Top 5 stories from BioPharma Dive

Merck & Co.’s cancer immunotherapy Keytruda is one of the pharmaceutical industry’s biggest successes. The drug's arrival in 2014 introduced a new way of treating cancer and, over time, it became standard therapy for a panoply of different tumors. Clinical achievements brought about commercial performance, making Keytruda the world's best-selling medicine.

After the repeated failure of past attempts to improve on Keytruda, a new class of drugs might finally offer a better backbone for immunotherapy's next decade.

Last September, biotechnology companies Summit Therapeutics and Akeso revealed clinical trial results showing one of these drugs significantly outperformed Keytruda. Called ivonescimab, it cut the risk of lung cancer progression in half compared to Keytruda in a Phase 3 study — a result so striking it sparked a wave of investment in oncology research practically overnight.

“This really was a ‘black swan’ event,” said Allen Yang, Summit’s chief medical officer. “It’s clearly what everybody’s been looking for.”

In the wake of Summit’s results, drugs like ivonescimab, which block cell signaling via proteins called PD-1 and VEGF, have become the “new shiny object” in cancer research, according to analysts with the investment bank William Blair. More than a dozen companies, from pharmaceutical giants to newly formed biotech startups, are now developing them.

Proponents see these “PD-1/VEGF inhibitors” as building upon Keytruda and drugs like it, such as Bristol Myers Squibb’s Opdivo. The hope, some say, is they’ll improve response rates, shrink tumors their predecessors can’t and become cornerstone cancer treatments of the future.

“These drugs are going to work,” said David Epstein, the former CEO of Seagen and head of Ottimo Pharma, a startup developing a PD-1/VEGF inhibitor. “The question is, how big is the order of magnitude going to be, and across how many different tumor types?”

Many aren’t as convinced as Epstein. Ivonescimab hasn’t shown it can extend overall survival by more than Keytruda. It wasn’t tested against the Keytruda-chemotherapy combination that’s standard of care in most lung cancers. And the trial demonstrating ivonescimab’s superiority to Keytruda took place only in China, leaving it unclear whether a similar benefit will be observed in broader testing. Those questions hang over not only Summit, but others working on PD-1/VEGF inhibitors, too.

“The jury is out,” said Samit Hirawat, the chief medical officer of Bristol Myers Squibb.

What are PD-1/VEGF inhibitors and how do they work?

Cancer cells are survivalists. They’re adept at siphoning the body’s resources to fuel their rampant growth, and skilled at slipping past immune defenses evolved to stop them. Even when beat back by drug therapies, malignant cells can acquire new abilities to thwart treatment.

Drugmakers and researchers have spent enormous effort studying cancer’s weaponry, uncovering along the way many tools that have improved care. Two breakthroughs from the 1990s helped researchers design protein drugs that can pinch off a tumor’s supply chains and, years later, unleash the immune system against cancerous growth.

In the former case, antibodies that block VEGF, such as Avastin, can stop tumors from forming new blood vessels. The latter kind of antibodies, which are called PD-1 or PD-L1 inhibitors for the proteins that they block, prevent cancer cells from shutting down powerful defenders known as T cells. Keytruda is the most famous example.

Both classes of medicines are now used to treat dozens of tumor types. PD-1 and PD-L1 immunotherapies, also called “checkpoint” inhibitors, are sometimes a patient’s first line of defense after a tumor is surgically removed — or even before.

Developers like Akeso and Summit aim to combine the power of both types of drugs into a single, multi-pronged antibody, typically termed “bispecific” or “bifunctional.” These medicines can interfere with PD-1 and VEGF signaling in ways their makers contend will maximize the benefits and minimize the flaws of their predecessors.

Akeso designed ivonescimab to have a “tetravalent” structure, in theory giving it better binding to PD-1 and to VEGF. Yang, Summit’s CMO, says the simultaneous targeting of both proteins helps increase the affinity the drug has for each.

“We believe that those two features make ivonescimab, and the whole class of PD-1/VEGFs, unique,” he added. “Now people seem to believe us.”

Others have different twists on the concept. BNT327, a drug acquired by German biotech BioNTech, binds to the ligand PD-L1 instead of the PD-1 receptor. A drug licensed by Merck consists of an anti-VEGF antibody fused to two PD-1-targeting antibodies, while Ottimo’s lead program, jankistomig, specifically targets a related protein called VEGF receptor 2.

