After a courtroom defeat, Trump administration health officials have revised the governing documents for a key federal vaccine panel to broaden its membership, increase its focus on potential harms of vaccines, and empower allies of health secretary Robert F. Kennedy Jr.
The new charter for the committee that advises the Centers for Disease Control and Prevention on vaccine use appears aimed at trying to evade the type of legal challenge that has left the currently appointed body in limbo. In addition, the document puts greater emphasis on the role of the Advisory Committee on Immunization Practices in studying injuries possibly linked to vaccination — though the committee has always paid close attention to any emerging evidence that called into question the safety of individual vaccines.
For decades, venture capitalists have relied on a tried-and-true recipe to make money in biotech: Start with compelling scientific research — usually out of a U.S. university lab — add a dash of veteran executives from a pharmaceutical goliath or big biotech, and finish with tens of millions of dollars. The approach has led to scores of new medicines, successful companies, and financial returns for VC firms and their investors.
Now, it’s being disrupted.
In the aftermath of biotech’s Covid-era rally and subsequent decline, the industry has been startled to find that Chinese scientists are conducting innovative research, faster and at lower costs, than their U.S. counterparts. In the United States and elsewhere, meanwhile, investors are being wooed by artificial intelligence, drawing attention and dollars away from biotech.
Neuroblastoma is the most common tumor among children under a year of age, and while in its gentlest form neuroblastoma can regress on its own, it can also take an aggressive form, with high-risk neuroblastoma carrying a five-year survival rate of about 40%.
Researchers at The Hebrew University of Jerusalem have now discovered a mechanistic explanation for how neuroblastoma sustains itself and identified a potential approach to severing that mechanism, by inhibiting nitric oxide (NO) production to suppress mTOR signaling. The collective results from work in human neuroblastoma cells and experiments in a mouse xenograft model showed that inhibiting the enzyme neuronal nitric oxide synthase (nNOS) to inhibit NO production suppressed mTOR signaling and slowed tumor growth.
Professor Haitham Amal, PhD, head of The Laboratory of Neuromics, Cell Signaling, and Translational Medicine, is senior and co-corresponding author of the team’s published paper in Brain Medicine, titled “Targeting nNOS suppresses AKT–TSC–mTOR signaling and inhibits neuroblastoma growth.” In their paper the team concluded “Inhibition of nNOS suppresses mTOR signaling, reduces cellular malignancy, and attenuates tumor growth in vivo, identifying the nNOS-mTOR axis as a promising therapeutic target in neuroblastoma.”
Neuroblastoma accounts for roughly 28% of all cancers diagnosed in infants across Europe and the United States. “Neuroblastoma (NB) refers to a spectrum of neuroblastic tumors that originate from the neural crest cells during fetal development,” the authors wrote. “Neuroblastoma is predominantly a pediatric malignancy, with approximately 97% of cases occurring in children.”
NBs can range from spontaneous regression to maturation to an aggressive, deadly metastatic disease. And as the investigators noted, “Despite major advances in multimodal therapy, high-risk neuroblastoma remains associated with poor prognosis, frequent relapse, and therapy resistance, underscoring the need for a better understanding of the signaling pathways that regulate tumor cell survival, differentiation, and metabolic adaptation.”
Nitric oxide (NO) is an essential regulator of carcinogenesis in various tumors, including NB, the authors pointed out. “Nitric oxide (NO) is a ubiquitous free radical signaling molecule produced in multiple organs and tissues), such as those of the central and peripheral nervous systems.” But at elevated concentrations NO becomes reactive, generating nitrogen species that chemically modify proteins through a process called S-nitrosylation. That modification has been implicated in every stage of cancer progression.
The relationship between nitric oxide and tumors is not simple. Very high concentrations can damage DNA and trigger apoptosis. Lower, sustained levels appear to do the opposite, promoting survival and metastasis. Amal and colleagues had previously demonstrated that nitric oxide drives glioblastoma progression. The question that remained was whether the same enzyme, neuronal nitric oxide synthase, was performing a similar service for neuroblastoma, and if so, through which downstream pathway. The answer turned out to be mTOR.
