Table 3 Overview of compounds inhibiting the CXCL8-CXCR1/CXCR2 interaction in vivo and in completed or ongoing clinical trials

Reparixin/

Repertaxin (Dompé)

CXCR1/2 antagonist

Pancreatic islet transplantation

for type 1 diabetes

Diabetic mice

Reduced leukocyte recruitment & improved pancreatic islet engraftment

[136]

NCT01220856

(Phase II: completed)

Improved transplant outcome

[136]

NCT01817959

(Phase III: completed)

No generally improved insulin secretion but upon transplantation of sufficient islet mass & use of anti-thymocyte globulin for immunosuppression induction

[301, 302]

Pancreatic islet auto-transplantation after pancreatectomy

NCT01967888

(Phase II/III: completed)

No improved diabetes outcomes: CXCL8 inhibition alone may be insufficient to prevent damage to transplanted islets

[303]

Delayed graft function after kidney transplantation

Rat kidney transplantation model

Reduced neutrophil infiltration & prevention of kidney graft function impairment

[138]

NCT00248040

(Phase II: completed)

Early allograft dysfunction after liver transplantation

Murine liver ischemia-reperfusion injury model

Reduced neutrophil recruitment, activation & migration in the liver

[139]

NCT03031470

(Phase II: completed)

Primary graft dysfunction after lung transplantation

NCT00224406

(Phase II: completed)

Breast cancer

Human breast cancer xenografts

Reparixin with paclitaxel inhibited tumor growth & metastasis by targeting cancer stem cells

[304, 305]

NCT02001974

(Phase I: completed)

Reparixin with paclitaxel was safe & partially effective in patients with metastatic breast cancer

[306]

NCT02370238

(Phase II: completed)

Reparixin with paclitaxel did not prolong progression-free survival

[307]

NCT05212701

(Phase II: recruiting)

COVID-19

Murine models of acute lung injury

Reduced neutrophil infiltration, vascular permeability & tissue injury after LPS stimulation

[308]

NCT04794803

(Phase II: completed)

Improved clinical outcomes

[187]

NCT04878055

(Phase III: completed)

NCT05254990

(Phase III: recruiting)

DF2755A (Dompé)

CXCR1/2 antagonist

Pain

Murine models of inflammatory & post-operative pain

DF2755A exerted anti-nociceptive effects

[151]

Rat model characterized by non-inflammatory peripheral neuropathy

Prevention & reversal of peripheral neuropathic pain by direct inhibition of chemokine-induced excitation of sensory neurons

[152]

Healthy volunteers

NCT04803396

(Phase I: completed)

Ladarixin (Dompé)

CXCR1/2 antagonist

Airway inflammation

Murine models of airway inflammation

Reduced neutrophil recruitment & improvement of neutrophil-dependent airway inflammation

[309]

Healthy volunteers

NCT04854642

(Phase I: completed)

Type 1 diabetes

Diabetic mice

Prevention & reversal of type 1 diabetes

[161]

NCT02814838

(Phase II: completed)

No appreciable effect of short-term treatment on the preservation of residual β-cell function

[188]

NCT04899271

(Phase II: ongoing)

NCT05368402

(Phase II: recruiting)

NCT04628481

(Phase III: recruiting)

SX-682

(Syntrix)

CXCR1/2 antagonist

Advanced solid tumors

Murine models of breast & lung cancer

SX-682 with anti-PD-L1 immunotherapy and TGF-β inhibition reduced EMT of tumor cells & infiltration of granulocytic MDSCs

[114]

NCT04574583

(Phase I/II: ongoing)

Myelodysplastic syndromes

NCT04245397

(Phase I: recruiting)

Melanoma

Melanoma xenografts

Reduced tumor growth & MDSC recruitment, enhanced CD8⁺ T-lymphocyte infiltration

[189]

NCT03161431

(Phase I: recruiting)

Colorectal cancer

NCT04599140

(Phase I/II: recruiting)

Metastatic pancreatic ductal adenocarcinoma

NCT04477343

(Phase I: recruiting)

Navarixin/

SCH527123/

MK-7123

(Merck)

CXCR1/2 antagonist

Psoriasis

NCT00684593

(Phase II: completed)

Advanced/metastatic solid tumors

Colon cancer xenografts

Inhibition of liver metastasis due to reduced angiogenesis & enhanced apoptosis

[310]

Reduced tumor growth & improved sensitivity to chemotherapy

[311]

Melanoma xenografts

Reduced tumor growth & angiogenesis

[312]

NCT03473925

(Phase II: completed)

Asthma

Animal models of pulmonary inflammation

Reduced neutrophil recruitment, mucus production & goblet cell hyperplasia

[313]

NCT00632502

(Phase II: completed)

Reduced sputum neutrophils

[190]

NCT00688467

(Phase II: completed)

Elubrixin/

SB656933

(GSK)

CXCR2 antagonist

Healthy volunteers

NCT00551811

(Phase I: completed)

Elubrixin is safe, well-tolerated & inhibited ozone-induced airway neutrophilia

[314]

NCT00504439

(Phase I: completed)

NCT00615576

(Phase I: completed)

Cystic fibrosis

NCT00605761

(Phase I: completed)

NCT00903201

(Phase II: completed)

Trends for improvement in sputum inflammatory biomarkers, but no changes in lung function

[191]

Danirixin/

GSK1325756 (GSK)

CXCR2 antagonist

Pulmonary diseases

Rat model

Reduced pulmonary neutrophil recruitment after LPS or ozone challenge

[315]

