Treatment with nanosomal paclitaxel lipid suspension versus conventional paclitaxel in metastatic breast cancer patients - a multicenter, randomized, comparative, phase II/III clinical study.

Background: A novel nanosomal paclitaxel lipid suspension (NPLS), free from Cremophor EL (CrEL) and ethanol, was developed to address the solvent-related toxicities associated with conventional paclitaxel formulation. Objective: To evaluate the efficacy and safety of NPLS versus CrEL-based paclitaxel (conventional paclitaxel) in patients with metastatic breast cancer (MBC). Design: A prospective, open-label, randomized, multiple-dose, parallel, phase II/III study. Methods: Adult (18-65 years) female patients with MBC who had previously failed at least one line of chemotherapy were randomized (2:2:1) to NPLS 175 mg/m2 every 3 weeks (Q3W, n = 48, arm A), NPLS 80 mg/m2 every week (QW, n = 45, arm B) without premedication or conventional paclitaxel (Taxol®, manufactured by Bristol-Myers Squibb, Princeton, NJ, USA) 175 mg/m2 Q3W (n = 27, arm C) with premedication. In the extension study, an additional 54 patients were randomized (2:1) to arm A (n = 37) or arm C (n = 17). Results: Pooled data from the primary study and its extension phase included 174 patients. The primary endpoint was the overall response rate (ORR). As per intent-to-treat analysis, ORR was significantly better in the NPLS QW arm as compared to conventional paclitaxel [44.4% (20/45) versus 22.7% (10/44), (p = 0.04)]. An improvement in ORR with NPLS Q3W versus conventional paclitaxel arm [29.4% (25/85) versus 22.7% (10/44)] (p = 0.53) was observed. Disease control rates observed were improved with NPLS Q3W versus conventional paclitaxel Q3W (77.7% versus 72.7%, p = 0.66) and with NPLS QW versus conventional paclitaxel Q3W (84.4% versus 72.7%, p = 0.20), although not significant. A lower incidence of grade III/IV peripheral sensory neuropathy, vomiting, and dyspnea was reported with NPLS Q3W versus conventional paclitaxel Q3W arms. Conclusion: NPLS demonstrated an improved tumor response rate and a favorable safety profile versus conventional paclitaxel. NPLS 80 mg/m2 QW demonstrated a significantly better response versus conventional paclitaxel 175 mg/m2 Q3W. Trial registration: Clinical Trial Registry-India (CTRI), CTRI/2010/091/001344 Registered on: 18 October 2010 (https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=MjEzNQ==&Enc=&userName=CTRI/2010/091/001344), CTRI/2015/07/006062 Registered on: 31 July 2015 (https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=MTE2Mjc=&Enc=&userName=CTRI/2015/07/006062).

Role of nanosomal paclitaxel lipid suspension (NPLS) in the treatment of patients with metastatic breast cancer (MBC) Why was the study done? Paclitaxel is a commonly used drug for the treatment of breast cancer. Conventional formulation of paclitaxel is known to cause side effects like injection site reactions. A newer formulation named NPLS was developed to overcome the limitations of the conventional paclitaxel. The current study was done to compare the safety and effectiveness of NPLS and conventional paclitaxel in patients with advanced breast cancer. What did the researchers do? The research team conducted a large study in multiple hospitals across India, involving women with advanced breast cancer who had experienced treatment failure with previous chemotherapy. A total of 174 patients were randomly assigned to receive either of the three treatment schedules: (1) NPLS every 3 weeks, (2) NPLS every week, (3) conventional paclitaxel every 3 weeks. What did the researchers find? The results showed that NPLS, in a weekly schedule, led to better tumor response rates compared to conventional paclitaxel given every 3 weeks. Additionally, NPLS demonstrated a favorable safety profile, as compared to conventional paclitaxel. What do the findings mean? These findings suggest that NPLS could be a promising alternative for women with advanced breast cancer. NPLS improved the response to treatment, with a better safety profile compared to conventional paclitaxel.