The team attacked nNOS from two directions. They treated human SH-SY5Y neuroblastoma cells with BA-101, a selective pharmacological inhibitor, at 100 μM for 24 hours. Separately, they silenced the nNOS gene with small interfering RNA. The reasoning was that if a drug and a genetic tool produce the same result, you are looking at biology, not pharmacological noise.
The experiments produced the same result. BA-101 reduced NADPH-diaphorase activity, the standard readout of NOS function, by 35-40%. Genetic silencing cut it by 45-50%. Nitrite levels, a stable proxy for nitric oxide production, fell 65-70% with BA-101 and 55-60% with siRNA. Colony formation, the most direct measure of proliferative capacity, dropped significantly after both BA-101 treatment (p < 0.001) and nNOS silencing (p < 0.01). The cells were losing their ability to multiply.
What followed downstream was systematic. Protein tyrosine nitration, measured by 3-nitrotyrosine immunoreactivity, fell sharply after BA-101 treatment (p < 0.01) and nNOS silencing (p < 0.001). The chemical signature of nitrosative stress was fading.
The results then confirmed that AKT phosphorylation decreased (p < 0.01 with BA-101; p < 0.05 with siRNA), while total AKT remained unchanged. Phosphorylation of mTOR itself declined under both conditions (p < 0.01 each). The downstream mTORC1 substrate ribosomal protein S6 followed (p < 0.05 with BA-101; p < 0.01 with siRNA).
And here, the most telling detail, that TSC2, a master negative regulator of mTOR signaling, rose significantly under both treatments (p < 0.05). Removing the nitric oxide signal had allowed the cell’s own braking system to re-engage. In summary, the authors noted, “Pharmacological inhibition of nNOS with BA-101 (100 μM, 24 h) or genetic silencing of nNOS with siRNA caused upregulation of the key negative regulator TSC2 and decreased phosphorylation of AKT, mTOR, and RPS6, indicating suppression of mTOR pathway activity.”
Synaptophysin, a neuroendocrine tumor marker used to gauge the malignant identity of neuroblastoma cells, decreased significantly with BA-101 (p < 0.01) and nNOS knockdown (p < 0.05). The tumor cells were not merely growing more slowly. They were becoming, at a molecular level, less recognizably cancerous. In summary, the investigators noted, “Our results show that inhibition of NO production in the human NB cell line (SH-SY5Y cells), either by pharmacological intervention using the selective nNOS inhibitor BA-101 (41) or by genetic ablation using the specific siRNA, successfully suppressed NB malignancy.”
Schematic model illustrating the NO-mTOR signaling axis in neuroblastoma. Under basal/pathological conditions (left panel), and nNOS inhibition (right panel). [Haitham Amal]
But if blocking nitric oxide suppresses mTOR signaling, then flooding the cell with nitric oxide should amplify it. The researchers tested this by exposing SH-SY5Y cells to SNAP, a nitric oxide donor, at 200 μM for 24 hours. This converse experiment produced the converse result. 3-nitrotyrosine rose (p < 0.05), and TSC2 fell (p < 0.01). Phosphorylation of AKT, mTOR, and RPS6 all increased (p < 0.05 for each).
The team then tested their findings in a xenograft mouse model of neuroblastoma, treated with BA-101. “Importantly, to extend these findings to an in vivo context, we further assessed the impact of pharmacological nNOS inhibition on tumor growth in a xenograft NB model,” they stated. The investigators found that while tumors in control animals grew to approximately 1.5 cm in their largest dimension, the treated tumors did not. Final tumor volume and weight were dramatically reduced in the BA-101 group. ‘Quantitative analysis revealed a dramatic decrease in the final tumor volume and weight in the BA-101-treated group (p < 0.001) compared with controls,” they noted.
Body weight did not differ significantly between groups, suggesting that the compound was tolerated without gross systemic toxicity. In summary, the authors wrote, “Our finding demonstrate that the pro-tumorigenic effects of nNOS in SH-SY5Y involve activation of themTOR signaling pathway.” Importantly, both genetic inhibition of nNOS using siRNA and pharmacological inhibition with BA-101 effectively suppressed mTOR pathway activation and reduced malignant properties of NB cells, highlighting the therapeutic relevance of targeting nNOS signaling. “These findings indicate that pharmacological inhibition of nNOS effectively suppresses xenograft tumor progression, highlighting the critical role of nNOS-derived NO in promoting neuroblastoma growth in vivo.”
