Category: 8. Health

Obstructive sleep apnea (OSA) is known as a chronic and potentially serious disorder in which the upper airway repeatedly collapses during sleep, causing intermittent drops in oxygen levels. It results from a combination of neuromuscular dysfunction during sleep and anatomical predispositions. OSA can affect patients of all genders, ages, ethnicities, and body types including those without obesity, and is estimated to impact 80 million patients in the United States. Despite the sleep disorder’s prevalence, up to 80% of cases remain undiagnosed and untreated.¹

Individuals with OSA may experience hundreds of breathing disruptions each night, leading to reduced oxygen levels that impair essential cellular functions. If left untreated, OSA can significantly increase the risk of long-term health issues such as cardiovascular disease, cognitive decline, metabolic disorders, and early death. However, most diagnosed patients either do not initiate, discontinue, or inconsistently use current treatments. Presently, there are no approved pharmacologic therapies that directly target the neuromuscular dysfunction central to the disorder.

The investigational oral therapy AD109 (Apnimed), a combination of aroxybutynin and atomoxetine, is currently being evaluated in the phase 3 LunAIRo study (NCT05811247), a randomized, double-blind, placebo-controlled, 1-year parallel-arm study of patients with mild to severe OSA. The trial, enrolling at least 660 participants aged 18 years and older from 64 clinical centers across the US, is designed to examine the efficacy and safety of the investigational agent compared with placebo.² The study’s primary end point includes measuring the proportion of participants who experience a reduction in apnea-hypopnea index (AHI) via polysomnography at 6 months and 1 year.

Patrick Strollo, MD, FACP, FCCP, FAASM

If successful, AD109 could become the first medication to address both the nighttime airway obstruction and oxygen deprivation central to OSA, as well as its daytime symptoms, such as fatigue. Taken once nightly at bedtime, this potential first-in-class combination targets neurological pathways involved in activating upper airway dilator muscles to help keep the airway open during sleep. Designed for use across varying levels of disease severity, AD109 offers the promise of a safe, effective, and more user-friendly alternative to current OSA treatments, which are often invasive or difficult for patients to tolerate.

Eligible participants of the trial were adults aged 18 years or older who met specific polysomnography parameters, including an AHI greater than 5, with no more than 25% of events classified as central or mixed apneas and a periodic limb movement arousal index of 15 or less. Individuals also needed to report significant fatigue, as indicated by a PROMIS-Fatigue raw score of at least 17. Additional requirements included intolerance to or refusal of positive airway pressure therapy and a body mass index ranging from 18.5 to 40 kg/m² for men or up to 42 kg/m² for women.

Participants were excluded if they had a diagnosis of narcolepsy, restless leg syndrome, or REM sleep behavior disorder. Those with insomnia marked by difficulty falling or staying asleep, or recent use of medications targeting insomnia symptoms, were also ineligible. Other exclusions included the presence of craniofacial syndromes such as Pierre Robin or Treacher Collins, or grade 3 or higher tonsillar hypertrophy. Individuals with clinically significant heart conditions, such as unstable coronary artery disease or ventricular arrhythmias, were excluded although stable atrial arrhythmia was permitted. Neurological exclusions encompassed neuromuscular disorders, epilepsy, and neurodegenerative diseases such as Parkinson, Alzheimer, or related conditions.

“The LunAIRo study is a complimentary study to SynAIRgy, a 6-month trial looking at safety and efficacy [of AD109]. LunAIRo is looking at safety and efficacy of [AD109] in a fairly similar population of over 600 participants,” Patrick Strollo, MD, FACP, FCCP, FAASM, professor of medicine and clinical translational science at the University of Pittsburgh, told NeurologyLive^® in a recent interview. “We’ll get additional insights in terms of safety and efficacy over 1 year with a fairly similar demographic group.”

“We’re also doing some substudies within LunAIRo looking at a more robust analysis of cardiovascular impact. There’s a substudy that we’ve done looking at ambulatory blood pressure. Those data are not fully analyzed. I imagine probably very shortly there will be an announcement of the topline results of LunAIRo, but right now I can’t really speak about results,” Strollo said. “But that’s the difference between LunAIRo versus SynAIRgy, and they should be complementary in terms of helping us understand safety and efficacy and also reassuring the FDA when the company goes to the agency, probably in early 2026.”

AD109 first demonstrated therapeutic potential in the phase 3 SynAIRgy trial (NCT05813275), which tested the agent across a broad range of patients with mild, moderate, and severe OSA. In the study, the treatment met its primary end point in reducing AHI over a 26-week treatment period. Based on these findings, Apnimed noted that it plans to submit a new drug application (NDA) to the FDA in early 2026 for AD109 as a potential treatment of OSA.¹

Considered the largest such drug trial for OSA, SynAIRgy included 646 adults with the disease who were intolerant of or currently refusing continuous positive airway pressure (CPAP). Coming into the study, 34.4% of patients had mild OSA, 42.4% had moderate, and 23.2% had severe. Overall, treatment with AD109 led to a statistically significant change in AHI, the primary end point, over a 26-week period relative to placebo (P = .001).

