Alto Neurosciences is halting work on its schizophrenia prospect after the brain-penetrant drug flunked a phase 2 study.
The Bay Area biotech evaluated 10 days of treatment with the phosphodiesterase-4 (PDE4) inhibitor, dubbed ALTO-101, or placebo in a mid-stage trial of 83 patients with cognitive impairment associated with schizophrenia. The trial’s primary endpoint was the therapy’s effect on cognition as measured by an electroencephalography (EEG) test of the brain’s activity.
ALTO-101—which is delivered through the skin—wasn’t able to demonstrate a statistically significant improvement on this measure when compared to placebo, Alto disclosed in a post-market release Wednesday.
Searching for some positives, the biotech claimed it identified “directional improvements across certain EEG measures,” which included a “near-significant effect” on theta-ITC, an EEG biomarker that has been associated with cognitive performance.
When drilling down into a pre-specified analysis in a more cognitively impaired subgroup of 59 patients, Alto said its therapy “exhibited nominally significant effects on theta-ITC compared to placebo.”
“Further, certain EEG measures, including theta-ITC, showed improvements from Day 5 to Day 10 in the trial, suggesting a longer treatment period may elucidate greater effects,” the company observed.
Approved PDE4 inhibitors like chronic obstructive pulmonary disease (COPD) drug roflumilast and Amgen’s psoriasis drug Otezla list nausea and vomiting as common side effects. Alto said rates of these side effects within the ALTO-101 cohort were in line with placebo rates, suggesting that the therapy could have better tolerability than other drugs in its class.
The biotech also noted that a “high rate of application site skin reactions” was seen in both the ALTO-101 and placebo cohorts of the phase 2 trial.
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Following the phase 2 fail, Alto has decided not to take ALTO-101 forward. The company has also been developing a modified-release oral formulation of the therapy, but the biotech won’t pursue either version of the drug unless it can find a partner.
Instead, Alto said it will prioritize ALTO-207. The company expects to “imminently” take the therapy—a combination of the approved Parkinson’s disease med pramipexole and the nausea prevention drug ondansetron—into a phase 2b study for treatment-resistant depression.
“While we are disappointed that the ALTO-101 data did not deliver the signal we were seeking, it is an exploratory program, and we remain heavily focused on ALTO-207, our most advanced program in development for treatment-resistant depression—which is supported by strong prior clinical data and external validation,” Alto CEO Amit Etkin, M.D., Ph.D., said in the release.
“We are excited about our oral, modified-release formulation of ALTO-101 to potentially provide benefit to patients, and we intend to seek partnering opportunities to drive future value for this program,” Etkin added.
While William Blair analysts branded the failure of ALTO-101 “disappointing,” they suggested that investors are already focused on ALTO-207 as well as the major depressive disorder prospect ALTO-300.
“We had always viewed the [ALTO-101] study as high risk given the signal-finding nature, short-term study, and difficult-to-treat cognitive impairment associated with schizophrenia population, and we ascribed minimal value to the program in our model,” the analysts explained in an April 1 note.
This morning’s news follows a separate phase 2 failure for Alto’s depression drug ALTO-203 last year. The histamine H3 receptor inverse agonist was unable to demonstrate a placebo-adjusted improvement in alertness and mood, although the company continues to list the asset in its pipeline.