Crescent Biopharma has a drug its CEO, Jonathan Violin, said on a conference call October was “purpose-built” to mimic the pharmacology of ivonescimab while enhancing its “stability and manufacturability.”

They’re joined by other companies pursuing more variations, such as drugs that block three proteins or use different strategies to block VEGF.

The glut of similar drugs means “many or most of the resulting companies seem unlikely to succeed,” wrote Paul Rennert, the head of consulting firm Sugarcone Biotech, in a February report. Still, Epstein, Ottimo’s CEO, said the sheer size of the commercial opportunity leaves ample room for many to prosper.

“How many PD-1s and PD-L1s are there? How big is the market currently? And how big is it going to be if people live twice as long, or at least twice as long before their cancer progresses?” Epstein said.

What are the advantages over drugs like Keytruda?

Keytruda and other checkpoint inhibitors like it are the standard choice for many tumor types because trial data has shown they can extend lives to degrees that weren’t possible with other cancer medicines.

There’s no better example than in lung cancer. Some studies have shown that, in the years before cancer immunotherapy, the average five-year survival rate for people with metastatic non-small cell lung cancer was around 5%. That rate has climbed since the arrival of Keytruda and its cousins. In Phase 3 testing, around 20% of people given a Keytruda-chemotherapy combination survived at least five years.

Yet that statistic also shows checkpoint inhibitors aren’t panaceas. In lung cancer and other malignancies, they still don’t work well for a good portion of people — particularly those whose tumors express little of the PD-L1 protein that’s linked to an immunotherapy response. They also struggle against so-called cold tumors that don’t tend to provoke as strong immune reactions.

In response, drugmakers have searched for more than a decade to find new immunotherapies that work better, but the hunt has yielded far more failures than successes.

“It’s been one disappointment, honestly, after another,” said Srini Akkaraju, a founder and managing general partner of Samsara BioCapital, and an investor in Ottimo.

Among the approaches tested, with mixed results, were combinations of PD-1 inhibitors together with anti-VEGF drugs. Roche found that pairing Avastin with its immunotherapy Tecentriq improved survival in liver cancer and won an approval in that tumor type as well as lung cancer. Further testing showed a limited survival benefit as well as significant side effects, however. And the combination hasn’t been as broadly successful as hoped.

Merck has had a similarly uneven experience. It has gained clearances of regimens involving Keytruda and the VEGF-inhibiting drugs Lenvima and Inlyta in a few tumors, but these combinations have fallen short in others.

“You see, in many cases, clear evidence of [delaying tumor progression]. But then as we go longer out, we're not able to hit [on survival] as often as we wish to,” said Merck research chief Dean Li, during a conference presentation in January.

At least so far, ivonescimab seems to work more effectively than delivering two separate drugs together. The initial evidence “raises the possibility that there may be some true synergy when the two are combined with a single molecule,” John Heymach, chair of thoracic, head and neck oncology at the MD Anderson Cancer Center, said in a September interview.

Supporters say that will play out with further testing. If they’re right, the “emerging blue sky story” is that these drugs might make immunotherapy useful to more people and against more tumors, wrote Stifel analyst Bradley Canino in a note last year.

More data could burst those expectations, too, though. Bristol Myers’ CMO Hirawat noted how ivonescimab hasn’t yet been proven to extend survival. Moreover, its advantage over Keytruda on tumor progression appeared to shrink after six months. And for earlier-stage drugs also targeting the PD-1 and VEGF pathways, promise in single-arm studies will need to be replicated in more rigorous tests.

“There is some level of additional data that is required,” Hirawat said. “We'll keep an eye on it and continue to look for what the right opportunities are from a scientific perspective, and what we need to continue to learn.”

In their December report, William Blair analysts had a similarly skeptical take. Citing the multiple “disappointing datasets” with checkpoint inhibitor and Avastin combinations, they wrote that developers need more results from global studies and a clear survival advantage to prove these drugs can become “a new standard of care.”

Safety is also a concern. VEGF-blocking drugs are associated with sometimes severe side effects like high blood pressure, bleeding or protein in the urine. In clinical practice, doctors can stop treatment when these instances occur. With a combined therapy, though, “if we see [concerning] proteinuria, then we have to hold the whole drug,” Jyoti Malhotra, director of thoracic medical oncology at City of Hope Orange County, said in a September interview.

