Interleukin-6 Receptor Inhibitor Research Articles

Comparison of treatment of COVID-19 with inhaled bromhexine, higher doses of colchicine and hymecromone with WHO-recommended paxlovid, molnupiravir, remdesivir, anti-IL-6 receptor antibodies and baricitinib

Millions of publications and thousands of clinical trials have not led to the discovery of an effective treatment for COVID-19. We believe that the reason for this is the inaccurate strategy of inhibiting target molecules involved in the pathogenesis of the disease. The leading cause of death in COVID-19 is the cytokine storm, which is caused by an NLRP3 inflammasome hyperreaction. WHO recommends for the outpatients treatment drugs blocking the replication of SARS-CoV-2. However, viral load and replication are not directly related to NLRP3 inflammasome hyperreactivity. This also explains the partial success of the WHO favorite paxlovid to reduce hospitalizations (51%). For hospital treatment, WHO suggests antibodies against the interleukin-6 receptor and Janus kinase (JAK) inhibition. Although important, IL-6 is one of dozens of cytokines elevated as a consequence of cytokine storm. The JAK inhibitor baricitinib inhibited the effect of not only IL-6 but also other elevated cytokines. But if the NLRP3 inflammasome is inhibited, the cytokines will not be elevated, and there will be no need for baricitinib. All medicines recommended by the WHO are distinguished by their very high prices. Our therapeutic strategy is based on inhibition of SARS-CoV-2 entry into the cell and inhibition of the NLRP3 inflammasome. We offer two readily available, cheap and well-known medications - bromhexine hydrochloride and colchicine. The many studies on the treatment of COVID-19 so far have not produced the expected result. The devil is buried in the details. For bromhexine, the reason is the way and its late application. Bromhexine is most effective when given prophylactically or started by inhalation after contact with a person with COVID-19. Its earliest possible application is crucial for its effect. Increased doses of colchicine are necessary for COVID-19 treatment due to the fact that it accumulates in leukocytes, and this leads to inhibition of NLRP3. The high doses we administer have been given widely in the past and are completely safe. Our highest dose is about 5 times lower per kg of weight than the lowest severe toxic dose of colchicine described. Our results show about a 5-fold decrease in hospital mortality and almost complete prevention of hospitalizations if outpatients are treated with inhaled bromhexine and colchicine.

A phase 3 randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of sarilumab in patients with giant cell arteritis

BackgroundGiant cell arteritis (GCA) is primarily treated with glucocorticoids (GCs), which have substantial toxicity. Tocilizumab, an interleukin-6-receptor inhibitor (IL-6Ri), showed beneficial effects in GCA, leading to its approval. This study investigated the efficacy and safety of sarilumab (another IL-6Ri) in GCA.MethodsThis Phase 3, double-blind study comprised a 52-week treatment period and a 24-week follow-up phase. Eligible GCA patients were randomized to receive sarilumab 200 mg (SAR200 + 26W) or 150 mg (SAR150 + 26W) with a 26-week GC taper, or placebo with a 52-week (PBO + 52W) or 26-week (PBO + 26W) GC taper. The primary efficacy endpoint was sustained remission (SR) at week 52. Additional endpoints were SR at week 24, cumulative GC dose, and safety. The study was discontinued prematurely due to protracted recruitment timelines, because of the impact of COVID-19. Therefore, only descriptive statistics were summarized.ResultsOf the planned 360 subjects, only 83 were randomized and 36 were included in the week 52 analysis. At week 52, 46% (n = 6/13) of patients in SAR200 + 26W, 43% (n = 3/7) in SAR150 + 26W, 30% (n = 3/10) in PBO + 52W, and 0 (n = 0/6) in PBO + 26W taper groups achieved SR. Sensitivity analyses, excluding acute-phase reactants from the SR definition, showed similar results for SAR groups, but 60% (n = 6/10) in PBO + 52W and 17% (n = 1/6) in PBO + 26W taper groups achieved SR at week 52. Similar findings were noted at week 24. The proportions of patients who adhered to GC taper from week 12 through week 52 in each group were as follows: 46% (n = 6/13, SAR200 + 26W), 43% (n = 3/7, SAR150 + 26W), 60% (n = 6/10, PBO + 52W), and 33% (n = 2/6, PBO + 26W). The median actual cumulative GC dose received in the SAR200 + 26W group was lower than other groups. Most patients (80–100%) experienced treatment-emergent adverse events, with similar incidences reported across groups.ConclusionsOwing to the small sample size due to the early termination, it is difficult to draw clear conclusions from this study. There were no unexpected safety findings.Trial registrationClinicalTrials.gov NCT03600805. Registered on July 26, 2018.

