Abivax (France)

Abstract Background Obefazimod (Obe) is an oral, once-daily (QD), small molecule which enhances expression of microRNA-124 and has been studied in two Phase 2 induction trials and subsequent open-label maintenance studies [1-3] in patients (pts) with moderately to severely active ulcerative colitis (UC). In Phase 3 ABTECT-1 [NCT05507203] and ABTECT-2 [NCT05507216] 8-week induction trials, Obe achieved clinically meaningful improvements in clinical, endoscopic and histologic endpoints. Here, we present a pooled analysis of the efficacy and safety of Obe in the North American (NA) subgroup of pts enrolled in the ABTECT induction trials. Methods The multicenter, randomized, double-blind, placebo-controlled ABTECT trials enrolled pts with moderate-to-severe UC (MMS≥ 5, with rectal bleeding sub-score (RBS) ≥ 1 and centrally read Mayo endoscopic score ≥2) who had inadequate response, loss of response, or intolerance to at least one prior systemic therapy (corticosteroids, immunosuppressants, biologics, S1P receptor modulators and/or JAK inhibitors), with no limit on the number of prior advanced therapy inadequate responders (ATIR). Pts were randomized 2:1:1 to Obe 50 mg QD (Obe-50), Obe 25 mg QD (Obe-25) or placebo (PBO) for 8 weeks. This post-hoc analysis focuses on the subgroup of pts recruited from study defined NA centers. Efficacy endpoints included clinical remission (per MMS), clinical response, endoscopic improvement, symptomatic remission, and histo-endoscopic mucosal improvement. All p-values are nominal. Treatment emergent adverse events (TEAEs), serious TEAEs and dropout rates were evaluated. Results Among the 1272 pts randomized in the ABTECT trials, 122 were NA pts (116 pts from USA and 6 pts from Canada). Baseline demographics and disease characteristics were well balanced between treatment groups and generally comparable between NA pts and the overall study population. In the pooled analysis, a higher proportion of NA pts receiving Obe-25 or Obe-50 vs. PBO achieved clinical remission (Obe-25-PBO difference: 13.6%, p = 0.0218; Obe-50-PBO difference: 13.2%, p = 0.0235), clinical response, and symptomatic remission with nominal significance (Table). Headache was the most common TEAE (Obe-25: 29.2%; Obe-50: 24.2%; PBO: 5.6%). Among NA pts, no serious TEAEs occurred with Obe-25, and the rate with Obe-50 was similar to PBO (3.2% vs 8.3%, respectively). TEAE leading to study discontinuations were less frequent with Obe-25 (4.2%) and Obe-50 (6.5%) vs PBO (13.9%). No opportunistic infections or malignancies were reported. Conclusion In the ABTECT induction trials, clinically meaningful improvements in efficacy measures were observed, and Obe treatment demonstrated a favorable safety profile in NA pts, consistent with the overall study population.

Abstract Background Obefazimod (Obe) is an oral, once-daily (QD), small molecule which enhances expression of microRNA-124 and has been studied in two Phase 2 induction trials and subsequent open-label maintenance studies [1-3] in patients (pts) with moderately to severely active ulcerative colitis (UC). In Phase 3 ABTECT-1 [NCT05507203] and ABTECT-2 [NCT05507216] 8-week induction trials, Obe achieved clinically meaningful improvements in clinical, endoscopic and histologic endpoints. Here, we evaluated the effect of concomitant corticosteroid (CS) use on the efficacy and safety of obefazimod in pts enrolled in ABTECT trials. Methods The multicenter, randomized, double-blind, placebo-controlled ABTECT trials enrolled pts with moderate-to-severe UC (modified Mayo score (MMS)≥ 5, with rectal bleeding sub-score (RBS) ≥ 1 and centrally read endoscopic score ≥2) who had inadequate response, loss of response, or intolerance to at least one prior therapy (CS, immunosuppressants, biologics, S1P receptor modulators and/or JAK inhibitors). Pts were randomized 2:1:1 to Obe 50 mg QD (Obe-50), Obe 25 mg QD (Obe-25) or placebo (PBO) for 8 weeks. Pts were categorized based on concomitant CS use at baseline (CS-yes/CS-no), the dose of which was held constant through week 8. Efficacy endpoints were clinical remission/response, endoscopic improvement/remission, symptomatic remission, and histo-endoscopic mucosal improvement (HEMI). All p-values are nominal. Treatment emergent adverse events (TEAEs), serious TEAEs and study discontinuation rates were examined. Results Among pts in ABTECT trials, 508 used concomitant CS at baseline through week 8 (CS-yes) and 764 did not (CS-no). In both trials, baseline demographics and disease characteristics were similar between treatment groups, regardless of baseline CS status. In the pooled analysis, a higher proportion of pts receiving Obe-25 or Obe-50 vs. PBO achieved clinical remission across CS-yes and CS-no subgroups (Obe-50-PBO difference: CS-yes: 12.5%; CS-no: 19.1%; Obe-25-PBO difference: CS-yes: 8.3%; CS-no: 16.4%) and met all other endpoints across CS-yes and CS-no subgroups with nominal significance (Table). Among CS-yes pts, TEAEs occurred in 56.5%, 45.0%, and 49.2% of those receiving Obe-50, Obe-25, and PBO, respectively. For CS-no pts, rates were 62.8%, 51.3%, and 51.8%. Headache was the most frequent TEAE when treated with Obe across both subgroups. Among CS-yes and CS-no pts, rates of serious TEAEs and TEAE leading to study discontinuation were comparable between treatments. No signal was observed for serious, severe, or opportunistic infections or malignancies. Conclusion In both ABTECT induction trials, Obe demonstrated consistent efficacy and safety irrespective of baseline CS status.