“The magnitude of the in vivo suppression caught our attention,” said Amal, the study’s corresponding author, who holds appointments at the Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, and the Rosamund Stone Zander and Hansjoerg Wyss Translational Neuroscience Center at Boston Children’s Hospital, Harvard Medical School. “We had demonstrated the role of nitric oxide in glioblastoma previously, but the consistency of the neuroblastoma results across every assay, from protein phosphorylation to colony formation to xenograft growth, points to nNOS as something more than a contributor. It appears to be a central driver of the signaling that sustains this tumor.”
Added first author Shashank Kumar Ojha, PhD, first author of the study and a researcher at the Institute for Drug Research, The Hebrew University of Jerusalem, added, “What convinced me was the concordance between the pharmacological and genetic approaches. When BA-101 and siRNA independently produce the same pattern of effects across NADPH-diaphorase activity, nitrosative stress markers, mTOR pathway phosphorylation, and clonogenic growth, you can be confident the biology is real. That reproducibility is what gives you a therapeutic hypothesis worth testing further.”
The authors acknowledged limitations to their study. The in vitro work relied on a single cell line, SH-SY5Y, which cannot capture the full genetic heterogeneity of neuroblastoma or the complexity of the tumor microenvironment. The chemical identity of BA-101 is currently undisclosed pending patent issuance, which means independent replication by other laboratories must wait. Whether nitrosative stress directly underlies its functional impairment, or whether an intermediary mechanism is involved, remains an open question that the authors explicitly flag for future investigation. “Future studies using patient-derived cells, organoids, or genetically engineered mouse models will be important to further validate and extend these observations,” they stated. Nevertheless, the authors suggest, the limitations do not diminish the central discovery of a druggable nNOS–mTOR axis.
mTOR inhibitors such as rapalogs and catalytic mTOR inhibitors have shown limited efficacy as monotherapies in neuroblastoma, undermined by feedback activation and resistance mechanisms. The present study suggests the potential for a different attack strategy. Rather than targeting mTOR at the lock, intervene upstream at the hand that turns the key. By reducing nitric oxide-dependent mTOR activation, nNOS inhibition may sidestep the compensatory pathways that have frustrated direct mTOR blockade. “Collectively, these results identify the nNOS-mTOR axis as a key driver of neuroblastoma progression and suggest that nNOS inhibition represents a promising strategy for NB treatment,” they concluded.
BackgroundCognitive impairment persists during partial or full remission in 50–70% of individuals with mood disorders and impacts daily functioning and clinical prognosis. Preclinical evidence suggests that extended exposure to moderate hypoxia, combined with motor-cognitive learning, may elevate neuroplasticity and improve cognition. In these individuals with remitted mood disorders, we found that cognitive training under repeated moderate normobaric hypoxia improved executive function, and here investigate neurobiological mechanisms.MethodsParticipants with major depressive disorder (MDD) or bipolar disorder (BD) in partial or full remission were randomized to 3 weeks of 3.5-h daily normobaric hypoxia (12% O2) combined with cognitive training five to 6 days per week or treatment-as-usual (TAU). Participants were assessed with cognitive tests and diffusion-weighted MRI at baseline and 1 month after treatment completion (week 8) as part of the ALTIBRAIN trial (ClinicalTrials.gov: NCT06121206). Prefrontal and hippocampal gray matter microstructure were modelled with Neurite Orientation Dispersion and Density Imaging (NODDI).ResultsFifty-seven participants (mean age 39 years, SD: 13, 70% female) with baseline MRI data were included. No significant effects of hypoxia-cognition training vs. TAU on neurite density index (NDI) or orientation dispersion index (ODI) were observed in either the prefrontal cortex or hippocampus (all p-FDR ≥ 0.832). No significant associations were observed between microstructural changes and changes in cognitive function in either region (all p-FDR ≥ 0.721). At baseline, microstructure in both regions was not associated with executive function or global cognition (all p > 0.40).ConclusionThe absence of detectable microstructural changes, despite selective improvements in executive function, indicates that NODDI-derived metrics did not capture structural correlates of the cognitive response to hypoxia-cognition training. Whether this reflects functional neural mechanisms, measurement insensitivity, or the timing of the single follow-up assessment remains to be determined. Future studies should incorporate multiple imaging time points to capture the dynamic trajectories of putative microstructural brain changes.