Which companies are developing PD-1/VEGF inhibitors?

More than a dozen companies are developing dual-targeting antibodies that block PD-1 or PD-L1 and VEGF in one way or another.

Akeso, a Guangdong, China-based cancer drug developer, originally discovered ivonescimab. Summit got involved in 2022 when it paid Akeso $500 million upfront. And earlier this year, Pfizer and Summit agreed to test ivonescimab alongside some of Pfizer’s targeted cancer medicines in the hopes of finding yet more powerful drug combinations.

BioNTech is best known for successfully developing a COVID vaccine with Pfizer. But the company’s initial focus was in cancer. It bought into PD-L1/VEGF drug development first by partnering with and then last year acquiring Biotheus, a cancer biotech based in Zhuhai, China.

Instil Bio went public in 2021 to fund work on cancer cell therapy. But manufacturing issues led the company to restructure and, last August, it licensed partial rights to a PD-L1/VEGF drug from Shanghai’s ImmuneOnco Biopharmaceuticals.

Ottimo Pharma was formed in 2020 by U.K. venture firm Medicxi and prolific biotech founder and former Pfizer researcher Jonny Finlay. The company emerged from stealth in October with Epstein, a former Seagen and Novartis executive, as its CEO and raised $140 million in Series A funding two months later. Ottimo’s lead prospect is a bifunctional antibody, meaning its “arms” can interact with both of its targets.

Crescent Biopharma spun out of Paragon Therapeutics last year armed with a PD-1/VEGF prospect and two other medicines. In October, it merged with struggling drug developer GlycoMimetics, giving the company enough cash to fund operations into 2027.

Merck in November paid $588 million for worldwide rights to a PD-1/VEGF drug discovered by Shanghai-based LaNova Medicines.

Joining them are at least 12 more companies, many of which of are based in China, reflecting a fast-advancing biotech sector there that’s created a broad pipeline of drug candidates in competitive areas of pharmaceutical research.

“They all have little variations. They all have a reason to be best in class,” said Yang, Summit’s CMO, of the medicines following ivonescimab. “But we think ours has all the features that are important, and that have been proven to be important.”

What is the status of their research?

The study result that set many of these investments in motion was signaled last May, when Summit trumpeted that ivonescimab had “decisively” beaten Keytruda in a Phase 3 trial. Details revealed at a medical meeting six months later backed up that claim, as ivonescimab kept tumors from progressing for a median of almost half a year longer than Merck’s medicine without an accompanying uptick in side effects.

The data “are really quite striking,” said Heymach, of MD Anderson, at the time.

Overall survival results from that study could be revealed later this year. Also coming in 2025 are data from a global, Phase 3 study in a subset of non-small cell lung cancer patients with so-called EGFR mutations that could prove ivonescimab is “equally safe/effective” in people outside of China, Stifel’s Canino wrote in February. An additional Phase 3 trial this year headed by Akeso could point to the type of benefit treatment offers on top of chemotherapy.

“We are watching carefully,” Merck’s Li told analysts in November.

BioNTech has reported promising early results for BNT327 in several tumor types, among them an aggressive and tough-to-treat form of breast cancer. Going forward, it intends to combine BNT327 with a variety of different medicines and has registrational trials either ongoing or planned in lung and breast cancer. Several Phase 2 readouts are expected in 2025.

The drug could be a “foundational component in the treatment regiment for multiple cancer types,” CEO Ugur Sahin told analysts last year.

Several others chasing Summit and BioNTech are either just starting human testing or soon will be.

Instil Bio should report results from an early-stage trial in lung cancer in China, and start a similar type of trial in the U.S., later this year. Merck’s prospect was in a Phase 1 trial in China when licensed from LaNova. Merck aims to explore its use in multiple tumor types, but hasn’t been specific.

Crescent could start testing in the fourth quarter and report early data in 2026. Ottimo, too, has said it should begin a trial in late 2025 or early 2026.

By then, the study that could establish how much of an advance PD-1/VEGF inhibitors really are will be well underway. Dubbed Harmoni-3, that trial has already begun enrolling what’s expected to be more than 1,000 lung cancer patients, who will receive chemotherapy and either ivonescimab or Keytruda. Initial results are due in 2027, according to a federal database. If positive, they could unlock a market opportunity Stifel’s Canino in March estimated to be worth around $20 billion.