In SynAIRgy, patients underwent a polysomnogram on treatment at week 4. Overall, treatment with the oral agent led to meaningful improvements in oxygenation, as assessed by hypoxic burden (P <.0001), and oxygen desaturation index (P = .001). Furthermore, 51.2% of treated patients experienced a reduction in OSA disease severity, and 22.3% achieved complete disease control, defined as an AHI of fewer than 5 events per hour.

“Existing data suggests that up to 50% of patients with sleep apnea cannot or will not tolerate CPAP in the long term. There’s a huge unmet need for all of these patients with sleep apnea, and there’s a range of different treatment options being developed. AD109 is one of them that really is targeting neuromuscular function,” study chair Sanjay R. Patel, MD, MS, professor of medicine, epidemiology, & clinical and translational science at University of Pittsburgh, told NeurologyLive^® in a recent interview. “There has been exciting data in the phase 2 short term studies and we’ve already very quickly filled enrollment for the phase 3 trial with 660 patients, which I think is just a testament of how many patients out there are interested in a pharmacologic treatment like this. We’re hopeful that we’ll get the results out there in about a year from now and, fingers crossed, there’s some promising results that give patients another treatment option.”

In a previous phase 2 trial, dubbed MARIPOSA (NCT05071612), treatment with AD109 demonstrated statistically significant improvements on both objective and subjective outcomes in patients with OSA. The study featured 211 patients (41% female) with a median age 55 (48-60) years and BMI of 32.2 (28.0-35.2) kg/m2 who were randomized to AD109, atomoxetine, or placebo. All told, AHI4 was reduced from a median of 20.5 to 10.8 events/hour in the AD109 2.5mg/75 mg dose (P <.001 vs placebo).³

Additional data showed that 41% of participants who completed the study achieved an AHI below 10 when treated with AD109, 44% had greater than 50% reduction from baseline, and 15%. Of treated patients had an 80% or greater reduction. Notably, atomoxetine, dosed as a monotherapy, did not improve daytime OSA symptoms, and statistically significantly worsened nighttime sleep subjectively and by the measurement of total sleep time, indicating that atomoxetine alone is an inappropriate therapy for OSA.

AD109-treated patients also demonstrated statistically significant improvements vs placebo in PROMIS-Fatigue, a scale of daytime functioning (P <.05). The investigational agent also showed a trend towards statistically significant on scales measuring other important OSA symptoms such as PROMIS-Sleep Impairment and PROMIS-Sleep Disturbance.

REFERENCES
1. Apnimed Announces Positive Topline Results in the First Landmark Phase 3 Clinical Trial of AD109, an Investigational Once-Daily Oral Pill for Obstructive Sleep Apnea. News Release. Apnimed. Published May 19, 2025. Accessed June 25, 2025. https://apnimed.com/article/ad109phase3toplineresults/
2. Apnimed Announces Completion of Enrollment in Phase 3 LunAIRo Study of AD109, the Potential First Nighttime Oral Treatment for Obstructive Sleep Apnea. News Release. Apnimed. Published May 9, 2024. Accessed June 25 2025. https://apnimed.com/article/apnimed-announces-completion-of-enrollment-in-phase-3-lunairo-study-of-ad109-the-potential-first-nighttime-oral-treatment-for-obstructive-sleep-apnea/
3. Apnimed Presented Positive Phase 2b Results on AD109, an Investigational Oral Drug for Obstructive Sleep Apnea, for the First Time at ATS 2023. News release. Apnimed. May 21, 2023. Accessed June 25, 2025. https://apnimed.com/article/apnimed-presented-positive-phase-2b-results-on-ad109-an-investigational-oral-drug-for-obstructive-sleep-apnea-for-the-first-time-at-ats-2023/

Allergy and asthma were linked with environmental events that are increasing in prevalence alongside natural disasters and other extreme weather events, including algal blooms, floods, heat stress, wild­fires, and thunderstorms that are coinciding with emissions of per-and polyfluoroalkyl substances (PFAS) and microplastics as downstream outcomes of these environmental events, according to a study published in Current Allergy and Asthma Reports.¹

Human activities, primarily the burning of fossil fuels, are largely responsible for the greenhouse gas emissions driving these environmental changes. Weather intensity like droughts and floods have experienced dramatic rises over the past 5 years, based on data from NASA.² Extreme weather is occurring more frequently, becoming longer-lasting, and more severe.

The respiratory tract is highly vulnerable to these environmental stressors.¹ Asthma, a common chronic disease, affects nearly 25 million Americans and is exacerbated by air pollutants and extreme weather. Similarly, allergic rhinitis, eczema, and food allergies, reported by 1 in 3 adults and 1 in 4 children in the US, are worsened by conditions like high temperatures and thunderstorms. As environmental threats increase respiratory contaminant exposure, continued investigation into these intertwined health outcomes is crucial.

Extreme heat events, or heat waves, are becoming more frequent, intense, and prolonged. This poses a higher risk of premature death from respiratory diseases, especially for vulnerable populations such as children, older adults, pregnant individuals, and those with chronic conditions. Heat stress commonly exacerbates asthma by increasing inflammation, activating sensory fibers, and disrupting epithelial barriers, leading to bronchoconstriction.

