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TORONTO – Philip G. Conaghan, MBBS, PhD, observed at the OARSI 2019 World Congress.
“Not only have things not improved during my time in osteoarthritis-land, they’ve gotten worse. We’ve lost therapies,” said Dr. Conaghan, professor of musculoskeletal medicine at the University of Leeds (England) and director of the Leeds Institute of Rheumatic and Musculoskeletal Medicine.
Specifically, opioids are now shunned because of the ongoing epidemic of addiction and a belated recognition that opioids are not a good option for pain relief in OA patients who want to have active lives. And acetaminophen has fallen by the wayside in light of recent evidence of lack of effectiveness: “It’s what our patients have been telling us for a long period of time,” he noted at the meeting sponsored by the Osteoarthritis Research Society International.
But change is in the air.
“I think we’ve got some things coming that look promising. What do I think will be the fastest to get to market? The peripheral nerve modulators look to me like the ones closest to going forward,” according to the rheumatologist, who provided an overview of the OA drug development pipeline, organized by treatment target.
Nerves
“Nerves as a treatment target in OA is a hot area. We’ve seen quite a slew of products recently looking at this. I think it’s a really fascinating area to play in: looking at how we modulate peripheral nociceptive pain,” Dr. Conaghan continued.
Tanezumab, an inhibitor of nerve growth factor, demonstrated very good pain relief and improvement in physical function in a phase 3 trial, although the occurrence of rapidly progressive OA in a subset of patients has bedeviled the drug development program. The hope is that a new subcutaneous drug delivery system coupled with careful patient pretreatment screening will mitigate the problem.
Tanezumab’s efficacy has contributed to a new understanding of the nature of pain in OA.
“I know I’m going to upset some people, but if you think central sensitization is the biggest driver of pain, I’d have to argue that the tanezumab program is the biggest single argument against that, since tanezumab is a large monoclonal antibody that doesn’t cross the blood-brain barrier and yet it has some of the best pain responses that we’ve seen,” Dr. Conaghan said.
Another peripheral nerve modulator, known for now as CNTX-4975, exhibited dose-dependent improvement in knee OA pain in the 175-patient, phase 2b TRIUMPH trial (Arthritis Rheumatol. 2019 Mar 19. doi: 10.1002/art.40894). CNTX-4975, which is delivered by intra-articular injection, is a synthetic form of capsaicin specific to pain nociceptors within the joint. Other sensory fibers remain unaffected.
Cartilage
Sprifermin, a recombinant human fibroblast growth factor 18 given by intra-articular injection, stimulates chondrocyte growth and decreases type 1 collagen expression. At year 2 in the ongoing 549-patient, 5-year, phase 2 FORWARD study, a dose-dependent increase in cartilage thickness at the tibiofemoral joint became apparent in sprifermin-treated patients, compared with those on placebo. This cartilage rebuilding effect was maintained at year 3, Dr. Conaghan said.
Bone
At the OARSI meeting, Dr. Conaghan and coinvestigators presented the results of a 6-month, open-label extension of their previously reported 6-month, placebo-controlled, phase 2 study of MIV-711, a potent selective reversible inhibitor of cathepsin K. The disease-modifying effects of MIV-711 seen in the first 6 months of the study, based on MRI-based measurements of changes in three-dimensional bone shape and cartilage thickness, were maintained in the second 6 months. Notably, MIV-711 slowed the rate of increase in bone area in the medial femur region and reduced loss of cartilage thickness relative to placebo. MIV-711 has also been shown to achieve a rapid and sustained reduction in the bone turnover biomarkers CTX-1 and -2, providing a rational mechanism to explain the drug’s observed structural benefits.
“So we’ve now got two agents – sprifermin for cartilage and MIV-711 for bone – showing that it’s possible to get some structural change, but no symptomatic benefit within the period of those trials,” the rheumatologist noted.
Wnt pathway inhibition
Samumed has launched a phase 3 clinical trials program, known as STRIDES, for lorecivivint, the company’s investigational small molecule inhibitor of the Wnt pathway. In phase 2 studies, including one led by Dr. Conaghan, intra-articular injection of lorecivivint, previously known as SMO4690, improved pain and physical function as well as medial joint space width. The drug’s potential effects on multiple tissues offers the promise of providing both symptomatic improvement and modification of the course of structural disease progression.