Efficacy and Safety of Nanosomal Docetaxel Lipid Suspension (NDLS) versus Conventional Docetaxel as Neoadjuvant and Adjuvant Therapy for Primary Operable Breast Cancer.

Objective: Nanosomal docetaxel lipid suspension (NDLS) is a novel formulation developed to overcome toxicity issues caused by excipients (polysorbate 80 and ethanol) present in commercially available docetaxel formulation. We conducted a prospective, observational study to compare the outcomes of nanosomal docetaxel lipid suspension (NDLS)-based versus conventional docetaxel-based chemotherapy in primary operable breast cancer. Methods: Sixty adult women with newly diagnosed stage IIb-III breast cancer were included. Patients received NDLS-based (n=30) or docetaxel-based (n=30) chemotherapy. Patients received (1) four cycles of preoperative doxorubicin and cyclophosphamide (AC) followed by four cycles of NDLS or docetaxel (T) and surgery (neoadjuvant AC→NDLS [n=9], or neoadjuvant AC→T [n=10]), or (2) four cycles of preoperative AC followed by surgery and postoperative NDLS or T (neoadjuvant AC→adjuvant NDLS [n=14], or neoadjuvant AC→adjuvant T [n=15]), or (3) surgery followed by postoperative AC→NDLS or T (adjuvant AC→NDLS [n=7], or adjuvant AC→T [n=5]) regimens. The study outcomes were pathological complete response (pCR) rates, clinical overall response rates (ORR), disease-free survival (DFS), overall survival (OS), and adverse event (AE) profile. Results: For neoadjuvant AC→T (n=10) vs neoadjuvant AC→NDLS (n=9), the pCR rates were 100% each, and the ORR were 100% vs 88.9% (p=1.0). All patients were alive at 6 months, and the median OS was not reached. Three patients had progressive disease (T: n=2, NDLS: n=1) with a DFS of 12 weeks in all three patients. Grade 3 infusion-related reactions were seen in five patients (16.7%) in T vs none in NDLS arms. Conclusion: NDLS-based neo/adjuvant chemotherapy was efficacious in the treatment of primary operable breast cancer and showed comparable pCR, ORR, DFS and OS rates versus conventional docetaxel. NDLS was better tolerated than conventional docetaxel.

Treatment Landscape of Macular Disorders in Indian Patients with the Advent of Razumab™ (World's First Biosimilar Ranibizumab): A Comprehensive Review.

Ranibizumab is approved for the treatment of several macular disorders, including wet age-related macular degeneration (wet AMD), diabetic macular edema (DME), retinal vein occlusion (RVO) and myopic choroidal neovascularization (mCNV), among others. The unaffordability of the innovator ranibizumab among patients from developing countries such as India led to the development of the world's first biosimilar ranibizumab, which is a cost-effective alternative that does not compromise efficacy and safety. Razumab™, developed and produced by Intas Pharmaceuticals Ltd., India, is the world's first biosimilar of ranibizumab, and is approved in India for the treatment of various macular disorders, including wet AMD, DME, RVO and mCNV. The efficacy and safety of Razumab for the treatment of these macular disorders have been evaluated in both prospective and real-world retrospective studies. Razumab has shown an efficacy similar to that of the innovator ranibizumab, achieving improved visual acuity, as measured by the best corrected visual acuity, and reduction in the central macular thickness, leading to improved patient outcomes. The safety profile of Razumab is comparable to that of the innovator ranibizumab and is well tolerated without any new safety concerns. Here, we review the clinical and real-world data of Razumab in the treatment of macular disorders.

Safety and efficacy of Razumab™ (world's first biosimilar ranibizumab) in wet age-related macular degeneration: a post-marketing, prospective ASSET study.

