Neuroscience drug development

Even for the most deep-pocketed drug companies, $14 billion dollars is no small investment. That kind of money can buy large manufacturing plants, offices in glossy skyscrapers and entire campuses dedicated to specific research. But Bristol Myers Squibb has different plans.

Late in 2023, the pharmaceutical giant agreed to spend that much acquiring Karuna Therapeutics, a Boston-based biotechnology company. Karuna’s most advanced medicine later won U.S. approval as aschizophrenia treatment, bringing to market for the first time in decades a new form of antipsychotic. Some Wall Street analysts expect the drug to become a megablockbuster.

Bristol Myers sees significant opportunity too, though not yet enough to make psychiatry a top priority. “Failure rates are still very high,” noted Richard Hargreaves, who leads the company’s main neuroscience research center. “That was one of the reasons why neuropsychiatry moved into the biotech industry.”

“The bigger players like Bristol Myers, we watch how [biotechs’ efforts] unfold without actually dedicating big resources ourselves,” he said. “Personally, I'm not seeing us changing from [that] strategy.”

Once a cornerstone of large pharmaceutical firms, psychiatric drugs have been passed over for much of the last 20 years. Developers and investors gave various reasons for the collective retreat, but their decisions ultimately came down to dollars and cents math. Brain research had become too difficult, expensive and risky, and easier money could be made elsewhere.

The pullback has left a void of novel treatments for the hundreds of millions of people with conditions like schizophrenia, depression and substance use disorder.

Now, for the first time in ages, neuropsychiatry is back in focus thanks to the acquisition of Karuna, the potential approval of its medicine, as well as a $9 billion proposal from AbbVie to buy Cerevel Therapeutics, a company working on a similar schizophrenia therapy. While doctors and researchers welcome the excitement and argue it’s necessary to propel the field forward, they also wonder whether the renewed investment will be short-lived, as many of the issues that historically held back this area of drug development remain unresolved.

“The past is a very good predictor of the future,” said Paul Kenny, chair of the neuroscience department and director of the Drug Discovery Institute at Mount Sinai’s Icahn School of Medicine. “I think pharma will likely remain skeptical and trepidatious, because that's been the case for at least the past 10 years.”

“I don't know what's going to change that,” Kenny said. “Something big would need to happen.”

Cracking the brain

In many ways, the brain seems straight out of science fiction. A mass of 85 billion nerve cells acts as the body’s control center, directing everything from mood, movement and the senses to how we think, dream and problem solve. It’s the organ that “makes us human.”

Unsurprisingly, it’s also the most complex. In, 2023 an international team of scientists identified north of 3,300 cell types in the brain.

Researchers are “only scratching the surface in terms of our understanding,” according to Kenny. “Basically, every week, a new paper comes out [showing us] how cells are wired in ways that we didn't understand before, how they're functioning in ways that we just didn't appreciate.”

For drugmakers, this lack of understanding has brought costly setbacks. In Alzheimer’s disease, companies like Eli Lilly, Roche and Biogen each spent hundreds of millions of dollars investigating medicines that were ultimately unsuccessful in big clinical trials. And in ALS, more than half a dozen potential treatments flunked key studies over the past few years.

In neuropsychiatry, failures are so commonplace that finding new therapies has become, as an article recently published by Nature highlights, “the purview of only a handful of smaller more risk-taking biotech companies and a few academic drug discovery programs.” Karuna is one such example, as its “KarXT” schizophrenia medication is made from a molecule Lilly discarded years ago.

While all drug development is expensive and time-consuming, with very slim odds of success, the challenges are acute in neuropsychiatry. Researchers believe mood and behavior disorders are likely caused by small contributions from a constellation of genes, rather than just one or two faulty DNA sequences. Those tangled roots make choices around which proteins or molecules to target much harder.

Once a target is selected, drugs are designed and then tested in animals to anticipate how they’ll work in people. But these “models” are less reliable in psychiatry, since they assume animals and humans similarly express complex emotions and behaviors. In a mouse, it’s easy enough to see whether a therapy shrinks a tumor or reduces swelling. It’s much more difficult to tell if a mouse's anxiety resembles what a person might feel, or whether such stresses can build into something akin to depression.

“Scientists like me have a lot to answer for,” Kenny said. “We took animal procedures and extrapolated into humans far too readily.”

With such a shaky foundation, psychiatry drug programs tend to fall apart once they move into humans. Most other areas of clinical research are at least able to lean on biological markers that, much like car dashboards do for drivers, signal what’s going on in the body. But scientists have discovered relatively few of these for brain drug development in general, and next to none in psychiatry.

That’s forced clinicians to rely on subjective assessments like surveys and questionnaires, which can be a particular problem in the large, placebo-controlled trials that are the gold standard of drug testing. Over the years, a laundry list of promising treatments for depression and other mood disorders fell short because patients in control groups did better than expected.

Psychiatry studies are “notoriously difficult to do, because you're trying to do everything you can to minimize a placebo response,” said Graig Suvannavejh, an analyst at Mizuho Securities who formerly held business development roles at AbbVie, Biogen and the biotech Alzheon.

“A lot goes into hopefully getting a high-quality trial outcome,” he said. “But in psychiatry, the variables are such that you can try so hard but still not know what you're going to get.”

The task for trial designers is made more complicated by the fact that diagnosing these diseases isn’t straightforward.

People with schizophrenia, for instance, can display a wide array of symptoms, from “positive” ones like hallucinations to “negative” ones like lack of motivation. Simultaneously, they may have other conditions like post-traumatic stress disorder, or be unable to consent and adhere to study rules.

“If somebody has just schizophrenia, that would be the most ideal, clean participant,” said Carol Lim, a psychiatrist at Massachusetts General Hospital. “In reality … it's a whole spectrum. If you have 1,000 people with schizophrenia, everyone will look different.”

Altogether, the pitfalls and obstacles have given psychiatry drug development an ominous reputation, with some experts describing an impassable chasm between the early science of their labs and the medicines pharma companies want.

Little progress has been made navigating this metaphorical gorge, which is why the KarXT story is so extraordinary.

Finding something new

The journey of KarXT is well documented, as it represents not only a rare win in an exceedingly tough field, but also how central a role luck has played in the discovery of antipsychotics.

In the 1990s, Lilly was exploring whether a drug called xanomeline could improve cognition in Alzheimer’s patients. A nearly 350-person trial showed it had a modest impact. But more surprisingly, researchers noticed the drug seemed to quell the disruptive behavior and psychotic symptoms that often accompany Alzheimer’s.

The findings were especially alluring because xanomeline wasn’t like available antipsychotics — all of which block dopamine, a chemical brain cells need to communicate but is thought to trigger psychosis when in excess. Instead, Lilly’s drug worked primarily by boosting certain “muscarinic receptors,” proteins that are found throughout the body and interact with a different neurotransmitter, acetylcholine.

Though effective, dopamine inhibitors frequently cause weight gain, sedation and other health issues that lead patients to switch medications or stop taking them altogether. A more tolerable option could be highly valuable, so Lilly, intrigued by what the researchers had seen, set up a separate study with a small number of schizophrenia patients.

Again, xanomeline had a positive impact on psychosis. But its reach extended beyond the brain and into the gut, where it caused digestive problems. Because of these side effects, Lilly ultimately shelved the drug until 2012, when Karuna licensed it for the paltry sum of $100,000.

Karuna had hatched three years earlier as the brainchild of Andrew Miller, who was at the time an executive at PureTech Health, the biotech startup creator that got Karuna off the ground. Miller believed xanomeline could still work; it just needed to be coupled with a drug that hindered muscarinic activity outside of the brain. The Karuna team found such a drug, and named the pairing KarXT.

"There was a huge amount of skepticism," PureTech CEO Daphne Zohar said. "Probably 100 investors passed on the idea."

Yet, since 2019, the therapy has succeeded in three medium to large clinical trials. Not only did KarXT significantly decrease the severity of schizophrenia symptoms, it didn’t cause excessive weight gain, restlessness or movement issues, though there were other side effects. The drug was approved by the FDA as Cobenfy in September 2024.

While there have been some innovations in antipsychotics, such as longer-acting shots, KarXT is viewed as a leap forward. “For the first time in 30 years you're seeing novel mechanisms now coming to fruition,” Hargreaves said.

At Mass General, Lim has found patients come to appointments asking about KarXT and eager to try it, based on what they’ve heard about it being effective without causing weight gain.

“It's the first time we're not directly targeting dopamine receptors. So we are avoiding a lot of side effects. That’s a really good thing,” Lim said.

In spite of the anticipation, doctors aren’t sure how much this milestone will actually benefit patients. They note how, in those KarXT studies, the main treatment periods lasted only five weeks and never pitted the drug against another antipsychotic. They’ve also said that, outside the tight controls of a clinical trial, patients might not find KarXT as effective or as easy to stay on.

How readily insurance providers would cover a drug like Karuna’s is another unknown, given the FDA has approved nearly two dozen antipsychotics, many of which have inexpensive generic versions.

“There's so much we don't know in terms of practical usage,” said Mitzi Gonzales, a neuropsychologist and director of translational research at Cedars-Sinai. “You really have to be sure it's better than everything else out there that's cheaper and more readily available.”

Jeffrey Lieberman, a psychiatry professor at the Columbia University Medical Center and a former member of Karuna’s scientific advisory board, foresees KarXT being a “huge” product initially. From there, physicians will closely watch how well the drug works, and whether it can meet their patients’ lofty expectations.