Inflammation
Lutikizumab, an anti–interleukin-1 alpha/beta immunoglobulin, proved to be a disappointment in a recent phase 2, placebo-controlled trial carried out in 350 patients with knee OA and synovitis. The IL-1 inhibitor had no benefit on synovitis, joint space narrowing, or cartilage thickness. Nor was it significantly better than placebo for pain reduction (Arthritis Rheumatol. 2019 Jul;71[7]:1056-69).
Anti–tumor necrosis factor agents haven’t exactly set the OA world on fire, either.
“In rheumatoid arthritis we know they’re stupendously effective, but the data from a number of trials in OA show they’re not so effective on symptoms and signs,” Dr. Conaghan said.
Colchicine and hydroxychloroquine are other anti-inflammatory agents which, while in theory might be helpful, have in actuality shown no benefit for OA symptoms in controlled clinical trials and are now considered dead ends.
On the other hand, the sustained delivery of intra-articular corticosteroids through the use of microsphere technology is advancing smartly through the developmental pipeline. Dr. Conaghan was first author of a multicenter, double-blind, phase 3 trial of FX006, a sustained-release formulation of triamcinolone acetonide, which showed that a single intra-articular injection provided at least 3 months of pain relief in knee OA patients, along with reduced systemic drug exposure, compared with standard intra-articular corticosteroids (J Bone Joint Surg Am. 2018 Apr 18;100[8]:666-77).
FX006 also performed well in another phase 3 trial, this one featuring repeated dosing on a flexible schedule based upon patient response (Rheumatol Ther. 2019 Mar;6[1]:109-24).
Reassuringly, this slow-release corticosteroid doesn’t appear to worsen glycemic control in knee OA patients with type 2 diabetes (Rheumatology [Oxford]. 2018 Dec 1;57[12]:2235-41).
“This is the start of a revolution in nanotechnology and the ability to slowly deliver a variety of drugs within the joint,” Dr. Conaghan predicted.
Although he was tasked at OARSI 2019 with providing an overview of the OA pharmacologic pipeline, he stressed that in his clinical practice, as opposed to his work as a clinical trialist, he functions more like a physical therapist.
“I actually spend my whole time in the OA clinic being a physical therapist and trying to get people strong, because that does work and it has no side effects. It’s just that nobody does it. We have a real adherence problem,” he said. “My favorite thought is this: keep people strong. If a patient can’t get out of a chair easily or can’t undo a jar, then they’ve got a problem.”
Dr. Conaghan reported receiving research funding from and serving as a consultant to many of the companies developing novel drug treatments for OA.
TORONTO – Philip G. Conaghan, MBBS, PhD, observed at the OARSI 2019 World Congress.
“Not only have things not improved during my time in osteoarthritis-land, they’ve gotten worse. We’ve lost therapies,” said Dr. Conaghan, professor of musculoskeletal medicine at the University of Leeds (England) and director of the Leeds Institute of Rheumatic and Musculoskeletal Medicine.
Specifically, opioids are now shunned because of the ongoing epidemic of addiction and a belated recognition that opioids are not a good option for pain relief in OA patients who want to have active lives. And acetaminophen has fallen by the wayside in light of recent evidence of lack of effectiveness: “It’s what our patients have been telling us for a long period of time,” he noted at the meeting sponsored by the Osteoarthritis Research Society International.
But change is in the air.
“I think we’ve got some things coming that look promising. What do I think will be the fastest to get to market? The peripheral nerve modulators look to me like the ones closest to going forward,” according to the rheumatologist, who provided an overview of the OA drug development pipeline, organized by treatment target.
Nerves
“Nerves as a treatment target in OA is a hot area. We’ve seen quite a slew of products recently looking at this. I think it’s a really fascinating area to play in: looking at how we modulate peripheral nociceptive pain,” Dr. Conaghan continued.
