C&EN’s Year in Pharma 2023

If 2022 was a sparse year for US Food and Drug Administration approvals of new molecular entities, 2023 was a return to the pace the agency had achieved from 2017 through 2021. By mid-September, the FDA had already surpassed the 37 approvals it had made in all of 2022 and by mid-November reached 50 approvals.

In addition to approving firsts in prescription drugs and vaccines, the agency approved over-the-counter versions of a birth control pill and naloxone, used for reversing opioid overdoses, for the first time. Also making headlines this year, FDA advisory panels scrutinized an ingredient in popular over-the-counter cold medicines and a trial of a first-in-class cancer drug.

Leqembi was approved to treat Alzheimer’s disease

Credit: Eisai

Eisai and Biogen’s Leqembi (lecanemab) became the second monoclonal antibody drug to receive accelerated FDA approval to treat Alzheimer’s disease on Jan. 6. It then received full approval from the agency—a first for this class of Alzheimer’s treatment—on July 6. In 2021, the FDA granted accelerated approval to Biogen and Eisai’s monoclonal antibody Aduhelm (aducanumab), but the decision was controversial; many doctors and scientists argued that clinical trials of Aduhelm showed no benefit to patients. Both drugs clear amyloid-β deposits in the brains of people with Alzheimer’s disease. But unlike Aduhelm, Leqembi slowed cognitive decline, albeit modestly, in clinical trials of people with early-stage Alzheimer’s. The FDA is expected to decide on approval for another monoclonal antibody treatment for Alzheimer’s, Eli Lilly and Company’s donanemab, by the end of the year.

Zurzuvae got the nod for the treatment of postpartum depression but not major depressive disorder

The FDA granted approval to Sage Therapeutics and Biogen’s Zurzuvae (zuranolone) as the first oral treatment for postpartum depression on Aug. 4. Previously approved treatments for postpartum depression have to be injected. Zurzuvae is a neuroactive steroid that modulates γ-aminobutyric acid (GABA) receptors in the central nervous system, thereby calming nerve activity. But the FDA rejected the drug as a treatment for major depressive disorder. That split decision was bad news for both firms, which saw their share prices take a knock. Sage subsequently announced a reorganization that included axing 40% of its workforce.

RSV immunizations became available

Credit: National Institute of Allergy and Infectious Diseases/Science Source

An artist’s depiction of respiratory syncytial virus

On May 3, the FDA approved GSK’s Arexvy, the first vaccine for respiratory syncytial virus (RSV) for use in people aged 60 and older. Before May was over, the agency also approved Pfizer’s Abrysvo, a second RSV vaccine for the same age group. On Aug. 21, Abrysvo also received the FDA’s approval for use in pregnant individuals between 32 and 36 weeks’ gestation to prevent RSV in babies from birth to 6 months of age. Both vaccines use an RSV surface protein called the fusion glycoprotein to initiate an immune response from the body. The agency green-lit a different type of RSV immunization on July 17 when it approved AstraZeneca and Sanofi’s Beyfortus (nirsevimab), a monoclonal antibody that can be given to babies and children up to 24 months in age. Moderna submitted an application to the FDA for its messenger RNA–based RSV vaccine in July. Bavarian Nordic’s vaccine, which featured a live virus decorated with RSV proteins, failed to meet all its primary end points, prompting the company to discontinue its RSV program.

A birth control pill and Narcan became available over the counter

Credit: Emergent BioSolutions/Perrigo

The FDA first approved norgestrel as a prescription oral contraceptive in 1973. Fifty years later, on July 13, the agency approved Perrigo’s Opill as a version of this birth control pill that doesn’t require a prescription.

In another notable over-the-counter approval, the FDA made Narcan (naloxone), Emergent BioSolutions’ nasal spray for reversing opioid overdoses, available to consumers without a prescription on March 29. Previously, advocates had managed to work around the drug’s prescription-only status via a patchwork of state laws, standing orders, and collaborative practice agreements among pharmacists.

