Patients receiving a long-acting beta-agonist (LABA) and inhaled glucocorticoid for asthma were given dupilumab, a monoclonal antibody to part of the IL-4 receptor, with the LABA and inhaled ...glucocorticoid withdrawn. There were fewer exacerbations with dupilumab than with placebo.
Recent estimates suggest that 24.6 million people in the United States, or 8.2% of the population, have received a diagnosis of asthma.
1
Despite therapy with inhaled glucocorticoids and long-acting beta-agonists (LABAs), the disease is not adequately controlled in 10 to 20% of patients
2
; these patients are at risk for poor clinical outcomes, and the cost of their care contributes substantially to the economic burden of asthma.
3
–
5
The mechanisms underlying this inadequate control remain poorly understood.
The clinical syndrome of persistent, moderate-to-severe asthma is increasingly recognized as comprising various phenotypes.
6
Data indicate that inflammatory processes associated with type 2 . . .
Dupilumab, a monoclonal antibody that inhibits signal transduction by interleukin-4 and interleukin-13, showed unexpected clinical efficacy in this group of small, randomized, controlled trials ...involving patients with atopic dermatitis, which were designed predominantly for safety.
Atopic dermatitis, which is characterized by a disturbed skin barrier, robust type 2 helper T-cell (Th2)–mediated immune responses to numerous environmental antigens, susceptibility to cutaneous infections, and intractable pruritus, is a common chronic skin condition with a worldwide prevalence of 1 to 20%.
1
Approximately 20% of patients with atopic dermatitis have moderate-to-severe disease,
1
and treatments approved by the Food and Drug Administration for atopic dermatitis, which include emollients, topical glucocorticoids, and calcineurin inhibitors,
2
,
3
have limited efficacy in moderate-to-severe disease.
4
,
5
The Th2 cytokines interleukin-4 and interleukin-13 are believed to play roles in the pathogenesis of atopic dermatitis,
6
,
7
but . . .
Background
Dupilumab, a fully human monoclonal antibody that binds IL‐4Rα and inhibits signaling of both IL‐4 and IL‐13, has shown efficacy across multiple diseases with underlying type 2 signatures ...and is approved for treatment of asthma, atopic dermatitis, and chronic sinusitis with nasal polyposis. We sought to provide a comprehensive analysis of the redundant and distinct roles of IL‐4 and IL‐13 in type 2 inflammation and report dupilumab mechanisms of action.
Methods
Using primary cell assays and a mouse model of house dust mite–induced asthma, we compared IL‐4 vs IL‐13 vs IL‐4Rα blockers.
Results
Intranasal administration of either IL‐4 or IL‐13 confers an asthma‐like phenotype in mice by inducing immune cell lung infiltration, including eosinophils, increasing cytokine/chemokine expression and mucus production, thus demonstrating redundant functions of these cytokines. We further teased out their respective contributions using human in vitro culture systems. Then, in a mouse asthma model by comparing in head‐to‐head studies, either IL‐4 or IL‐13 inhibition to dual IL‐4/IL‐13 inhibition, we demonstrate that blockade of both IL‐4 and IL‐13 is required to broadly block type 2 inflammation, which translates to protection from allergen‐induced lung function impairment. Notably, only dual IL‐4/IL‐13 blockade prevented eosinophil infiltration into lung tissue without affecting circulating eosinophils, demonstrating that tissue, but not circulating eosinophils, contributes to disease pathology.
Conclusions
Overall, these data support IL‐4 and IL‐13 as key drivers of type 2 inflammation and help provide insight into the therapeutic mechanism of dupilumab, a dual IL‐4/IL‐13 blocker, in multiple type 2 diseases.
The IL‐4Rα antibody, dupilumab, binds IL‐4Rα with high affinity, directly blocks IL‐4 and IL‐13/IL‐13Rα1 complex binding to IL‐4Rα, and thereby prevents IL‐4Rα‐mediated signaling induced by both IL‐4 and IL‐13. IL‐4 and IL‐13 play distinct and overlapping roles and blockade of both cytokines is required to broadly block type 2 inflammation, which translates to protection from allergen‐induced lung function impairment. Only dual IL‐4/IL‐13 blockade with dupilumab prevents eosinophil infiltration into lung tissue without affecting circulating eosinophils, demonstrating that tissue, but not circulating eosinophils contribute to disease pathology.
