NEW YORK (Reuters Health) – Adding the selective 5-hydroxytryptamine-6 receptor antagonist (5-HT6) idalopirdine to a cholinesterase inhibitor does not improve cognition or reduce cognitive loss in patients with mild-to-moderate Alzheimer disease (AD), according to results of three phase 3 randomized trials published online January 9 in a single article in JAMA.
“These findings do not support the use of idalopirdine for the treatment of Alzheimer disease,” conclude the authors, led by Dr. Alireza Atri from the Ray Dolby Brain Health Center, California Pacific Medical Center, in San Francisco.
All three trials were 24-week, parallel-group, double-blind, placebo-controlled studies. Together they involved 2,525 patients (mean age, 74; close to two-thirds women) who had a mean baseline AD Assessment Scale (ADAS-Cog) total score of 26, or mild-to-moderate AD.
The trials tested a single daily dose of 10 mg, 30 mg, or 60 mg idalopirdine as an adjunct to background treatment with a cholinesterase inhibitor.
In all three trials, six months of idalopirdine had no significant effect on the primary outcome – change in ADAS-Cog total score from baseline to 24 weeks – at any of the doses tested.
Effects on the drug on key secondary outcomes, including AD Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) Scale and Activities of Daily Living (ADCS-ADL) Inventory scores, also were nonsignificant.
The phase 3 data are in contrast to findings from two phase 2 trials that supported the potential of idalopirdine to improve cognition when added to a cholinesterase inhibitor. However, several “major” differences between the phase 2 and phase 3 trials could have affected the newly published study’s results, the investigators say. Notably, the phase 2 trials used a daily idalopirdine dose of 90 mg (30 mg thrice daily), while the phase 3 trials tested 10-, 30- and 60-mg once daily.
The decision to lower the dose for the phase 3 study was made in conjunction with the Food and Drug Administration and was based on results of an idalopirdine PET imaging study showing a high 5-HT6 receptor occupancy (>80%) at daily doses of 30 and 60 mg, which is maintained for 24 hours, supporting the use of once-daily dosing, the investigators explain.
Another factor was the higher dropout rate related to treatment-emergent adverse events associated with 90-mg/day idalopirdine in the phase 2 testing (12.4% vs. 5.3% with placebo).
“There is always this balance between not wanting to hurt people, obviously, and whether we get the dose right and also do we get the dose right for the right patient,” Dr. Atri said in a phone interview with Reuters Health.
The rationale for this drug was “sound” in that idalopirdine has “cholinergic, glutamatergic, dopaminergic, and noradrenergic properties and the potential to augment multiple neurotransmitter systems to improve cognition,” Dr. David Bennett, from the Rush Alzheimer’s Disease Center in Chicago, writes in a linked editorial.
“Right now for Alzheimer’s we have cholinesterase inhibitors and memantine,” Dr. Atri told Reuters Health. “And what we’ve learned over the last decade or so is that the medicines have value but the disease itself progresses in the brain so people can stabilize for six months or a year, some benefit for longer – but in the long term these medicines can’t slow down the actual progression of the disease.” A next step, said Dr. Atri, is to test idalopirdine or another 5-HT6 inhibitor in combination with both a cholinesterase inhibitor and memantine.
Looking at the big picture, Dr. Bennett notes in his editorial that during the past 15 years, “more than 400 clinical trials of therapeutics for Alzheimer disease have been registered, with a failure rate of nearly 100% in those trials for which results have been reported. The report by Atri et al adds 3 more failed trials to this list.”
“The lack of progress in the treatment and prevention of Alzheimer disease is frustrating for patients, families, physicians, researchers, industry, funders, and policy makers. Understanding the causes for these failures is essential for informing future trials,” writes Dr. Bennett.
However, there is reason for hope. Despite these failures and despite the complexity of the disease, “the field is generating new knowledge at an unprecedented pace. It is just a matter of time before that knowledge is translated into effective strategies for the treatment and prevention of Alzheimer disease dementia,” Dr. Bennett concludes.
This research was supported by H. Lundbeck A/S, which makes idalopirdine. Several authors reported financial relationships with Lundbeck and various other pharmaceutical companies. All are listed with the original article.
SOURCE: http://bit.ly/2mkUryb
JAMA 2018.
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