Lumakras study was called into question

A Phase 3 trial that was meant to confirm the data that won Amgen’s Lumakras (sotorasib) expedited approval didn’t pass muster with a panel of FDA advisers. In October, the panel voted 10–2 that the CodeBreaK 200 trial results could not be reliably interpreted.

In 2021, the FDA granted expedited approval to Lumakras to treat people who have advanced non-small-cell lung cancer driven by theKRAS G12C mutation and had previously taken another chemotherapy. Lumakras was the first drug to inhibit KRas, a notoriously challenging target.

The FDA required further data to convert its accelerated approval into full drug approval. The study that was intended to provide those data, CodeBreaK 200, showed that progression-free survival was about a month longer for people who took Lumakras compared with people who took docetaxel, a standard second-line treatment for this type of cancer. The study found no difference in overall survival.

But the FDA advisers questioned CodeBreaK 200’s results. They cited a high dropout rate among patients in the docetaxel arm of the study, which may have introduced bias. The advisers were also concerned because independent reviews of tumor imaging scans differed significantly from those conducted by the study’s investigators.

The advisory panel’s conclusion does not mean that Lumakras will be withdrawn from the market, but further studies may be needed. The FDA will make its decision on Lumakras’s full approval later this month.

Phenylephrine isn’t an effective oral decongestant, according to an FDA panel

In 2022, people in the US spent an estimated $1.8 billion on over-the-counter pills and liquids containing phenylephrine, such as DayQuil and Sudafed PE, according to manufacturer sales data compiled by the FDA. But this September, an FDA advisory panel agreed in a unanimous vote that the ingredient doesn’t work as a decongestant when taken orally.

Credit: Bethany Halford/C&EN

Drug store shelves are full of oral cough and cold medicines that contain phenylephrine.

Phenylephrine, which has been used medically since the 1930s, constricts blood vessels. The FDA has deemed it generally recognized as safe and effective, or GRASE in the agency’s parlance, for over-the-counter medications since 1976. For decades, though, scientists have argued that the FDA’s decision was based on flawed data. They say that when taken orally, phenylephrine is quickly metabolized in the gut to inactive molecules and never makes its way into the bloodstream. Nasal sprays that contain phenylephrine are still considered effective at stopping runny noses.

The drug came into widespread use in oral formulations after the US federal government enacted the Combat Methamphetamine Epidemic Act of 2005. That legislation required pharmacies to keep cold remedies with a different decongestant—pseudoephedrine, which can be easily converted to methamphetamine —behind the counter, and it required consumers to show identification to purchase them. Drugmakers used phenylephrine to fill the public’s demand for cold medicines.

The FDA panel reviewed the old data along with the results of more recent clinical trials that showed that oral phenylephrine didn’t work, even at doses higher than those recommended on the packaging. The FDA is considering the panel’s recommendation and will make the final decision about whether phenylephrine should keep its GRASE designation, but the process could take more than a year.

Credit: Shutterstock

Debate continues on how the Inflation Reduction Act will affect the pharmaceutical industry

David Mitchell has a rare form of blood cancer. In the US, that’s not a cheap diagnosis. “My cancer drugs keep me alive, but my disease is incurable because nothing works forever. Currently, my doctors have me on a four-drug combination that carries a list price of more than $960,000 per year,” he says. Fortunately, Mitchell benefits from Medicare, a federal health insurance plan available for people 65 and over, so most of that cost is covered by the government. Even so, he still faces an annual bill of about $17,000.

“The Inflation Reduction Act is going to help patients like me,” he says. “After 20 years of fighting, the government is finally going to do what the British already do. They’re going to negotiate on the prices for the most expensive drugs.” Prescription drugs cost roughly 40% more in the US than in Europe, according to analysts at the private bank LGT.

Mitchell is also the president and founder of Patients for Affordable Drugs, an organization that advocates for cheaper prescription drugs and lobbied for the Inflation Reduction Act (IRA) to be passed by Congress, which it was and then subsequently signed into law by the president in August 2022. The implications of the legislation will begin to be felt in the coming years, but some are warning that not all effects will be positive.

