Chemokines: Key Players in the Innate and Adaptive Immunity
The immune system is made up of a complex network of cells and molecules that function together to defend the body from external pathogens such as viruses, bacteria, parasites, and fungi, as well as against the growth of cancer cells1. The immune system, which is dependent on the coordinated migration of cells, is particularly dependent on chemokines for its function. Chemokines are chemo-attractants that lure-in several different cell-types to sites of inflammation and damage, including monocytes and macrophages, neutrophils, eosinophils, mast cells, and T-lymphocytes2.
Additionally, chemokines promote interactions between the innate and adaptive immune systems, thus shaping and providing the necessary context for the development of optimal adaptive immune responses. The roles that chemokines and their receptors play in the immune response and cell migration have made them a research focus in studying autoimmune diseases and cancer3 4 5.
Chemokines are recognized as the most critical mediators for selective neutrophil recruitment during inflammatory conditions6. Neutrophils are the largest population of myeloid leukocytes, which normally comprise 50-70% of all white blood cells. Neutrophils differentiate in the bone marrow from hematopoietic stem cells and, after full maturation, enter the bloodstream. NETosis is a program for the formation of neutrophil extracellular traps (NETs), which consist of modified chromatin decorated with bactericidal proteins from granules and cytoplasm. Various pathogens, antibodies and immune complexes, cytokines, microcrystals, and other physiological stimuli can cause NETosis7.
Our research
Over the years, we have developed potent and selective inhibitors capable of blocking the action of chemokines (CXCR1/2) and thus inflammatory processes. Some of these molecules are currently in clinical trials in various therapeutic areas.
Why we think NETosis is key
A key area of focus for our research is the role of NETosis, a process carried out by a particular population of white blood cells: neutrophils. When a pathogen enters the body, circulating neutrophils are recruited by chemokines to the site of inflammation. They are activated and form special trap-like structures called NETs, which can encompass the pathogens and thus eliminate their threat 8. Although NETs play a positive role in this context, a growing number of studies show that the process of NET formation, if not tightly controlled, is an aggravating factor in many diseases. For this reason, several research programs have directed their efforts toward the development of molecules capable of blocking NETosis. Dompé has initiated a series of national and international collaborations to establish a global multidisciplinary network of experts and thus accelerate the development of new compounds that effectively inhibit NETosis by selectively inhibiting the effect of certain chemokines on neutrophils.
Type 1 Diabetes
Type 1 diabetes (T1D) is an autoimmune disease in which the pancreas cannot produce insulin because the immune system destroys the beta-cells of the pancreatic islets. The incidence rate is greatest in youth aged 10–14 years (45.5 cases/100,000 person-years); however, because adulthood spans a longer period than childhood, there is a greater number of new cases in adults than in youth (n = 19,174 adults; n = 13,302 youth). Approximately 64,000 youths and adults are diagnosed with T1D every year just in the US9.
The exact cause of type 1 diabetes is not fully understood. However, it has been observed that the immune system "interferes with the cells that produce insulin and manifests itself as the presence of antibodies targeting antigens found in insulin-producing cells. The damage that the immune system causes to the insulin-producing cells is thought to be related to hereditary and environmental factors10.
Over the last few years, scientific evidence on the role of NETosis in diabetes has grown. As Dompé's research efforts are focused on finding a possible therapeutic solution for the many patients affected by type 1 diabetes, one of our objectives is to understand how the NETosis process is activated in people with type 1 diabetes and how to potentially delay beta cell destruction.
Cancer Related Fatigue and Inflammation
Dompé is committed to researching fatigue induced by cancer and cancer treatments. This is a common symptom that affects most patients in diseases with a significant inflammatory component—such as cancer. Fatigue occurs in nearly all patients with breast cancer and may have a negative impact on their quality of life11, treatment interruption12, and decreased overall survival. Multiple factors 13 14 can lead to the development of cancer-related fatigue (CRF), including an overactive inflammatory response. Specifically, increases in the proinflammatory molecule, IL-8, have been associated with the worst fatigue in patients with breast cancer 15. Chemotherapy treatment of patients with breast cancer has also been shown to lead to significant increases in IL-816, which correlated with symptoms including fatigue.
Dompé has invested considerable resources in researching components for blocking or reducing inflammation. This has also led to the discovery of investigational oral agent Reparixin, a non-competitive allosteric inhibitor of the CXCL8 (formerly interleukin-8) receptors, CXCR1 and CXCR2. The interaction of Reparixin with CXCL8 receptors may inhibit the intracellular signal transduction events activated by binding of CXCL8 to CXCR1 and CXCR2. Reparixin may inhibit CXCL8-induced chemotaxis of human polymorphonuclear leukocytes (PMN). In vivo, Reparixin has been shown to inhibit PMN recruitment by 40 to 90% and to prevent tissue damage by 50 to 80% (in animal models11).
Chemokines pipeline
Ladarixin
INN (International Non-proprietary Name): Ladarixin
Ladarixin is a non-competitive allosteric inhibitor of CXCL8 receptors, CXCR1 and CXCR2, able to inhibit the intracellular signal transduction events activated by CXCL8 without affecting binding of CXCL8 to CXCR1 and CXCR2. Chemical computational studies and alanine-replacement mutagenesis studies have identified the binding site of Ladarixin on CXCR1/2 in the transmembrane domain of the receptors.
