Campbell, Daniel

ImportanceMyeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.ObjectiveTo determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.Design, Settings, and ParticipantsVerdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.InterventionsEligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale–Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.ResultsA total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability = 0.57 for slowing of disease progression [DRR <1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, −23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.Conclusions and RelevanceResults demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.Trial RegistrationClinical Trial Identifiers: NCT04297683 and NCT04436510

Abstract Resident memory T cells (TRM) provide localized protective immunity in non-lymphoid tissues, but the signals and interactions within non-lymphoid tissues involved in generating TRM are incompletely defined. Inducible T-cell costimulator (ICOS) is a costimulatory molecule with well elaborated roles in regulating differentiation of CD4+ T cell populations, its function in CD8+ T cells is largely unexplored. With acute infection models, we found that ICOS-deficient CD8+ T cells showed minimal defects in the initial effector expansion and the generation of recirculating memory subsets. However, consistent with its high expression in TRM, ICOS deficiency significantly compromised the establishment of CD8+ TRM cells in diverse non-lymphoid tissues. We further confirmed that rather than pre-programming the TRM fate during initial T cell priming, the interaction between ICOS ligand (ICOSL) and ICOS in the non-lymphoid tissues during CD8+ T cell recruitment is critical for efficient tissue retention and acquisition of tissue residency signatures. ICOS signaling through PI3K pathway is key for TRM generation and ICOS stimulation promotes downregulation of KLF2, a transcription factor that regulates T cell trafficking, in CD8+ T cells after entering non-lymphoid tissues. Altogether, our data illustrate that engagement of ICOS is one of the critical local costimulatory cues that promote the establishment of tissue-resident populations, with potential implication for therapeutic manipulation.