Background: Digital mental health technologies (DMHTs) are playing an increasing role in mental health services. The quality of evidence for DMHTs is variable, and there are concerns that evidence is not sufficient to support decision-making. Objective: This study used a cross-sectional analysis of evidence supporting DMHTs included in National Institute for Health and Care Excellence (NICE) evaluations to examine the strength of evidence available for decision-making. Methods: We identified all NICE evaluations relating to DMHTs by reviewing details of published NICE evaluations on the NICE website. From each of these evaluations, we identified included DMHTs and reviewed committee documentation to identify studies that provided supporting evidence for each of these technologies. We extracted information on a series of items relating to study quality and summarized the characteristics of evidence both at the level of individual studies and across the package of evidence from multiple studies supporting DMHTs. We also identified key evidence gaps in available evidence. Results: We included nine NICE evaluations relating to anxiety, depression, psychosis, insomnia, attention deficit hyperactivity disorder (ADHD), and tic disorders. These evaluations included 30 DMHTs and referenced 78 supporting studies. We identified common evidence gaps relating to effectiveness compared to relevant comparators, use of appropriate outcomes, including health-related quality of life, cost of delivery, and impact on resource use, and reporting of adverse events. Conclusions: Our study highlights that some DMHTs have been supported by high-quality studies and that evidence to support DMHTs is likely to be developed across a series of studies. However, there are often key evidence gaps that need to be addressed to provide a stronger case for adoption. Developers should ensure that they consider these gaps while planning evidence generation, and where possible, address them earlier in the product lifecycle.
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ObjectiveTo analyze the prevalence of dyslipidemia and related influencing factors in patients with early-onset schizophrenia (EOS).MethodsWe recruited 289 pediatric and adolescent EOS patients from October 2021 to June 2024 in the Third People’s Hospital of Fuyang. Researchers gathered comprehensive demographic and clinical records. Utilizing the 2023 Chinese Guidelines for Lipid Management, they calculated dyslipidemia prevalence and the incidence of irregularities in total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, and non-HDL cholesterol. Subsequently, differences in dyslipidemia among different genders, body mass index, and antipsychotic medication groups were analyzed. Finally, independent influencing factors of dyslipidemia in EOS patients were explored.ResultsThe overall prevalence of dyslipidemia was 24.9% (72/289), with abnormal rates of TG, TC, HDL-C, LDL-C, and non-HDL-C being 15.9%, 6.6%, 6.6%, 4.2%, and 7.3%, respectively. Male patients, those who were overweight or obese, and those taking two antipsychotic drugs had significantly higher rates of dyslipidemia. Regression analysis showed that male gender (OR = 2.04, P = 0.016), overweight/obesity (OR = 4.55, P < 0.001), body roundness index (OR = 1.53, P = 0.005), and the use of two antipsychotic drugs (OR = 1.90, P = 0.030) were risk factors for dyslipidemia in EOS patients.ConclusionThe prevalence of dyslipidemia in EOS patients is relatively high. When monitoring lipid levels in clinical practice, particular attention should be paid to male patients, those who are overweight or obese, and those receiving combined drug therapy.
BackgroundEsketamine has a significant and rapid antidepressant effect. Although studies have shown that Neuregulin 1 (NRG1) and it’s signaling pathway are associated with depression, the possible regulatory relationship of esketamine on the NRG1-ErbB4 pathway is not yet clear.MethodsTo induce depressive-like behavior in mice, a Chronic Social Defeat Stress (CSDS) model was established. Behavioral indicators were then employed to assess depression in these mice, categorized into control, susceptible, and resilient groups. Following intraperitoneal injection of a subanesthetic dose of esketamine, behavioral tests were conducted at 30 minutes and 24 hours post-injection to observe any improvements in depressive-like behavior. Additionally, changes in immunofluorescence and protein expression levels of NRG1-ErbB4 and GAD67 in the prefrontal cortex were evaluated.ResultsCompared with the control group, the CSDS susceptible group mice showed decreases in social interaction ratio in the contact area, sucrose preference ratio, NRG1 immunofluorescence protein expression in the prefrontal cortex and NRG1 expression in tissue homogenate; showed significant increases in immobility time; the expression of NRG1 decreased;no significant change in GAD67 and ErbB4 expression level. in After 30 minutes of intraperitoneal injection of esketamine, the expression of NRG1 in the prefrontal cortex of susceptible mice increased significantly. no significant change in GAD67 and ErbB4 expression level. After 30 minutes and 24 hours of intraperitoneal injection of esketamine, the social interaction ratio of susceptible group improved compared to the control group, and the duration of forced swimming immobility was significantly shortened.ConclusionThe subanesthetic dose of esketamine may regulate the NRG1-ErbB4 signaling pathway and improve depressive like behavior in mice.