Ladarixin in obese pre-diabetic patients eligible to bariatric surgery
A Study to Assess Efficacy/Safety of Ladarixin in Type 1 Diabetes Patients With Preserved ß-cell Function at Baseline
A Study of Oral Ladarixin in New-onset Type 1 Diabetes and a Low Residual β-cell Function
A Single Dose Study About the Influence of Food on the Oral Bioavailability of Ladarixin Capsule in Healthy Volunteers
A Phase 2, Multicentre, Randomized, Double-blind, Placebo-controlled Study in Patients With New-onset Type 1 Diabetes
Reparixin L-lysine salt
INN (International Non-proprietary Name): Reparixin L-lysine salt
Reparixin is a non-competitive allosteric inhibitor of CXCL8 receptors, CXCR1 and CXCR2, able to inhibit the intracellular signal transduction events activated by the binding of CXCL8 to CXCR1 and CXCR2. The binding site hypothesis derived through computational studies was confirmed by alanine scanning mutagenesis, and a region in the transmembrane of CXCR1 and CXCR2 was identified.
Study on Efficacy and Safety of Reparixin in the Treatment of Hospitalized Patients With Severe COVID-19 Pneumonia
A Double-blind Study of Paclitaxel in Combination With Reparixin or Placebo for Metastatic Triple-Negative Breast Cancer (FRIDA)
Pilot Study to Evaluate Safety & Biological Effects of Orally Administered Reparixin in Early Breast Cancer
Pilot Study to Evaluate Reparixin With Weekly Paclitaxel in Patients With HER 2 Negative Metastatic Breast Cancer (MBC)
Chemokines publications
Breast Cancer Research and Treatment September 2021
A randomized, placebo-controlled phase 2 study of paclitaxel in combination with reparixin compared to paclitaxel alone as front-line therapy for metastatic triple-negative breast cancer (fRida)
Pharmaceuticals June 2021
Unexpected Salt/Cocrystal Polymorphism of the Ketoprofen-Lysine System: Discovery of a New Ketoprofen-l-Lysine Salt Polymorph with Different Physicochemical and Pharmacokinetic Properties
Frontiers in Immunology October 2020
CXCR1 and CXCR2 Inhibition by Ladarixin Improves Neutrophil-Dependent Airway Inflammation in Mice
Immunity April 2020
CXCR1 and CXCR2 Chemokine Receptor Agonists Produced by Tumors Induce Neutrophil Extracellular Traps that Interfere with Immune Cytotoxicity
Aging January 2020
Autocrine CXCL8-dependent invasiveness triggers modulation of actin cytoskeletal network and cell dynamics
Breast Cancer Research January 2020
A window-of-opportunity trial of the CXCR1/2 inhibitor reparixin in operable HER-2-negative breast cancer
Diabetes Care January 2020
Targeting CXCR1/2 does not improve insulin secretion after pancreatic islet transplantation: A phase 3, double-blind, randomized, placebo-controlled trial in type 1 diabetes
Molecules October 2019
Catalyst-Free Synthesis of Polysubstituted 5-Acylamino-1,3-Thiazoles via Hantzsch Cyclization of α-Chloroglycinates
Nature August 2019
DF2726A, a new IL-8 signalling inhibitor, is able to counteract chemotherapy-induced neuropathic pain
Adv Ther. August 2019
Towards an Effective and Safe Treatment of Inflammatory Pain: A Delphi-Guided Expert Consensus
International journal of molecular sciences June 2019
Chemokine Signaling in Chemotherapy-Induced Neuropathic Pain
Frontiers in oncology February 2019
The CXCL8-CXCR1/2 Axis as a Therapeutic Target in Breast Cancer Stem-Like Cells
The American journal of pathology February 2019
Inflammatory Stress Causes N-Glycan Processing Deficiency in Ocular Autoimmune Disease
ACS Omega November 2018
1,3-Dibromo-1,1-difluoro-2-propanone as a Useful Synthon for a Chemoselective Preparation of 4-Bromodifluoromethyl Thiazoles
Int J Paediatr Dent October 2018
Efficacy of ketoprofen lysine salt and paracetamol/acetaminophen to reduce pain during rapid maxillary expansion: A randomized controlled clinical trial
JCI Insight August 2018
IL-6 and CXCL8 Mediate Osteosarcoma-Lung Interactions Critical to Metastasis
Cancer Research July 2018
IL6 and CXCL8 mediate redundant, targetable tumor-host interactions that drive osteosarcoma lung metastasis
British Journal of Pharmacology June 2018
Therapeutic inhibition of CXCR2 by Reparixin attenuates acute lung injury in mice
British journal of pharmacology May 2018
Antinociceptive effect of two novel transient receptor potential melastatin 8 antagonists in acute and chronic pain models in rat
European journal of medicinal chemistry April 2018
Challenging clinically unresponsive medullary thyroid cancer: Discovery and pharmacological activity of novel RET inhibitors
Molecular Cancer Therapeutics April 2018
Differential alteration of IL-8 in liver cancer stem cell enrichment in response to PI3K/Akt/mTOR inhibitors and sorafenib
European Journal of immunology March 2018
CXCR2 Is Critical for Bacterial Control and Development of Joint Damage and Pain in Staphylococcus Aureus-Induced Septic Arthritis in Mouse
Frontiers in immunology January 2018
Intravital Microscopic Evaluation of the Effects of a CXCR2 Antagonist in a Model of Liver Ischemia Reperfusion Injury in Mice
Frontiers in immunology December 2017
CXCR1/2 Antagonism Is Protective During Influenza and Post-Influenza Pneumococcal Infection
Italian Journal of Pediatrics October 2017
Management of acute respiratory diseases in the pediatric population: the role of oral corticosteroids
Clinical Cancer Research September 2017
Phase Ib Pilot Study to Evaluate Reparixin in Combination with Weekly Paclitaxel in Patients with HER-2-Negative Metastatic Breast Cancer.
