Kevin Kunzmann

The US Food and Drug Administration (FDA) has approved Genentech’s baloxavir marboxil (Xofluza) for the treatment of acute, uncomplicated 

 in healthy children aged 5 to ≤12 years old who have been symptomatic with the flu for ≤48 hours.

The supplemental New Drug Application (sNDA) for the novel antiviral therapy also indicates its use for post-exposure prevention of flu in children from the same age group who have made contact with a person infected with influenza. Baloxavir marboxil is now the first single-dose oral medication approved for treating flu in children of this age group.

This second FDA approval is based on results from the phase 3 miniSTONE-2 and BLOCKSTONE trials—the former showing baloxavir marboxil’s benefit in treating influenza in children aged 5 to ≤12 years old after 48 hours versus oseltamivir, and the latter showing its benefit as a prophylactic treatment for household members living with someone infected with influenza versus placebo.

Investigators observed common adverse events such as vomiting and diarrhea in approximately 5% of the pediatric populations treated with baloxavir marboxil in each study.

MiniSTONE-2 investigator Pedro Piedra, MD, professor of molecular virology, microbiology and pediatrics at Baylor College of Medicine, emphasized the historic and significant role of school-aged children in the community-level transmission of influenza every flu season. Per the Centers for Disease Control and Prevention (CDC), US pediatric flu cases prior to prominent public masking due to COVID-19 were upward of 6 million cases annually.

“The annual influenza vaccine continues to be the most important first step to prevent illness in children, though there can still be breakthrough cases where antiviral treatment is needed,” Piedra said in a 

. “Today’s FDA approval provides children with a single-dose antiviral option, Xofluza, to treat influenza."

Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Genentech, praised the added indications for baloxavir marboxil to cover flu treatment and prevention of nearly every at-risk pediatric patient.

“Despite the ongoing COVID-19 pandemic, influenza continues to be a threat to public health, and effective influenza antivirals remain critical to alleviating the burden on healthcare systems,” Garraway said. “Xofluza has proven to be an important tool in fighting and preventing influenza in adults as well as adolescents, and we are pleased to now offer households and younger children our single-dose oral treatment.”

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The newest indications for the novel oral antiviral drug will make it available as an acute treatment and prophylaxis for children this flu season.

FDA Approves Baloxavir Marboxil to Treat, Prevent Flu in Younger At-Risk Children

The American tobacco industry is at an inflection point. While financial forecasters anticipate a continued revenue growth of 

approximately $4 billion annually through 2026

, the means by which the formidable industry thrives are in flux.

assessment from the 2020 National Health Interview Survey

 showed approximately 1 in 5 Americans were current tobacco users of any kind at the time. But only 12.5% of all adults were using combustible cigarettes—the lowest prevalence of smokers in nearly 60 years of data. The traditional deliveries of tobacco are becoming less common among the newest generation of users.

 published last month showed that while current e-cigarette use—defined as any use in the last 30 days—was on the decline among young adult Americans, daily use is on the climb. What that indicates, against the context of reduced daily combustible cigarette use, is a shift in the prioritization of tobacco delivery. Young adults are no longer experimenting with e-cigarettes; they are habitually using them in place of combustible products.

“And transitioning from occasional use to daily use is an indication of some form of nicotine dependence, because now you have to use it daily,” investigator Ellen Boakye, MD, MPH, a postdoctoral fellow with the Johns Hopkins Ciccarone Center, told 

. “And research has shown that for people who use e-cigarettes daily, particularly among young adults, they are more likely to transition to combustible cigarette use.”

For decades, a multifactorial and comprehensive public health strategy to reduce the rate and burden of combustible cigarette use among young adults, adolescents and children has been carried out by factions of organizations, experts and legislators. Just as these strategies neared the closest they’ve been to completion, the goal posts have moved. E-cigarettes are becoming the common tobacco delivery product among the next generation of nicotine-addicted users, just a decade after their introduction to the market was under-met by the regulatory powers of the US Food and Drug Administration (FDA).

Now, whether it be strategic or coincidental, new federal efforts to curb tobacco use among young Americans is colliding directly with this major shift in tobacco product preferences. The FDA is attempting to put e-cigarettes and flavored tobacco in check before long-term damage is done to nationwide cessation efforts. But is it too little, too late?

