Two More Alzheimer's Drug Candidates Fail

December 09, 2019

Two more Alzheimer's drug candidates have been added to the list of failures in trying to find a treatment for the disease.

Lanabecestat (Lilly), a beta-site amyloid precursor protein–cleaving enzyme (BACE) inhibitor, and the antibiotic minocycline both failed to slow cognitive decline in randomized controlled trials in patients with mild Alzheimer's disease.   

Two lanabecestat studies have been reported together in one article published online November 25 in JAMA Neurology, and the minocycline study was published online on November 18 in the same journal.  

Lanabecestat Fails to Impress

In an audio interview with JAMA Neurology, John Sims, MD, senior medical director at Lilly, and senior author of the lanabecestat article, explained that the drug was designed to block the formation of the amyloid beta protein, characteristic of Alzheimer's disease, by blocking the BACE enzyme.   

"We have shown that lanabecestat blocks 50% to 75% of the protein forming, and it has shown robust reduction of amyloid beta in brain and cerebrospinal fluid (CSF) in animal models and as well as in human CSF and plasma," said Sims.

The authors note that the negative results of the two current lanabecestat trials are consistent with previously reported phase 3 studies of two other BACE inhibitors, umibecestat and verubecestat, both of which also failed to slow cognitive decline.

"Although it appears unlikely that current BACE inhibitors will be an effective disease-modifying treatment for symptomatic Alzheimer's, future studies are needed to determine if reduction in amyloid beta production can provide meaningful clinical benefit in earlier stages of the disease continuum or in other high-risk populations," they conclude.

Sims described the current results as "certainly disappointing."

"Prior to these results there was a feeling that going in earlier in the disease state was a good idea — maybe even before symptoms develop. But we have since learned that another BACE inhibitor that was tested very early was also stopped for futility and there was even a suggestion of worsening on the drug.

"Now there are a handful of chemical molecules that inhibit the BACE enzyme and none of them have worked," Sims pointed out. "We are now in the process of putting all these data together to see if we can understand if there is a space here that is still tractable for this mechanism."

The two trials currently reported are the AMARANTH and DAYBREAK-ALZ studies, which were funded by Lilly.

AMARANTH was a phase 2/3, randomized, double-blind, study that enrolled 2218 patients with early Alzheimer's, defined as the continuum of patients with mild cognitive impairment attributable to Alzheimer's and patients diagnosed as having mild Alzheimer's dementia.

DAYBREAK-ALZ was a phase 3, randomized, double-blind study of lanabecestat that enrolled 1722 patients with mild Alzheimer's dementia.

In both studies, patients had the presence of amyloid confirmed and were randomized to once-daily oral doses of lanabecestat 20 mg, lanabecestat 50 mg, or placebo.

Both trials were stopped early because of futility, with 539 patients completing AMARANTH and 76 patients completing DAYBREAK.

The primary outcome of both studies was change from baseline on the 13-item Alzheimer 's Disease Assessment Scale — cognitive subscale. Secondary outcomes included Alzheimer's Disease Cooperative Study — Instrumental Activities of Daily Living Inventory, Clinical Dementia Rating, Functional Activities Questionnaire, Mini-Mental State Examination (MMSE), and Neuropsychiatric Inventory.

Interim results showed no consistent, reproducible dose-related findings on primary or secondary efficacy measures.

"Overall, neither of the doses were sufficiently having an effect on the disease. It looked as though there might have been a very small effect of the low dose in the AMARANTH trial but this was not replicated in the DAYBREAK study where the low dose looked slightly worse than placebo," Sims commented. 

On the functional scores, he added, "essentially the lines were on top of each other in AMARANTH. In DAYBREAK, there was a slightly worse effect with the low dose and a slightly better effect with the higher dose but overall there was no significant movement."

The researchers report that in AMARANTH, lanabecestat produced substantial dose-related reductions in CSF Aβ1-40 and Aβ1-42 concentrations. Furthermore, the drug was associated with a greater reduction from baseline in β-amyloid neuritic plaque density compared with placebo, but also a greater hippocampal volume loss.

The drug was also associated with adverse effects, with psychiatric symptoms, weight loss, and hair color changes reported in a higher percentage of patients receiving lanabecestat than placebo.

Noting that the BACE enzyme processes a range of other proteins in addition to amyloid beta, he suggested that this could be the mechanism behind some of the safety signals seen with the drug.

Sims said it is not known why these molecules have not worked as anticipated.

"One hypothesis is that the amyloid hypothesis is not a valid one. That has received a lot of credence lately as other anti-amyloid approaches have failed," he noted. "But I think we are still hopeful that the amyloid hypothesis is true and we have a lot of scientific data that supports that."

"We still don't know if targeting amyloid beta requires going in even earlier than what we've seen here and using drugs that are safer with less off-target issues. I think this will continue to be a big debate over the next few years," said Sims.