Journal of Cellular Physiology July 2017
Differential protein modulation by ketoprofen and ibuprofen underlines different cellular response by gastric epithelium
Oncotarget May 2017
Multiple Anti-Tumor Effects of Reparixin on Thyroid Cancer
Oncotarget. April 2017
CXCR1/2 pathways in paclitaxel-induced neuropathic pain
Oncotarget February 2017
Ladarixin, a Dual CXCR1/2 Inhibitor, Attenuates Experimental Melanomas Harboring Different Molecular Defects by Affecting Malignant Cells and Tumor Microenvironment
Central nervous system agents in medicinal chemistry January 2017
Synthesis and Antioxidant Properties of Novel Memantine Derivatives
Clin Cancer Res. August 2016
Tumor-Produced Interleukin-8 Attracts Human Myeloid-Derived Suppressor Cells and Elicits Extrusion of Neutrophil Extracellular Traps (NETs)
Cancer Research July 2016
A single arm, preoperative, pilot study to evaluate the safety and biological effects of orally administered reparixin in early breast cancer patients who are candidates for surgery
Multidiscip Respir Med June 2016
Prospective study of the efficacy of antibiotics versus antitussive drugs for the management of URTI-related acute cough in children
Frontiers in Immunology May 2016
Allosteric Modulation of Chemoattractant Receptors
Cancer Research February 2016
A randomized, placebo-controlled phase 2 study of paclitaxel in combination with reparixin compared to paclitaxel alone as front-line therapy for triple-negative breast cancer (fRida)
Pharmacological research January 2016
DF2755A, a Novel Non-Competitive Allosteric Inhibitor of CXCR1/2, Reduces Inflammatory and Post-Operative Pain
The journal of pharmacology & experimental therapeutics January 2016
DFL23448, A Novel Transient Receptor Potential Melastin 8-Selective Ion Channel Antagonist, Modifies Bladder Function and Reduces Bladder Overactivity in Awake Rats
Oncotarget. December 2015
Targeting CXCR1 on breast cancer stem cells: signaling pathways and clinical application modelling.
Annual of the rheumatic diseases December 2015
A Homeostatic Function of CXCR2 Signalling in Articular Cartilage
Pharmacological research August 2015
Novel Immunological Strategies for Islet Transplantation
American Diabetes Association April 2015
CXCR1/2 Inhibition Blocks and Reverses Type 1 Diabetes in Mice
J Cell Physiol April 2015
Gastroprotective Effects of L-Lysine Salification of Ketoprofen in Ethanol-Injured Gastric Mucosa
Curr Med Chem. March 2015
P2X receptors and diabetes
World Journal of Pharmacology March 2015
Improving cancer therapy by targeting cancer stem cells: Directions, challenges, and clinical results Improving cancer therapy by targeting cancer stem cells: Directions, challenges, and clinical results
Transplantation December 2014
Islet allotransplantation in type 1 diabetes: Phase 2 pilot study with CXCL8 inhibitor (reparixin)
Nanoscale November 2014
Targeting FR-expressing cells in ovarian cancer with Fab-functionalized nanoparticles: a full study to provide the proof of principle from in vitro to in vivo Targeting FR-expressing cells in ovarian cancer with Fab-functionalized nanoparticles: a full
Cancer Immunology, Immunotherapy October 2014
Armed antibodies for cancer treatment: A promising tool in a changing era
Toxicol In Vitro March 2014
Oxidative stress and innate immunity responses in cigarette smoke stimulated nasal epithelial cells
Annals of the Rheumatic Diseases January 2014
A phase IB clinical trial in rheumatoid arthritis of dekavil (F8-IL10), a novel anti-inflammatory immunocytokine
Clin Exp Rheumatol. May 2013
Efficacy of ketoprofen vs. ibuprofen and diclofenac: a systematic review of the literature and meta-analysis
J Pain Symptom Manage December 2012
Episodic (breakthrough) pain prevalence in a population of cancer pain paitents. Comparison of clinical diagnoses with the QUDEI - Italian Questionnaire for intense episodic pain
The Journal of Clinical Investigation October 2012
CXCR1/2 inhibition enhances pancreatic islet survival after transplantation CXCR1/2 inhibition enhances pancreatic islet survival after transplantation
Trends Med October 2012
A new ketoprofen lysine salt formulation: 40 mg orodispersible granules
Transplantation International September 2012
CXCR2 inhibition improves islet transplantation
Immunology letters July 2012
Current Status of Chemokine Receptor Inhibitors in Development
ACS Medicinal Chemistry Letters August 2011
Aryltriflates as a Neglected Moiety in Medicinal Chemistry: A Case Study from a Lead Optimization of CXCL8 Inhibitors
British Journal of Pharmacology June 2011
Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor.