Efficacy of olokizumab in patients with mild or moderate COVID-19 and risk factors of progression

The COronaVIrus Disease 2019 (COVID-19) is a common infectious disease characterized by hyperactivation of the immune response and the development of a “cytokine storm” upon progression. The aim of this study was to obtain additional information about the efficacy of the drug olokizumab in comparison with the Janus kinase inhibitor upadacitinib in real clinical practice in patients with mild to moderate COVID-19 and combined risk factors for disease progression. Methods. A single-center, non-interventional, prospective study was conducted in specialized day hospital patients (n = 125) who received therapy with olokizumab (n = 62) (64 mg once intravenously) and the Janus kinase inhibitor upadacitinib (n = 63) (orally, according to selected dosing regimen). The primary endpoint was the frequency of hospitalizations in the 24-hour hospital over the entire observation period. We also analyzed the frequencies of intensive care unit (ICU) transfer, prescription of respyratory therapy, use of “rescue” therapy (monoclonal antibodies/therapeutic proteins acting on interleukins (IL) and their receptors: IL-6 receptor inhibitors and Janus kinase inhibitors (baricitinib, tofacitinib, upadacitinib, etc.)), mortality, dynamics of laboratory and instrumental parameters, as well as frequency of negative and positive changes according to the clinical progression scale of the World Health Organization. Results. All study subjects showed rapid clinical improvement and recovery. Patients in both groups did not experience any negative clinical events, such as admission to a 24-hour hospital, prescription of respyratory therapy, use of “rescue” therapy, etc. Thus, the hyperinflammatory reaction and adverse clinical outcomes are effectively prevented by the timely use of both drugs. Those who received olokizumab had slightly higher levels of C-reactive protein (CRP) at baseline than those who received upadacitinib (p < 0.001). The median CRP value returned to normal on the 4th day in both groups. Patients treated with olokizumab showed a more pronounced change in CRP levels relative to baseline values. A similar trend was also established in body temperature. Conclusion. The study confirmed that early administration of olokizumab in patients with mild to moderate COVID-19 with several risk factors for the severe course is as effective a method of preemptive anti-inflammatory therapy as the use of Janus kinase inhibitors but more stronger suppression of markers and symptoms of intoxication.

Markov model in evaluating the efficiency of various COVID-19 treatment regimens

Objective. To consider the evidence-based approaches to treating virus-associated lung tissue lesions, the rationale for using the Markov model to evaluate the clinical and economic efficacy of interleukin (IL)-6 (IL-6) receptor inhibitors in patients with COVID-19. Subjects and methods. To evaluate the clinical and economic effectiveness of using the receptor inhibitors in COVID-19 patients, the investigators formed two groups: 1) 187 patients received the standard therapy; 2) 104 patients had IL-6 receptor inhibitors in addition to the standard therapy. Results and conclusion. The logistic regression method was used to determine the need for prescribing these drugs depending on the individual characteristics of patients, the key points were the length of a patient's stay in the intensive care unit, as well as the duration of oxygen support. In the context of new challenges to the healthcare system, it is necessary to further search for comprehensive methods of monitoring the condition and prognosis with promising ways to assess the validity of using therapeutic procedures and drugs.

Markov model in evaluating the efficiency of various COVID-19 treatment regimens

Objective. To consider the evidence-based approaches to treating virus-associated lung tissue lesions, the rationale for using the Markov model to evaluate the clinical and economic efficacy of interleukin (IL)-6 (IL-6) receptor inhibitors in patients with COVID-19. Subjects and methods. To evaluate the clinical and economic effectiveness of using the receptor inhibitors in COVID-19 patients, the investigators formed two groups: 1) 187 patients received the standard therapy; 2) 104 patients had IL-6 receptor inhibitors in addition to the standard therapy. Results and conclusion. The logistic regression method was used to determine the need for prescribing these drugs depending on the individual characteristics of patients, the key points were the length of a patient's stay in the intensive care unit, as well as the duration of oxygen support. In the context of new challenges to the healthcare system, it is necessary to further search for comprehensive methods of monitoring the condition and prognosis with promising ways to assess the validity of using therapeutic procedures and drugs.