IntroductionSchizophrenia is conceptualized as a disorder of brain network dysconnectivity, yet relationships between neural alterations, cognitive deficits, and genetic risk remain unclear.MethodsWe examined 86 participants: schizophrenia patients (SCZ), unaffected siblings (SCZ-SIB), healthy controls (CON), and control siblings (CON-SIB). We used a multiscale graph-theoretic analysis of task-based fMRI during N-back working memory and unsupervised clinical-cognitive clustering.ResultsWe found that reduced cerebellum-sensorimotor (CER-SM) and cerebellum-cingulo-opercular (CER-CO) connectivity during the 1-back condition robustly discriminated SCZ from CON (AUC = 0.89). Critically, these dysconnectivity patterns were linked to clinical state, present in SCZ vs. SCZ-SIB but absent in SCZ-SIB vs. CON-SIB, suggesting illness expression rather than familial risk. Unsupervised clustering revealed three data-driven subtypes with distinct cognitive- symptomatic profiles: subtype 1 with relative preservation of verbal abilities (predominantly controls), subtype 2 with marked fluid cognitive impairment (enriched in SCZ), and subtype 3 with intermediate performance with working memory sparing (mixed composition). Cerebellar-cortical hypoconnectivity showed graded alignment across these profiles.DiscussionThese findings demonstrate that cerebellar dysconnectivity is most detectable under moderate cognitive load, tracks with clinical state, and covaries with transdiagnostic cognitive profiles, advancing circuit-based understanding of schizophrenia heterogeneity.
Large language models are rapidly becoming embedded in everyday life through artificial intelligence (AI) chatbots that people use for practical assistance and companionship, as well as for support with mental health and emotional wellbeing. Alongside clear benefits, clinicians and public reports increasingly describe a minority of users whose interactions seem to drift over days or weeks toward strongly questionable convictions, delusions or suicidal crises. Importantly, clinically meaningful deterioration can occur even without overtly unsafe text outputs, via more insidious processes such as compulsive use and sleep disruption, as well as withdrawal from human contact and progressive narrowing of attention around the chatbot relationship. In this Viewpoint, we argue that risk often arises not at a single tipping point but through trajectory effects that accumulate across extended dialogue, and that prevailing safety evaluation approaches are misaligned with this reality because they primarily score risk at discrete conversational endpoints often reached through scripted dialogues lasting just a single turn or several turns. Mental health benchmarks and safety suites (including clinician-informed efforts) have advanced the field by testing refusal behaviour, toxicity, and adversarial prompting, but they often treat the last message as the unit of analysis and therefore miss when risk-relevant relational cues, signs of validation, contradiction handling, and shifts in certainty first emerge and how they compound. We propose that mental health safety assessment should shift from endpoints to trajectories by 1) treating the whole dialogue, not just the end result, as the focus of evaluation; 2) reporting turn-by-turn dynamics such as delusion confirmation and harm enablement, as well as timing and persistence of safety interventions; and 3) calibrating short multi-turn tests against longer, clinically realistic interaction sequences that can reveal context-length effects and drift. We further argue that transcript-only evaluation is insufficient in mental health contexts. Similar language can reflect very different internal states, and the relationship between expressed psychopathology and real-world harm is non-linear. Safety research should therefore incorporate proximal human outcomes after interactions (e.g., shifts in certainty, openness to counterevidence, arousal, urge to continue, and subsequent sleep or behaviour) and build prospective clinical surveillance infrastructure that supports consented transcript donation and linkage to health outcomes. Together, these steps would enable benchmarks that are clinically relevant and better aligned with the kinds of harms now being observed in real-world chatbot use.
