Insilico Medicine CEO Alex Zhavoronkov’s mad dash across the BIO International Convention in June attracted plenty of eyes. But the executive would prefer industry watchers gawk at the billions of dollars’ worth of deals his company has struck.

Alex Zhavoronkov, CEO of Insilico Medicine, slides into the tall chair next to me and hands over a postcard-sized list of clinical programs. “Do you want to buy some drugs?” he quips.

I decline, politely, but do examine the postcard. It looks just like Insilico’s website, a list of stacked green bars with disease names, targets and clinical trial phases. There’s also a collection of available AI programs—Insilico’s bread and butter, but not necessarily its most lucrative products.

It’s the pipeline deals that have made Insilico a rising star in biotech. Zhavoronkov was admittedly rushing around the BIO International Convention in June, meeting with dozens of executives. “Now people know us,” he said as he took a break for an interview with BioSpace at his company’s booth.

Insilico has always presented itself differently. The webpage is meant to look like a standard webstore interface, Zhavoronkov explains. This signals the tech industry’s creep into biotech, which Zhavoronkov is unapologetic about.

He believes that AI platform biotechs can’t survive using the industry’s typical model.

“You can make a deal or two to keep lights running, but the reality of life is that pharma companies are also very competent in AI,” Zhavoronkov explained.

To differentiate, Insilico made the partnering process as smooth as possible, putting all its programs online so that potential buyers can browse like they were shopping for a book or a gift. “We made platform partnerships very smooth. You basically buy it as a software. Some of those you can check out with your credit card.”

To keep the lights burning bright, Insilico focuses on high quality, first-in-class assets but does so at a high quantity, too. The company has signed myriad multi-billion partnerships this year alone, with Eli Lilly, Takeda, Exelixis, Boehringer Ingelheim and more all buying in.

“My new modus operandi, I want to achieve sustainable profitability. Imagine that for a company running 40 programs and investing massively into AI,” Zhavoronkov said. While he wouldn’t give specific guidance as to when Insilico might become profitable, the CEO promised that the company is “reasonably close.”

Insilico aims to partner its programs in the preclinical stage. The biotech has no plans to become a clinical or commercial company, the CEO explained.

“If any startup, or whoever, tells you that they are better than pharma in clinical trials using AI, absolute nonsense,” Zhavoronkov said. “I used to say that too. I regret it.” Pharma is clearly better at getting trial sites up and running, building relationships with investigators, engaging with regulators and so on, he said.

“Those massive machines, they actually are very well tailored for development, so for us we cannot compete with them,” Zhavoronkov said. “If we can kind of convince them to license early, that’s amazing.”

To start off the BIO conference, Insilico announced a partnership with China’s SK Biopharmaceuticals that could be worth up to $2.5 billion in milestones. This deal stood out because a China-based biotech was buying into tech elsewhere when the flow of deals in the pharma industry has been going the other way of late. Zhavoronkov noticed this too. It’s why Insilico set up shop there, with scientific and technology headquarters in Hong Kong and Shanghai.

He watched as pharmas signed very early-stage deals with Chinese companies and thought Insilico could do it too. “Until I understood that I couldn’t partner” because the company had been working on very novel targets, Zhavoronkov said.

If you’ve been watching Insilico closely, you’ll notice that some of its new programs have shifted to what Zhavoronkov calls the “low to moderate novelty space.” This deliberate shift has helped bring in some of the major deals. He pointed to the Lilly transaction, which could be worth up to $2.75 billion. The companies will work on oral drugs against a variety of undisclosed diseases.

“We are now on fire. I had to run here, and I will have to run out of here, because we are basically the ultimate AI drug dealer, so to speak,” Zhavoronkov said.

The CEO was joined by four Insilico colleagues with similar meeting agendas doing the same across the massive San Diego Convention Center at BIO. Zhavoronkov knew that his hustle had been noticed—he even caught someone filming a video of his mad dash across the conference floor.

And if interested buyers couldn’t squeeze into the Insilico employees’ busy schedules, they could use the company’s newly created AI chat bot to initiate business inquiries. It’s a whole new world of biotech drug development.

“That’s why I actually am not shy to run from place to place. You can see me running and people are making fun of it. . . . I’m not sorry about that, because this is the most important show,” Zhavoronkov said. “Every hour is important.”

And he promised that Insilico would have plenty to report from his hustle at BIO. “You haven’t seen anything yet.”

AbCellera Biologics’ reduction in hot flashes sets it apart from currently commercial oral drugs, including Astellas’ Veozah and Bayer’s Lynkuet, according to BMO Capital Markets.

AbCellera Biologics’ investigational antibody significantly lowered the frequency and severity of hot flashes in a Phase 1/2 study of post-menopausal women to a degree that BMO Capital Markets said could reinforce the asset as a “potentially best-in-class treatment.”

In women given AbCellera’s ABCL635, the daily number of moderate and severe hot flash episodes dropped at week four by an average of 8.8 as compared to baseline, according to a Monday news release. Comparators on placebo, meanwhile, saw a mean decrease of 3.5 events per day. The treatment difference was statistically significant.

AbCellera closed Monday’s trading session up nearly 35% to $9.34.

For BMO, ABCL635’s benefit “sets [a] new efficacy bar” in the treatment of vasomotor symptoms, the medical term used to describe hot flashes in post-menopausal women. ABCL635’s efficacy numbers “appear differentiated vs. current oral agents,” the firm continued in a Monday note, specifically naming Astellas’ Veozah and Bayer’s Lynkuet, both indicated for hot flashes.

More broadly, the group considers this readout to be “transformational for AbCellera’s business,” with a forecast of unadjusted worldwide peak sales of $2.3 billion for ABCL635.

Aside from cutting the frequency of hot flashes, AbCellera on Monday also reported that ABCL635 eased the severity of episodes by 58% versus 12% in placebo counterparts, a treatment effect that was statistically significant. Sleep also improved in patients on ABCL635.

As for safety, AbCellera noted that its asset was well-tolerated over four weeks, with no serious or severe toxicities. There were also no side effects prompting patients to drop out of the trial.

This safety profile could help to further differentiate ABCL635 from other hot flash treatments, BMO noted. Other drugs have been held back by off-target activity and liver toxicities, “forcing dose selection below levels that” fully engage their molecular targets, the analyst said, in turn limiting their overall efficacy.

AbCellera’s Phase 2 trial is ongoing, with 12-week follow-up data that could inform optimal dosing expected in the coming months, according to a company presentation on Monday.

AbCellera plans to meet with the FDA to discuss the late-stage development of the asset.

Three years after Qalsody was approved by the FDA as the first drug to target a genetic cause of ALS, some patients are reporting not only disease stabilization but also improvement of symptoms.

Saskatchewan is known for its harsh winters. For Paula Trefiak, a ballet dancer and mother of three, the winter of 2016 was harsher than most. Trefiak was diagnosed with ALS in February and given two to five years to live.

Later that year, however, Trefiak got a glimmer of hope—a call from The Montreal Neurological Institute and Hospital, inviting her to participate in a clinical trial for a drug in development for her specific type of ALS that’s linked to a superoxide dismutase (SOD1) gene.

“I jumped at the opportunity,” she recalled. “By late that afternoon, it was a Friday, I had my flights already ready to go to Montreal.” She flew out on Sunday and received the first dose of tofersen, an antisense oligonucleotide (ASO) developed by Biogen and Ionis Pharmaceuticals, in a Phase 1b trial.

