Esketamine Hydrochloride

iStock, BlackSalmon 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.”

Major vaccine makers reported significant declines in U.S. sales and demand in the third quarter. Anti-vaccine sentiment is alive and well, especially in the U.S. And it was evident in recent weeks as drugmakers revealed their third-quarter earnings, replete with declining vaccine sales.Pfizer’s numbers (PDF) were particularly indicative of the erosion in demand for immunizations in the U.S. While sales of its Prevnar franchise of pneumococcal vaccines were up 18% year over year outside of the U.S., they were down 12% in the U.S. The same was true of COVID shot Comirnaty, which saw a 9% sales increase internationally and a 25% decline domestically.Meanwhile, sales of Pfizer’s new respiratory syncytial virus (RSV) vaccine Abrysvo were up 81% outside of the U.S. and down 34% in the U.S., with CEO Albert Bourla, Ph.D., saying the company was “experiencing the headwind of a more difficult-to-activate population as we enter the third season of RSV.”Sanofi, for its part, sustained an 8% year-over-year decline in its vaccine revenues, with Chief Financial Officer François Roger noting a “negative buzz” around the jabs. In the company's earnings announcement, CEO Paul Hudson attributed the shortfall to “increased price competition and lower vaccination rate.”GSK managed to squeak out a 2% overall increase in vaccine revenue despite a 15% decline of sales in the U.S., which the company chalked up largely to plummeting demand for its shingles jab Shingrix.As for Merck, which has been hindered for more than a year by declining demand in China for its HPV shot Gardasil, sales of each of its vaccines were down in the third quarter except for Capvaxive, which CFO Caroline Litchfield said is off to a “very strong launch.” The shot, which is the first designed specifically to prevent pneumococcal disease in adults, has generated sales of $530 million in its first four quarters on the market. The third-quarter results were even more grim for companies that specialize in vaccines and depend largely on U.S. sales. Moderna sustained a 45% year-over-year decrease in revenue during the quarter as its RSV shot mResvia drummed up sales of just $2 million and its COVID vaccine Spikevax pulled in $971 million, which was down from $1.8 billion during the same period last year. With the result, Moderna reduced the top end of its 2025 guidance from $2.2 billion to $2 billion.Another company that has been impacted by declining demand for vaccines has been CSL. Last month, the Australian drugmaker backtracked on its plan to spin out its vaccine division, CSL Seqirus, because of the “heightened volatility in the current U.S. influenza vaccine market,” Chairman Brian McNamee explained. He added that the timing of the transaction would “not fully capture Seqirus’ value potential.”Citing insurance claims data, CSL’s leaders said they expect this season's flu vaccination rates in the U.S. to decline by 12% overall and by 14% for people ages 65 and older compared with last year.  Lilly is No. 1 again Among the industry's largest companies, there was no surprise at the top of the growth rankings as Eli Lilly pulled off a whopping 54% increase. It was the fourth straight period in which the Indianapolis company delivered the highest sales bump among large biopharma companies. It also was the largest quarterly sales bump for a top-25 drugmaker since the COVID years.The performance is more evidence that Lilly has widened the gap on its rival in the diabetes and obesity market, Novo Nordisk. The Danish company had just a 5% revenue increase in the third quarter. Novo also saw a 2% quarter-to-quarter sales slide, which was its second straight period with a sequential revenue decline.Lilly’s boost was fueled by sales of its tirzepatide products, which exceeded $10 billion for the quarter. The figure included $6.5 billion sales for diabetes drug Mounjaro and $3.6 billion for obesity treatment Zepbound.The only time in history that a single drug has exceeded sales of $10 billion in a quarter came in the COVID years, when Pfizer and BioNTech’s Comirnaty passed the threshold in three straight periods, maxing out at $13.2 billion in the first quarter of 2022. On its current trajectory, sales of tirzepatide products figure to increase again in the coming periods. The scale-up has been remarkable this year, starting at $6.1 billion in the first quarter. In the second quarter, tirzepatide’s combined sales finally topped those of Novo’s semaglutide products, which was significant because Novo’s Ozempic was first to the market in 2017, compared to Mounjaro, which came along five years later.Tirzepatide also has supplanted Merck’s cancer treatment Keytruda as the current top-selling drug, a crown it has held since 2023. Through the first three quarters of the year, tirzepatide has generated sales of $24.8 billion compared to $23.2 billion for Keytruda. Big gainers in Q3 No company in the industry approached Lilly’s revenue bump in the quarter. The only other top-25 companies by sales that achieved a double-digit increase in the third quarter were the Japanese duo of Astellas (13%) and Daiichi Sankyo (12%), followed by Amgen (12%), AstraZeneca (11%) and Vertex (11%).Another company that thrived in the third quarter was AbbVie, with a 9% sales gain thanks in large part to Skyrizi, which the company is now projecting will achieve sales of $17.3 billion this year, up from $11.7 billion in 2024. The Illinois company also is back in the good graces of investors as it enjoyed a 25% increase in its market cap in the third quarter, according to a report from GlobalData.Johnson & Johnson, meanwhile, turned in a 7% sales increase, which was its largest quarterly boost since 2023. The showing is further evidence that J&J’s shedding of its consumer health unit has helped facilitate growth. Two of the catalysts for the performance were autoimmune star Tremfya, which grew sales 41% to $1.4 billion, and depression drug Spravato, which became a blockbuster last year and accomplished a 61% sales increase in the third quarter.Amgen’s double-digit increase (PDF) came on top of 9% increases in the first two quarters of this year as the company appears to be hitting its stride after its 2023 acquisition of Horizon Therapeutics. There were many plusses with Amgen, including its biosimilars, which were up 52% thanks largely to its Eylea knockoff, Pavblu. Its older medicines, like Prolia and Repatha—both on the market for more than a decade—had big surprise sales boosts in the third quarter. AbbVie, J&J and Amgen were among the group of drugmakers that bumped up their annual revenue projection after reporting third-quarter numbers. The only top-25 companies that reduced their annual revenue estimates were Takeda (PDF) and Merck, which dropped its projection by $300 million as Keytruda’s sales in the third quarter failed to meet expectations.Lilly increased (PDF) its guidance by more than $2 billion, while Bristol Myers Squibb bumped up (PDF) its estimate by $1.2 billion. Despite its U.S. vaccine sales struggles, GSK boosted (PDF) the top end of its 2025 revenue projection from an increase of 5% to 7%. Astellas and Daiichi each increased (PDF) their revenue projection by 100,000 million Japanese yen, which works out to about $650 million. U.S. rebound continued in Q3 Aside from the decline in vaccine sales, it was a strong quarter for biopharma overall as 21 of the world’s top 25 drugmakers achieved year-over-year revenue increases.It was another period of recovery following an unusual first quarter in which seven of the world’s top 25 companies saw falling sales, with each of the seven decliners based in the U.S. In the second quarter, the trend faded as four of the seven U.S. companies accomplished sales increases. Then, in the third quarter, Pfizer was the only U.S. company that sustained a revenue decrease.Of the non-U.S. companies that saw their sales decline in the third quarter, none were a surprise. Takeda had the largest sales falloff (PDF) among the industry’s top 25 companies at 8%, which matched its decline in the previous quarter. Meanwhile, Roche was down by 1% after a flat performance in the second quarter. Bayer was the other decliner (PDF), at 3%, following a trend that has been in place since 2023.