BACKGROUND: Razumab™ (world's first biosimilar ranibizumab) is approved for several macular disorders including wet age-related macular degeneration (AMD). We evaluated the safety and efficacy of biosimilar ranibizumab in wet AMD. METHODS: This prospective, multicentre, rAnibizumab bioSimilar Safety Efficacy postmarkeTing (ASSET) study enrolled patients aged ≥ 50 years with wet AMD having best-corrected visual acuity (BCVA) between 20/40 and 20/320. The patients received intravitreal biosimilar ranibizumab 0.5 mg every 4 weeks for 24 weeks. Safety endpoints included the incidence of adverse events (AEs), serious AEs (SAEs), and immunoreactivity after 6 months. The efficacy endpoints were the proportion of patients who lose fewer than 15 letters, increase in BCVA, change in central retinal thickness (CRT), and change in Visual Function Questionnaire-25 (VFQ-25) score, from baseline to 24 weeks. RESULTS: Of the 126 enrolled patients, majority (95.24%) of the patients received all 6 doses of biosimilar ranibizumab (total 3 mg). Nineteen AEs were reported (n = 16; 12.7%); majority (78.9%) were mild. There were no serious AEs reported, except one AE of death which was unrelated to the study drug. None of the patients discontinued the study due to an AE. The most common ocular AE was increase in intraocular pressure (4 events) and non-ocular AE was pyrexia (5 events). A total of 7.9% (10/126) patients prior to dosing and 7.1% (9/126) patients post-treatment were positive for anti-ranibizumab antibodies. No AEs suggestive of immunogenicity were noted. At 24-weeks, 97.60% patients in the intent-to-treat (ITT) population (N = 125) and 97.41% patients in the per-protocol (PP) population (N = 116) lost < 15 letters from baseline visual acuity. In the ITT and PP populations, 31.20% and 32.76% patients, respectively, showed improved visual acuity by ≥ 15 letters. Significant improvements in BCVA (mean difference: 8.8, 9.2, p < 0.001 for ITT, PP) and VFQ-25 (8.5, 9.2, p < 0.001 for ITT, PP) were seen; CRT reduced significantly (125 µm, 119.3 µm, p < 0.001 for ITT, PP). CONCLUSION: Razumab™ (world's first biosimilar ranibizumab) was well-tolerated without new safety concerns and significantly improved visual acuity in wet AMD patients. Trial registration CTRI/2016/03/006739. Registered 18 March 2016-Prospectively registered, http://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=13141&EncHid=&userName=2016/03/006739.

Thymoquinone with Metformin Decreases Fasting, Post Prandial Glucose, and HbA1c in Type 2 Diabetic Patients.

OBJECTIVE: Antihyperglycemic activity of Thymoquinone (TQ) was evaluated in diabetic mouse model and patients. METHODS: TQ (50 mg/kg) was orally administered daily for 21 days in combination with metformin in diabetic mice and a reduction on blood glucose level was monitored. In human, a 90-day randomized study was carried out in 60 Type 2 Diabetes mellitus patients to evaluate safety and efficacy of TQ administration with metformin in a 3-arm study. Patients in arm 1 (T1) received 1 tablet of metformin SR 1000 mg and 1 tablet of TQ 50 mg once daily. The second arm (T2) patients received 1 tablet of metformin SR 1000 mg and 2 tablets of TQ 50 mg once daily. Patients in arm 3 (R) received 1 tablet of metformin SR 1000 mg only. RESULTS: The diabetic mice treated with combination of TQ and metformin showed significant decrease in blood sugar compared to those treated with only metformin. In patients who completed the study, the glycated hemoglobin (HbA1c) values in T1, T2 and R decreased after 3 months from 7.2, 7.2 and 7.3 to 6.7, 6.8, and 7.1, respectively. A greater reduction in Fasting Blood Glucose and Post Prandial Blood Glucose was also observed in T1 and T2 arms compared to R. CONCLUSION: At dose levels of 50 and 100 mg of TQ combined with a daily dose of 1000 mg Metformin demonstrated a reduction in the levels of HbA1c and blood glucose compared to the standard treatment of diabetic patients with metformin alone.

Endoxifen: A new, protein kinase C inhibitor to treat acute and mixed mania associated with bipolar I disorder.

