Table 3.
Inhibitors of the lysyl oxidase family and their current clinical development.
| Inhibitor | Company | Molecule Type | Target | Clinical Details | Clinical Trial Identifier and Name | Disease | Summary Results | Reference |
|---|---|---|---|---|---|---|---|---|
| Beta-aminopro pionitrile (BAPN) | National heart Institute | Small molecule inhibitor | Pan-LOXs, SSAO and DAO | Phase 1–3 g/day for 22–67 days n = 4 |
Scleroderma |
↑urine HYD ↑α:β collagen chains implying ↓crosslinks Bone formation changes |
[171] | |
| Beta-aminopro pionitrile (BAPN) | University of Arizona | Small molecule inhibitor | 250 mg 4 times daily for 3 weeks n = 5 |
Fibrous based urethral strictures | No adverse effects. Unclear therapeutic benefit. Demonstrated efficacy. ↑ in acid-soluble collagen. ↓ dermal scar strength. | [162] | ||
| Simtuzumab (GS-6624) | Gilead | Humanised Antibody | LOXL2 | Simtuzumab (200 or 700 mg) with Ruxolitinib 6 cycles of 28 days (~6 months) n = 54 |
Phase 2 NCT01369498 |
Thrombocythaemia myelofibrosis | No clinical benefit in bone marrow fibrosis | [172] |
| Simtuzumab (GS-6624) | Gilead | Humanised Antibody | LOXL2 | 75 mg or 125 mg subcutaneous for 96 weeks n = 234 | Phase 2 NCT01672853 |
Liver fibrosis in adults with primary sclerosing cholangitis | No significant clinical benefit to patients | [173] |
| Simtuzumab (GS-6624) | Gilead | Humanised Antibody | LOXL2 | Subcutaneous 125 mg/mL single dose once a week. Up to 254 wks |
Phase 2 NCT01769196, NCT01759511 |
Idiopathic pulmonary fibrosis | No ↑ progression free survival. Not recommended to progress in IPF | [174] |
| Simtuzumab (GS-6624) | Gilead | Humanised Antibody | LOXL2 | Intravenous 700 mg every 2 wks for 22 wks (~6 months) | Phase 2 NCT01707472 |
Chronic Liver fibrosis in HIV and HCV–infected adults | Well tolerated and modulation of TGFB3 |
[175] |
| Simtuzumab (GS-6624) | Gilead | Humanised Antibody | LOXL2 | Combined with Gemcitabine (1000 mg/m2) Simtuzumab either 200 or 700 mg (~3 months of treatment) n = 240 |
Phase 2 NCT01472198 |
Metastatic pancreatic adenocarcinoma | No ↑ OS (overall survival) | [176] |
| Simtuzumab (GS-6624) | Gilead | Humanised Antibody | LOXL2 | Combination with FOLFIRI, Simtuzumab 200 or 700 mg n = 249 (second line) (~6 months of treatment) | Phase 2 NCT01479465 | Metastatic KRAS mutant colorectal adenocarcinoma | Simtuzumab did not improve clinical outcomes | [177] |
| Simtuzumab (GS-6624) | Gilead | Humanised Antibody | LOXL2 | Subcutaneous weekly injections of 75 or 125 mg of Simtuzumab over 240 wks n = 219 |
Phase 2 NCT01672866; NCT01672879; |
Liver Fibrosis (nonalcoholic steatohepatitis, NASH) | Simtuzumab did not improve clinical outcomes | [178] |
| Simtuzumab (GS-6624) | Gilead | Humanised Antibody |
LOXL2 |
200 mg, 700 mg or placebo by intravenous infusion every 2 weeks n = 258 |
Phase 2 (NCT01672879) |
Nonalcoholic Steatohepatitis | Regression of fibrosis associated reduced liver-related complications | [179] |
| Epigallocatechin Gallate (EGCG) |
Northumbria University | Polyphenol | Aldehydes | Oral 135 and 270 mg single dose | Phase 1 NCT00981292 | Healthy subjects | No adverse effects | No Results Posted |
| Epigallocatechin Gallate (EGCG) |
The University of Texas Health Science Center at San Antonio | Polyphenol | Aldehydes | Oral 450 mg twice a day for 1 year n = 50 | Phase 1 NCT02891538 | Primary colon or rectal adenocarcinoma | Study completion in 2023 | No Results Posted |
| Epigallocatechin Gallate (EGCG) |
National Cancer Institute (NIH) | Polyphenol | Aldehydes | Oral 800 or 1200 mg for 14–28 days prior to resection | Phase 2 | Bladder cancer | PK: EGG levels increased. No significant changes in biomarkers | [180] |
| Epigallocatechin Gallate (EGCG) |
