1Q26 Update. ALTO-207 P2b Trial Initiated in TRD and New ALTO-101 EEG Analyses

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1Q26 Update. ALTO-207 P2b Trial Initiated in TRD and New ALTO-101 EEG Analyses

■ ...failures across the industry. The 10-day treatment duration probably limited the study's ability to detect a clean signal, and

the trending theta-ITC improvement from day 5 to day 10 hints that a longer treatment window may have told a different

story.

■ Biomarkers going into the ALTO-101 readout. The biomarker approaches that drive Alto are a huge work in progress and

probably don't yet tell us much about the size of treatment effects in chosen groups. The new readout looks like a learning

experience for the type of correlations that give positive hints rather than definitive treatment results, so they are worth

keeping in mind. The primary endpoint was based on a specific EEG signature (termed ITC) that reflects slower neural function

AND is well established to correlate with cognitive dysfunction. This primary endpoint looked reasonably derisked after Alto

showed that ALTO-101 treatment produces positive effects on ITC while others have established the correlations betweenBIOTECHNOLOGY

CIAS and ITC (further reinforced by earlier Alto data sets).

■ Hard to argue with ALTO-207 enthusiasm. Interest in Alto has increased since the acquisition of ALTO-207, a combination

containing a serotonin D3 > D2 receptor agonist Pramipexole that is approved in PD and has shown outsized treatmentEQUITY effects in depression (about 3x the size of many approved drugs). ALTO-207 adds ondansetron to reduce adverse effects of

D3 stimulation including nausea. The approach, as validated by COBENIFY, makes sense to us as the combination can now be

titrated to effective doses 5x faster and to higher levels to produce greatly improved safety, while retaining the compelling

treatment effects.