Medivation's Dimebon , Elan/Wyeth's bapineuzumab and AstraZeneca/Targacept's AZD3480 are among several novel drugs targeting new mechanisms of action that are now moving into later stages of development for Alzheimer's disease.

These next generation medications offer not only the potential for efficacy and side-effect benefits over existing drugs used to treat symptoms of the disease - primarily acetylcholinesterase inhibitors like Pfizer/Eisai's Aricept (donepezil), Novartis' Exelon (rivastigmine) and Johnson & Johnson's Razadyne (galantamine), as well as Forest's N-methyl-D-asparate receptor agonist Namenda (memantine) - but could also offer the first opportunity to modify the disease.

Medivation's investigational drug Dimebon is one drug that has piqued the interest of physicians who specialize in the disease. During a panel discussion on Alzheimer's drugs at the BIO CEO & Investor Forum in New York Feb. 13, Sid Gilman, Professor of Neurology at University of Michigan, said of Dimebon, "I expect that if the second trial replicates the first trial there will be a substantial interest among prescribing physicians."

"Assuming this drug is as good as it appears to be, which is remarkable ... we have not seen this in any other medication used so far for Alzheimer's treatment, then if it were that good in the second trial, then I believe that yes, I would likely prescribe it," he said.

Gillman, a specialist in the field of Alzheimer's, is the chair of the Safety Monitoring Committee for another potential breakthrough therapy: Elan/Wyeth's immunotherapy bapineuzumab, in Phase III.

Dimebon and bapineuzumab are among several novel drugs in development, targeting new mechanisms of action, that are now moving into later stages of development for Alzheimer's disease.

Medivation's drug appears to work by blocking a new target that involves mitochondrial pores, thought to play a role in cell death associated with neurodegenerative diseases.

The San Francisco firm expects to initiate a confirmatory Phase III trial evaluating the oral small molecule in the second quarter and file for FDA approval for mild-to-moderate Alzheimer's in 2010. The Phase III trial will enroll over 500 patients with Alzheimer's disease, with the aim of re-creating results seen in an earlier Phase II trial conducted in Russia. FDA has already indicated the Russian trial can be used as one of two pivotal studies for the filing.

In the completed double-blind, placebo-controlled trial, mild to moderate Alzheimer's patients treated with Dimebon showed statistically significant benefits over placebo on all five study endpoints after one year of treatment. Additionally, on every endpoint of the study, including the primary endpoint of Alzheimer's Disease Assessment Scale-Cognitive Subscale score, the benefits of Dimebon over placebo at one year were stable or greater compared to benefits at six months.

Dimebon Effect "Increases Over Time"

"One of the hallmarks of disease modification is a drug effect that increases over time," Medivation CEO David Hung said during the BIO panel. "We will have to do other studies for longer durations to determine whether or not our drug is disease modifying, [but] we certainly consider the widening effects of our drug over time as encouraging."

Despite a potential disease-modifying benefit, Medivation plans to seek an initial indication for Dimebon for symptomatic treatment. "We believe as a company it is most important to get revenues as soon as we can, so we're going for a symptomatic label to begin with. Then, after that, we can expand our label to include disease modification with the appropriate trials," Hung said.

Carving out a pathway to approval for disease- modifying Alzheimer's drugs will be challenging since no drug manufacturers have yet blazed that trail.

Elan/Wyeth, which are evaluating bapineuzumab for its disease-modifying effect, are enrolling patients in trials running 18 months, a timeframe that could support a disease-modifying claim. The companies strayed from the traditional development path with bapineuzumab, when they announced in May 2007 that they would move forward with a Phase III program evaluating the monoclonal antibody without awaiting final Phase II study results.

The program, which includes four randomized, double-blind placebo-controlled studies in approximately 4,000 patients with mild to moderate Alzheimer's disease, is the first late-stage investigation for an antibody for the treatment of Alzheimer's. The drug is thought to induce an immune response that can clear beta amyloid plaque buildup from the brain.

The companies said the decision to move into Phase III was based on data on their immunotherapy programs and an interim Phase II look. Patients in the program have been stratified based on the presence or absence of the ApoE4 gene, the presence of which was shown in Phase II to predispose patients to vasogenic edema. The Phase II data are expected to be released in mid-2008 (¹ Also see "JPMorgan Healthcare Conference In Brief" - Pink Sheet, 14 January, 2008., p. 12).

Nonetheless, Gilman said it remains unclear how FDA will respond to an application for a disease-modifying agent. "I talked to [Division of Neurology Director Russell Katz] at the FDA about this question, and he has punted on what they would do in respect to terming disease modification/not disease modification," he said. He predicted the decision would involve input from FDA's Central Nervous System Drugs Advisory Committee.

AstraZeneca/Targacept Pursuing AZD3480

AstraZeneca and partner Targacept are also evaluating a new mechanism of action for Alzheimer's disease: a neuronal nicotinic receptor agonist. Their drug, AZD3480, targeting the alpha 4 beta 2 subtype, is being studied in a Phase IIb trial in 500 patients with mild to moderate disease compared to placebo and an active comparator over 12 weeks of treatment. The study is expected to finish at the end of 2008. Targacept CEO J. Donald deBethizy noted the firms intend to pursue a symptomatic indication for AZD3480.

"We do strongly believe in disease modification as well as symptomatic treatment because we believe they are going to be used in synergy," AstraZeneca Neuroscience Strategic Planning VP Johan Hoegstedt said during the panel discussion.

Development of effective Alzheimer's disease medications has been wrought with challenges, particularly when it comes to targeting the disease versus symptoms. Last year, Neurochem faced a major setback to its Alzheimer's program when it abandoned development of Alzhemed after Phase III data showed no significant difference over placebo. Alzhemed would have been the first drug to target amyloid plaques characteristic of the disease rather than Alzheimer symptoms.

- Jessica Merrill (j.merrill@elsevier.com)

Trailblazing Alzheimer’s Drugs Move Into Late-Stage Development

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