At first the drug appeared to disappoint. Trefiak was given the lowest dose of 20 mg and continued to decline. Then the trial ended, Trefiak stopped receiving the drug and her disease kept progressing. “I was having more issues with my ankles, a lot more issues stuttering, my lip was drooping a lot more. . . . gripping things was becoming an issue.”

Finally, in March 2018, Trefiak began taking a 100 mg dose of tofersen in an open label extension study, and things started to change. By the summer of that year, “I started to feel stronger,” she recalled. Her ankles were stronger; her shoulders—which would freeze when she tried to reach for something—weren’t freezing anymore; she could hold herself up longer in a ballet move called demi-pointe. Her overall quality of life improved.

“I started to notice I was having a better sleep,” Trefiak said. “I wasn’t constantly waking up in agony for hours on end with cramping.”

Today, more than 10 years after her diagnosis, Trefiak can still do all those things and more. “I can dance, I can swim again without drowning,” she said. Her forced vital capacity (FVC)—a key measure of disease progression in ALS—was down to 72% at its lowest, she said. In May, it was at 101%—well within normal range.

It’s a striking outcome for the brutal neurodegenerative disease with only a handful of drugs on the market. And Trefiak is not alone. At least one patient in the Phase 2 trial of AL-S’s AP-101 has also experienced a reversal of decline, Angela Genge, chief medical officer at AL-S Pharma and the top recruiter for Qalsody’s Phase 1, 2 and 3 trials, told BioSpace.

In a study of seven patients with SOD1-ALS treated with the therapy at Washington University in St. Louis from November 2021 to February 2024, all patients saw either disease stabilization or slight improvement in function as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R), per the ALS Association.

On the basis of biomarker data from the Phase 3 Valor trial, tofersen won FDA approval in April 2023 for patients with SOD1-ALS. Health Canada greenlit the therapy under its Special Access Program two years later. The drug is marketed in both countries as Qalsody.

It’s been a tough slog for the ALS treatment space. Amylyx’s Relyvrio, approved in 2022, was voluntarily withdrawn from U.S. and Canadian markets in 2024 after failing to show significant benefit in a Phase 3 trial, and more late-stage trials have failed to show efficacy.

But Qalsody’s success offers hope that researchers are on to something by targeting SOD1. Qalsody is currently indicated only for patients with ALS who have an SOD1 mutation. Notably, pathological levels of misfolding also occur in at least a third of sporadic ALS cases, according to Genge. AL-S Pharma is developing an antibody targeting this mutated protein.

Researchers are hopeful that Qalsody can also help more patients than it’s currently indicated for. Most cases of ALS are sporadic, while 5 to 10% are familial, with approximately 2% linked to a SOD1 mutation. This subset of the disease affects less than 500 people in the U.S.

Genge believes targeting SOD1 can be a real gamechanger in the treatment of ALS.

“We’re looking at targeting a pathway [SOD1] that really seems to be fundamental,” she said.

SOD1 and beyond
The SOD1 gene encodes an enzyme that plays an important role in protecting cells from oxidative stress. Mutations in this gene can lead to a defective form of SOD1 protein, which has been implicated in ALS. Qalsody works by reducing the amount of toxic SOD1 in the body.

While the antisense therapy missed the primary endpoint of a statistically significant change from baseline to week 28 on ALSFRS-R in the Phase 3 VALOR study, the FDA granted an accelerated nod based on its ability to reduce neurofilament light chain, a biomarker of neurodegeneration that the agency deemed “reasonably likely” to predict clinical benefit.

WashU is running a Phase 2 study of the drug in patients with non-SOD1 ALS to test whether more patients could be helped.

“In other neurodegenerative diseases . . . there’s often a link between the genetic causes of disease and what we find in terms of the pathophysiology of the disease,” Timothy Miller, co-director of WashU’s ALS Center and the study’s lead investigator, told BioSpace. In terms of a connection between SOD1 and sporadic ALS, he said the data are “mixed.”

WashU’s study, per ClinicalTrials.gov, has a primary completion date of January 2027.

Meanwhile, AL-S Pharma is targeting misfolded mutant and wildtype SOD1 with AP-101. Unlike Qalsody, the antibody treatment does not affect the level of healthy SOD1, according to Genge. This is important, she said, because “SOD1 is an obligatory protein in our biology, and so we don’t know how low we can knock it before we start building long-term side effects.”

Notably, the company is testing AP-101 in both SOD1-ALS and sporadic forms of the disease.

AL-S Pharma presented data at the ENCALS 2026 Congress in June from a Phase 2 trial of patients with both familial and sporadic ALS. The results showed that early treatment with AP-101 prolonged survival and delayed the need for patients to use a ventilator as compared to patients who were given placebo for six months followed by six months of treatment with the candidate. The results were consistent across patients with both SOD1- and sporadic ALS with moderately to significantly elevated levels of misfolded SOD1, Genge said. A Phase 3 trial is set to kick off in early 2027.

It’s also becoming clear to drug developers that early treatment is key when it comes to neurodegenerative disease.

While speaking with BioSpace last month about Biogen and Ionis’ tau-targeted Alzheimer’s therapy diranersen, Ionis Head of Development Holly Kordasiewicz compared the ASO to the companies’ other partnered therapies, Qalsody, and Spinraza—also an ASO—for spinal muscular atrophy.

“Earlier intervention in any of these neurodegenerative diseases where you have a lifetime of pathology accumulation, like in SOD1-ALS or like in [Alzheimer’s disease], I think earlier is going to be better,” she said.

When children were dosed with Spinraza at birth, Ionis started to see them meet normal motor milestones, Kordasiewicz recalled. “With [Qalsody], there’s a portion of the patients who, if you go in early enough, it’s looking like there’s reports that they’re now doing better as well.”

Biogen is running the Phase 3 ATLAS trial studying Qalsody’s efficacy in presymptomatic individuals with a confirmed SOD1 mutation and elevated neurofilament. Primary completion is expected in August 2027.

Not a cure
Several members of Trefiak’s family have died from SOD1-ALS. Currently, Qalsody is keeping the disease at bay for her sister and two of her cousins—all of whom were showing early symptoms of ALS when they started on the drug.

“They haven’t had the reversal like I have, but at least they’re not deteriorating,” she said. “They’re maintaining their health, which is significant.”

Still, Qalsody is not a cure. Trefiak must undergo an intrathecal injection of Qalsody once every four weeks to maintain the stability of her disease.

“I’ve now had officially 120 lumbar punctures or treatments with this drug that have gone into my spine. I don’t know what that’s doing to my spine long term,” she said. Intrathecal-related side effects can include benign intracranial hypertension and spinal cord inflammation. “To get this drug fewer times per year would be great as well,” Trefiak added.

This is where a treatment like AP-101—if approved—could be especially valuable. As a human monoclonal antibody, AP-101 is delivered intravenously, so it is “very easy to give,” Genge said, adding that the drug is “very well tolerated.”

For now, Trefiak and her family remain grateful for Qalsody. Her 18-year-old son learned, three days after Qalsody’s approval in Canada, that he also carries the G37R-SOD1 mutation. “His first reaction,” she said, “was, ‘at least I now have a treatable disease.’ It’s wonderful that we finally have something that works for our family.”

Despite the recent emergence of a new drug class, schizophrenia remains one of the most challenging neuropsychiatric diseases to treat—and Cobenfy’s first steps into the market indicate there is still room to grow.

When the FDA greenlit Bristol Myers Squibb’s Cobenfy in 2024 as the first novel drug for schizophrenia in 35 years, it was widely seen as a turning point in treating the intractable neuropsychiatric disease. But with the drug struggling out of the gate and a still imperfect side effect profile, there is plenty of room for improvement—and competitors.