Biological sex is associated with heterogeneous responses to IL-6 receptor inhibitor treatment in COVID-19—A retrospective cohort study

COVID-19 is associated with higher inflammatory markers, illness severity and mortality in males compared to females. Differences in immune responses to COVID-19 may underpin sex- specific outcome differences. We hypothesised that anti-IL-6 receptor monoclonal antibodies are associated with heterogenous treatment effects between male and female patients. We conducted a retrospective cohort study assessing the interaction between biological sex and anti-IL-6 receptor antibody treatment with respect to hospital mortality or progression of respiratory failure. We used a Cox proportional hazards regression model to adjust for age, ethnicity, steroid use, baseline C-reactive protein, and COVID-19 variant. We included 1274 patients, of which 58% were male and 15% received anti-IL-6 receptor antibodies. There was a significant interaction between sex and anti-IL-6 receptor antibody use on progression to respiratory failure or death (p = 0.05). For patients who did not receive anti-IL-6 receptor antibodies, the risk of death was slightly higher in males (HR = 1.13 (0.72–1.79)), whereas in patients who did receive anti-IL-6 receptor antibodies, the risk was lower in males (HR = 0.65 (0.32–1.33)). There was a heterogenous treatment effect with anti-IL-6 receptor antibodies between males and females; with anti-IL-6 receptor antibody use having a greater benefit in preventing progression to respiratory failure or death in males (p = 0.05).

Interleukin-6 receptor blockade improves bone healing following ischemic osteonecrosis in adolescent mice

ObjectiveJuvenile ischemic osteonecrosis (JIO) of the femoral head is one of the most serious hip disorders causing a permanent deformity of the femoral head in childhood. We recently reported that interleukin 6 (IL-6) is significantly increased in the hip synovial fluid of patients with JIO and that articular chondrocytes are primary source of IL-6. Adolescent JIO is particularly challenging to treat and has poor outcome. This study determined if IL-6 receptor blockade prevents bone loss and improves the bone healing in adolescent JIO. MethodAdolescent mice (12-week-old) surgically induced with JIO were treated with either saline or MR16-1, an IL-6 receptor blocker. ResultsMicro-CT assessment showed significantly increased bone volume (p ​< ​0.001, Cohen's d ​= ​2.0) and trabecular bone thickness (p ​< ​0.001, d ​= ​2.3) after the MR16-1 treatment. Histomorphometric assessment showed significantly increased osteoblast number (p ​< ​0.01, d ​= ​2.3), bone formation rate (p ​< ​0.01, d ​= ​4.3), and mineral apposition rate (p ​< ​0.01, d ​= ​4.1) after the MR16-1 treatment. The number of osteoclasts was unchanged. Histologic assessment showed significantly increased revascularization (p ​< ​0.01) and restoration of the necrotic marrow with new hematopoietic bone marrow (p ​< ​0.01). Vascular endothelial growth factor (VEGF) expression was increased in the revascularized area and the articular cartilage, and in the cultured chondrocytes treated with IL-6 receptor inhibitor. ConclusionIL-6 blockade in adolescent mice with JIO enhanced bone formation and revascularization. The findings suggest IL-6 receptor blocker as a potential medical therapy for adolescent JIO.

IL-6 inhibitors and JAK inhibitors as favourable treatment options for patients with anaemia and rheumatoid arthritis: ANSWER cohort study.

Anaemia, a common comorbidity of RA, is related to high disease activity and poor prognosis. It is unknown which biologic/targeted synthetic (b/ts)-DMARDs are optimal for patients with anaemia and RA in regulating anaemia and controlling disease activity. We investigated the change in haemoglobin (Hb) levels, drug retention rates and disease activities after the administration of b/ts-DMARDs with different modes of action [TNF inhibitors (TNFis), immunoglobulin fused with cytotoxic T-lymphocyte antigen (CTLA-4-Ig), IL-6 receptor inhibitors (IL-6Ris) and Janus kinase inhibitors (JAKis)] in patients with RA stratified by baseline Hb levels using the multicentre observational registry for patients with RA in Japan (ANSWER cohort). A total of 2093 patients with RA were classified into three groups based on tertiles of the baseline Hb levels (Hblow, anaemic; Hbint, intermediate; Hbhigh, non-anaemic). IL-6Ri increased Hb levels in all groups (the mean change at 12 months in Hblow was +1.5 g/dl, Hbint +0.7 g/dl and Hbhigh +0.1 g/dl). JAKis increased the Hb level in patients with anaemia and RA and retained or decreased the Hb level in non-anaemic patients (the mean change at 12 months in Hblow was +0.6 g/dl, Hbint 0 g/dl and Hbhigh -0.3 g/dl). In patients with anaemia and RA, overall adjusted 3-year drug retention rates were higher in JAKi followed by IL-6Ri, CTLA4-Ig and TNFi (78.6%, 67.9%, 61.8% and 50.8%, respectively). Change of disease activity at 12 months was not different among different b/ts-DMARDs treatments. IL-6Ri and JAKi can effectively treat patients with anaemia and RA in a real-world setting.

Acute non-ST segment elevation myocardial infarction as the first manifestation of Takayasu arteritis in a 16-year-old female patient: a case report and literature review.

