Efficacy and safety of bovhyaluronidase azoximer (Longidase) in patients with post-COVID syndrome: results of an open, prospective, controlled, comparative, multicenter clinical trial DISSOLVE.

Post-COVID syndrome develops after COVID-19 (COronaVIrus Disease 2019) and leads to cumulative effects in the form of shortness of breath and impaired lung function. Notably, patients with airway inflammation and COVID-19 were found to have increased concentrations of hyaluronic acid (HA). Since bovhyaluronidase azoximer (Longidase) catalyzes the hydrolysis of HA, this drug has the potential to reduce HA levels and improve lung function in patients with post-COVID syndrome. The aim of the DISSOLVE trial, which was conducted early in the pandemic, was to investigate the efficacy and safety of bovhyaluronidase azoximer in patients with symptoms associated with post-COVID syndrome. Methods. An open, prospective, controlled, comparative, multicenter clinical trial (NCT04645368) included adult patients (n = 160) who had post-COVID syndrome. Patients in the treatment group (n = 81) received bovhyaluronidase azoximer, and individuals in the control group (n = 79) were followed up without intervention. The study included physical examination, evaluation of forced vital capacity (FVC), assessment of dyspnea with the Modified Medical Research Council Dyspnea Scale (mMRC), 6-minute walking test, and pulse oximetry. These indicators were measured on 3 visits, at days 1 (baseline), 75, and 180. In addition, the number of patients who experienced adverse events and serious adverse events were recorded. Results. Baseline patient characteristics in the treatment group and the control group were similar. In the treatment group, there was a statistically significant reduction in residual pulmonary abnormalities after visit 2 (day 75) and visit 3 (day 180). In addition, FVC, pulse oximetry values, and functional exercise tolerance increased statistically significantly at days 75 and 180 compared to baseline. The mMRC scores for dyspnea decreased statistically significantly in the treatment group over 75 days. The safety profile of the drug was reported to be favorable throughout the study. Conclusion. Treatment with bovhyaluronidase azoximer in patients with post-COVID syndrome showed improvement in FVC, pulse oximetry, functional exercise tolerance, and mMRC dyspnea.Copyright © Chuchalin A.G. et al., 2023.

Efficacy and safety of bovhyaluronidase azoximer (Longidase) in patients with post-COVID syndrome: results of an open, prospective, controlled, comparative, multicenter clinical trial DISSOLVE

Post-COVID syndrome develops after COVID-19 (COronaVIrus Disease 2019) and leads to cumulative effects in the form of shortness of breath and impaired lung function. Notably, patients with airway inflammation and COVID-19 were found to have increased concentrations of hyaluronic acid (HA). Since bovhyaluronidase azoximer (Longidase®) catalyzes the hydrolysis of HA, this drug has the potential to reduce HA levels and improve lung function in patients with post-COVID syndrome. The aim of the DISSOLVE trial, which was conducted early in the pandemic, was to investigate the efficacy and safety of bovhyaluronidase azoximer in patients with symptoms associated with post-COVID syndrome. Methods. An open, prospective, controlled, comparative, multicenter clinical trial (NCT04645368) included adult patients (n = 160) who had post-COVID syndrome. Patients in the treatment group (n = 81) received bovhyaluronidase azoximer, and individuals in the control group (n = 79) were followed up without intervention. The study included physical examination, evaluation of forced vital capacity (FVC), assessment of dyspnea with the Modified Medical Research Council Dyspnea Scale (mMRC), 6-minute walking test, and pulse oximetry. These indicators were measured on 3 visits, at days 1 (baseline), 75, and 180. In addition, the number of patients who experienced adverse events and serious adverse events were recorded. Results. Baseline patient characteristics in the treatment group and the control group were similar. In the treatment group, there was a statistically significant reduction in residual pulmonary abnormalities after visit 2 (day 75) and visit 3 (day 180). In addition, FVC, pulse oximetry values, and functional exercise tolerance increased statistically significantly at days 75 and 180 compared to baseline. The mMRC scores for dyspnea decreased statistically significantly in the treatment group over 75 days. The safety profile of the drug was reported to be favorable throughout the study. Conclusion. Treatment with bovhyaluronidase azoximer in patients with post-COVID syndrome showed improvement in FVC, pulse oximetry, functional exercise tolerance, and mMRC dyspnea. © Chuchalin A.G. et al., 2023.