On Wall Street, expectations are equally high. Analysts at the investment firm Cantor Fitzgerald predicted KarXT sales will reach $1 billion a year starting in 2026, while Stifel analyst Paul Matteis has estimated peak annual sales will top $10 billion.

Matteis has also said three other companies advancing muscarinic receptor drugs — Neurocrine Biosciences, Neumora Therapeutics and MapLight Therapeutics — could see more interest from dealmakers in the wake of the Karuna and Cerevel acquisitions.

“The fact that they're just such a completely different mechanism and the majority of schizophrenia patients aren't well controlled, that can lead these drugs to being a really big class,” Matteis said.

Building the pipeline

Beyond muscarinics, a handful of other drug classes are drawing attention back to neuropsychiatry.

Stimulating “orexin” proteins has been shown to help patients with narcolepsy, so companies like Takeda Pharmaceutical, Jazz Pharmaceuticals and Alkermes are trying to speed orexin-targeting medications to market.

Another group of proteins known as “TAARs” are seen as promising targets for treating schizophrenia and other psychoses. The most advanced of these drugs, from the Japanese developers Sumitomo Pharma and Otsuka Pharmaceutical, was recently evaluated across two late-stage clinical trials, but failed to meet the main goals of either.

A gene named TRPC encodes for proteins involved in nerve cell function, and research has suggested inhibiting two of those may be helpful in a variety of psychiatric conditions. German drugmaker Boehringer Ingelheim is testing this hypothesis with a medicine in mid-stage testing for PTSD and major depression. Karuna is invested, too, having acquired exclusive rights to experimental therapies from the now-defunct Goldfinch Bio.

Drug hunters are also revisiting a well-known family of proteins that affects stress, mood and pain. Earlier attempts to regulate these “kappa opioid receptors” led to therapies that were held back by side effects. Cerevel, Johnson & Johnson and Neumora are developing new versions for the treatment of major depression that they designed to be safer.

Arguably the buzziest area of research are psychedelic compounds. Long dismissed because of thorny legal and scientific issues, psychedelics are being taken more seriously as possible treatments for anxiety, depression and psychosis.

Last summer, the FDA issued initial guidance for drugmakers interested in this research — a pool that has expanded considerably since 2019, when the agency granted a first-of-its-kind approval to a derivative of ketamine that J&J developed for depression.

Envisioning big returns, investors have been pouring money into psychedelic-focused biotechs. Bristol Myers’ Hargreaves expects the psychedelic field to advance as more drugs get cleared for human testing. “We’ll find new approaches into neuropsychiatry that way, I think as much as anything else.”

On a broader scale, Suvannavejh feels as though he’s seeing an increase in the number of mid- to late-stage trials for psychiatry drugs. The data is “pretty rich” compared to prior years, he said.

Still, psychiatry continues to make up a fraction of clinical research. A recent report from Iqvia, a healthcare services and information provider, found neurology accounted for 10% of all human studies started in 2023. There were around 60 in both schizophrenia and depression, and far fewer in anxiety and sleep disorders.

“I don't think the pipeline should be as empty as it is, based on our really burgeoning understanding [of the brain],” Kenny said. “We're really feeling the pinch, in the sense that those pipelines don't really exist.”

Keeping hope alive

Experts don’t think the pinch will last forever, though. Breakthroughs in neuropsychiatry are already happening, such as the use of light and chemicals to control nerve cell activity. Imaging technologies are improving as well, offering a look at brain circuitry with never-before-seen clarity.

"If you combine imaging together with highly selective chemical tools, which are the drugs, you can begin to understand [how therapies affect] brain circuitry, and which brain regions are involved in which responses," said Hargreaves.

"This has long been a goal in the field, but I think it's become a lot better in recent years."

Bristol Myers is willing to wait, however. Rather than build a large neuropsychiatry organization around Karuna, the company is content to lean on external partners, Hargreaves said.

Other pharmas may take a similar approach. That means smaller, more specialized drugmakers will likely shoulder much of the neuropsychiatry research. Some might argue that could be for the better. Drug programs like KarXT can more easily slip through the cracks at big, multinational firms, which typically split their attention and resources across units dedicated to different diseases.

Whether the presence of these larger companies is necessary for the field to bloom is also a point of debate. Several biotechs, from Intra-Cellular Therapies to Acadia Pharmaceutical to Alkermes, have successfully developed and commercialized psychiatry drugs on their own.

What’s important, according to researchers, is to build on each incremental step and keep resources flowing into the field. “Whenever any [neuropsychiatry] news comes out, I think we have to somewhat get excited, because otherwise there would be no reason for hope,” said Gonzales. “And we have to have hope. We have to invest in the things that look promising.”

For drug developers, the brain represents a final frontier of sorts, much like ocean’s depths or the reaches of space do for other scientists. Cracking it is “not for the faint of heart,” according to Lieberman.

“At the same time, there's a huge unmet clinical need, and tremendous profitability to be had,” he said. “So that's to say, if you're up for the challenge, it's certainly worth the effort.”

Visuals Editor Shaun Lucas contributed photo research to this story.

For the first time in more than two decades, a completely new form of antipsychotic medication will be available in the U.S. following a September 2024 approval by the Food and Drug Administration.

While momentous, the approval may also put a renewed spotlight on an enduring defect of the American healthcare system. An effective medicine is coming to market, but patients may have a hard time getting it at first because of insurance barriers. Analysts on Wall Street are optimistic there won't be many such hurdles, but some psychiatry specialists are cautious, citing past experience with new drugs.

The medicine, which will be sold as Cobenfy, was developed by Boston-based biotechnology company Karuna Therapeutics. In three medium- to large-sized clinical trials, Karuna showed that treatment with Cobenfy significantly relieved schizophrenia symptoms in people with the mental disorder.

Not only that, the drug didn’t cause excessive weight gain, restlessness or movement issues — side effects that are common to existing antipsychotics and, historically, have led patients to either switch medications or stop taking them altogether.

The results have been met with excitement, especially since substantial portions of the schizophrenia population don’t respond to or stay on other therapies. Yet doctors, while eager to have another treatment option, say they aren’t sure how much Cobenfy will ultimately benefit patients.

One main concern is to what extent insurance providers will cover such a drug, given the abundance of cheaper alternatives. The FDA has already approved more than a dozen antipsychotics for schizophrenia, and many have inexpensive generic versions that patients may be encouraged to try first. Cobenfy, meanwhile, carries a list price of $22,500 for a year’s supply, before accounting for insurer rebates or discounts.

A Bristol Myers spokesperson said the company priced the drug “in line with the landscape of branded oral antipsychotics.” Most patients, the spokesperson added, won’t pay the list price.

“You really have to be sure it’s better than everything else out there that’s cheaper and more readily available,” Mitzi Gonzales, a neuropsychologist and director of translational research at Cedars-Sinai, said in an interview earlier this year.

Carol Lim, a psychiatrist at Massachusetts General Hospital, noted in an interview this year how, after approval of the schizophrenia drug Caplyta in 2019, it was hard to get insurance coverage until after other treatments failed.

Cobenfy’s rollout will be handled by Bristol Myers Squibb, which recently acquired Karuna for $14 billion. Bristol Myers’ Chief Commercial Officer, Adam Lenkowsky, said on an earnings call in late July that payers have given “very positive feedback” to the company and acknowledged Cobenfy “fills a significant unmet need.”

Lenkowsky added that a team at Bristol Myers has, for months, been pitching Cobenfy to state Medicaid directors and Medicare payers. Estimates hold that more than 80% of schizophrenia patients are on those programs, meaning buy-in from them will be “critical,” according to Lenkowsky.

Citing data from Clarivate, Bristol Myers estimates the U.S. schizophrenia population totals around 1.6 million.

Cobenfy’s labeling includes warnings of risks that include urinary retention, increased heart rate and swelling of the face and lips. The FDA advises against using the drug in people with moderate to severe kidney impairment, or with known liver impairment.

On Wall Street, expectations for Cobenfy are high. The investment firm Cantor Fitzgerald envisions annual sales reaching $1 billion starting in 2026. More broadly, analysts have predicted the drug will generate north of $3 billion by 2030, according to Leerink Partners.

“I think you’re going to get a massive bolus of early adopters,” Paul Matteis, an analyst at Stifel who previously covered Karuna, said late last year. “And I think Bristol [Myers] just has to not mess it up.”

Sales could rise higher if Cobenfy notches additional approvals, a goal Bristol Myers is already working toward. A roughly 400-person study is evaluating the drug as an add-on therapy for schizophrenia patients who aren’t adequately responding to their current atypical antipsychotics. Data from that experiment should come next year.

Also in 2025, Bristol Myers plans to push the drug into late-stage testing for both bipolar disorder and the agitation that often accompanies Alzheimer’s disease.

Then, in 2026, the company anticipates results from two trials of some 800 people with psychosis tied to Alzheimer’s.

Cobenfy isn’t like available antipsychotics, all of which work by balancing levels of the chemical messengers dopamine or serotonin. It instead activates “muscarinic receptors,” a type of protein researchers believe harmonizes certain brain circuits that aren’t properly functioning in schizophrenia and some other psychiatric conditions.

Boosted by Karuna’s results, muscarinic receptors have become a hot commodity. Just two weeks before Bristol Myers announced its acquisition plans, AbbVie agreed to buy Cerevel Therapeutics for almost $9 billion.

A Pfizer spinout, Cerevel has been developing a muscarinic drug, emraclidine, that could ultimately rival Cobenfy. A pair of emraclidine studies, which, together, have enrolled around 750 participants with schizophrenia, should produce initial data before the end of the year.