Takayasu arteritis (TA) is now recognized worldwide and is a disease that mainly affects the aorta and its main branches. TA rarely involves the small or medium-sized vessels. Certain vascular lesions, such as arterial stenosis, occlusion, and aneurysm are common with TA. However, patients with new-onset TA who present with left main trunk acute non-ST segment elevation myocardial infarction are extremely rare. We report a 16-year-old female patient with non-ST segment elevation myocardial infarction due to severe stenosis of the left main coronary artery that was caused by TA. She was eventually diagnosed with TA and underwent successful coronary artery stenting combined with glucocorticoids and folate reductase inhibitor therapy. Over the 1-year follow-up, she experienced two episodes of chest pain and was admitted to the hospital. During the second hospitalization, coronary angiography (CAG) revealed 90% stenosis of the original left main trunk (LM) stent. Following percutaneous coronary angiography (PTCA), drug-coated balloon (DCB) angioplasty was performed. Fortunately, a clear diagnosis of TA was made, and treatment was initiated with an interleukin-6 (IL-6) receptor inhibitor. Early diagnosis and therapy for TA are emphasized.

Selective immune suppression using interleukin-6 receptor inhibitors for management of immune-related adverse events

BackgroundManagement of immune-related adverse events (irAEs) is important as they cause treatment interruption or discontinuation, more often seen with combination immune checkpoint inhibitor (ICI) therapy. Here, we retrospectively evaluated the...

Tocilizumab for Cytokine Release Syndrome Management After Haploidentical Hematopoietic Cell Transplantation With Post-Transplantation Cyclophosphamide-Based Graft-Versus-Host Disease Prophylaxis

Cytokine release syndrome (CRS) is a common complication after haploidentical hematopoietic cell transplantation (HaploHCT). Severe CRS after haploHCT leads to higher risk of non-relapse mortality (NRM) and worse overall survival (OS). Tocilizumab (TOCI) is an interleukin-6 receptor inhibitor and is commonly used as first-line for CRS management after chimeric antigen receptor T cell therapy, but the impact of TOCI administration for CRS management on Haplo HCT outcomes is not known. In this single center retrospective analysis, we compared HCT outcomes in patients treated with or without TOCI for CRS management after HaploHCT with post-transplantation cyclophosphamide- (PTCy-) based graft-versus-host disease (GvHD) prophylaxis. Of the 115 patients eligible patients who underwent HaploHCT at City of Hope between 2019 to 2021 and developed CRS, we identified 11 patients who received tocilizumab for CRS management (TOCI). These patients were matched with 21 patients who developed CRS but did not receive tocilizumab (NO-TOCI) based on age at the time of HCT (≤64 years or >65 years or older), conditioning intensity (myeloablative versus reduced-intensity/nonmyeloablative), and CRS grading (1, 2, versus 3-4). Instead of 22 controls, we chose 21 patients because there was only 1 control matched with 1 TOCI treatment patient in 1 stratum. With only 11 patients in receiving tocilizumab for CRS treatment, matching with 21 patients who developed CRS but did not receive tocilizumab, we had 80% power to detect big differences (hazard ratio [HR]=3.4 or higher) in transplantation outcomes using a 2-sided 0.05 test. The power would be reduced to about 20% to 30% if the difference was moderate (HR=2.0) using the same test. No CRS-related deaths were recorded in either group. Median time to neutrophil engraftment was 21 days (range 16-43) in TOCI and 18 days (range 14-23) in NO-TOCI group (HR=0.55; 95% confidence interval [CI]=0.28-1.06, P=.08). Median time to platelet engraftment was 34 days (range 20-81) in TOCI and 28 days (range 12-94) in NO-TOCI group (HR=0.56; 95% CI=0.25-1.22, P=.19). Cumulative incidences of day 100 acute GvHD grades II-IV (P=.97) and grades III-IV (P=.47) were similar between the 2 groups. However, cumulative incidence of chronic GvHD at 1 year was significantly higher in patients receiving TOCI (64% versus 24%; P=.05). Rates of NRM (P=.66), relapse (P=.83), disease-free survival (P=.86), and overall survival (P=.73) were similar at 1 year after HCT between the 2 groups. Tocilizumab administration for CRS management after HaploHCT appears to be safe with no short-term adverse effect and no effect on relapse rate. However, the significantly higher cumulative incidence of chronic GvHD, negates the high efficacy of PTCy on GvHD prophylaxis in this patient population. Therefore using tocilizumab for CRS management in the HaploHCT population with PTCy maybe kept only for patients with severe CRS. The impact on such approach on long term outcome in HaploHCT with PTCy will need to be evaluated in a larger retrospective study or a prospective manner.