Hyaluronan 2016–2021

More than 1100 published papers during 2016–2021 have "hyaluronan” in the title. This Encyclopedia of Cell Biology update focuses on 25 of these publications that we considered having important new directions for research on this fascinating Zen macromolecule that has a simple disaccharide structure and a very complex biology. There are likely several more publications during this time that fit this criteria. As hyaluronan has its own International Society (ISHAS) that meets biannually, the on-line booklets of meetings during this time provide insight into the wide range of ongoing hyaluronan research. © 2023 Elsevier Inc. All rights reserved.

Efficacy and safety of bovhyaluronidase azoximer (Longidase) in patients with post-COVID syndrome: results of an open, prospective, controlled, comparative, multicenter clinical trial DISSOLVE.

Post-COVID syndrome develops after COVID-19 (COronaVIrus Disease 2019) and leads to cumulative effects in the form of shortness of breath and impaired lung function. Notably, patients with airway inflammation and COVID-19 were found to have increased concentrations of hyaluronic acid (HA). Since bovhyaluronidase azoximer (Longidase) catalyzes the hydrolysis of HA, this drug has the potential to reduce HA levels and improve lung function in patients with post-COVID syndrome. The aim of the DISSOLVE trial, which was conducted early in the pandemic, was to investigate the efficacy and safety of bovhyaluronidase azoximer in patients with symptoms associated with post-COVID syndrome. Methods. An open, prospective, controlled, comparative, multicenter clinical trial (NCT04645368) included adult patients (n = 160) who had post-COVID syndrome. Patients in the treatment group (n = 81) received bovhyaluronidase azoximer, and individuals in the control group (n = 79) were followed up without intervention. The study included physical examination, evaluation of forced vital capacity (FVC), assessment of dyspnea with the Modified Medical Research Council Dyspnea Scale (mMRC), 6-minute walking test, and pulse oximetry. These indicators were measured on 3 visits, at days 1 (baseline), 75, and 180. In addition, the number of patients who experienced adverse events and serious adverse events were recorded. Results. Baseline patient characteristics in the treatment group and the control group were similar. In the treatment group, there was a statistically significant reduction in residual pulmonary abnormalities after visit 2 (day 75) and visit 3 (day 180). In addition, FVC, pulse oximetry values, and functional exercise tolerance increased statistically significantly at days 75 and 180 compared to baseline. The mMRC scores for dyspnea decreased statistically significantly in the treatment group over 75 days. The safety profile of the drug was reported to be favorable throughout the study. Conclusion. Treatment with bovhyaluronidase azoximer in patients with post-COVID syndrome showed improvement in FVC, pulse oximetry, functional exercise tolerance, and mMRC dyspnea.Copyright © Chuchalin A.G. et al., 2023.

Antioxidant and Anti-Breast Cancer Properties of Hyaluronidase from Marine Staphylococcus aureus (CASMTK1)

