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In February 2017, Lundbeck and Otsuka announced the failure of idalopirdine in demonstrating efficacy in its pivotal Phase III clinical trial program for Alzheimer’s disease, and indicated that the lack of efficacy will end plans for regulatory submission. The companies conducted three pivotal trials of idalopirdine as an adjunctive to acetylcholinesterase inhibitors in mild to moderate Alzheimer’s disease at a dose range of 10–60mg daily: STARSHINE, STARBEAM, and STARBRIGHT (ClinicalTrials.gov identifiers: NCT01955161, NCT02006641, NCT02006654; Trialtrove, 2016). The primary endpoint of all three studies was change in cognition after 24 weeks, as measured by the Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog). While Lundbeck and Otsuka announced the failure of STARSHINE in September 2016, the replication of the negative outcome in both STARBEAM and STARBRIGHT further solidified the lack of efficacy of this drug in patients with mild to moderate Alzheimer’s disease and may have implications for drugs in development with similar mechanisms of action.

 

The trial designs of the Phase III studies are summarized in the table below.

 

Idalopirdine Phase III trials in Alzheimer’s disease

Trial

Sample size

Target patients

Study design

Treatment arms

Primary endpoint

Start date/primary completion date

STARSHINE

(NCT01955161)

(Phase III)

930

Patients with mild to moderate Alzheimer’s disease treated with donepezil

Randomized, parallel-assignment, double-blind, placebo-controlled

Arm 1:idalopirdine 30mg/day adjunct to 10mg/day donepezil

Arm 2:idalopirdine 60mg/day adjunct to 10mg/day donepezil

Arm 3:placebo tablet/day adjunct to 10mg/day donepezil

Duration:24 weeks

Change from baseline in ADAS-Cog scale

October 2013/July 2016

STARBEAM

(NCT02006641)

(Phase III)

840

Patients with mild to moderate Alzheimer’s disease treated with donepezil

Randomized, parallel-assignment, double-blind, placebo-controlled

Arm 1:idalopirdine 10mg/day adjunct to 10mg/day donepezil

Arm 2:idalopirdine 30mg/day adjunct to 10mg/day donepezil

Arm 3:placebo tablet/day adjunct to 10mg/day donepezil

Duration:24 weeks

Change from baseline in ADAS-Cog scale

February 2014/December 2016

STARBRIGHT

(NCT02006654)

(Phase III)

720

Patients with mild to moderate Alzheimer’s disease treated with an AChEI

Randomized, parallel-assignment, double-blind, placebo-controlled

Arm 1:idalopirdine 30mg or 60mg/day adjunct to AChEI

Arm 2:placebo tablet/day adjunct to AChEI

Duration:24 weeks

Change from baseline in ADAS-Cog scale

March 2014/January 2017

 

 

Idalopirdine is a 5-HT6 receptor antagonist that promotes the release of acetylcholine. Lundbeck and Otsuka were hoping that the use of idalopirdine alongside acetylcholinesterase inhibitors would further potentiate the cholinergic system and that the drug would provide Alzheimer’s patients with a greater boost in cognition. By betting on this complementary mode of action, Axovant Sciences is also developing another 5-HT6 receptor antagonist as an adjunctive treatment for patients with mild to moderate Alzheimer’s disease, RVT-101. Trailing idalopirdine’s development, RVT-101 is another closely watched drug with a Phase III trial due to be completed by October 2017. While the failure of idalopirdine’s clinical program may cast doubt over this class of drugs, it can be argued that this may not apply to RVT-101. Firstly, idalopirdine’s failure is not necessarily surprising considering that the trial design of this Phase III clinical program differed from its Phase II study, in that it evaluated a lower dose (30–60mg/day) whereas the experimental arm for the Phase II study was 90mg/day. Hence, a lower dose difference could partly account for the failure to replicate the Phase II findings. In RVT-101’s case, there are no major changes in the trial design of the Phase III study – particularly with regards to the dose – and the study is likely better powered to show an effect, with higher patient numbers recruited per study arm. In addition, while the effects are moderate, RVT-101 has demonstrated not only cognitive benefits but also functional improvements in the Phase II study, suggesting that it has an improved clinical profile over idalopirdine, and may thus present with a higher likelihood of a positive outcome in Phase III trials.

 

Nevertheless, despite these differences in trial designs and the products’ distinct clinical attributes, Datamonitor Healthcare cannot fully ignore the fact that drugs acting through this pathway are likely to present with weak effects that are not sufficient to demonstrate efficacy in large pivotal Phase III trials, especially when considering that this is not the first failure for a 5-HT6 antagonist. Pfizer has had two drugs with this mechanism of action fail in Alzheimer’s, PF-05212377 and SAM-531, although there was still some hope for the class under a similar claim that the failures were due to clinical trial design limitations. As such, Axovant’s main hope for a positive outcome is that RVT-101’s well-designed Phase III clinical trial will help to redeem this class of drugs.

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