The law means that from 2026, Medicare will haggle directly with drugmakers over the prices of some of its most costly drugs. The US Department of Health and Human Services announced the names of the first 10 drugs earlier this year. The number of drugs covered by the act is expected to reach 60 by 2030. To be eligible for price negotiations, a drug needs to have been approved by the US Food and Drug Administration for at least 9 years if it’s a small-molecule drug and at least 13 years if it’s a large-molecule drug. The development and rollout of large molecules are more expensive and time consuming than small molecules, which is why they’re being granted a longer exemption from price negotiations, but some pharmaceutical industry executives have criticized this distinction and would prefer a longer time for all drugs. The new law will also limit the out-of-pocket expenses for Medicare users to $2,000 per year.

“It’s putting price controls on drugs for the first time in the US, and people say, ‘That already exists in foreign countries, so what’s the big deal?’ says John LaMattina, a former president of global research and development at Pfizer. “People don’t appreciate the consequences, though. Pharma companies currently invest 25% of their revenues into R&D. That’s significant, and that’s the industry standard. Companies will have less revenue, and so they’ll have less money for R&D.”

Less money for R&D will ultimately lead to fewer new drugs in the future, LaMattina says. Using estimates from the Committee for a Responsible Federal Budget —which states that the US government will save $300 billion from the IRA—LaMattina says the legislation would translate to a reduction of $75 billion in R&D spending from the pharmaceutical industry.

The only reason that other markets, such as the UK and the European Union, get away with tighter price controls is because they rely on drug companies’ making larger profits from the US to fuel their drug development, LaMattina argues. “Other jurisdictions basically freeload off the US. Should the US go to the UK system, you’d slash R&D by a third or more,” he says.

Others share his concerns. “It’s going to discourage innovation,” says Laura Hobbs, the director of health-care policy at the American Action Forum, a think tank in Washington, DC, that describes itself as center right in its political leaning.

Studies have shown a link between diminished income for drug companies and fewer new molecules coming onto the market. A 2019 report from the Galen Institute estimated that the US had access to close to 90% of new drugs launched between 2011 and 2018. At the same time, higher-​income countries with price-​control policies had access to only 47% of the same novel medicines. That doesn’t necessarily mean that price control thwarts innovation; it’s possible that the authorities in countries with price controls just decided that some new drugs weren’t worth paying for.

Mitchell says the new law still provides plenty of opportunity for pharmaceutical companies to make money. First, the legislation covers only Medicare drug purchases, he points out. It has no effect on the price that private insurers pay for medicine. The think tank KFF estimated that Medicare spending accounts for roughly 30% of US prescription drug sales. Second, companies still get to choose the launch price, and, initially at least, only 10 drugs out of thousands are going to be subject to price negotiations.

These arguments irritate LaMattina, however, who says that proponents of the act simultaneously praise how much money will be saved while trying to downplay the impact of lost revenues for pharmaceutical companies. “You can’t have it both ways,” he says.

Even putting the question of profits to one side, LaMattina remains unconvinced of the legislation’s merits. “In the past, you’d develop a drug for a rare cancer or disease because you get approvals quicker and so you start to generate revenue faster,” he says. Once that initial approval is achieved, drugmakers often seek to gain additional clearance to market the same drug for more-profitable diseases. That pattern is less likely to happen under the new system, he argues, because the first approval would start to run down the clock on exclusivity before a drug is potentially eligible for Medicare price negotiations. “This is going to change drug companies’ philosophy on clinical trials; they’ll wait on results until they can apply for approvals for more-profitable cancers,” he says. “That penalizes patients. There are a bunch of unintended consequences.”

But for patient advocate Mitchell, price negotiation is just common sense. He believes the warnings from the pharmaceutical industry are exaggerated. “When I hear them say this stuff, it’s infuriating to me as a patient,” he says. “Medicare already negotiates for everything else it pays for—​doctors, hospitals, and tests. All we’re going to do is negotiate over 60 drugs at full implementation of the Inflation Reduction Act.”