The Family Smoking Prevention and Tobacco Control Act was signed into law June 2009, placing more distinct restrictions on tobacco product marketing toward children. Key national provisions from the act include bans on sales to minors; tobacco-brand sponsorship of sports, entertainment, or other social/cultural events; promotional giveaways of sample tobacco products; and more. It also increased the FDA’s capability in regulating nicotine and ingredient levels in tobacco products, as well as in banning characterizing product flavors aside from menthol and tobacco.

The 2009 law “empowered the FDA to regulate tobacco and nicotine products for the first time,” Rob Crane, MD, et. al wrote for 

 last year. Just as importantly, it preempted state and regional government from their own regulation standards for tobacco product manufacturers.

“The usual argument for preemption is that companies have difficulty complying with different regulations in different localities,” Crane and colleagues wrote. “However, an industry that promotes nicotine addiction should not be granted such considerations. Doing what works to reduce youth nicotine use is a far more important imperative.”

In the immediate years following the act, current tobacco product use among US high school students decreased from 24.2% in 2011 to 19.6% in 2017, per annual 

National Youth Tobacco Survey (NYTS) data

. In those 7 years, cigarette use among high school students halved from 15.8% to 7.6%.

The significance and timing of these changes imply public health strategy and marketing standards set by the 2009 act are responsible—to which some extent they are. But that’s excluding the whole truth. From 2011 to 2013, as the rate of combustible cigarette use among adolescents substantially dropped, the rate of e-cigarette use skyrocketed—a 3-fold increase in use among smoking-naïve students in middle school and high school during that time, 

Early e-cigarette marketing and messaging were mostly excluded from the rigors set by the Family Smoking Prevention and Tobacco Control Act, American Lung Association (ALA) Assistant Vice President of National Advocacy Erika Sward told 

 stating the FDA could not regulate e-cigarettes as drug delivery devices.

The suit was after the FDA seized vaping devices for inhaled nicotine from Smoking Everywhere Inc. and NJOY in 2008; the agency claimed the devices were unsafe, unapproved products falsely marketed as combustible cigarette alternatives. The ruling judge at the time stated the FDA provided no evidence that e-cigarettes were “any more an immediate threat to public health and safety than traditional cigarettes.” Sward described the mass influx of e-cigarette products and ill-defined FDA regulation standards as a “perfect storm” for rampant use among youths.

“So the FDA was trying to figure out how it was going to regulate e-cigarettes as a tobacco product once this court case was decided in 2010,” she said. “And then we had a number of years of stalling, but at the time, the early-use products were pretty, pretty bad.”

Over the next decade, competing thoughts on the matter of e-cigarette utility and health risks resulted in 

. States such as New York set precedent for establishing indoor e-cigarette and vape bans similar to those in place for cigarettes. San Francisco outright banned flavored vapor products including menthol. Thirty states passed a vaping device or e-cigarette taxation. Finally, the 

Federal Food, Drug, and Cosmetic Act was amended in 2019

 to raise the federal minimum age to buy tobacco products to 21 years old, with strict fines and penalties in place for noncompliant retailers.

 for tobacco product review applications for vapor and smokeless products in July 2017—meaning companies with products available under lesser-defined regulatory standards as far as 6 years ago had until this month to submit premarket applications for FDA review. Sward described the move as a “open welcome to come on the market,” despite there being lesser regulation keeping manufacturers in check. After decades of waged war against combustible cigarette safety and marketing standards, the agency’s moves against e-cigarettes were softened by agency capability and timeline of action.

“I think there's an inherent false belief that once the FDA were to allow a product on the market, it would be ‘safe’,” Sward said. “But I think that there's no inherent right to sell a product that is dangerous to its consumers. And there is a certain role…the federal government has in protecting the nation's public health, whether that be through vaccinations, whether that be through clean air, whether that be through making sure that tobacco products are very carefully regulated across the board.”

Public health officials were also daunted by the initial marketing behind the first generations of e-cigarettes. Sward likened the industry’s messaging to those used by tobacco companies in the 1950s and 60s: “making claims that they were less harmful without any sort of scientific evidence,” while also targeting younger demographics with unique and appealing flavors.

Whether e-cigarettes are safe, less harmful than combustible cigarette options, or beneficial tools for smoking cessation are 3 entirely separate thoughts that generally get wrapped together as 1 point in the argument for their lessened regulation on the US market. Experts express caution at endorsing even any 1 of those messages as completely true, though.