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Although immunoglobulin G (IgG) normally protects the body against pathogens, it can become problematic in many autoimmune diseases like lupus, rheumatoid arthritis, Graves’ disease, myasthenia gravis, and Sjögren’s disease.
“In these conditions, the immune system is creating defective IgGs—called autoantibodies—that are no longer fighting infections,” explained Eric Venker, MD, PharmD, CEO of Immunovant. “Instead, they are attacking a part of your normal functioning body and causing dysfunction.”
Leonard L. Dragone, MD, PhD Disease Area Leader Johnson & Johnson Innovative Medicine.
Historically, autoimmune conditions have been challenging to treat because therapies like steroids rely on broad immune suppression, noted Leonard L. Dragone, MD, PhD, disease area leader of autoantibody and rheumatology at Johnson & Johnson Innovative Medicine. These non-specific approaches are often inconsistently effective and lead to adverse side effects.
“For many autoimmune diseases, there is a need for more targeted strategies that address disease-causing autoantibodies directly, rather than broadly suppressing the immune system,” emphasized Dragone. Beginning in 1998, the U.S. Food and Drug Administration (FDA) approved infliximab, a tumor necrosis factor (TNF)-α inhibitor, for the treatment of Crohn’s disease. This marked the first approval of a monoclonal antibody for the treatment of a chronic condition. Since then, targeted therapies for autoimmune diseases have expanded to address cytokine signaling pathways (TNF-α, IL-6, IL-17, IL-23), Janus kinase (JAK–STAT) signaling, and immune cell surface markers (CD20).
Another such targeted strategy involves an emerging drug class called FcRn blockers, which are now showing considerable promise in the treatment of certain autoimmune diseases.
FcRn blockers, which typically consist of monoclonal antibodies or antibody fragments, work by blocking the function of a protein receptor called FcRn (neonatal Fc receptor). This prevents IgG recycling, thereby reducing IgG levels in the body.
FcRn maintains levels of IgG in circulation by preventing IgG degradation in the lysosomes of cells. However, FcRn drugs block this pathway.
Venker compares FcRn inhibitors to cholesterol-lowering drugs such as statins. “LDL is the disease-causing agent that healthcare providers target to prevent many cardiovascular diseases. Likewise, in the case of FcRn blockade, we are aiming to lower IgG. We believe that deeper IgG reduction may provide improved results.”
As of early 2026, the FDA has approved three FcRn inhibitors for the treatment of myasthenia gravis, a chronic autoimmune disorder affecting up to 100,000 people in the U.S. Efgartigimod (approved in 2021), rozanolixizumab-noli (approved in 2023), and nipocalimab-aahu (approved in 2025) all work by reducing pathogenic IgGs associated with the disease.
Myasthenia gravis results from harmful antibodies (anti-AChR or anti-MuSK) produced by the immune system that interfere with signaling in the neuromuscular junction.
“With FcRn blockers, it is exciting to know that there is now a targeted mechanism for patients around the world with autoimmune diseases caused by an IgG autoantibody,” said Venker.
Tackling Graves’ disease
In Graves’ disease, an IgG autoantibody called thyrotropin receptor antibody (TRAb), which targets the thyroid-stimulating hormone (TSH) receptor of the thyroid, is produced. The condition, which is the most common cause of hyperthyroidism, causes elevated heart rate, shakiness, irritability, muscle weakness, and weight loss.
“TRAb is an IgG antibody, but it is a badly behaving one that is basically hijacking the thyroid system,” noted Venker. “It doesn’t serve any purpose that is normal at all.”
Mark A. Lupo, MD Founder and Medical Director Thyroid & Endocrine Center of Florida
Unfortunately, the toolkit for treating Graves’ disease hasn’t changed much since 1950, when the FDA approved the drug methimazole, said Mark A. Lupo, MD, founder and medical director of the Thyroid & Endocrine Center of Florida.
Methimazole is an anti-thyroid drug that slows down the production of thyroid hormones. Although Graves’ patients benefit from anti-thyroid drugs, Lupo estimates a 50% relapse rate within two years of discontinuing these drugs.
