Women have twice the risk of depression compared to men, which experts have long chalked up to factors such as hormone fluctuations and unique life pressures. But there may be another factor at play — gene expression — that Arrivo BioVentures is betting could turn its depression drug flop into a success story.
A few years ago, company researchers received disappointing results from an initial phase 2 trial of their potentially first-in-class drug SP-624, a sirtuin 6 (SIRT6) activator for major depressive disorder. Despite producing an effect on the Montgomery-Asberg Depression Rating Scale, which rates the severity of depressive episodes in adults, the impact wasn’t statistically significant. But something about the results didn’t add up, said Arrivo CEO Steve Butts.
“Our stats group said, ‘Something weird is going on here because we see a lot of people getting better but this is just not making sense to us,’” he recalled.
They dug into the results to find out why.
“As it turns out, males did not perform well at all on the drug, and females performed very well,” Butts said.
A quarter of the female patients taking the drug achieved remissions by their fourth week and 38% saw a reduction in symptoms of 50% or more.
While investigating the findings, company officials came across the work of a University of Pittsburgh associate professor and scientist, Marianne Seney, an expert in gender differences in depression. She led a 2018 study that showed males and females express opposite genes from one another when they’re depressed. A light bulb went on at Arrivo.
“Our drug has an epigenetic mechanism. It's a gene silencer, so it silences certain gene pathways,” Butts said. “Apparently, based on the data from our first study, it silences the gene pathways that are preferentially important to females with depression.”
“If we continue to be successful, this is going to change the way our industry looks at drug development for depression."
Steve Butts
CEO, Arrivo BioVentures
Targeting SIRT6, an enzyme that plays a role in a number of cellular functions including DNA repair and gene expression, could explain why women, who comprised two-thirds of the study population, saw clinically significant results, while the men saw none.
“SIRT6 specifically silences inflammatory pathways, of which, NF-kB is the most well understood,” the company said in an emailed statement. “SIRT6 also inhibits certain gene promoters that affect genes involved in glucose homeostasis.”
The revelation prompted a pivot to pursue SP-624 as a female-specific depression treatment, Butts said. But now comes the hard part — proving the theory. With that goal in mind, Arrivo is studying SP-624 in a new larger phase 2b trial that enrolled both men and women but will only include women in the primary endpoint of reduced symptoms, Butts said.
“We want this study to have the possibility of being a registration study, and the only way to make that happen is to have a primary endpoint that's successful,” he said. “And we're convinced this drug works preferentially in females.”
Past studies have also found modest differences in how men and women respond to depression treatments.
“Females tend to respond better to selective serotonin reuptake inhibitors, but males tend to respond better to norepinephrine-based products,” Butts said.
Women also tend to have different depression symptoms than men.
It's not clear yet how well SP-624 will perform against approved depression drugs, but it could provide a new option for female patients in a market starved for innovation.
“The important piece is that depression is an epidemic in this country and we have not solved it,” Butts said.
The company expects a data readout from the phase 2b study in late 2025 or early 2026 and is hoping the drug will also have potential in other applications, including age-related and neurodegenerative diseases, diabetes and obesity. If the drug performs as hoped in depression, Butts believes it could send a signal to the rest of pharma.
“If we continue to be successful, this is going to change the way our industry looks at drug development for depression and probably other neuropsychiatric diseases,” Butts said. “We're going to show that you can get to the biological basis of what's going on in these patients, as opposed to just trying something that's moderately effective in everyone, like receptor-based products [such as] SSRIs or SNRIs.”