Tanezumab, an inhibitor of nerve growth factor, demonstrated very good pain relief and improvement in physical function in a phase 3 trial, although the occurrence of rapidly progressive OA in a subset of patients has bedeviled the drug development program. The hope is that a new subcutaneous drug delivery system coupled with careful patient pretreatment screening will mitigate the problem.
Tanezumab’s efficacy has contributed to a new understanding of the nature of pain in OA.
“I know I’m going to upset some people, but if you think central sensitization is the biggest driver of pain, I’d have to argue that the tanezumab program is the biggest single argument against that, since tanezumab is a large monoclonal antibody that doesn’t cross the blood-brain barrier and yet it has some of the best pain responses that we’ve seen,” Dr. Conaghan said.
Another peripheral nerve modulator, known for now as CNTX-4975, exhibited dose-dependent improvement in knee OA pain in the 175-patient, phase 2b TRIUMPH trial (Arthritis Rheumatol. 2019 Mar 19. doi: 10.1002/art.40894). CNTX-4975, which is delivered by intra-articular injection, is a synthetic form of capsaicin specific to pain nociceptors within the joint. Other sensory fibers remain unaffected.
Cartilage
Sprifermin, a recombinant human fibroblast growth factor 18 given by intra-articular injection, stimulates chondrocyte growth and decreases type 1 collagen expression. At year 2 in the ongoing 549-patient, 5-year, phase 2 FORWARD study, a dose-dependent increase in cartilage thickness at the tibiofemoral joint became apparent in sprifermin-treated patients, compared with those on placebo. This cartilage rebuilding effect was maintained at year 3, Dr. Conaghan said.
Bone
At the OARSI meeting, Dr. Conaghan and coinvestigators presented the results of a 6-month, open-label extension of their previously reported 6-month, placebo-controlled, phase 2 study of MIV-711, a potent selective reversible inhibitor of cathepsin K. The disease-modifying effects of MIV-711 seen in the first 6 months of the study, based on MRI-based measurements of changes in three-dimensional bone shape and cartilage thickness, were maintained in the second 6 months. Notably, MIV-711 slowed the rate of increase in bone area in the medial femur region and reduced loss of cartilage thickness relative to placebo. MIV-711 has also been shown to achieve a rapid and sustained reduction in the bone turnover biomarkers CTX-1 and -2, providing a rational mechanism to explain the drug’s observed structural benefits.
“So we’ve now got two agents – sprifermin for cartilage and MIV-711 for bone – showing that it’s possible to get some structural change, but no symptomatic benefit within the period of those trials,” the rheumatologist noted.
Wnt pathway inhibition
Samumed has launched a phase 3 clinical trials program, known as STRIDES, for lorecivivint, the company’s investigational small molecule inhibitor of the Wnt pathway. In phase 2 studies, including one led by Dr. Conaghan, intra-articular injection of lorecivivint, previously known as SMO4690, improved pain and physical function as well as medial joint space width. The drug’s potential effects on multiple tissues offers the promise of providing both symptomatic improvement and modification of the course of structural disease progression.
Inflammation
Lutikizumab, an anti–interleukin-1 alpha/beta immunoglobulin, proved to be a disappointment in a recent phase 2, placebo-controlled trial carried out in 350 patients with knee OA and synovitis. The IL-1 inhibitor had no benefit on synovitis, joint space narrowing, or cartilage thickness. Nor was it significantly better than placebo for pain reduction (Arthritis Rheumatol. 2019 Jul;71[7]:1056-69).
Anti–tumor necrosis factor agents haven’t exactly set the OA world on fire, either.
“In rheumatoid arthritis we know they’re stupendously effective, but the data from a number of trials in OA show they’re not so effective on symptoms and signs,” Dr. Conaghan said.
Colchicine and hydroxychloroquine are other anti-inflammatory agents which, while in theory might be helpful, have in actuality shown no benefit for OA symptoms in controlled clinical trials and are now considered dead ends.
On the other hand, the sustained delivery of intra-articular corticosteroids through the use of microsphere technology is advancing smartly through the developmental pipeline. Dr. Conaghan was first author of a multicenter, double-blind, phase 3 trial of FX006, a sustained-release formulation of triamcinolone acetonide, which showed that a single intra-articular injection provided at least 3 months of pain relief in knee OA patients, along with reduced systemic drug exposure, compared with standard intra-articular corticosteroids (J Bone Joint Surg Am. 2018 Apr 18;100[8]:666-77).