“The magnitude of our effect is deep,” Laura Gault, senior vice president and head of neuroscience development at BMS, told BioSpace in an interview. “Cobenfy is a novel [mechanism of action] with a very different side effect profile compared to what people have been using for the last 75 years.”

Cobenfy—formerly KarXT—is a combination of xanomeline, a muscarinic agonist, and trospium chloride, also a muscarinic antagonist, that came to BMS in the $14 billion acquisition of Karuna Therapeutics in 2023.

However, side effects are still a part of the Cobenfy story, particularly with regard to pro-cholinergic symptoms that impact the gastrointestinal system, according to Christopher Kroeger, CEO of MapLight Therapeutics, which is also developing a muscarinic receptor agonist and hopes to compete with BMS’s first-to-market entry.

“The challenge with Cobenfy has been that it is not proven to be particularly tolerable,” Kroeger told BioSpace. Because the components of the drug “have to be in exquisite balance, you can have high interpatient variability.”

Two years in, however, BMS has already heard a lot of success stories, Gault said, where even after a short time on treatment, patients are seeing “very meaningful changes in terms of a reduction in symptoms, but also their ability to engage in life in a way that they had been unable to do.”

Sales numbers, however, reflect a smaller splash.

Cobenfy brought in $155 million in sales for BMS in 2025, well below some analysts’ predictions during the drug’s late phase development at Karuna. Early sales forecasts for Cobenfy were more than double this number, Mizuho analyst Graig Suvannavejh told BioSpace.

Still, Gault said BMS isn’t concerned with the slow start. Since re-entering the neuroscience space with its $74 billion mega-merger with Celgene in 2019, the company has built up its acumen in the arena, which has enjoyed something of a Big Pharma renaissance over the past few years.

“Anytime you bring a new drug, especially a drug with a new [mechanism of action], into the field … [doctors] need to take some time to get to know it,” Gault said.“They need to see those first few experiences with their own eyes before they feel confident to prescribe it regularly.”

Suvannavejh agreed that with schizophrenia in particular, requiring a “Goldilocks approach” to balance side effects and efficacy, Cobenfy has strong potential. “I do think Cobenfy can be a good drug,” he said.

A balancing act

In schizophrenia, decades of treatment have laid bare the challenges inherent in the disease—and the tightrope drug developers must walk between efficacy and tolerability.

Older drugs that primarily affect the brain’s dopamine receptor leave patients with “very potent, very harsh side effects,” Suvannavejh said.

From earlier medicines like Eli Lilly’s Zyprexa to Johnson & Johnson’s Risperdal to next generation antipsychotics such as BMS’ Abilify and more recently, AbbVie’s Vraylar and J&J’s Caplyta, the mechanism of action remained the same despite differences in potency.

“These are just different mousetraps with the same biology, trying to optimize efficacy and safety tolerability,” Suvannavejh said.

Enter muscarinics. Marked by sizable acquisitions, including BMS’s purchase of Karuna and AbbVie’s $8.7 billion pick-up of Cerevel Therapeutics in 2023 and emraclidine—which ultimately led to a high-profile clinical failure in schizophrenia—muscarinic receptor inhibitors gained a good deal of attention for their potential to avoid some of the worst side effects of drugs targeting the dopamine receptors.

In addition to MapLight, AbbVie continues to progress emraclidine in Phase 2, while smaller biotechs like Neurocrine BioSciences and Neumora Therapeutics are also hoping to challenge BMS in the muscarinic space.

Because muscarinic receptors are not expressed in key brain regions, patients avoid many of the side effects associated with the classic dopamine-based drugs, Carlos Dortrait, senior vice president of neuroscience commercialization and global commercial strategy, told BioSpace prior to Cobenfy’s approval.

But Cobenfy’s main muscarinic agonist xanomeline comes with other adverse effects, primarily gastrointestinal, which require an additional ingredient to balance them out and avoid conditions that can lead to poor patient compliance—already a challenge among those with schizophrenia or Alzheimer’s disease psychosis, Suvannavejh said.

MapLight hopes to differentiate and challenge Cobenfy on a couple of fronts.

MapLight posted mixed trial results from a Phase 2 trial of its candidate earlier this month, garnering significant scrutiny from analysts. The results for ML-007-MA “muted” the competitive threat to Cobenfy, BMO Capital Markets said in a note to investors on July 27.

A twice-daily formulation of MapLight’s ML-007C-MA met the Phase 2 ZEPHYR trial’s primary endpoint, reducing symptoms of schizophrenia on the Positive and Negative Syndrome Scale (PANSS) at five weeks, with patients seeing a 4.5-point improvement. However, a once-a-day version of the pill that the company hoped would rival Cobenfy’s twice-daily regimen failed to meet the same expectation.

Cobenfy demonstrated an 8-to-10-point reduction in a pair of Phase 3 trials dubbed EMERGENT, according to BMO.

Still, Kroeger believes MapLight showed what it needed to earn a place next to Cobenfy on the market. He additionally argued that the results have been “misinterpreted” in the public sphere.

The misinterpretation, he said, stems from trying to compare specific PANSS scores across trials and ignoring aspects that are important in the real world, such as cognition and a secondary endpoint measuring clinicians’ global impression of disease severity.

MapLight’s drug also demonstrated important signals in cognition, according to Kroeger. While PANSS measures alleviation of so-called positive symptoms such as hallucination, delusion and disordered thinking and negative symptoms including apathy, withdrawal and lack of engagement with the world, 80% of patients with schizophrenia also suffer from cognitive challenges that have a meaningful impact on quality of life, the CEO noted.

Unlike Cobenfy—whose cognitive signal data were drawn from post-hoc pooled analyses, according to a MapLight spokesperson—ML-007C-MA hit a prespecified secondary endpoint in the ZEPHYR trial, which looked at cognitive performance.

Cobenfy’s market challenges are an opportunity for MapLight to showcase “significant differences in safety we’ve seen in the clinic [that are] going to be even larger when we get to real-world experience,” Kroeger said.

“The whole idea was to develop a drug that can give you the same kind of efficacy that Cobenfy delivered in a way that patients can tolerate,” Kroeger said. “And that’s what we showed in the study.”

Rates of discontinuation in MapLight’s program were lower than with Cobenfy, Kroeger said, attributing this result to fewer moderate and severe adverse events despite instances of mild side effects such as nausea and vomiting.

BMO in its note conceded this point, writing that MapLight’s pill could be more impactful in older adults with schizophrenia alongside Alzheimer’s disease due to lower rates of symptoms such as dry mouth, blurry vision and constipation. MapLight saw a GI discontinuation rate of just 2% in ZEPHYR, the biotech reported. However, BMO said the effect will likely not be enough to derail Cobenfy’s leadership from a market share perspective.

Comparing across clinical trials from different drugmakers is messy at best, Suvannavejh said. While acknowledging that MapLight’s “efficacy seemed to fall short of what was shown in the Karuna clinical trials,” the analyst said that given the high unmet need in schizophrenia, there’s room for more than just one or two of the same kind of drug.

“Just because we have one muscarinic right now in Cobenfy doesn’t mean there can’t be another five more,” Suvannavejh said.

Foundayo clocked $98 million in sales in Q2, the first quarter it was available, compared to Novo’s $355 million for the same sales period.

After entering the obesity market and soundly stealing market share from rival Novo Nordisk’s Wegovy, Eli Lilly isn’t used to being behind. But Foundayo, the Indiana pharma’s new obesity pill, is a different beast.

After receiving FDA approval on April 1, Lilly has seen slow uptake as it introduces patients and caregivers to a completely new product. Novo, on the other hand, had simply captured its successful injectable GLP-1 in a pill.

