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*Only for medical professionals to read for reference.
Is the current effect of osteoarthritis not good? Come follow up the progress of international cutting-edge treatments, and discuss the latest drug efficacy for different targets! The annual Asia Pacific Rheumatism Alliance Conference (APLAR) is a grand event in the field of rheumatism and immune diseases, and is a report and research conference on the latest developments in rheumatism around the world
.
From August 28th to 31st this year, the 23rd APLAR Annual Conference has held an online conference in Kyoto, Japan
.
At the conference, Professor Philip Conaghan from the University of Leeds shared a report on the treatment progress of osteoarthritis (OA)
.
Figure 1: Professor Philip Conaghan's topic According to the different targets of drugs, Professor Philip summarized new drugs for the treatment of OA into four categories: targeting cartilage, targeting bone, targeting inflammatory factors, and targeting nerves
.
This report mainly focuses on the efficacy of new drugs and shares the latest Phase II/III clinical trial results
.
1 New drugs targeting cartilage: improving the thickness of articular cartilage and reducing pain in patients.
Fibroblast growth factor 18 (FGF18) protein plays an important role in the growth and development of bones
.
Compared with other growth factors, FGF18 not only has the effect of repairing the wound surface, but also has potential clinical value for the treatment of cartilage disorders, achondroplasia and bone repair and other skeletal diseases, with a wider range of effects [1]
.
The results of the current phase II clinical trial (FORWARD) of recombinant human fibroblast growth factor 18 (Sprifermin) show that compared with the placebo group, Sprifermin can significantly improve cartilage thickness, and 100μg injection every 6 months in the joint cavity has the best effect [1]
.
In addition, some studies have shown that Sprifermin treatment can significantly reduce the WOMAC score of patients, that is, reduce the pain of patients [2]
.
Figure 2: The main results of the FORWARD trial 2 New bone-targeted drugs: Can zoledronic acid not treat OA? Cathepsin is a type of enzyme expressed by osteoclasts, which participates in the degradation of organic matter and is closely related to the occurrence of osteoporosis
.
Among them, cathepsin K is the most important enzyme, and cathepsin K inhibitors can treat osteoporosis by inhibiting the degradation of organic matter [3]
.
At present, the cathepsin K inhibitor (MIV-711) that has completed the clinical phase IIa randomized controlled trial (RCT) has been confirmed to be more effective than the placebo group in the treatment of OA [3]
.
Zoledronic acid is widely used clinically for pain caused by osteolytic bone metastasis of malignant tumors
.
In the latest RCT trial, there was no difference in efficacy between zoledronic acid and placebo in OA patients with positive bone marrow edema-like lesions (BML)
.
Therefore, the use of zoledronic acid in the treatment of knee OA is not supported [4]
.
3 New drugs targeting inflammation: new drugs vs.
old drugs for new use, each with "magic power" triamcinolone acetonide belongs to corticosteroid drugs.
Studies have shown that repeated (2 times) injections of triamcinolone acetonide sustained-release agent (TA- ER) Treating patients with symptomatic knee OA can improve their symptoms [5]
.
Similarly, the traditional drug methotrexate also showed good results in the RCT test (PROMOTE test) of patients with knee OA, and the overall knee pain in the methotrexate group was significantly reduced [6]
.
The RCT test of colchicine for knee OA patients (COLKOA) showed that colchicine did not significantly reduce the pain of patients [7]
.
However, whether colchicine affects the expression of high-sensitivity C-reactive protein (hsCRP) and some inflammatory factors in the body still needs to be further studied, and there may be surprising results
.
Interleukin-1 (IL-1) plays an important role in the occurrence of inflammation
.
However, the results of the Phase II trial (ILLYSTRATE-K trial) of anti-IL-1α/β dual variable domain immunoglobulin (lutikizumab) showed that inhibiting IL-1 is not an effective analgesic/anti-inflammatory treatment option for most OA patients [8 ]
.
However, the results of another clinical trial for cardiovascular events (CANTOS) found that [9], the use of 150 mg of Kanazumab (IL-1β monoclonal antibody) every 3 months, compared with placebo The recurrence rate of vascular events is significantly reduced, that is, the progression of inflammation leading to atherosclerotic thrombosis is inhibited
.