Benjamin Plackett is a freelance writer based in London.

Credit: Associated Press

An aerial view shows the damage that a tornado caused to a Pfizer pharmaceutical factory in North Carolina in July.

Ongoing drug shortages in the US reached their highest rates in a decade in 2023, according to the American Society of Health-System Pharmacists. A series of regrettable events conspired to worsen persistent supply chain problems, and survey data show that these shortages are beginning to affect patient care. Chemotherapies and local anesthetics are some of the drugs most commonly in short supply.

“Shortages have definitely felt worse this year,” says Erin Fox, an associate chief pharmacy officer at the University of Utah Health who studies drug shortages. Intense pricing competition is partly to blame, she says. “The FDA rates all generic drugs as equal, and that means that they can only compete on price. And many companies will undercut each other.”

This price competition has two knock-on effects. The first is that the quality of the production line—not the medicine itself—decreases in a bid to save on cost, increasing the risk of a fault and causing delays. According to the US Food and Drug Administration, manufacturing quality issues are the principal cause of recent disruptions. Second, the intense competition to manufacture generics simply drives some firms out of business, further reducing the supply. For example, generics manufacturer Akorn Operating Company filed for bankruptcy in February. “This led to a large number of shortages, as they were the sole supplier of many drugs,” Fox says.

But the economics of the generic-drug market are only part of the picture. In July, Meera Bhavsar, who leads Pfizer’s sterile injectables portfolio, had to write to customers to explain how a 130,000 m² manufacturing facility in North Carolina had been damaged by a tornado.

“Luckily the production lines weren’t damaged, just the distribution areas and some of the already- prepared products,” Fox says. “But this also has stretched some supplies thin.”

Shortages are also exacerbated by geopolitical tensions, such as the US-China trade war and Russia’s invasion of Ukraine. COVID-19 disruptions also linger. Some of these problems are being resolved, but the underlying issue of manufacturing quality needs to be remedied if shortages are ever going to become a thing of the past, Fox says. “This is a problem that I’ve been following for over 20 years. While I am always optimistic that progress can be made, I don’t think shortages will completely go away in 2024.”

Benjamin Plackett is a freelance writer based in London.

If you thought 2022 was bad for biotechnology, this year managed to hit an even lower point.

Capital markets remained largely closed, leaving companies gasping for cash, and steadily rising interest rates have dragged down valuations. The SPDR S&P Biotech ETF (XBI), an index that tracks biotech companies, has fallen 12% since the start of the year. Though XBI’s value is a hair’s breadth higher than it was at its lowest point in 2022, its performance stands in contrast with the S&P 500 Index, which rose more than 18% during the same period.

As a result, the industry largely hunkered down in survival mode in 2023. Many companies were forced to undertake serious belt-tightening to stay afloat. As of Nov. 28, 173 companies had announced layoffs, compared with 119 in all of 2022, according to Fierce Biotech. Twenty-seven companies have shuttered completely this year, compared with just 7 in 2022.

Tellingly, the successes of GLP-1 agonists—a new class of medicines for diabetes and weight loss—have dominated the pharmaceutical news this year, but these successes have been for Big Pharma, not biotech.

In investor calls in late October and early November, “universally, the sentiment was the absolute worst it’s ever been in biotech,” says Michael Perrone, a biotech specialist at Baird. “I would say this year there was a little more despair” simply because the slump has dragged on for so long.

Much of the biotech sector’s pain reflects the ongoing correction from the wild highs experienced during the pandemic, experts say. “We are still living through the hangover from the free-money party we saw in 2020 and 2021,” says Barbara Ryan, senior adviser for life sciences at the professional services firm EY.

That glut of cash drove investors to fund risky research programs that had slim chances of success, Perrone says. Too many companies went public too early with not enough experienced managers to run them. “We needed some of these companies to go away,” he says. “It’s essentially culling the herd—and the herd getting stronger by losing its weakest members.”