Further behind, companies like Neurocrine Biosciences, Neumora Therapeutics and MapLight Therapeutics are working on their own muscarinic agents.

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When Katherine Wisner began studying postpartum mental health in the 1980s, the field barely existed. Relatively little research was focused on psychiatric illness related to pregnancy, and postpartum depression wasn’t yet well understood.

Wisner, now an associate chief of perinatal mental health at Children’s National Hospital in Washington, D.C., recalls a senior male supervisor dismissing a case she flagged of a new mother experiencing severe depression and suicidal thoughts. “You have to be wrong,” she remembers him responding. “Women aren't depressed in pregnancy, because they're fulfilled.”

For years, the idea that having a baby is one of the happiest times in a mother’s life persisted despite research indicating that’s not always the case. Over time, though, researchers and physicians began to acknowledge the range of mental health effects a postpartum woman can experience, spurring research into medicines that might help.

Now, doctors in the U.S. have two drugs they can prescribe specifically for postpartum depression, or PPD, a condition that affects an estimated 1 in 8 women following birth and can be severe. Both are from biotechnology company Sage Therapeutics. An intravenous injection called Zulresso was approved in 2019, while a daily oral pill called Zurzuvae got clearance in 2023. 

Their approvals were many years in the making. Yet both come with risks and limitations, and adoption has been slow — a fact some experts attribute to still-evolving awareness of PPD, and how to treat it.

“We are not recognizing it as a country and as a society,” Wisner said.

Slow recognition

Mental health professionals have relied on a guidebook called the Diagnostic and Statistical Manual of Mental Disorders, or DSM, to diagnose and treat their patients for more than 70 years.

But the DSM didn’t recognize PPD until the 1990s, when its fourth edition codified the condition as a “major depressive disorder occurring within four weeks of giving birth.”

The next edition, in 2013, went a bit further, defining PPD as a major depressive episode occurring during pregnancy or within four weeks after giving birth. The most recent update also highlights possible coexisting symptoms of anxiety and panic.

“Slowly the field grew so that eventually there actually was a formal diagnosis of depression,” said Wisner.

The drawn-out recognition of PPD left women dealing with the condition to fend for themselves for decades. It wasn’t until 2015, for instance, that the American College of Obstetricians and Gynecologists issued its first guidance on screening for symptoms in both pregnant and postpartum women.

The U.S. Preventative Services Task Force and American Psychological Association soon followed with similar recommendations.

“Historically, the messaging was that pregnancy is the greatest time in a woman's life, and there's no happier time than after a baby’s delivered,” said Julia Riddle, a reproductive psychiatrist and assistant professor at the University of North Carolina School of Medicine. “And it took a lot to really demonstrate that, maybe, it's a little more complicated.”

Difficulties in diagnosis

Even with formal screening recommendations, diagnosis can still be challenging. Questionnaires like the Edinburgh Postnatal Depression Scale and the Patient Health Questionnaire are often used by doctors to determine whether new mothers may be experiencing PPD or anxiety.

If PPD is suspected, psychotherapy, or “talk therapy,” is typically the first option. Drug intervention is usually reserved for more severe cases or for women who were previously on medication.

Actually receiving treatment can be a hurdle, too. Michelle Visser, a mother and psychotherapist for pregnant and postpartum women, recalled how few people asked about her mental health after she gave birth.

“A lot of people don't necessarily know when they need help, because people aren't talking about it,” Visser said. “You don't know what you don't know.”

Partly as a result, PPD is often underdiagnosed and, even when it is, not well treated. According to the Centers for Disease Control and Prevention, approximately 60% of women with symptoms of postpartum depression go undiagnosed, and half of those diagnosed aren’t treated.

“People tend to do the [Edinburgh] scale and then move on,” said Judith Joseph, a psychiatrist at NYU Langone Health and a researcher on trials of Sage’s PPD drugs. “Many times, there's shame in reporting any type of sadness to the provider because if your baby's happy and healthy, you should be happy and healthy too.”

Moreover, not every OB-GYN is trained to treat PPD since it has not always been a part of standard care. Access to therapies can also vary depending on a person’s insurance coverage, resources, or other health concerns.

Treatment shortcomings

Before Sage’s drugs were available, physicians treating PPD typically turned to standard antidepressants like selective serotonin reuptake inhibitors, or SSRIs.

These medicines can help, but their effects don’t usually kick in for four to 10 weeks, if at all. The evidence supporting their use in PPD is also limited.

“When people are having depression, that impacts their functioning and their quality of life,” Joseph said. “Telling them they'll get relief in eight to 10 weeks is very difficult to hear for someone who has a lot of responsibilities, who wants to be able to bond with their child, who wants to be able to get back to the life that they once had.”

Antidepressants can also cause weight gain, gastrointestinal issues, agitation and sleep disturbance.

Doctors need to evaluate prospective patients for bipolar disorder before they prescribe an antidepressant, too. Up to 1 in 5 people screened for PPD may instead have bipolar disorder, a mental illness that causes mood swings and psychosis. Antidepressants can exacerbate bipolar disorder.

Additionally, treatment can be a difficult choice for pregnant or postpartum women, who may feel pressured to go without therapy or fear a drug might affect their child through breastfeeding. (Breastfeeding while on medication doesn’t necessarily present a risk to the infant, however.)

“There is stigma because people assume that motherhood should be inherent to being a woman,” Joseph said. “But [people] don't necessarily acknowledge the challenges.”

Socioeconomic status, ethnicity and familial support can also affect how someone might view receiving help.

“We treat in the medical system, for the most part, people of color totally different,” Visser said. “Those families are very concerned they're going to be seen as unfit parents and that action will be taken against them.”

A sparse drug pipeline

Despite a push for better treatments, the development of drugs specifically for PPD has been sluggish. Research has largely centered on psychotherapy and existing antidepressants.

“We weren't even recognizing these [postpartum] illnesses decades ago, so we weren't going to do trials trying to find a medication specifically for these illnesses,” said Nancy Byatt, a perinatal psychiatrist and professor at UMass Chan Medical School.

Compounding the difficulty is the fact that clinical studies have historically not always included women, nor have drugmakers focused on illnesses that primarily affect women. Clinical trials frequently exclude pregnant women over concerns an experimental drug may harm a fetus and, as a result, researchers don’t know as much about how different types of drugs can affect pregnant women.

Enrolling postpartum women in trials is complicated, too, as the window of time to test a therapy is small.

“It’s still hard because we're talking about nine months. People are often not talking about their pregnancy until three months in,” Riddle said. “So you have a very brief time to consent them, get them onto a protocol and follow them into the postpartum. It's a hard thing to study.”

Sage has been one of the few biotechnology firms to try. The company set out early last decade to develop the drug that became Zulresso, which was approved in 2019 for moderate-to-severe PPD. Its modest efficacy and 60-hour infusion requirement has kept adoption minimal, however.

Working with Biogen, Sage later developed an oral drug called Zurzuvae that it sought to get approved for both PPD and in major depressive disorder. In 2023, the FDA approved it for PPD, but not MDD — a blow to the company that led to layoffs.

Earlier academic research had set the stage for Sage’s drugs. Studies found that depressive symptoms caused by changes in certain brain chemicals during pregnancy might be alleviated with drugs that act on so-called GABA-A receptors. Both of Sage’s PPD drugs are synthetic versions of a neurosteroid called allopregnanolone, a brain hormone that affects GABA-A receptors. They essentially work similarly to hormone therapy, suggesting the role hormones might play in PPD.

“For a long time, it's been debated whether postpartum depression is just another form of major depressive disorder or it's an entity by itself,” said Bassem Maximos, an OB-GYN in League City, Texas and a trial investigator. “A lot of us OB-GYNs believe there has to be a different mechanism because a lot of our patients are different from regular major depressive disorder patients.”

Beyond Sage’s drugs, the pipeline of therapies in development for postpartum depression is thin. Brii Biosciences, another biotechnology company, has a drug in mid-stage testing, but there are few others. 

Will PPD drugs succeed?

While Zulresso and Zurzuvae’s approvals were a milestone for PPD drug research, neither has been widely used.

Zulresso’s lengthy administration must take place in a healthcare facility, keeping adoption low, while Sage faced pushback for the drug’s $34,000-per-course price tag. Sales were $6.7 million in Zulresso’s first full year on the U.S. market, and only $10.5 million in 2023.

The FDA, as well as psychiatrists like Byatt, agreed Zulresso’s “benefits outweigh the negatives.” But the drug’s requirements make it a hard sell, especially for women who lack additional support, or are a single parent.

Zurzuvae, which launched commercially in the U.S. in December 2023, is more attractive. As an oral medicine, the drug can be shipped to a patient’s home and is taken daily for two weeks. Still, sales have been been only modest at best.

Zurzuvae takes effect rapidly, which could help it stand out compared to other medications, such as SSRIs, that have a slower onset of action. In clinical trials, Sage also found its drug could relieve symptoms of anxiety.

“The fact that this medication works quickly, and also gives [patients] that added relief for sleep and anxiety is beneficial compared to an SSRI that works slower, and may not necessarily relieve sleep and anxiety as rapidly,” Joseph said.

Zurzuvae, which is being co-marketed with Biogen, costs $15,900 at list price for a two-week course — less than Zulresso, but still high enough to raise access concerns.

While Zulresso’s and Zurzuvae’s side effects are modest, both carry black box safety warnings. Zulresso’s warns of excessive sedation and loss of consciousness, while Zuruvae’s cautions of impaired ability to drive. However, Maximos claims the drowsiness was a “positive side effect” for some mothers in the clinical trials who suffered from a lack of sleep and exhaustion.

