AAN 2010: 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, the epilepsy drugs will likely 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 (read our editorial Hope for an Alzheimers breakthrough remains despite Dimebon's failure), 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, Gammagard's prospects should be treated with caution until Q3 2011 when results of the 360-patient Phase III study are expected.

Epilepsy: long-term data for new drugs thehighlights

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, the inconvenient dosing regimen and reasonably high level of treatment-related side effects will probably 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. Potential future indication expansions in pediatric patients as well as primary generalized tonic-clonic seizures is predicted to hold the key for Vimpat's commercial success in epilepsy.

Related reports:

• Pipeline Insight: Alzheimer's Disease - The ultimate high-risk, high-reward therapy market
• The CNS Market Outlook to 2013: Competitive landscape, pipeline analysis and growth opportunities
• Diagnostics in Neurology - Predictive biomarkers expand drug revenues

Hope for an Alzheimer’s breakthrough remains despite Dimebon's failure

On March 3rd we highlighted a press release issued by Medivation/Pfizer announcing that a Phase 3 study of Dimebon in Alzheimer's disease had failed to meet any of its clinical endpoints, despite high hopes of the drug after promising Phase 2 results. This is a significant setback for Dimebon's developers, particularly Medivation, however as recently discussed in our recent feature, Pipeline Insight: Alzheimer's Disease, there remains significant hope for the millions of Alzheimer's sufferers and their caregivers in the pipeline.

On March 3, Medivation and Pfizer announced that its big hope for Alzheimer's disease, Dimebon (latrepirdine; Medivation/Pfizer), failed to achieve clinical benefit over placebo in one of its pivotal Phase 3 trials. In the trial, dubbed the CONNECTION study by the company, investigators were unable to demonstrate that Dimebon significantly slowed the progression of the disease based on any of the five commonly used endpoints. Speaking in a press conference, Medivation's CEO David Hung stated: "The outcome of the trial was unexpected, and is obviously a major disappointment, especially for Alzheimer's patients and their caregivers."

The result certainly comes as a surprise to those tracking the progress of the drug. The CONNECTION data stand in stark contrast with positive Phase 2 results released in 2006, which served to greatly raise expectations of what was purported to be a future blockbuster for Alzheimer's disease. Indeed, on the strength of these data, Dimebonhad previously been forecast to achieve annual sales of around $5 billion in the seven major markets by 2018, placing it as one of the biggest-selling drugs at this time.

Early analysis of the CONNECTION data suggests that the placebo response was greater than that previously seen and that Dimebon showed 'a materially weaker response'. The study results, drawn from 598 participants across the US, Europe and Latin America, contradict those from the preceding Phase 2 trial, which involved 183 patients in Russia. These Phase 2 data were so encouraging that they were published in the July 2008 issue of the Lancet (Doody et al).

However, even before the CONNECTION data were revealed, some experts were skeptical of the outcome of the Russian trial. In its press announcement for the Phase 3 trial, Medivation conceded that the Russian results may have been limited by the small sample size, the involvement of just one geographical location and the use of only one language to communicate disease severity.

In June of 2009 we featured a report Emerging Clinical Trial Locations Eastern Europe which focussed on decision by the the biopharmaceutical industry to reduce costs by conducting clinical trials in what are referred to as the emerging markets. This report analyzed implications and factors which need to be taken into consideration when conducting clinical trials in Eastern Europe. The discord between Phase 2 study data and CONNECTION highlights one negative aspect of off-shoring trials. According to another recent report Global Clinical Trial Business Report & Analysis 2008-2018 the global clinical trials business was worth $50bn in 2008, with a growth of rate of 10%. Broadly we ask what affect CONNECTION will have on this market.

For the moment however it is time to focus on Dimebon. Despite the reservations of Medivation many remained highly encouraged by the Phase 2 data and regarded Dimebon as one of the most promising candidates in late-stage development for Alzheimer's disease. Indeed, Pfizer's decision to in-license the drug at such a high cost is testimony to these high hopes.

Medivation will face a rough patch, though it is not yet over for Dimebon

Medivation has suffered as a result of Dimebon's failure, with its share price plummeting by 68% to $13.04 from an all-time high of $40.49 only the day before the announcement. With future milestone payments and royalties hanging in the balance and no products currently on the market, Medivation has undoubtedly suffered a major blow. However, although the CONNECTION results are certainly a setback, they do not necessarily spell the end for Dimebon. The company is expected to now pin its hopes on additional Alzheimer's trials already underway such as CONCERT and CONTACT as well as Dimebon's secondary indication in Huntington's disease, for which it is currently in Phase 3 development in the HORIZON trial.

If the currently ongoing Phase 3 trials also fail, Pfizer, which signed a collaboration deal with Medivation in September 2008 and has since co-developed the drug, stands to lose most or all of the return on its large investment. The company's initial upfront payment to Medivation was $225m, one of the largest of its type in recent years. Still, the CONNECTION setback is limited somewhat by Pfizer's existing presence in the Alzheimer's marketplace, through its market-leading compound Aricept (donepezil) and the extensive portfolio of pipeline candidates which it inherited following the acquisition of Wyeth.

One positive to come out of the failure is that there will not be significant ramifications for other drugs in development for Alzheimer's disease. We have featured the Alzheimer's pipeline in recent months (see Pipeline Insight: Alzheimer's Disease). The area is characterized by high risk and high reward. At the time of publication Dimebon and Johnson & Johnson/Wyeth's bapineuzumab were forcasted to reach blockbuster status. As discussed in the report, within the current pipeline, Dimebon is unique in its mode of action. The drug is a small molecule mitochondrial permeability transition pore (MPTP) blocker, as well as an NMDA receptor antagonist and cholinesterase inhibitor. Unlike Dimebon, the majority of the other pipeline candidates are targeted towards the hypothesized Alzheimer's disease etiology. Drug developers' focus has shifted from neurotransmitter replacements to biological agents that affect beta-amyloid and tau protein, both hallmarks of the disease. The next eagerly awaited compound for which Phase III results will be announced is likely to be bapineuzumab (Johnson & Johnson/Pfizer), a humanized monoclonal antibody for beta-amyloid. However, given the high attrition rate in the pipeline, expectations will be tempered.

As other markets stall, the high risk/high reward of Alzheimer's is tempting

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 to them 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. However, despite this need, drug developers have struggled to get new agents to market and the pipeline over the past 10 years is littered with late-stage failures. Indeed, excluding reformulations, no new drugs have launched for Alzheimer's disease since Namenda (memantine; Forest/Merz/Lundbeck) arrived in 2002. Since then, around 20 products have failed Phase III trials.

With this in mind, then, the news about Dimebon may not be such a surprise after all. It is, of course, a big disappointment to those in the Alzheimer's community, but the future looks bright. As other core therapy markets become less profitable, both major pharmaceutical and biotech firms are increasingly looking to the huge potential of the untapped Alzheimer's disease market. Investment into Alzheimer's drug R&D continues to grow exponentially and, ultimately, this is the best news for sufferers: it is only a matter of time before an effective therapy arrives.

Related research

• Pipeline Insight: Alzheimer's Disease - The ultimate high-risk, high-reward therapy market priced ($11,400 August 2009)
• New Approaches to Pharma R&D: Evolving strategies to rejuvenate R&D efficiency priced ($5,700 May, 2009)
  
• Pipeline Insight: Mild Cognitive Impairment - Unlocking the potential of prodromal Alzheimer's disease and beyond ($11,400 April 2009)
  
• Updates-Plus-Nicotinic Receptors (Monthly intelligence service)