“I truly believe that if e-cigarettes were safe, or effective in helping smokers quit, and somebody had figured that out, they would have made a beeline to the (FDA) Center for Drug Evaluation and Research really quickly,” Sward said. “Because they would have known that they could have made a ton of money selling that product to ultimately help smokers quit.”

Sward added the discussion around e-cigarette safety risks is often muddled by the fact that vaping devices are heterogenous; Juul and NJOY create products with different function and pods with different ingredients and chemical exposures. She called the belief any of these devices are safer than combustible cigarettes an industry-borne claim—one that the FDA had opportunities and evidence to challenge for more than a decade now. “I mean, the FDA not only left the barn door open, but they actively drove the horses out,” she said.

Clinical experts see a bit more complexity in defining the role of e-cigarettes as a smoking alternative or cessation tool. Boakye alluded to upcoming research by her colleagues that shows combustible cigarette users who are looking to quit are generally more successful when transitioned to e-cigarettes. That outcome would alter perspective on the 2 currently established facts that combustible cigarette use is gradually declining, and daily e-cigarette use is climbing—especially if the latter trend is buoyed by former combustible cigarette smokers.

If the climb in daily e-cigarette use is represented by tobacco-naïve users, though, there are greater potential risks. Addiction is highly prevalent with any nicotine product, and there are currently no evidence-based nor expert-supported cessation methods for young daily e-cigarette users.

“There's a lot of evidence to actually support this gateway hypothesis, where young adults who are using e-cigarettes are more likely to transition to combustible cigarettes use more so if they are using it daily,” Boakye said. “But some looking at it from the other end among combustible cigarettes users who want to quit daily use, it may actually be helpful.”

There is also an issue of heightened health risks in users alternating between combustible and electronic cigarettes, regardless of which they started with. “The benefits of e-cigarettes are actually realized only when smokers are able to transition fully to e-cigarettes, not when they are using both concurrently,” Boakye said.

Boakye’s team is trying to interpret e-cigarette impact more intricately, assessing the role of individual device characteristics and patient demographics in the transition from occasional to daily use. “Because if we get to know the device characteristics, then the FDA can regulate such characteristics so that people who are experimenting with e-cigarettes will not be likely to move on to the more harmful patterns of use,” she explained.

It would be fruitless for clinicians, investigators, regulators and users alike to altogether disregard the unique factors of e-cigarettes as they become better defined, Boakye said. She stressed frontline physicians to question the intricacies of patient tobacco use.

“Health care providers should follow the conversation, they should gain comfort in asking their patients—and also comfort in being able to respond to patients who are inquisitive enough to ask about e-cigarettes, because it's very important,” she said.

Recent events have only emphasized the issue of clearly defining the FDA’s role in regulating e-cigarettes. The agency issued a 

marketing denial order to Juul Labs in late June

, requiring the most popular e-cigarette and vaping device company in the country to remove all its products from retail and marketing.

The FDA’s unprecedented order followed a review of Juul’s premarket tobacco product applications, in which the agency deemed evidence supporting the toxilogical profile of Juul products were insufficient. The FDA described “insufficient and conflicting data” regarding the e-cigarette and vaping devices’ genotoxicity and user exposure to harmful chemicals via proprietary vape pods. Additionally, they cited concerns over the potential harmful use of third-party vape pods with a Juul device—or vice versa—similar to Sward’s concern over heterogenous products with similar usability but differentiating components.

 and received a temporary marketing stay from the US Court of Appeals while the agency conducted its investigation into product safety. Though much of the ban’s discourse is focused on the constitution, prevalence and burden of a handful of chemicals observed in the company’s vape pods, the overarching opinions on the role of e-cigarettes is discernable in both side’s arguments—and they’re somewhat nontangential. The FDA would argue that Juul caters to young, tobacco-naïve users without sufficient proof of a positive benefit-risk profile, Juul argues that e-cigarettes are a successful cigarette cessation tool for smokers.

Juul—which as of 2020 had comprised two-thirds of the US e-cigarette market—has stated approximately 2 million adult smokers have quit combustible cigarettes through aid of their products. “We remain confident in the quality and substance of our applications and believe that ultimately we will be able to demonstrate that our products do in fact meet the statutory standard of being appropriate for the protection of the public health,” Juul Labs chief regulatory officer Joe Murillo said in a 

The agency and supporting experts, meanwhile, seem focused on the long-term public health impact of a would-be ban for Juul. Previous FDA commissioner 

 at the time of the initial marketing ban that Juul was the “fulcrum of the youth vaping crisis,” driven by the company’s product and marketing practices.