He says there is still potential in targeting the other major Alzheimer's protein, tau, and studies are now underway in that area. And the availability of blood-based biomarkers will ease recruiting the right patients into trials, which will help in the next wave of research in Alzheimer's, he added.

No Joy With Minocycline

The minocycline study was conducted by a UK group led by Robert Howard, MD, University College London.

They explain that minocycline was investigated in Alzheimer's because of its anti-inflammatory action. Alzheimer's disease is associated with immune-related and inflammatory genes, and accumulation of amyloid beta stimulates microglial production of proinflammatory agents that are associated with neurodegeneration.

Minocycline is an anti-inflammatory tetracycline that crosses the blood–brain barrier and inhibits proinflammatory microglia. It has shown many anti-amyloid actions in laboratory and animal studies including reducing neuronal death and learning deficits in rats after amyloid beta administration.

For the current MADE (Minocycline in Alzheimer's Disease Efficacy) study, researchers investigated whether minocycline slows the decline of cognitive and functional ability in people with mild Alzheimer's over a 2-year period and whether giving minocycline at a higher 400-mg dose than the 200-mg dose used in standard practice enhanced efficacy.

The MADE trial was funded by the UK National Institute of Health Research and UK Medical Research Council.

The study involved 32 National Health Service memory clinics and randomized 554 patients with a diagnosis of mild Alzheimer's to receive minocycline (200 or 400 mg/day) or placebo for 24 months.

Primary outcome measures were decrease in standardized MMSE (sMMSE) score and Bristol Activities of Daily Living Scale (BADLS).

Results showed that fewer participants completed treatment with minocycline 400 mg (28.8%) than minocycline 200 mg (61.9%) or placebo (63.7%), mainly because of adverse effects including gastrointestinal and dermatologic symptoms and dizziness.

Decrease in sMMSE scores over 24 months in the combined minocycline group was similar to that in the placebo group (4.1 vs 4.3 points). The decrease in mean sMMSE scores was less in the 400-mg than in the 200-mg minocycline group (3.3 vs 4.7 points).

Worsening of BADLS scores over 24 months was similar in all groups: 5.7 in the 400-mg group, 6.6 in the 200-mg group, and 6.2 in the placebo group.

Results were similar in different patient subgroups and in sensitivity analyses adjusting for missing data.

Researchers say the failure of minocycline treatment to slow the progression of cognitive and functional decline in patients with mild Alzheimer's is disappointing given the evidence suggesting that neuroinflammation is instrumental in Alzheimer's progression and given minocycline's anti-inflammatory and neuroprotective effects. But they believe their findings from the current study to be robust.

They point out that nonsteroidal anti-inflammatory drugs similarly failed to slow Alzheimer's progression in clinical trials.

"Our findings parallel those of trials of minocycline in other neurodegenerative disorders in which, despite preclinical research suggesting neuroprotection, minocycline worsened outcomes in amyotrophic lateral sclerosis, had no effect in Huntington disease, multiple system atrophy, and negative symptoms of schizophrenia; and only short-term benefits in multiple sclerosis," they report.

They suggest three broad potential explanations for the negative results of the trial. First, neuroinflammation in Alzheimer's may be a reaction to pathologic characteristics of the disease rather than an important factor in neurodegeneration. Second, minocycline at the doses administered in the MADE trial may not have had sufficient activity to show efficacy. And third, minocycline could have some efficacy against Alzheimer's but the treatment effects were too small to be detectable.

In an accompanying editorial, Lon S. Schneider, MD, Keck School of Medicine, University of Southern California, Los Angeles, writes: "In light of dozens of therapeutic failures, lack of efficacy evidence for any drug or drug class other than cholinesterase inhibitors, prior negative minocycline trials for other neurological disorders, and absence of a clear, validated drug target for Alzheimer disease, minocycline's lack of effectiveness was not surprising."

But he points out that the MADE trial was a pragmatic inexpensive study and is an example of "an efficient use of resources, a potentially rapid way to bring a repurposed drug forward and to get an answer."

Even Negative Studies Are Helpful 

Commenting on these latest studies for Medscape Medical News, Keith Fargo, PhD, director of Scientific Programs & Outreach, Alzheimer's Association, said: "The results from these clinical trials are disappointing. However, we learn new things from every research studies — regardless of whether the results are positive or negative."

"Alzheimer's and other dementias are complex diseases and we must advance all potential treatment targets to solve the mystery of these devastating conditions. We are thankful to the researchers and individuals who participated in these studies to advance our scientific knowledge on the road to finding an effective treatment for Alzheimer's and all dementias," he added.  

JAMA Neurol. Published online November 18, 2019. Full text (minocycline trial), Editorial

JAMA Neurol. Published online November 25, 2019. Full text (lanabecestat trials)

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