Recombinant Humanized Monoclonal Antibody Research Articles

33431 Efficacy of 80 mg/week dose of adalimumab (Humira) in treatment of hidradenitis suppurativa

Hidradenitis suppurativa (HS) is an inflammatory skin condition involving the apocrine gland-bearing regions, such as the axillae, groin, anogenital, and inframammary areas. Though its etiology is unknown, disease manifests when hair follicles become obstructed, leading to the release of inflammatory mediators, such as TNF-α and IL-17. Levels of TNF-α have been found to be elevated in lesions of HS, providing a basis for the use of biologics in treatment of severe HS. Adalimumab is a recombinant human IgG1 anti-TNF monoclonal antibody which acts via antagonism of TNF-α.

33431 Efficacy of 80 mg/week dose of adalimumab (Humira) in treatment of hidradenitis suppurativa

Hidradenitis suppurativa (HS) is an inflammatory skin condition involving the apocrine gland-bearing regions, such as the axillae, groin, anogenital, and inframammary areas. Though its etiology is unknown, disease manifests when hair follicles become obstructed, leading to the release of inflammatory mediators, such as TNF-α and IL-17. Levels of TNF-α have been found to be elevated in lesions of HS, providing a basis for the use of biologics in treatment of severe HS. Adalimumab is a recombinant human IgG1 anti-TNF monoclonal antibody which acts via antagonism of TNF-α. Although adalimumab has been studied in phase 2 and 3 trials and has been approved as a treatment modality for HS at a 40 mg weekly dose, numerous patients still suffer on a day-to-day basis due to the severity of their disease and do not respond to this conventional dosing. We present a series of 6 such patients whose response to an 80 mg/week dose of adalimumab has been positive, with a decrease in severity and number of HS lesions, leading to improvement in the Hidradenitis Suppurativa Clinical Response (HiSCR) in the absence of serious adverse effects. Although this dosing regimen has not been well-documented in literature, it is important to consider the lasting benefits of treatment with a higher dose in individuals afflicted with treatment-resistant HS, including a decreased likelihood of comorbidities and complications and an improved quality of life.

Abstract PO003: Combination therapy with Nivolumab/Bevacizumab is safe and effective in patients with recurrent hepatocellular carcinoma after liver transplant

Abstract Recurrent hepatocellular carcinoma (HCC-R) after Liver Transplant (LT) is difficult to manage and often characterized by relevant aggressiveness and extrahepatic localizations. Currently TKIs are the only therapeutic option, but results in term of overall survival (OS) and progression-free survival are disappointing. Immune checkpoint inhibitors in association with recombinant humanized monoclonal antibody to VEGF were to be proved effective in non-LT patients with metastatic hepatocellular carcinoma in determining tumor stabilization and improved survival. However, as in LT patients immunotherapy may increase the risk of acute liver rejection, such combination therapy has not been used so far. We designed a proof-of-concept study to analyze safety and efficacy of Nivolumab and Bevacizumab in LT patients as treatment for HCC-R after LT. Combination therapy received nominal authorization from the Provincial Medicines Commission. Candidate patients underwent routine blood test (hepatic, renal, and cardiac function), echocardiogram and a total body CT as baseline assessment. Patients with creatinine higher than 1.5 ULN or with ejection fraction lower than 45% were excluded. Five patients who experienced HCC-R 2 to 8 years after LT with pulmonary, lymph node, adrenal, bones, and hepatic localization and were either intolerant to TKIs or had had progression on TKIs, were included. All recurrent tumors and extra-hepatic localizations were characterized by high biologic aggressiveness. Patients received Nivolumab infusion every 14 days at a dose of 240 mg. Total body CT scan was performed every 8 weeks. When progression disease (PD) was detected at CT scan, Bevacizumab was added at a dose of 5 mg/kg every 14 days. One patient received a single Nivolumab infusion but was withdrawn because of rapid tumor progression, eventually followed by death. Another patient experienced moderate/severe rejection, which resolved with 1g/day Methylprednisolone e.v. for 3[EV1] days followed by Prednisone 50mg/day for 1 week then tapered and stopped. This patient was maintained on double therapy without residual problems. The 4 alive patients are still on double therapy after a mean period of treatment of 36±21 weeks. Disease stability with the combination of Nivolumab/Bevacizumab has been achieved in all patients at hepatic and all extra-hepatic HCC localization but bone, where 2/2 patients experienced progression. It should be underlined, however, that progression was very slow and mean survival of these two patients on combination therapy is 54±2 weeks. Combination therapy was very well tolerated, with few side effects throughout treatment period. These results indicate that the combination Nivolumab/Bevacizumab can be safely used in liver transplant patients. The risk of acute allograft rejection is minimal and manageable. Bone metastases remain an unsolved issue and need further alternative therapeutic approach. For patients with hepatic or other extra-hepatic localization, this combination obtained a relevant and protracted stabilization of disease. Citation Format: Lorenza Di Marco, Alessandra Pivetti, Nicola De Maria, Francesco Giuseppe Foschi, Dante Romagnoli, Federico Casari, Cristian Caporali, Paolo Magistri, Barbara Catellani, Fabrizio Di Benedetto, Erica Villa. Combination therapy with Nivolumab/Bevacizumab is safe and effective in patients with recurrent hepatocellular carcinoma after liver transplant [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO003.