“It's exciting that we're here,” Riddle said “It's exciting that women have spoken up about their struggles, and that women have taken the time to say, ‘hold on, [motherhood] was actually hard.”

Beyond drug-specific challenges, new mothers face other hurdles that can impact PPD care. Paid maternity leave is not guaranteed in the U.S. and many women are in so-called maternity care deserts, making finding adequate support difficult.

“We always want better treatments that work but the reality is we're not getting the treatments we have to the people who need it right now,” Wisner said. “That's where the big gains are going to come from.”

In an effort to make treatment easier, Sage and Biogen have launched a patient support program, and are working with organizations on PPD education initiatives.

Some experts think a bigger change around culture and access is needed, however.

“The main way that we could possibly address mental health — what's been a crisis for years and is now an emergency — is by supporting resilient and healthy families, and we have to start with perinatal mental health to be able to do that,” Byatt said.

Still, there is some optimism. Joseph sees Sage’s approvals as opening the door to more drug research, for instance.

“This is an opportunity to pave the way for a huge amount of research in this space,” Joseph said. “It's just the beginning.”

After months of searching, the drug hunters had tracked down the prized game they believed could help launch the next chapter of their company.

The team from Biohaven Pharmaceutical moved fast, fearful that rivals were in close pursuit. On Christmas Eve, CEO Vlad Coric and a company board member flew 400 miles west from their home base in Connecticut, on a mission code-named “Project Rudolph.” They hoped to return bearing a valuable gift: an experimental medicine with the potential to treat a variety of brain disorders.

More than three years later, the medicine is one of Biohaven’s most important assets. Fine-tuned over years by researchers at Pittsburgh-based Knopp Biosciences, it’s designed to activate certain kinds of microscopic tunnels known as ion channels. These proteins are found on all human cells and perform essential tasks. They move muscles, govern the five senses, rouse the immune system and foster communication between cells — functions that also make them prime targets for drugmakers.

“There's nothing you can think about in your body that doesn't involve ion channels,” said Gregory Kaczorowski, the former senior director of ion channel research at Merck & Co.

For patients, ion channel drugs offer a wealth of benefits. They’re used to lower blood pressure, calm seizures, beat back infections and steady heartbeats. And for developers, they can be extremely lucrative. Vertex Pharmaceuticals revolutionized how cystic fibrosis is treated with a series of ion channel therapies and, in doing so, became one of the world’s largest biotechnology companies. Its market value has surpassed $120 billion.

Vertex has also spent decades developing ion channel blockers for pain, and in January won U.S approval of its most advanced candidate. Wall Street analysts expect the medication will be a much-needed, non-opioid option for pain management, and forecast annual sales to peak at more than $5 billion.

In spite of the potential payoffs, few pharmaceutical firms dedicate research units to ion channels. Experts say that has to do with how incredibly challenging it is to study these proteins and to drug them safely. Paul Negulescu, head of Vertex’s pain research, likens them to bucking broncos. Hard to capture, and even harder to tame.

But with the help of futuristic science, researchers can now see the architecture of ion channels and the ways these speedy proteins move in real time, allowing them to construct drugs that, at least in theory, have a better shot at being safe and effective. Those advances have renewed interest and investment, especially among brain drug developers. Companies like Biohaven, Neurocrine Biosciences and Jazz Pharmaceuticals are betting the field will produce new treatments for epilepsy, tremor, depression and bipolar disorder in the not-too-distant future.

“Ion channels really have the potential for us to change the way we treat neuropsychiatric and neurological disorders,” Coric said. “It's ripe for moving quickly.”

Very unlucky squid

It can be difficult to picture just how small a human cell is. On average, it’s one-tenth as wide as a strand of hair and 25 times smaller than a grain of salt. Tinier still are the thousands of ion channels anchored into the fluid, oily shells that encase these microscopic worlds.

The channels act as canals; though, instead of water, they control the movement of electrically charged particles like sodium, potassium, calcium and chloride. When cells are stimulated in certain ways, the canals open, permitting ions to flood in or out. They then shut and return to a “resting” state. The opening and closing happens hundreds of times a second and actually jolts the cell, in essence telling it, “Something is happening, react!”

Researchers know this thanks to two English physiologists — and some very unlucky squid. Between 1939 and 1952, Alan Hodgkin and Andrew Huxley published groundbreaking papers about giant, squid-harvested nerves that can grow as thick as a penny and longer than a yardstick. They found the nerves signaled via the rush of electric currents across membranes. And even though Hodgkin and Huxley couldn’t see them, they correctly predicted the presence of ion channels.

Their work won a Nobel Prize in 1963, and has since served as the foundation for other breakthroughs that would earn the prestigious award.

In the 1980s, two cell specialists, Erwin Neher and Bert Sakmann, created a technique to measure the current passing through a single ion channel. This “patch clamping” is a bit like the cupping therapy popularized by Olympic athletes. It uses an ultra-thin glass tube to suction up a tiny piece of the cell membrane so researchers can study the ways drugs affect an individual channel.

The technique was “revolutionary” and "gave biochemists and biologists the ability to work on ion channels,” according to Kaczorowski.

More tools arrived by the early 2000s. American neurobiologist Roderick MacKinnon provided the first look at the atomic structure of an ion channel, while biochemist Roger Tsien invented a pallet of colorful dyes that made it possible to record the activity of the proteins.

This period also marked the rise of businesses built around automating the patch clamping process, which increased the volume of drug screenings that could be done in a day from a handful to thousands.

Together, these developments brought control and precision to an area of research where victories were often the product of guesswork. Older anti-seizure and blood pressure medications were discovered because their effects were easy to observe, not because scientists knew exactly how they regulated ion channels. And, without the clear picture of protein activity researchers now have at their disposal, large players like Merck and Bristol Myers Squibb turned their focus elsewhere.

“A lot of what was done, was done — I don't want to say irrationally, but phenotypically. When you have to do it rationally, it's difficult,” Kaczorowski said. “It's easy to cut and paste DNA and RNA and stuff like that. It's a little more conceptually difficult to understand electricity. And to be honest, pharma executives don't really understand this.”

Double-edged swords

If their dollars are any indication, drugmakers seem to slowly be coming back around to ion channels.

In November 2023, Merck wagered up to $610 million on a young biotech that’s investigating whether Parkinson’s disease can be treated by regulating calcium channels. A week before, Jazz agreed to collaborate with the GSK spinout Autifony in a deal worth as much as $771 million.

Venture investors are buying in as well. Westlake Village Partners led a $135 million fundraising round for Latigo Biotherapeutics, a California-based startup that launched in February 2024, hoping to follow in Vertex’s footsteps with a pipeline of sodium channel-blocking, non-opioid painkillers.

“It's been a long, long journey, but we are capitalizing on it,” said Stephen Waxman, a neurology professor at the Yale School of Medicine who’s credited with major discoveries about the role ion channels play in pain. “It's a very exciting time,” he added. “There are scientific issues, all the regulatory issues. But translation is achievable, and it's happening.”

The new investments are a step up from just a few years ago. In 2019, a subsidiary of Jazz spent $53 million to acquire a small company focused on a group of calcium channels that regulate muscle activity. The deal expanded Jazz’s research into movement disorders while handing it a medicine in mid-stage testing for a common type of tremor.

“We were quite convinced we had a target that was worth going after, and a drug that was highly differentiated in the class,” said Robert Iannone, the company’s head of research and development.

Around the same time, Neurocrine licensed experimental therapies from Idorsia and Xenon Pharmaceuticals. Both drugs are meant to treat rare epilepsies affecting children, with the former blocking the same channels as Jazz’s medicine and the latter inhibiting “Nav1.6,” one of the nine known sodium channels.

Biohaven, too, was struck by the work going on at Xenon, which in 2017 bought rights to a drug intended to keep some potassium channels open for longer. The thinking was this effect could stabilize neurons and, in turn, treat illnesses tied to the cells overfiring. Four years later, Xenon had in hand positive results from a study of adults with focal epilepsy, and was evaluating the drug against major depression as well.

Coric said that and other data convinced him the time was right to “pounce” on ion channels. Biohaven, he thought, may even repeat the success it had with a new class of migraine medications. Despite competition from much larger companies, Biohaven’s Nurtec ODT carved out market share and pop culture relevance through ads on racecars and TikTok and endorsements from celebrities like Khloe Kardashian. Pfizer bought that drug and the rest of the biotech’s migraine business in 2022 for $11.6 billion.

As Coric and his team began searching for an ion channel therapy of their own, they came across a perennial problem for this area of development. Since the proteins are everywhere in the body, drugs aimed at them must be selective, or else the consequences may be dire.

A promiscuous channel blocker might sneak into the chest, causing the heart to literally skip a beat. In the brain, it could trigger neurological issues like dizziness, drowsiness and fatigue. In one stark example, the numbing agent lidocaine and the deadly poison of the Japanese puffer fish both block a category of sodium channels. What differentiates them is selectivity.

“Ion channels are a double-edged sword,” Kaczorowski said. “They’re the targets of therapeutics, but they’re also the targets of toxicity. You don't get something for nothing with ion channels.”

Over the past decade, new technologies have given scientists the power to construct more precise drugs. One such technology, known as “cryo-electron microscopy,” takes a sample of proteins and, through a flash-freezing technique, locks them into a thin sheet of ice colder than the surface of Jupiter. A beam of particles is then shot through the sheet, creating many images of the trapped proteins.

