‘Bright future’ for growth factor therapy in osteoarthritis

 

LIVERPOOL, ENGLAND – With many active phase 3 trials of promising agents, the “future looks bright for growth factors and disease modification” in osteoarthritis (OA), according to David Hunter, MBBS, PhD.

Dr. Hunter, who is the Florance and Cope Chair of Rheumatology and professor of medicine at the University of Sydney and the Royal North Shore Hospital, Sydney, Australia, outlined some of the recent research with these agents in OA.

Sara Freeman/MDedge News

There has been declining mortality from all causes over the years, thanks to improvements in cardiovascular and other fields of medicine, with subsequent increasing life expectancy, Dr. Hunter pointed out. This is important if you consider that OA remains one of the most prevailing forms of joint disease, and data suggest people are developing OA at younger ages than in the past.

In 2013, a U.S. study (Arthritis Care Res. 2013;65[5]:703-11) showed that the 2007-2008 incidence of symptomatic knee OA was highest between the ages of 54 and 64 years, with the estimated median age at diagnosis of 55.8 years. Patients were substantially younger than were those who had been diagnosed at a median age of 68.5 years more than a decade earlier in 1991-1992.

“So, we’re developing [OA] at a much earlier age, but we’re obviously living longer and living with that morbidity for a substantial period of time,” Dr. Hunter said at the World Congress on Osteoarthritis, sponsored by the Osteoarthritis Research Society International.

“It’s within that context that we really need to think about both the individual and societal burden of osteoarthritis, and why we’re developing agents such as growth factors to help retard symptoms related to disease,” continued Dr. Hunter, chair of the Institute of Bone and Joint Research, deputy dean of the Northern Clinical School, and consultant rheumatologist at North Sydney Orthopaedic and Sports Medicine Centre, Sydney.

OA is characterized by articular cartilage damage, low-grade synovial inflammation, and hypertrophic bone changes that lead to pain and functional deterioration (Expert Opin Emerg Drugs. 2015;20[3]:361-78). Attempts to modify the disease process have thus focused on these three areas, aiming to regulate cartilage catabolism and anabolism, control inflammation, and remodel subchondral bone (Rheumatology [Oxford]. 2018;57[suppl. 4]:iv108-iv123).

 

Growth factors fall under the category of regulating cartilage catabolism and anabolism, playing a “significant role in musculoskeletal tissues’ homeostasis and repair,” Dr. Hunter explained. “They influence chemotaxis, differentiation, proliferation, and synthetic activity of cartilage and bone cells, and can regulate physiological remodeling and cartilage healing.”

Examples of growth factors of interest in OA include transforming growth factor-beta superfamily and bone morphogenic proteins 2 and 7, fibroblast growth factors 2 and 18, and insulin-like growth factor-1.

Two currently unproven and somewhat controversial ways of regulating cartilage catabolism and anabolism is the use of mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP). Neither are ready for widespread use, Dr. Hunter observed, and more data on these approaches still need to be gathered.

The rationale behind the use of MSCs is that all joint tissues contain these cells, and they can potentially differentiate into cartilage, bone, or other tissues. There are changes in the quantity, phenotype, and differentiation potential of these cells in patients with OA, however, leading researchers to see if intra-articular injection of MSCs could be a possible therapeutic strategy. MSCs can be isolated from a number of different tissues and differentiate into multiple cells types. Animal model data suggest that their transplantation into an affected joint can stimulate articular repair.

 

“From a clinical perspective, there have been a vast array of clinical trials looking at different types of MSCs and different types of administration,” Dr. Hunter noted. Pooled data suggest that stem cell therapy does help to improve pain and function. However, the quality of trials has been called into question, with a positive publication bias suggested. There’s no clear evidence of any structural benefits, Dr. Hunter stated. “There’s a lot of stem cells being used for clinical purposes without the evidence to support their efficacy,” he cautioned. “We need much better regulation.”

There are several PRP agents, which deliver growth factors, cytokines, adhesive proteins, and other plasma proteins, such as clotting factors. It’s unknown how PRP therapy works in OA, whether it is just pain relieving or could affect the progression of joint damage. So far, studies have been done only in knee OA, so data in other joints need to be obtained.

“Whilst they have great potential, the literature on the use of PRP is conflicting,” Dr. Hunter said. “There are a lot of positive trials out there, but their quality in general is quite low.”