This work studied the antioxidant and anti-breast cancer properties of hyaluronidase, extracted from a potential marine strain, Staphylococcus aureus (CASMTK1), isolated from Parangipettai coastal waters in southeast coast of India. The Staphylococcal enzyme production was tested under different carbon and nitrogen sources;and recorded the maximum production when the microbial strain was cultured with starch as the carbon source and ammonium sulphate as the inorganic nitrogen source with the enzyme production of 92.5 U/mL and 95.0 U/mL, respectively. The hyaluronidase enzyme production was also tested in different pH and temperature;and recorded the maximum yield of 102.5 U/mL in pH 5 and that of 95.5 U/mL in 45 °C. The partially purified enzyme was subjected to FTIR and FT Raman technique and found the presence of the amide- I and II, Carboxyl, N-H bending, C-H stretching and α-helices and β-sheet proteins between wave number 1500–1700 cm−1. The partially purified enzyme also exhibited strong antioxidant and in-vitro breast cancer properties. The enzyme showed the highest hydroxyl radical scavenging activity of 79% at the 50 µg/mL concentration, and this activity increased in a dose-dependent manner. The enzyme inhibited proliferation of the breast cancer cell line of MCF-7, and it caused 100% cell death at the concentration of 80 µg/mL. The enzyme generated capacity of producing free radicles that damage the cancer cells, and this effect was very nearer to the standard drug, paclitaxel. The enzyme damaged the cancer cells and induced apoptosis in 78% of cancer cells as evident by condensed or fragmented chromatin at 40 µg/mL. Further purification of the enzyme, analysis of its molecular aspects, and elucidation of exact mechanisms of its biological activities will throw new light on the utility of staphylococcal hyaluronidase in anticancer chemotherapy.

Successful management of delayed hyaluronidase hypersensitivity after subtenon's anesthesia during the COVID-19 pandemic: A rare case report.

Subtenon's block is commonly used to achieve akinesia, analgesia, and anesthesia for ophthalmic surgeries. This case study detailed a rare hypersensitivity report in a 65-year-old female who had underwent manual small incision cataract surgery under subtenon's anesthesia (STA) in the left eye. On postoperative day 1, she presented with acute onset proptosis, periorbital edema, conjunctival chemosis, and restriction of extraocular movements. The pupillary reaction and dilated fundus examination were normal. A differential diagnosis of orbital cellulitis, Mucormycosis, and hyaluronidase hypersensitivity (HH) was considered. Since the patient was afebrile, and pupillary reactions, ENT, neurological, and fundus examination were normal, the diagnosis was narrowed down to delayed HH. The patient was managed with a 1 cc IV injection of dexamethasone once a day for 3 days, along with routine postoperative drugs. As per detailed literature review, this is probably a second case report of delayed HH post-STA.

Subcutaneous nivolumab versus intravenous nivolumab in patients with previously treated, advanced, or metastatic clear cell renal cell carcinoma

Background: Nivolumab (NIVO), a programmed death-1 immune checkpoint inhibitor, has demonstrated clinical efficacy across patients with different tumor types, including clear cell renal cell carcinoma (ccRCC), when administered via IV infusion. As an alternative to IV infusion, subcutaneous (SC) administration alleviates the need for IV ports, thereby lowering the risk of associated complications such as infections and phlebitis. SC formulation also reduces the time for dose preparation and administration, which may decrease overall treatment burden and reduce patient time in the clinic, benefiting patients and healthcare providers and improving overall healthcare resource utilization. SC-administered NIVO consists of NIVO co-formulated with the recombinant human hyaluronidase PH20 enzyme (NIVO + rHuPH20), which aims to increase the dispersion and absorption of NIVO within the SC space. SC NIVO + rHuPH20 was shown to be safe and well tolerated in a phase 1/2 study, warranting further investigation (Lonardi S et al. J Clin Oncol 2021;39(suppl 15):2575). Methods: CheckMate 67T is a multicenter, randomized, open-label, phase 3 study that will evaluate the noninferiority of SC NIVO + rHuPH20 versus IV NIVO in patients with advanced or metastatic ccRCC who have progressed after receiving ≤ 2 prior systemic treatment regimens. Key inclusion criteria are age ≥ 18 years, histologically confirmed advanced or metastatic ccRCC, measurable disease by RECIST v1.1 within 28 days prior to randomization, and a Karnofsky performance status ≥ 70. Key exclusion criteria are untreated symptomatic metastases to the central nervous system, other malignancy, autoimmune diseases, HIV-positive status with AIDS-defining infection within past year or current CD4 count < 350 cells/μL, other serious or uncontrolled disorders including severe, acute SARS-CoV-2 infection, and prior treatment with immune checkpoint inhibitors, other T-cell-targeting antibody drugs, or live attenuated vaccines within 30 days of first study treatment. At least 454 eligible patients will be randomized to receive SC NIVO + rHuPH20 or IV NIVO. The primary objectives are to demonstrate pharmacokinetic (PK) noninferiority of SC NIVO versus IV NIVO, as measured by time-averaged serum concentration over the first 28 days (Cavgd28) and trough serum concentration at steady state (Cminss) (co-primary endpoints). Secondary endpoints include objective response rate by blinded independent central review, additional PK parameters, safety, efficacy, and immunogenicity of SC NIVO and IV NIVO. This study is currently enrolling patients globally.