FX006 also performed well in another phase 3 trial, this one featuring repeated dosing on a flexible schedule based upon patient response (Rheumatol Ther. 2019 Mar;6[1]:109-24).
Reassuringly, this slow-release corticosteroid doesn’t appear to worsen glycemic control in knee OA patients with type 2 diabetes (Rheumatology [Oxford]. 2018 Dec 1;57[12]:2235-41).
“This is the start of a revolution in nanotechnology and the ability to slowly deliver a variety of drugs within the joint,” Dr. Conaghan predicted.
Although he was tasked at OARSI 2019 with providing an overview of the OA pharmacologic pipeline, he stressed that in his clinical practice, as opposed to his work as a clinical trialist, he functions more like a physical therapist.
“I actually spend my whole time in the OA clinic being a physical therapist and trying to get people strong, because that does work and it has no side effects. It’s just that nobody does it. We have a real adherence problem,” he said. “My favorite thought is this: keep people strong. If a patient can’t get out of a chair easily or can’t undo a jar, then they’ve got a problem.”
Dr. Conaghan reported receiving research funding from and serving as a consultant to many of the companies developing novel drug treatments for OA.
TORONTO – Philip G. Conaghan, MBBS, PhD, observed at the OARSI 2019 World Congress.
“Not only have things not improved during my time in osteoarthritis-land, they’ve gotten worse. We’ve lost therapies,” said Dr. Conaghan, professor of musculoskeletal medicine at the University of Leeds (England) and director of the Leeds Institute of Rheumatic and Musculoskeletal Medicine.
Specifically, opioids are now shunned because of the ongoing epidemic of addiction and a belated recognition that opioids are not a good option for pain relief in OA patients who want to have active lives. And acetaminophen has fallen by the wayside in light of recent evidence of lack of effectiveness: “It’s what our patients have been telling us for a long period of time,” he noted at the meeting sponsored by the Osteoarthritis Research Society International.
But change is in the air.
“I think we’ve got some things coming that look promising. What do I think will be the fastest to get to market? The peripheral nerve modulators look to me like the ones closest to going forward,” according to the rheumatologist, who provided an overview of the OA drug development pipeline, organized by treatment target.
Nerves
“Nerves as a treatment target in OA is a hot area. We’ve seen quite a slew of products recently looking at this. I think it’s a really fascinating area to play in: looking at how we modulate peripheral nociceptive pain,” Dr. Conaghan continued.
Tanezumab, an inhibitor of nerve growth factor, demonstrated very good pain relief and improvement in physical function in a phase 3 trial, although the occurrence of rapidly progressive OA in a subset of patients has bedeviled the drug development program. The hope is that a new subcutaneous drug delivery system coupled with careful patient pretreatment screening will mitigate the problem.
Tanezumab’s efficacy has contributed to a new understanding of the nature of pain in OA.
“I know I’m going to upset some people, but if you think central sensitization is the biggest driver of pain, I’d have to argue that the tanezumab program is the biggest single argument against that, since tanezumab is a large monoclonal antibody that doesn’t cross the blood-brain barrier and yet it has some of the best pain responses that we’ve seen,” Dr. Conaghan said.
Another peripheral nerve modulator, known for now as CNTX-4975, exhibited dose-dependent improvement in knee OA pain in the 175-patient, phase 2b TRIUMPH trial (Arthritis Rheumatol. 2019 Mar 19. doi: 10.1002/art.40894). CNTX-4975, which is delivered by intra-articular injection, is a synthetic form of capsaicin specific to pain nociceptors within the joint. Other sensory fibers remain unaffected.
Cartilage
Sprifermin, a recombinant human fibroblast growth factor 18 given by intra-articular injection, stimulates chondrocyte growth and decreases type 1 collagen expression. At year 2 in the ongoing 549-patient, 5-year, phase 2 FORWARD study, a dose-dependent increase in cartilage thickness at the tibiofemoral joint became apparent in sprifermin-treated patients, compared with those on placebo. This cartilage rebuilding effect was maintained at year 3, Dr. Conaghan said.