Comparative effectiveness of TNF inhibitor vs IL-6 receptor inhibitor as monotherapy or combination therapy with methotrexate in biologic-experienced patients with rheumatoid arthritis: An analysis from the CorEvitas RA Registry

ObjectiveRandomized controlled trials (RCTs) in biologic-naïve rheumatoid arthritis (RA) patients with high disease activity and inadequate response/intolerance to methotrexate have shown interleukin-6 (IL-6) receptor inhibitors (IL-6Ri) to be superior to tumor necrosis factor inhibitors (TNFi) as monotherapy. This observational study aimed to compare the effectiveness of TNFi vs IL-6Ri as mono- or combination therapy in biologic/targeted synthetic (b/ts) -experienced RA patients with moderate/high disease activity.MethodsEligible b/ts-experienced patients from the CorEvitas RA registry were categorized as TNFi and IL-6Ri initiators, with subgroups initiating as mono- or combination therapy. Mixed-effects regression models evaluated the impact of treatment on Clinical Disease Activity Index (CDAI), patient-reported outcomes, and disproportionate pain (DP). Unadjusted and covariate-adjusted effects were reported.ResultsPatients initiating IL-6Ri (n = 286) vs TNFi monotherapy (n = 737) were older, had a longer RA history and higher baseline CDAI, and were more likely to initiate as third-line therapy; IL-6Ri (n = 401) vs TNFi (n = 1315) combination therapy initiators had higher baseline CDAI and were more likely to initiate as third-line therapy. No significant differences were noted in the outcomes between TNFi and IL-6Ri initiators (as mono- or combination therapy).ConclusionThis observational study showed no significant differences in outcomes among b/ts-experienced TNFi vs IL-6Ri initiators, as either mono- or combination therapy. These findings were in contrast with the previous RCTs in biologic-naïve patients and could be explained by the differences in the patient characteristics included in this study. Further studies are needed to help understand the reasons for this discrepancy in the real-world b/ts-experienced population.Key Points• Patients with rheumatoid arthritis (RA) often require switching between biologics or targeted synthetic (b/ts) disease-modifying anti-rheumatic drugs (DMARDs) to achieve their treatment target.• Head-to-head randomized controlled trials (RCTs) in biologic-naïve RA patients with high disease activity and inadequate response/intolerance to methotrexate have shown interleukin-6 receptor inhibitors (IL-6Ri) to be superior to tumor necrosis factor inhibitors (TNFi) as monotherapy; however, there are no RCTs comparing these therapies in a population previously treated with b/tsDMARDs (i.e., b/ts-experienced patients).• This observational study compared the effectiveness of TNFi vs IL-6Ri (as mono- or combination therapy) in b/ts-experienced RA patients with moderate or high disease activity and found no significant differences in clinical outcomes for the two treatments.• A discrepancy is noted between our study and RCTs, which have shown superiority of IL-6Ri therapy (albeit in biologic-naïve patients). Further analyses may help elucidate the reason for this discrepancy in the real-world b/ts-experienced population.

Comparative safety and effectiveness of TNF inhibitors, IL6 inhibitors and methotrexate for the treatment of immune checkpoint inhibitor-associated arthritis

ObjectivesTo compare the safety and effectiveness of biologic and conventional disease-modifying antirheumatic drugs (DMARDs) for immune checkpoint inhibitor-associated inflammatory arthritis (ICI-IA).MethodsThe retrospective multicentre observational study included patients with a diagnosis...

The effect of targeted rheumatoid arthritis therapeutics on systemic inflammation and anemia: analysis of data from the CorEvitas RA registry

BackgroundTo evaluate the effects of tumor necrosis factor inhibitors (TNFi), interleukin-6 receptor inhibitors (IL-6Ri), and Janus kinase inhibitors (JAKi) on hemoglobin (Hb) and C-reactive protein (CRP) levels in adults enrolled in CorEvitas (formerly Corrona), a large US rheumatoid arthritis (RA) registry.MethodsPatients who initiated TNFi, IL-6Ri, or JAKi treatment during or after January 2010, had Hb and CRP measurements at baseline and 6-month follow-up (± 3 months) and had continued therapy at least until that follow-up, through March 2020, were included in the analysis. Changes in Hb and CRP were assessed at month 6. Abnormal Hb was defined as < 12 g/dL (women) or < 13 g/dL (men); abnormal CRP was ≥ 0.8 mg/dL. Differences in Hb and CRP levels were evaluated using multivariable regression.ResultsOf 2772 patients (TNFi, 65%; IL-6Ri, 17%; JAKi, 17%) evaluated, 1044 (38%) had abnormal Hb or CRP at initiation; an additional 252 (9%) had both abnormal Hb and CRP. At month 6, the IL-6Ri group had a greater Hb increase than the TNFi (mean difference in effect on Hb: 0.28 g/dL; 95% CI 0.19–0.38) and JAKi (mean difference in effect on Hb: 0.47 g/dL; 95% CI 0.35–0.58) groups, regardless of baseline Hb status (both p < 0.001). The CRP decrease at month 6 was greater with IL-6Ri compared with TNFi and JAKi, regardless of baseline CRP status (both p < 0.05).ConclusionThese real-world results align with the mechanism of IL-6R inhibition and may inform treatment decisions for patients with RA.