High temperatures can also alter cytokine expression and T helper cell ratios, affect mucus production, and disrupt airway structural proteins. The interplay between environmental substances and extreme heat requires further research to understand additive, synergistic, or antagonistic health effects. Additionally, longer pollen seasons are introducing new allergenic species, likely worsening asthma and allergy cases.

Warmer weather, earlier snowmelt, and hotter spring and summer temperatures are escalating the intensity, frequency, and duration of wildfires. These fires release harmful emissions like carbon monoxide, carbon dioxide (CO₂), nitric oxide, ozone, particulate matter, volatile organic compounds, and polycyclic aromatic hydrocarbons.

Exposure to wildfire smoke is directly linked to more emergency department visits for respiratory issues, as well as increased respiratory illness and mortality. Perinatal wildfire smoke exposure can lead to earlier use of upper respiratory medications and a higher risk of respiratory birth defects in children. Wildfire smoke also worsens asthma symptoms and increases asthma-related hospitalizations, particularly for young children. Epigenetic changes may contribute to these health outcomes, requiring further research.

The expansion of the wildland-urban interface, where human development meets wildlands, increases the risk of human-ignited wildfires. Fires in these areas are unique because they burn not only biomass but also homes, vehicles, and other synthetic materials, creating a distinct and poorly understood pulmonary toxicity profile. According to the authors, a key goal is to develop effective interventions to prevent adverse wildfire smoke exposure outcomes for communities, especially vulnerable populations like those with asthma and allergic rhinitis.

Changing temperatures, weather patterns, and water acidi­fication from increased CO₂ emissions have altered aver­age surface water conditions, which in turn increases the risk of harmful algal blooms by expanding both the geographic range and seasonal growth windows of the different marine and freshwater phytoplankton species that comprise harmful algal blooms. While harmful algal blooms may seem like a niche public health burden, 15% of global asthma cases in coastal regions can be attributed to aerosol­ized harmful algal blooms toxins. Pulmonary exposure to harmful algal blooms has linked toxins to rapid onset of respiratory irri­tation symptoms such as cough and congestion, along with increases in hospital admission rates for respiratory diseases. The distance harmful algal blooms aerosols can travel is also unclear, especially as it relates to the size of the at-risk population and the mix­tures of aerosolized harmful algal blooms toxins amongst other atmospheric copollutants.

Floods, whether from sea or freshwater, heighten the risk of respiratory diseases, infections, and asthma exacerbations. This is primarily due to mold and microbial growth in flooded buildings. The sensitization to mold and fungi spores creates a proinflammatory environment, triggering conditions like allergic asthma and allergic rhinitis. Further research is needed to understand chronic flood-induced pulmonary issues and identify the specific mold and fungal strains responsible.

Thunderstorm asthma is a global phenomenon characterized by an increase in asthma attacks after thunderstorms. It’s likely caused by a combination of high aeroallergen concentrations like ryegrass pollen, rain, and storm conditions that bring pollen to ground level. During a storm, pollen grains can rupture into smaller, more easily aerosolized subparticles due to physical disturbances. While fungal spores are abundant aeroallergens, their link to asthma exacerbations and thunderstorm asthma is not yet firmly established.

PFAS are pervasive, persistent organic compounds used in consumer goods for their nonstick properties. Their strong carbon-fluorine bonds make them extremely difficult to degrade, posing a significant threat to environmental and human health. Humans are exposed through ingestion, absorption, and inhalation. PFAS exposure can alter inflammasome function in the lung, impacting immune response. Further research is needed to establish comprehensive limits, legislation, and public awareness regarding these chemicals.

Microplastics are expected to increase in the environment and human bodies due to climate change impacts like increased precipitation and melting glaciers. Once released, microplastics do not easily degrade, persisting in environmental media. Inhaled microplastics, with their hydrophobic surfaces, may carry other pollutants and are linked to adverse respiratory outcomes such as irritation, interstitial lung disease, wheezing, and inflammation. More research is needed to understand their biological effects on pulmonary health, exposure routes, internal transport, and overall impact.

“In the future, meta-anal­yses to quantify the health effects of natural disasters could be an important tool to inform public health measures. It is thus especially relevant for the scientific community also to begin exploring prevention and mitigation techniques in preparation for future disasters,” the authors concluded.

References

1. Chou CK, Winker R, Rebuli ME, et al. Respiratory health impacts from natural disasters and other extreme weather events: the role of environmental stressors on asthma and allergies. Curr Allergy Asthma Rep. 2025(25);3-19. doi:10.1007/s11882-025-01206-9
2. Harrabin R. Nasa data reveals dramatic rise in intensity of weather events. The Guardian. June 17, 2025. Accessed June 30, 2025. https://www.theguardian.com/world/2025/jun/17/nasa-data-reveals-dramatic-rise-in-intensity-of-weather-events

Advanced lab-grown tissues help show how special lung cells develop, shedding light on rare ACDMPV disease and suggesting potential ways to repair damage from viral infections such as COVID-19

CINCINNATI, June 30, 2025 /PRNewswire/ — A team of experts at Cincinnati Children’s reports another powerful step forward in organoid medicine: success at making human lung tissue that can produce its own blood vessels.