Implementing the intravenous (IV) pertuzumab/ trastuzumab to subcutaneous (SC) Phesgo switch in a tertiary oncology centre

Background: In February 2021 Roche announced a new subcutaneous (SC) product to the market;Phesgo. Phesgo was a combination pertuzumab and trastuzumab product which was funded by NHS England for all HER2 positive breast cancer indications. Day case unit capacity is a local and national issue, which has been further highlighted through the COVID19 pandemic with the reduction in treatment chairs due to social distancing and increase in cancer diagnosis and required treatments caused by the backlog from the pandemic. Aim: The aim of this project was to switch all intravenous (IV) pertuzumab and trastuzumab combination patients to SC Phesgo;to alleviate day case unit capacity and to improve the patient experience by June 2021. Methods: A report from CIS Healthcare was run within the electronic prescribing system to highlight all patients and regimes receiving and containing IV pertuzumab;a total of 148 patients network wide. A patient information letter was drafted explaining the change underway which was then emailed or posted out to all patients across the network receiving IV pertuzumab. Alternative regimens containing SC Phesgo were built into the electronic prescribing system;from week commencing 19.04.21 any patient receiving treatment at the tertiary centre (Weston Park Hospital(WPH)) who had received IV pertuzumab and trastuzumab previously would receive SC Phesgo. A patient evaluation questionnaire was distributed to all patients who participated in the switch to SC Phesgo at WPH, to gain qualitative feedback on the switch from the patient perspective. Results: All 148 identified patients receiving IV pertuzumab and trastuzumab were switched to SC Phesgo. Of the 148 patients 81 patients were receiving treatment at WPH, 49 patient evaluation questionnaires were completed;96% of patients were happy with the switch to SC Phesgo. By switching to SC Phesgo there was a weekly average of 48.1 h of chair time saved per week;a 56.9% reduction in chair time for this cohort of treatments and an overall reduction of 5.5% of chair time for the day case unit. In additional to the chair time saved, there was also on average 21.2 nurse hours saved per week;a reduction of 53.5% in nurse time for this cohort and an overall reduction of 4.6% of nurse time for the day case unit. Discussion/Conclusion: By administering SC Phesgo instead of the IV equivalents there have been significant reductions in patient, chair and nurse time. This reduction has help alleviate chair and nurse time capacity issues which were critical prior to the switch in April 2021 due to the COVID19 pandemic. There is an associated cost saving for commissioners despite the number of treatments remaining stable, in March 2021 the cost to the commissioners for all IV pertuzumab and trastuzumab given to breast cancer patients was £320,532.70;in May 2021 this figure (for SC Phesgo) had reduced to £145,956.00. In conclusion the switch the SC Phesgo has improved the patient experience, increased chair and nurse capacity on the day case unit.