OBJECTIVES: Endoxifen is a protein kinase C inhibitor. The objective of the present phase III study was to demonstrate the safety and efficacy of endoxifen in treating bipolar I disorder (BPD I) patients. METHODS: A multicenter, double-blind, active-controlled study was conducted using a daily dose of 8 mg endoxifen compared to 1000 mg divalproex, the current standard treatment, in patients with BPD I acute manic episodes with/without mixed features. The primary endpoint of our study was the mean change in total Young Mania Rating Scale (YMRS) score at day 21. RESULTS: Endoxifen (n = 116) significantly (p < 0.0001) reduced total YMRS score (from 33.1 to 17.8. A significant (p < 0.001) improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) score was observed for endoxifen (4.8 to 2.5). Early time to remission of the disease was observed with endoxifen compared to divalproex. None of the patients required rescue medication and there was no drug-associated withdrawals. Changes in Clinical Global Impressions-Bipolar Disorder and Clinical Global Impression-Severity of Illness scores showed that treatment with endoxifen was well-tolerated. CONCLUSIONS: Endoxifen at a low daily dose of 8 mg was as efficacious and safe in patients with BPD I acute manic episodes with/without mixed features.

A Multicenter, Retrospective Study (RE-ENACT 2) on Razumab™ (World's First Biosimilar Ranibizumab) in Retinal Vein Occlusion.

PURPOSE: The REal life assessmENt of safety And effeCTiveness of Razumab 2 (RE-ENACT 2) study evaluated the long-term effectiveness of biosimilar ranibizumab. We present the subgroup analysis of patients with retinal vein occlusion (RVO). METHODS: Data of patients who received pro re nata (PRN) biosimilar ranibizumab (November 2015 to December 2018, 17 centers) were analyzed. Endpoints were change from baseline in best corrected visual acuity (BCVA, Snellen's/logMAR), central subfield thickness (CSFT), intraocular pressure (IOP), and proportions of patients having intraretinal fluid (IRF) and subretinal fluid (SRF) at weeks 4, 8, 12, 16, 20, 24, 30, 36, and 48. RESULTS: Of 101 patients, 48.51% were men, and the majority (79.21%) were treatment naïve and had received 3 (range 1-5) injections (53.5%). Significant improvements (P < 0.05) were observed from baseline to all timepoints for BCVA [baseline, 0.89 ± 0.06 (n = 94); week 48, 0.41 ± 0.08 (n = 14)] and CSFT [baseline, 527.58 ± 19.9 (n = 85); week 48, 307.47 ± 16.4 (n = 15)]. Changes in IOP (mmHg) were non-significant [baseline, 15.38 ± 0.4 (n = 94); week 48, 13.94 ± 0.6 (n = 16); P = 0.5575). Proportions of patients having IRF [baseline, 71.3% (n = 84) vs week 48, 0% (n = 15)] and SRF [baseline, 52.5% (n = 83) vs week 48, 0% (n = 15)] were decreased. Similar results for BCVA, CSFT, IOP, IRF, and SRF were observed for BRVO and CRVO subgroups. There were no new safety concerns. CONCLUSIONS: Biosimilar ranibizumab demonstrated improvements in visual acuity and disease outcomes up to 48 weeks in patients with RVO without any new safety concerns.

A Multicenter, Retrospective Study (RE-ENACT 2) on the Use of Razumab™ (World's First Biosimilar Ranibizumab) in Wet Age-Related Macular Degeneration.