“We’re making pretty meaningful progress on the Foundayo performance and building out the brand,” said Ilya Yuffa, president of Lilly USA and global customer capabilities, on the company’s second quarter earnings call Wednesday.

Foundayo clocked $98 million in sales in Q2, the first quarter it was available, compared to Novo’s $355 million for the Wegovy pill for its initial sales period. Approved in December 2025, the Wegovy pill rose to $496 million for the second quarter, Novo reported Tuesday afternoon. Foundayo narrowly missed consensus estimates, but analysts weren’t surprised by the weakness.

Lilly has focused on building brand awareness in Foundayo, educating doctors on the drug’s profile, offering access and affordability for patients, and reaching consumers directly, Yuffa explained.

The drug is undoubtedly growing, he insisted. Volume has doubled from just a month ago and nearly one in four patients are choosing Foundayo for initial starts.

“We’re starting to see an inflection point on Foundayo now,” Yuffa said.

But that’s just in the U.S. Analysts pointed to Foundayo’s performance elsewhere as a particular strong point. “Although Foundayo U.S. disappointed, Foundayo ex-U.S. (solely sales in UAE), is an indicator of Foundayo’s ex-U.S. potential,” Leerink Partners’ Senior Research Analyst David Risinger said.

The therapy brought in $31 million in the UAE in the second quarter, “which bodes well for Foundayo’s global potential,” according to Leerink.

Without the ex-U.S. sales for Foundayo, RBC Capital Markets wondered if Lilly’s overall results would have been so strong. “Foundayo’s U.S. performance remains uncertain,” the firm wrote.

Foundayo launched with about 8,000 subscribers but has now grown that to 36,000, RBC noted.

A ‘blowout’ performance

Otherwise, Leerink dubbed Lilly’s second quarter performance a “blowout.” The company notched $23 billion in revenue and raised its outlook to a range of $85 to $87 billion, as compared to $82 to $85 billion previously projected.

Lilly executed a number of transactions in the second quarter, including buying Orna Therapeutics, Ajax Therapeutics, Centessa Pharmaceuticals and Kelonia Therapeutics. Lilly has also since picked up psychedelics biotech AtaiBeckley, diving deeper into neuroscience.

Analysts asked for insight into Lilly’s revived interest in psychiatry during the call, as well as a triple-acquisition in vaccines from earlier in the year. Jacob Van Naarden, president of Lilly Oncology and head of corporate business development, said the company is are simply seeking out unmet needs.

“What these two areas have in common is just the immense unmet need that still remains, and that really is the throughline of all of the work that we do, both internally and through business development,” he said. “It’s not actually that different, frankly, than the many other deals that we’ve done year to date.”

Van Naarden, as well as CEO David Ricks, hinted on the call that more deals could be in the future but were fairly mum on specifics.

“Whether we continue to build more around infectious diseases and psychiatry specifically … I don’t want to forward-look too much on that because we’ll be opportunistic based on what we see that’s available for acquisition and partnering,” Van Naarden said.

Novo Nordisk CEO Maziar Mike Doustdar on a second quarter earnings call argued that failure is par for the course in the drug development business. The Danish pharma is focused on building out its pipeline to move past recent clinical roadblocks.

To bounce back from a series of clinical stumbles, Novo Nordisk is leaning heavily on its innovation engine and an early-stage pipeline that could set the pharma up for long-term growth.

“We stay alive—or not—based on our ability to innovate,” Doustdar told reporters during a press call early Wednesday morning to present the Danish pharma’s second quarter earnings results. He additionally alluded to “really good early signs” of innovation but declined to provide further details “because they’re early pipeline products.”

Still, Doustdar appeared to be highly confident in these up-and-coming prospects. “In terms of the magnitude of the assets and areas we would like to operate in—as well as the speed of operations—we will be second to none,” he said.

These assertions come just days after Novo suffered a surprise late-stage blow when the IL-6 inhibitor ziltivekimab failed the Phase 3 ZEUS trial, unable to significantly lower the risk of major adverse cardiovascular events in patients with atherosclerotic cardiovascular disease, chronic kidney disease and inflammation.

Ziltivekimab is a key part of Novo’s strategy of branching out to obesity-adjacent indications, looking to stand out in the cardiometabolic arena as key rival Eli Lilly cements its leadership status in the weight loss game.

In February, Novo suffered back-to-back defeats at the hands of Lilly, with two head-to-head trials pointing to the superiority of the Indiana pharma’s assets. The Phase 3 REDEFINE 4 trial, for instance, showed that Novo’s next-generation obesity candidate CagriSema elicited weaker weight loss than the FDA-approved Zepbound. Then, the late-stage ACHIEVE-3 study demonstrated that Lilly’s Foundayo led to better blood sugar control and weight reduction than Novo’s oral semaglutide.

Doustdar on Wednesday’s call didn’t seem too bothered by these events. “It’s true that we have had a couple of setbacks recently on R&D,” he told reporters. “But that’s part of, and the nature of, this industry. If you don’t like setbacks and you don’t like failure, don’t get into the pharma industry.

“We need to learn from the failures and reinvent ourselves again,” Doustdar continued, noting that for each of these setbacks, Novo is working to “demonstrate that we can progress multiple times more the innovations and bring them into the hands of the patients.”

To this end, the CEO on the call also confirmed that Novo is on the lookout for external opportunities. “I believe strongly that we need bolt-on acquisitions to complement what we are doing ourselves,” he said.

In house, the Danish giant had some clean up to do around the edges of the pipeline. The pharma revealed that it had ended work on the oral cannabinoid receptor blocker monlunabant, which was in mid-stage development for obesity. The drug came from Novo’s $1 billion acquisition of Inversago Pharma in August 2023. In September 2024, Novo revealed that the drug had spurred weight loss in a Phase 2a trial but also reported mild- to- moderate neuropsychiatric side effects.

In the second quarter, Novo reported net sales of DKK 78.5 billion ($12.1 billion), representing a 3% year-on-year increase and landing ahead of analysts’ expectations. Delivering a narrow miss, however, was oral Wegovy, which made DKK 3.22 billion ($496 million) in the quarter, 2% below consensus.

U.S.-listed shares of the company slid nearly 6% before the opening bell on Wednesday to $44.28.

Nevertheless, Novo’s strong performance in the first half of the year, particularly within the GLP-1 franchise, emboldened the pharma to lift its full-year outlook. The Danish drugmaker now expects sales to remain flat or drop by just 6%, as opposed to prior guidance of a 4% to 12% decrease.

Asked on a second quarter earnings call if Pfizer could direct more money to M&A amid a feeding frenzy across the pharma industry, CEO Albert Bourla defended his strategy.

Pfizer only has about $7 billion to spend on M&A right now. As its peers snap up promising biotechs left and right, analysts wondered if now is the time to cut the dividend paid to shareholders to take advantage of the moment.

But CEO Albert Bourla put the kibosh on the idea during a second quarter earnings call Tuesday. He defended the company’s M&A record and promised a bolt-on deal would be possible with the cash on hand. The company will thus maintain its long-term dividend, with plans to raise it after the company emerges from a key loss of exclusivity period.

“Look, guys, Pfizer has placed the business development bets already. And we are executing on that,” Bourla said, noting that Pfizer has spend $80 billion on transactions since 2022. In that timeframe, Pfizer has picked up Seagen for about $44.56 billion, Biohaven’s migraine portfolio for $12.56 billion and Metsera for $10 billion.

“In Metsera, we are moving at the speed of light,” Bourla said.

