Durability of Platelet Response When Switching from Eltrombopag or Romiplostim to Avatrombopag in Immune Thrombocytopenia (ITP): A Multicenter Study

BACKGROUND : Thrombopoietin receptor agonists (TPO-RAs) are widely utilized second-line treatments for immune thrombocytopenia (ITP). The TPO-RAs eltrombopag and romiplostim have been FDA approved for over a decade with established efficacy and safety profiles. Avatrombopag is a newer oral TPO-RA approved in 2019 for ITP. Avatrombopag was efficacious in raising platelet counts in clinical trials, and it has an exposure-adjusted safety profile generally comparable to placebo with no boxed warning for hepatotoxicity as does eltrombopag. Also unlike eltrombopag, avatrombopag does not chelate polyvalent cations; therefore, it is administered with food and without restrictions regarding meal composition. A high proportion of patients (~90%) respond to avatrombopag; however, data describing the durability of platelet response on avatrombopag following treatment with other TPO-RAs is limited. AIMS : Understand the time until patients treated with avatrombopag experienced their first loss of response, if any, and their percent of time with a response following switch from eltrombopag or romiplostim. METHODS : We retrospectively evaluated all adults with ITP who switched from eltrombopag or romiplostim to avatrombopag at four U.S. tertiary ITP referral centers from July 2019 through December 2020. Reason for switching from eltrombopag or romiplostim (ineffectiveness, adverse event, convenience) was collected. Patients were treated with avatrombopag for at least two months to evaluate effectiveness. Response was defined as a platelet count ≥30,000/uL. Loss of response was defined as two consecutive platelet counts at least 7 days apart <30,000/uL. In these analyses, platelet counts were disqualified if <8 weeks from receipt of rescue corticosteroids or <4 weeks from intravenous immunoglobulin. RESULTS: 44 patients were included, with a median (range) age of 60 (21-87) years; 55% were female. At avatrombopag initiation, patients had an ITP diagnosis for a mean of 8.1 years with a mean of 4.8 unique prior ITP therapies. 42/44 (95%) of patients responded to avatrombopag at least once and 36/44 (81.8%) responded without the need for rescue therapy. 6/44 (13.6%) responded to avatrombopag and required at least one rescue therapy during exposure. 31/42 (73.8%) of patients never experienced a loss of response. All patients who responded to avatrombopag maintained response for 88.7% of their time on treatment. Patients who responded without the need for rescue therapy maintained their response for 93.6% of their time on avatrombopag. Patients who switched for convenience maintained a response for 96.5% of the time on avatrombopag. Patients who switched for adverse events maintained a response for 90.2% of the time. Patients who switched for efficacy maintained a response for 68.2% of the time. Overall, the median platelet count for all avatrombopag exposure was 107×10 9/L. The median platelet count for convenience switchers was 129×10 9/L, efficacy switchers was 60×10 9/L, and adverse event switchers was 93×10 9/L. CONCLUSION: In a heavily pretreated chronic ITP population who switched from another TPO-RA to avatrombopag, the initial response to avatrombopag was both durable (with up to 74% of patients never experiencing a loss of response) and stable (with patients maintaining a response on average for up to 89% of the time). Figure 1 Figure 1. Disclosures Al-Samkari: Argenx: Consultancy; Dova/Sobi: Consultancy, Research Funding; Novartis: Consultancy; Amgen: Research Funding; Rigel: Consultancy; Agios: Consultancy, Research Funding; Moderna: Consultancy. Gernsheimer: Principia: Research Funding; Rigel: Research Funding; Amgen: Honoraria; Novartis: Honoraria; Cellphire: Consultancy; Dova: Consultancy; Sanofi: Consultancy. Liebman: Pfizer: Consultancy; Dova: Consultancy, Honoraria; Argenx: Research Funding; Amgen: Consultancy; Sanofi/Genzyme: Research Funding; Novartis: Consultancy, Research Funding. Lee: Dova: Honoraria. Bernheisel: Sobi, Inc.: Current Employment. Kolodny: Sobi, Inc.: Current Employment. Wojdyla: Sobi, Inc.: Current Employment. Vredenburg: Sobi, Inc.: Current Employment. Jamieson: Sobi, Inc.: Current Employment. Cuker: Takeda: Research Funding; Sanofi: Research Funding; Spark Therapeutics: Research Funding; Pfizer: Research Funding; Novo Nordisk: Research Funding; Novartis: Research Funding; Bayer: Research Funding; Alexion: Research Funding; UpToDate: Patents & Royalties; Synergy: Consultancy.