INTRODUCTION: The REal life assessmENt of safety And effeCTiveness of Razumab (RE-ENACT) and long-term RE-ENACT 2 retrospective studies have evaluated the use of Razumab™ (world's first biosimilar ranibizumab) in retinal disorders in Indian patients. This report presents the subgroup analysis from the RE-ENACT 2 study in patients with wet age-related macular degeneration (wet AMD). METHODS: Medical charts of patients administered biosimilar ranibizumab injections as PRN treatment regimen between September 2015 and June 2018, at 17 centers across India, were reviewed. Changes from baseline in best-corrected visual acuity (BCVA, based on Snellen's or logMAR chart), central subfield thickness (CSFT), intraocular pressure (IOP), and proportions of patients having intraretinal fluid (IRF) and subretinal fluid (SRF) at weeks 4, 8, 12, 16, 20, 24, 30, 36, and 48 were evaluated. RESULTS: Of 103 patients with wet AMD, 62.1% were men and the majority (74.8%) were treatment naïve. The majority (57.9%) of the patients had received 3 (range 1-5) injections. Significant improvements were observed from baseline to all timepoints for BCVA (baseline, 0.92 ± 0.6 [n = 94]; week 48, 0.51 ± 0.4 [n = 14]; P = 0.0014) and CSFT (baseline, 430.83 ± 14.4 [n = 85]; week 48, 301.26 ± 11.6 [n = 15]; P < 0.0001). Changes in IOP from baseline to 48 weeks were minimal and not significant (14.92 ± 3.2 [n = 94] vs. 14.50 ± 2.1 [n = 18]; P = 0.9068). A decrease in proportions of patients having IRF (baseline, 63.6% [n = 99] vs. week 48, 15% [n = 20]) and SRF (baseline, 82.3% [n = 96] vs. week 48, 5% [n = 20]) were also observed. Similar results were observed for occult and classic subgroups. There were no new safety concerns. CONCLUSION: Razumab (biosimilar ranibizumab) demonstrated improvements in visual acuity and disease outcomes in patients with wet age-related macular degeneration without new safety issues.

Efficacy and Safety of Nanosomal Docetaxel Lipid Suspension-Based Chemotherapy in Sarcoma: A Multicenter, Retrospective Study.

OBJECTIVE: To evaluate the efficacy and safety of nanosomal docetaxel lipid suspension (NDLS, DoceAqualip) based chemotherapy in patients with sarcoma. METHODS: In this retrospective, multicenter (6 centers), observational study, we analyzed the medical charts of adult patients of either sex, who were treated with NDLS (75 mg/m2 in 3-weekly cycles) based chemotherapy for the treatment of sarcoma. The efficacy outcomes were overall response rate (ORR: complete response (CR) + partial response (PR)) and disease control rate (DCR: CR + PR + stable disease (SD)) in patients who received NDLS-based chemotherapy in neoadjuvant and metastatic settings. Overall survival (OS) and safety were evaluated for all settings. RESULTS: Of 11 patients (neoadjuvant: 1, adjuvant: 3, and metastatic: 7) in this study, majority had leiomyosarcoma (63.6%, 7/11) followed by extraskeletal myxoid chondrosarcoma (EMC), high grade pleomorphic sarcoma of mandible, malignant fibrous histiocytoma of right thigh, and osteosarcoma of femur (9.1% each, 1/11 each). NDLS plus gemcitabine combination was used in 10 patients (90.9%), and NDLS plus cyclophosphamide was used in one patient with EMC (9.1%). Efficacy evaluation was performed for 7 patients (neoadjuvant: 1/1; metastatic: 6/7). Complete response was reported in one patient (soft tissue sarcoma of mandible) treated in neoadjuvant setting. In metastatic setting, ORR was 50% and DCR was 66.7% (CR: 16.7% (1/6), PR: 33.3% (2/6), SD: 16.7% (1/6)). At a median follow-up of 6.5 months (range: 0.06-20.2 months), median OS was not reached in neoadjuvant and adjuvant settings, but it was 15.8 months in metastatic setting. At least 1 AE was reported in 7 (63.6%) patients. Neutropenia, thrombocytopenia, lymphopenia, and anemia were the hematological AEs, whereas nausea, vomiting, and diarrhea were the most common nonhematological AEs. NDLS treatment was well tolerated without any new safety concerns. CONCLUSION: Nanosomal docetaxel lipid suspension-based chemotherapy was efficacious and well tolerated in the treatment of sarcoma. Further prospective trials are needed to confirm the data.

Real-Life Clinical Effectiveness of Razumab® (the World's First Biosimilar of Ranibizumab) in Retinal Vein Occlusion: A Subgroup Analysis of the Pooled Retrospective RE-ENACT Study.