Comparison of the Patients with Chronic Urticaria Who Responded and Did Not Respond to Omalizumab Treatment: A Single-Center Retrospective Study

Introduction: Chronic urticaria (CU) is a condition usually lasting longer than 6 weeks, with wheals and angioedema, sometimes both. Omalizumab is a recombinant humanized monoclonal IgG antibody developed against IgE. In some patients with CU, treatment response to omalizumab is good, but in some patients, it is poor. We aimed to compare the clinical features and laboratory parameters of the patients who responded and did not respond to omalizumab treatment among patients diagnosed with CU. Methods: Patients treated with omalizumab for the diagnosis of CU were evaluated retrospectively. Treatment response to omaliz­umab was evaluated by urticaria control test (UCT) (responder to omalizumab: UCT score ≥12 at 6 months and an increase of ≥3 compared to baseline). The clinical features and laboratory parameters of the patients who responded and did not respond to treatment were compared. Results: The mean age of the 220 patients, 66 (30%) men and 154 (70%) women, who received 300 mg of sc omalizumab every 4 weeks for CU was 38.89 ± 12.76 years. One hundred eighty-nine (85.9%) patients had good response to omalizumab treatment at the end of 6 months. Atopy (n = 73 [38.6%], p = 0.026), eosinophil count (median = 190 [0–800] [cells/µL], p < 0.001), basophil count (median = 40 [0–100] [cells/µL], p = 0.021), and total IgE (median = 240.5 [45–2,644] [kU/L], p < 0.001) level were significantly higher in the omalizumab responder patients (UCT score ≥12 at 6 months and an increase of ≥3 compared to baseline). Psychiatric disorders (n = 13 [41.9%], p = 0.008) and anti-TG (n = 11 [35.5%] [>2 IU/mL positive], p = 0.024) were significantly higher in the oma­lizumab nonresponder patients (UCT score ≤11 at 6 months). A weak but significant clinical correlation was found between blood eosinophil count (r = 0.168, p = 0.013), blood lymphocyte count (r = −0.149, p = 0.027), total IgE level (r = 0.207, p = 0.002), and increase in UCT score. As a result of the ROC curve analysis, the blood eosinophil count (AUC: 0.763, p < 0.001), total IgE level (AUC: 0.866, p < 0.001), and blood basophil count (AUC: 0.662, p = 0.004) had diagnostic value in predicting the response to omalizumab treatment in patients with CU. Conclusion: The patients with CU who were atopic with high eosinophils, high basophils, and high total IgE levels had good response to omalizumab treatment, but the patients with concomitant psychiatric disease and positive thyroid autoantibodies had poor response to omalizu­mab treatment. These findings obtained in our study should be tested in randomized controlled studies.

Tocilizumab induced immunosuppression in a case of adult-onset still’s disease: are these newer biologics double edged sword?