He promised that the $7 billion the company has in cash right now would go far, with opportunities possible in oncology, immuno-inflammation or primary care, such as obesity. Vaccine deals are also possible, Bourla said, though less likely as there is little in the marketplace available for vaccine innovation.

“I think that we have invested a lot, and we will continue doing small pieces,” the CEO said.

Pfizer returned $4.9 billion in cash dividends to shareholders in the first half of the year, representing 86 cents per share of common stock owned. Elsewhere, $5.3 billion in capital was directed toward internal R&D projects and $170 went to business development transactions.

“We feel extremely confident that even in the most stretched scenarios that we are running, we will be able to maintain our dividend,” Bourla said. “I want, once and for all, to make that clear to all that the dividend will be maintained.”

Pfizer has also been executing a rigorous cost-cutting program, and announced additional reductions on Tuesday. The company now expects to reap $2.5 billion more in savings, with cuts coming in the form of “technology and simplification efforts” across the New York pharma’s commercial, R&D and manufacturing functions, according to the second quarter earnings release.

Pharma is definitely interested in making more deals. But what biotechs will come under the magnifying glass? BioSpace takes a look at companies that analysts see as near-term targets for buyouts.

Where one deal occurs, others follow. That’s the theme emerging as analysts parse potential M&A targets with the biopharma deal environment heating up.

With a strong return to M&A in the first half, most experts agree we’re going to see plenty more deals to come.

Despite the flood of recent deals, Big Pharmas are still facing tough patent expiries and appear to have a lot of cash to spend, H.C. Wainright wrote in a June 29 note. Buyers are especially seeking companies with assets in MASH, rare disease, immunology, oncology and central nervous system (CNS) disorders, following on other deals in these disease areas.

Wainright flagged Beam Therapeutics, Immunocore and psychedelics drug developer AtaiBekley as potential targets at the time. The latter, of course, went on to be acquired by Eli Lilly for $3.8 billion a few weeks later.

Below, BioSpace takes a look at biotechs that analysts see as potential targets for M&A, from sleep disorder biotech Alkermes to CAR T icon Legend Biotech.

Alkermes

Thanks to Eli Lilly’s $6.3 billion acquisition of Centessa Pharmaceuticals in March, Alkermes is looking like a strong next bet in the sleep market, according to a July 19 note from Stifel.

Centessa’s lead asset was cleminorexton, an oral orexin receptor 2 (OX2R) agonist being trialed for narcolepsy types 1 and 2 as well as idiopathic hypersomnia (IH). Orexin is a key neuropeptide that regulates the sleep-wake cycle; drugs that activate the pathway could help address excessive daytime sleepiness as well as improve attention, cognition and fatigue.

The orexin class has pipeline-in-a-product potential that is drawing significant M&A interest, Leerink said in a July 19 note covering other activity in the space.

Alkermes is one of the companies on the forefront of the orexin class. The company is expecting a Phase 2 readout for its lead asset, alixorexton, in IH in the fourth quarter. Experts told Stifel that IH could be the next big thing in the insomnia market behind narcolepsy.

A win in these studies could also suggest a future for the drug class in non-sleep indications like attention deficit hyperactivity disorder (ADHD), the firm wrote.

“There’s reasons for optimism that this could show real proof-of-concept and increase excitement for the orexin class beyond sleep,” Stifel said.

In this vein, Alkermes is also developing the orexin ALKS 7290, with Phase 1b data from 50 patients with ADHD expected in the fourth quarter. A Phase 2 will likely follow in 2027 with 300 adults.

After all was said and done, the Centessa deal amounted to a value of just under $8 billion. Alkermes’ current market cap slightly tops that, at $9 billion, according to Stifel. The company has four approved medicines in the neuro space already, Lybalvi, Aristada, Vivitrol and Lumryz.

“Alkermes offers an opportunity to participate in the new/exciting OX2R class, but with a meaningful floor value that offers downside protection,” Stifel wrote.

Dyne Therapeutics

If you ask analysts, Alnylam Pharmaceuticals needs to make an acquisition. The RNAi specialist cut $200 million off its full-year guidance when reporting second quarter earnings last week, losing $10.8 billion in market cap in the process as investors reeled.

Oppenheimer believes that neuromuscular disease biotech Dyne Therapeutics could be a natural fit, according to a July 16 note. The company is awaiting a January 2027 decision from the FDA on the approval of exon skipper zeleciment rostudirsen (z-rostudirsen) for Duchenne muscular dystrophy, with a confirmatory Phase 3 trial underway. If approved, the therapy could tap into a $700 million market opportunity, according to Jefferies.

The biotech’s profile has risen as competitors like Avidity Biosciences have produced positive data, according to Oppenheimer. Avidity was bought by Novartis last year for $14.6 billion, showing that Big Pharma is willing to spend big cash for neuromuscular disease assets.

Dyne recently received the FDA’s go ahead to advance the siRNA therapy DYNE-302 into human trials for facioscapulohumeral muscular dystrophy (FSHD). Avidity’s RNA therapy delpacibart braxlosiran (del-bax) provided early validation for Novartis’ gambit with positive biomarker data in FSHD that was released in June 2026. Both therapies target the DUX4 gene.

FSHD could be even bigger than DMD. Jefferies predicts the market to be worth about $3 billion, according to a July 30 note. With competitors set to read out trials in the indication in the second half, Jefferies sees this as a key period to “help frame DYN’s differentiation.”

“DYN is becoming an attractive platform play,” the firm wrote.

First Tracks Biotherapeutics

Another company to benefit from deals elsewhere is First Tracks Biotherapeutics, a clinical-stage immunology biotech that is firmly entrenched in a pharma hot spot.

Argenyx helped buoy First Tracks with the $2.2 billion takeout of rival Forte Biosciences earlier this month. Argenyx specifically highlighted the early performance of Forte’s CD122 therapy FB102 in vitiligo and celiac disease.

But First Tracks has something better, according to Leerink Partners. The biotech’s CD122 candidate ANB033 binds to a different isotope than FB102 does and has shown better potency in animal testing. First Tracks’ asset also offers subcutaneous administration, whereas FB102 is delivered via IV infusion.

Forte is also singularly focused on FB102, whereas First Tracks has a small pipeline beyond CD122. It includes ANB101 for inflammatory diseases and rosnilimab, which has shown positive Phase 2 results in rheumatoid arthritis, according to Leerink.

“We view IL-15/CD122 antagonism is emerging as a new immunology & inflammation (I&I) class which has the potential to address several diseases with significant unmet need, implying ‘pipeline in a product’ potential,” the firm wrote in a July 27 note.

Legend Biotech

With Big Pharmas snapping up biotechs in the CAR T space—see Sail Biomedicines below or Gilead Sciences’ $7.8 billion buy of Arcellx—analysts see Legend Biotech as having one of the strongest pipelines in the space.

Last month, Legend revealed a readout for the in vivo CAR T therapy LB2501 in non-Hodgkin lymphoma that Oppenheimer analysts called “best case scenario.” The therapy showed a clean safety profile and efficacy that “stacked up well” to other modalities currently at use in the disease, the analysts wrote in a June 2 note.

Oppenheimer noted that Kelonia Therapeutics was acquired by Eli Lilly for $7 billion just four months after presenting similarly exciting data last year.

“Positive in vivo CART data strengthens chances of LEGN acquisition in our view,” Oppenheimer wrote. “LEGN is perhaps (one of) the most advanced-stage in vivo CART companies that is currently available for acquisition/partnership.”

Legend is already well known for Carvykti, which it markets with Johnson & Johnson for two types of multiple myeloma. The therapy booked $597 million in sales for the first quarter of the year, a 62% increase over the same period a year before, according to Legend’s first quarter earnings report.