BACKGROUND: This subgroup analysis of the RE-ENACT study evaluates the effectiveness of Razumab® (the world's first biosimilar of ranibizumab by Intas Pharmaceuticals Ltd.) in Indian patients with retinal vein occlusion (RVO). METHODS: The data on patients with RVO who had received ≥3 injections of Razumab® between January and August 2016 were analyzed. Endpoints were: improvement in best corrected visual acuity (BCVA), and a decrease in central macular thickness (CMT), intraretinal fluid (IRF), and subretinal fluid (SRF) from baseline at weeks 4, 8, and 12. RESULTS: Of 160 patients, the majority (61.87%) were men. The mean (±SE) BCVA improved from baseline (0.76 ± 0.04) to week 4 (0.73 ± 0.03; p = 0.0656), which attained significance at week 8 (0.55 ± 0.02; p < 0.0001) and week 12 (0.47 ± 0.02; p < 0.0001). The mean (±SE) CMT significantly decreased from baseline (447.60 ± 10.91 µm) to week 4 (431.84 ± 10.92 µm; p = 0.0028), week 8 (339.28 ± 8.12 µm; p < 0.0001), and week 12 (298.23 ± 6.68 µm; p < 0.0001). The proportion of patients with IRF and SRF significantly (p < 0.0001) decreased from baseline to weeks 4, 8, and 12 (IRF: from 70.63 to 45.63, 39.38, and 30.00%, respectively; SRF: from 65.63 to 37.50, 28.13, and 24.38%, respectively). A subgroup analysis of branch RVO and central RVO showed similar results. No new safety concerns were observed. CONCLUSION: Razumab® (biosimilar of ranibizumab) effectively improved visual acuity and disease outcomes in patients with RVO in a real-world setting with no new safety concerns.

Securing the food supply chain: understanding complex interdependence through agent-based simulation.

The food industry has many points of vulnerability in its supply chain. It currently lacks integrated crisis management and response programs to understand the importance of decision-making during and in the aftermath of a bioterrorist attack on the food supply. Computer simulations have been used successfully in other industries as training and analysis tools. This paper describes an agent-based simulation for food defense training and analysis. Production information, consumption patterns, morbidity/mortality rates, recall costs and additional information were collected and provided to a data-driven simulation to anticipate the impact of decision-making on economic and public health during a terrorist attack. A case study is given with a representative exercise involving forty industry representatives who participated in a food defense simulation. Their decisions (recall and microbiological and toxicological testing) were derived from testing results, press releases, epidemiological data, and discussions with other industry and regulatory teams. Decisions made during the simulation resulted in over 76,000 illnesses, 45 deaths, and $132 million in recall costs. The no intervention, baseline scenario estimated to result in 91,000 illnesses and 54 deaths, indicating the improved public health outcomes resulting from players' decisions. Participants identified three key learning points: 1) communication between all groups is pertinent and challenging, 2) approaches to solve inherent food safety problems cannot be used to address food defense situations, and 3) human resource procedures regarding new hires and disgruntled employees should involve additional security measures. This computer simulation could be a valuable resource in food defense awareness and help educate companies and regulators about food defense risks and decision-making consequences.

Simulation tools for developing policies for complex systems: modeling the health and safety of refugee communities.

The U.S. Committee for Refugees and Immigrants estimated that there were over 33 million refugees and internally displaced persons (IDPs) in the world at the beginning of 2005. IDP/Refugee communities behave in complex ways making it difficult to make policy decisions regarding the provision of humanitarian aid and health and safety. This paper reports the construction of an agent-based model that has been used to study humanitarian assistance policies executed by governments and NGOs that provide for the health and safety of refugee communities. Agent-based modeling (ABM) was chosen because the more widely used alternatives impose unrealistic restrictions and assumptions on the system being modeled and primarily apply to aggregate data. We created intelligent agents representing institutions, organizations, individuals, infrastructure, and governments and analyzed the resulting interactions and emergent behavior using a Central Composite Design of Experiments with five factors. The resulting model allows policy makers and analysts to create scenarios, to make rapid changes in parameters, and provides a test bed for concepts and strategies. Policies can be examined to see how refugee communities might respond to alternative courses of action and how these actions are likely to affect the health and well-being of the community.