Other options for treating Graves’ disease include surgical removal of the thyroid or the use of radioactive iodine to induce destruction of the thyroid gland. However, these approaches result in permanent hypothyroidism, and patients typically require lifelong thyroid hormone replacement after treatment.
Because TRAb is an IgG, FcRn drugs represent a potential autoimmune solution for Graves’ disease. Like all FcRn blockers, they may work by decreasing TRAb recycling and lowering TRAb levels.
Lupo highlights Immunovant’s recent proof-of-concept study of an FcRn inhibitor for Graves’ disease, the first such study for the condition. “Despite the small number of patients (around 25), the results from this study suggest a potential, durable remission six months off treatment,” said Lupo.
While study participants experienced an increase in total IgG levels following treatment, TRAb levels remained low over a six-month period. The thyroid also decreased in size. “To see TRAb levels down six months off the study drug caught the attention of the endocrine thyroid community,” noted Lupo.
“What was unexpected was that TRAb, the disease-causing antibody, stayed down for many months after stopping the investigational therapy,” added Venker.
“I think we are overdue for a new option in Graves’ disease that could help break some of these methimazole cycles and potentially address not the innocent thyroid gland but the underlying immune system issues,” concluded Lupo.
But are they safe?
Venker recalls that safety was an initial concern with FcRn inhibition. After all, these drugs work by reducing IgG, an essential part of the immune system. “Any time you are using an autoimmune drug that potentially suppresses your immune system, you have to think about going too far. Am I going to cause an infection or weaken the immune system?
“So far, this investigational drug has demonstrated a safety profile we expected, and appears positive,” noted Venker. “That makes sense mostly because FcRn blockade is pretty targeted.”
“Although there are no head-to-head comparative safety trials yet, most clinicians and principal investigators view FcRn blockers as relatively safe,” added Lupo. “There are FcRn blockers on the market, and they have demonstrated a good safety record in patients.” The most common side effect tends to involve injection site reactions with either intravenous or subcutaneous delivery.
Preventing fetal exposure
During pregnancy, maternal antibodies—called alloantibodies—can cross the placenta and attack the organs and tissues of the fetus, explained Dragone.
A distinguishing feature of Johnson & Johnson’s nipocalimab is its pH-independent binding to FcRn. This allows it to bind with high affinity in the placenta, a low-pH environment.
The drug is currently showing potential in the treatment of two alloimmune diseases of pregnancy: hemolytic disease of the fetus and newborn (HDFN) and fetal and neonatal alloimmune thrombocytopenia (FNAIT), said Dragone. These conditions can arise during alloimmunized pregnancies, when the pregnant person’s immune system forms alloantibodies against fetal red blood cells (HDFN) and/or fetal platelets (FNAIT). Importantly, published data on nipocalimab suggest minimal transfer of the drug to the fetus or infant. “Therapies like nipocalimab offer a blueprint for how precision medicine can expand to include pregnant people, a population that has historically been excluded from drug development,” noted Dragone. “Our approach with nipocalimab has the potential to change how we think about treating autoantibody-driven diseases in people of childbearing age.”
Nipocalimab (IMAAVY®) and other FcRn blockers bind to FcRn receptors and reduce levels of both normal and harmful IgG antibodies.
The FDA has granted a fast track designation to nipocalimab for both FNAIT and HDFN, and Phase III studies are underway to further investigate the drug in both diseases.
Expanding indications
“There are probably 20 trials out there for FcRn blockers, and many are likely to work,” noted Venker. “There are a ton of potential new indications under investigation, including rare diseases that have been ignored historically.”
He notes that Immunovant’s pipeline alone includes potential indications in endocrinology (Graves’ disease), rheumatology (rheumatoid arthritis, Sjögren’s disease, and cutaneous lupus erythematosus), and neurology (myasthenia gravis and chronic inflammatory demyelinating polyneuropathy).
Venker stresses that no FDA-approved solutions exist for Sjögren’s disease, which affects as many as four million Americans. The condition causes severe dry eyes and mouth, fatigue, and joint and muscle pain. Immunovant and Johnson & Johnson are conducting clinical trials to evaluate FcRn blockers for the disease.
