Merck & Co. Inc.is studying GE Healthcare’s investigational imaging agent flutemetamol as a potential companion diagnostic for its Alzheimer’s disease therapy, MK-8931, under a partnership announced Dec. 18. The announcement comes on the heels of Merck’s Dec. 3 announcement that it started a Phase II/III study of the novel oral beta amyloid precursor protein site cleaving enzyme (BACE) inhibitor, pitting it in a tight race with Eli Lilly & Co. to bring the first BACE inhibitor to market.

Under the deal, Merck will use flutemetamol – a positron emission tomography (PET) imaging agent – to select patients for clinical trials of MK-8931, with particular emphasis on a future trial in prodromal Alzheimer’s disease patients. That’s the phase in which patients have only mild cognitive impairments and have not yet been diagnosed with Alzheimer’s disease. Flutemetamol is being developed by GE Healthcare to detect beta amyloid deposits in the brain, the buildup of which is believed to be a hallmark of Alzheimer’s disease. In Phase III testing, flutemetamol images showed a strong concordance with Alzheimer’s disease-associated beta amyloid brain pathology demonstrated in brain autopsy and in vivo-cortical biopsies, according to GE.

Currently, Alzheimer’s disease is diagnosed through clinical exams, certain laboratory tests and PET scan, Magnetic Resonance Imaging [MRI] scan or Computed Tomography [CT] scan, but diagnosis is only confirmed through evaluation of post-mortem brain samples, including the presence of beta amyloid plaques.

“[Flutemetamol] is a good diagnostic tool to identify people that may progress into Alzheimer’s disease but also a tool that can confirm the diagnosis you have is very likely,” said Merck Research Laboratories’ Johan Luthman, PhD, Project Leader, BACE.

Drug makers need tools in their arsenal to identify Alzheimer patients for clinical trials and potentially treatment, especially as scientists start to target patients earlier in the course of the disease, when they have minimal or no symptoms. That is particularly important in the case of a BACE inhibitor like MK-8931, which is believed to turn off a key enzyme in the production of amyloid beta and thus reduce amyloid plaque formation and modify disease progression, rather than reverse plaque buildup. It is also vital to identify patients who could most benefit from treatment – those with amyloid plaque formation – versus those with unexplained loss of cognitive function and no beta amyloid plaque buildup.

A diagnostic tool would have significant implications for the commercial market too, as payers would likely be willing to pay a high price for a drug if they could be assured patients would benefit from the treatment.

GE’s imaging agent works similarly to Lilly’s PET tracer Amyvid (florbetapir). FDA approved Amyvid, which shows the amount of beta-amyloid plaque in the brain, in April as the first such agent for Alzheimer’s disease Also see "Lilly Gains Amyvid Approval, But Reimbursement Still A Hurdle" - Pink Sheet, 9 April, 2012.. Nonetheless, the procedure is invasive and expensive, and not currently reimbursed by Medicare. Thus, the $1,600 cost will likely keep many patients from undergoing the test, particularly given that no disease-modifying treatments are available. CMS opened a national coverage analysis Oct. 9 on amyloid PET in dementia and neurodegenerative disease in response to a request from Lilly. A final determination is expected in July 2013 Also see "Medicare Coverage Decision For Amyvid Due July 2013" - Pink Sheet, 15 October, 2012..

Lilly, which has several drugs in development for Alzheimer’s disease including the Phase II BACE inhibitor LY2886721 that is neck-and-neck with Merck’s drug and the Phase III monoclonal antibody solanezumab, The pharma gained Amyvid through the acquisition in 2010 of Avid Radiopharmaceuticals for $300 million upfront and $500 million in regulatory and commercial milestones Also see "Lilly Continues To Bet On Alzheimer's With Avid Acquisition" - Pink Sheet, 8 November, 2010..

Merck said it opted to partner with GE Healthcare on flutemetamol because the company has a long history in imaging and access to the necessary infrastructure for conducting imaging including PET scanners and the Cyclotron that produces the radioactive isotopes used in the procedure. PET imaging is a pretty big barrier to entry, “but General Electric Healthcare is, to us, a very good partner because they have a long experience in imaging,” Luthman said.

GE continues to own rights to the agent, is studying it independently, and plans to file the product with regulators in the near-term.

Merck Development Plans Call For Prodromal Trial

Merck plans to use the agent to help select appropriate patients for its MK-8931 clinical trials. “The number one way we look at it is for identifying subjects at risk to convert into Alzheimer’s disease,” said Luthman. “You could have mild cognitive impairment for many different reasons….We would really like to fish out those subjects that have the true pathology of Alzheimer’s disease.”

The deal will extend across multiple trials, however. The primary effort involving PET imaging will be a future trial in patients with prodromal Alzheimer’s disease. The timeline for that trial has not yet been announced, but Luthman said planning is underway.

PET imaging will also be used in the recently-initiated Phase II study in mild to moderate Alzheimer’s disease patients, but that trial will use PET imaging in just a small subset of patients. “We don’t have big expectations that we will move plaque very much, but we will look at it to see if we may have some effect,” Luthman said. That trial, called EPOCH, will evaluate the safety of MK-8931 in 200 patients before advancing into a larger Phase III study that will enroll up to 1,700 patients.

The timing of the safety portion of the trial will depend on recruitment, but Merck expects to have data read-out in mid-2013. The full trial is a 78-week randomized, placebo-controlled, double-blind trial that will evaluate the safety and efficacy of one of three oral doses of MK-8931 dosed once-daily versus placebo. The primary efficacy outcomes are changes from baseline in Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAS-Cog) score and the change from baseline in the Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) score.

Lilly initiated a Phase II trial in March testing its BACE inhibitor in patients with mild cognitive impairment due to Alzheimer’s disease or mild Alzheimer’s who test positive for amyloid plaque, giving it a 9-month head start on Merck. The trial is expected to complete in February 2014, according to clinicaltrials.gov.

Merck Partners On Alzheimer’s Diagnostic With GE Healthcare

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