Adult-onset still’s disease (AOSD) is a rare multisystemic inflammatory disorder of unknown etiology characterised by high spiking fever, evanescent skin rash, arthralgias, arthritis, neutrophilic leucocytosis. Initial treatment strategy includes use of hands-on drugs like non-steroidal anti-inflammatory drugs, low dose corticosteroids, conventional DMARDs. But as the disease progresses to severe form, targeted and biologic DMARDs could be the option for management. Interleukin-6 being one among the many cytokines involved in the pathogenesis of AOSD, has made itself a target for the treatment of refractory cases. Tocilizumab, a recombinant humanized anti IL-6 monoclonal antibody, is one such biologic drug available in the market that has proven its therapeutic efficacy in several clinical trials. We are presenting a case of 37-year-old female patient, known case of AOSD for 4 years. Patient was initially maintained on low dose corticosteroid and conventional DMARD like hydroxychloroquine and methotrexate. Flare ups of the disease warranted the use of tocilizumab and tofacitinib in this patient. After clinical as well as pathological improvement with tocilizumab 2 years before, signs of immunosuppression were observed when tocilizumab was reintroduced for the treatment. Patient suffered from acute pyelonephritis, septicemia, shock, oropharyngeal candidiasis and bronchitis which could be owned to immunosuppressive action of tocilizumab. One can reduce the chances of infection and other adverse effects by careful periodic monitoring of various laboratory parameters like total W.B.C., total platelet count and liver enzymes. Cautious selection of the patient is needed for the treatment with newer biologic agents.

Analytical and functional similarity of biosimilar Elizaria® with eculizumab reference product

A recombinant humanized monoclonal antibody (mAb) Eculizumab, C5-complement cascade inhibitor, is an important treatment of complement-based diseases recommended by international guidelines. Elizaria® Drug Product (DP), developed by IBC Generium, Russia, is the world's first registered biosimilar of eculizumab (Soliris®, Alexion Pharmaceuticals). Using sensitive state-of-the-art analytical techniques extensive similarity assessment has been conducted to demonstrate the structural and functional similarity of original Soliris® (Eculizumab Reference Product, RP) and the biosimilar Elizaria®, focusing on the physicochemical and biological quality attributes, including those known to affect the mechanisms of action. A multitude of analyses revealed that amino acid sequence is identical, the higher order structures, post-translational modifications, purity, and product variants are highly similar between Elizaria® DP and Eculizumab RP, except for minor differences in the relative abundance of the charge variants and glycan moieties considered not clinically significant. The results demonstrate that Elizaria® is highly analytically similar to Eculizumab RP in terms of physicochemical properties and biological activities.

Bevacizumab encapsulation into PLGA nanoparticles functionalized with immunouteroglobin-1 as an innovative delivery system for atherosclerosis

Atherosclerosis represents one of the main causes of death in the Western world. It is a multifactorial pathology characterized by lesions that reduce the lumen of the vessels causing serious clinical events. The extra-domain B of fibronectin is overexpressed during angiogenesis and in tissues undergoing growth and extensive remodeling, i.e., atherosclerotic plaque. Bevacizumab is a recombinant humanized monoclonal antibody that can play a central role against angiogenesis reducing the risk associated with this process in atherosclerosis. In this work, an innovative nanosystem for the targeted delivery of bevacizumab to the atherosclerotic lesion is proposed.A production protocol for poly(lactic-co-glycolic acid)-polyethylene glycol nanoparticles loaded with bevacizumab and functionalized with immunouteroglobin-1 was designed. Once functionalized nanoparticles with immunouteroglobin-1 were produced, they were characterized in terms of morphology, mean diameter, ζ-potential, association and conjugation efficiencies, bevacizumab release profile, both in phosphate buffered saline and in serum, bevacizumab stability after release, cytocompatibility, and hemocompatibility. Nanoparticle mean diameter was in the range of 217–265 nm, their surface charge was between −22 and −8 mV, and the association and conjugation efficiencies of about 76 and 59 %, respectively. Fourier transform infrared spectroscopy analysis confirmed the functionalization of their surface with immunouteroglobin-1. In vitro assays showed that the studied nanoparticles were cytocompatible, once in contact with human endothelial and murine macrophage cell lines up to 72 h, and hemocompatible, once in contact with red blood cells, at different concentrations of encapsulated bevacizumab (0.1, 1, 10, and 100 μg/mL).

