

Upsher-Smith cited Proximagen’s ability to buttress its earlier-stage research presence as a rationale for the acquisition. “We view Proximagen as having a high degree of scientific expertise and a solid R&D engine that, coupled with our strength at Upsher-Smith, which is really more product development and commercialization, would blend the respective strengths of both organizations,” Chief Operating Officer Tom Burke said Also see "Upsher-Smith To Buy U.K. Biotech Partner Proximagen For $347 Million" - Pink Sheet, 13 June, 2012..

Upsher-Smith currently has two Phase III epilepsy candidates, both novel formulations of generic drugs: a midazolam nasal spray, USL261, currently enrolling patients in the ARTEMIS1 pivotal trial for outpatient rescue treatment of seizure clusters, and USL255, an extended-release formulation of topiramate being studied in the Phase III PREVAIL trial as adjunct therapy for partial onset seizures.

Proximagen brings Upsher-Smith new molecular entity projects. Proximagen has two clinical-stage epilepsy programs, according to a June 13 SEC filing: tonabersat, a first-in-class gap junction blocker, and naluzotan, a selective 5HT1a agonist. Tonabersat was already licensed to Upsher-Smith [See Deal].

Looking For A Cure

Epilepsy R&D has been productive, in the sense of testing and launching new products, but has lacked the breakthrough moment that Novartis’ Gleevec brought to oncology or Vertex ‘s Incivek (telaprevir) and Merck & Co. Inc.’s Victrelis (boceprevir) are bringing to hepatitis C – a drug that fundamentally changes the disease equation.

New York University neurologist Daniel Friedman used a baseball metaphor to describe the state of the epilepsy pipeline at the Epilepsy Therapy Project conference: “Late stage compounds don’t appear to be the home runs that we need, but do appear to advance the runners around the bases to better, safer treatments.”

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The research advocacy organization CURE lamented that “we focus 75-80% of [epilepsy] research on better controlling outcomes, such as seizure frequency and severity,” and still, “despite this allocation, only incremental improvements have been made to marketed anti-convulsants in the last ten years, with 40% of patients refractory to treatment and up to 60,000 deaths occurring annually due to seizure-related causes.” The group’s State of Epilepsy Research 2010 report went on to note that the “mechanisms of epilepsy are clearly not well understood,” and concludes that “an increased focus on basic discovery – today only 20-25% of research – is required if we hope to someday find a true cure.”

Two years later, the complaint is almost unchanged. “To date, treatment of epilepsy has been focused on suppressing seizures rather than curing the disorder,” an Institute of Medicine consensus report on epilepsy, released March 30, states. “With further research it is hoped that symptomatic treatment will be replaced with curative treatment and with prevention strategies.”

But moving forward with R&D on curative treatments may require deeper pockets and greater risk tolerance than the companies in the space can provide, especially in the absence of big pharma interest and with an anemic funding environment. And epilepsy, as a research field, is filled with pitfalls for any sponsor.

A Difficult Playing Field For Clinical Trials

NYU’s Friedman outlined some of the challenges specifically facing epilepsy drug developers in an address to the Epilepsy Therapy Project conference earlier this year. “Epilepsy trials are difficult to perform,” he said. “They’re certainly expensive. There’s a lot of inherent noise in epilepsy.”

Friedman presented analyses by the Tufts Center for the Study of Drug Development to show that CNS drugs have the “lowest chances of success in clinical drug development.” A Tufts CSDD analysis published in Scientific American July 29, 2011 concludes that CNS agents are “far more difficult to develop” than other types of drugs; they take longer in human testing, have a higher clinical failure rate and take more time to gain regulatory approval Also see "Sounding The Alarm On The Future Of CNS Drug Development" - Pink Sheet, 1 August, 2011..

Friedman posited that poor clinical performance could reflect the “lack of well-defined targets” and the “lack of biomarkers of efficacy,” which leads to reliance on patient self-reporting. And with few surrogate markers, the transfer from early to late stage development in epilepsy is “tricky,” he noted. Drugs active in the nervous system are also prone to extensive side effect profiles.

In epilepsy specifically, “there’s diagnostic uncertainty,” Friedman said. Developers are often “not sure all patients in a trial have epilepsy.” Additionally, “we have a known unreliable outcome reporting system – patient diaries, patient self-reports, which we know are inaccurate – and therefore we need large studies to determine efficacy of our treatments.”