Health and Quality of Life Outcomes April 2011
Comparison of numerical and verbal rating scales to measure pain exacerbations in patients with chronic cancer pain
The Journal of Clinical Investigation February 2010
CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts
Journal of bone and mineral research December 2009
Tartronates: A New Generation of Drugs Affecting Bone Metabolism
Bioorganic & medicinal chemistry letters August 2009
Structure-Activity Relationship of Novel Phenylacetic CXCR1 Inhibitors
Journal of chromatography B July 2009
Development and Validation of an LC-MS/MS Method for Determination of Methanesulfonamide in Human Urine
Arthritis and Rheumatism August 2008
The chemokine receptors CXCR1/CXCR2 modulate antigen-induced arthritis by regulating adhesion of neutrophils to the synovial microvasculature
American Journal of Respiratory Cell and Molecular Biology July 2008
Role of the chemokine receptor CXCR2 in bleomycin-induced pulmonary inflammation and fibrosis
Neuroimmunomodulation April 2008
Chemokine MIP-2/CXCL2, acting on CXCR2, induces motor neuron death in primary cultures
Journal of leukocyte biology November 2007
Crucial pathophysiological role of CXCR2 in experimental ulcerative colitis in mice
British Journal of Pharmacology September 2007
Blockade of the chemokine receptor CXCR2 ameliorates adjuvant-induced arthritis in rats
Journal of Pharmacology and experimental Therapeutics June 2007
Reparixin, an inhibitor of CXCR2 function, attenuates inflammatory responses and promotes recovery of function after traumatic lesion to the spinal cord
Transplantation Proceedings May 2007
Protective effect of an inhibitor of interleukin-8 (Meraxin) from ischemia and reperfusion injury in a rat model of kidney transplantation
Molecular Medicine April 2007
The interleukin-8 (IL-8/CXCL8) receptor inhibitor reparixin improves neurological deficits and reduces long-term inflammation in permanent and transient cerebral ischemia in rats
Journal of Medical Chemistry January 2007
Design of Noncompetitive Interleukin-8 Inhibitors Acting on CXCR1 and CXCR2
International Journal of Immunopathology and Pharmacology January 2007
Reparixin, a specific interleukin-8 inhibitor, has no effects on inflammation during endotoxemia
Pharmacology & therapeutics October 2006
ELR+ CXC Chemokines and Their Receptors (CXC Chemokine Receptor 1 and CXC Chemokine Receptor 2) as New Therapeutic Targets
Xenobiotica May 2006
Species differences in the pharmacokinetics an metabolism of reparixin in rat and dog
European cytokine network March 2006
The role of CXCR2 activity in the contact hypersensitivity response in mice
European Cytokine Network March 2006
Development of a systemically-active dual CXCR1/CXCR2 allosteric inhibitor and its efficacy in a model of transient cerebral ischemia in the rat
Antioxid Redox Signal October 2005
Requirements for the Different Cysteines in the Chemotactic and Desensitizing Activity of Human Thioredoxin
Journal of chemical chemistry June 2005
2-Arylpropionic CXC chemokine receptor 1 (CXCR1) ligands as novel noncompetitive CXCL8 inhibitors
Cytokine May 2005
Neuroprotection with the CXCL8 inhibitor repertaxin in transient brain ischemia
Journal of Medicinal Chemistry April 2005
Predicting human serum albumin affinity of interleukin-8 (CXCL8) inhibitors by 3D-QSPR approach
Biochemical pharmacology February 2005
Inhibition of interleukin-8 (CXCL8/IL-8) Responses by Repertaxin, a New Inhibitor of the Chemokine Receptors CXCR1 and CXCR2
PNAS, Proceedings of the National Academy of Sciences August 2004
Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: Prevention of reperfusion injury
Immunology April 2004
Key Role of Proline-Rich Tyrosine Kinase 2 in interleukin-8 (CXCL8/IL-8)-mediated Human Neutrophil Chemotaxis
European citokine network April 2003
Glycosylation Enhances Functional Stability of the Chemotactic Cytokine CCL2
European cytokine network June 2002
Thioredoxin specifically cross-desensitizes monocytes to MCP-1
Biochemical pharmacology October 2001
Role of tumor necrosis factor-alpha in endotoxin-induced lung parenchymal hyporesponsiveness in mice
Journal of immunology March 2001
Lymphocytes From Autoimmune MRL Lpr/Lpr Mice Are Hyperresponsive to IL-18 and Overexpress the IL-18 Receptor Accessory Chain
European cytokine network March 2001
Balance between autocrine interleukin-1beta and caspases defines life versus death of polymorphonuclear cells
Journal of immunology September 2000
The membrane form of the type II IL-1 receptor accounts for inhibitory function
European cytokine network September 2000
IL-18 and IL-18 receptors in the development of autoimmunity
European cytokine network June 2000
R- And S-isomers of Nonsteroidal Anti-Inflammatory Drugs Differentially Regulate Cytokine Production
Pulmonary pharmacology & therapeutics January 2000
Lipopolysaccharide-induced Lung Injury in Mice. II. Evaluation of Functional Damage in Isolated Parenchyma Strips
Methods September 1999
Interleukin-1 and interleukin-1 Fragments as Vaccine Adjuvants
The journal of experimental medicine June 1999
Thioredoxin, a Redox Enzyme Released in Infection and Inflammation, Is a Unique Chemoattractant for Neutrophils, Monocytes, and T Cells
European cytokine network December 1997
Interaction Between interleukin-1 and Ciliary Neurotrophic Factor in the Regulation of Neuroblastoma Cell Functions
European cytokine network June 1997
Interleukin-1 Beta Primes interleukin-8-stimulated Chemotaxis and Elastase Release in Human Neutrophils via Its Type I Receptor
European cytokine network June 1997
Functional Epitope Mapping of Human interleukin-1 Beta by Surface Plasmon Resonance
Frontiers in bioscience: a journal and virtual library October 1996
Structure-function Relationship in the IL-1 Family
Journal of leukocyte biology March 1996
IL-1 beta primes IL-8-activated human neutrophils for elastase release, phospholipase D activity, and calcium flux
The American journal of pathology December 1995
Transfected Type II interleukin-1 Receptor Impairs Responsiveness of Human Keratinocytes to interleukin-1
Vaccine January 1993
Cytokines as Vaccine Adjuvants: Interleukin 1 and Its Synthetic Peptide 163-171
Reasearch in immunology June 1992
Non-inflammatory Peptide Fragments of IL1 as Safe New-Generation Adjuvants
Chemokines stories
LDX0219
A Single Dose Study About the Influence of Food on the Oral Bioavailability of Ladarixin Capsule in Healthy Volunteers
Primary objective:
- to investigate the effect of food on the bioavailability of DF 2156Y after single dose administration of 400 mg of ladarixin to healthy male and female volunteers under fed and fasting conditions.