Mammaglobin 1 mediates progression of trastuzumab-resistant breast cancer cells through regulation of cyclins and NF-κB.

Overexpression of human epidermal growth factor receptor 2 (HER2) in various cancers is correlated with poor patient survival. Trastuzumab, a recombinant humanized monoclonal antibody against HER2, has been considered to be a first‐line therapy for HER2‐positive breast cancer patients, but its usefulness is limited by the development of resistance. In this study, we established resistant cells by long‐term treatment with trastuzumab. These cells showed higher proliferation, invasion, and migration abilities than the wild‐type cells. Mammaglobin 1 (MGB1), cyclin D1, E1, A2, and phosphorylated NF‐κB (p‐p65) were upregulated in resistant cells. These proteins regulate cell proliferation, migration, and invasion of resistant cells. Depletion of MGB1 decreased cyclin and p‐p65 expression. Cyclin D1 and A2, but not E1 expression, were affected by p‐p65 downregulation. In summary, our results indicate that MGB1 expression is increased in breast cancer cells that have gained resistance to trastuzumab, and suggest that MGB1 promotes aggressiveness through cyclin and NF‐κB regulation.

Amubarvimab/Romlusevimab: First Approval.

Amubarvimab 安巴韦单抗注射液/romlusevimab 罗米司韦单抗注射液 is a combination of two neutralizing recombinant human IgG1 monoclonal antibodies (amubarvimab and romlusevimab) against the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19). Jointly developed by Brii Biosciences, Tsinghua University and the Third People’s Hospital of Shenzhen, it has been approved (in December 2021) by the National Medical Products Administration of China for the treatment of mild COVID-19 in patients aged ≥ 18 years, and those aged 12–17 years with a bodyweight of ≥ 40 kg (conditional approval) who are at high risk of progressing to severe disease, including hospitalization or death. An Emergency Use Authorization application for amubarvimab/romlusevimab is currently under review in the USA. This article summarizes the milestones in the development of amubarvimab/romlusevimab leading to this first approval for the treatment of COVID-19.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40265-022-01759-3.

Population Pharmacodynamic Analyses of Human Anti-Rabies Virus Monoclonal Antibody (Ormutivimab) in Healthy Adult Subjects.

Ormutivimab is the first recombinant human anti-rabies monoclonal antibody (rhRIG) approved for clinical application in China. In this study, a population pharmacodynamic (PPD) model was established to compare the neutralizing antibody activities of Ormutivimab and human rabies immunoglobulin (HRIG), alone or combined with human rabies vaccine (Vero), in a phase II clinical trial, and to recommend a target dose for the phase III trial. The model was verified to fit the PPD data well. The stability of the model was verified by the bootstrap method. The level of neutralizing antibodies in vivo increased rapidly after administration of Ormutivimab or HRIG. Neutralizing antibodies with a strong activity were produced at 7 days (Ormutivimab + vaccine) or 10 days (HRIG + vaccine) after induction by the vaccine in vivo. Compared to that induced by HRIG + vaccine, the level of the neutralizing antibodies induced by Ormutivimab + vaccine peaked higher and faster. The levels of neutralizing antibodies induced by Ormutivimab + vaccine and HRIG + vaccine were similar within 21 days after administration. According to these results and the safety data, 20 IU·kg−1 was recommended as the target dose in the confirmatory study of Ormutivimab. Registration: ClinicalTrials.gov #NCT02559921.

Efficacy and safety of omalizumab therapy in urticaria vasculitis.

