Aviptadil: Class Effect of a Synthetic Vasoactive Intestinal Peptide as a Treatment Option in Patients with COVID-19 with Severe Respiratory Failure

Despite dynamic drug and vaccine development processes to reduce the disease burden of COVID-19, the treatment options are still very limited. Vasoactive intestinal peptide (VIP) has a diversified physiological action with specific features of lung protection-related activities. VIP inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) gene replication in human monocytes and the viral replication in Calu-3 cells, thus further reducing the generation of proinflammatory mediators. Aviptadil, a synthetic form of VIP, is the only pulmonary therapeutic agent to have been granted ‘fast track’ status by the U.S. Food and Drug Administration (FDA) and to be allowed into both Phase II and III clinical trials. Initial binding of Aviptadil with non-structural protein (nsp) 10 and nsp16, which may inhibit the 2’-O-methyltransferase activity of the SARS-CoV-2 nsp10 and nsp16 complex. Aviptadil has already proved to be an effective option in the treatment of severe respiratory failures due to sepsis and other related lung injuries. Interim analysis results of this drug used in respiratory failure caused by SARS-CoV-2 has evolved a new hope in regard to safety and efficacy. The final results from a recently completed trial, as well as all currently ongoing trials, will clarify the class effect of this drug in the treatment of COVID-19 in future days.

Steroid use in Pregnancy with Severe COVID-19

Managing women who are pregnant with severe COVID-19 is complex. This paper focuses on the debate surrounding steroid use in this group. Unfortunately, despite international efforts to identify treatments for COVID-19, there is very little research which has focussed specifically on pregnant women. Therefore current guidance is based on consensus and expert opinion, with variation in these guidelines worldwide, and reports that 73% of pregnant women do not receive steroids at all. There is an assumption of a steroid class-effect implicit within the UK guidelines for the mother with COVID-19 which is at odds with established within-class differences for effects on the foetus. This now warrants further discussion given the increasing numbers of pregnant women being admitted to hospital with COVID-19.

Steroid use in Pregnancy with Severe COVID-19

Managing women who are pregnant with severe COVID-19 is complex. This paper focuses on the debate surrounding steroid use in this group. Unfortunately, despite international efforts to identify treatments for COVID-19, there is very little research which has focussed specifically on pregnant women. Therefore current guidance is based on consensus and expert opinion, with variation in these guidelines worldwide, and reports that 73% of pregnant women do not receive steroids at all. There is an assumption of a steroid class-effect implicit within the UK guidelines for the mother with COVID-19 which is at odds with established within-class differences for effects on the foetus. This now warrants further discussion given the increasing numbers of pregnant women being admitted to hospital with COVID-19.

Discordant diagnostic criteria for pneumonia in COPD trials: a review

Inhaled corticosteroids (ICS) have a class effect of increasing pneumonia risk in patients with COPD. However, pneumonia incidence varies widely across clinical trials of ICS use in COPD. This review clarifies methodological differences in defining and recording pneumonia events in these trials and discusses factors that could contribute to the varying pneumonia incidence. Literature searches and screening yielded 40 relevant references for inclusion. Methods used to capture pneumonia events in these studies included investigator-reported pneumonia adverse events, standardised list of signs or symptoms, radiographic confirmation of suspected cases and/or confirmation by an independent clinical end-point committee. In general, more stringent pneumonia diagnosis criteria led to lower reported pneumonia incidence rates. In addition, studies varied in design and population characteristics, including exacerbation history and lung function, factors that probably contribute to the varying pneumonia incidence. As such, cross-trial comparisons are problematic. A minimal set of standardised criteria for diagnosis and reporting of pneumonia should be used in COPD studies, as well as reporting of patients’ pneumonia history at baseline, to allow comparison of pneumonia rates between trials. Currently, within-trial comparison of ICS-containing versus non-ICS-containing treatments is the appropriate method to assess the influence of ICS on pneumonia incidence.

349 Tolerability of tivozanib vs. sorafenib in elderly and/or immunotherapy-pretreated patients with metastatic renal cell cancer (mRCC) in TIVO-3

BackgroundThe TIVO-3 trial demonstrated improved progression-free survival (PFS) with TIVO when compared to sorafenib (SOR; 5.6 mo. vs 3.9 mo., respectively; HR 0.73) and better tolerability with reduced need for dose interruptions (p = 0.0164), dose reductions (p = 0.0147), and discontinuations< sup >1</sup >. As the majority of patients diagnosed with mRCC in the US are >65 years, with the largest recent increase in incidence among those ≥75, and front-line treatment now standardly includes immunotherapy (IO), tolerability of new therapies for relapsed or refractory (R/R) mRCC must be acceptable in the elderly and/or IO pretreated populationMethodsData was analyzed to identify relationships between tolerability and advanced age or IO pretreatment. In addition to measures of drug exposure, any grade ≥3 treatment related adverse events (TRAEs) and VEFGR TKI class effect grade ≥3 TRAEs are reported by age (<65, 65–74, ≥75) and prior IO (yes, no)ResultsOf the 343 patients treated on study, 120 (35%) were between age 65 and 75 and 34 (10%) were over 75. Patients received 1.5-2x more cycles of TIVO compared to SOR and fewer overall grade ≥3 TRAEs in all age groups and irrespective of prior IO. Differences in VEGFR TKI class effect TRAEs seen in the total population were retained across most subgroups (table 1). Among patients 75 and over, there were almost half the rate of the dose reductions or discontinuations with TIVO compared to SOR. Prior IO was associated with less asthenia overall, more HTN with TIVO, and more rash but less diarrhea with SORAbstract 349 Table 1Drug exposure, dose modifications, and TRAEs in TIVO-3 by age and prior IOConclusionsTolerability benefits with TIVO compared to SOR in mRCC are retained in elderly patients and those previously treated with IO. This finding, paired with consistently improved PFS in these subpopulations (age >65: HR 0.59, prior IO: HR 0.55), suggests TIVO is a safe and effective option in the context of the current R/R mRCC treatment paradigmTrial RegistrationClinicalTrialsgov Identifier: NCT02627963ReferenceRini B, Pal S, Escudier B, Atkins M, Hutson T, et al. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol 2020;21:95–104Ethics ApprovalThis trial was approved by the institutional review board or ethics committee at every centre and complied with Good Clinical Practice guidelines, the Declaration of Helsinki, and local laws. All patients provided written informed consent before any trial procedure. The trial protocol including the relevant centres is provided in the appendix of the reference 1