University of California, San Francisco | Polyphenol | Aldehydes | Patients: 600 mg EGCG capsules once daily by mouth for two weeks | Phase1 NCT03928847 | Idiopathic pulmonary fibrosis | Reduction in serum biomarkers collagen oligomeric matrix protein (COMP) and periostin and in tissue Col1, snail, pSMAD3, fibronectin; n = 4 | [181] |
| Tetrathiomolybdate (TM) | University of Michigan | Copper chelator | Copper | n = 23 | Phase1/2 NCT00189176 | Idiopathic pulmonary fibrosis | Completed in 2006 | No Results Posted |
| Tetrathiomolybdate (TM) | New York University School of Medicine & University of Michigan |
Copper chelator | Copper | n = 30 | Phase 2 | Malignant Pleural Mesothelioma | Following cytoreduction surgery, antiangiogenic effects observed with minimal toxicity. | [182] |
| Tetrathiomolybdate (TM) | University of Michigan | Copper chelator | Copper | Oral 180 mg/day n = 15 | Phase 2 | Advanced kidney cancer | Well-tolerated and reduces copper in serum. Potential as an antiangiogenic therapy | [183] |
| Tetrathiomolybdate (TM) | University of Michigan | Copper chelator | Copper | n = 18 90, 105, 120 mg/day 90 days | Phase 1 | Metastatic solid tumors including breast, colon, lung, and prostate cancers | Toxicity: mild anemia | [184] |
| Tetrathiomolybdate (TM) | Weill Cornell Medicine Iris Cantor Breast Center | Copper Chelator | Pan-LOXs | Oral 8–17 mg/dL for 2 years n = 75 | Phase 2 NCT00195091 |
Breast Cancer stage II triple-negative breast cancer (TNBC), stage III and stage IV without any evidence of disease (NED) |
No significant ↑ OS |
[185] |
| ATN-224 | Cancer research UK | Copper chelator | Copper | Once daily | Phase 2 NCT00674557 | Breast cancer | Terminated 2009 No results posted | No Results Posted |
| D-penicillamine |
National institute of respiratory diseases in Mexico City | Copper Chelator | Non specific Pan-LOXs | Daily 600 mg n = 56 Combined with colchicine 1 mg daily and prednisone 15 mg/d 5 year study |
Phase 2 | Idiopathic pulmonary fibrosis | No improvement in disease progression | [186] |
| D-penicillamine |
university of California | Copper Chelator | Non specific Pan-LOXs | Oral 750–1000 mg/day or 125 mg n = 134 24 months study |
Phase 2 | Diffuse cutaneous systemic sclerosis | High dose had 80% adverse event related withdrawal A reduction in cardiomegaly | [187] |
| D-penicillamine |
New approaches to brain tumour therapy CNS consortium (NCI) | Copper Chelator | Non specific Pan-LOXs | 250 mg/day n = 40 |
Phase 2 | Glioblastoma —post resection | Adverse effects: hypocupremia No change in survival |
[188] |
| PXS-5505 | Pharmaxis | Small molecule inhibitor | Pan-LOXs | Orally as 2 × 100 mg twice a day | Phase 1/2a NCT04676529 | Myelofibrosis | NA | NA |
| PXS-5505 | university of Rochester | Small molecule inhibitor | Pan-LOXs | Orally 100–200 mg BID in combination with Atezolizumab (Anti-PD-L1) 1200 mg every 3 weeks and Bevacizumab (Anti-VEGF) 15 mg/kg every 3 weeks | Phase 1b/2 NCT05109052 | Unresectable hepatocellular Carcinoma | NA | NA |
| PXS-6302 | Pharmaxis | Small molecule inhibitor | Pan-LOXs | Escalating dose 0.6–8 mg for 7 days topical | Phase 1/1c SOLARIA I ACTRN12621000322831 |
Healthy subjects Acute and established scar | NA | NA |
| PXS-5382 | Pharmaxis | Small molecule inhibitor | LOXL2/3 | Single dose | Phase 1 NCT04183517 | Healthy subjects | No adverse effects | No Results Posted |
| PXS-5338 | Pharmaxis | Small molecule inhibitor | LOXL2/3 | Single dose | Phase 1 ACTRN12617001444370 |
Healthy subjects | No adverse effects | No Results Posted [160] |
| PAT-1251 (GB2064) | PharmAkea (Now with Galecto) | Small molecule inhibitor | LOXL2 | Oral 150–4000 mg single dose | Phase 1 NCT02852551 | NA | No adverse effects | NCT02852551 |
| PAT-1251 (GB2064) | PharmAkea (Now with Galecto) | Small molecule inhibitor | LOXL2 | Oral 150–4000 mg single dose orally as 4 × 250 mg tablets twice a day | Phase 2a MYLOX-1 NCT04679870 NCT04054245—withdrawn MD Anderson |
Myelofibrosis. | NA | NCT04679870 |