“Keytruda is the biggest oncology drug in the world,” said Akkaraju, of Samsara. “Is this finally the thing that unseats it? It’s quite possible.”

Gwendolyn Wu, Jonathan Gardner and Ned Pagliarulo contributed reporting.

Soon after starting a new biotechnology company, David Li realized he needed to rethink his strategy. 

Li had been conducting the competitive research biotech entrepreneurs typically undertake before soliciting investment. He drew up a list of drug targets that his startup, Meliora Therapeutics, could pursue and checked them against the potential competition. 

Li quickly found that biotechs in China were already working on many of the targets he had on his list. Curious, he visited Shanghai and Suzhou and witnessed a buzzing scene of startups set frenetically to task. 

“They're not really thinking about the U.S. at all. They're just trying to create more value and stay alive to differentiate themselves from the next guy in China,” he said. “They're moving quick. There are a lot of them and they're just quite competitive.”

Li’s experience is illustrative of a trend that could pressure biotech companies in the U.S. and alter their drug development strategies. More and more, large pharmaceutical companies are licensing experimental drugs from China. Venture companies are testing similar tactics by launching new U.S. startups around compounds sourced from China’s laboratories. This shift has been sudden, with licensing deals ramping rapidly over the past two years. And it is occurring even as the shadow of U.S.-China competition within biotech grows longer. 

Executives and investors interviewed by BioPharma Dive at the J.P. Morgan Healthcare Conference in January share Li’s outlook. They expect such deals will accelerate and, in the process, force U.S. biotechs to work harder to stand out. 

“We’ve been warning people for a while, we're losing our edge,” said Paul Hastings, CEO of cell therapy maker Nkarta and former chair of the U.S. lobbying group the Biotechnology Innovation Organization. “Innovation is now showing up on our doorstep.”

There’s perhaps no clearer example of this than ivonescimab, a drug developed by China-based Akeso Therapeutics and licensed by U.S.-based Summit Therapeutics. Recent results from a lung cancer study run in China showed ivonescimab outperformed Keytruda, Merck’s dominant immunotherapy and currently the pharmaceutical industry’s most lucrative single product. 

The finding “put a huge focus on what’s happening in China,” said Boris Zaïtra, head of business development at Roche, which sells a rival to Keytruda. 

Fast-moving research

Today’s deal boom has roots in efforts by the Chinese government to upgrade the country’s biotech capabilities by upping investment in technological innovation. In the life sciences, the initiative provided funding, discounted or even free laboratory space and grants to support what Li described as a “robust ecosystem” of biotechs. 

The results are clear. Places like Shanghai and Suzhou are home to a skilled workforce of scientists and hundreds of homegrown companies that employ them. Science parks akin to the U.S. biotech hubs of Cambridge, Massachusetts and San Francisco have sprouted up. 

Chinese companies generally can move faster, and at a lower cost, than their U.S. counterparts. Startups can go from launch to clinical trials in 18 months or less, compared to a few years in the U.S., Li estimated. Clinical trial enrollment is speedy, while staffing and supply chain costs are lower, helping companies move drugs along more cost effectively. 

“If you're a national company within China running a trial, just by virtue of the networks that you work within, you pay a fraction of what we pay, and the access to patients is enough that you can go really fast,” said Andy Plump, head of research at Takeda Pharmaceutical. “All of those are enablers.” 

And what they’ve enabled is a large and growing stockpile of drug prospects, many of which are designed as “me too better” versions of existing medicines, analysts at the investment bank Jefferies wrote in a December report. Initially focused in oncology, China-based companies are now churning out high-quality compounds across multiple therapeutic areas, including autoimmune conditions and obesity. 

“There was a huge boom of investment in China, cost of capital was very low, and all these companies blew out huge pipelines,” said Alexis Borisy, a biotech investor and founder of venture capital firm Curie.Bio. ”Anything that anybody was doing in the biotech and pharmaceutical industry, you could probably find 10 to 50 versions of it across the China ecosystem.”