The images collectively serve as a blueprint, illustrating the layout of proteins and the best spots for potential medicines to latch onto. That’s especially useful with ion channels, since they contort into distinct shapes as they open and close. And some of those contours are more useful to drugmakers. Jazz’s medicine, for instance, is selective not only for one kind of calcium channel, but also for a particular form the channel takes.

“By bringing in this additional layer of selectivity ... you can actually target the neurons that are pathologically firing while sparing the ones that are undertaking their normal function,” said Margaret Lee, the company’s head of central nervous system pharmacology.

Even with better imaging, selectivity remains a major obstacle. At Knopp, a research team led by Steven Dworetzky and Michael Bozik analyzed thousands of molecules before pinpointing one they felt was precise enough — the one that would ultimately catch Biohaven’s eye.

“Almost every drug program is like Whac-A-Mole. You fix one thing and you break something else,” said Dworetzky, who now serves as Biohaven’s senior vice president of ion channel R&D.

Far-off symphonies

That dynamic has played out time and again in ion channel research. Setbacks still frequently happen. Xenon’s drug stumbled in a depression study in late 2023, while Jazz’s medicine in June 2024 missed the key goals of an essential tremor clinical trial.

That may be why more money hasn’t flowed in just yet. “Investors are sort of missing this,” said Phil Nadeau, an analyst at the investment bank TD Cowen. “This is an area where there have been developments over the last decade, and it seems like there still could be. But investors aren’t putting these developments into a single category.”

Against this shadow, Vertex may be a guiding light to some.

Negulescu warns that ion channels require patience. In cystic fibrosis, the genetic cause of the disease is well understood. Yet Vertex worked for more than a decade before its first therapy, Kalydeco, came to market. In pain, it’s taken a quarter of a century.

With the pain program, the company not only developed drugs, but its own system to measure their activity. The system included stimulation tools that function like tiny defibrillation paddles, as well as fast cameras to capture the movement of the sodium channels. Other companies might need to do the same, since recording the hectic hum of ion channels is, as Waxman describes, like trying to eavesdrop on a symphony happening several towns over.

"And to make sense of it," he said, "we need to not only eavesdrop on it, but we need to isolate what is the sound of the oboe? And what is the French horn doing? And how do they interact? This is challenging work."

Ion channels also differ from other proteins, so companies seeking to enter the space might have to reframe how they approach drug development. These proteins sit in membranes and are exposed to a relatively huge electrical field. Studying them in their natural environment is therefore tricky. Aspects like the type of cell they’re in matter, because the sites where drugs attach can vary from species to species.

According to Negulescu, Vertex decided early on to do its laboratory work in human cells, which ended up being a good choice, since Kalydeco was “uniquely active” on the human form of the channel tied to cystic fibrosis. "If we had done our screening in rodents or used rodent models, we would have missed it altogether,” he said.

Negulescu expects that, in pain, the “power and the potential” of ion channel drugs will become more evident in the next five to 10 years. He’s not alone. Dworetzky has been in the industry for nearly three and a half decades, and says during that time he’s “seen the rise, the fall and the resurrection” of ion channels, with the last several years feeling like a turning point.

Waxman sees Vertex’s drug as analogous to the first statins — a good base hit, but not a home run — and predicts many more medicines will follow. And pain could just be the start. He envisions ion channels becoming a route to treatments for psychiatric disorders, cardiovascular illnesses like chronic heart failure, nerve-destroying diseases like Alzheimer’s, and even perhaps immune system conditions like arthritis.

“The future is bright,” he said.

For the last quarter century, one of the world’s most capable drug developers toiled to make a new, non-addictive kind of painkiller. The journey was fittingly excruciating.

Pain, as Vertex Pharmaceuticals found out, is wildly complex. It starts simple enough, with a sliced hand or burned finger or broken bone. But it convolutes fast. Special nerve cells, activated by potentially dozens of chemicals and proteins, sense the pain and launch a signal up the spine like a firework, lighting up a patchwork of brain regions that interprets this message and decides how the body will feel.

Much about how this process unfolds in any given person remains hazy. Scientists suspect genetics, past experiences and the environment each play some role, perhaps explaining why two people who suffer the same injuries can have such dissimilar pain. This intricate web tripped up many large pharmaceutical firms, a key reason why no truly innovative medicines have come forward in more than two decades.

Vertex was one of the few to trudge ahead. Its pain labs in San Diego discovered, fine-tuned and tested promising compound after promising compound. Invariably, though, studies would show them not safe or potent enough to meet Vertex’s exacting standards. Not until about 20 years into its hunt did the company find a molecule worth championing.

In January, the Food and Drug Administration approved that molecule, now called Journavx, as a treatment for the sharp, short-lived “acute” pain usually felt after an accident or a surgery. Expectations around Journavx are high. With the U.S. still mired in an overdose crisis that’s killed hundreds of thousands of people, Vertex is positioning its medicine as a valuable alternative to opioid-based therapies.

Doctors say they’re eager to have another tool at their disposal. Wall Street views Journavx as a billion-dollar product.

Journavx has a real chance to “bend the curve on the opioid epidemic,” said Stuart Arbuckle, who, as Vertex’s chief operating officer, is overseeing the drug’s launch. “This is the first real alternative. The other is to leave these people in pain, and that's not an acceptable choice.”

Yet the true impact of Journavx will hinge on whether Vertex can contend with a healthcare system that favors the cheapest possible option — a system which, at the hands of drugmakers, insurance companies and pharmacy middlemen, was gamed for opioid use. Doctors across the country, from Oregon to West Virginia to Massachusetts, envision the biggest barrier to prescribing Journavx being insurers, as they tend to resist covering new, higher-cost pain drugs. Vertex set the medicine’s price at $31 a day, many times more expensive than generic opioids like hydrocodone.

Pain is unlike any other drug market, presenting both an opportunity and a challenge for Vertex. The least expensive therapies have ruined countless lives, and wreckage from the opioid epidemic has, for some time, prompted a shift to a layered treatment approach that tries to use these powerful drugs only as a last resort. Vertex’s mission is to convince doctors and insurers that Journavx belongs somewhere in the mix.

Arbuckle claims, as industry executives often do, that his team has had fruitful conversations with these stakeholders, that they appreciate Journavx may fill a major gap in pain management. They’ll need to for most patients to have a shot at accessing the drug.

“In some ways, talk is cheap,” Arbuckle said. “It really will depend on what we see from people in terms of action in the days and weeks following approval.”

Debating value

Supporting Vertex’s case are a pair of large clinical trials that assessed Journavx in people who underwent either a “tummy tuck” or a bunion removal, two notoriously painful surgeries. Both experiments showed the drug was significantly better than a placebo at easing pain. It also worked decently fast. Participants reported some relief within a few hours.

Unlike all other approved pain drugs, Vertex’s blocks tube-shaped proteins found almost exclusively in nerve cells located outside the brain and spinal cord. These “NaV1.8” proteins act like cell towers, transmitting pain waves to the central nervous system. In addition to being effective, studies have found Journavx to be remarkably safe. It doesn’t appear to have the addictive qualities of opioids, which bribe the brain’s pleasure centers, and compared to a placebo it actually was associated with lower rates of common ailments like nausea, constipation and headache.

Vertex took these results and asked the FDA for a broad approval in moderate-to-severe acute pain. With that now in hand, Vertex can enter the segment of the pain market where opioids are more readily prescribed. The company has also been sponsoring research to expand into different types of chronic pain.

There, Journavx has delivered mixed results. Vertex lost $15 billion in market value in December when data from a lower back pain trial disappointed investors. A year earlier, however, a study focused on the chronic nerve pain caused by diabetes showed Journavx to be about as effective as the main ingredient in Lyrica. Analysts described that performance as “solid” and “strong.”

Journavx has other limitations. The two acute pain studies explored whether it is superior to a combination of Tylenol and a commonly prescribed opioid. On that measure the drug fell short, a “glaring” outcome for Richard Vaglienti, medical director of the Center for Integrative Pain Management at West Virginia University, which treats roughly 1,600 patients a month.

Vertex rejects that this finding will be a hangup. “Go and ask physicians and patients,” Arbuckle said, “they'll tell you that's not what they're looking for.”

Vertex did just that last year, commissioning a survey of around 550 healthcare providers and 1,000 adults recently treated for acute pain. Their bigger concerns, according to the company, were the addictive potential of opioids and the exigencies of having few non-opioid options.

Taken together, Vertex’s data have left many experts with a positive view of Journavx, yet no firm agreement on precisely which scenarios it is best suited for. Vaglienti thinks it’s “possible” the drug could have a “decent role to play” managing non-severe chronic pain, and might be particularly useful for patients who can’t tolerate more potent drugs.

Kimberly Mauer, vice chair of the pain center at Oregon Health & Science University, sees it as more widely applicable. “This sounds like an exciting option, because it's going to be opioid-like, and maybe not have the side effects or the risk,” she said. “And if it doesn't work as well as opiates, I'm OK with that. Because I can maybe pair it with something else.”

While drug research and opioid mitigation strategies often focus on chronic pain, having a pill like Vertex’s in the acute setting is “extraordinarily important,” said Theodore Price, director of the Center for Advanced Pain Studies at the University of Texas at Dallas. That’s because many people are susceptible to opioid addiction but don’t realize it until they’ve been prescribed the drugs following a trauma or operation.

Tens of millions of surgeries happen annually in the U.S. And while estimates vary depending on the period studied, recent research indicates a large portion of surgery patients are still prescribed an opioid.

“There's nothing you could say that could convince me this doesn't have an impact on what happens to them later on in their life, at least some portion of them,” Price said.