STUDY OF EFFECT OF MONOCLONALANTIBODIES IN COVID 19 INFECTION.

Background The death rate was overwhelmingly high during COVID 19 pandemic with very few treatment options and the main cause leading to death being the cytokine storm.Monoclonal antibodies like Tocilizumab ( IL-6 receptor inhibitor) was said to be an effective treatment option in severe COVID 19 patients with increased inammatory markers. Objectives To determine the outcome of monoclonal antibodies in COVID 19 patients. To determine the risk of mechanical ventilation in patients who are treated with monoclonal antibodies in COVID 19 patients. Methods A retrospective study conduction during the second wave of COVID 19 in India (Sri Devraj Urs Medical College, Tamaka, Kolar, Karnataka ) . The study includes 2 groups - one treated with Tocilizumab and the other not treated with Tocilizumab. Chi-square test or Fischer's exact test (for 2x2 tables only) was used as test of signicance for qualitative data. Results 106 patients observed were divided into 2 groups of 53 ensuring similar baseline characteristics. While one group of 53 was treated with IV Tocilizumab (TCZ group) and the other group was not treated (Non - TCZ group). Signicant difference was found with regard to mortality (p value - 0.032) in the TCZ and Non TCZ groups (Mortality rate - 41.5% vs 62.3% ). Additionally while the patients who needed invasive ventilation in Tocilizumab was lower than that of Non Toclizumab group (52.8 % vs 71.7 %) it was not statistically signicant (p = 0.071). Conclusion Based on the observations in this study, patients treated with Tocilizumab had signicantly better survival rate .The impact of Tocilizumab on the risk of mechanical ventilation in this Cohort is not conclusive.

Levilimab clinical efficacy for interleukin-6 receptor inhibition in COVID-19 and its potential for treating cytokine release syndrome of other aetiologies

The COVID-19 mortality is associated with an increase in interleukin-6 (IL-6) levels. Levilimab is an anti–IL-6 receptor antibody with proven clinical efficacy in patients with severe COVID-19.The aim of the study was to assess the association of COVID-19 severity and levilimab effectiveness with IL-6 levels and to explore the potential for using levilimab in other conditions accompanied by cytokine release syndrome.Materials and methods: the subgroup analysis was based on the data of COVID patients with known baseline IL-6 levels from the CORONA clinical study. Subgroups were formed according to baseline IL-6 levels: ≤5 pg/mL (normal) and &gt;5 pg/mL (elevated). The subgroup analysis included descriptive statistics of the patients and time courses of their clinical and laboratory findings (at screening, on the day of investigational product administration, and further until day 14). In order to compare the percentages of patients who had required rescue therapy, the authors used Fisher's exact test.Results: the subgroup analysis included 91 patients (47 from the levilimab group and 44 from the placebo group). At baseline, the authors observed elevated levels of IL-6 in 31/47 (66%) subjects in the levilimab group and 29/44 (48.4%) subjects in the placebo group. The subjects with elevated IL-6 demonstrated more pronounced clinical signs of pneumonia and abnormalities in inflammatory markers. Elevated baseline IL-6 levels were associated with the need for rescue therapy (OR=3.714; 95% CI: 1.317–9.747; p=0.0183); this association was stronger in the placebo group (OR=8.889; 95% CI: 2.098–33.31; p=0.0036). Also, the placebo group showed long-term abnormalities in the clinical and laboratory findings.Conclusions: IL-6 is one of the key elements in the pathogenesis of cytokine release syndrome related to COVID-19 and other conditions. Elevated IL-6 levels are associated with the severity of COVID-19. Inhibition of IL-6 receptors by levilimab leads to clinical improvement in patients with severe COVID-19, suggesting the effectiveness of levilimab in pathogenesis-oriented therapy for cytokine release syndrome of other aetiologies.

