Muna’s oral Alzheimer’s candidate shifts age-associated markers in Phase 1

Why it matters: Alzheimer’s has no cure, and the EU-approved antibodies lecanemab and donanemab only slow decline in selected early-stage patients with confirmed amyloid and no more than one copy of the ApoE4 gene variant, while requiring infusions and monitoring for brain swelling and bleeding. Rather than targeting amyloid deposits, Muna’s pill aims to strengthen microglia, the brain’s immune cells, through TREM2, a receptor whose impaired function raises Alzheimer’s risk.

• “Seeing a shift in selected age-associated biology in elderly participants, alongside a favorable tolerability profile, strengthens our confidence in MNA-001’s differentiated approach and best-in-class potential as a once-daily oral therapy,” CEO Michel Detheux said in a press release.

Zoom in: Muna’s randomized, double-blind, placebo-controlled Phase 1 trial tested single and multiple ascending doses in younger volunteers and included an elderly cohort.

• Most adverse events were mild, with no serious adverse events or discontinuations due to adverse events reported.

• The drug reached the cerebrospinal fluid, with plasma exposure rising proportionally with dose. Muna says its pharmacokinetics support once-daily dosing.

• Soluble TREM2, a marker of target engagement, fell with increasing doses in spinal fluid and plasma, with reductions reaching “an apparent response plateau at well-tolerated exposures.”

• After repeated dosing, exploratory analyses found age-associated markers of microglial and innate immune activity and neuronal stress in older volunteers shifting toward levels seen in younger people.

Reality check: Earlier TREM2 trials illustrate the difficulty of translating biological activity into clinical benefit, while two competing programmes have reached Phase 2.

• Muna’s release gives no participant numbers, doses, effect sizes or placebo-adjusted results for the exploratory biomarker shifts, and does not identify the individual markers.

• Alector’s TREM2 antibody AL002 also reduced soluble TREM2 and showed signs of activating microglia but missed its main goal of slowing Alzheimer’s progression in a 2024 Phase 2 trial.

• Novartis has a Phase 2 Alzheimer’s trial of VHB937 with 407 planned participants, although the antibody failed in ALS in September.

• Sanofi’s competing oral drug SAR448851 has published Phase 1 results from 115 participants, including Alzheimer’s patients, and is recruiting up to 160 patients for Phase 2.

What’s next: Muna plans to start a placebo-controlled Phase 2 trial in early Alzheimer’s disease in early 2027, measuring cognition and biomarkers of disease progression. The release gives no trial size or locations.

• “Our next milestone is to determine whether this biological activity translates into meaningful benefit for patients,” Detheux said.