New treatments address unmet needs in Alzheimer's and epilepsy

A number of leading drug makers used this year's meeting of the American Academy of Neurology to present new data for promising pipeline candidates. Despite promising results, however, Datamonitor believes that the epilepsy drugs will struggle to find their place in the market. Moreover, the positive Phase II data for Baxter’s potential Alzheimer’s therapy Gammagard do not guarantee later success.

Alzheimer's disease: hope remains despite setbacks

There remains an enormous unmet need in the treatment of Alzheimer's disease. For the millions of elderly people worldwide, there are just four drugs available that can only offer a modest symptomatic effect. Even so, these treatments cannot slow or modify the course of this neurodegenerative disease, which is the ultimate goal in Alzheimer's therapy. While it was announced in March 2010 that in a Phase III trial Medivation/Pfizer's Dimebon (latrepirdine) failed to meet any of its clinical endpoints, there remains hope in the pipeline for Alzheimer's sufferers and their caregivers. One such drug, Baxter's Gammagard (intravenous immune globulin; IGIV), is actively recruiting for a Phase III trial, and at the American Academy of Neurology Annual Meeting (AAN 2010) the company presented new data from the extension phase of its Phase II trial.

Gammagard is a human antibody preparation already launched for the treatment of primary immunodeficiency diseases in the US and Western Europe. The drug is currently being assessed in Phase III clinical trials in patients with mild-to-moderate Alzheimer's disease. At AAN 2010, Baxter presented clinical trial results for the first time measuring function and cognition in patients who received uninterrupted Gammagard for a period of 18 months for mild-to-moderate Alzheimer's disease. After 18 months, patients who received Gammagard continuously averaged approximately 1.36 points higher than patients who initially received placebo on the Alzheimer's disease Cooperative Study-Clinical Global Impression of Change rating (ADCS-CGIC).

While clarifying that the study involved only a very small number of patients, Baxter is clearly encouraged by these data and has stated that it plans to initiate a second, concurrent Phase III study of the drug in this patient population. However, in light of the recent setback with Dimebon and other numerous late-stage trial failures in the last 10 years, Datamonitor remains cautious about Gammagard's prospects until Q3 2011 when results of the 360-patient Phase III study are expected.

Epilepsy: long-term data for new drugs the highlight

The second half of 2008 and first half of 2009 saw a flood of generic second-generation anticonvulsants enter the US market as Lamictal (lamotrigine; GlaxoSmithKline), Keppra (levetiracetam; UCB), Depakote IR and ER (valproate semisodium; Abbott) and Topamax (topiramate; Johnson & Johnson) lost patent protection. As the market environment for new and prospective drug candidates becomes increasingly price-sensitive and competitive, both Valeant/GlaxoSmithKline and UCB presented long-term safety and efficacy data for their respective novel anti-epileptic candidates in order to support their positions in the growing treatment arsenal.

Valeant's retigabine is a first-in-class anti-epileptic drug that reduces neuronal excitability by enhancing the activity of neuronal KCNQ (Kv7) potassium channels and through its gamma aminobutyric acid type A (GABA-A) receptor agonistic properties. In August 2008, Valeant entered into an exclusive worldwide collaboration agreement for retigabine with GlaxoSmithKline, and in October 2009 the companies filed a New Drug Application (NDA) in the US and a Marketing Authorization Application (MAA) in Europe for the adjunctive treatment of partial-onset seizures in adults with refractory epilepsy.

The efficacy and safety of retigabine in patients with refractory partial-onset epilepsy was demonstrated in two pivotal Phase III trials, RESTORE 1 and RESTORE 2. At AAN 2010, Valeant provided insight into the maintenance of efficacy and the safety profile of retigabine at doses of 600mg-1,200mg/day, as demonstrated in the long-term open-label extensions of the trials. With 81% of patients transitioning from RESTORE 1 and 92% doing so from RESTORE 2, median percent reduction in 28-day total partial-seizure frequency was 57% and 53%, respectively. Furthermore, safety assessments supported what Valeant called an acceptable safety profile for an adjunctive therapy.

With both US and EU regulatory bodies currently appraising the drug, Datamonitor believes that the inconvenient dosing regimen and reasonably high level of treatment-related side effects will deter some treatment-refractory epilepsy patients and their physicians from using retigabine, despite the strong efficacy data demonstrated thus far.

UCB's Vimpat (lacosamide) was the subject of numerous studies and analyses at this year's AAN conference. Indicated as an adjunct therapy for the treatment of partial-onset seizures in adults with epilepsy, Vimpat was approved in the EU in September 2008 and shortly after in October in the US, making it one of the most recent novel entrants to the epilepsy market. Although monotherapy trial data is anticipated by mid-2011, long-term analysis from adjunct trials presented on the conference provides additional support to Vimpat's growing safety and efficacy profile.