Secondary objectives:
- to investigate the effect of gender on the bioavailability of DF 2156Y and its metabolites (DF 2108Y and DF 2227Y) after single dose administration of 400 mg of ladarixin to healthy male and female volunteers
- to evaluate safety and tolerability of a single dose administration of ladarixin 400 mg to healthy male and female volunteers.
This is a Single center, single dose, open label, randomized, two-way, crossover, food effect on bioavailability study.
More precisely, a single oral dose of 400 mg of ladarixin (two 200 mg capsules) was administered to healthy male and female volunteers under fed (Test treatment) and fasting (Reference treatment) conditions in two consecutive study periods, according to a two-way crossover design, with a wash-out interval of at least 14 days between the two administrations.
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Ladarixin in obese pre-diabetic patients eligible to bariatric surgery
Effect of oral ladarixin 400 mg twice a day on insulin sensitivity. A phase 2, randomized, double-blind, placebo-controlled explorative study in obese patients with pre-diabetes eligible to bariatric surgery.
Effect of the experimental drug ladarixin administered orally at a dose of 400 mg twice a day on insulin sensitivity. A phase 2, randomized, double-blind, placebo-controlled explorative study in obese patients with pre-diabetes eligible to bariatric surgery.
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A Study to Assess Efficacy/Safety of Ladarixin in Type 1 Diabetes Patients With Preserved ß-cell Function at Baseline
The objectives of this clinical trial are:
- to evaluate whether a 12 month treatment with ladarixin is effective to improve glycemic control in newly diagnosed T1D adult patients with preserved beta-cell function.
- to evaluate the safety of ladarixin in the specific clinical setting
The study is a phase 2, multicenter, double-blind, placebo-controlled study. It will randomize approximately 75 adult patients with new-onset type 1 diabetes (T1D) and preserved beta-cell function (fasting C-peptide >0.205 nmol/l) at baseline. Patients will be assigned (2:1) to receive either oral ladarixin treatment (400 mg b.i.d. for 13 cycles of 14 days on/14 days off - treatment group) or placebo (control group).
Recruitment will be competitive among the study sites, until the planned number of patients is randomized.
Ladarixin and placebo will be both administered for 1 year. All patients will be followed-up for 18 months from the 1st administration of the study medication. The study database will be locked and data analyzed when the last patient randomized has completed month 12 follow-up visit. After this time point, the follow-up will continue under open-label conditions up to month 18.
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A Study of Oral Ladarixin in New-onset Type 1 Diabetes and a Low Residual β-cell Function
The objective of this clinical trial is to assess whether ladarixin treatment is effective in preserving beta-cell function and delaying the progression of type 1 diabetes (T1D) in adolescent and adult patients. The safety of ladarixin in the specific clinical setting will be also evaluated.
This is a phase 3, multicenter, double-blind, placebo-controlled study. It has been designed to further evaluate whether ladarixin is effective in preserving beta-cell function and slowing-down the progression of T1D) in patients with a more severe disease presentation.
The study is planned to be performed at about 40 study centers in EU, US and in other countries, if appropriated. At each study center, the Principal Investigator (PI) will be responsible for ensuring that the investigation is conducted according to the signed Investigator agreement, the protocol, GCP guidelines, and local regulations.
The study is planned to involve -327 patients with new-onset T1D, to include about 200 adolescents (14-17 years). Patients will be randomly (2:1) assigned to receive either ladarixin treatment (400 mg b.i.d. for 13 cycles of 14 days on/14 days off - treatment group) or matched placebo (control group). The two groups will be balanced within centers.
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A Phase 2, Multicentre, Randomized, Double-blind, Placebo-controlled Study in Patients With New-onset Type 1 Diabetes
The objective of this clinical trial is to investigate whether ladarixin has sufficient activity (preservation of β-cell function and slow-down of the progression of T1D) to warrant its further development (proof of concept trial). The safety of ladarixin in the specific clinical setting will be also evaluated.
The study is a phase 2, multicentre, double-blind study. 72 patients with new-onset type 1 diabetes (T1D) were planned to be involved, randomly (2:1) assigned to receive either ladarixin treatment (400 mg b.i.d. for 3 cycles of 14 days on/14 days off - treatment group) or placebo (control group).
Recruitment was competitive among the study sites, until the planned number of patients was enrolled. A total of 76 patients were actually recruited.
T1D is an organ-specific autoimmune disease in which the immune system attacks the insulin-producing β-cells. The onset of the disease typically occurs before adulthood and seriously affects a person's quality of life.
T1D is treated with life-long daily exogenous insulin injections and monitoring of blood glucose levels. However, even optimization of glucose control through the most recent technologies cannot adequately substitute for the finely tuned normal balance of the glucose levels. Therefore, despite marked improvements in diabetes care in recent years, insulin-dependent diabetes results in secondary long-term complications and is one of the leading causes of end-stage renal disease, blindness and amputation. Additionally, hypoglycaemia unawareness is a serious consequence of recurrent hypoglycaemia often requiring emergency care.