Better data are perhaps available for the recombinant human fibroblast growth factor–18 sprifermin, with recent 3-year data from an ongoing 5-year randomized, placebo-controlled, phase 2 study showing increased total cartilage thickness in the tibiofemoral joint relative to placebo. “There does appear to be a structure benefit,” Dr. Hunter said of sprifermin’s effects in the study versus intra-articular saline.

 

Although improvement in total Western Ontario and McMaster Universities Osteoarthritis Index scores were seen in the patients with knee OA, there was no real differentiation by dose or by placebo. The rationale for having a longer trial follow-up – the last dose of sprifermin was given at 18 months – is to see if there is a later effect.

In the later stages of development is Invossa TissueGene-C; this is drug that consists of patients’ normal and genetically-modified chondrocyte cells that express transforming growth factor-beta 1. Phase 2 findings have shown that it can improve pain and function scores in patients with moderate to advanced knee OA (BMC Musculoskelet Disord. 2017;18[1]:461). Based on those findings, two phase 3 trials are currently underway, with some further findings presented elsewhere at the OARSI meeting.

Even though there is still no disease-modifying osteoarthritis drug currently licensed for use, “I’m really positive about all of what we’ve learned, particularly with the application to future trials and ongoing trials in this space,” Dr. Hunter observed.

“Future strategies should differentiate between those agents aiming to reduce pain, and those targeting structural evolution, incorporating a combination of anabolic and anti-catabolic therapies,” Dr. Hunter suggested. One of the challenges, however, is to address the placebo effect, which can be exaggerated by the context of administration or surgery.

 

Furthermore, he proposed that new treatments should “fit into the natural progression of OA” by focusing on early disease where changes might still be reversible. “We’re getting more nuanced about where to intervene,” Dr. Hunter said.

Emerging treatments should also take the location of the disease and its heterogenic nature into account.

Dr. Hunter has consulted for Zynerba, TLC, Kolon TissueGene, and Merck Serono, and he disclosed receiving royalties from DJO for a patellofemoral brace patent.

SOURCE: Lohmander S et al. Osteoarthritis Cartilage. 2018:26(1):S6. Abstract I-18

 

LIVERPOOL, ENGLAND – With many active phase 3 trials of promising agents, the “future looks bright for growth factors and disease modification” in osteoarthritis (OA), according to David Hunter, MBBS, PhD.

Dr. Hunter, who is the Florance and Cope Chair of Rheumatology and professor of medicine at the University of Sydney and the Royal North Shore Hospital, Sydney, Australia, outlined some of the recent research with these agents in OA.

Sara Freeman/MDedge News

There has been declining mortality from all causes over the years, thanks to improvements in cardiovascular and other fields of medicine, with subsequent increasing life expectancy, Dr. Hunter pointed out. This is important if you consider that OA remains one of the most prevailing forms of joint disease, and data suggest people are developing OA at younger ages than in the past.

In 2013, a U.S. study (Arthritis Care Res. 2013;65[5]:703-11) showed that the 2007-2008 incidence of symptomatic knee OA was highest between the ages of 54 and 64 years, with the estimated median age at diagnosis of 55.8 years. Patients were substantially younger than were those who had been diagnosed at a median age of 68.5 years more than a decade earlier in 1991-1992.

“So, we’re developing [OA] at a much earlier age, but we’re obviously living longer and living with that morbidity for a substantial period of time,” Dr. Hunter said at the World Congress on Osteoarthritis, sponsored by the Osteoarthritis Research Society International.

“It’s within that context that we really need to think about both the individual and societal burden of osteoarthritis, and why we’re developing agents such as growth factors to help retard symptoms related to disease,” continued Dr. Hunter, chair of the Institute of Bone and Joint Research, deputy dean of the Northern Clinical School, and consultant rheumatologist at North Sydney Orthopaedic and Sports Medicine Centre, Sydney.

OA is characterized by articular cartilage damage, low-grade synovial inflammation, and hypertrophic bone changes that lead to pain and functional deterioration (Expert Opin Emerg Drugs. 2015;20[3]:361-78). Attempts to modify the disease process have thus focused on these three areas, aiming to regulate cartilage catabolism and anabolism, control inflammation, and remodel subchondral bone (Rheumatology [Oxford]. 2018;57[suppl. 4]:iv108-iv123).