Urticarial vasculitis (UV) is a small-vessel leukocytoclastic vasculitis characterized by different clinical manifestations ranging from long-lasting urticarial lesions to severe and potentially life-threatening multi-organ involvement. Omalizumab (OMA), anti-IgE recombinant humanized IgG1 monoclonal antibody, has been successfully used to treat few cases of severe and/or refractory UV. In this study we report our experience on 6 patients with refractory normocomplementemic UV successfully treated with anti-IgE therapy (OMA), suggesting that this biological therapy may be a safe and effective therapeutic option in UV.

Use of REGEN-COV in children after heart transplantation for treatment and post-exposure prophylaxis of COVID-19.

COVID-19 pandemic continues to evolve and new variants like Delta and Omicron have been discovered. REGEN-COV is a recombinant human monoclonal antibody to the spike protein of SARS-CoV-2 which received emergency use authorisation for treatment and post-exposure prophylaxis in patients with high risk of progression to severe disease. We review our experience with use of REGEN-COV in paediatric heart transplant patients.

Successful combined treatment with omalizumab and tocilizumab in a case of chronic spontaneous urticaria and rheumatoid arthritis: A case report and literature review

Omalizumab is a recombinant humanized monoclonal anti-IgE antibody used to treat uncontrolled chronic spontaneous urticaria (CSU). Sometimes patients with CSU also have other autoimmune conditions. Recent studies have demonstrated the safety and efficacy of a combination treatment with omalizumab and other biologics. Here, we report the first successful treatment with omalizumab for CSU and tocilizumab for rheumatoid arthritis. Since omalizumab is unlikely to cause severe immunosuppression, it may be a treatment option for CSU, even in patients treated with other biologics.

The Utilization of Bevacizumab in Patients with Advanced Ovarian Cancer: A Systematic Review of the Mechanisms and Effects.

Most ovarian cancer cases are diagnosed at an advanced stage (III or IV), in which a primary debulking surgery combined with adjuvant systemic chemotherapy is the standard management. Since targeted therapy is less toxic to human cells than systemic chemotherapy, it has drawn much attention and become more popular. Angiogenesis is a critical process during the proliferation of ovarian cancer cells. Currently, many studies have put emphases on anti-angiogenetic medication, such as bevacizumab, the first and most investigated angiogenesis inhibitor that can exert anti-neoplastic effects. Bevacizumab is a recombinant humanized monoclonal antibody that has been approved for first-line maintenance treatment of advanced ovarian cancer. This review is a summary of current literature about the molecular mechanisms of actions, safety, and effects of bevacizumab for use in advanced epithelial ovarian cancer. Some common side effects of bevacizumab will be also discussed. As an inhibitor of angiogenesis, bevacizumab binds to circulating vascular endothelial growth factor (VEGF) and thereby inhibits the binding of VEGF to its receptors on the surface of endothelial cells. Neutralization of VEGF prevents neovascularization and leads to apoptosis of tumor endothelial cells and a decrease in interstitial fluid pressure within the tumors, which allows greater capacity for chemotherapeutic drugs to reach specific targeted sites. Grossly, bevacizumab has demonstrated some significant therapeutic benefits in many randomized trials in combination with the standard chemotherapy for advanced epithelial ovarian cancer. Based on the available evidence, a higher dosage and a longer duration of bevacizumab appear to achieve better therapeutic effects and progression-free survival. On the other hand, patients with more severe diseases or at a higher risk of progression seem to benefit more from bevacizumab use. However, many unknown aspects of bevacizumab, including detailed mechanisms of actions, effectiveness, and safety for the treatment of ovarian cancer, warrant further investigation.

A Randomized Controlled Dose-Escalation Study of LY06006, a Recombinant Humanized Monoclonal Antibody to RANKL, in Chinese Healthy Adults.