Others acquired in the space include earlier-stage biotechs Capstan Therapeutics (AbbVie) for $2.1 billion and Orbital Therapeutics (Bristol Myers Squibb) for $1.5 billion.

Legend is going through some growing pains at the moment. CEO Ying Huang stepped down last week to be replaced on an interim basis by Alan Bash, who currently leads the company’s Carvykti business unit. Oppenheimer said that Huang has deep experience in the space but investors have nevertheless been dissatisfied.

“We believe the new CEO, and their interactions/board alignment, will be critical to turning the story around ahead of Anito-cel market entry in December and potential M&A discussions,” the firm said on July 27.

Sail Biomedicines

We know that Johnson & Johnson wants to buy Sail Biomedicines. The healthcare giant secured the right to acquire the Flagship Pioneering biotech for $2.58 billion down the line as part of a larger immunology research partnership that was revealed last week. The research portion of the deal involved $785 million in initial payments, including a $465 million equity investment.

But the big question is when. Leerink Partners pointed out on July 29 that the deal could happen soon, since J&J’s press release noted that the agreement could dilute its shares this year or early next.

In the meantime, the new partners will work on Sail’s lead program SAIL-0839, an in vivo CAR T cell therapy that targets CD4+ and CD8+.

Sail emerged in October 2023 when Flagship folded two of its entities—Laronde and Senda Biosciences— into one company to work on programmable medicines.

After seeing its lead candidate rejected by the FDA last year, Capricor Therapeutics (Nasdaq: CAPR) is hoping for a better outcome for its resubmitted biologics license application (BLA) for its lead pipeline candidate Deramiocel, a cell therapy indicated as a treatment for cardiomyopathy in Duchenne muscular dystrophy (DMD).

That hope appeared less likely than ever as the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee on Wednesday recommended against agency approval of Deramiocel, concluding in a 9-3 vote with no abstentions that the available evidence from the Phase III HOPE-3 trial (NCT05126758) did not “provide substantial evidence of effectiveness” for Deramiocel as a treatment for cardiomyopathy in Duchenne muscular dystrophy (DMD).

The advisory committee vote is likely to influence how the FDA acts on the resubmitted BLA for Deramiocel, with the agency having set an August 22 target decision date under the Prescription Drug User Fee Act (PDUFA). The FDA typically (but not always) heeds the advice of its advisory committees or “adcomms,” which in turn typically (but not always) heed the evaluations of agency staff.

Deramiocel is an allogeneic cardiosphere-derived cell (CDC) therapy candidate. CDCs are designed to act by secreting exosomes that target macrophages and alter their expression profile to adopt a healing rather than pro-inflammatory phenotype.

According to Capricor, preclinical and clinical studies have shown Deramiocel to preserve cardiac and skeletal muscle function in muscular dystrophies such as DMD by exerting strong immunomodulatory and anti-fibrotic activity.

Negative FDA evaluation

FDA reviewers paved the road to Deramiocel’s poor reception from the adcomm on July 27 with a negative evaluation of the resubmitted BLA. Their assessment concluded that data submitted to the FDA from HOPE-3 and the earlier Phase II HOPE-2 trial (NCT03406780) “does not provide substantial evidence of effectiveness for Deramiocel in DMD”—though Capricor’s indication for Deramiocel is specifically cardiomyopathy in DMD.

The unnamed FDA staffers took issue with:

• Whether Deramiocel achieved HOPE-3’s primary and secondary endpoints.
• The hypersensitivity shown by 42% of Deramiocel patients vs. 15% of placebo patients;
• Capricor’s failing to submit to the agency an updated statistical analysis plan (SAP) for review before it resubmitted its BLA for Deramiocel in February.

Capricor declared HOPE-3 a successful trial in December, citing as a statistically significant benefit the reported 54% slowing of skeletal muscle disease progression on the primary endpoint, Performance of the Upper Limb version 2.0 (PUL 2.0) percentage change from baseline in the 105-patient intent-to-treat (ITT) population with evaluable PUL v2.0 assessments at 12 months. Capricor also reported a 91% slowing of progression measured by left ventricular ejection fraction (LVEF) in the 83-patient ITT population with centrally reviewed and evaluable cardiac MRI LVEF assessments at 12 months.

The FDA, however, says HOPE-3 can only be deemed a success after the company made changes to its SAP that included modifications to the primary and key secondary endpoint definitions, its analytical methods; and the data imputation strategy for intercurrent events.

“Although the applicant provides justifications for these changes, FDA does not agree that the scientific rationale for those changes was supported and considers the changes unwarranted based on the study’s design, powering, and original statistical assumptions,” the FDA staffers contended.

The reviewers also alleged that the distinctive adverse event profiles seen between Deramiocel and placebo patients “raises the possibility that treatment assignment could be inferred even under formal blinding conditions.”

“This risk of functional unblinding,” they added, “was further extended by the open-label period of HOPE-3, during which additional treatment-related data accumulated and may have made treatment assignment more apparent.”

Capricor answers back

Capricor answered back the same day. CEO Linda Marbán, PhD, told Reuters she was “completely shocked at how they decided to review and analyze ​this data,” while the company issued a statement faulting the FDA for relying on an “obsolete” analysis: “Our results are governed by the final analysis plan, SAP version 3.0, which was finalized prior to unblinding.”

“It is critical to understand that the post-hoc analyses in the FDA’s briefing materials rely on SAP version 1.1, an unsigned incomplete internal draft which became obsolete with the addition of cohort B and did not include content specifically requested by FDA,” Capricor explained. “We believe Deramiocel offers a meaningful treatment option for boys and young men living with Duchenne, who continue to face a significant unmet medical need.”

The company sought to back up that contention on Wednesday, when it released updated data from HOPE-3 that were published in The Lancet. The updated data showed Deramiocel to have improved cardiac and skeletal muscle function in Phase I–II studies of DMD, and also found that deramiocel could slow muscle weakening in boys and young men with advanced DMD, and may also slow heart damage in those who already have heart muscle disease.

But at 12 months of follow-up, Deramiocel’s performance on the study’s key secondary endpoint of LVEF “did not reach statistical significance, although the difference [favored] Deramiocel,” researchers reported, as the Deramiocel group vs. placebo showed a least-squares mean ranked change in LVEF of 57·47 ranks compared with 45·82 for placebo.

“These findings reinforce deramiocel as a safe, effective, and promising therapy for individuals living with DMD. Longer follow-up is needed to establish durability, long-term safety, and effects on clinically important cardiac outcomes,” the research team from Capricor and its clinical partners wrote in the study.

They added: “A 54% reduction in mean skeletal-muscle disease progression over 12 months, if sustained, would be equivalent to delaying approximately 1 year of untreated progression over 2 years.”

Investors unpersuaded

Capricor’s responses during the week failed to persuade investors. They responded to the negative FDA staff briefing on Deramiocel with a sharp sell-off that sent the company’s shares nosediving 64.5% to $7.00, from $19.70 at the close of trading July 24. The decline reached 85% when Capricor shares hit a 52-week low of $2.97 early Thursday.

After the downgrades and second stock plunge of the week, however, Capricor investors began to “buy the dip” and sent the company’s shares partially rebounding to $4.19 on Thursday (a 36% one-day slide) and $3.85 at Friday’s closing bell, down 8%. Overall for the week, Capricor’s stock suffered an 80% one-week decline.