Healthy volunteers

NCT01209052

(Phase I: completed)

Danirixin is safe & may have benefit in neutrophil-predominant inflammatory diseases

[316]

NCT01209104

(Phase I: completed)

Danirixin is safe & may have benefit in neutrophil-predominant inflammatory diseases

[316]

NCT01453478

(Phase I: completed)

Danirixin is safe & no advantages of a bioenhanced over an immediate-release formulation

[317]

NCT03136380

(Phase I: completed)

Danirixin is safe

[318]

NCT03457727

(Phase I: completed)

Food has a negative effect on the pharmacokinetics of danirixin

[319]

NCT02453022

(Phase I: completed)

Superior biopharmaceutical properties of the hydrobromide salt compared to the free base form

[320]

NCT01267006

(Phase I: completed)

NCT02169583

(Phase I: completed)

Healthy volunteers & RSV-infected children

NCT02201303

(Phase I: completed)

Influenza

NCT02469298

(Phase II: completed)

Well tolerated & no impedance of viral clearance

[194]

COPD

NCT02130193

(Phase II: completed)

Improved respiratory symptoms & health status of patients with mild-to-moderate COPD

[192]

NCT03034967

(Phase II: completed)

Absence of a clear efficacy benefit, unfavorable benefit-risk profile

[193]

AZD5069 (AstraZeneca)

CXCR2 antagonist

Healthy volunteers

NCT00953888

(Phase I: completed)

AZD5069 is safe, rapidly absorbed & twice-daily administration is supported

[321]

NCT01332903

(Phase I: completed)

Rapid absorption & extensive metabolization

[321]

NCT01051505

(Phase I: completed)

Steady-state plasma concentrations are achieved within 2–3 days

[321]

NCT01480739

(Phase I: completed)

Moderate inter- and intra-subject variability in total AZD5069 exposure.

[321]

NCT01989520

(Phase I: completed)

No major influence of drug formulation on total exposure of AZD5069

[321]

NCT01100047

(Phase I: completed)

No major influence of ethnicity on total exposure of AZD5069

[321]

NCT01083238

(Phase I: completed)

No major influence of food or age on total exposure of AZD5069

[321]

NCT01735240

(Phase I: completed)

Increased total exposure & peak plasma levels upon co-administration of ketoconazole

[321]

NCT01962935

(Phase I: completed)

Asthma

NCT01890148

(Phase I: completed)

AZD5069 is safe & reduced neutrophil recruitment

[322]

NCT01704495

(Phase II: completed)

No reduced frequency of severe asthma exacerbations

[323]

Bronchiectasis

NCT01255592

(Phase II: completed)

Reduced sputum neutrophil counts but no improvement in clinical outcomes

[324]

COPD

NCT01233232

(Phase II: completed)

AZD5069 was well tolerated with no increase in infection rates, supporting further studies

[195]

Metastatic pancreatic ductal carcinoma

Pancreatic ductal carcinoma murine model

AZD5069 (and immunotherapy) extended survival & reduced metastasis

[196]

NCT02583477

(Phase I/II: completed)

Metastatic castration-resistant prostate cancer

Prostate cancer xenograft

AZD5069 in combination with radiotherapy attenuated tumor growth & progression

[115]

NCT03177187

(Phase I/II: ongoing)

Advanced solid tumors & head and neck carcinoma

NCT02499328

(Phase I/II: ongoing)

AZD4721/

RIST4721 (AstraZeneca)

CXCR2 antagonist

Healthy volunteers

NCT01889160

(Phase I: completed)

NCT04105959

(Phase I: completed)

NCT05023811

(Phase I: completed)

NCT01962935

(Phase I: completed)

Palmoplantar pustulosis

NCT03988335

(Phase II: completed)

Well tolerated supporting further clinical development

[197]

NCT05194839

(Phase II: recruiting)

Hidradenitis suppurativa

NCT05348681

(Phase II: recruiting)

Familial Mediterranean Fever

NCT05448391

(Phase II: recruiting)

ABX-IL8

(Abgenix)

Anti-CXCL8 monoclonal antibody

COPD/chronic bronchitis

NCT00035828

(Phase II: completed)

No clinical impact on COPD exacerbations, lung function & health-related quality of life

[198]

Melanoma

Melanoma xenograft

Inhibition of angiogenesis, tumor growth & metastasis

[199]

Bladder cancer

Orthotopic bladder cancer xenografts

Reduced tumor growth through downregulation of MMPs & NF-κB

[200]

HuMax-IL8/

BMS-986253 (Bristol-Myers Squibb)

Anti-CXCL8 monoclonal antibody

Advanced solid tumors

Breast cancer xenografts

Reduced tumor infiltration of granulocytic MDSCs & reversal of EMT

[201]

NCT02536469

(Phase I: completed)

HuMax-IL8 is safe & well tolerated

[325]

NCT04572451

(Phase I: recruiting)

NCT03400332

(Phase I/II: recruiting)

Pancreatic carcinoma

Humanized pancreatic cancer murine model

Potentiation of the anti-tumor effects of immunotherapy

[117]

NCT02451982

(Phase II: recruiting)

Hepatocellular carcinoma

NCT04050462

(Phase II: ongoing)

NSCLC & hepatocellular carcinoma

NCT04123379

(Phase II: recruiting)

Head & neck squamous cell carcinoma

NCT04848116

(Phase II: recruiting)

Prostate cancer

NCT03689699

(Phase I/II: ongoing)

Myelodysplastic syndromes

NCT05148234

(Phase I/II: recruiting)