The number of initial public offerings (IPOs) of stock this year reflects this trend: 24 US biotech companies have notched IPOs as of Nov. 15, according to the business intelligence firm PitchBook. That’s on par with the 25 IPOs in all of 2022 but well off the 109 in 2021.

Amid the pain, however, there have been some bright spots. Mergers and acquisitions among public companies are strong, numbering 31 deals announced so far in 2023. They have “been a savior for many investors,” Ryan says. And in a record high, she adds, 15 of the deals have been worth more than $1 billion—most notably, Pfizer’s $43 billion purchase of Seagen, announced in March.

Big companies often buy biotechs to help offset the loss of products that go generic. And considering that a slew of therapies— representing some $200 billion in product sales —will go off patent at the end of the 2020s, the trend is likely to continue, Perrone says. “They really need to start filling that late-stage pipeline.”

As the new year approaches, there are strong hints that the Federal Reserve Board will cut interest rates in 2024, Perrone says. “That, I think, will be the single biggest catalyst” for bringing general investors back to biotech and nudging the industry toward regaining its balance.

Alla Katsnelson is a freelance writer based in Southampton, Massachusetts.

Credit: Science Source

Messenger RNA vaccines are usually delivered in lipid nanoparticles like this one.

The impact of messenger RNA (mRNA) as medicine hardly needs to be stated. Billions of people worldwide have received at least one mRNA vaccine for COVID-19. This year, the research that enabled this global immunization was recognized with a Nobel Prize, while the candidate vaccines and therapeutics that companies hope will become the next generation of mRNA medicines advanced through large clinical trials. Despite these successes, research investment has slowed compared with the frenzy of recent years.

In a highly anticipated Nobel nod, Katalin Karikó of the University of Szeged and Drew Weissman of the University of Pennsylvania received the Nobel Prize in Physiology or Medicine in October for discovering a way to slip RNA past a cell’s defenses so that it can be translated into protein.

“The whole world has now seen . . . that RNA therapeutics could allow for making fast, potent, flexible vaccines that can generate very strong immune responses,” says Vinod Balachandran, a physician-­scientist at Memorial Sloan Kettering Cancer Center who is testing mRNA vaccines for pancreatic cancer.

Credit: Peggy Peterson/PennToday

Winners of the 2023 Nobel Prize in Physiology or Medicine, Katalin Karikó (left) and Drew Weissman

The use of RNA for medicine is not new; a number of therapies use short RNA molecules to block protein production. But for now, COVID-19 vaccines are the only products approved by the US Food and Drug Administration that use mRNA, which encodes proteins, to produce new proteins in cells. Multiple mRNA drug candidates are advancing through clinical trials.

Buoyed by the success of COVID-19 shots, research to develop mRNA vaccines for other infectious diseases is well underway. Companies have completed clinical trials and requested approval for vaccines for influenza and respiratory syncytial virus (RSV), and Moderna is testing a combination shot against COVID-19 and the flu. Cocktail vaccines against multiple antigens are “one of the key advantages of mRNA,” says Yusuf Erkul, CEO of Kernal Biologics, a biotechnology company working on mRNA therapeutics.

Another advantage is the speed with which mRNA can be produced and manufactured. These attributes, along with their robust immune activation, make mRNA vaccines attractive to oncologists who hope to train the immune system to recognize cancer cells. Researchers are pursuing mRNA vaccines against markers shared by multiple cancers. They are also working on individualized cancer vaccines; study teams assess a tumor’s genome, use an algorithm to predict which mutations will make the best targets, and manufacture patient-specific doses in just weeks. This year, the FDA gave breakthrough therapy designation to a personalized mRNA vaccine for melanoma under joint development by Moderna and Merck & Co. after a promising midstage trial.

But researchers hope that mRNA can deliver much more than immune system training. Some investigators are aiming to treat rare metabolic diseases by using mRNA therapies to replace key enzymes in the body; others want to deliver gene editors via mRNA. One preclinical study in mice used targeted, mRNA-loaded nanoparticles to edit genes only in bone marrow, a potential alternative to stem cell editing in a lab. Improving tissue-specific delivery is also an area of active research.