Accidental overdoses involving an opioid remain high. Nearly 82,000 people in the U.S. died that way in 2022. Almost 15,000 of those deaths involved a prescription opioid. Price himself lost one of his best friends to an overdose about 15 years ago, after the friend was first exposed to opioids for pain management.

“It's a tragedy,” he said. “If we could have a drug that would help us to avoid this, it would be an absolutely massive benefit to humankind.”

The price point

Jose Zeballos understands this need well. As an anesthesiologist and leader of the acute postoperative pain management service at Brigham and Women’s Hospital, Zeballos cares for hundreds of patients every year. A few advances in treatment have emerged during his tenure, like new, longer-lasting local anesthetics, but overall “nothing else has come out that really has helped.”

Vertex’s medicine could therefore be an “amazing” addition, he said, as it may offer some relief not only after surgery, but in everyday pain management as well. Journavx might dull persistent back aches or take the edge off a sports injury. And, since opioids can confuse and disorient, it could be an especially valuable alternative for elderly patients.

Despite the many use cases, Zeballos speculates that doctors will reach for Journavx only if it’s “easily accessible,” and that depends on insurance companies stomaching the drug’s price tag. “It probably all comes down to financials more than anything else.”

Arbuckle says price and access are by far the biggest issues brought up when Vertex’s commercial team discusses Journavx. Millions of prescriptions for acute pain are written every year in the U.S., so, from the payer perspective, “if you're seen millions of anything, you're worried about the budget impact.”

Generic opioids like hydrocodone cost less than $2 a day. Advil and Tylenol are cheaper still, making Journavx’s price of $31 a day high enough to draw close examination from insurers.

Arbuckle argues that’s the wrong comparison, since it doesn’t account for the devastation opioids bring to both the healthcare system and society at large. A report from the Congressional Joint Economic Committee tried to calculate this cost and, looking just at 2020, assessed the total at nearly $1.5 trillion, one-third higher than three years prior.

“This is not an academic, side-by-side, two things have equivalent efficacy and one's cheap and the other one isn't [exercise],” Arbuckle said. “Every time a physician and patient chooses [our drug] when they would previously have chosen an opioid, that is one less opportunity that person is exposed to the potential liabilities of opioids, gets opioid use disorder and becomes a horrible statistic.”

Vertex is beholden to investors as well as patients. The price set by the company may have societal value baked in, but it’s also meant to drive revenue. One analyst expects Vertex’s pain portfolio, which includes Journavx and a series of follow-on drugs already in development, could eventually generate north of $10 billion a year.

Analysts at the investment bank Cantor Fitzgerald recently spoke to a senior director of product development at one of the nation’s largest insurers, UnitedHealth Group. The director predicted Journavx will get broad coverage, as payers are under serious pressure to cover non-opioid medications.

He also doesn’t anticipate the drug will be subject to “step therapy,” a controversial insurer practice that requires patients to “fail” on cheaper drugs before trying newer, pricier medicines.

Optum, a pharmacy benefit manager owned by UnitedHealth Group, declined to answer BioPharma Dive questions on its coverage plans for Journavx. Insurers Humana, Cigna and CVS Health did not respond to requests for comment. Vertex has talked to payers as well as parties that “paid billions of dollars for their role in the opioid epidemic,” according to Arbuckle, and the conversations have been “really positive.”

“Virtually everybody we speak to totally gets it,” he said. “Does that mean we're going to have tough negotiations on price? Of course. Do we think we’ll have to negotiate access? Of course. Do we have to go through formulary procedures? Of course. But it's not like we're getting a stiff arm from people.”

If Vertex does get payer buy-in, Journavx could be an exception to a longstanding, unwritten rule in pain management: fresh therapies take a while to reach patients. One of the company’s immediate goals is to cut down this timeline and to make sure, if patients are prescribed Journavx, they can pick it up over the counter at their local pharmacy.

At OHSU’s pain clinic, Mauer said her team rarely uses new medications within months of them coming to market, because insurers haven’t yet decided coverage plans and the out-of-pocket costs are too high for most patients. Nine times out of 10 the wait is “pretty long.”

“The problem with any new drug is the reluctance of insurance companies to pay for it because of the heavy upfront cost,” Vaglienti said. “So even though there are risks with opioids, from the insurance company side, 30 Percocet really only costs a few dollars.”

A turning tide

Journavx, then, may serve as a proving point for Vertex. The Boston-based biotechnology company has grown to a $115 billion valuation by selling big-ticket medicines for uncommon diseases with few to no other remedies. Pain has a trove of generic treatments and, just in the acute setting, Vertex approximates 80 million adults in the U.S. are prescribed a medicine each year.

Pricing barriers like the ones facing Journavx can be overcome, though success often takes time. Between 2018 and 2020, a novel class of injectable migraine drugs came onto a market flush with generics. While one is now approaching blockbuster status — $1 billion or more in annual sales — the others remain only modestly successful. A similar dynamic awaits a new schizophrenia treatment from Bristol Myers Squibb, which, while pegged for success, faces numerous, lower-cost competitors.

Journavx’s launch comes at what might be considered an opportune time. The reckoning over opioids still lingers in the public eye. In January, members of the Sackler family and Purdue Pharma agreed to pay as much as $7.4 billion in a revised legal settlement over the OxyContin maker’s role in the epidemic.

Federal and state lawmakers are also taking action. Two Congressional bills — one enacted this month, the other introduced in the Senate last year — aim to amend Medicare so older Americans can more easily access and afford a list of certain non-opioid pain medications. Journavx is eligible to join this list, though it likely won’t be added until at least 2026.

Policies like these could help “level the playing field” in the pain market, Arbuckle said, and their arrival represents a “turn in the tide.”

The executive is adamant that Vertex can make the most of this momentum. It’s been preparing for Thursday’s approval for “a number of years now,” he said, and has amassed 150 staff to sell Journavx.

Still, there are doubts the launch will go as smoothly as Vertex — or its investors — might hope.

RBC Capital Markets analyst Brian Abrahams is braced for “limited initial adoption” and thinks the $90 million figure that other analysts have forecast for 2025 sales is “optimistic.” Paul Matteis of Stifel shares those reservations. In acute care, he said, "it's almost impossible to find a good drug launch" for anything non-lifesaving, in large part because the field "moves really slow" to adopt new treatments.

Both analysts note that, for Journavx to hit that $90 million mark, hundreds of thousands of patients would need to take the drug. "No one has a clue how to model it," Matteis said.

The medical and research communities may be holding their breath, too. Price, of the University of Texas, fears that if Vertex doesn’t make a strong enough case, it could dampen enthusiasm around Journavx or even broader pain research.

“Any medication that is effective for treating pain of any type, that doesn't have all the negative things associated with opioid therapy, would be extremely valuable,” said Vaglienti. “And I know the company is probably banking on this being one of those medications. That will remain to be seen.”

In the notoriously expensive business of drug development, SiteOne Therapeutics made do with little. The biotechnology startup formed in 2010, aiming to create new, non-addictive pain relievers at a time when overdoses involving opioids were killing more than 20,000 people in the U.S. each year.

Yet the dire need for safer medications didn’t resonate with most investors. To them, pain was too risky. Scientists knew the general outline of how it worked: a cut, scald, break, pinch, slam or zap would alert special proteins and chemicals, which, like sentries, relay pain signals through the body. But the finer details of this process were — and, in many cases, still are — fuzzy, like how people who suffer the same injuries can report very different pain experiences.

This uncertainty meant SiteOne had to, for most of its life, rely on small grants to stay afloat. “There was certainly a difficult period,” CEO John Mulcahy said late last year. “Pain was out of favor, so it was difficult to raise capital around these assets.”

That period now appears over. In the last eight months, SiteOne not only closed a $100 million fundraising round led by Novo Holdings, the controlling stakeholder of Ozempic-maker Novo Nordisk, but also agreed to sell to Eli Lilly in a deal that could be worth up to $1 billion.

The newfound interest and investment can be attributed, in good part, to Vertex Pharmaceuticals, which has led the charge investigating a group of tube-shaped, pain-regulating proteins called sodium ion channels. After a quarter century of meticulous, onerous work, Vertex’s labs finally crafted a channel-blocking molecule the company viewed as safe, effective and precise enough to help address the opioid epidemic.

In January, the Food and Drug Administration approved this molecule, known commercially as Journavx, as a treatment for the sharp, short-lived “acute” pain felt after an accident or surgery. Ken Harrison, a senior partner at Novo Holdings, said a core reason his firm decided to back SiteOne was that Vertex had established these drugs can be successfully studied and brought to market.

While Journavx has so far proven remarkably safe and absent of addictive properties, doctors remain torn about how useful it will ultimately be for patients. At its best, the drug looks to be only as potent as a weak opioid. At least 5,800 Journavx prescriptions were written during the third week of June; millions more will need to come for it to meet Wall Street’s blockbuster forecasts.

Still, TD Cowen analysts recently described the drug’s approval as a “watershed moment that could pave the way for a new era of non-opioid pain treatments.” Indeed, SiteOne and at least 10 other developers want to follow in Vertex’s footsteps with their own medicines that stopper either the “NaV1.8” sodium ion channel, as Journavx does, or a close cousin, “NaV1.7.”

What are sodium channel inhibitors, and how do they work?

Found in the outermost layers of many cells, these proteins function like faucets for charged sodium particles. They open in response to various stimuli — a bright light switching on, a bite of a salty food, a handful of ice from the freezer — at which point ions flood into the cell. This rush creates an electrical pulse that travels through the nervous system and to the brain, where it's used as information to determine how the body should feel and react.

