ACKR3 Antagonism Enhances the Repair of Demyelinated Lesions Through Both Immunomodulatory and Remyelinating Effects.

Addressing inflammation, demyelination, and associated neurodegeneration in inflammatory demyelinating diseases like multiple sclerosis (MS) remains challenging. ACT-1004-1239, a first-in-class and potent ACKR3 antagonist, currently undergoing clinical development, showed promise in preclinical MS models, reducing neuroinflammation and demyelination. However, its effectiveness in treating established disease and impact on remyelination after the occurrence of demyelinated lesions remain unexplored. This study assessed the therapeutic effect of ACT-1004-1239 in two demyelinating disease models. In the proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE) model, ACT-1004-1239 administered upon the detection of the first signs of paralysis, resulted in a dose-dependent reduction in EAE disease severity, concomitant with diminished immune cell infiltrates in the CNS and reduced demyelination. Notably, efficacy correlated with elevated plasma concentrations of CXCL11 and CXCL12, two pharmacodynamic biomarkers of ACKR3 antagonism. Combining ACT-1004-1239 with siponimod, an approved immunomodulatory treatment for MS, synergistically reduced EAE severity. In the cuprizone-induced demyelination model, ACT-1004-1239 administered after 5 weeks of cuprizone exposure, significantly accelerated remyelination, already quantifiable one week after cuprizone withdrawal. Additionally, ACT-1004-1239 penetrated the CNS, elevating brain CXCL12 concentrations. These results demonstrate that ACKR3 antagonism significantly reduces the severity of experimental demyelinating diseases, even when treatment is initiated therapeutically, after the occurrence of lesions. It confirms the dual mode of action of ACT-1004-1239, exhibiting both immunomodulatory effects by reducing neuroinflammation and promyelinating effects by accelerating myelin repair. The results further strengthen the rationale for evaluating ACT-1004-1239 in clinical trials for patients with demyelinating diseases.

Combination treatment of a novel CXCR3 antagonist ACT-777991 with an anti-CD3 antibody synergistically increases persistent remission in experimental models of type 1 diabetes.

Treatment of patients with recent-onset type 1 diabetes with an anti-CD3 antibody leads to the transient stabilization of C-peptide levels in responder patients. Partial efficacy may be explained by the entry of islet-reactive T-cells spared by and/or regenerated after the anti-CD3 therapy. The CXCR3/CXCL10 axis has been proposed as a key player in the infiltration of autoreactive T cells into the pancreatic islets followed by the destruction of ß cells. Combining the blockade of this axis using ACT-777991, a novel small-molecule CXCR3 antagonist, with anti-CD3 treatment may prevent further infiltration and ß-cell damage and thus, preserve insulin production. The effect of anti-CD3 treatment on circulating T-cell subsets, including CXCR3 expression, in mice was evaluated by flow cytometry. Anti-CD3/ACT-777991 combination treatment was assessed in the virally induced RIP-LCMV-GP and NOD diabetes mouse models. Treatments started at disease onset. The effects on remission rate, blood glucose concentrations, insulitis, and plasma C-peptide were evaluated for the combination treatment and the respective monotherapies. Anti-CD3 treatment induced transient lymphopenia but spared circulating CXCR3+ T cells. Combination therapy in both mouse models synergistically and persistently reduced blood glucose concentrations, resulting in increased disease remission rates compared to each monotherapy. At the study end, mice in disease remission demonstrated reduced insulitis and detectable plasma C-peptide levels. When treatments were initiated in non-severely hyperglycemic NOD mice at diabetes onset, the combination treatment led to persistent disease remission in all mice. These results provide preclinical validation and rationale to investigate the combination of ACT-777991 with anti-CD3 for the treatment of patients with recent-onset diabetes.

ACT-1004-1239, a first-in-class CXCR7 antagonist with both immunomodulatory and promyelinating effects for the treatment of inflammatory demyelinating diseases.