Their findings, published in the same month as a similar success involving liver organoids, reflect a new wave of advanced lab-grown tissues that can be used immediately in many research applications while moving ever closer to serving as living tissues that can directly repair damaged organs.

Details were posted online June 30, 2025, in the journal Cell.

“Prior to our study, the development of lung organoids with organotypic vasculature had not been achieved,” says co-corresponding author Mingxia Gu, MD, PhD. “Notably, this method also could be applied to other organ systems such as intestine and colon.”

Gu, now at UCLA, was a member of the Center for Stem Cell and Organoid Medicine (CuSTOM) and Division of Pulmonary Biology at Cincinnati Children’s while this research was conducted. Co-first and co-corresponding author Yifei Miao, PhD, (now at the Chinese Academy of Sciences, Beijing) also was with Cincinnati Children’s for this work. Co-corresponding author Minzhe Guo, PhD, remains with Cincinnati Children’s along with several co-authors involved in this study.

Overcoming a major challenge

Researchers have been working for years to grow organoids — sometimes called “organs in a dish.”

Creating organoids involves converting mature human cells (such as blood or tissue cells) back into fetal-like stem cells that can be coaxed into growing a wide range of other tissue types. Unlike disconnected human cells kept alive in a dish, these are growing, developing mini-organs that form into seed-sized spheres that mimic the unique functions of full-sized organs.

Intestines that absorb and secrete. Stomachs that produce digestive acids. Hearts that pulse. Brain tissues with firing nerve cells and so on.

Cincinnati Children’s has been a leader in organoid development since 2010 when experts here produced the world’s first functional intestinal organoid grown from induced pluripotent stem cells (iPSCs).

More recently, the challenge has been learning how to grow organoid tissues that can connect with the rest of the body to integrate nerve connections, blood vessels, bile ducts, immune systems and more. During pregnancy, these differing tissue types naturally find each other as the fetus matures and becomes more complex. Organoid developers seek to re-produce these steps in the laboratory, which eventually may allow people to receive custom-grown tissues that could patch damage or boost disrupted functions.

Simpler forms of organoids have already begun transforming medical research, allowing many scientists to use living human tissue models to study disease while reducing current reliance on animal models to develop new medicines. But without the ability to make internal blood vessels, the tiny seeds lack the ability to grow into larger, more useful tissues.

How the team solved the vascular riddle

The new study thoroughly recounts the results of many experiments the team conducted to demonstrate success at inducing blood vessel formation. The work spanned four years and involved more than 20 people at Cincinnati Children’s plus collaborations with experts at several other organizations.

“The challenge in vascularizing endodermal organs, particularly the lung, stems from different signaling requirements for lung epithelial versus vascular differentiation,” says Miao. “Our success in this endeavor is attributable to our unique differentiation method.”

In essence, the team grew iPSCs from multiple cell types then found the right moment to introduce them to each other. The resulting cell signals helped flip a developmental switch so that progenitor cells that could have become either blood vessels or the outer walls of the lung wound up becoming blood vessels. In achieving this vital step, the team:

• Produced lung organoids that include respiratory bronchial epithelial cells (RAS cells), a human cell type not previously reported in conventional lung organoid models.
• Pinned down the developmental moments when a rudimentary gut tube begins to send some cells to form the lungs while sending other cells to form the stomach and intestine. While the basic steps of this transformation have been studied in animals, it had not been possible to study this stage of development in humans without killing fetuses.
• Demonstrated that the rare disease ACDMPV occurs when cell signaling “crosstalk” gets disrupted during this early blood vessel formation stage. Within days of birth, infants born with Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV) struggle to breathe because their lungs’ air sacs (alveoli) and blood vessels are malformed. Nearly all infants with this condition die within the first month of life, according to the National Organization for Rare Disorders.
• Revealed key functional information about the cells involved in gas exchange inside the human lung. Their learnings help explain the damage within tiny blood capillaries that occurs in the lungs in response to injuries. These new clues offer fresh ideas for developing ways to protect and potentially restore affected lung tissues.

What’s Next?

Cincinnati Children’s has filed patent applications related to the methods developed here to produce organoids with blood vessel formation capabilities and the CuSTOM team is moving to further develop this technology.

“We look forward to continuing to learn more about the fundamental biology involved in organ formation and applying those discoveries to improving outcomes across a wide range of difficult human diseases and conditions,” says Aaron Zorn, PhD, co-director of CuSTOM and director of the Division of Developmental Biology.

In addition to publishing these findings in Cell, co-authors plan to present their work at the Keystone conference in Kyoto, Japan (iPSCs: Progress, Opportunities, and Challenges) in January 2026.

About the study

Cincinnati Children’s co-equal first authors were Miao, Nicole Pek, BS, and Cheng Tan, MD.