Sodium–Glucose Cotransporter 2 Inhibitor Use Associated With Fournier's Gangrene: A Review of Case Reports and Spontaneous Post-Marketing Cases

Sodium–glucose cotransporter 2 (SGLT2) inhibitors are effective for glycemic control and have demonstrated cardiorenal benefits. The U.S. Food and Drug Administration (FDA) released a boxed warning in 2018 regarding the potential development of Fournier’s gangrene (FG) with the use of SGLT2 inhibitors. FG is a serious perineal infection with a mortality rate of up to 88% in some cases.

Sodium–Glucose Cotransporter 2 Inhibitor Use Associated With Fournier's Gangrene: A Review of Case Reports and Spontaneous Post-Marketing Cases

Sodium–glucose cotransporter 2 (SGLT2) inhibitors are effective for glycemic control and have demonstrated cardiorenal benefits. The U.S. Food and Drug Administration (FDA) released a boxed warning in 2018 regarding the potential development of Fournier’s gangrene (FG) with the use of SGLT2 inhibitors. FG is a serious perineal infection with a mortality rate of up to 88% in some cases.

The role of leukotriene modifying agent treatment in neuropsychiatric events of elderly asthma patients: a nested case control study

Background In March 2020, the US Food and Drug Administration decided that the dangers related to neuropsychiatric events (NPEs) of montelukast, one of the leukotriene modifying agents (LTMAs), should be communicated through ‘boxed warning’. In case of NPEs, the prevalence has been the highest in elderly people. Because the characteristics of the elderly such as old age itself can act as risk factors. Therefore, an investigation on safety of LTMAs related to NPEs in elderly using LTMAs is needed. Method A nested case-control study using an elderly sample cohort from the Korean National Health Insurance Service database was used. The asthma cohort included asthma patients newly diagnosed between 2003 and 2013. Within the asthma cohort, the case group was defined as patients who were diagnosed with NPEs. Among patients who had never been diagnosed with NPEs, the control group was selected by matching 1:1 by propensity score. Patients who were prescribed LTMAs for 1 year prior to index date were defined as the exposure group. The logistic regression model was used to measure the effect of LTMAs on NPEs. Results We identified 141,165 patients with newly diagnosed asthma, and selected 31,992 patients per each case and control group. Exposure to LTMAs significantly increased the risk of overall NPEs about in comparison with the absence of exposure (crude odds ratio [OR] 1.58, 95% CI 1.50–1.68). After adjusting for confounding factors, the overall NPEs risk increased (adjusted OR, 1.67, 95% CI 1.58–1.78). Conclusion This study suggests that elderly asthma patients prescribed LTMAs had a higher risk of NPEs than patients who were not treated with LTMAs. Therefore, clinicians should be aware of the potential risks of LTMAs.

Quantifying the severity of adverse drug reactions using social media

Adverse drug reactions (ADRs) impact the health of 100,000s of individuals annually in the United States with associated costs in the hundreds of billions. The monitoring and analysis of the severity of adverse drug reactions is limited by the current qualitative and categorical system of severity classifications. Previous efforts have generated quantitative estimates for a subset of ADRs, but were limited in scope due to the time and costs associated with the efforts. We present a semi-supervised approach that estimates ADR severity by using a lexical network of ADR word embeddings and label propagation. We use this method to estimate the severity of 28,113 ADRs, representing 12,198 unique ADR concepts from MedDRA. Our Severity of Adverse Events Derived from Reddit (Saedr) scores have good correlations with real-world outcomes. Saedr scores had Spearman correlations with ADR case outcomes in FAERS of 0.595, 0.633, and −0.748 for death, serious outcome, and no outcome, respectively. We investigate different methods for defining initial seed term sets and evaluate their impact on severity estimates. We analyzed severity distributions for ADRs based on their appearance in Boxed Warning drug label sections, as well as ADRs with sex-specific associations. We find that ADRs discovered postmarket have significantly greater severity compared to those discovered in the clinical trial. We create quantitative Drug RIsk Profile (Drip) scores for 968 drugs that have a Spearman correlation of 0.377 with drugs ranked by FAERS cases resulting in death, where the given drug was the primary suspect. We make the Saedr and Drip scores publicly available in order to enable more quantitative analysis of pharmacovigilance data.