Impact of reducing the post infusion observation time of pertuzumab-trastuzumab on efficiency and safety in the chemotherapy unit

Objective: The systemic anti-cancer therapy (SACT) work stream of the East of England Cancer alliance identified variation in SACT administration times as a potential area to counter the impact of Covid-19 capacity restrictions within chemotherapy day units. The aim is to assess the impact of reducing post infusion observation time of pertuzumab-trastuzumab on efficiency and safety. Methods: The recommendation from East of England Cancer Alliance was to adopt one hour observation post pertuzumab and one hour post trastuzumab for cycle 1, 30 min after each infusion for cycle 2 and 3 and a zero observation time thereafter for patients who have had no reaction. All patients administered IV pertuzumab-trastuzumab between October 2020 and May 2021 were identified. The number of patients experiencing hypersensitivity reactions with the original and reduced observation time was compared. The impact of reduced observation time on chair capacity was also calculated. Results: Of the 26 patients treated with the original observation time between October 2020 to January 2021, two patients reacted and received Hydrocortisone IV 100 mg and Chorphenamine IV 10 mg. Patients continued treatmnet at a slower rate. No patients discontinued treatment due to the reaction. Reactions included flushing, stomach pain, uncontrolled bladder and face swelling. Between February and May 2021,18 patients were treated with reduced observation times and 3 patients reacted. Reactions included hypertension, chills, vomiting and shivering. The total number of patients between the cohorts differs due to the conversion of some patients to Phesgo from April 2021. These patients were managed similarly to the previous cohort with added IV ondansetron and IV metoclopramide. No patient discontinued treatment following the reaction. Chair times savings were 5 h for cycle 1, 2 h for cycle 2 and 3, and 3 h from cycle 4 onwards. In total, 53 chair hours in the chemotherapy day unit were released between February to May 2021. Conclusion: The pressure on chemotherapy units has been exacerbated by staff absence, reduced capacity due to social distancing and use of PPE. Whilst the SPC for trastuzumab states patients should be observed for 6 h post first infusion and for 2 h post subsequent infusions, the implementation of reduced observation times post infusion of pertuzumab-trastuzumab did not impact on patient safety and encouragingly increased the capacity of the day unit by 53 h in four months.

Subcutaneous Administration: Evolution, Challenges, and the Role of Hyaluronidase.

BACKGROUND: The subcutaneous (SC) route has evolved significantly. More than two dozen chemotherapy and supportive therapies have been approved for use in the oncology setting. Several IV therapies have been approved for the SC route and require a significantly higher volume than historical maximum limits. Differences exist in how these drugs are administered as compared to older chemotherapy agents. OBJECTIVES: The purpose of this article is to provide a brief history of the SC route and describe its role in cancer treatment. The use of recombinant hyaluronidase is reviewed within the context of SC monoclonal antibodies. Proper administration techniques and interventions for reducing patient discomfort are discussed. METHODS: Sentinel medical texts, pharmacokinetic studies, manufacturer's recommendations, and peer-reviewed articles were examined. FINDINGS: The SC route offers several advantages over the oral and IV routes. A clear understanding of anatomical site selection and injection techniques is beneficial for providing requisite patient education.

Unraveled roles of hyaluronan in severe COVID-19.

Coronavirus disease 2019 (COVID-19) is a pandemic viral pneumonia caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2). Most of the severe COVID-19 patients come up with trouble breathing, persistent pressure in the chest and developing to acute respiratory distress syndrome (ARDS) with a high mortality rate. Infected lung brings about uncontrolled inflammation followed by the fluid leakage and accumulation of extracellular matrix. Hyaluronan (HA) is an essential component of the extracellular matrix (ECM) and plays crucial roles in both biological and pathological states. It is also primarily located within the respiratory airways and is uprising during COVID-19 infection. Hitherto, the association between COVID-19 pathophysiology and HA is still unclear. Herein, we provide an overview of the pathophysiology of SARS-CoV-2 infection in conjunction with the involvement of HA and the diminution of HA for therapeutic potential of COVID-19. For severe patients, HA depletion may be beneficial for preventing ARDS while monitoring and managing HA level in lung may improve survival rate of patients.