Contributing co-authors from Cincinnati Children’s were Cheng Jiang, MS, Zhiyun Yu, PhD, Kentaro Iwasawa, MD, PhD, Min Shi, MD, PhD, Daniel Kechele, PhD, Nambirajan Sundaram, PhD, Victor Pastrana-Gomez, MSTP student, Debora Sinner, PhD, Cheng-Lun Na, PhD, Keishi Kishimoto, PhD, Jason Tchieu, PhD, Jeffrey Whitsett, MD, Kyle McCracken, MD, PhD, Michael Helmrath, MD, James Wells, PhD, Takanori Takebe, MD, PhD, and Aaron Zorn, PhD.

Contributing co-authors included experts from Harvard Medical School, Icahn School of Medicine at Mount Sinai, Sophia Children’s Hospital (The Netherlands), Boston University

This research also was supported by the Discover Together Biobank, the Bio-Imaging and Analysis Facility, and the Integrated Pathology Research Core at Cincinnati Children’s and the University of Cincinnati Proteomics Laboratory.

Funding sources for this work included: the National Institutes of Health (R01HL166283, DK128799-01, N01-75N92020C00005 and R01HL095993); an Endowed Scholar Award from the Cincinnati Children’s Research Foundation; the American Heart Association (1013861 and 906513); the Falk Transformational Awards Program; and the Brigham Research Institute.

Learn more about working with CuSTOM

Learn how donors can support ongoing organoid research at Cincinnati Children’s

SOURCE Cincinnati Children’s Hospital Medical Center

June is Men’s Health Awareness Month. In recognition of this event, we spoke with Justin Dubin, MD, a urologist at Memorial Healthcare Systems in South Florida, about the current landscape of care in men’s health.

Dubin acknowledged that while progress has been made in normalizing conversations around issues such as erectile dysfunction, stigma around men’s health conditions remains a large concern in 2025. This has created an opportunity for artificial intelligence (AI) to take off in this space, with many men turning to large language models to find information.

“Men being men, we always want to fix problems ourselves,” Dubin explained. “And instead of going to talk with a provider, they go online. Initially it was social media. It has advanced to things like podcasts and naturally, Dr. Google, Dr.TikTok, and has now progressed to Dr. ChatGPT.”

Dubin touched on both sides of this issue, highlighting both the challenges with AI in health care as well as the potential opportunities for use in the men’s health space.¹ One such opportunity is in patient education. Technology such as ChatGPT gives patients the chance to take ownership of their health, allowing them to better understand health concerns, ask informed questions, and feel more confident about seeking care.

For health care professionals, this also means a shift in the way they’re delivering care, with a new focus on making sure that men are using the right tools.

“In general, this is a very interesting time in men’s health. I think a lot of men who [were] always interested in having autonomy over their education and how they learn and autonomy over their bodies, finally have an opportunity to do that in a good way,” Dubin concluded. “You have a lot of information and a lot of opportunity for autonomy at your hands. It’s just really having the appropriate guidance to do so.”

REFERENCE

1. Panken EJ, Patel AU, Schammel J, Dubin J. Man and machine: exploring the intersection of artificial intelligence and men’s health. Curr Opin Urol. 2025;35(3):236-242.

doi: 10.1097/MOU.0000000000001274

As the first phase 3 trial to investigate an Fc-silent, anti-TIGIT agent in patients with solid tumors, the STAR-221 study (NCT05568095) may further clarify the therapeutic role of domvanalimab plus zimberelimab (Sepalizumab) and chemotherapy in patients with gastric cancers, potentially reshaping first-line treatment paradigms, particularly for PD-L1–positive disease, according to Kohei Shitara, MD.

STAR-221 is investigating the combination of the TIGIT monoclonal antibody domvanalimab, the PD-1 inhibitor zimberelimab, and FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) vs nivolumab (Opdivo) plus FOLFOX or CAPOX in the first-line setting for patients with locally advanced unresectable or metastatic gastric, gastroesophageal junction (GEJ), and esophageal adenocarcinoma.¹ Overall survival (OS) serves as the primary end point. Secondary end points include progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), safety, and quality of life outcomes.

The initiation of STAR-221 is based on positive findings from the phase 2 EDGE-Gastric trial (NCT05329766).² Updated findings from arm A1 of the study showed that in all evaluable patients with first-line, locally advanced unresectable or metastatic gastric/GEJ/esophageal adenocarcinoma (n = 41), at a median follow-up of 13.9 months, the confirmed ORR with domvanalimab plus zimberelimab and FOLFOX was 59% (95% CI, 42%-74%). Among patients with a PD-L1 tumor activity positivity (TAP) score of at least 5% (n = 16), this rate was 69% (95% CI, 41%-89%). Among those with a TAP score of less than 5%, the ORR was 50% (95% CI, 29%-71%).

“Maybe the benefit [will be limited to] patients in the PD-L1–high population, but we should see the actual data [from STAR-221],” Shitara said in an interview with OncLive®. “If we have positive findings, this may give us important insight about the structure of the antibody and whether Fc-silent or Fc-activated [agents] give us different stories [in the context of] past negative trials.”

In the interview, Shitara discussed the mechanism of action and clinical activity of the TIGIT-targeted agent domvanalimab; preclinical and phase 2 data that support the continued investigation of domvanalimab plus zimberelimab and chemotherapy in patients with gastric/GEJ/esophageal cancers; and the potential clinical implications of results from STAR-221, which may be influenced by PD-L1 status.