“FDA is right to be circumspect,” he wrote. “Electronic devices offer opportunity for adult smokers to transition off combustible products but must be conceived, marketed by responsible actors.”

Kevin Walton, PhD, chief of the clinical research grants branch at the National Institute on Drug Abuse (NIDA), discussed the actions against Juul in concert with another FDA decision from earlier this year: 

a proposed ban on menthol-flavored cigarettes

. The prevailing argument against menthol flavoring is the same against flavored e-cigarette and vape pods: they can serve as something of a gateway to daily use.

“To ban menthol is part of the regulatory effort to reduce the attractiveness of cigarettes,” Walton said. “It's very common for youth who use (cigarettes) to start off with menthol, because it's a less harsh flavor. And so it's easier to start smoking, using that thought.”

While Walton is interested in learning more from upcoming research and the FDA’s deliberation on Juul and similar e-cigarette products, he maintained that a key regulatory priority should be on fixed nicotine levels for any approved products, as well as improving access to cessation treatments—especially among underserved populations who may be more adversely impacted by the likes of menthol cigarette and e-cigarette marketing.

I think that these changes the FDA has proposed could have a really big, positive impact for reducing smoking, and we'll just have to see how those processes go forward,” he said. “Making tobacco less addictive and less attractive seems like an appropriate way to move forward.”

Boakye echoed the idea that the real key to combating any public health effect of cigarette products should focus on nicotine; smoking cessation is a major individual accomplishment, but complete nicotine abstinence is the ultimate goal. Lost amid the argument that e-cigarettes are a beneficial smoking cessation tool is the fact that some e-cigarette users are trying to quit those products as well, she said. Greater options to aid them are necessary as long as they are available.

Sward maintained hope that that some of the tobacco products currently in the FDA’s crosshairs are eventually removed from market, saying this current time is “the closest we’re going to get as a nation to a fresh start” in the public health push for mitigated smoking harms. But regardless of the FDA’s fight against Juul, menthol, and everything in between, the affected users are owed help that’s been lacking for years.

“We need to do more as a nation to put into place policies and systems for cessation,” Sward said. “And I think that is something that that that we owe to the people who were essentially allowed to be addicted by a country that didn't always pay attention to what the tobacco companies were doing.”

The agency has taken new action against Juul while experts worry about youth addiction and health impacts. But the e-cigarette market has been already well established in the US.

Up in Smoke: The FDA's Retroactive Fight to Limit E-Cigarettes

A promising dual pathway inhibitor molecule for the treatment of 

chronic obstructive pulmonary disease (COPD)

 has reached significant marks in phase 3 data and will now be considered by the US Food and Drug Administration (FDA).

Verona Pharma announced trial results from its pivotal phase 3 ENHANCE-2 study showing that novel inhaled ensifentrine nebulizer therapy was associated with a significant and clinically meaningful improvement in forced expiratory volume over 1 second (FEV

) among patients with COPD versus placebo.

With non-peer reviewed, unpublished findings announced Tuesday, Veron shared intention to submit a New Drug Application (NDA) for ensifentrine as a COPD treatment in early 2023—dependent on outcomes from the coinciding ENHANCE-1 study.

Ensifentrine is an investigational dual inhibitor of phosphodiesterase 3 and 4 (PDE3; PDE4)—a pair of enzymes associated with COPD bronchial and inflammatory effect. The agent was shown in prior phase 2 trials to significantly improve patient lung function and quality-of-life outcomes when used as either a monotherapy or add-on to maintenance bronchodilator in patients with COPD.

The ENHANCE-2 trial is part of a phase 3 randomized, double-blind, placebo-controlled program to assess the efficacy and safety of ensifentrine as either a monotherapy or add-on to long-acting muscarinic antagnonist (LAMA) or long-acting beta agonist (LABA) bronchodilators, versus placebo.

The patient population for ENHANCE-1 and ENHANCE-2 included approximately 800 patients with moderate to severe symptomatic COPD across North America and Europe. Patients in ENHANCE-2 were randomized to either 3 mg nebulized ensifentrine or placebo twice daily over 24 weeks.

Investigators sought a primary endpoint of lung function improvement per FEV

 area under the curve (AUC) at 0-12 hours post-dose in week 12. They additionally sought safety outcomes over 24 weeks, and secondary efficacy endpoints including peak and morning trough FEV

, COPD symptoms and health-related quality of life via St. George’s Respiratory Questionnaire (SGRQ) and Evaluating Respiratory Symptoms (E-RS) scores, and exacerbations.