Tocilizumab for the Management of Cytokine Release Syndrome after Haploidentical Hematopoietic Transplant with Post-Transplant Cyclophosphamide-Based GvHD Prophylaxis

Haploidentical hematopoietic cell transplant (HaploHCT) with post-transplant cyclophosphamide (PTCy) has expanded the donor pool and made HCT available to patients without a matched donor. Cytokine release syndrome (CRS) is a syndrome of systemic inflammation with massive cytokine release, originally described after chimeric antigen receptor T cell (CAR T) therapy, is a frequent complication early after HaploHCT. Severe CRS after HaploHCT has been associated with higher non-relapse mortality (NRM) and worse overall survival (OS). Currently, no standard guidelines exist for CRS management in HaploHCT patients other than general supportive measures. Here, we described the impact of tocilizumab, an interleukin-6 receptor inhibitor used to manage CRS in CAR T therapy setting, on clinical outcomes in patients who experienced CRS after HaploHCT. We retrospectively identified a case series of 120 patients who experienced CRS after undergoing HaploHCT with PTCy-based GvHD prophylaxis at City of Hope from 06/2019 to 06/2021; of whom 11 patients received tocilizumab for CRS management. We matched these patients in a 1:2 ratio with 21 patients with CRS post-Haplo-HCT who did not receive tocilizumab (based on age, primary diagnosis, conditioning regimen, and CRS grading), then analyzed and compared OS, disease-free survival (DFS), relapse rate (RR), NRM, cumulative incidence (CIN) of grade II-IV and III-IV acute GvHD, and chronic GvHD between the two groups by univariate analysis. P-values were 2 sided at a significance level of 0.05. Table 1 summarize patient and transplant characteristics. Median age of patients in tocilizumab (TOCI) and no-tocilizumab (NO-TOCI) cohorts were 64 years (range: 27-70) and 62 years (range: 20-76). HLA 6/12 mismatch was the most common in both cohorts (81.8% in TOCI and 66.7% in NO-TOCI). All patients received mobilized peripheral blood stem cells (PBSC) as graft source. Majority of patients received non-myeloablative or reduced intensity conditioning regimens (81.8% in TOCI and 76.2% in NO-TOCI). Grade 2 CRS was most common in both cohorts (72.2% in TOCI and 71.4% in NO-TOCI); and grade 3-4 CRS was documented in 1 patient (9.1%) in TOCI and 2 patients (9.5%) in NO-TOCI cohort. Tocilizumab doses were 4 mg/kg (n=2), or 8 mg/kg (n=9). All patients but one (90.9%) received one single dose of tocilizumab and 1 patient received 2 doses of tocilizumab at 8 mg/kg/dose. All tocilizumab doses were administered either on day +3 (45%) or day +4 (55%) post-HCT (the patient with 2 doses was counted towards day +3). No high-grade tocilizumab-related side effects were documented in those 11 patients. Day 28 CIN of neutrophil engraftment was lower in TOCI compared to NO-TOCI patients (54.5% vs 76.2%, 95% CI: 21-79 and 50-90%, P=0.07 - Figure 1a). At 12 months post HaploHCT, survival outcomes were similar with NRM of 18.2 and 19% (95% CI: 3-46% and 6-38%, P=0.92); and RR of 19.5 and 14.3% (95% CI: 3-49% and 3-33%, P=0.78) in TOCI and NO-TOCI cohorts, respectively. DFS and OS were not affected by tocilizumab administration (P=0.90 and P=0.98; respectively). Three patients in TOCI and 7 patients in NO-TOCI cohort died; their causes of death were not directly related to CRS. While CIN of day 100 grade II-IV (P=0.97) and grade III-IV acute GvHD (P=0.47) were not affected by tocilizumab administration, CIN of chronic GvHD was significantly higher in TOCI compared to NO-TOCI (60.6 vs 23.8%, 95% CI: 19-86% and 8-44%, P=0.05 - Figure 1b). In conclusion, our results indicates that tocilizumab used for CRS management after in HaploHCT setting with PTCy-based GvHD prophylaxis was well tolerated and had no effect on survival outcomes. However, our study showed a trend towards delayed neutrophil engraftment and a statistically significant higher incidence of chronic GvHD in patients who received tocilizumab. It is possible that tocilizumab may interfere with T cell expansion, which could impact PTCy-mediated elimination of alloreactive T cell clones and/or affect regulatory T cells function; both mechanisms could lead to higher incidence of chronic GvHD. Using this approach to mitigate CRS risk should be reserved to patients with high grade CRS where mortality is high. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CTIM-21. NRG-BN010: A SAFETY RUN-IN AND PHASE II STUDY EVALUATING THE COMBINATION OF TOCILIZUMAB, ATEZOLIZUMAB, AND FRACTIONATED STEREOTACTIC RADIOTHERAPY IN RECURRENT GLIOBLASTOMA – TRIAL IN PROGRESS