Maintenance of residual β-cell function (as measured by C-peptide response) was demonstrated to be associated with reduced rate of microvascular complications and hypoglycaemia, improved quality of life, and overall reduction in morbidity and associated management costs. Therefore, pharmacological approaches aimed at controlling the autoimmune response and restoring self-tolerance to pancreatic β-cells had attracted the clinical/scientific interest.
Among these, rituximab, CD3-specific monoclonal antibodies, GAD65, DiaPep277 have progressed to phase III clinical trials. Other agents, including cytokines modulators such as anti-TNF or anti-IL1, are under clinical evaluation. Unfortunately, even if safe preservation of β-cell function and improvement of glycaemic control have been evidenced for some of the pharmacological approaches evaluated so far, none has been definitely approved for the "treatment" of diabetes onset. New strategies are being evaluated which combine agents targeting sequential arms of the immune and inflammatory response involved in β-cell disruption. In this regard, IL-8 appears to be an important mediator in the progression of type 1 diabetes. Production and secretion of pro-inflammatory IL-8 has been demonstrated from human pancreatic islets upon enterovirus infections, and LPS-induced production of IL-8 by neutrophils is increased in type 1 pre-diabetic and diabetic patients. In parallel, circulating levels of IL-8 were elevated in children with T1D compared to non-diabetic controls. Specifically, levels of IL-8 correlate with glycaemic control, higher level being associated to poorer or unfavorable glucose control.
As a result of these findings, the modulation or inhibition of IL8 activity is considered a valid target for the development of innovative treatments aimed to control the progression of T1D.
Results obtained with ladarixin in mouse models of T1D, and particularly reversal of "diabetes" in the NOD mice, clearly showed the ability of this CXCR1/2 inhibitor to protect β-cells and either prevent or delay the progression of hyperglycaemia. The positive effects of ladarixin, coupled with the safety shown in phase 1 studies, provided a sound rationale for a clinical study aimed at evaluating the effect of ladarixin in patients with new onset diabetes and supported the conduct of the present study.
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Study on Efficacy and Safety of Reparixin in the Treatment of Hospitalized Patients With Severe COVID-19 Pneumonia
The study objective is to assess Efficacy and safety of Reparixin treatment as compared to placebo (both on top of standard treatment) in adult patients with severe COVID-19 pneumonia.
This is a phase 3 clinical trial designed as a randomized, double-blind, placebo-controlled, multicentre study to evaluate the efficacy and safety of Reparixin in hospitalized adult patients with severe COVID-19 pneumonia.
Patients will be screened for the participation in the study and eventually randomized based on an unbalanced randomization scheme (2:1) to Reparixin oral tablets (2 x 600 mg TID) for up to 21 days or to placebo.
An unequal randomization is justified by the need to gain experience and more safety data with the investigated treatment and by an expected better acceptability of the trial by patients.
The placebo control arm is justified by the unavailability of a well-defined standard of care for subjects with COVID-19 pneumonia who are candidates for this study.
All patient will receive the standard supportive care based on the patient's clinical need. Follow-up information on the patient's clinical condition will be collected until day 90.
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A Double-blind Study of Paclitaxel in Combination With Reparixin or Placebo for Metastatic Triple-Negative Breast Cancer (FRIDA)
The Objectives of this study:
The primary objective of the study was to evaluate progression-free survival (PFS) (defined as the number of days between the date of randomization and the date of clinical disease progression (PD) according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1, as assessed by Independent Radiology Review, or death for any cause, whichever occured first) in patients with metastatic triple-negative breast cancer (TNBC) treated with the combination of paclitaxel and orally administered reparixin compared to paclitaxel alone.
The secondary objectives were:
- To determine overall survival (OS).
- To evaluate objective response rates (ORR).
- To determine median PFS (mPFS).
- To assess the safety of the combination of paclitaxel and orally administered reparixin (referred to as combination treatment).
The study is a two arm, phase 2 study to evaluate the efficacy of the combination of paclitaxel and reparixin compared to paclitaxel and placebo in metastatic TNBC patients.
In the study two groups There were two groups:
Group 1: paclitaxel 80 mg/m2 intravenous (i.v.) (Days 1, 8, and 15 of 28-day cycle) + reparixin oral tablets 1200 mg three times a day (t.i.d.) continuing from Day 1 to Day 21.
Group 2: paclitaxel 80 mg/m2 i.v. (Days 1, 8, and 15 of 28-day cycle) + placebo oral tablets 1200 mg t.i.d. continuing from Day 1 to Day 21.
Study drug (reparixin/placebo) was administered with water prior to the start of the i.v. paclitaxel infusion on Cycle 1, Day 1 and then administered approximately every eight hours (six to ten hours) for 21 consecutive days during each cycle with seven days off-treatment between each cycle. It was preferable that reparixin was taken with food. However, if the patient was unable to eat, study drug was allowed to be administered. When in combination with paclitaxel (Day 1, 8 and 15 of each cycle), reparixin or placebo was administered every approximately eight hours with about 250 mL water and a light meal or snack. Paclitaxel was administered in combination with study drug (reparixin/placebo) as an i.v. infusion on Days 1, 8 and 15 of each 28-day cycle.
On Cycle 1, Day 1, paclitaxel was administered at the clinic after the administration of study drug (reparixin/placebo). From that point forward, study drug (reparixin/placebo) was self-administered t.i.d. for 21 days. Combination treatment (three weeks on and one week off) continued until PD according to RECIST criteria version 1.1, withdrawal of consent or unacceptable toxicity, whichever occurred first.