The Wnt signaling pathway plays an important role in the occurrence and development of OA, and it is involved in bone remodeling, osteosclerosis, synovitis, joint capsule injury, cartilage degeneration, chondrocyte hypertrophy, meniscal degeneration, etc.
[10]
.
Figure 3: The important role of Wnt signaling pathway in the occurrence and development of OA Lorecivivint is a small molecule inhibitor that targets the Wnt signaling pathway
.
The results of the Phase IIa clinical trial of Lorecivivint showed that compared with placebo, Lorecivivint has not yet suggested the effect of improving cartilage thickness, but it can reduce pain in patients with OA [11]
.
4 New drugs targeting nerves: popular new drugs, whose efficacy remains to be seen.
There are a variety of neurotransmitters that cause OA peripheral neuralgia
.
Currently, the hottest researches are nerve growth factor (NGF), nerve growth factor receptor (TrkA) and capsaicin receptor (TRPV1) [12]
.
Figure 4: Phase IIb/III clinical trials of the neurotransmitter NGF antibody (fasinumab) involved in OA peripheral neuralgia found that in patients with knee and hip joint OA, fasinumab had no obvious analgesic effect compared with the placebo group [13]
.
The phase III clinical trial of the NGF inhibitor analgesic tanezumab showed that tanezumab can effectively relieve pain in patients with knee and hip OA [14]
.
In addition, studies have also shown that tanezumab combined with non-steroidal anti-inflammatory drugs (NSAID) drugs have a more significant analgesic effect [15]
.
An RCT test confirmed that intra-articular injection of TrkA inhibitors can significantly reduce the WOMAC score of patients with OA [16]
.
Professor Philip also pointed out at the end that the development of new drugs does make OA patients and doctors hopeful for the future
.
Experts comment that OA is a complex heterogeneous disease, which is related to many factors such as age, heredity, machinery, inflammation, and metabolism
.
The purpose of OA treatment is to relieve pain, reduce inflammation, delay progression, improve function, and correct deformity
.
At present, there is still a lack of effective therapeutic drugs for OA, and prevention and treatment are challenging
.
Accurate targeted therapy based on bone and joint classification and classification, and biomarkers is a research hotspot
.
This content mainly focuses on targeted therapy for OA cartilage, bone, inflammatory factors and nerves
.
Clinical trials have shown that recombinant human fibroblast growth factor 18 (Sprifermin) has the effect of improving the thickness of articular cartilage and reducing pain in patients; the small molecule inhibitor of Wnt signaling pathway (Lorecivivint) has no effect on improving cartilage thickness, but can reduce OA Patient pain; a variety of neurotransmitter targeted drugs for OA pain sensitization can significantly relieve pain
.
The clinical efficacy of a variety of new drugs represented by this needs to be further confirmed, but it is worth looking forward to
.
Expert profile Chen Yingjuan, Deputy Chief Physician, Deputy Chief Physician, Department of Rheumatology and Immunology, Beijing Hospital, Deputy Chief Physician, Chinese Medical Doctor Association, Deputy Chairman, Rheumatology and Immunology Committee, Cross-Strait Medical Exchange Association, Member of Rheumatology and Immunology Expert Committee, Beijing Medical Association Reference: [1] Eckstein F.
et al.
Ann Rheum Dis 2021.
[2]Guehring H et al.
Semin Arthritis Rheum 2021.
[3]Conaghan PG et al.
Ann Intern Med 2020.
[4]Cai G et al.
JAMA 2020.
[5] Spitzer A et al.
Rheumatol Ther 2019.
[6]Conaghan et al.
OARSI 2019.
[7]Leung et al.
Osteoarthritis Cartil 2018.
[8]Fleischmann et al.
Arthritis Rheumatol 2019.
[9]Ridker PM et al.
N Engl J Med 2017.
[10]Lories&Monteagudo.
Rheumatol Ther 2020.
[11]Yazici Y et al.
Arthritis Rheumatol 2020.
[12]Ji RR et al.
Nat Rev Drug Discov 2014.
[13]Dakin P et al.
Arthritis Rheumatol 2019.
[14]Schnitzer T et al.
JAMA 2019.
[15]Hochberg MC et al.
Arthritis Rheum 2016.
[16]Krupka E et al.
Osteoarthrits Cartilage 2019.