Background: This study was conducted to explore the safety, tolerance, pharmacokinetics, pharmacodynamics, and immunogenicity of LY06006, a recombinant humanized monoclonal antibody to RANKL, when administrated subcutaneously in Chinese healthy adults. Research design and methods: This was a randomized, double-blinded, placebo-controlled, single ascending dose study performed in 32 healthy Chinese adults, who were randomly assigned to receive a single injection dose of 18, 60, 120 mg study drug or placebo with a follow-up of 140–252 days. Results: No deaths or drug-related serious adverse events occurred. LY06006 was rapidly absorbed in the 60 mg group with a Tmax range of 120–480 h and serum LY06006 concentrations decreased slowly 11–13 days after dosing with a long mean (SD) half-life of 389.58 (63.44) h. The most frequent AEs were elevated serum parathyroid hormone (PTH) level (83.3%), hypocalcemia (54.2%), and hypophosphatemia (45.8%). None of the 32 subjects tested positive for anti-drug antibody during the trial. Conclusion: Single-dose subcutaneous administration of LY06006 was safe and well-tolerated in healthy Chinese adults. Cmax showed linear pharmacokinetic characteristics in the dose range of 18–120 mg based on dose-exposure proportionality analysis.

392-P: Phase 1, Randomized, Controlled Trial of GFB-024, a Once-Monthly CB1 Inverse Agonist, in Healthy Overweight and Obese Participants and in Participants with Type 2 Diabetes Mellitus

Evidence from nonclinical studies suggests a role of cannabinoid-1 receptor (CB1) in the development of diabetic nephropathy (DN) . Kidney CB1 expression is upregulated in podocytes and tubular cells in murine models of obesity and diabetes mellitus (DM) . Inhibition by CB1 inverse agonists has been shown to ameliorate diabetes-induced albuminuria, inhibit kidney fibrosis and inflammation, and prevent podocyte dysfunction. Mouse models of DM have shown that genetic deletion of CB1 in podocytes or proximal tubular cells protects against glomerular and tubular dysfunction. GFB-024 is a recombinant humanized monoclonal antibody functioning as a CB1-specific inverse agonist that protects human podocytes in vitro. Targeting the CB1 pathway with GFB-024 is a potentially novel approach to protecting podocytes from injury in patients with CB1-associated DN. In a phase 1, randomized, double-blind, placebo-controlled single ascending dose (SAD) trial, we evaluated the safety, tolerability, pharmacokinetics (PK) , and immunogenicity of GFB-024 in 38 healthy overweight and obese (BMI 25 - 40 kg/m2) participants, receiving single doses of 5 mg to 300 mg administered subcutaneously. GFB-024 was well tolerated, and there were no dose-limiting adverse effects. PK exposures achieved in the trial exceeded the estimated efficacious exposure, based on in vitro activity assays. Absorption was prolonged with flat exposure over the first 7 days, with a Tmax ranging from approximately 4-7 days. Elimination half-life was approximately 12-13 days, with exposures remaining in the estimated efficacious range at 28 days for all but the lowest dose tested. In summary, GFB-024 was safe and well tolerated following single doses of up to 300 mg. PK analysis demonstrated potentially efficacious exposure, a prolonged absorption phase, and elimination half-life compatible with once-monthly dosing. Disclosure G.Gaich: Consultant; 89 bio, Inc., Employee; Goldfinch Bio, Inc. S.Bilic: Consultant; Goldfinch Bio, Inc. Y.Dagon: Employee; Goldfinch Bio, Inc. T.Gustafson: Employee; Goldfinch Bio, Inc., Janssen Pharmaceuticals, Inc. J.Lawler: Employee; Goldfinch Bio, Inc. L.Johnson: Employee; Goldfinch Bio, Inc. L.Rudolph-owen: Employee; Goldfinch Bio, Inc.

NSABP FC-12: A single-arm, phase II study to evaluate treatment with gevokizumab in patients with stage II/III colon cancer who remain ctDNA+ after curative surgery and adjuvant chemotherapy.