Me-toos become me-betters

For years now, Western biopharma executives have scouted the pipelines of China’s biotech laboratories — exploration that yielded a smattering of licensing deals and research collaborations. Borisy was among them, starting in 2020 a company called EQRx that sought to bring Chinese versions of already-approved drugs to the U.S. and sell them for less. EQRx’s plan backfired amid scrutiny by the U.S. Food and Drug Administration of medicines tested only in people from a single country.

Now, however, the pace of deals has accelerated rapidly. There are a few reasons for this. According to Plump, one is the improving quality of the drug compounds being developed. The “me toos” are becoming “me betters” that could surpass available therapies and earn significant revenue for companies — like BeiGene’s blood cancer drug Brukinsa, which, in new prescriptions for the treatment of leukemia, overtook two established medicines of the same type last year. 

Another reason, Plump said, is that China-based companies are becoming more innovative, studying drug targets that might not have yet yielded marketed medicines, or for which the most advanced competition is in early testing. Li notes how Chinese companies are going after harder “engineering problems,” like making complex, multifunctional antibody drugs, or antibody-drug conjugates. 

“There are so many [companies] that the new assets are going to keep coming,” Li said. 

Much as in the U.S., China-based biotechs are also fighting for funding, pushing them to consider licensing deals with multinational pharma companies. At the same time, these pharmas are hunting for cheap medicines they can plug into their pipelines ahead of looming patent cliffs. The two trends are “colliding,” said Kristina Burow, a managing director with Arch Venture Partners. “I don’t see an end to that.”

The statistics bear Burow’s view out. According to Jefferies, the number and average value of deals for China-developed drugs reached record levels last year. Another report, from Stifel’s Tim Opler, showed that pharma companies now source about one-third of their in-licensed molecules from China, up from around 10% to 12% between 2020 and 2022. 

“I see huge opportunities for us to partner and work together with Chinese companies,” said Plump, of Takeda. 

Several venture-backed startups have been built around China-originated drugs, too, among them Kailera Therapeutics, Verdiva Bio, Candid Therapeutics and Ouro Medicines, all of which launched with nine-figure funding rounds. 

“There's been a lot of really good, high quality molecules and data that have emerged from China over the last couple of years,” said Robert Plenge, the head of research at Bristol Myers Squibb. “It's also no longer just simply repeating what's been done with the exact same type of molecule.”

Geopolitical risks

These deals are happening against an uncertain backdrop. The U.S. Congress has spent the last year or so kicking around iterations of the Biosecure Act, a bill that would restrict U.S. biotechs from working with certain China-based drug contractors. A committee in the House of Representatives is calling for new limits on clinical trials that involve Chinese military hospitals. And the incoming Trump administration has threatened tariffs that could ripple across industrial sectors. 

“We don’t know what this new administration is going to do,” said Jon Norris, a managing director at HSBC Innovation Banking.

The Biosecure Act “keeps going sideways,” added Hastings, who believes that any impact from the legislation, if passed, would be minimal. Instead, Hastings wonders if future tariffs may be more problematic. “There will be tariffs on other goods coming from China. Does that include raw materials and innovation? It’s hard to imagine that it won’t,” he said. 

But executives and investors expect deals to continue, meaning U.S. biotechs will have to do more to compete. 

“U.S. companies will need to figure out what it is they’re able to bring to the table that others can’t,” said Burow, of Arch. 

Borisy said startups working on first-of-their-kind drugs need to be more secretive than ever. “Do not publish. Do not present at a scientific meeting. Do not put out a poster. Try to make your initial patent filing as obtuse as possible,” he cautioned. 

“The second that paper comes out, or poster at any scientific meeting, or talk or patent, assume it has launched a thousand ships.”

Those that are further along should assume companies in China will be quick on their heels with potentially superior drugs. “The day when you could come out with a bad molecule and open up a field is over,” he said. 

Greater competition isn’t necessarily a bad thing, according to Neil Kumar, CEO of BridgeBio Pharma. Drug development could become more efficient as pharmas acquire medicines from a “cheaper” starting point and advance them more quickly. 

Venture dollars could be directed towards newer ideas, rather than standing up a host of similar companies.“If all of a sudden this makes us less ‘lemming-like,’” Kumar said, “I have no problem with that.”

Li similarly argues that, going forward, U.S. companies need to focus on “novelty and innovation.” At his own company, Li is now working on things “we felt others were not able to access.”