Of the nine known types of sodium ion channels, three are primarily found in the peripheral nervous system, where they play key roles in pain signaling. The signaling process resembles a line of dominoes. At the start is the root of the pain, at the end the brain. By blocking these channels, scientists are effectively removing a couple of the earliest tiles so they can’t continue the cascade.

“You’re stopping the pain as close as you can to the source,” and leaving “other modalities of sensory signaling intact,” explained Stephen Waxman, a neurology professor at the Yale School of Medicine who’s made significant discoveries about the role ion channels play in pain, on a 2023 podcast run by The New England Journal of Medicine.

For drugmakers, NaV1.7 and NaV1.8 have emerged as the two most popular pain targets. One reason is their location; being on the outer edge of the nervous system, rather than thoroughly embedded in organs like the heart or brain, reduces the risk that channel-blocking drugs will disrupt other vital body functions.

These proteins also work in different ways, offering researchers a shot at treating a variety of pain types. NaV1.7 acts like a light switch, abruptly turning the pain signal on and off, while NaV1.8 is more akin to a dimmer. SiteOne’s Mulcahy has said NaV1.8 could therefore be a more desirable target for chronic pain management, since the goal there usually is not to shut pain off, but to dial it back down to “normal.”

Designing medicines that bind to a specific sodium channel remains exceptionally challenging, as the subtypes all share very similar structures. Additionally, the proteins move extremely fast — opening and closing in milliseconds — and are exposed to relatively large electrical fields. Only in the last 15 or so years, with the creation of new tools, have drugmakers been able to adequately study and precisely drug ion channels.

What are the advantages over other drugs for pain?

Scientists believe that, by avoiding the central nervous system, sodium channel blockers can alleviate pain without eliciting the side effects or addictive risks posed by opioids. The late-stage studies that led to Journavx’s approval support this theory.

Together, the two trials recruited more than 2,000 people who had just undergone either a “tummy tuck” surgery or a bunion removal. Participants received either Vertex’s drug, a placebo, or a combination of Tylenol and a commonly prescribed opioid that served as an “active comparator.” Investigators found lower rates of nausea, dizziness and headache among those given Journavx than in the other groups.

Journavx was generally safe and well-tolerated, according to Vertex, and nearly all of the adverse events seen in these studies were mild to moderate in severity. Drug-treated patients did, however, show higher rates of itchiness, rash and muscle spasms compared to their placebo-treated counterparts.

As for its effectiveness, Journavx proved significantly better than the placebo at alleviating acute pain. Both trials measured this with a 0-to-10 scale wherein patients rate their pain intensity at a series of time intervals over two days.

Notably, the drug was not more effective than the active comparator regimen. That’s raised debate about its ultimate utility in a setting like acute pain, where both patients and healthcare providers are typically looking for a powerful, quick-acting medication. While Vertex leadership has maintained this finding won’t deter doctors from prescribing Journavx, some pain experts have described the pill’s effects as modest. Richard Vaglienti, medical director of the Center for Integrative Pain Management at West Virginia University, even classified the results as “glaring.”

That could leave the door open for other developers to compete — even those working outside the field of sodium ion channels. In May, Pittsburgh-based Viatris reported positive results from late-stage studies evaluating a reformulated version of an old medication, an “NSAID” called meloxicam, in people who had bunion removal or hernia repair surgeries. Viatris said its drug didn’t just beat a placebo at providing acute pain relief, an after-the-fact analysis found it also offered “significantly superior pain control” to tramadol, an opioid less potent than the one used in Vertex’s studies.

Following this release, Brian Skorney, an analyst at the investment firm Baird, noted how Viatris’ data “highlight a number of concerns we have with Journavx’s profile, in particular, onset of action, a critical factor for post-operative pain.”

The results, Skorney argued, make Journavx “look like an inferior option” compared to a “pretty old” drug. “If NSAID’s don’t have the highest efficacy, as Vertex is fond of saying, what does that say about Journavx?” he wrote.

Which companies are developing NaV1.7 and NaV1.8 inhibitors?

The majority of developers researching sodium ion channels for pain are small biotechs.

One, Dogwood Therapeutics, formed late last year through the reverse merger of Wex Pharmaceuticals and Virios Therapeutics. It had 12 full-time employees at the end of December. Another, Channel Therapeutics, had four, and is now in the process of combining with a subsidiary of drug commercialization specialist Ligand Pharmaceuticals.

Such deals could suggest that, while this area is receiving more attention, building a company around it remains challenging and may require less conventional methods for raising money at a time when investors are viewing biotech more skeptically.

Other players include Praxis Precision Medicines, Newron Pharmaceuticals, RaQualia Pharma and Xenon Pharmaceuticals. Two more, Sangamo Therapeutics and privately held Navega Therapeutics, are taking a genetic approach, with therapies built to suppress the gene that encodes for NaV1.7 proteins.

Latigo Biotherapeutics is further ahead, and like SiteOne touts a drug aimed at NaV1.8 in mid-stage testing. That drug, LTG001, is being evaluated in acute pain following a tummy tuck, bunionectomy or wisdom teeth removal.

Latigo is backed by prominent life sciences investors such as Westlake Village BioPartners, 5AM Ventures and Alexandria Venture Investments, and in March announced the closing of a $150 million funding round that CEO Nima Farzan said should keep the company going at least until it has late-stage data for LTG001.

Vertex and Eli Lilly, with its pending purchase of SiteOne, currently appear to be the sole big pharmaceutical firms in this space, though others have shown interest. AbbVie had “ABBV-318,” an oral molecule designed to inhibit both NaV1.7 and NaV1.8, but no longer lists the drug in its pipeline. Scientific American reported last year how Merck & Co.’s patent activity also suggests it may be stealthily exploring ion channels for pain.

A Merck spokesperson said the company is “committed to neuroscience research,” including chronic and acute pain. “At this time, it’s too early to share information related to sodium ion channel inhibitors, but we will continue to collaborate with scientists and investigators worldwide to advance innovation and find solutions that may address complex and debilitating neurological diseases.”

At Vertex, company leaders are trying to expand Journavx’s approval beyond acute pain and into chronic, though testing has thus far delivered mixed results. Vertex is working on a series of other, small molecule pain drugs, too, including a “next-generation” NaV1.8 inhibitor named VX-993.

The investment bank Stifel models Journavx sales reaching $1.1 billion in 2030 and $3.6 billion in 2038. The average analyst estimate on Wall Street, according to Stifel, is that sales of the drug will hit nearly $2 billion by the end of this decade.

What is the status of these companies’ research?

Vertex is now enrolling a Phase 3 study to evaluate Journavx as a treatment for the chronic nerve pain experienced by some patients with diabetes. Simultaneously, it’s running a smaller study of VX-993 in the same setting.

The assets from Latigo, Newron and Dogwood have either entered or gone through mid-stage trials. A roughly 250-participant study is exploring Latigo’s LTG001 for wisdom teeth removal pain, with results set to arrive sometime in the next couple months. The active ingredient in Dogwood’s Halneuron is actually the neurotoxin found in pufferfish. Investigators are now hoping to enroll about 200 patients in an experiment that will assess the drug as a treatment of chemotherapy-induced neuropathic pain.

Meanwhile, a federal database of clinical trials shows the most recent listings for Newron’s ralfinamide were last updated in 2009 and 2017. The Italy-based company didn’t respond to requests for more recent information about the program.

SiteOne hopes to “rapidly advance” into Phase 2 testing the medicine that caught Lilly’s eye and encouraged it to pursue an acquisition. Like Journavx, this “STC-004” therapy is designed to obstruct NaV1.8.

Mark Mintun, group vice president of Lilly’s neuroscience research and development, in May said that the company is “eager to continue” advancing STC-004. “Innovation in pain management is critical to address the unmet needs of millions of patients around the world.”

Editor's note: This story was first published in January 2020, before drug approvals in Alzheimer's disease, ALS and depression revived, to some degree, pharmaceutical company interest in neuroscience drug research. We included this story as a comparator to current industry sentiment about the field. We've updated tenses and references when needed for clarity.

One by one, they left. The world’s largest pharmaceutical companies, skilled at creating drugs for the heart, lungs and joints, couldn’t find the same success in the brain, leading them to either pull back or shutter development over the last decade.

A handful have kept brain drugs a focus, but that’s in stark contrast to 25 years ago, when almost every major developer was pouring money in. Sales of Eli Lilly’s Prozac enticed rivals to find their own blockbuster antidepressants. Pfizer then brought Zoloft to market, followed by GlaxoSmithKline with Paxil. By the early 2000s, a new wave of antipsychotics was helping build multibillion-dollar neurology businesses for AstraZeneca and Bristol-Myers Squibb.

But AstraZeneca, Bristol-Myers, GSK, Pfizer and Amgen no longer devote significant resources to neuroscience. Others, such as Lilly, Sanofi and Merck & Co., have narrowed their investments and number of drug programs. Often these retreats came after a series of clinical failures that called into question whether money would be better spent elsewhere.

Neuroscience still receives healthy levels of early investment, though. It attracted $1.5 billion from venture capitalists in 2018, putting it second only to cancer and suggesting these financiers expect payoffs in the not-too-distant future, perhaps through a big pharma buyout.

Their bet may be well placed too, as industry watchers foresee big pharma mounting a return to neuroscience in the next few years, lured by emerging treatments for epilepsy, mood disorders and genetic diseases of the CNS, or central nervous system.

Though cancer draws the lion’s share of venture capital dollars, brain drugs also attract significant funding.

Venture funding, in billions, by therapeutic area. Mouse-over a therapeutic area to highlight related venture funding.