Hani Houshyar, PhD Strategy Team Lead argenx
Meanwhile, argenx’s FcRn inhibitor efgartigimod has been used in 19,000 people worldwide for myasthenia gravis and other autoimmune conditions, said Hani Houshyar, PhD, FcRn asset strategy lead for argenx.
“However, we believe myasthenia gravis is just the beginning,” she said. As of 2026, the company has active clinical trials to test the drug’s effectiveness in additional autoimmune diseases with high unmet medical need, like myositis, Sjögren’s disease, ocular myasthenia gravis, systemic sclerosis, Graves’ disease, and autoimmune encephalitis.
UCB’s rozanolixizumab was the first FcRn blocker to be approved for the treatment of generalized myasthenia gravis in adults who are positive for anti-AChR or anti-MuSK antibodies, who together account for approximately 90% of cases, said Omar Sinno, MD, UCB’s U.S. medical strategy lead of rare disease. So far, the drug has been approved in the U.S., Canada, the EU, Australia, Switzerland, China, Turkey, and Korea.
Omar Sinno, MD Medical Strategy Lead, UCB
Rozanolixizumab is administered via a convenient subcutaneous infusion rather than intravenously. The company’s long-term studies demonstrate robust IgG reductions (up to 75%) with sustained benefit across multiple treatment cycles. UCB is also investigating rozanolixizumab as a potential treatment for a rare autoimmune condition called myelin oligodendrocyte glycoprotein antibody-associated disease.
Finally, Johnson & Johnson’s nipocalimab is in mid-to-late-stage studies for Sjögren’s disease, lupus, warm autoimmune hemolytic anemia, and chronic inflammatory demyelinating polyneuropathy.
Drugs in development
Viridian Therapeutics is currently investigating two FcRn inhibitors, VRDN-006 and VRDN-008, said Steve Mahoney, president and CEO. Both candidates are designed as subcutaneous products that can be conveniently self-administered by the patient.
Steve Mahoney President and CEO Viridian Therapeutics
VRDN-006 is an Fc fragment in Phase I trials, while VRDN-008 is made up of an Fc fragment and an albumin-binding domain designed to prolong IgG suppression. Mahoney notes that VRDN-008 showed a longer half-life and more sustained IgG reduction than efgartigimod in a high-dose, head-to-head study in non-human primates.
Clinical trial results of VRDN-008 in healthy volunteers are expected later in 2026. “What we believe differentiates VRDN-008 from other FcRn inhibitors is a longer half-life, which has the potential to support less frequent dosing for patients to enhance convenience,” said Mahoney.
Although three FcRn blockers are currently FDA-approved to treat myasthenia gravis in the U.S., Venker notes that Immunovant is continuing to investigate the condition with the company’s follow-on FcRn candidate, imeroprubart (IMVT-1402).
In Immunovant’s proof-of-concept study for Graves’ disease, TRAb stayed low even six months after the investigational treatment was discontinued. But how long will this effect last? “We don’t know that yet because our randomized trials with IMVT-1402 are ongoing,” Venker said. “However, Graves’ disease has given us the first hint that FcRn drugs may be able to put certain autoimmune conditions into permanent remission.”
Viridian’s VRDN-006 (top) is an Fc fragment, whereas VRDN-008 (bottom) is made up of an Fc fragment and an albumin-binding domain designed to prolong IgG suppression.
“A key question for autoimmune disease, the holy grail, so to speak, is whether we can reset the immune system so the person can function normally without medication for the rest of their lives,” he added.
Finally, argenx is developing ARGX-213, a next-generation FcRn inhibitor engineered to extend half-life and sustain IgG reduction.
“Looking ahead, FcRn inhibition represents an increasingly important approach across IgG-driven disease,” noted Sinno. “By selectively reducing pathogenic IgG, these agents enable more targeted autoimmune care. And as clinical experience with FcRn inhibition grows, treatment paradigms may shift toward earlier intervention.”
Tiffany Yesavage, PhD is a freelance writer from Denver, Colorado.
![Schematic model illustrating the NO-mTOR signaling axis in neuroblastoma. Under basal/pathological conditions (left panel), and nNOS inhibition (right panel). [Haitham Amal]](https://www.genengnews.com/wp-content/uploads/2026/04/Low-Res_Amal-Figure1-2026-Screenshot-2026-04-01-at-11.41.51-300x153.jpg)