Vaccination remains our main defence against influenza, which causes substantial annual mortality and poses a serious pandemic threat. Influenza virus evades immunity by rapidly changing its surface antigens but, even when the vaccine is well matched to the current circulating virus strains, influenza vaccines are not as effective as many other vaccines. Influenza vaccine development has traditionally focused on the induction of protective antibodies, but there is mounting evidence that T cell responses are also protective against influenza. Thus, future vaccines designed to promote both broad T cell effector functions and antibodies may provide enhanced protection. As we discuss, such vaccines present several challenges that require new strategic and economic considerations. Vaccine-induced T cells relevant to protection may reside in the lungs or lymphoid tissues, requiring more invasive assays to assess the immunogenicity of vaccine candidates. T cell functions may contain and resolve infection rather than completely prevent infection and early illness, requiring vaccine effectiveness to be assessed based on the prevention of severe disease and death rather than symptomatic infection. It can be complex and costly to measure T cell responses and infrequent clinical outcomes, and thus innovations in clinical trial design are needed for economic reasons. Nevertheless, the goal of more effective influenza vaccines justifies renewed and intensive efforts.

Advanced therapies have transformed the treatment of inflammatory bowel disease; however, many patients fail to respond, highlighting the need for therapies tailored to the underlying cell and molecular disease drivers. The first-in-class oral molecule ABX464 (obefazimod), which selectively upregulates miR-124, has demonstrated its ability to be a well-tolerated treatment with rapid and sustained efficacy in patients with ulcerative colitis (UC). Here, we provide evidence that ABX464 affects the immune system in vitro, in the murine model of inflammatory bowel disease, and in patients with UC. In vitro, ABX464 treatment upregulated miR-124 and led to decreases in proinflammatory cytokines including interleukin (IL) 17 and IL6, and in the chemokine CCL2. Consistently, miR-124 expression was upregulated in the rectal biopsies and blood samples of patients with UC, and a parallel reduction in Th17 cells and IL17a levels was observed in serum samples. In a mouse model of induced intestinal inflammation with dextran sulfate sodium, ABX464 reversed the increases in multiple proinflammatory cytokines in the colon and the upregulation of IL17a secretion in the mesenteric lymph nodes. By upregulating miR-124, ABX464 acts as “a physiological brake” of inflammation, which may explain the efficacy of ABX464 with a favorable tolerability and safety profile in patients with UC.

RNA-Seq enables the generation of extensive transcriptome information providing the capability to characterize transcripts (including alternative isoforms and polymorphism), to quantify expression and to identify differential regulation in a single experiment. To reveal the capacity of new anti-HIV ABX464 candidate in modulating the expression of genes, datasets were generated and validated using RNA-seq approach. This comprehensive dataset will be useful to deepen the comprehensive understanding of the progression of human immunodeficiency virus (HIV) associated with mucosal damage in the gastrointestinal (GI) tract and subsequent inflammation, providing an opportunity to generate new therapies, diagnoses, and preventive strategies.