Current strategies for the treatment of demyelinating diseases such as multiple sclerosis (MS) are based on anti-inflammatory or immunomodulatory drugs. Those drugs have the potential to reduce the frequency of new lesions but do not directly promote remyelination in the damaged central nervous system (CNS). Targeting CXCR7 (ACKR3) has been postulated as a potential therapeutic approach in demyelinating diseases, leading to both immunomodulation by reducing leukocyte infiltrates and promyelination by enhancing myelin repair. ACT-1004-1239 is a potent, selective, insurmountable, and orally available first-in-class CXCR7 receptor antagonist. The effect of ACT-1004-1239 was evaluated in the myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) and the cuprizone-induced demyelination mouse models. In addition, ACT-1004-1239 was assessed in a rat oligodendrocyte precursor cell (OPC) differentiation assay in vitro. In the MOG-induced EAE model, ACT-1004-1239 treatment (10-100 mg/kg, twice daily, orally) showed a significant dose-dependent reduction in disease clinical scores, resulting in increased survival. At the highest dose tested (100 mg/kg, twice daily), ACT-1004-1239 delayed disease onset and significantly reduced immune cell infiltrates into the CNS and plasma neurofilament light chain concentration. Treatment with ACT-1004-1239 dose-dependently increased plasma CXCL12 concentration, which correlated with a reduction of the cumulative disease score. Furthermore, in the cuprizone model, ACT-1004-1239 treatment significantly increased the number of mature myelinating oligodendrocytes and enhanced myelination in vivo. In vitro, ACT-1004-1239 promoted the maturation of OPCs into myelinating oligodendrocytes. These results provide evidence that ACT-1004-1239 both reduces neuroinflammation and enhances myelin repair substantiating the rationale to explore its therapeutic potential in a clinical setting.

CXCR7 Antagonism Reduces Acute Lung Injury Pathogenesis.

Loss of control in the trafficking of immune cells to the inflamed lung tissue contributes to the pathogenesis of life-threatening acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS). Targeting CXCR7 has been proposed as a potential therapeutic approach to reduce pulmonary inflammation; however, its role and its crosstalk with the two chemokine receptors CXCR3 and CXCR4 via their shared ligands CXCL11 and CXCL12 is not yet completely understood. The present paper aimed to characterize the pathological role of the CXCR3/CXCR4/CXCR7 axis in a murine model of ALI. Lipopolysaccharide (LPS) inhalation in mice resulted in the development of key pathologic features of ALI/ARDS, including breathing dysfunctions, alteration in the alveolar capillary barrier, and lung inflammation. LPS inhalation induced immune cell infiltration into the bronchoalveolar space, including CXCR3+ and CXCR4+ cells, and enhanced the expression of the ligands of these two chemokine receptors. The first-in-class CXCR7 antagonist, ACT-1004-1239, increased levels of CXCL11 and CXCL12 in the plasma without affecting their levels in inflamed lung tissue, and consequently reduced CXCR3+ and CXCR4+ immune cell infiltrates into the bronchoalveolar space. In the early phase of lung inflammation, characterized by a massive influx of neutrophils, treatment with ACT-1004-1239 significantly reduced the LPS-induced breathing pattern alteration. Both preventive and therapeutic treatment with ACT-1004-1239 reduced lung vascular permeability and decreased inflammatory cell infiltrates. In conclusion, these results demonstrate a key pathological role of CXCR7 in ALI/ARDS and highlight the clinical potential of ACT-1004-1239 in ALI/ARDS pathogenesis.

Long-term patient acceptance of and satisfaction with implanted device remote monitoring.

AIMS: To evaluate patients' acceptance and satisfaction of the Home Monitoring (HM) remote control system after 1 year of follow-up by a self-made questionnaire (HM Acceptance and Satisfaction Questionnaire, HoMASQ) specifically designed for this purpose. METHODS AND RESULTS: The HoMASQ contains 12 items designed to investigate five different aspects strictly connected to patient's acceptance and satisfaction of remote monitoring: (i) relationship with their healthcare provider, (ii) easy of use of HM technology, (iii) related psychological aspects, (iv) implications on general health, and (v) overall satisfaction. Each item was rated on a five-point scale: from 0 to 4 with favourable responses score > or =2. The theoretical maximum total score (the highest detected acceptance and satisfaction level) was 48. The HoMASQ was given to 119 patients followed by HM during the 1-year follow-up visit. Ninety-nine percent of all the administered questionnaire items were answered. The mean total score was 40.8 +/- 5.4 with a mean percentage of favourable answers of 96.3 +/- 18.8% (CI 95.2 - 97.2%). The mean scores for each of the five areas of the HoMASQ were: 3.0 +/- 0.9 for relationship, 3.4 +/- 0.6 for easy of use, 3.4 +/- 0.9 for psychological aspects, and 3.4 +/- 0.8 for clinical implication and overall satisfaction. Cronbach's alpha for reliability of the HoMASQ was 0.73. CONCLUSION: A high level of acceptance and satisfaction after 1-year remote control by HM was detected by the five-point scale HoMASQ, which showed a good internal reliability.