Shitara is the director of the Department of Gastrointestinal Oncology at the National Cancer Center Hospital East in Kashiwa, Japan.

OncLive: How do domvanalimab and zimberelimab work alongside chemotherapy to elicit antitumor responses?

Shitara: The important target molecule is TIGIT, especially for this combination. TIGIT is an inhibitory checkpoint receptor expressed on various types of immune cells, especially exhausted CD8 cells and regulatory T cells [Tregs], where it usually competes with activating molecules, such as CD20 and CD26, for binding its ligands. If there is TIGIT expression, this usually leads to inhibition of a specific immunophenotype like T cells, Tregs, and natural killer cells. Importantly, [TIGIT] is usually observed with other immune checkpoint molecules, such as PD-1 and LAG-3 [inhibitors]. It is expressed at a relatively later stage of exhaustion. That’s why blocking TIGIT has emerged as an attractive strategy in cancer immunotherapy. This is usually combined with anti–PD-1 and –PD-L1 agents.

An important aspect [of some] TIGIT antibodies is [the] Fc-maintained or Fc-activated [state, which] retains Fc receptor binding capabilities, leading to antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity to deplete TIGIT-expressing immune cells. For example, an Fc-maintained IgG1 antibody may deplete Tregs. This may be good for antitumor response, but it may also increase autoimmune toxicity because of the depletion of Tregs.

Another class of agents is the Fc-silent TIGIT antibody, which is engineered to lack Fc receptor engagement. It doesn’t deplete Tregs—instead, it [mainly] enhances the expansion of effector cells. On the other hand, if Fc is maintained, there is also a risk of depletion of activated effector cells. There are always pros and cons for this kind of structure.

In preclinical studies, there’s a good paper for both classification of Fc-silent and Fc-maintained antibodies. This was published in Cancer Research and supports that Fc-silent IgG1 antibodies for TIGIT may be better compared with Fc-maintained [agents]. However, another group published a different paper in Nature that supports that Fc-activated TIGIT antibodies are better, especially regarding depletion of immunosuppressive cells, like Tregs.

Based on these preclinical studies, TIGIT inhibition is attractive. However, there are 2 types of anti-TIGIT antibodies. Domvanalimab is mainly an Fc-silent IgG1 antibody. This may not deplete inhibitory cells, but [it may] mainly activate exhausted effector cells. Because of its lack of depletion of Tregs, the toxicity profile is expected to be feasible. This is usually combined with the anti–PD-1 [agent] zimberelimab. Zimberelimab is an IgG4 monoclonal antibody [with a mechanism of action] similar to that of nivolumab and pembrolizumab [Keytruda]. This combination has been tested in various clinical trials.

What phase 2 data contributed to the rationale for STAR-221?

This combination’s development is further supported by results from the ongoing EDGE-Gastric trial. This is a first-line gastric cancer trial [planning] to enroll approximately 40 patients to test domvanalimab and zimberelimab in combination with a cytotoxic FOLFOX regimen. Initial data were presented at the 2024 ASCO Annual Meeting and showed an ORR of 59% in the entire population, with a median PFS of 12.9 months. Although the small sample size is a relatively major limitation of the study, [the findings], in direct comparison with [those from] previous pivotal trials like the phase 3 CheckMate 649 [NCT02872116] and KEYNOTE-859 [NCT03675737] studies, suggested an increased ORR and longer median PFS.

The subgroup analysis [data] also support [population] enrichment by PD-L1 status. This TIGIT-directed domvanalimab/zimberelimab/chemotherapy combination seemed to work better in patients with high PD-L1 expression, such as a combined positive score [CPS] or TAP score of 5% or higher. This is in line with our expectations, because TIGIT is usually co-expressed with other checkpoints like PD-1 [T] effector cells. Additionally, the safety profile looks manageable; because of a lack of Treg depletion, autoimmune reactions seem to not be increased.

The phase 3 STAR-221 trial is ongoing to test domvanalimab/zimberelimab in combination with first-line FOLFOX or CAPOX vs the current standard of chemotherapy plus nivolumab in the first-line setting. We needed to test PD-L1 status before patient enrollment. Patients could be enrolled regardless of PD-L1 status, but stratification by PD-L1 status was important, considering the mode of action [of the combination demonstrated in] the subgroup analysis of the phase 2 study. That’s why PD-L1 TAP score was included as one of the stratification factors for the primary end point for OS in this study. Subgroups will also be tested according to TAP score or CPS status. Enrollment [to STAR-221] is completed, and we are waiting for survival follow-up and analysis.

Concerning the current other trials for TIGIT-targeted therapy, unfortunately, no phase 3 trial has shown the benefit of TIGIT inhibitors in any solid tumors. For example, there were negative trials in melanoma, gynecological cancer, and lung cancer. The lung cancer trial showed a borderline benefit of TIGIT inhibition, especially in the PD-L1–positive population.

