Anti-Amyloid Still All The RAGE At Alzheimer’s Disease Conference

A little more than a week after an article published in The Lancet raised questions about the assumption that removing amyloid plaque is key to modifying Alzheimer's disease - an assumption upon which most drug makers are pinning their hopes - Wyeth, Lilly and Pfizer unveiled data on their respective agents at the International Conference on Alzheimer's Disease in Chicago.

As companies try to move beyond the current treatment paradigms, like acetylcholinesterase inhibitors, which offer symptomatic benefits, and try to develop disease-modifying Alzheimer's treatments, much of the research has been on beta amyloid therapies, which would reduce the plaques that are thought to be a characteristic of the disease (¹ (Also see "Trailblazing Alzheimer’s Drugs Move Into Late-Stage Development" - Pink Sheet, 25 Feb, 2008.), p. 16).

Bapineuzumab Data Disappoints

By all accounts, industry observers were most curious about data on Wyeth/Elan's bapineuzumab, a monoclonal antibody thought to induce an immune response to clear beta amyloid plaque buildup in the brain.

The firms were so confident in their drug, they moved it directly into Phase III before a Phase II trial completed. However, the hype turned out to be somewhat unwarranted - the Phase II study failed to meet its primary efficacy endpoints.

The firms released a post hoc analysis during ICAD showing a benefit in non-carriers of apolipoprotein E4, a subgroup estimated to include 40 to 70 percent of AD patients. The companies touted the data as a positive, but failed to impress investors, who took issue with the post-hoc analysis' use of a modified intent-to-treat population (² (Also see "Wyeth’s Pipeline Star Bapineuzumab Looks More Long Shot Than Sure Bet" - Pink Sheet, 30 Jul, 2008.)).

Beta Amyloid Development Hasn't Worked Yet

The results prompt the question of whether bapineuzumab is headed in the direction of Alzhemed (tramiprosate), the much anticipated Neurochem drug that crashed and burned in Phase III last November (³ (Also see "Neurochem Drops Phase III Alzheimer’s Disease Candidate, Refocuses Pipeline" - Pink Sheet, 8 Nov, 2007.)).

The buildup of amyloid plaque is thought to be a key characteristic of the disease, but so far no company has successfully developed an anti-amyloid therapy.

Neurochem's failed Alzhemed targeted beta amyloid. More recently, Myriad and H. Lundbeck pulled the plug on Flurizan (tarenflurbil), which also lowered amyloid beta, after it failed to show a benefit on cognition or daily living in a Phase III study (⁴ (Also see "Lundbeck/Myriad Marriage: Short But Not Sweet" - Pink Sheet, 30 Jun, 2008.)).

One of the most advanced compounds in development, in fact, is a non-amyloid agent, Medivation's Phase III Dimebon (dimebolin), which works by blocking a target that involves mitochondrial pores.

Medivation impressed ICAD attendees with a presentation of 18-month results showing that patients taking Dimebon maintained the level of function they had upon entering the trial, measured across key aspects of Alzheimer's: memory and thinking, behavior, activities of daily living and overall function.

Lancet Article Questions The Approach

The July 19 Lancet article that raised questions about the strategy of treating Alzheimer's disease by targeting amyloid plaque was based on a six-year follow up of the first Phase I study of beta amyloid therapy. The findings showed that plaque removal in patients immunized with amyloid beta 42 did not lead to statistically significant improvements in cognitive function or survival.

While the data could be a cause for alarm that drug makers have spent years "barking up the wrong tree," an editorial accompanying the article advises against jumping to conclusions.

The Phase I data "should not lead to complete abrogation of a major role for Aß in the pathogenesis of Alzheimer's disease, nor should they lead to the premature abandonment of research into therapies directed at Aß," Peter H. St. George-Hyslop and John C. Morris write. They note there was a clear biological effect on brain amyloid, and point out some aspects of the trial that make definitive assumptions difficult.

Pfizer is one company that remains certain the anti-amyloid hypothesis is a durable one.

"This is a field in evolution," Pfizer VP, Global Medical Steve Romano noted during a July 30 interview. However, "there's no question" amyloid plaque buildup is a trigger for AD, he added, pointing to the bapineuzumab data.

Pfizer Pipeline Hits Beta Amyloid Plus

Pfizer, which markets the blockbuster cholinesterase inhibitor Aricept for Alzheimer's, has held its cards fairly close to the vest when it comes to the other drugs in its AD pipeline, but revealed a few details on its early stage programs during the meeting.

PF-04494700, in Phase II, is an antagonist of receptor of advanced glycation end-products, thought to be important in causing brain cell damage in people with Alzheimer's. The agent blocks interaction between RAGE and beta amyloid.

At ICAD, Pfizer unveiled results of a 67-patient, 10-week safety study including two regimens - 30 mg/day for six days, followed by 10 mg/day for 63 days, and 60 mg/day for six days, followed by 20 mg/day for 63 days. Data demonstrated the drug was well tolerated. The most frequent adverse events were falls, upper respiratory tract infection, urinary tract infection and headache.

During a July 28 ICAD presentation, Pfizer said it intends to enroll approximately 400 mild-to-moderate AD patients in the Phase II study that will include three arms - high dose (60 mg/day for six days then 20 mg/day), low dose (15 mg/day for six days, then 5 mg/day) and placebo.

"We are looking at ADAS-cog [Alzheimer's Disease Assessment Scale-Cognitive Subscale] as the primary endpoint, meaning the usual secondary endpoints that are built into these long durations and these modification type studies," Pfizer Executive Director of Neuroscience Jim Kupiec said.

"We're very interested in this sample size, [and] we're looking for changes of two points to three points [in ADAS-cog score] over the course of 18 months."

Romano noted that Pfizer is interested in developing therapies for both disease modification and for symptoms of AD.

The firm also has two Phase I drugs in the pipeline for AD: PF-04360365, an anti-amyloid monoclonal antibody, and a PDE-9 inhibiting compound that may stabilize synaptic function.

Lilly Also Making Big Play For Alzheimer's

Lilly presented Phase II data on its anti-amyloid beta monoclonal antibody LY2062430 at the conference. The 12-week trial randomized 52 mild to moderate Alzheimer's patients to either placebo or two LY2062430 regimens - 100 mg or 400 mg once a week or every four weeks. Results were assessed using magnetic resonance imaging and cerebrospinal fluid examinations.

There was no change in patients' cognitive score or the amount of plaque in the brain; however, there was an increase in blood and cerebrospinal fluid of two major types of amyloid beta protein as well as two other types of the amyloid beta protein thought to be present only in amyloid plaques.

The biomarker effects lasted several weeks, which Lilly said suggests that longer term treatment with the compound may slow disease progression.

Based on those results, the company plans to move the compound into Phase III next year. Its gamma secretase inhibitor LY 450139 is already in Phase III for Alzheimer's.

However, cognizant of the risk involved in developing AD therapies, Lilly is relying on outside help in advancing its program. On July 24, the firm announced an agreement under which private equity group TPG-Axon Capital would provide $300 million in funding and a Quintiles subsidiary would offer guidance on clinical trial strategies (⁵ (Also see "Lilly Creates Three-Way Deal To Share Risk In Alzheimer’s Drug Development" - Pink Sheet, 28 Jul, 2008.), p. 19).

- Brooke McManus ([email protected])