This phase 3, placebo-controlled platform trial evaluated a single infusion of casirivimab and imdevimab (REGEN-COV) at 2400-mg and 1200-mg doses in outpatients with acute SARS-CoV-2 infection. The ...incidence of Covid-19–related hospitalization was lower and recovery was faster among patients who received the antibody combination than among those who received placebo.
Objective
To evaluate the efficacy and safety of sarilumab in combination with methotrexate (MTX) for the treatment of rheumatoid arthritis (RA).
Methods
Adults with moderate‐to‐severe RA and an ...inadequate response to MTX were randomized (1:1:1) to receive sarilumab (doses of 150 mg or 200 mg) or placebo every 2 weeks in conjunction with weekly MTX for 52 weeks. Co–primary end points were the proportion of patients achieving American College of Rheumatology 20% (ACR20) improvement responses at week 24, change from baseline in the Health Assessment Questionnaire (HAQ) disability index (DI) at week 16, and change from baseline in the modified Sharp/van der Heijde score (SHS) of radiographic damage at week 52.
Results
Baseline characteristics were similar among the groups. For all 3 co–primary end points, the sarilumab 150 mg and 200 mg groups demonstrated statistically significant improvements as compared with the placebo group (ACR20 response rate at week 24, 58.0%, 66.4%, and 33.4%, respectively P < 0.0001; least squares mean change in HAQ DI at week 16, −0.53, −0.55, and −0.29, respectively P < 0.0001; and mean change in SHS at week 52, 0.90, 0.25, and 2.78, respectively P < 0.0001). The most common treatment‐emergent adverse event was infection. In the sarilumab 150 mg, sarilumab 200 mg, and placebo groups, the incidence of serious infections was 2.6%, 4.0%, and 2.3%, respectively. Elevations in alanine aminotransferase levels >3‐fold the upper limit of normal occurred in 9.5%, 8.0%, and 2.1% of patients, respectively; in 24 patients, this led to discontinuation of treatment. Elevated total cholesterol levels were observed in 36.8%, 43.0%, and 18.3% of patients, respectively. In patients receiving 150 mg and 200 mg sarilumab, neutrophil counts of 0.5 to <1.0 × 109/liter were observed in 5.1% and 7.8% of patients, respectively, while neutrophil counts of <0.5 × 109/liter were observed in 0.9% and 0.7% of patients, respectively; none of the patients receiving placebo experienced changes in neutrophil counts.
Conclusion
In RA patients treated with sarilumab (150 mg or 200 mg every 2 weeks) in combination with MTX, both doses provided sustained clinical efficacy, as shown by significant improvements in symptomatic, functional, and radiographic outcomes. Sarilumab was generally well tolerated. The adverse events observed in this study were consistent with the effects of interleukin‐6 signaling blockade.
Household contacts of persons infected with SARS-CoV-2 are at risk for infection. A single subcutaneous injection of two anti–SARS-CoV-2 monoclonal antibodies in such persons within 4 days after the ...detection of infection in a household contact reduced this risk by two thirds in the first 28 days after exposure.
To compare efficacy and safety of 2 dosing regimens of intravitreal aflibercept injection (IAI) with macular laser photocoagulation for diabetic macular edema (DME).
Two similarly designed, ...randomized, phase 3 trials, VISTA(DME) and VIVID(DME).
Patients (eyes; n=872) with type 1 or 2 diabetes mellitus who had DME with central involvement.
Eyes received IAI 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 monthly doses (2q8), or laser control.
The primary end point was mean change from baseline in best-corrected visual acuity (BCVA) at week 52. This report presents the 100-week results including mean change from baseline in BCVA, proportion of eyes that gained ≥15 letters, and proportion of eyes with a ≥2-step improvement in the Diabetic Retinopathy Severity Scale (DRSS) score.
Mean BCVA gain from baseline to week 100 with IAI 2q4, IAI 2q8, and laser control was 11.5, 11.1, and 0.9 letters (P < 0.0001) in VISTA and 11.4, 9.4, and 0.7 letters (P < 0.0001) in VIVID, respectively. The proportion of eyes that gained ≥15 letters from baseline at week 100 was 38.3%, 33.1%, and 13.0% (P < 0.0001) in VISTA and 38.2%, 31.1%, and 12.1% (P ≤ 0.0001) in VIVID. The proportion of eyes that lost ≥15 letters at week 100 was 3.2%, 0.7%, and 9.7% (P ≤ 0.0220) in VISTA and 2.2%, 1.5%, and 12.9% (P ≤ 0.0008) in VIVID. Significantly more eyes in the IAI 2q4 and 2q8 groups versus those in the laser control group had a ≥2 step improvement in the DRSS score in both VISTA (37.0% and 37.1% vs. 15.6%; P < 0.0001) and VIVID (29.3% and 32.6% vs. 8.2%; P ≤ 0.0004). In an integrated safety analysis, the most frequent serious ocular adverse event was cataract (2.4%, 1.0%, and 0.3% for 2q4, 2q8, and control).
