Steven Kozlowski

Purpose: Pharmacy chains can differ with respect to the characteristics of their patient populations as well as their nonprescription products, services, and practices, and thus may serve as a surrogate for potential unmeasured confounding in observational studies of prescription drugs. This study evaluates whether a single‐source drug can have different patient outcomes based on the dispensing pharmacy chain.Methods: Separate analyses for two anticoagulant drugs, rivaroxaban and apixaban, were conducted using Medicare Fee‐for‐Service claims evaluating the association between dispensing pharmacy chain and outcomes of acute myocardial infarction, ischemic stroke, intracranial hemorrhage, gastrointestinal (GI) bleeding, all‐cause mortality, and major GI bleeding. Inverse probability of treatment weighting (IPTW) was used to balance baseline covariates across pharmacy chain cohorts, and outcome association was assessed with a Cox Proportional Hazards model.Results: We observed no differences in outcomes across pharmacy chains for apixaban recipients. Rivaroxaban recipients from pharmacy chain C, however, had lower rates of GI bleeding (adjusted HR 0.83; 95% CI 0.69–1.00) and ischemic stroke (adjusted HR 0.57; 95% CI 0.38–0.87) as compared to chain A in primary analyses with a 3‐day grace period. The results moved closer to the null when 14‐ and 30‐day grace periods were implemented.Conclusions: These results suggest that dispensing pharmacy chains may have the potential to act as a confounder of associations between drug exposure and outcome in some observational studies. Additional studies of potential confounding by pharmacy chain are needed. Further evaluation of potential pharmacy chain effects on safe use would be of value.

Biosimilar products can increase access and reduce treatment costs for chronic and life-threatening diseases. As of March 1, 2023, 40 biosimilar products were approved by the US Food and Drug Administration (FDA).¹ Biosimilar uptake has varied, potentially due to factors such as health care setting, pricing, and market entrance timing.²

Background: The mechanism for anaphylaxis following mRNA COVID-19 vaccination has been widely debated; understanding this serious adverse event is important for future vaccines of similar design. A mechanism proposed is type I hypersensitivity (i.e., IgE-mediated mast cell degranulation) to excipient polyethylene glycol (PEG). Using an assay that, uniquely, had been previously assessed in patients with anaphylaxis to PEG, our objective was to compare anti-PEG IgE in serum from mRNA COVID-19 vaccine anaphylaxis case-patients and persons vaccinated without allergic reactions. Secondarily, we compared anti-PEG IgG and IgM to assess alternative mechanisms. Methods: Selected anaphylaxis case-patients reported to U.S. Vaccine Adverse Event Reporting System December 14, 2020 – March 25, 2021 were invited to provide a serum sample. mRNA COVID-19 vaccine study participants with residual serum and no allergic reaction post-vaccination (“controls”) were frequency matched to cases 3:1 on vaccine and dose number, sex and 10-year age category. Anti-PEG IgE was measured using a dual cytometric bead assay. Anti-PEG IgG and IgM were measured using two different assays. Laboratorians were blinded to case/control status. Results: All 20 case-patients were women; 17 had anaphylaxis after dose 1, 3 after dose 2. Thirteen (65%) were hospitalized and 7 (35%) were intubated. Time from vaccination to serum collection was longer for case-patients vs controls (post-dose 1: median 105 vs 21 days). Among Moderna recipients, anti-PEG IgE was detected in 1 of 10 (10%) case-patients vs 8 of 30 (27%) controls (p=0.40); among Pfizer-BioNTech recipients, it was detected in 0 of 10 case-patients (0%) vs 1 of 30 (3%) controls (p>0.99). Anti-PEG IgE quantitative signals followed this same pattern. Neither anti-PEG IgG nor IgM was associated with case status with both assay formats. Conclusion: Our results support that anti-PEG IgE is not a predominant mechanism for anaphylaxis post-mRNA COVID-19 vaccination.

Hereditary Angioedema (HAE) is a rare genetic disease generally caused by deficiency or mutations in the C1-inhibitor gene, SERPING1, a member of the Serpin family. HAE results in acute attacks of edema, vasodilation, GI pain and hypotension. C1INH is a key inhibitor of enzymes controlling complement activation, fibrinolysis and the contact system. In HAE patients, contact system activation leads to uncontrolled production of bradykinin, the vasodilator responsible for the characteristic symptoms of HAE. In this study, we present the first physiological in vivo model to mimic acute HAE attacks. We evaluate hypotension, one of the many hallmark symptoms of acute HAE attacks using Serping1 deficient mice (serping1−/−) and implanted telemetry. Attacks were induced by IV injection of a silica nanoparticle (SiNP) suspension. Blood pressure was measured in real time, in conscious and untethered mice using implanted telemetry.SiNP injection induced a rapid, reversible decrease in blood pressure, in the presence of angiotensin converting enzyme (ACE) inhibition. We also demonstrate that an HAE therapeutic, ecallantide, can prevent HAE attacks in this model. The in vivo murine model described here can facilitate the understanding of acute HAE attacks, support drug development and ultimately contribute to improved patient care.

Neutralizing antibodies to the SARS CoV-2 spike proteins have been issued Emergency Use Authorizations and are a likely mechanism of vaccines to prevent COVID-19. However, benefit of treatment with monoclonal antibodies has only been observed in clinical trials in outpatients with mild to moderate COVID-19 but not in patients who are hospitalized and/or have advanced disease. To address this observation, we evaluated the timing of anti SARS-CoV-2 antibody production in hospitalized patients with the use of a highly sensitive multiplexed bead-based immunoassay allowing for early detection of antibodies to SARS-CoV-2. We found significantly lower levels of antibodies to the SARS-CoV-2 spike protein in the first week after symptom onset in patients who expired as compared to patients who were discharged. We also developed a model to characterize the relationship between each patient’s individual antibody level trajectory and eventual COVID 19 outcome which can be adapted into a prediction model with more data.

Neutralizing antibodies to the SARS CoV-2 spike proteins have been issued Emergency Use Authorizations and are a likely mechanism of vaccines to prevent COVID-19. However, benefit of treatment with monoclonal antibodies has only been observed in clinical trials in outpatients with mild to moderate COVID-19 but not in patients who are hospitalized and/or have advanced disease. To address this observation, we evaluated the timing of anti SARS-CoV-2 antibody production in hospitalized patients with the use of a highly sensitive multiplexed bead-based immunoassay allowing for early detection of antibodies to SARS-CoV-2. We found that significantly lower levels of antibodies to the SARS-CoV-2 spike protein in the first week after symptom onset were associated with patients who expired as compared to patients who were discharged. We also developed a model, based on antibody level trajectory, to predict COVID 19 outcome that is compatible with greater antibody benefit earlier in COVID 19 disease. Author Summary We evaluated antibodies to SARS-CoV-2 over time in patients that were hospitalized with COVID 19. Early detection of Anti-SARS-CoV-2 antibodies was associated with survival in patients hospitalized with COVID 19. Early antibody levels predicted outcome in our study. This result is consistent with the benefit of therapeutic antibodies early in the course of COVID 19 disease. With additional study, early antibody levels may be helpful in deciding on appropriate therapies.