Patients treated with ensifentrine reported a 94 mL change in mean FEV

 <.0001). Investigators additionally observed significant improvements for treated subgroups based on sociodemographic and clinical backgrounds, including age, smoking status, disease severity and more.

 of treated patients reached 146 mL at 0-4 hours post-dose in week 12 (

 <.0001), and increase in morning trough FEV

 = .0017). Investigators noted the latter secondary endpoint confirms a twice-daily dosing regimen for ensifentrine treatment in COPD.

Additionally, patients treated with ensifentrine reported a 42% reduction in COPD exacerbations over 24 weeks versus placebo (

 = .0109), as well as clinically-important differences in E-RS and SGRQ scores at week 24.

Ensifentrine was observed to have good tolerability in ENHANCE-2, with a similar safety profile to placebo. Commonly observed adverse events included pneumonia, gastrointestinal effects and cardiovascular events.

 accompanying the findings, Verona president and chief executive officer David Zaccardelli, Pharma, said the successful ENHANCE-2 findings and the ENHANCE-1 findings anticipated for later this year are expected to support the company’s NDA submission to the FDA.

“We are very pleased by the successful outcome of our ENHANCE-2 study and remain committed to bringing ensifentrine to COPD patients as quickly as possible,” Zaccardelli said.

Investigator Antonio Anzueto, MD, professor of medicine and chief of the pulmonary section at South Texas Veterans Healthcare System, highlighted the discernible improvements to lung function and retained safety associated with ensifentrine.

“I am extremely excited by the clinically meaningful 42% reduction in the rate of exacerbations observed over 24 weeks in these symptomatic patients, many receiving background therapym,” he said. “Based on these meaningful results, I believe ensifentrine, if approved, will be an important new class of bronchodilator and non-steroidal anti-inflammatory therapy for COPD patients providing a much needed alternative to existing treatments.”

New phase 3 ENHANCE-2 data support a potential submission by Verona Pharma to the FDA.

Ensifentrine Significantly Improves COPD Lung Function, Exacerbations

One of the most persistent burdens surrounding 

 is the frequently delay in diagnosis by clinicians and initiated care for affected patients. It’s critical for caregivers and at-risk persons alike to identify the telling signs and symptoms of apnea risk—and the initial steps necessary to begin managing the chronic disease.

, Reena Mehra, MD, MS, director of sleep disorders research at the Cleveland Clinic, spoke with American Lung Association (ALA) chief medical officer Albert Rizzo, MD, on the most common or undercooked symptoms in obstructive sleep apnea. She noted how often patients present to her clinic with symptoms of excessive daytime sleepiness and general fatigue.

“That is by far and away the most common symptoms of obstructive sleep apnea, and it’s by virtue of the disruptive sleep that’s introduced from these repetitive episodes of stopped breathing—and probably some other pathways by which hypoxia may alter certain areas of the brain and lead to that sleepiness as well,” Mehra said.

Mehra additionally highlighted the importance of identifying persistent snoring, drowsing driving—an “important one” to quickly address—altered mood, or even nocturia as signs of untreated sleep apnea.

Rizzo and Mehra additionally discussed the misconception that obesity is a direct correlation with sleep apnea, highlighting the risk persons with unique airway anatomy and tissue accumulation face with the disease.

“It’s not everyone who is obese has sleep apnea, and not everyone who has sleep apnea is obese,” Mehra said.

Lastly, the pair reviewed differences in use of at-home and in-lab testing for sleep apnea.

“There’s a lot that’s monitored during an in-lab, attended polysomnogram,” Mehra said. ”It’s great from the standpoint of being able to collect a lot of helpful, important information about the degree of severity of sleep apnea…it allows us to more carefully and in a detailed way characterize the sleep-disordered breathing.”

“There can be some underestimation of the true degree of sleep apnea with home sleep apnea tests, so it’s important to recognize if you have high test probability, you’re doing the home sleep apnea test but it’s not conclusive nor revealing of a diagnosis, then one should pursue in-lab diagnostic testing to really confirm if there’s presence of sleep apnea,” she added.

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Reena Mehra, MD, MS, reviews telling signs, the role of obesity, and the importance of proper testing for sleep apnea.

Kevin Kunzmann

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