“Because there are so many drugs available, especially in the U.S. and Western Europe, recruiting for drug trials is very difficult, so many drug trials have gotten global,” he observed. “With that comes increased expense and increased noise.”

Epilepsy drugs “are costlier to develop now than they were before,” Friedman contended. As costs have increased, NMEs have decreased, he observed.

Nonetheless, a continuing stream of new formulations of generically available drugs (with branded pricing) highlights the challenge that the epilepsy armamentarium poses for payers.

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Wanted: Comparative Efficacy Data

Governments have identified the epilepsy field as a good focus for comparative efficacy research. Epilepsy patients have an abundance of drugs to choose from – more than 30 drugs have been approved for the disorder – but adverse effects are common and about a third of epilepsy patients are still refractory to the existing armamentarium. And, the first generation of drugs is available generically. With this dynamic, regulators are starting to make sponsors of novel agents sing for their supper.

The U.S. Agency for Healthcare Research and Quality sparked controversy with its comparison of newer and older epilepsy drugs. The study, released Dec. 31, 2011, found that a first-generation drug, carbamazepine, “had advantages in epilepsy control over the newer antiepileptic medications it was compared with but had more adverse effects,” while two other older AEDs, valproic acid and phenytoin, “provided similar epilepsy control to newer antiepileptic medications.”

The American Epilepsy Society, American Academy of Neurology, and Epilepsy Foundation responded with a Feb. 16 press statement on their “grave concerns.” AHRQ “fails to recognize the different types of epilepsy and deals with this multiform disorder as if it were a monolithic and homogenous condition,” the groups contended, asserting that the report “is irrelevant to clinical practice.”

Meanwhile, new drugs in Europe must get past national cost-effectiveness gatekeepers like Germany’s health technology assessment body, the Institute for Quality and Efficiency (IQWiG), and the U.K.’s National Institute for Health and Clinical Excellence (NICE). IQWiG recently rejected GSK/Valeant’s retigabine (Trobalt in Europe, approved in the U.S. as Potiga) Also see "Germany’s IQWiG Downs Two Drugs In One Day" - Pink Sheet, 15 February, 2012..

The Institute of Medicine’s Committee on the Public Health Dimensions of the Epilepsies emphasized the need for comparative effectiveness studies in its March consensus report. “Given the many approaches (e.g. medications, devices, surgery, diets, behavioral interventions) used to treat epilepsy, comparative effectiveness studies would be valuable in providing rigorous assessment of these options for different types of epilepsy,” the IOM report stated.

The IoM report acknowledged that “one of the challenges of conducting comparative effectiveness research in epilepsy is specifying the methods and measures that should be used to collect data.” The IoM epilepsy committee observed that “seizure frequency is a widely used measure of the clinical efficacy of epilepsy medications.” However, the report notes, “the relationship between seizure frequency and the degree of disability resulting from the seizures is poor, and instruments that are sensitive to the behavioral, affective, and cognitive comorbidities … need wide implementation,” including measures that “focus not only on freedom from seizures but also on improved quality of life and decreased disability.”

Despite interest in the outcome of trials comparing active agents, head-to-head studies are still few and far between in epilepsy, although UCB is currently studying Vimpat (lacosamide) in Phase III trials with carbamazepine controlled-release (Novartis’ Tegretol) and Pfizer has a Phase III trial comparing Lyrica (pregabalin) with levetiracetam (UCB’s Keppra) as adjunct therapy for partial onset seizures.

Whose Priorities?

The multiple, even competing, data needs and priorities of regulators, payors, physicians, disease advocates, academic and government researchers involved in epilepsy research and treatment would test even the deepest big pharma pockets. But without big pharma taking risks in the CNS space, the more focused – and more limited – abilities of the small and specialty companies remaining in epilepsy R&D will be tested.

The continued need for incremental improvements – what NYU’s Friedman called “base hits” – could easily drive an epilepsy pipeline dominated by reformulations and next-generation compounds. The challenge will be to meet the call for novel approaches and even the grand slam of disease-modifying treatments if the lean partnering and financing markets persist.

There are rewards to be reaped in epilepsy therapeutics, but history shows that the disease presents no shortage of ways to strike out on the way to approval. For there to be a game-changer, sponsors will need to persevere in the face of those high hurdles.

Specialty Pharma Dominates Epilepsy Market, But Does It Have Resources To Develop Disease-Modifying Agents?

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