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The R&D pipeline for depression therapies faced a demoralizing 2025 as five high-pro including KOR antagonists by Johnson & Johnson and Neumora Therapeutics, flunked late-stage clinical trials, underscoring the persistent challenges of CNS drug development.
The pipeline of investigational depression treatments has had a difficult year. It often seems the only news coming out of this space is bad news, with potential therapies
being
abandoned
and
endpoints missed
. Even Johnson & Johnson, which
aims
to become the number one company in neuroscience by 2030,
axed
a Phase III trial in major depressive disorder.
The reality is that developing treatments targeting the central nervous system (CNS) is challenging, and drug candidates often come off the rails when moving into mid-to-late-stage trials. There is an
estimated
85% failure rate of CNS drugs in Phase II and III trials, according to WCG Clinical Services.
Between 2009 and 2025
, the FDA approved just 15 medications for depressive disorders, despite major depression
affecting more than 8%
of the U.S. population each year.
But the market potential for successful candidates is so great that companies keep trying, Myles Minter, partner at William Blair, told
BioSpace
.
“You’ve got 21 million patients in the U.S. and around 50% of them get treated,” he said. “But, of these, there are 8 million that really don’t respond after several lines of therapy, including all the relapses.” There are several reasons for this, Minter explained, including side effects, lack of efficacy and time to efficacy—selective serotonin reuptake inhibitors (SSRIs) take around six weeks to work and even then, only work half the time. “Hence, the unmet need.”
Minter said there are various hurdles to successful clinical development, but the major barrier is placebo response. Due to the naturally subjective endpoints in depression trials, which rely on the patients’ self-reported outcomes, there is a higher likelihood of patients in the placebo cohort reporting improvements, he explained.
This was the key factor that led J&J to
discontinue development of aticaprant
in March, as the kappa opioid receptor (KOR) blocker was unable to show greater efficacy than placebo in major depressive disorder (MDD). For Minter, this was the most significant trial failure in recent years, representing a major blow to the KOR antagonist class.
Here,
BioSpace
takes a closer look at this development and four more trial failures that rocked the depression space in 2025.
Johnson & Johnson’s Aticaprant
It’s been an especially rough year for the KOR antagonist class, cemented by the Phase III failure of J&J’s aticaprant.
The KOR antagonist class in depression emerged from the National Institutes of Health, which had been
searching
for signals relating to brain reward circuitry. KOR antagonists surfaced as a potential therapeutic approach for depression after showing potential in preclinical studies.
This promise led J&J, as well as other companies—including Neumora Therapeutics—to pursue the development of KOR assets for MDD. J&J, for its part, took aticaprant as far as Phase III trials as an adjunct therapy for MDD with anhedonia—the inability to experience joy—before
abandoning
the program in March due to “insufficient efficacy in the target patient population.”
Prior to the readout, expectations were very high for this drug class, Minter said. Now, those expectations “are absolutely rock bottom.”
Neumora’s Navacaprant
J&J’s KOR disappointment may have been presaged in January, when Neumora
announced
that the first of its Phase III trials for its KOR antagonist navacaprant in MDD failed to show statistically significant improvement over placebo. Unlike J&J, however, the company elected not to discontinue development in MDD, but did
make adjustments
to two ongoing Phase III studies,
KOASTAL-2
and
KOASTAL-3
.
The adjustment involved reducing the number of sites used, adding medical monitoring, and implementing a screening tool to prevent people enrolled in multiple clinical trials at once from participating in the KOASTAL studies. The results from these ongoing studies are expected to read out in 2026.
“We believe these changes strengthen the studies and look forward to delivering topline data in 2026,” Neumora CEO Paul Berns
said
during the company’s fourth-quarter 2024 business update in March.
Minter noted that site variability and trial execution have been major issues facing the broader depression drug development space, as the diverse conduct of clinical trial sites adds to the heterogeneity of results.
KOASTAL-2 has a primary completion date of May 2026, while KOASTAL-3 is expected to read out in February.
Alto’s ALTO-203
Another asset that failed to meet expectations was Alto Neuroscience’s ALTO-203. The oral H3 receptor blocker was unable to significantly improve mood in patients with MDD, Alto
reported
in June. However, as the trial was considered exploratory and proof-of-concept, the biotech pointed to other treatment outcomes that could validate further development, such as reported improvements to sustained attention and wakefulness.
The news emerged less than a year after Alto’s other depression asset, ALTO-100, which targets the BDNF protein, also
failed
to improve symptoms in MDD compared to placebo in a mid-stage trial.
One of the compounding factors for these trial issues, according to Minter, could be patient adherence to the treatments. In ALTO-100’s Phase IIb trial, upwards of 30% of patients assigned to take the study drug failed to do so, he said.
This marks one of the challenges broadly for depression trials, Minter noted. “It’s very different from oncology trials, where they’re coming in for an infusion or a scan, as the patients are going to be 100% compliant, unless adverse events put them off therapy.”
Supernus’ SPN-820
Another contender, Supernus Pharmaceuticals, took a different approach with an oral activator of the mTORC protein. The outcome was the same, however—a Phase IIb trial for SPN-820 in February
failed to meet
its primary endpoint in treatment-resistant depression (TRD).
The asset failed to show a statistically significant difference in the reduction of depressive symptoms compared to placebo, according to Supernus’
press release
at the time. The secondary endpoint, which sought a treatment difference between SPN-820 and placebo from baseline to week four of the trial, was also missed.
Supernus might have expected better, as the trial followed a
positive Phase IIa readout in MDD
in October 2024. However, Jefferies analysts at the time cautioned that drugs that could work for both major depressive disorder and TRD are “rare.”
As for SPN-820’s future in TRD, Supernus CEO Jack Khattar said in a statement alongside the February press release that the company would “continue to analyze these data” with development partner Navitor Pharmaceuticals.
In its third-quarter report
, the company confirmed plans to initiate a follow-on Phase IIb trial for SPN-820 in MDD, with no mention of further trials in TRD.
Neurocrine’s NBI-770
Last month, Neurocrine Biosciences became the latest company to run into trouble at the Phase II mark with NBI-1070770, also known as simply ‘770. The drug, a negative allosteric modulator of the NMDA NR2B receptor in development for MDD, failed to significantly improve depression severity, missing the study’s primary endpoint.
Neurocrine CMO Sanjay Keswani said in the company’s
press release
that there are “aspects of the data that warrant further exploration,” and that Neurocrine will assess these before determining next steps.
NBI-1070770’s failure to show efficacy came as something of a surprise to analysts, with BMO Capital Markets
noting
that it had a similar mechanism of action to J&J’s esketamine TRD treatment Spravato, first approved in 2019. The FDA has also
approved
Axsome Therapeutics’ oral NMDA receptor antagonist for MDD. With this treatment precedent set, BMO analysts said the asset was viewed as “somewhat derisked.”
For all the challenges drug developers have faced in the depression space in 2025, Minter stressed that significant steps are being made by the treatments that do make it across the regulatory finish line. Of Spravato, he said, “Most people say the product is literally a lifesaver because you don’t know when that patient is coming back. If you can’t treat a depressive episode, then that may be the last time you see them.”