Abstract BACKGROUND The glioblastoma (GBM) tumor microenvironment (TME) is characterized by a paucity of effector T cells and massive infiltration of immunosuppressive tumor-associated macrophages (TAMs). Inhibition of the interleukin-6 receptor (IL6R) has been demonstrated in preclinical models to repolarize TAMs toward an immunostimulatory phenotype, rendering GBM more susceptible to PD-1/PD-L1 inhibition. Additional preclinical data suggest that fractionated stereotactic radiotherapy (FSRT) can stimulate the release and presentation of tumor-specific antigens, acting as an in-situ vaccine and potentially converting a “cold” TME to a T cell-inflamed state. We designed a safety run-in and phase II study to evaluate the efficacy, safety, and impact on the TME of the combination of IL6R inhibition (tocilizumab), PD-L1 inhibition (atezolizumab), and FSRT in patients with recurrent GBM (rGBM). METHODS NRG-BN010 (NCT04729959) is open to enrollment for adults with rGBM following prior radiotherapy and has 3 components: a safety run-in to determine the recommended phase II dose (RP2D) of the treatment regimen, a phase II single-arm nonsurgical cohort to assess efficacy of the treatment regimen at the RP2D, and a window-of-opportunity surgical cohort. Once the safety run-in (n=12, 3 + 3 design) has determined the RP2D, the phase II and surgical cohorts will open. Phase II patients (n=25, Simon 2-stage design, primary endpoint objective radiographic response) receive an initial pre-FSRT cycle of tocilizumab (plus atezolizumab if included in the RP2D). Within 3-7 days later, the patient receives FSRT (8 Gy x 3 fx), followed by resumption of systemic therapy. Surgical cohort patients (n=16, 1:1 randomization) receive a neoadjuvant cycle of atezolizumab with (n=8) vs. without (n=8) tocilizumab, then FSRT 3-7 days later, then surgical resection 7-14 days after FSRT. Post-operatively, all patients resume systemic therapy at the RP2D. Fresh tumor tissues will be subjected to deep immune profiling to understand the impact of tocilizumab on TAMs in the GBM TME.

Bone-sparing effects of tocilizumab in rheumatoid arthritis: a monocentric observational study.

Bone loss is a common feature in several autoimmune and chronic inflammatory diseases, such as rheumatoid arthritis (RA). Indeed, the high levels of pro-inflammatory cytokines seem to enhance bone resorption and to diminish bone formation, thus producing an uncoupling between osteoclast and osteoblast function and favoring the onset of juxtarticular as well as systemic osteoporosis. Many papers underline the high prevalence of osteoporosis in RA, as well as the negative correlation between interleukin 6 (IL-6) serum levels and bone mineral density (BMD). The aim of this study was to assess the effectiveness of one-year treatment with tocilizumab (TCZ), the first approved IL-6 receptor inhibitor, in reducing bone loss in RA. We enrolled 18 patients fulfilling 2010 ACR and EULAR criteria for RA from our arthritis outpatient clinic, assessing clinical and biochemical parameters during a 12-month period. The patients received TCZ 8 mg/kg i.v. every 4 weeks and underwent dual energy X-ray absorptiometry (DXA) for the measurement of bone mineral density (BMD) at baseline and at the end of study. Serum levels of C-reactive protein (CRP), erythrocytes sedimentation rate (ESR), IL-6, serum CrossLaps, osteoprotegerin (OPG), receptor activator of nuclear factor κβ ligand (RANK-L) and dickkopf-1 (DKK-1) were measured at baseline, at 6 months and 1 year. No significant difference in IL-6, RANK-L, DKK-1, OPG and serum CrossLaps levels between baseline, 6 months and 1 year were found. A significant increase of lumbar spine BMD was evidenced after 1 year of TCZ treatment. No difference in total body and femoral neck BMD was documented the end of the study. This study suggest the bone-sparing effect of TCZ in RA affected individuals.

Experience of anticipatory therapy with IL-6 receptor inhibitors and perspectives for its use in the evolution of COVID-19

The Advisory Board chaired by the chief specialist in infectious diseases of the Ministry of Health of Russian Federation, Professor V.P. Chulanov was held on June 18, 2022 in Saint Petersburg. Aim. The main purpose of the Board was following discussion: the analysis of the real-world data of levilimab as an anticipatory therapy for COVID-19 in hospitalized patients; the review of the experience and perspectives of levilimab as an anticipatory anti-inflammatory option for outpatient patients who meet defined clinical and laboratory criteria. Results. The analyzed data on clinical efficacy and safety formed the basis of recommendations proposed by experts for the use of levilimab in the inpatient and outpatient medical care for COVID-19.