by Youness Bousenna at Lilly's Erl Wood site
ERL WOOD, UK, Nov 25 (APM) - Beta-secretase (BACE) inhibitors are better for reducing beta-amyloid levels than solanezumab, which failed in Alzheimer's disease (AD) in Phase III, chief scientific officer global medicinal chemistry neurodegeneration Magnus Walter told APM during a press trip to the U.S. pharma's R&D site at Erl Wood.
A Lilly spokesman told APM on Thursday that BACE inhibitor LY3314814/AZD3293, developed with AstraZeneca and currently in Phase III, could be approved in Europe and the U.S. in 2020 or 2021. The U.S. group is developing another BACE inhibitor, LY3202626, which is currently in Phase II.
Amyloid peptide is the main therapeutic target in Alzheimer's disease, but this strategy has been subject to repeated failures.
On Wednesday, Lilly announced that its monoclonal antibody solanezumab, targeting amyloid, had failed to significantly slow cognitive decline in mild Alzheimer's in the Phase III EXPEDITION3 trial (APMMA 50576). Two previous Phase III trials in mild to moderate Alzheimer's had also produced negative results in 2012 (APMMA 30748).
This latest setback led to Lilly - whose share price fell more than 10% to $68 on Wall Street on Wednesday - to announce that it will review its forecast in mid-December.
"The problem is that solanezumab is an antibody, not a small molecule," Walter told APM. As a "large biomolecule" it is difficult for it to reach the brain, which is why it is relatively unsuccessful in removing beta-amyloid 1-42 peptide.
"The advantage with small molecules such as BACE inhibitors is that they reach the brain much more easily... We hope they will be better at reducing beta-amyloid 1-42," he added.
Orally administered BACE inhibitors act by blocking the production of amyloid peptide. It is hoped that they can slow the symptoms of Alzheimer's or even prevent the disease.
"It may not work, we really don't know, but we think it's important not to do the same thing, [as] the definition of stupidity is doing the same wrong thing over and again," said Walter.
"Targeting amyloid alone is not sufficient, it's just one possibility," he said.
Lilly's chief scientific officer neurodegeneration Michael Hutton added that combining drugs targeting amyloid with those targeting tau protein - the area of research at Erl Wood - has "real potential" in the long term.
After a succession of failures with candidate amyloid inhibitors, pharmas have turned to tau protein. Few data are available as yet, but the first Phase III results presented by TauRx in July were negative (APMMA 48942). Several pharmas have started Phase I trials, but Lilly is not among them.
While no definitive decision has yet been taken to end the solanezumab programme, Hutton said that the only possible approach is to test the molecule in patients at an earlier stage in the disease. In this case, "we do not know" whether solanezumab will "have a bigger effect". "We really need to think about it, we have a decision to take," he declared.
Trials of solezanumab are under way in elderly people at the prodromal or pre-symptomatic stage of Alzheimer's - ExpeditionPRO and A4, according to U.S. trials register ClinicalTrials.gov - with results due in 2020-2021.
Questioned about the fate of solanezumab, Walter said: "It's too early to say". The drug was not used in an effective way, but that does not mean it is "dead," he added.
Hutton said BACE inhibitors are one of Lilly's biggest hopes for meeting its objective of preventing the dementia associated with Alzheimer's by 2025.
Lilly has invested more than $3 billion in Alzheimer research over the past 27 years.
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