“The game has always been the same. Bring something super differentiated to market,” he said. But “the bar has risen.” 

Gwendolyn Wu and Jacob Bell contributed reporting. 

Patents reward drugmakers for their inventions and, effectively, the large sums of money they invest in research and development. The legal monopoly that patents provide keeps generic copies at bay for many years, even decades, and allows pharmaceutical companies to set higher prices than they otherwise could.

Executive decisions are often closely linked to the patent life of blockbuster medicines. Ahead of so-called patent cliffs, when patent expirations permit waves of lookalike competitors to enter the market, companies typically seek to restock their pipelines by investing in R&D, licensing experimental therapies or acquiring other drugmakers.

A major patent cliff faces the pharma industry later this decade, putting more than $200 billion in annual revenue at risk through 2030. This will force companies into major decisions: Will they pour more money into research? Or will they buy their way out of trouble? 

Below, BioPharma Dive has compiled upcoming expiration dates for the key patents protecting the 30 top-selling drugs, by 2023 sales. We’ll be updating this database as the relevant dates and products change. If we’ve missed anything, or there’s any additional information you’d like to see, please reach out and let us know.

The standard term for patents granted in the U.S. is 20 years. Drugmakers usually will have already secured patents on a new drug ahead of any regulatory approval, meaning the protected time on market can be less.

There are strategies to offset this, however, as companies can piece together different forms of regulatory exclusivity, seek what’s known as patent term restoration or create “thickets” of various patents on everything from a dosing schedule to an injection device. 

These thickets — now the target of government scrutiny in the U.S. — can sometimes stave off generic competition for two decades or more. Enbrel, an inflammatory disease drug sold by Amgen, will have enjoyed more than 30 years of protected time on market when a key patent expires in 2029, for example. 

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 late summer or early fall. 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.”

Ally Schott felt lonely when she was diagnosed with endometriosis at the age of 12. With few treatment options and limited information to go on, she and her family had to become self-taught medical researchers.

Even the diagnosis was the result of Schott’s mother connecting the dots between the pain her daughter was experiencing and the symptoms described by women in a patient organization she had found.

“That's ultimately what convinced my parents that this is what I was dealing with — seeing and reading about the experience of others, and recognizing that I was going through something similar,” Schott said.

In some ways, Schott’s case is rare. Her diagnosis came early, unlike some women who don’t learn they have endometriosis for a decade or more due to lack of disease awareness, misdiagnosis or even bias that assumes severe menstrual pain is normal.

“It's very, very easy to dismiss someone's discomfort if you believe something is meant to be uncomfortable,” said Somer Baburek, CEO and co-founder of Hera Biotech, a biotechnology company developing a nonsurgical tool to diagnose endometriosis.

Caused by the growth of uterine tissue outside of the uterus, endometriosis typically affects people who menstruate, but it can occur in post-menopausal women, too. The disease is characterized by chronic pelvic pain, especially during menstruation, but can also cause problems across other parts of the body. It is usually identified through a surgical procedure called a laparoscopy, as ultrasounds can’t always image the abnormal tissue growth.

Although physicians’ understanding of the disease has improved, endometriosis’ root causes remain debated even as it affects some 10% of women and girls globally.

“[Endometriosis research] has been very underfunded and so, despite the prevalence of this disease, it's not very well understood at all,” said Marina R. Walther-Antonio, an assistant professor of surgery at the Mayo Clinic in Minnesota and a microbiome researcher.

When Schott received her diagnosis, there was little she could do about it — a reality that frustrated her and her family. “I just felt like I finally had the answer, and that if we had the answer to what was wrong, there would be a solution,” she said. Even since, only two new drugs for endometriosis-related pain have been approved in the U.S.

That pattern is typical of diseases, like endometriosis, that primarily or only affect women. Insufficient funding of women’s health research has stifled development of new products, resulting in prevalent conditions with hardly any available treatments. And while clinical trials are more inclusive than they were in the 1990s and earlier, studies are not always set up to tease out why or how disease symptoms may differ on the basis of biological sex.

Information deficits

Development of a drug is no easy feat for any condition. But the process is more difficult when the disorder isn’t well understood, as with endometriosis.

“We're starting from multiple deficits, and one of them is an information deficit,” said Hera’s Baburek. “And I think that's something that all founders in women's health struggle from.”