Diagnostic power and healthcare resource consumption of a dedicated workflow algorithm designed to manage thoracic impedance alerts in heart failure patients by remote monitoring.

PURPOSE: Modern cardiac implantable devices provide diagnostic information on several physiological variables which are associated with worsening heart failure, creating an opportunity for early intervention to prevent heart failure symptoms and hospitalizations. We evaluated diagnostic accuracy and workload of a remote monitoring (RM) workflow algorithm which leverages intrathoracic impedance and other device diagnostics. METHODS: In our RM workflow a team of expert nurses was responsible for continuity of care, direct relationship with patients and implementation of a specific protocol to evaluate RM alerts and to limit unnecessary resource consumption. Each patient was univocally assigned to a reference nurse. End points were diagnostic accuracy, healthcare utilization, defined as any hospital admission, and actionability of alerts, defined as medication change or other clinical action. RESULTS: One-hundred twenty-six consecutive patients with implantable cardioverter defibrillator/cardiac resynchronization therapy defibrillator were followed for a median time of 23 months. Out of 2176 remote transmissions, 893 (41%) in 111 patients (88.1%) showed clinically relevant events triggered by 574 alerts [2.2 (95% confidence interval = 2.0-2.4) per patient per year]. Among 309 alerts with intrathoracic impedance crossing, heart failure deterioration was confirmed in 116 (37.5%). Clinical actions followed 76/116 (65.5%) true heart failure alerts and 17/193 (8.8%) false-positive alerts (P < 0.001). In particular, drug therapy change followed 72/116 (62.1%) true heart failure alerts and 15/193 (7.8%) false-positive alerts (P < 0.001). Healthcare utilization occurred in 65.5% true heart failure alerts and in 24.9% false-positive alerts (P < 0.001). CONCLUSION: A dedicated workflow algorithm results in more focused clinical surveillance leading to prompt detection and treatment of acute heart failure events without wasting healthcare resource.

Implantable cardioverter defibrillator remote monitoring is well accepted and easy to use during long-term follow-up.

INTRODUCTION: Remote monitoring (RM) is becoming the new standard for follow-up of patients with cardiac implantable electronic devices. The aim of the present study was to evaluate patients' acceptance and satisfaction of RM by using a specific designed questionnaire. METHODS: The questionnaire is composed of 12 items aimed at analyzing 5 aspects of patient's acceptance and satisfaction of RM, with a scale ranging from 0 (the worst) to 4 (the best). The questionnaire was submitted to 163 ICD patients (147 male, 71 ± 12 years, 39 CRT-D), and followed by the CareLink Network Medtronic system, after a median follow-up of 20 months (13-26 months). Cronbach's alpha for reliability of the administered questionnaire was 0.73. RESULTS: The mean score of all 12 items was 3.5 ± 0.3; in detail: (i) relationship with healthcare provider 3.3 ± 0.7; (ii) ease of use of network technology 3.5 ± 0.5; (iii) related psychological aspects 3.5 ± 0.4; (iv) implication of general health 3.4 ± 0.6; (v) overall satisfaction 3.8 ± 0.3. CareLink naïve patients had better scores than those with previous in-person follow-up experience (3.6 ± 0.6 vs. 3.4 ± 0.7, p = 0.027), while no differences were observed between wireless and inductive systems, neither considering the living distance from the hospital. The main independent predictor of patient satisfaction was the implantation of CRT-D [Exp(beta) = 6.80 (1.34-34.62)] (p = 0.021). No correlation was found between age and ease of use of RM, while a positive correlation was observed between age and benefits on psychological aspects (p < 0.01). CONCLUSIONS: ICD patients showed a high level of acceptance and satisfaction for RM. Patients with CRT-D perceived the greatest benefit.