Although all trials [with TIGIT inhibition] have been negative, there [are opportunities to use TIGIT inhibitors with] different modes of action, especially [regarding] the Fc portion. Previously reported phase 3 trials have almost always applied Fc-maintained or Fc-activated TIGIT inhibitors. STAR-221 is the first study to test an Fc-silent anti-TIGIT antibody. [Therefore], we may observe a difference [in outcomes from this trial] compared with previous negative trials.

How might positive results from STAR-221 affect the development of domvanalimab and the placement of the investigational combination among current chemoimmunotherapy regimens for gastric cancers?

It should depend on the result. If [domvanalimab/zimberelimab/chemotherapy] shows an OS benefit compared with chemotherapy plus nivolumab, it should be at least the standard in some populations. However, this depends on the subgroup analysis [where patients are stratified] by PD-L1 status. If it only shows a benefit in the PD-L1–high population, it should be the treatment used for that population [only].

However, if [the combination] shows an [OS] benefit regardless of PD-L1 status, this is also attractive, because usually patients with low PD-L1 status achieve limited benefit with chemotherapy plus a PD-[L]1 inhibitor. If this trial turns out to be positive, why not test this agent in other types of tumors [beyond those] where previous anti-TIGIT therapy failed to show a survival benefit? It should be interesting.

Chemotherapy/nivolumab is standard, especially for patients with a PD-L1 CPS of 1 or higher. [In patients with a] CPS less than 1, [this combination] didn’t show benefit, but there’s no detrimental effect. The [STAR-221] trial was started before the FDA’s Oncologic Drugs Advisory Committee meeting about the restriction of [frontline PD-1 inhibitors to patients with HER2-negative, microsatellite-stable gastric/GEJ adenocarcinoma with a PD-L1 CPS greater than 1]. I don’t expect any large barriers or any differences in this [trial] population compared with the general gastric cancer population regarding CPS frequency.

Additionally, the main objective in this study is to see the treatment effect, especially in patients with a CPS or a TAP score of 5% or higher. [CPS] is being monitored during the trial. It does not seem different from the usual frequency [seen in this population], but the exact results should be reported after the analysis.

References

1. A clinical trial of a new combination treatment, domvanalimab and zimberelimab, plus chemotherapy, for people with an upper gastrointestinal tract cancer that cannot be removed with surgery that has spread to other parts of the body (STAR-221). ClinicalTrials.gov. Updated June 26, 2025. Accessed June 30, 2025. https://www.clinicaltrials.gov/study/NCT05568095
2. Janjigian Y, Oh D, Pelster M, et al. Updates on abstract 433248: EDGE-Gastric arm a1: phase 2 study of domvanalimab, zimberelimab, and FOLFOX in first-line (1l) advanced gastroesophageal cancer. Presented at: 2024 ASCO Annual Meeting. May 31-June 4, 2024. Chicago, IL.

V116, a 21-valent, adult-specific pneumococcal conjugate vaccine (PCV21; Merck) indicated for protection against pneumonia and invasive pneumococcal disease (IPD), was found to exhibit consistent immunogenicity and safety profiles across 3 different manufacturing lots, according to investigators of a study published in Med.¹

Importance of Vaccine Lot Consistency

Ensuring that vaccine efficacy, potency, and safety are consistent across manufacturing lots is critical. Vaccine production is a complex process that can occur over multiple sites and involve numerous stakeholders, with myriad opportunities for mistakes that could impact the health of patients. Investigators say that even subtle changes in the production process can alter the purity, efficacy, or safety of a vaccine lot. These risks are compounded with ever-present barriers in procuring necessary supplies for vaccines and navigating shortages.²

“This compounded risk of biological and physical variability makes vaccine manufacturing more challenging than typical small molecule pharmaceuticals and is a primary root cause of the high proportion of vaccine manufacturing failures and supply shortages,” the authors of a review of the vaccine manufacturing process published in Vaccine wrote.²

Vaccines to protect against Streptococcus pneumoniae (S. pneumoniae) infection, which can lead to community-acquired pneumonia and IPD, have been increasingly manufactured and proliferated across the globe. These conditions lead to significant morbidity and mortality, especially among older adults and those with risk factors that would cause severe disease. Several vaccines targeting S pneumoniae have been developed, most prominently PCVs, which target multiple pneumococcal-causing serotypes that circulate in the community.^1,3

V116 (PCV21) was approved by the FDA in 2024 for the prevention of invasive disease and pneumonia caused by S pneumoniae for patients aged 18 years and older. According to a series of clinical trial data from the STRIDE family of trials, V116 was found to elicit higher immune responses than a comparator vaccine for serotypes unique to V116. Furthermore, the Advisory Committee on Immunization Practices (ACIP) has recommended that adults 65 years and older who had not previously received a pneumococcal vaccine and those 16 to 64 years with known risk factors receive PCV21.^3,4

V116 is Similarly Efficacious Across Vaccine Lots

Although the efficacy of V116 has been proven, the lot consistency of V116—how similar the potency and efficacy of the vaccine is across manufacturing lots—has yet to be determined. These insights could serve as critical indications of the strength of V116’s manufacturing process and identify areas where refinements to the process are necessary. Therefore, investigators of a global phase 3 trial (STRIDE-4; NCT05464420) sought to evaluate the manufacturing consistency of V116.¹

