Objective : Efficacy and safety of Itolizumab, an immunomodulatory mAb, in treating moderate-to-severe acute respiratory distress syndrome (ARDS) due to cytokine release in COVID-19 patients was evaluated in a multi-centric, open-label, two-arm, controlled, randomized, phase-2 study. Methods : Patients were randomized (2:1) to Arm-A (best supportive care [BSC]+Itolizumab) and Arm-B (BSC). Primary outcome of interest was reduction in mortality 30-days after enrollment. Results : Thirty-six patients were screened, five treated as first-dose-sentinels and rest randomized, while four patients were screen-failures. Two patients in Arm-A discontinued prior to receiving one complete infusion and were replaced. At end of 1-month, there were three deaths in Arm-B, and none in Arm-A (p = 0.0296; 95% CI = −0.3 [−0.61, −0.08]). At end of study, more patients in Arm-A had improved SpO2 without increasing FiO2 (p = 0.0296), improved PaO2 (p = 0.0296), and reduction in IL-6 (43 vs 212 pg/ml; p = 0.0296) and tumor necrotic factor-α (9 vs 39 pg/ml; p = 0.0253) levels. Transient lymphopenia (Arm-A: 11 patients) and infusion reactions (7 patients) were commonly reported treatment-related safety events. Conclusion : Itolizumab is a promising, safe and effective immunomodulatory therapy for treatment of ARDS due to cytokine release in COVID-19 patients, with survival and recovery-benefit.

Design of experiments (DOE), a component of Quality by Design (QbD), is systematic and simultaneous evaluation of process variables to develop a product with predetermined quality attributes. This article presents a case study to understand the effects of process variables in a bead milling process used for manufacture of drug nanoparticles. Experiments were designed and results were computed according to a 3-factor, 3-level face-centered central composite design (CCD). The factors investigated were motor speed, pump speed and bead volume. Responses analyzed for evaluating these effects and interactions were milling time, particle size and process yield. Process validation batches were executed using the optimum process conditions obtained from software Design-Expert® to evaluate both the repeatability and reproducibility of bead milling technique. Milling time was optimized to <5 h to obtain the desired particle size (d90 < 400 nm). The desirability function used to optimize the response variables and observed responses were in agreement with experimental values. These results demonstrated the reliability of selected model for manufacture of drug nanoparticles with predictable quality attributes. The optimization of bead milling process variables by applying DOE resulted in considerable decrease in milling time to achieve the desired particle size. The study indicates the applicability of DOE approach to optimize critical process parameters in the manufacture of drug nanoparticles.

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An uncontrolled increase in cytokine production may lead to systemic hyperinflammation, vascular hypo-responsiveness, increased endothelial permeability, hypercoagulation, multi-organ dysfunction and eventually death in moderate to severely ill COVID-19 patients. Targeting T-cells, an important driver of the hyperinflammatory response, in the treatment of COVID-19, could potentially reduce mortality and improve survival rates. Itolizumab is an anti-CD6 humanized monoclonal antibody with an immunomodulating action on Teffector cells that downregulates T-cell activation, proliferation and subsequent production of various chemokines and cytokines. The efficacy and safety of Itolizumab for the treatment of cytokine release syndrome in patients with moderate to severe acute respiratory distress syndrome (ARDS) due to COVID-19 was evaluated in a multi-centric, open-label, two-arm, controlled, randomized, phase 2 study. Eligible patients were randomized (2:1) to arm A (best supportive care + Itolizumab) and arm B (best supportive care). The primary outcome of interest was reduction in all-cause mortality 30 days after enrolment. Thirty-six patients were screened, 5 were treated as first dose sentinels and the rest were randomized, whilst 4 patients were considered screen failures. Two patients in the Itolizumab treatment arm discontinued prior to receiving the first dose and were replaced. At the end of 1 month, there were 3 deaths in arm B, and none in arm A (p= 0.0296). At the end of the follow-up period, more patients in Arm A had improved SpO2 without increasing FiO2 (p=0.0296), improved PaO2 (p=0.0296), and reduction in IL-6 (43 pg/ml vs 212 pg/ml; p=0.0296) and tumor necrotic factor-α (9 pg/ml vs 39 pg/ml; p=0.0253) levels. Itolizumab was generally safe and well tolerated, and transient lymphopenia (11 patients in Arm A) and infusion reactions (7 patients) were the commonly reported treatment related safety events. These encouraging results indicate that larger clinical trials are warranted to establish the role of Itolizumab in controlling immune hyperactivation in COVID-19.

Purpose The phase 3 HERITAGE trial demonstrated that the biosimilar trastuzumab-dkst is well tolerated with similar efficacy (measured by overall response rate [ORR] and progression-free survival [PFS]) compared with originator trastuzumab combined with taxane followed by monotherapy in patients with HER2-positive metastatic breast cancer (MBC). Herein, we present final overall survival (OS) from HERITAGE. Methods HERITAGE is a multicenter, double-blind, randomized, parallel-group study. Patients were randomized 1:1 to receive trastuzumab-dkst or trastuzumab plus taxane followed by continued monotherapy until disease progression. Overall survival was to be assessed at 36 months or after 240 deaths, whichever occurred first, as observed from time of randomization of last patient. Results At the final analysis (36 months), 242 patients in the intention-to-treat population had died during the study: 116 and 124 in the trastuzumab-dkst and trastuzumab groups, respectively, and 1 untreated patient from each treatment group. Median OS by Kaplan–Meier analysis was 35.0 months with trastuzumab-dkst and 30.2 months with trastuzumab. Evaluation of PFS showed a median of 11.1 months in both treatment groups. No new safety concerns were reported from week 48 until the end of the survival follow-up. Conclusion This is the first phase 3 trial of a trastuzumab biosimilar to report long-term survival data similar to originator trastuzumab in patients with MBC. The comparable long-term OS between the trastuzumab-dkst and originator trastuzumab groups further supports the similarity of trastuzumab-dkst with originator trastuzumab and establishes trastuzumab-dkst as a safe and effective treatment option for patients with HER2-positive MBC. ClinicalTrials.gov NCT02472964; 6/16/2015