For instance, researchers sometimes use biobanks — collections of medical and biological data from tissue, blood and DNA samples — to identify molecular markers of a disease, or develop effective diagnostics. If collected by a government-funded program, the data is often published or made available to scientists, providing a starting point for drug research.

But such resources are more limited in endometriosis, according to Baburek and Joseph Nassif, an associate professor of obstetrics and gynecology at Baylor College of Medicine and a clinician. While such work has advanced further in other countries, the U.S. is just getting started.

“So now in the states, we're trying to do a database about all patients who have [endometriosis],” Nassif said. “We have banks for cancer and banks for other diseases. Once you have a lot of patients, we can study it better.”

With less of a foundation, drug developers taking aim at endometriosis, or other women’s health conditions like polycystic ovary syndrome or premenstrual dysphoric disorder, can have a harder time starting out.

“When you're building the ‘data story’ of your company, yours looks weaker than companies who are focused on indications outside of women's health, because they have access to all of those resources,” Baburek said.

Such information deficits have deep roots. Up until 30 years ago, the Food and Drug Administration recommended excluding women of childbearing age from participating in Phase 1 and 2 clinical trials, even if they were using contraception. The policies were made in response to birth defects caused by the drug thalidomide, which was prescribed to women to treat nausea in the 1950s and 1960s.

A 1993 law mandated the inclusion of women and minorities in clinical research funded by the National Institutes of Health, but the effects of discouraging women from participating in trials have carried through to today.

For example, a 2022 study found women made up 41% of participants in Phase 1 through Phase 3 trials for drugs and medical devices run between 2016 and 2019 in the U.S. Women were underrepresented compared to their estimated proportion of the overall patient population for a number of conditions, such as heart disease and psychiatric disorders.

Those research gaps, and the knowledge deficits they can cause, ultimately put the “lives of girls, women and their families” at a “huge disadvantage,” Schott said.

Federal efforts have tried to compensate. Most recently in February, the Biden administration committed to investing $100 million into women’s health research. The FDA also recently updated draft guidance to ensure sponsors run more diverse clinical trials, supporting the Food and Drug Omnibus Reform Act of 2022, which requires specific documents and strategic plans.

“It's really important when you're going to try to understand the efficacy, tolerability and safety of a drug that you're testing it in the representative population of people who you anticipate actually using the product,” said Katherine Seay, head of sales and operations at Clinical Trial Media, a patient recruitment and retention company.

Limited options

Compared to other areas of drug R&D, women’s health remains underfunded. An analysis of NIH-backed research found that diseases largely affecting men received more funding. The conditions primarily affecting women that do get investment are typically within oncology, such as breast and ovarian cancer, and reproductive medicine.

Baburek didn’t intend to make reproduction Hera’s focus, for instance. But the company only gained interest from investors when she mentioned the negative impact endometriosis can have on fertility. “While our reproductive organs may be involved in some of these chronic conditions, our ability to reproduce shouldn't be the focus,” Baburek said.

Hera's struggle for attention isn't an anomaly. Despite its prevalence, endometriosis remains low on drugmaker radar screens.

Women with the disease typically take birth control, other hormonal therapies and pain medication to manage symptoms and their menstrual cycles. They may also turn to surgery to either remove the lesions endometriosis causes or, in severe cases, remove their uterus entirely.

When Schott was young, the drug Lupron Depot, a hormonal therapy initially approved for the treatment of prostate cancer, was cleared in the U.S. to manage pain associated with endometriosis. The drug can cause side effects similar to that of menopause and was a “horrific” experience for Schott, who was about 13 years old when it was prescribed to her.

Within the past decade, two other products have been approved by the FDA for pain management with endometriosis: AbbVie’s Orilissa in 2018, and Pfizer and partner Myovant Sciences’ Myfembree in 2022.

The drugs come with hefty price tags: Orilissa and Myfembree each cost over $1,000 per month at their respective list prices. They also don’t address the disease’s roots, and use is limited to a maximum of two years due to their potential to decrease bone density.

“Those options are not widely discussed or celebrated because they're not actually treating the disease,” Baburek said. “[They are] just quieting some of the symptoms that make your life unbearable, but then you get a whole host of other symptoms that also might make your life unbearable.”