Data presented during the meeting focused largely on providing long-term safety/tolerability and efficacy of Vimpat from Phase II-III double-blind and/or open-label extension trials. While one study reported the efficacy of Vimpat in cohorts of patients completing successively longer durations of lacosamide exposure, another indicated that lacosamide improved 50% responder rates and reduced median seizure frequencies by up to 42% and 86% for complex partial seizures and secondarily generalized seizures (the two most commonly reported seizure types), respectively. A third poster provided insight into the drug's long-term safety profile; an important consideration for a drug dosed in such a chronic fashion.

However, with questions previously raised regarding the drug's side-effect profile in comparison to first-line treatments like levetiracetam and lamotrigine, Vimpat is likely to encounter difficulty in taking significant market share from its well-tolerated competitors. Datamonitor predicts that potential future indication expansions in pediatric patients as well as primary generalized tonic-clonic seizures will hold the key for Vimpat's commercial success in epilepsy.

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Lundbeck Inc. Announces FDA Marketing Approval for Sabril for the Treatment of Two Difficult-to-Treat Epilepsies

Lundbeck Inc. , a wholly owned subsidiary of H. Lundbeck A/S in Denmark (Copenhagen: LUN), announced today that the U.S. Food and Drug Administration (FDA) has granted two New Drug Application (NDA) approvals for Sabril® (vigabatrin) Tablets and Oral Solution. Lundbeck plans to launch Sabril in the United States in the third quarter.

Sabril is indicated as monotherapy for pediatric patients one month to two years of age with infantile spasms (IS) for whom the potential benefits outweigh the potential risk of vision loss, and as adjunctive (add-on) therapy for adult patients with refractory complex partial seizures (CPS) who have inadequately responded to several alternative treatments and for whom the potential benefits outweigh the risk of vision loss.1,2 Sabril is not indicated as a first line agent for CPS.

Sabril causes permanent bilateral concentric visual field constriction in 30 percent or more of patients that ranges in severity from mild to severe, including tunnel vision to within 10 degrees of visual fixation and can result in disability. In some cases, Sabril also can damage the central retina and may decrease visual acuity. Sabril causes permanent vision loss in infants, children and adults. The onset is unpredictable and can occur within weeks of starting treatment, or sooner, or at any time during treatment, even after months or years. Because of this risk of permanent vision loss, Sabril approval is accompanied by an FDA-mandated Risk Evaluation and Mitigation Strategy (REMS) and is available only through a special restricted distribution program called SHARE (Support Help and Resources for Epilepsy).

Sabril is the first therapy approved for the treatment of IS and an important new option as add-on therapy for the approximately 30 to 36 percent of adults with CPS whose seizures remain uncontrolled in spite of having many antiepileptic therapies already available.3,4

“The approval of Sabril is great news for patients and their families who have been waiting a long time for access to this new therapy,” said Dr. W. Donald Shields, Director of the Pediatric Epilepsy Program at the University of California at Los Angeles. “Having more than a decade of experience with Sabril, I have felt this drug was important to the epilepsy community. Lundbeck shared my commitment to getting this important therapy approved and without their support, Sabril would not be available today in the U.S.”

Commenting on the approval of the lead compound in its central nervous system (CNS) pipeline, Jeffrey S. Aronin, President and Chief Executive Officer of Lundbeck Inc., said, “We have been working hard to address the unmet medical needs of patients faced with infantile spasms and to offer a new add-on option for treating refractory complex partial seizures. FDA approval of Sabril is an important victory for the entire epilepsy community.”

In conjunction with marketing approval of Sabril, Lundbeck has developed an FDA-mandated REMS to manage the risk of permanent vision loss associated with Sabril. The Sabril REMS, a critical component in receiving FDA approval, specifies elements, such as restricted product distribution, required vision testing and mandatory benefit-risk assessments, to manage the risk of permanent vision loss associated with Sabril. The Sabril REMS is administered through Lundbeck’s SHARE program, a comprehensive patient and physician support program designed to provide tools and resources for all of Lundbeck’s epilepsy products, including Sabril. Through SHARE and the recently established SHARE Call Center, patients, caregivers and physicians will have access to information and tools to help manage severe and uncontrolled epilepsy, programs to help facilitate initial and ongoing use of Sabril, and support from a team dedicated to helping people fully understand and navigate the Sabril prescribing process.

Source : www.businesswire.com

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Drug Prevents Seizure Progression In Model Of Epilepsy

Carnegie Mellon University researchers have identified a new anticonvulsant compound that has the potential to stop the development of epilepsy. The findings are published in the current issue of the journal Epilepsia.

The research discovery builds on previous work identifying a specific molecular target whose increased activity is associated with seizure disorders, a potassium channel known as the BK channel.

"We have found a new anticonvulsant compound that eliminates seizures in a model of epilepsy," said Alison Barth, associate professor of biological sciences at Carnegie Mellon's Mellon College of Science. "The drug works by inhibiting ion channels whose role in epilepsy was only recently discovered. Understanding how these channels work in seizure disorders, and being able to target them with a simple treatment, represents a significant advance in our ability to understand and treat epilepsy."