In both VISTA and VIVID, the 52-week visual and anatomic superiority of IAI over laser control was sustained through week 100, with similar efficacy in the 2q4 and 2q8 groups. Safety in these studies was consistent with the known safety profile of IAI.
Objective
To prospectively assess the efficacy, general safety, and joint safety of fasinumab, an anti–nerve growth factor monoclonal antibody, in osteoarthritis (OA) hip and/or knee pain.
Methods
...Patients with moderate‐to‐severe OA pain (knee or hip) and history of inadequate response or intolerance to analgesics were randomized to receive fasinumab (at 1 mg, 3 mg, 6 mg, or 9 mg) or placebo every 4 weeks over 16 weeks and were followed up to week 36. Efficacy end points were the change from baseline to week 16 in the pain and physical function subscale scores of the Western Ontario and McMaster Universities OA Index (WOMAC), and patient global assessment (PGA) of OA. Joints were monitored at scheduled assessments (by plain film radiography and magnetic resonance imaging) during treatment and follow‐up, and if prompted, at the time of active joint symptoms.
Results
Of the 421 patients randomized, 342 completed the 36‐week study. All doses of fasinumab yielded statistically significant and clinically important reductions in pain compared to placebo (least squares mean difference in WOMAC pain subscale scores at week 16 ranging −0.78 to −1.40), without any clear dose dependence. Physical function and PGA scores improved in parallel. Treatment‐emergent adverse event rates were 17% with fasinumab and 10% with placebo, and 4% and 1% of patients, respectively, discontinued treatment. Arthropathies (25 in total, 7% of fasinumab‐treated patients and 1% of placebo‐treated patients) occurred in a dose‐dependent manner, with 2 occurring in patients receiving the lowest dose of fasinumab and 10 in patients receiving the highest dose. Most of the arthropathies (16 of 25) were discovered with scheduled radiographs and not based on symptoms. Destructive arthropathy (in 1 of 337 treated patients) occurred in 1 patient who was receiving 6 mg fasimumab.
Conclusion
Fasinumab provided improvements in OA pain and function, even in those benefitting little from previous analgesics. The observed benefit‐to‐risk relationship favors further clinical development to explore the lowest doses of fasinumab in patients with knee or hip OA.
Neural Induction by the Secreted Polypeptide Noggin Lamb, Teresa M.; Knecht, Anne K.; Smith, William C. ...
Science (American Association for the Advancement of Science),
10/1993, Letnik:
262, Številka:
5134
Journal Article
Recenzirano
The Spemann organizer induces neural tissue from dorsal ectoderm and dorsalizes lateral and ventral mesoderm in Xenopus. The secreted factor noggin, which is expressed in the organizer, can mimic the ...dorsalizing signal of the organizer. Data are presented showing that noggin directly induces neural tissue, that it induces neural tissue in the absence of dorsal mesoderm, and that it acts at the appropriate stage to be an endogenous neural inducing signal. Noggin induces cement glands and anterior brain markers, but not hindbrain or spinal cord markers. Thus, noggin has the expression pattern and activity expected of an endogenous neural inducer.
The DiscovEHR collaboration between the Regeneron Genetics Center and Geisinger Health System couples high-throughput sequencing to an integrated health care system using longitudinal electronic ...health records (EHRs). We sequenced the exomes of 50,726 adult participants in the DiscovEHR study to identify ~4.2 million rare single-nucleotide variants and insertion/deletion events, of which ~176,000 are predicted to result in a loss of gene function. Linking these data to EHR-derived clinical phenotypes, we find clinical associations supporting therapeutic targets, including genes encoding drug targets for lipid lowering, and identify previously unidentified rare alleles associated with lipid levels and other blood level traits. About 3.5% of individuals harbor deleterious variants in 76 clinically actionable genes. The DiscovEHR data set provides a blueprint for large-scale precision medicine initiatives and genomics-guided therapeutic discovery.
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