FROM JAMA
Idalopirdine suffered the final nail in its coffin with the complete release of its phase 3 data detailing its failure to improve cognitive outcomes in patients with mild to moderate Alzheimer’s disease.
The 5-HT6 receptor antagonist idalopirdine was given on a background of stable cholinesterase inhibitor therapy in three Lundbeck-sponsored phase 3 trials: STARSHINE , STARBEAM , and STARBRIGHT . But none of the STAR studies reproduced the results of idalopirdine’s modestly successful phase 2 study, LADDER , wrote Alireza Atri , MD, PhD, and his colleagues. The report appears Jan. 9 in JAMA .
Last year, the STAR studies’ top-line readouts prompted the Danish company to scrap its idalopirdine program. The full data readout documents the hard truth of this Alzheimer’s therapeutic candidate: No matter what dose, or on what background therapy, idalopirdine was no better than placebo at improving cognitive scores on any of the tested endpoints, reported Dr. Atri of the California Pacific Medical Center, San Francisco, and his coinvestigators.
STARSHINE, STARBEAM, and STARBRIGHT were all 24-week, fixed-dose, randomized placebo-controlled studies with the same endpoint: change on the Alzheimer’s Disease Cooperative Scale–cognitive (ADAS-cog) measure. Together, they enrolled 2,525 patients with mild to moderate AD. Patients were a mean of 74 years old, with a mean Mini Mental State Exam Score of 17-18 and a mean baseline ADAS-cog of 26.
Study 1 (STARSHINE) randomized patients to background donepezil plus placebo, or idalopirdine 30 mg or 60 mg. Study 2 (STARBEAM) randomized patients to background donepezil plus placebo or idalopirdine 10 mg or 30 mg. Study 3 (STARBRIGHT) randomized patients to background donepezil, rivastigmine, or galantamine plus placebo or 60 mg idalopirdine.
Cohort retention was good in all three studies, with about a 9% dropout rate for those taking placebo, 10% for those taking 10 mg or 30 mg idalopirdine, and 11% for those taking the 60-mg dose. The adverse event profile was also acceptable. However, there were no statistically significant cognitive improvements in any study.
In study 1, the mean 24-week change in ADAS-cog total score was 0.37 for the 60-mg group, 0.61 for the 30-mg group, and 0.41 for the placebo group. Compared with placebo, the mean difference in ADAS-cog score change was 0.05 for the 60-mg dose group and 0.33 for the 30-mg group.
In study 2, the mean 24-week change in ADAS-cog score was 1.01 for the 30-mg group, 0.53 for the 10-mg group, and 0.56 for the placebo group. Compared with placebo, the adjusted mean difference in ADAS-cog was 0.63 for the 30-mg group and −0.09 for the 10-mg group.
In study 3, the mean ADAS-cog change was 0.38 for the 60-mg group and 0.82 for the placebo group. Compared with placebo, the mean difference was –0.55.
Adverse events were similar across the studies. The most common treatment-related adverse events were accidental overdose (idalopirdine treatment groups: 5%-11%; placebo: 9%-12%). Falls were the next most common (idalopirdine treatment groups: 4%-6%; placebo: 3%-6%). Cholinergic adverse events were also more common among those taking the study drug, with nausea and vomiting occurring in up to 4% of patients. About 5%-7% of patients taking idalopirdine discontinued because of a treatment-emergent adverse event, compared with 3%-5% of those taking placebo.
Five patients taking idalopirdine and three taking placebo died during the study; no death was related to the study drug. There was no indication of suicidal ideation or behavior associated with idalopirdine.
One striking difference between the modestly successful phase 2 and the clearly negative phase 3 studies was dosage, Dr. Atri noted. LADDER tested 90 mg of idalopirdine, split into three 30-mg doses each day. The STAR-series opted for a lower dose because PET studies on healthy volunteers showed high binding on the 5-HT6 receptors (more than 80%) at both the 30- and 60-mg doses.
“Although there is an approximate 40% decrease in 5-HT6 receptor expression among patients with Alzheimer disease compared with healthy individuals, there are also potential limitations in translating occupancy data from healthy individuals to those with a diseased brain,” the authors noted.
Based on the soundly negative data, and disappointing results with idalopirdine’s close competitor, intepirdine, it may be time to retire this area of investigation entirely, Dr. Atri concluded.
“Placing the results of this study in the broader context of the 5-HT6 antagonism adjunctive to cholinesterase inhibitor therapy mechanism of action suggests a lack of efficacy for this approach in the treatment of Alzheimer disease. In the phase 3 MINDSET study, intepirdine (another 5-HT6 antagonist) was administered at a dose of 35 mg daily added to background donepezil therapy in patients with mild to moderate Alzheimer disease and it failed to meet cognitive and functional efficacy outcomes.”
As if on cue with the idalopirdine data, Axovant Life Sciences, the New York company developing intepirdine, announced on Jan. 8 that it would shelve that drug. The announcement came on the heels of negative findings in its last best-hope studies aimed at patients with Lewy body dementia.
In the HEADWAY Lewy body dementia study, neither 35 mg nor 70 mg of intepirdine significantly improved cognition, compared with placebo. The 70-mg dose was associated with a small but insignificant improvement in motor function, but the 35-mg dose was associated with a 2-point worsening.
In a phase 2 study of intepirdine in patients with dementia and gait impairment, 35 mg of intepirdine did not improve gait speed.
“Based on the totality of intepirdine data to date, there is no evidence to support its further development. We are incredibly disappointed and saddened for the millions of people living with these difficult conditions, and are deeply grateful to the patients, caregivers and investigators who participated in our trials,” David Hung, MD, chief executive officer of Axovant, said in a press statement.
Dr. Atri reported financial relationships with numerous pharmaceutical companies, including Lundbeck, which sponsored the STAR trials.