Venture funding, in billions, by therapeutic area. Click on a therapeutic area to highlight related venture funding.

Therapeutic areas:

Select an area▼

“My prediction is that within the next five years, and certainly within the next 10 years, you’re going to see another golden era of these neuroscience products,” said Steven Paul, who was at Lilly when it developed the blockbuster antipsychotic Zyprexa and now serves as CEO of the neuroscience biotech Karuna Therapeutics.

Paul isn’t alone in that view. In January 2020, the then CEO of Roche Pharmaceuticals said the 2020s could see neuroscience make the same kind of enormous strides that oncology did during the 2010s. Jeremy Levin, head of neurology-focused Ovid Therapeutics and chair to biotech’s largest trade group, expects “radical” new therapies to emerge even quicker, likely in the next three years. Overall, nearly a dozen industry executives and analysts who spoke with BioPharma Dive envision brain drugs making a comeback soon, and with big pharma in tow.

“This is a repeated pattern that you see in the industry,” Levin said in an interview. “People leave things alone, they think it’s a waste of time, waste of money. Then they see some success. The smart big companies dive in, buy the companies out or board with them, and the result is a complete break-open of the field.”

‘Fraught with uncertainty’

Exits from the field at the end of the last decade, however, were hints that neuroscience isn’t always seen as a near-term opportunity.

Amgen terminated drug programs in schizophrenia and Alzheimer’s disease before leaving neuroscience almost entirely in late 2019. The biotech’s head of R&D, David Reese, told BioPharma Dive how the exit rested on several factors, including the industry’s “fairly rudimentary” understanding of neurological diseases, the long development programs some of these drugs require, as well as the clearer opportunities Amgen saw with oncology, inflammation and cardiovascular medicines.

Reese also said his company didn’t want to invest 10 years and billions of dollars in an area so “fraught with uncertainty,” and therefore concluded that standing up biotechs or establishing public-private partnerships would be more encouraging approaches.

Pfizer’s story was similar. It had drugs fail in Alzheimer’s and Huntington’s disease in the years leading up to 2018, when the company decided to take a handful of compounds and create a CNS-focused spin-out with Bain Capital. Pfizer said the move allowed it to redirect money to areas of greater expertise.

Across neuroscience, clinical failures have stacked up because drugmakers didn’t know enough about how the diseases work. These failures then made further investments a riskier proposition for big pharma.

At the same time, researchers were developing impressive new drugs in different diseases, most notably cancer, which spurred large companies to re-prioritize. Since most didn’t have an extensive list of promising brain drugs, neuroscience proved easier research to discontinue.

Now, a consequence of the reprioritization is a relative lack of big pharma resources invested in developing new, effective therapies for some of the world’s most common illnesses. While “me-too” cancer drugs proliferate, there are few, if any, novel treatments for diseases like Alzheimer’s, Parkinson’s and depression, each of which affect millions of patients.

A handful of large pharmas still consider neuroscience a focus area

Each square represents a large pharmaceutical company that focuses on the selected therapeutic area. Click on other therapeutic areas to highlight the companies at work in each field.

“It wasn’t about exiting neuroscience,” Levin said. “It was about not taking risks and, as a consequence, diverting cash into areas that they think are going to be incredibly productive in the near-term.“

Executives at small biotechs, though, say it’ll take just a few positive studies for the giants to come back. That’s been true with gene therapy as well as immuno-oncology, which produced some of the world’s best-selling drugs, including Merck’s Keytruda and Bristol-Myers’ Opdivo.

“This is a business of momentum, and you don’t want to be left out,” said Richard Peters, former head of rare diseases at Sanofi Genzyme and current CEO of Yumanity, a biotech making drugs for neurodegenerative illnesses. “So if you see a few successes, boards of directors at these companies are quickly going to ask management, ‘Why aren’t we doing that?’”

That pressure may explain why many big pharma companies continue to study Alzheimer’s drugs even if they’re not deeply involved in neuroscience. Analysts expect the first Alzheimer’s treatment on the market that shows an effect on the disease, rather than just its symptoms, would become an instant blockbuster.

Yet neurodegenerative disorders like Alzheimer’s and Parkinson’s have proven exceptionally challenging, due in part to their tangled biological roots.

AstraZeneca, Lilly, ​Merck, Novartis, Pfizer and Roche each saw experimental Alzheimer’s treatments fail in late-stage testing. Biogen, a top player in neuroscience, won approvals for Aduhelm and Leqembi, Alzheimer's approvals it developed with partner Eisai, but controversy over the data supporting Aduhelm led the companies to abandon marketing of the former medicine.

Going after genes

Though Alzheimer’s isn't solved by any means, drugmakers have notched victories in other neurological diseases like spinal muscular atrophy, in which a genetic defect causes patients’ muscles to waste away. Effective therapies from Biogen and Novartis have come to market since the end of 2016, and a third from Roche could be approved before June.

Drugmakers now have better tools to manipulate and correct genes than in the 1990s and early 2000s. As a result, diseases tied to single genetic defects, such as spinal muscular atrophy, seem easier to target and less risky — attributes that would appeal to large players looking for an entry point back into neuroscience. There are already a couple examples of this, with Pfizer getting into Duchenne muscular dystrophy through its acquisition of Bamboo Therapeutics and Roche showing interest in a Huntington’s program developed by Ionis Pharmaceuticals.

Besides Biogen and Roche, large drugmakers have advanced only a few neurology drugs into late-stage testing

Chart shows the number of neuroscience programs by study stage. Click on the buttons to see how many programs for each company are at each stage of clinical testing.

Chart shows the number of neuroscience programs by study stage. Use the dropdown to see how many programs for each company are at each stage of clinical testing.

Phase 1 Phase 2 Phase 3 Registration

Phase 1▼

• Phase 1
• Phase 2
• Phase 3
• Registration

That’s not to say these illnesses are easily treatable. The newfound excitement around Huntington’s, for example, belies the fact that no drug has yet been proven to change the course of the disease.

“My cautionary point on the whole hype-train surrounding monogenic CNS diseases is: the more we’ve dug into them, the more we’ve realized they’re not as simple as you might hope,” Stifel analyst Paul Matteis said.

Even so, Matteis said monogenic diseases would be a reasonable place for big pharma to invest as it rebuilds in neuroscience.​

But past that broad category, there’s not much consensus. Levin from Ovid sees epilepsy as a promising target, as do others, but believes psychiatric breakthroughs will be harder to find. Karuna’s Paul disagrees, and says the industry is “right on the verge of having very positive” late-stage data in depression and schizophrenia. Such forecasts are perhaps to be expected: Levin’s company is developing an epilepsy drug while Paul’s is working on a schizophrenia medication.

Drugmaking technologies may also be more valuable than the specific disease target. Ted Dawson, director of the Institute for Cell Engineering at Johns Hopkins Medicine, says he’s seen “an enormous amount of excitement” around antisense therapies that regulate gene expression. Ionis’ business revolves around the antisense platform responsible for developing Biogen’s muscular atrophy drug, while Alnylam Pharmaceuticals has a similar platform that’s at the center of a $1 billion CNS research pact with Regeneron.

Buying back in?

Analysts note that any reinvestment in neuroscience will depend on big pharma’s goals. If a company’s aim is to make brain drugs a core part of its business, then a single, small disease that has no relationship to anything else in its pipeline might be an unlikely target. If that’s not the plan, a company may be fine acquiring a niche, low-risk product, with the potential to tuck it into a broader platform later.

In any case, analysts say big pharma’s interest in neuroscience, if renewed, wouldn’t be focused on just large markets, but also extend to incredibly small, or orphan, diseases. Drugs for those conditions come with regulatory incentives and can be sold at high price tags, potentially making an investment more attractive.

“These days, it does seem like pharma is increasingly interested in the orphan business model,” Phil Nadeau of investment bank Cowen & Co said. “If there were products that seemed like they’d be very successful orphan therapies in neuroscience, I think pharma would probably be interested in acquiring those.”

Acquisitions, as Nadeau points out, would hallmark a big pharma return. Since many large developers don’t have deep research and commercialization teams in neuroscience, a buyout would likely be faster than building from the ground up.

“It certainly seems like a device that companies have used time and again to quickly get back into an area they’ve exited,” Nadeau said.

Deals, though, carry risk even when the science appears validated. Last spring, SVB Leerink analyzed transactions done by the 21 largest drug companies and found just one-third of deals valued at $1 billion or more were “unequivocally successful,” meaning they resulted in new products or better-than-expected revenue growth. On the other hand, one-fifth were failures.

“A skeptic would say the return on invested capital of acquisitions in the biopharma industry is relatively poor. So although it may be quicker, it may not be better,” Nadeau said.

Whether they’re good for the target companies is also up for debate. Many potential buyers wouldn’t have a neuroscience infrastructure for a newly acquired biotech to latch onto, which might make integration more complicated.

There are also concerns that, after the initial wave of excitement, big pharma might retreat again if positive data and drug approvals don’t come steadily.

“The risk is pharma swoops in and buys companies at lower valuations, extracts the value, and then you might be in the cycle,” Vlad Coric, CEO of Connecticut-based Biohaven Pharmaceutical, told BioPharma Dive. “They’ll keep you as long as neuroscience is important to them, and then they’ll be out of it again.”

These worries, combined with easy access to money from venture capital or public markets, may force big pharma to craft better sales pitches if they want to court neuroscience biotechs.

“Capital markets have opened up sufficiently, at least in the United States, to allow for companies to take action themselves,” Levin said.

“You don’t need big pharma’s confidence restored” in neuroscience, he added.