Despite the Nobel recognition and profusion of research and development, 2023 has been a “reset year” for mRNA commercially, says Fenwick Eckhardt, senior manager of consulting and analytics at Citeline. Revenues for COVID-19 vaccines have dipped, and investors are hanging back, waiting to see whether large trials succeed and position candidate drugs for FDA approval.

Those approvals may come more slowly than investors once expected, Eckhardt says. The next generation of mRNA vaccines and other drugs will follow a more traditional regulatory path than the superfast approvals seen during the pandemic years.

Open-source drug discovery prepared for the next pandemic

New antiviral drug leads were reported by an open-source drug discovery effort, the COVID Moonshot Consortium (Science 2023, DOI: 10.1126/science.abo7201). Since March 2020, 212 scientists across 25 countries have contributed to the project. The team’s lead compound is now being advanced by the Drugs for Neglected Diseases initiative, while the consortium will continue developing antiviral drugs for viruses of pandemic concern.

Credit: Frank von Delft group/Center for Medicines Discovery, University of Oxford

Results of an early screen to find molecules that bind to the main protease of SARS-CoV-2

Doxycycline helps prevent STIs

In October, the US Centers for Disease Control and Prevention shared draft guidelines recommending that people take the antibiotic doxycycline to prevent sexually transmitted infections (STIs). The strategy is named doxycycline postexposure prophylaxis, or doxy PEP.

In trials, researchers found that the drug helped transgender women as well as men who have sex with men, who have increased chances of getting an STI. For participants who took a single dose of the tetracycline-based drug after having sex without a condom, bacterial STIs were reduced by two-thirds. Cities such as San Francisco had already started providing the drug to at-risk communities.

In October, about 2 years after recommending the first malaria vaccine, the World Health Organization endorsed a second one to protect children against the deadly disease. The R21/Matrix-M vaccine was developed by the University of Oxford and is manufactured by the Serum Institute of India.

More insight into COVID-19 antivirals

Data presented at the IDWeek conference in Boston in October suggested that an antiviral called ensitrelvir could help with loss of smell and taste in people with mild COVID-19. While Pfizer’s drug Paxlovid (nirmatrelvir/ritonavir) and Merck & Co’s Lagevrio (molnupiravir) are both used for people at high risk of severe disease, Japanese regulators gave emergency use approval to Shionogi’s 3CL protease inhibitor Xocova (ensitrelvir) for people irrespective of risk status or disease severity. The drug is not licensed in the US. Meanwhile, researchers found that molnupiravir can accelerate SARS-CoV-2 mutations (Nature 2023, DOI: 10.1038/s41586-023-06649-6).

New hope for mental health

Designing new psychiatric drugs has been a particular challenge for the pharmaceutical industry, but a couple of biotechnology moves this year suggest that the field might be reviving. Neuromedicine-focused Rapport Therapeutics launched in March and raised $250 million total in series A and B funding rounds. And in May, Boehringer Ingelheim signed a $181 million deal with Kinoxis Therapeutics to develop therapies for neuropsychiatric disorders. After positive trial results, Karuna Therapeutics submitted its new schizophrenia medicine to the US Food and Drug Administration for approval in September.

Another xenotransplantation milestone

Credit: University of Maryland School of Medicine

Lawrence (left) and Ann Faucette pre-operation at the University of Maryland Medical Center

In September, Lawrence Faucette became the second-ever patient to receive a genetically altered pig’s heart. Although Faucette did well after the operation, he later died. “He never imagined he would survive as long as he did, or provide as much data to the xenotransplant program,” his wife, Ann Faucette, says in a statement. In the US, 17 people die each day waiting for an organ transplant, according to the Health Resources and Services Administration. To meet that need, various groups of scientists are genetically modifying pigs to make their organs more humanlike, but more data are needed before the US Food and Drug Administration will sign off on human trials.