Participants were randomly assigned to receive a single dose of V116 from 1 of 3 lots or the 23-valent pneumococcal polysaccharide vaccine (PPSV23). Thirty days post-vaccination, investigators associated geometric mean titers (GMTs) and immunoglobulin G (IgG) geometric mean concentrations (GMCs) for patients. In addition, systemic and injection-site adverse events (AEs) were examined for 5 days postvaccination, according to the investigators.¹

Results from the analysis indicate that all 3 lots of V116 met equivalence criteria based on GMTs for all 21 serotypes included in the vaccine. GMTs and GMCs were found to be comparable between the combined V116 lots and PPSV23 for shared serotypes and were higher in the combined V116 lots for serotypes unique to V116, reaffirming the superior efficacy of V116 versus PPSV23. Importantly, the AE profiles were similar across the 3 V116 lots, and between the combined V116 lots and PPSV23, the study authors found.¹

Ultimately, these results both reinforce the strong protection provided against S pneumoniae from V116 and solidify the consistent safety and efficacy across vaccine lots of V116. Recipients of V116 can be assured that there are no significant differences between their vaccine and another, with the same protection provided regardless of lot. Pharmacists can discuss a typical vaccine manufacturing process with their patients to address any lingering concerns regarding safety and efficacy.¹

REFERENCES

1. Scott P, Ukkonen B, Caraco Y, et al. A phase 3, randomized trial to evaluate lot-to-lot consistency of V116, an adult-specific pneumococcal conjugate vaccine (STRIDE-4). Med. 2025;100748. doi:10.1016/j.medj.2025.100748

2. Plotkin S, Robinson JM, Cunningham G, Iqbal R, Larsen S. The complexity and cost of vaccine manufacturing—An overview. Vaccine. 2017;35(33):4064-4071.

3. Halpern L. Pneumococcal 21-valent conjugate vaccine generates positive response in adults at increased risk of disease. Pharmacy Times. Published October 21, 2024. Accessed June 30, 2025. https://www.pharmacytimes.com/view/pneumococcal-21-valent-conjugate-vaccine-generates-positive-response-in-adults-at-increased-risk-of-disease

4. Gallagher A. FDA approves V116 for prevention of invasive pneumococcal disease and pneumonia. Pharmacy Times. Published June 18, 2024. Accessed June 30, 2025. https://www.pharmacytimes.com/view/fda-approves-v116-for-prevention-of-invasive-pneumococcal-disease-and-pneumonia

Every protein in the body is encased in a water shell that directs protein structure, provides vital stability and steers function. Because of this, water molecules represent a powerful but largely underappreciated foothold in drug binding studies. Yet structural data about these water networks, usually collected at freezing temperatures, often carry temperature-based structural artifacts. St. Jude Children’s Research Hospital scientists have unveiled a new computational tool called ColdBrew to address this problem. The tool leverages data on extensive protein water networks to predict the likelihood of water molecule positions within experimental protein structures, potentially aiding drug discovery efforts. ColdBrewwas published today in Nature Methods.

Proteins have evolved to fold precisely according to the repulsion and attraction of their amino acid building blocks to water. Water is also key to their activity since it helps guide other molecules, including drug molecules, to bind effectively. Drug discovery efforts based on protein structures use techniques such as X-ray crystallography and cryo-electron microscopy, but these techniques use freezing, or “cryogenic” temperatures, which can distort how water molecules appear. Marcus Fischer, PhD, St. Jude Department of Chemical Biology & Therapeutics, recognized this as a missed opportunity. 

Water molecules in protein structures have so many degrees of freedom that drug discoverers typically throw them out. They’re kind of inconvenient.”

Marcus Fischer, PhD, St. Jude Department of Chemical Biology & Therapeutics, corresponding author on the study

With ColdBrew, seeing is believing

To put this lost information to work, Fischer and first author Justin Seffernick, PhD, St. Jude Department of Chemical Biology & Therapeutics, developed ColdBrew. “Our goal was to make a tool that’s easy to use and understand,” said Seffernick. “For each water molecule, our method can tell us how likely water is to be present at higher temperatures. We also found that this same metric can give us clues about how ligands bind to proteins.”

This is particularly important to drug discovery. “When ligands bind to proteins, they kick out water from binding sites, so we need to pay attention to them in ligand design,” said Fischer. “Encouragingly, we’ve seen in our data that our predictions were best within these binding sites and around ligands.” 

Considering that cryogenic structure-solving techniques can artificially increase the number of water molecules present in a structure, a tool such as ColdBrew can assure researchers that seeing is believing. To this end, Fischer and Seffernick have amassed and made publicly available a comprehensive library based on ColdBrew calculations. 

“To enable the wide use of ColdBrew, we performed calculations on every structure that fit our criteria in the entire Protein Data Bank. We have over 100,000 predictions, which is over 46 million water molecules,” Fischer said. “Remarkably, our results show that drug designers unknowingly avoid tightly bound waters, so actually knowing which ones to avoid could guide the process.”

Authors and funding

The study was supported by grants from the National Institutes of Health (R35GM142772) and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.