News of the FDA adcomm vote led to downgrades of Capricor stock and severe 12-month price target downgrades by at least six investment firms:

• Piper Sandler (Edward Tenthoff)—From “Overweight” to “Neutral,” all but wiping out its price target 97%, from $58 to $2.
• Cantor Fitzgerald (Kristen Kluska)—From “Overweight” to “Neutral,” eviscerating its price target 94%, from $62 to $3.50.
• Ladenburg Thalmann (Aydin Huseynov, MD)—From “Buy” to “Neutral,” no price target announced.
• Maxim Group (Jason McCarthy, PhD)—From “Buy” to “Hold,” no price target announced.
• C. Wainwright (Joseph Pantginis, PhD)—From “Buy” to “Neutral,” removing its $60 price target reiterated in May.
• Oppenheimer (Leland Gershell, MD, PhD)—From “Outperform” to “Perform,” removing its $54 price target reiterated in March.

“The briefing documents raise many ​more concerns versus what we originally were anticipating, putting Capricor in a tough situation” for the adcomm meeting, Kluska said Monday in remarks reported by Reuters.

The six firms joined three others that lowered their ratings on Capricor shares earlier in the week:

• Alliance Global Partners (Matthew Venezia)—From “Buy” to “Neutral,” chopping its price target 86%, from $51 to $7 on Tuesday.
• Riley Financial (Madison El-Saadi, PhD)—From “Buy” to “Neutral,” slashing its price target 84% from $63 to $10 on Monday.
• Roth Capital Partners (Boobalan Pachaiyappan, PhD)—From “Buy” to “Neutral,” slicing its price target 82% from $38 to $7 on Monday.

MapLight data divides investors, analysts

Investors and the Wall Street analysts who cover their favorite companies sometimes don’t see eye to eye. That was apparent this past week when MapLight Therapeutics (Nasdaq: MPLT) shares went on something of a roller-coaster ride, as mixed clinical results for its lead drug in a mid-stage trial in schizophrenia sent the stock nosediving on investor fears—until reassurances from analysts reversed the slide and sent those shares back in the positive direction.

The up-and-down week ended with MapLight shares sliding 64%.

MapLight’s wayward week started on July 27 when the company released data from its 307-patient Phase II ZEPHYR trial (NCT07038876) assessing its lead pipeline candidate ML-007C-MA in adults with an acute exacerbation of schizophrenia. ML-007C-MA is an oral, extended-release, fixed-dose combination of the M1/M4 muscarinic agonist candidate ML-007, co-formulated with a peripherally acting anticholinergic.

MapLight trumpeted what it termed positive results from ZEPHYR, though the data appeared to be more mixed: On the positive side, the 210/3 mg twice-daily (BID) dose of ML-007C-MA showed statistically significant and clinically meaningful reduction in its Positive and Negative Syndrome Scale (PANSS) total score compared to placebo at Week 5 in a In the modified intent-to-treat (mITT) population, with an effect size of 0.37 and a least squares mean 4.5-point improvement vs. placebo (p=0.015).

However, the 330/6 mg once-daily (QD) dose of ML-007C-MA did not achieve statistical significance on the primary endpoint, even as it showed an effect size of 0.23 and a 2.8-point improvement over placebo (p=0.110)—as well as separation on CGI-S (p=0.036), PANSS positive Marder factor (p=0.045), and Readiness for Discharge Questionnaire (p=0.027), and numerical separation on other endpoints.

That result investors scurrying to sell off their MapLight shares, since it raised questions about whether ML-007C-MA could effectively with Cobenfy^® (xanomeline and trospium chloride), the schizophrenia drug marketed by Bristol Myers Squibb (BMS; NYSE: BMY). Cobenfy, which won FDA approval in 2024, showed larger PANSS reductions of 8.4 and 9.6 points in a pair of Phase III trials compared with placebo.

Cobenfy generated $119 million in product revenues in the first half of this year, nearly double (up 92%) from January–June 2025), in addition to $155 million during all of last year.

The BID dose also showed robust and clinically meaningful improvement in cognitive performance, based on the pre-specified secondary endpoint assessed via the Cogstate battery in participants with baseline cognitive impairment (effect size=0.51; 0.44 points vs. placebo; p=0.041). But the cognitive benefit did not show correlation with the change in PANSS score, something that MapLight said suggested that “the effect was independent of, and not secondary to, improvement in psychotic symptoms.”

“We are very encouraged by these results, which show that ML-007C-MA delivered clinically meaningful antipsychotic efficacy alongside a favorable tolerability profile designed to translate into real-world use,” Chris Kroeger, MD, MapLight’s co-founder and CEO, said in a statement.

Encouraged enough, Kroeger added, that MapLight plans to discuss a path forward for ML-007C-MA in schizophrenia, including the design of a Phase III trial, at an End-of-Phase II (EOP2) meeting with FDA officials. Data from that trial, combined with results from ZEPHYR, are intended to support an initial New Drug Application (NDA) submission for the drug.

Investors sharply disagreed with MapLight’s optimism, sending the company’s shares plummeting 73% on July 27, from $36.56 to $9.90. But several analysts questioned the wisdom of investors selling off shares on a single PANSS number.

“The PANSS score is but one component of what might drive success from a commercial point of view,” cautioned Sumant Kulkarni, a senior analyst covering biotechnology with Canaccord Genuity, wrote in a research note. “At the same time, we need to see more data from additional trials on safety and efficacy.”

That data could come, he continued, from the Phase II VISTA trial (NCT06887192) assessing ML-007C-MA as a treatment for hallucinations and delusions associated with Alzheimer’s disease psychosis, a potentially larger market for the drug.

However, Kulkarni cut Canaccord Genuity’s peak-year 2037 sales forecast for ML-007C-MA by more than half in schizophrenia, from approximately $1 billion to approximately $400 million. He also shrunk by one-third his firm’s peak sales forecast for ML-007C-MA in ADP, from $3 billion to $2 billion, and lowered ***HOW its forecast of MapLight’s operating expenses.

As a result of these changes, Kulkarni cut Canaccord Genuity’s 12-month price target on MapLight shares 44%, from $43 to $24.

“Although [ML-007C-MA] did not meet the Street’s upside expectations, there are still several positives to consider,” Jefferies equity analyst Andrew Tsai wrote Friday. He said ZEPHYR was still successful enough as a pivotal Phase II trial to count as one of two positive Phase II or III trials needed for FDA approval. And twice daily ML-007C-MA showed competitive adverse event percentages among patients compared to Cobenfy, he added, citing:

• Constipation—9% for ML-007C-MA vs. 13–21% for Cobenfy.
• Nausea—29% vs. 19%.
• Vomiting—13% vs. 9–16% for Cobenfy.

By mid-week, investors appeared to take the analyst commentary to heart. MapLight shares rebounded, climbing 24% to $12.31 on Tuesday, then jumped another 22% to $15.02 Wednesday. The rest of the week didn’t look as good for MapLight, however, as its shares fell about 7% to $14.03 Thursday and dropped another 7% Friday, finishing the week at $13.03.