Schott was prescribed Myfembree as an adult, but never took it because of its limitations and potential effects on bone density. She says she likely wouldn't take Orilissa for the same reasons.

“For the moment being, we have some ways to manage [endometriosis], whether medical or surgical, definitely with some percentage of success and failure either way,” said Nassif. “But definitely, we need a lot of research for the future.”

A bare pipeline

Neither Orilissa nor Myfembree are big sellers and don’t seem to rate high on their makers’ priority lists.

Three years after Orilissa’s approval, AbbVie tried to sell the women’s health unit the drug was housed in, but the deal never materialized. Sales of the drug are no longer reported individually and are instead lumped in with “other key products” in AbbVie’s earnings report. The last time AbbVie reported Orilissa’s net revenue was for its 2021 fiscal year, when it recorded $139 million in U.S.sales.

AbbVie did not provide additional details about the drug’s development or sales when contacted by BioPharma Dive.

In 2022, Japan-based Sumitomo Pharma agreed to acquire Myfembree developer Myovant Sciences for $2.9 billion. The drug is now sold by Sumitomo in Europe, while Pfizer jointly markets it in the U.S. and Canada.

Pfizer doesn’t report net sales, but lists Myfembree revenue as contributing to “alliance revenue” in financial filings.

The two drugs don’t face much competition. Women’s health company ObsEva had licensed a compound known as linzagolix from the Japan-based biotechnology company Kissei Pharmaceutical. However, the company terminated the deal and withdrew an approval application after the FDA informed it of deficiencies in its submission.

ObsEva shut down operations earlier this year, one of several companies in women’s health that had to refocus its research efforts recently.

Pharma company Bayer has long sold a hormonal drug called Visanne for endometriosis-related pain, but the company has not submitted it for U.S. approval in that indication.

“We focus our research efforts on innovative options in areas of high unmet medical need,” a Bayer spokesperson said in comments to BioPharma Dive. “We regularly review our research and development portfolio to prioritize the advancement of the most promising projects.”

Working with researchers in the U.S. and U.K., Bayer also helped identify an inflammation gene that may be linked to endometriosis. While the discovery seemed to point to a possible non-hormonal drug target, further research “did not end up moving forward into development,” according to a Bayer spokesperson.

In 2023, Bayer shifted its focus away from women’s health altogether. While new R&D could still yield women’s health products, a Bayer executive told Reuters that the company’s work in the field overall had “fallen short of expectations.”

Elsewhere, Organon agreed in 2021 to acquire Forendo Pharma in a deal worth $75 million upfront, handing it a drug candidate targeting endometriotic lesions without affecting hormones. Other startups have emerged, including Gynica, FimmCyte and SLBST Pharma.

Looking forward

While endometriosis research continues, Barburek argues that finding a non-hormonal target for treating the condition has to be a priority.

“We've got to mechanistically understand [endometriosis] so we know which levers to pull and which knobs to push,” she said. “So more research needs to go into the mechanistic side of it.”

There is some momentum. Alongside the $100 million the Biden administration pledged to women’s health research, the Advanced Research Projects Agency for Health, or ARPA-H, also launched a “sprint for women’s health” to fund health solutions for conditions that primarily or disproportionately affect women.

It’s not clear whether such efforts will remain a priority under President-elect Donald Trump’s administration, however. Trump nominated Robert F. Kennedy Jr. to helm the Department of Health and Human Services, which oversees health agencies including the FDA. While Kennedy has made clear his views on vaccines and the pharmaceutical industry, his views on women’s health research are less clear and his stance on abortion has been inconsistent.

In a rally prior to the election, Trump said Kennedy is “so into women’s health,” and would let him “go wild” on healthcare.

Some experts worry state abortion bans might hinder recruitment into trials involving in vitro fertilization, or other conditions that might require documenting a woman’s medical history.

“I think, once you take that freedom of choice away from women and leave it in the hands of politicians, state or federal, it's not a great thing,” Schott said. “It's a devastating impact that's going to be further reaching than I think we even have the context to understand right now, and I do think that involves endometriosis.”

Amid such concerns, there is hope of progress in treating endometriosis. Yet, Baburek said, sustained interest and investment will require a “concentrated effort to highlight, educate and draw attention to the issues or consequences of being a woman.”