Xanamem misses cognition goal in depression trial, eases mood symptoms
Actinogen's Phase 2 XanaCIDD trial did not improve attention as designed to test, but a secondary MADRS analysis found an antidepressant signal, most pronounced in patients on background SSRIs.
Executive Summary
- A Phase 2 trial testing whether Xanamem improves attention and working memory in adults with major depressive disorder and measurable cognitive impairment did not meet that cognitive goal.
- A secondary analysis of mood symptoms found Xanamem separated from placebo on a standard depression rating scale, with the effect strongest in patients also taking a common class of antidepressants and emerging only after the double-blind treatment period ended.
- The cognitive result is the trial's answer to its own primary question; the mood finding, while statistically significant, was not what the study was built or sized to prove and needs confirmation in a trial designed around that endpoint.
- The same drug and dose are being tested in a larger ongoing Alzheimer's disease trial where a data monitoring committee has already cleared the study to continue, with topline results due in November 2026.
The result
Actinogen Medical Limited said results from its randomized, double-blind, placebo-controlled Phase 2 trial of Xanamem in major depressive disorder with cognitive impairment were published in the British Journal of Psychiatry. The trial's registered primary endpoints centered on short-term safety and tolerability and on Xanamem's effect on attention and working memory. The published result was direct: there was no demonstrable benefit of Xanamem on cognition, and improvements in cognition and depression were not correlated, cutting against the premise that treating one would resolve the other. Xanamem+1Xanamem proof-of-concept trial demonstrating anti-depressant activity published in the British ...Jul 20, 2026Xanamem® in Adults With Major Depressive Disorder and Impaired Cognition (XanaCIDD)NCT05657691
Probability of SuccessBased on the AppliedXL Probability of Success model. For more information about the methodology, read the research here.
The design
The trial, known as XanaCIDD, randomized 167 adults to Xanamem 10 mg once daily or placebo for six weeks, followed by four weeks of blinded follow-up. Participants had a confirmed MDD diagnosis, persistent depressive symptoms on the Hamilton Depression Rating Scale, and measurable cognitive dysfunction; about 80% were on background antidepressant therapy and had a mean of ten prior depressive episodes. The trial completed in July 2024 with enrollment landing at 167 against an original 160, a change the trial's own operational baseline model classifies as within the routine band for a completed study. NCT05657691+1Xanamem® in Adults With Major Depressive Disorder and Impaired Cognition (XanaCIDD)NCT05657691Xanamem proof-of-concept trial demonstrating anti-depressant activity published in the British ...Jul 20, 2026
The secondary signal
Xanamem separated from placebo on the Montgomery-Asberg Depression Rating Scale (MADRS), a secondary measure, by 2.7 points in the overall population, with the effect reaching its maximum four weeks after the treatment period ended rather than during active dosing (p<0.05). In the 46% of patients on background SSRI therapy, the gap widened to 4.2 MADRS points, also peaking during the blinded follow-up phase (p<0.05). Actinogen's own release frames the delayed onset as consistent with the known timecourse of cortisol-related effects reversing after treatment, similar to patterns seen when chronic steroid therapy starts or stops. Professor Michael Berk, a co-author, called the results a 4.2-point MADRS gap in the SSRI subgroup for the same 10 mg dose used in the company's Alzheimer's program. Safety and tolerability findings from the trial were not detailed in the disclosed results. XanamemXanamem proof-of-concept trial demonstrating anti-depressant activity published in the British ...Jul 20, 2026
The landscape
No other industry trial pairs an 11beta-HSD1 inhibitor with major depressive disorder, and this is the only Phase 2 asset in that combination on record. The broader MDD field is active and mechanistically varied, with Phase 3 programs from Takeda's vortioxetine, Janssen's esketamine, and Neurocrine's NBI-1065845 targeting serotonin, NMDA, and other pathways. Xanamem's own mechanism has prior human testing outside depression: AstraZeneca, Boehringer Ingelheim, Merck, and Incyte each ran early-phase 11beta-HSD1 inhibitor trials in metabolic indications such as diabetes and obesity, and Actinogen's own UE2343 program tested the same target in Alzheimer's disease. None of that prior human precedent was in a depression population, so XanaCIDD is the first test of this mechanism against mood symptoms specifically.
The next catalyst
Actinogen's larger and registrational-track program, the Phase 3 XanaMIA trial testing Xanamem 10 mg against placebo in 247 Alzheimer's disease patients, has already cleared an independent data monitoring committee review of unblinded safety and efficacy data on two separate occasions without a call to amend the trial. The company says topline results from that fully enrolled trial are expected in November 2026. Because XanaMIA uses the identical 10 mg dose, the depression finding from XanaCIDD functions as a dose-level readthrough: it demonstrates the drug crosses into the brain and produces a detectable clinical effect at that dose, a fact relevant to interpreting whatever XanaMIA reports in November. Actinogen+1Actinogen receives positive Interim Analysis recommendation from its independent Data ...Feb 2, 2026Xanamem proof-of-concept trial demonstrating anti-depressant activity published in the British ...Jul 20, 2026
This analysis was produced using AI-assisted reporting systems, AppliedXL data, and official public records. These systems undergo editorial review, quality checks, and regular audits by human experts. Errors may still occur, as with any automated system. Always consult the linked primary sources. Read our AI Editorial Policy.