Bone
At the OARSI meeting, Dr. Conaghan and coinvestigators presented the results of a 6-month, open-label extension of their previously reported 6-month, placebo-controlled, phase 2 study of MIV-711, a potent selective reversible inhibitor of cathepsin K. The disease-modifying effects of MIV-711 seen in the first 6 months of the study, based on MRI-based measurements of changes in three-dimensional bone shape and cartilage thickness, were maintained in the second 6 months. Notably, MIV-711 slowed the rate of increase in bone area in the medial femur region and reduced loss of cartilage thickness relative to placebo. MIV-711 has also been shown to achieve a rapid and sustained reduction in the bone turnover biomarkers CTX-1 and -2, providing a rational mechanism to explain the drug’s observed structural benefits.
“So we’ve now got two agents – sprifermin for cartilage and MIV-711 for bone – showing that it’s possible to get some structural change, but no symptomatic benefit within the period of those trials,” the rheumatologist noted.
Wnt pathway inhibition
Samumed has launched a phase 3 clinical trials program, known as STRIDES, for lorecivivint, the company’s investigational small molecule inhibitor of the Wnt pathway. In phase 2 studies, including one led by Dr. Conaghan, intra-articular injection of lorecivivint, previously known as SMO4690, improved pain and physical function as well as medial joint space width. The drug’s potential effects on multiple tissues offers the promise of providing both symptomatic improvement and modification of the course of structural disease progression.
Inflammation
Lutikizumab, an anti–interleukin-1 alpha/beta immunoglobulin, proved to be a disappointment in a recent phase 2, placebo-controlled trial carried out in 350 patients with knee OA and synovitis. The IL-1 inhibitor had no benefit on synovitis, joint space narrowing, or cartilage thickness. Nor was it significantly better than placebo for pain reduction (Arthritis Rheumatol. 2019 Jul;71[7]:1056-69).
Anti–tumor necrosis factor agents haven’t exactly set the OA world on fire, either.
“In rheumatoid arthritis we know they’re stupendously effective, but the data from a number of trials in OA show they’re not so effective on symptoms and signs,” Dr. Conaghan said.
Colchicine and hydroxychloroquine are other anti-inflammatory agents which, while in theory might be helpful, have in actuality shown no benefit for OA symptoms in controlled clinical trials and are now considered dead ends.
On the other hand, the sustained delivery of intra-articular corticosteroids through the use of microsphere technology is advancing smartly through the developmental pipeline. Dr. Conaghan was first author of a multicenter, double-blind, phase 3 trial of FX006, a sustained-release formulation of triamcinolone acetonide, which showed that a single intra-articular injection provided at least 3 months of pain relief in knee OA patients, along with reduced systemic drug exposure, compared with standard intra-articular corticosteroids (J Bone Joint Surg Am. 2018 Apr 18;100[8]:666-77).
FX006 also performed well in another phase 3 trial, this one featuring repeated dosing on a flexible schedule based upon patient response (Rheumatol Ther. 2019 Mar;6[1]:109-24).
Reassuringly, this slow-release corticosteroid doesn’t appear to worsen glycemic control in knee OA patients with type 2 diabetes (Rheumatology [Oxford]. 2018 Dec 1;57[12]:2235-41).
“This is the start of a revolution in nanotechnology and the ability to slowly deliver a variety of drugs within the joint,” Dr. Conaghan predicted.
Although he was tasked at OARSI 2019 with providing an overview of the OA pharmacologic pipeline, he stressed that in his clinical practice, as opposed to his work as a clinical trialist, he functions more like a physical therapist.
“I actually spend my whole time in the OA clinic being a physical therapist and trying to get people strong, because that does work and it has no side effects. It’s just that nobody does it. We have a real adherence problem,” he said. “My favorite thought is this: keep people strong. If a patient can’t get out of a chair easily or can’t undo a jar, then they’ve got a problem.”
Dr. Conaghan reported receiving research funding from and serving as a consultant to many of the companies developing novel drug treatments for OA.
EXPERT ANALYSIS FROM OARSI 2019