Regulatory landscape with U.S. patient requirements and Clinical Trial Diversity expectations.

The Food and Drug Administration (FDA) has an expectation that products filed for marketing authorization have to include data that are representative of the US patient population. Any foreign clinical data that is submitted has to represent an ethnically diverse population that is generated utilizing qualified Principal Investigators (PIs) and conducted according to Good Clinical Practices (GCP) requirements outlined in 21 CFR 312.120, Foreign clinical studies not conducted under an IND. With the recent passing of the Omnibus Legislation, FDA now also has the authority to require Diversity Plans for all Phase 3 clinical trials of new drugs or "as appropriate, another pivotal study of a new drug." The FDA has released a guidance document, "Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials" (April 2022), for the industry with expectations to update the document in 2023 now that legislation is passed. This whitepaper discusses the FDA guidance and expectations of sponsors with regards to foreign clinical data and the intersection with enrolling ethnically diverse populations in clinical studies.

Targeting the ubiquitin system by fragment-based drug discovery.

The ubiquitin system contains a wealth of potential drug targets for many diseases and conditions, including neurodegenerative, immune, metabolic and developmental diseases, as well as multiple cancers. Despite years of research, relatively few clinical inhibitors or specific chemical probes for proteins within the ubiquitin system exist, with many interesting target proteins yet to be explored. Fragment-based drug discovery (FBDD) offers efficient and broad coverage of chemical space with small libraries, using covalent and non-covalent approaches. Coupled with advances in structural biology and proteomics, FBDD now provides a thorough screening platform for inhibitor discovery within the ubiquitin system. In this mini review, we summarise the current scope of FBDD and how it has been applied to ubiquitin-activating (E1), ubiquitin-conjugating (E2), ubiquitin ligase (E3) and deubiquitinating (DUB) enzymes. We also discuss the newest frontiers of FBDD and how they could be applied to enable inhibitor and novel chemical probe discovery and provide functional insight into the ubiquitin system.

The effect of HLA matching and donor relatedness on the risk of autoimmune haemolytic anaemia in haematopoietic stem cell transplant recipients: A systematic review and meta-analysis.

Recent studies have identified autoimmune haemolytic anaemia (AIHA) as a haematopoietic stem cell transplant (HSCT) complication that represents a significant cause of morbidity and mortality for these patients. In order to understand this autoimmune phenomenon, emerging research has focused on the prognostic factors associated with the development of the disorder. These studies have identified numerous possible associations with often contrasting and conflicting results. A systematic review and meta-analysis were performed in order to determine the effect of human leucocyte antigen (HLA) matching and donor relatedness on the risk of AIHA post-HSCT. PubMed, SCOPUS and ProQuest were searched from 1 January 1995 to 1 August 2021 using a range of keywords. Meta-analysis was performed using OpenMeta-Analyst software using a random effects model and arcsine risk difference (ARD). Eight eligible articles were identified, and meta-analysis showed an increased risk of AIHA in those who received HLA-mismatched transplants (ARD -0.082; 95% confidence interval [CI] -0.157, -0.007; p = 0.031) and those who received donations from unrelated donor sources (ARD -0.097; 95% CI -0.144, -0.051; p < 0.001). Patients who receive HSCT from HLA-matched and related donor sources have a reduced risk of developing AIHA. Healthcare practitioners should be mindful of the risk of AIHA, especially in those who receive HLA-mismatched and unrelated donor-sourced stem cells. While these findings provide further evidence for researchers investigating the pathogenesis of this HSCT complication, more studies are needed to fully understand the cause.

A Probe for NLRP3 Inflammasome Inhibitor MCC950 Identifies Carbonic Anhydrase 2 as a Novel Target.

Inhibition of inflammasome and pyroptotic pathways are promising strategies for clinical treatment of autoimmune and inflammatory disorders. MCC950, a potent inhibitor of the NLR-family inflammasome pyrin domain-containing 3 (NLRP3) protein, has shown encouraging results in animal models for a range of conditions; however, until now, no off-targets have been identified. Herein, we report the design, synthesis, and application of a novel photoaffinity alkyne-tagged probe for MCC950 (IMP2070) which shows direct engagement with NLRP3 and inhibition of inflammasome activation in macrophages. Affinity-based chemical proteomics in live macrophages identified several potential off-targets, including carbonic anhydrase 2 (CA2) as a specific target of IMP2070, and independent cellular thermal proteomic profiling revealed stabilization of CA2 by MCC950. MCC950 displayed noncompetitive inhibition of CA2 activity, confirming carbonic anhydrase as an off-target class for this compound. These data highlight potential biological mechanisms through which MCC950 and derivatives may exhibit off-target effects in preclinical or clinical studies.