TPS3642 Background: Detection of circulating tumor DNA (ctDNA) in patients (pts) following surgery is indicative of presence of minimal/molecular residual disease (MRD) and confers a near-certain risk of disease recurrence. Therapeutic strategies to treat MRD following standard curative therapies are needed because the risk of recurrence is high and therapeutic intervention may provide clinical benefit to patients. Gevokizumab is a recombinant humanized monoclonal antibody targeting interleukin-1β (IL-1β), which is involved in all phases of the malignant process (tumorigenesis, invasion, metastasis, angiogenesis, progression, and the modulation of anti-tumor immunity). Gevokizumab has been validated in pre-clinical colon cancer (CC) models and safety established in the advanced-stage clinical setting. In this trial in progress, we aim to test the efficacy of gevokizumab in pts with early-stage CC with MRD (ctDNA-positivity) following definitive treatment. Methods: NSABP FC-12 is a single-arm, multi-centered phase II study that will include pts with stage II/III CC who test MRD+ within 6 wks following completion of curative surgery and ≥3 mos of adjuvant chemotherapy. MRD will be assessed using a personalized and tumor-informed ctDNA assay (Signatera bespoke assay). Gevokizumab will be given at a flat dose of 120 mg IV every 28 days for 13 cycles. The primary endpoint is relapse-free survival (RFS) following initiation of study therapy through one year of follow-up. Secondary endpoints are rate of ctDNA clearance at 8 wks from start of study therapy, as well as safety, toxicity, pharmacokinetics, and immunogenicity of gevokizumab. Exploratory and correlative endpoints will include outcomes associated with ctDNA clearance kinetics, tumor mutations, tumor mutational burden, circulating methylated DNA, tumor immune microenvironment profile, peripheral blood immune profile, and stool microbiome analyses. The enrollment period will be ̃12 mos. Pts will be followed for 18 mos following enrollment with ctDNA analysis at prespecified timepoints until imaging is positive for recurrence of disease or death. CT scans will be at 6-mo intervals. RFS will be determined in pts who clear ctDNA at 8 wks compared to those who do not. A single-stage design to test the null hypothesis that the 12-mo RFS is P≥0.20 versus the alternative (HA) that P≥0.35 has a sample size of 31 (alpha=0.151; power 0.811). If ≥9 of 31 pts (29%) are alive and recurrence-free at 12 mos, then gevokizumab will be considered promising for further study. Enrollment continues towards the primary endpoint. Clinical trial information: 05178576.

Efficacy and safety profile of 2-year netakimab treatment in patients with moderate-to-severe plaque psoriasis in terms of the randomized double-blind placebo-controlled BCD-085-7/PLANETA clinical trial

Background. Netakimab, a recombinant humanized monoclonal antibody, specifically binding to IL-17 blocks its activity resulting in plaque psoriasis signs decrease. The results of the first year of BCD-085-7/PLANETA study showed high efficacy and a favorable safety profile in the treatment of patients with moderate-to-severe psoriasis.&#x0D; Aims. Efficacy and safety assessments of netakimab through 2 years of treatment in patients with moderate-to-severe psoriasis.&#x0D; Materials and methods. BCD-085-7/PLANETA study is ongoing Randomized, Double-blind, Placebo-Controlled Phase III clinical study. In the study, 213 patients with moderate-to-severe plaque psoriasis were randomly assigned to one of three study groups. In the first two groups of patients, after weekly drug administration, received netakimab at a dose of 120 mg every two or four weeks. In the third group the patients received placebo. During 12-week double-blind study period the efficacy were evaluated based on the proportion of patients achieved PASI 75. After that all patients were switched to netakimab (once in 4 weeks). Patients who failed to achieve PASI 75 at Week 52 were withdrawn from the study. The open period lasts about 3 years. Herein we focus on the results of 2-year netakimab treatment (120 mg, weekly for 3 weeks, then once in 4 weeks), the recommended per label dose. Taking into account the epidemiological situation (COVID-19) and results limitation due to missing visits, additionally to the efficacy analysis in patients received, at least, one dose of netakimab, analysis in those of them who had relevant data on each visit per Protocol was conducted (ITT and PP populations).&#x0D; Results. At Year 1, PASI 75/90/100 responses were achieved in 88,7/74,5/56,6% patients, respectively (ITT-population) and in 100/85/66% patients, respectively (ITT-population). In 2 year, 69,3/58,0/40,6% sustained their responses in ITT-population and 93,2/78,2/53,1% in PP-population. Through 2 years, the high quality of life sustained among patients. The safety profile remained favorable and immunogenicity was low.&#x0D; Conclusions. Treatment with netakimab at a dose of 120 mg every 4 weeks results in high rates of sustained clinical response and quality life improvement in patients with moderate-to-severe plaque psoriasis with remains of a favorable safety profile.