Epilepsy is a neurological disorder marked by abnormal electrical activity in the brain that leads to recurring seizures. A person who has a first seizure is statistically much more likely to have a second, and with each subsequent seizure, the chance of having another seizure grows. A person is often diagnosed with epilepsy after having two or more seizures that have no other apparent cause.

In prior studies, Barth and colleagues were the first to link BK channels, ion channels that allow electrically charged potassium ions to move out of cells, to sporadic epilepsy. Previous studies had shown that these channels were genetically altered in a few rare individuals who suffer from the disease, but Barth and colleagues demonstrated that seizures themselves could lead to the same alterations in BK channel function.

Potassium ions move through the channels, starting and stopping the electrical impulses that allow neurons to communicate with one another. The Carnegie Mellon researchers found that after a first seizure, BK channel function was markedly enhanced. As a result, the neurons became overly excitable and were firing with more speed, intensity and spontaneity, leading Barth to believe that the abnormal increased activity of the channels might play a role in causing subsequent seizures and the emergence of epilepsy.

In the current study, Barth tested this theory by blocking the ion channels using a BK-channel antagonist called paxilline. Using an experimental model for epilepsy, Barth asked whether paxilline could reduce or prevent experimentally induced seizures, as it could normalize aberrant brain activity induced by previous seizures. Remarkably, Barth and colleagues Jesse Sheehan and Brett Benedetti discovered that the compound was effective at completely blocking subsequent seizures.

"The drug is orally available, and works in the low nanomolar range," said Barth, noting that these characteristics, which mean the drug is effective in low concentrations and can be taken as a pill, make it an especially promising compound for treatment in epilepsy patients. While most anticonvulsants currently used to treat epilepsy work to directly inhibit the activity of neurotransmitters that causes seizures, few compounds interact with specific ion channels, especially potassium channels. The researchers believe that targeting the BK channels and the abnormal brain activity that they induce might one day be used as a way to prevent the progression of seizure disorders over time, thus attacking the root cause of epilepsy.

According to Barth, the next steps will be to further investigate paxilline to see whether it is an effective anticonvulsant treatment for multiple types of seizures. The investigators continue to look at how BK channels are regulated by seizures to better understand the development of epilepsy.

Co-authors of the study include Sheehan and Benedetti, doctoral students in the Department of Biological Sciences and Center for the Neural Basis of Cognition at Carnegie Mellon. The study was funded by the National Institutes of Health, the Milken Family Foundation for Translational Research and the Alfred P. Sloan Foundation.

Source : www.sciencedaily.com

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I.Q. Harmed by Epilepsy Drug

Pregnant women who took a popular epilepsy drug, also widely used to treat migraines, pain and psychiatric disorders, had children whose I.Q. scores were significantly lower than those whose mothers took a different antiseizure medication, a new study has found.

The drug, valproate, sold generically and under the brand name Depakote, remains the second-most-popular antiseizure medication used for epilepsy, but earlier studies found that use during pregnancy also increased the risk of developmental delays and major malformations.

The risks that other epilepsy drugs may pose are not clear, experts say. While some are likely to be safer than others, there have not been enough studies to guide patients and their doctors. About half of the women who take valproate are not epileptics.

The new study is to be published on Thursday in The New England Journal of Medicine.

Three-year-olds whose mothers had taken valproate during pregnancy had I.Q. scores that were nine points lower on average than children whose mothers had taken a different antiseizure medication, lamotrigine. The I.Q. scores of toddlers whose mothers took valproate were also lower than scores of children whose mothers took two other antiseizure medications, phenytoin and carbamazepine.

Physicians involved in the study warned that valproate should never be the first choice for use in women of childbearing age, though exceptions may be made if a woman’s epileptic seizures cannot be controlled with other available medications.

“My thought is that if I make a mistake and the patient has a breakthrough seizure, I can change the medication and switch the patient to valproate,” said Dr. Kimford J. Meador, professor of neurology at Emory University School of Medicine in Atlanta, and first author of the new report. “If I put the patient on valproate as a first choice and the baby has cognitive impairment or a malformation, I can’t repair that.”

Dr. Meador and his colleagues enrolled 303 pregnant women who were each using an antiepileptic drug and were treated at 25 epilepsy centers in the United States and Britain from October 1999 to February 2004.

Cognitive assessments were conducted in 258 2- and 3-year-olds born to 252 mothers, of whom 53 had taken valproate.

Over all, children’s I.Q. scores were strongly related to mothers’ I.Q. scores, except among the children of mothers treated with valproate, the study found.

At age 3, children exposed to valproate in utero had a mean I.Q. of 92, compared with 101 for children exposed to lamotrigine, 99 for those exposed to phenytoin, and 98 for those exposed to carbamazepine, the study found.

Some 13,000 to 21,000 babies each year are born to women with epilepsy, and the vast majority are healthy, researchers and advocates emphasized.

Experts warned that women should not stop taking valproate without talking to their doctors.

“It’s important to stress to readers that if they become frightened, they should not simply stop taking the drug, because that can be even more dangerous,” said Eric Hargis, president of the Epilepsy Foundation in Washington.

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