The next clinic visits were on Days 8 and 15 when a paclitaxel infusion was administered to the patient. The patients returned to the clinic again on Day 29/Day 1 of the next cycle.
Tumor response and/or progression assessments were performed and documented every eight weeks according to RECIST criteria version 1.1. Metastatic tissue samples were analyzed for evaluation of CD24-CD44+ and aldehyde dehydrogenase positive (ALDH+) CSCs.
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Pilot Study to Evaluate Safety & Biological Effects of Orally Administered Reparixin in Early Breast Cancer
This is a pilot "window of opportunity" clinical study in patients with operable breast cancer investigating use of reparixin as single agent in the time period between clinical diagnosis and surgery.
The primary objectives of this study were:
1- to evaluate the effects of orally administered reparixin on CSCs in the primary tumor and the tumoral microenvironment in an early breast cancer population:
A. CSC were measured in tissue samples by techniques that could include: ALDEFLUOR assay and assessment of CD44/CD24 by flow cytometry, or examination of RNA transcripts by RT-PCR, aldehyde dehydrogenase-1, CD44/CD24 and epithelial mesenchymal transition markers (Snail, Twist, Notch) by immunohistochemistry (IHC). CSC were defined as ALDEFLUOR positive (ALDH-1+) and/or CD44 high/CD24 low by flow cytometry or RT-PCR and IHC and by the detection of ALDH-1+ cells with or without epithelial mesenchymal transition (EMT) transcription factor in IHC assays.
B. Serine-threonine protein kinase (AKT), focal adhesion kinase (FAK), phosphatase and tensin homolog (PTEN) and chemokine receptor-1 (CXCR1) levels were measured in tissue samples by IHC.
C. Measurement of markers of inflammation (interleukin-1beta [IL-1β], interleukin-6 [IL-6], interleukin-8 [IL-8], tumor necrosis factor-alpha [TNF-α], granulocyte macrophage colony stimulating factor [GM-CSF], vascular endothelial growth factor [VEGF], basic fibroblast growth factor [b-FGF] and high-sensitivity C-reactive protein [hsCRP]) in plasma, leukocyte subsets (enumerate T subsets, B, and natural killer/natural killer T [NK/NKT] cells) and study polymorphonuclear leukocyte [PMN] biology in peripheral blood samples. D. Measurement of markers of angiogenesis (CD31 staining), tumor-infiltrating leukocytes (CD4, CD8, NK and macrophages), autophagy (P62 and LC3 by IHC), EpCAM and EMT markers (CD326, CD45, Twist1, SNAIL1, SLUG, ZEB1, FOXC2, TG2, Akt2, P13k and CK19 by RT-PCR) and tissue cellularity (residual disease characterization in tumor bed) in tumor tissue samples.
2. To evaluate the safety of oral reparixin administered three times daily (t.i.d.) for 21 consecutive days.
The secondary objective was to define the pharmacokinetic (PK) profile of orally administered reparixin.
According to the cancer stem cell (CSC) model, tumors are organized in a cellular hierarchy maintained by a subpopulation of cells displaying stem cell properties. These properties include self-renewal (which drives tumorigenesis) and differentiation (which generates the tumor bulk and contributes to cellular heterogeneity).
CSCs were first observed in hematological malignancies but have also been identified in solid tumors of breast, prostate, brain, colon and pancreas. CSCs are thought to be resistant to conventional chemotherapies and this may be why relapse occurs in many patients and this might explain the failure to develop therapies that are consistently able to eradicate solid tumors. Although currently available drugs can shrink metastatic tumors, these effects are usually transient and often do not appreciably extend the life of patients. One reason for the failure of these treatments is the acquisition of drug resistance by the cancer cells as they evolve; another possibility is that existing therapies fail to kill CSCs effectively. Existing therapies have been developed largely against the bulk population of tumor cells because they are often identified by their ability to shrink tumors. Because most cancer cells have limited proliferative potential, an ability to shrink a tumor mainly reflects an ability to kill these cells. It seems that normal stem cells from various tissues tend to be more resistant to chemotherapeutics than mature cell types from the same tissues. The reasons for this are not clear, but may relate to high levels of expression of anti-apoptotic proteins or adenosine triphosphate-binding cassette transporters such as the multidrug resistance gene. If the same were true of CSCs, then one would predict that these cells would be more resistant to chemotherapeutics than tumor cells with limited proliferative potential. Even therapies that cause complete regression of tumors might spare enough CSCs to allow re-growth of the tumors. Therapies that are more specifically directed against CSCs might result in much more durable responses and even cures of metastatic tumors.