Is the current effect of osteoarthritis not good? Come follow up the progress of international cutting-edge treatments, and discuss the latest drug efficacy for different targets! The annual Asia Pacific Rheumatism Alliance Conference (APLAR) is a grand event in the field of rheumatism and immune diseases, and is a report and research conference on the latest developments in rheumatism around the world
.
From August 28th to 31st this year, the 23rd APLAR Annual Conference has held an online conference in Kyoto, Japan
.
At the conference, Professor Philip Conaghan from the University of Leeds shared a report on the treatment progress of osteoarthritis (OA)
.
Figure 1: Professor Philip Conaghan's topic According to the different targets of drugs, Professor Philip summarized new drugs for the treatment of OA into four categories: targeting cartilage, targeting bone, targeting inflammatory factors, and targeting nerves
.
This report mainly focuses on the efficacy of new drugs and shares the latest Phase II/III clinical trial results
.
1 New drugs targeting cartilage: improving the thickness of articular cartilage and reducing pain in patients.
Fibroblast growth factor 18 (FGF18) protein plays an important role in the growth and development of bones
.
Compared with other growth factors, FGF18 not only has the effect of repairing the wound surface, but also has potential clinical value for the treatment of cartilage disorders, achondroplasia and bone repair and other skeletal diseases, with a wider range of effects [1]
.
The results of the current phase II clinical trial (FORWARD) of recombinant human fibroblast growth factor 18 (Sprifermin) show that compared with the placebo group, Sprifermin can significantly improve cartilage thickness, and 100μg injection every 6 months in the joint cavity has the best effect [1]
.
In addition, some studies have shown that Sprifermin treatment can significantly reduce the WOMAC score of patients, that is, reduce the pain of patients [2]
.
Figure 2: The main results of the FORWARD trial 2 New bone-targeted drugs: Can zoledronic acid not treat OA? Cathepsin is a type of enzyme expressed by osteoclasts, which participates in the degradation of organic matter and is closely related to the occurrence of osteoporosis
.
Among them, cathepsin K is the most important enzyme, and cathepsin K inhibitors can treat osteoporosis by inhibiting the degradation of organic matter [3]
.
At present, the cathepsin K inhibitor (MIV-711) that has completed the clinical phase IIa randomized controlled trial (RCT) has been confirmed to be more effective than the placebo group in the treatment of OA [3]
.
Zoledronic acid is widely used clinically for pain caused by osteolytic bone metastasis of malignant tumors
.
In the latest RCT trial, there was no difference in efficacy between zoledronic acid and placebo in OA patients with positive bone marrow edema-like lesions (BML)
.
Therefore, the use of zoledronic acid in the treatment of knee OA is not supported [4]
.
3 New drugs targeting inflammation: new drugs vs.
old drugs for new use, each with "magic power" triamcinolone acetonide belongs to corticosteroid drugs.
Studies have shown that repeated (2 times) injections of triamcinolone acetonide sustained-release agent (TA- ER) Treating patients with symptomatic knee OA can improve their symptoms [5]
.
Similarly, the traditional drug methotrexate also showed good results in the RCT test (PROMOTE test) of patients with knee OA, and the overall knee pain in the methotrexate group was significantly reduced [6]
.
The RCT test of colchicine for knee OA patients (COLKOA) showed that colchicine did not significantly reduce the pain of patients [7]
.
However, whether colchicine affects the expression of high-sensitivity C-reactive protein (hsCRP) and some inflammatory factors in the body still needs to be further studied, and there may be surprising results
.
Interleukin-1 (IL-1) plays an important role in the occurrence of inflammation
.
However, the results of the Phase II trial (ILLYSTRATE-K trial) of anti-IL-1α/β dual variable domain immunoglobulin (lutikizumab) showed that inhibiting IL-1 is not an effective analgesic/anti-inflammatory treatment option for most OA patients [8 ]
.
However, the results of another clinical trial for cardiovascular events (CANTOS) found that [9], the use of 150 mg of Kanazumab (IL-1β monoclonal antibody) every 3 months, compared with placebo The recurrence rate of vascular events is significantly reduced, that is, the progression of inflammation leading to atherosclerotic thrombosis is inhibited
.