Leaders & laggards

• Novo Nordisk (Nasdaq Copenhagen: NOVO-B) shares slumped 8% from DKK 330.90 ($51.03) to DKK 306.50 ($47.27) Friday, while its American Depositary Shares (Nasdaq: NVO) skidded 9% from $51.61 to $47.08, after the cardiometabolic drug giant acknowledged that its once-monthly 15 mg dose of ziltivekimab failed the Phase III ZEUS trial (NCT05021835) assessing the IL-6 inhibitor vs. placebo in reducing the risk of major adverse cardiovascular events (MACE), defined as cardiovascular death, non-fatal heart attack, or non-fatal stroke. Ziltivekimab failed to translate reductions in cardiovascular inflammation into fewer major cardiovascular events, Novo Nordisk said. Overall rates of adverse events (AEs) and serious AEs in ziltivekimab patients were similar to those seen with placebo. A higher proportion of people treated with ziltivekimab had serious infections compared to placebo—a finding consistent with targeting IL-6 inhibition, according to the company—while no difference in all-cause mortality was seen.
• Replimune Group (Nasdaq: REPL) shares more than doubled, jumping 107% from $5.41 to $11.20 Friday, the day after the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee sided with the company by voting 10-3 that the results from the Phase I/II IGNYTE trial (NCT03767348) were evaluable and clinically meaningful. Repligen is seeking FDA approval of its third biologics license application (BLA) for RP1 (vusolimogene oderparepvec, a genetically engineered oncolytic viral immunotherapy, in combination with nivolumab, the programmed death-1 (PD-1) immune checkpoint inhibitor marketed by Bristol Myers Squibb (NYSE: BMY) as Opdivo^®, as a treatment for advanced melanoma in patients who have progressed on prior anti-PD-1 therapy. “We are encouraged by today’s outcome and would like to thank the committee for its thoughtful discussion of the IGNYTE data,” Repligen CEO Sushil Patel, PhD, said in a statement. Cantor Fitzgerald analyst Li Watsek upgraded Replimune shares from “Neutral” to “Overweight,” with no price target on the stock.

During ketamine anesthesia the brain’s nerve cells fall silent, and as consciousness returns, they begin to reconnect. A study in mice by researchers at the Institute of Science and Technology Austria (ISTA) and colleagues at Allen Institute for Brain Science in Seattle, has now for the first time shown that immune cells in the brain play a critical role in this process, and indicates that there are differences between female and male brains.

Senior and corresponding author Sandra Siegert, PhD, at ISTA, reported on their findings in Science Advances, in a paper titled “Corticosterone-linked microglial activity underpins sexually dimorphic neuroplasticity after ketamine anesthesia,” in which they concluded “Our study uncovers significant sex-specific differences in neuronal adaptation during recovery from ketamine anesthesia, driven by microglia.”

Recovery from anesthesia is critical for resuming normal physiological and neuronal functions, but the mechanisms involved remain elusive, the authors wrote. “Ketamine distinguishes itself from other anesthetics by its unique pharmacological properties as an N-methyl D-aspartate (NMDA) receptor antagonist, which preferentially targets GABAergic inhibitory interneurons.”

And unlike many other anesthetics, ketamine does more than induce unconsciousness. It alters how we perceive pain and form memories. It dampens communication between neurons—the very network that must later resume normal function as the patient awakens. Exactly how this recovery process unfolds—and whether male and female brains differ in this regard—has been unclear. “… ketamine anesthesia induces mild anxiety behavior phenotypes, interestingly, only in females,” the team continued, “suggesting inherent sex differences in anesthesia recovery with neuronal consequences that extend beyond the immediate sex-dependent metabolic processing described for low-dose ketamine.”

Working with mice, Siegert, together with Alessandro Venturino, PhD, and their colleagues at ISTA, and researchers at the Allen Institute, now offer the first answers to some of these questions. Microglia are specialized immune cells that constantly scan the brain and, when needed, trigger anti‑inflammatory responses. They also monitor neurons and their connections, thus helping to maintain optimal brain function. “Ketamine, across different dosages, affects microglia, which are embedded within the neuronal network,” the team explained. “Locally, microglia influence the synaptic machinery and neuronal firing properties by responding to environmental changes.”

As early as 2017, Siegert’s group at ISTA noticed that male and female mice respond differently to ketamine anesthesia, and more precisely, their microglia do.

For the newly reported study, using a cranial window—a surgically implanted opening that allows microscopic access to the living brain—Venturino analyzed how microglia and neurons behave while mice recover from ketamine anesthesia. Both cell types were labeled with fluorescent markers to glow under the microscope.

The researchers observed microglia processes in their dynamic action towards neurons. Surprisingly, as female mice recovered from anesthesia, microglia began forming prolonged contacts with neurons, coinciding with the onset of synaptic remodeling and plasticity. Notably, this phenomenon was not observable in male mice.

Furthermore, in mice lacking microglia, no such synaptic remodeling occurred, indicating that microglia are critical mediators of this recovery-associated plasticity. “What was fascinating,” Venturino explains, “was that we observed this plasticity—the brain’s ability to change, adapt, and in this case recover—only in females.”

Despite many other projects—or perhaps because of them—the researchers kept returning to their initial observation. “I’ve always believed that women have greater brain plasticity,” Siegert said with a smile. “Alessandro and I just couldn’t let it go—we wanted to know why.”

Further experiments revealed that this plasticity depends on corticosterone, one of the major stress hormones. “During recovery from anesthesia, corticosterone levels rise,” Venturino explained. “In female mice, this specifically activates the stress‑response gene Fkbp5 in microglia. The gene encodes the protein FKBP51, which helps the cell manage stress signals—and apparently prompts microglia to interact with neurons.”

The authors further noted, “Mechanistically, we found that female microglia selectively up-regulated the cochaperone Fkbp5/FK506-binding protein 51 (FKBP51), which is a key intermediary in the corticosteroid-induced stress response … Our findings underscore that microglia serve as a relevant interface between the endocrine stress response and the brain -immune cell system.”

To confirm this link, the team removed the adrenal glands—the endocrine organs that produce corticosterone. Without them, the close contact between microglia and neurons during recovery disappeared. “These results clearly show that corticosterone triggers this reaction in female mice,” said Venturino.

Siegert added, “They also remind us that stress is not always harmful—stress hormones are essential for certain processes in the brain.” In their paper the investigators commented, “The selective hypothalamic activation and elevated blood plasma corticosterone levels during the recovery phase in females shape the microglia-neuron interactions, highlighting a link between the endocrine and the brain-immune axes.”

Why this process differs between female and male mice remains uncertain; it is still unclear whether the male brain uses a similar mechanism, just delayed, or has another strategy. “Microglia enable rapid adaptation, and these cells in females are likely more sensitive to specific stress signals,” Siegert noted.

From an evolutionary viewpoint, she speculates, females may have faced greater demands for social, emotional, and multitasking adaptability—for example, in childcare, food gathering, or coordinating group activities. The female brain, therefore, had to adapt and respond more swiftly. “That’s a good thing,” Siegert added “But if this plasticity becomes too frequent or too intense, it can increase the risk of depression. We also know that psychiatric disorders are more prevalent in women than in men.”

Siegert further pointed out that during the literature review, her team found very few studies in which ketamine had been tested in females. “There were only a handful of anecdotal studies showing that women experience nausea and sickness more often after ketamine anesthesia,” she stated. Given that ketamine is also used as an antidepressant, understanding how its mechanisms differ between the sexes is all the more important. “It’s astonishing how readily people assume that men and women respond to drugs in the same way—when clearly they do not,” Siegert stressed.

Research like this is a step in the right direction: it highlights that medications can act differently in women and men and serves as a call to consider sex‑specific differences in future studies. “Our findings contribute to a growing body of evidence recognizing sex-specific differences in brain function and immune responses, the latter of which is already well known for increased susceptibility to infection and autoimmune diseases,” the team pointed out. “Our results identified a link between microglia-specific Fkbp5 expression and ketamine action, warranting a reevaluation of assumptions that ketamine is a general anesthetic and fully reversible across sexes.”

Insights into the microglia response to ketamine have since inspired Siegert and Venturino to co‑found Syntropic Medical, a start‑up in ISTA’s XISTA ecosystem exploring how 60 Hz flickering light can soften such neural networks in the brain.