There are limited data on the impact of treatment tailoring based on CSC detection. Gene profiling of CSCs could lead to identification of therapeutic targets on CSCs (e.g. hormone receptors (HR), human epidermal growth factor receptor-2 [HER-2] expression, epidermal growth factor receptor [EGFR] expression), and could represent tumor biopsy in "real time". Several groups showed frequent discordance of HER-2 status between primary tumor and CSCs, and case reports showed clinical utility for the use of trastuzumab-based therapy based on HER-2 CSCs status. Similarly, the hormonal status of CSCs could be different from that of the primary tumor, which could lead to increase the number of patients suitable for endocrine therapy, but also could explain why endocrine therapy fails in a subset of HR positive (HR+) patients. More specifically, a recent observation from Ginestier et al. demonstrated that over expression of chemokine receptor 1 (CXCR-1) is associated with the aldehyde dehydrogenase positive (ALDH+) cells. In breast carcinomas, the ALDEFLUOR+ phenotype shows partial overlap with the CD44+CD24-Lin-CSC phenotype. Cellular hierarchies have been identified in a series of molecularly characterized breast cancer cell lines and it has been demonstrated that these lines contained ALDEFLUOR+ components that were both tumorigenic and metastatic in NOD/SCID mice. Furthermore, previous observations demonstrated that the addition of recombinant interleukin-8 (IL-8) increased the CSC population as well as increasing its propensity for invasion. Moreover, tissue damage induced by chemotherapeutic agents may induce IL-8 as part of the injury response. This suggests that strategies aimed at interfering with the IL 8/CXCR-1 axis may be able to target CSCs, increasing the efficacy of current therapies. This experimental data provides another therapeutic target in breast cancer.
Reparixin seems to be a good candidate for use in breast cancer patients because of its very acceptable toxicity profile shown in the Phase I and II clinical trials conducted so far, along with its observed activity in vitro against breast cancer cell lines and in vivo in tumor xenografts in mice. A phase 1 study is currently underway to study the effects of reparixin in combination with paclitaxel in metastatic breast cancer.
This small pilot study aims at exploring the effects on breast CSC markers as well as the safety and PK profile of orally administered single agent reparixin in HER-2 negative (HER-2-) early breast cancer patients in the 3 weeks prior to surgery.
The study will be performed in the interval between disease diagnosis and planned surgery and may lead to a minimal delay in surgery. This is balanced by the potential benefits of the study by evaluating CSCs and their prognostic importance as well as obtaining information about the impact of reparixin therapy.
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Pilot Study to Evaluate Reparixin With Weekly Paclitaxel in Patients With HER 2 Negative Metastatic Breast Cancer (MBC)
This is a phase I study to evaluate the safety and define the pharmacokinetic (PK) profile of orally administered reparixin in combination with paclitaxel in HER 2 (Human epidermal growth factor receptor-2) negative metastatic breast cancer patients.
The primary objective of this study was to evaluate the safety and define the pharmacokinetic (PK) profile of orally administered reparixin in combination with paclitaxel in HER-2 negative MBC patients.
The secondary objectives were to:
- Evaluate the effects of orally administered reparixin on cancer stem cell (CSC) markers, the tumoral microenvironment and markers of cytokine inflammation;
- Evaluate peripheral blood samples for enumeration of circulating tumor cells (CTCs), molecular characterization as CSCs and perform epithelial-mesenchymal transition (EMT) biomarker profiling;
- Assess disease response for indication of efficacy.
The CSC (Cancer stem cell) concept has important implications for understanding carcinogenesis as well as for the development of cancer therapeutics. According to this concept, tumors are initiated and maintained by a cellular subcomponent that displays stem cell properties. These properties include self-renewal, which drives tumorigenesis, and differentiation (albeit aberrant), which contributes to tumor cellular heterogeneity. The existence of CSCs has been described in a variety of hematologic and solid tumors including those of the breast, brain, colon, pancreas, lung, liver, and head and neck. In addition to driving tumorigenesis, CSCs may contribute to tumor metastasis as well as to tumor recurrence after treatment.
One of the therapeutic strategies being pursued to target CSCs involves inhibition of self renewal or survival pathways in these cells. These pathways include NOTCH (Notch signaling pathway), Hedgehog, and WNT (Wnt signaling pathway). Such strategies may be limited by the role of these pathways in normal stem cell function, which could result in systemic toxicities from pathway inhibition. In addition to intrinsic pathways regulating stem cell functions, normal and malignant stem cells are regulated by extrinsic signals generated in the microenvironment or CSC niche. In the breast, this niche is composed of immune cells, mesenchymal elements that include fibroblasts, endothelial cells, adipocytes, and extracellular matrix components. These components play an important role in normal breast development and carcinogenesis. If the cellular microenvironment plays an important role in the regulation of CSC growth and survival, then strategies aimed at interfering with these interactions represent a rational approach to target breast CSCs.
There are limited data on the impact of treatment tailoring based on CSCs detection. Gene profiling of CSCs could lead to identification of therapeutic targets on CSCs (e.g. hormone receptors, HER-2 [Human epidermal growth factor receptor-2] expression, EGFR [Epidermal growth factor receptor] expression), and could represent tumor biopsy in "real time". Several groups showed frequent discordance of HER-2 status between primary tumor and CSCs, and case reports showed clinical utility to use of trastuzumab-based therapy based on HER-2 CSCs status. Similarly, the hormonal status of CSCs could be different from that of the primary tumor, which could lead to increase the number of patients suitable for endocrine therapy, but also could explain why endocrine therapy fails in a subset of hormone receptor-positive patients. The study provided the in vivo demonstration that CXCR-1 (Chemokine receptor 1) targeting with specific blocking antibodies or reparixin is associated with reduced systemic metastases. The experimental data provides another therapeutic target in metastatic disease and warrants a pilot study investigation in humans to further explore effects of reparixin on breast CSCs and the tumoral microenvironment.
Reparixin seems to be a good candidate for use in breast cancer patients because of its very acceptable toxicity profile shown in the Phase I and II clinical trials conducted so far, along with its observed activity in vitro against breast cancer cell lines and in vivo in tumor xenografts in mice. It potentially addresses another therapeutic target in metastatic disease. The current pilot study thus aims at exploring the safety and PK profile of orally administered reparixin in HER-2 negative metastatic breast cancer patients and its effects on breast CSC markers.
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