Real-World Effectiveness of Belimumab in Systemic Lupus Erythematosus: A Systematic Literature Review.

IntroductionBelimumab is a recombinant human monoclonal antibody that binds to soluble B-lymphocyte stimulator and inhibits its biological activity. Since receiving approvals for the treatment of systemic lupus erythematosus (SLE), several observational studies have investigated the effectiveness of belimumab in the real-world setting. This study reports a systematic review and meta-analysis of the literature to evaluate the real-world effectiveness of belimumab for the treatment of SLE.MethodsA literature search following PRISMA Guidelines and limited to studies in English was performed (2014−2020) to identify relevant studies reporting effectiveness outcomes of belimumab in patients with SLE. A modified version of the Newcastle–Ottawa Scale was used to assess study quality. Outcomes, including SLE Disease Activity Index (SLEDAI) score, prednisone-equivalent use, and SLE flare were pooled and analyzed using statistical aggregation methods.ResultsThe literature search identified 514 articles for initial review. Of these, 17 articles were suitable for data extraction and summary. Baseline characteristics of patients in real-world studies were generally similar to those of relevant clinical trials, including age, sex, disease duration, SLEDAI score, and prednisone-equivalent use. Real-world use of belimumab was associated with reductions in SLEDAI score (mean baseline score to month 6: 10.1–4.4; 57% reduction), prednisone-equivalent dosing (mean baseline dose to month 6: 12.1 mg/day to 6.9 mg/day; 43% reduction), and flare frequency (12 months prior to belimumab to 12 months after belimumab: 1.15–0.39 mean flares per patient per year; 66% reduction). Long-term data (up to 2 years post-treatment initiation) for SLEDAI score and prednisone-equivalent dose indicated that improvements in both outcomes continue over time among patients remaining on therapy.ConclusionsIn the real-world setting, observed outcomes with belimumab for the treatment of SLE are consistent with those reported from randomized clinical trials. Improvements persist long-term for SLEDAI activity and prednisone-equivalent use with belimumab.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-022-00454-9.

Pharmacokinetics and pharmacodynamics of a proposed tocilizumab biosimilar MSB11456 versus both the US-licensed and EU-approved products: a randomized, double-blind trial

ABSTRACT Background Tocilizumab is a recombinant humanized monoclonal immunoglobulin G1 antibody against the interleukin-6 receptor (IL-6 R). MSB11456 is a proposed tocilizumab biosimilar. Objectives To assess the pharmacokinetic and pharmacodynamic similarity of MSB11456 to both US-licensed and EU-approved tocilizumab. Methods Healthy adult volunteers (N = 685) received a single 162 mg subcutaneous injection of MSB11456, US-licensed tocilizumab, or EU-approved tocilizumab in this randomized, double-blind, parallel-group study. Blood samples were taken pre-dose and for up to 48 days post-dose. Primary endpoint pharmacokinetic parameters were analyzed using analysis of covariance. Secondary pharmacodynamic measures included serum-soluble IL-6 R and serum C-reactive protein. Safety data were analyzed descriptively. Results Pharmacokinetic equivalence (with all corresponding 90% confidence intervals for the geometric least squares mean ratios within the predefined 80.00% to 125.00% equivalence margin) was demonstrated between MSB11456 and both US-licensed and EU-approved tocilizumab, as well as between the reference products. Pharmacodynamic analyses demonstrated similarity of MSB11456 and both US-licensed and EU-approved tocilizumab, as well as between the reference products. Safety, tolerability, and immunogenicity were comparable between treatments. Conclusion Pharmacokinetic and pharmacodynamic similarity of MSB11456, US-licensed tocilizumab, and EU-approved tocilizumab were demonstrated, and the three products had comparable immunogenicity and safety, supporting MSB11456 as a biosimilar to tocilizumab.