The Wnt signaling pathway plays an important role in the occurrence and development of OA, and it is involved in bone remodeling, osteosclerosis, synovitis, joint capsule injury, cartilage degeneration, chondrocyte hypertrophy, meniscal degeneration, etc.
[10]
.
Figure 3: The important role of Wnt signaling pathway in the occurrence and development of OA Lorecivivint is a small molecule inhibitor that targets the Wnt signaling pathway
.
The results of the Phase IIa clinical trial of Lorecivivint showed that compared with placebo, Lorecivivint has not yet suggested the effect of improving cartilage thickness, but it can reduce pain in patients with OA [11]
.
4 New drugs targeting nerves: popular new drugs, whose efficacy remains to be seen.
There are a variety of neurotransmitters that cause OA peripheral neuralgia
.
Currently, the hottest researches are nerve growth factor (NGF), nerve growth factor receptor (TrkA) and capsaicin receptor (TRPV1) [12]
.
Figure 4: Phase IIb/III clinical trials of the neurotransmitter NGF antibody (fasinumab) involved in OA peripheral neuralgia found that in patients with knee and hip joint OA, fasinumab had no obvious analgesic effect compared with the placebo group [13]
.
The phase III clinical trial of the NGF inhibitor analgesic tanezumab showed that tanezumab can effectively relieve pain in patients with knee and hip OA [14]
.
In addition, studies have also shown that tanezumab combined with non-steroidal anti-inflammatory drugs (NSAID) drugs have a more significant analgesic effect [15]
.
An RCT test confirmed that intra-articular injection of TrkA inhibitors can significantly reduce the WOMAC score of patients with OA [16]
.
Professor Philip also pointed out at the end that the development of new drugs does make OA patients and doctors hopeful for the future
.
Experts comment that OA is a complex heterogeneous disease, which is related to many factors such as age, heredity, machinery, inflammation, and metabolism
.
The purpose of OA treatment is to relieve pain, reduce inflammation, delay progression, improve function, and correct deformity
.
At present, there is still a lack of effective therapeutic drugs for OA, and prevention and treatment are challenging
.
Accurate targeted therapy based on bone and joint classification and classification, and biomarkers is a research hotspot
.
This content mainly focuses on targeted therapy for OA cartilage, bone, inflammatory factors and nerves
.
Clinical trials have shown that recombinant human fibroblast growth factor 18 (Sprifermin) has the effect of improving the thickness of articular cartilage and reducing pain in patients; the small molecule inhibitor of Wnt signaling pathway (Lorecivivint) has no effect on improving cartilage thickness, but can reduce OA Patient pain; a variety of neurotransmitter targeted drugs for OA pain sensitization can significantly relieve pain
.
The clinical efficacy of a variety of new drugs represented by this needs to be further confirmed, but it is worth looking forward to
.
Expert profile Chen Yingjuan, Deputy Chief Physician, Deputy Chief Physician, Department of Rheumatology and Immunology, Beijing Hospital, Deputy Chief Physician, Chinese Medical Doctor Association, Deputy Chairman, Rheumatology and Immunology Committee, Cross-Strait Medical Exchange Association, Member of Rheumatology and Immunology Expert Committee, Beijing Medical Association Reference: [1] Eckstein F.
et al.
Ann Rheum Dis 2021.
[2]Guehring H et al.
Semin Arthritis Rheum 2021.
[3]Conaghan PG et al.
Ann Intern Med 2020.
[4]Cai G et al.
JAMA 2020.
[5] Spitzer A et al.
Rheumatol Ther 2019.
[6]Conaghan et al.
OARSI 2019.
[7]Leung et al.
Osteoarthritis Cartil 2018.
[8]Fleischmann et al.
Arthritis Rheumatol 2019.
[9]Ridker PM et al.
N Engl J Med 2017.
[10]Lories&Monteagudo.
Rheumatol Ther 2020.
[11]Yazici Y et al.
Arthritis Rheumatol 2020.
[12]Ji RR et al.
Nat Rev Drug Discov 2014.
[13]Dakin P et al.
Arthritis Rheumatol 2019.
[14]Schnitzer T et al.
JAMA 2019.
[15]Hochberg MC et al.
Arthritis Rheum 2016.
[16]Krupka E et al.
Osteoarthrits Cartilage 2019.