 

Growth factors fall under the category of regulating cartilage catabolism and anabolism, playing a “significant role in musculoskeletal tissues’ homeostasis and repair,” Dr. Hunter explained. “They influence chemotaxis, differentiation, proliferation, and synthetic activity of cartilage and bone cells, and can regulate physiological remodeling and cartilage healing.”

Examples of growth factors of interest in OA include transforming growth factor-beta superfamily and bone morphogenic proteins 2 and 7, fibroblast growth factors 2 and 18, and insulin-like growth factor-1.

Two currently unproven and somewhat controversial ways of regulating cartilage catabolism and anabolism is the use of mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP). Neither are ready for widespread use, Dr. Hunter observed, and more data on these approaches still need to be gathered.

The rationale behind the use of MSCs is that all joint tissues contain these cells, and they can potentially differentiate into cartilage, bone, or other tissues. There are changes in the quantity, phenotype, and differentiation potential of these cells in patients with OA, however, leading researchers to see if intra-articular injection of MSCs could be a possible therapeutic strategy. MSCs can be isolated from a number of different tissues and differentiate into multiple cells types. Animal model data suggest that their transplantation into an affected joint can stimulate articular repair.

 

“From a clinical perspective, there have been a vast array of clinical trials looking at different types of MSCs and different types of administration,” Dr. Hunter noted. Pooled data suggest that stem cell therapy does help to improve pain and function. However, the quality of trials has been called into question, with a positive publication bias suggested. There’s no clear evidence of any structural benefits, Dr. Hunter stated. “There’s a lot of stem cells being used for clinical purposes without the evidence to support their efficacy,” he cautioned. “We need much better regulation.”

There are several PRP agents, which deliver growth factors, cytokines, adhesive proteins, and other plasma proteins, such as clotting factors. It’s unknown how PRP therapy works in OA, whether it is just pain relieving or could affect the progression of joint damage. So far, studies have been done only in knee OA, so data in other joints need to be obtained.

“Whilst they have great potential, the literature on the use of PRP is conflicting,” Dr. Hunter said. “There are a lot of positive trials out there, but their quality in general is quite low.”

Better data are perhaps available for the recombinant human fibroblast growth factor–18 sprifermin, with recent 3-year data from an ongoing 5-year randomized, placebo-controlled, phase 2 study showing increased total cartilage thickness in the tibiofemoral joint relative to placebo. “There does appear to be a structure benefit,” Dr. Hunter said of sprifermin’s effects in the study versus intra-articular saline.

 

Although improvement in total Western Ontario and McMaster Universities Osteoarthritis Index scores were seen in the patients with knee OA, there was no real differentiation by dose or by placebo. The rationale for having a longer trial follow-up – the last dose of sprifermin was given at 18 months – is to see if there is a later effect.

In the later stages of development is Invossa TissueGene-C; this is drug that consists of patients’ normal and genetically-modified chondrocyte cells that express transforming growth factor-beta 1. Phase 2 findings have shown that it can improve pain and function scores in patients with moderate to advanced knee OA (BMC Musculoskelet Disord. 2017;18[1]:461). Based on those findings, two phase 3 trials are currently underway, with some further findings presented elsewhere at the OARSI meeting.

Even though there is still no disease-modifying osteoarthritis drug currently licensed for use, “I’m really positive about all of what we’ve learned, particularly with the application to future trials and ongoing trials in this space,” Dr. Hunter observed.

“Future strategies should differentiate between those agents aiming to reduce pain, and those targeting structural evolution, incorporating a combination of anabolic and anti-catabolic therapies,” Dr. Hunter suggested. One of the challenges, however, is to address the placebo effect, which can be exaggerated by the context of administration or surgery.

 

Furthermore, he proposed that new treatments should “fit into the natural progression of OA” by focusing on early disease where changes might still be reversible. “We’re getting more nuanced about where to intervene,” Dr. Hunter said.

Emerging treatments should also take the location of the disease and its heterogenic nature into account.

Dr. Hunter has consulted for Zynerba, TLC, Kolon TissueGene, and Merck Serono, and he disclosed receiving royalties from DJO for a patellofemoral brace patent.

SOURCE: Lohmander S et al. Osteoarthritis Cartilage. 2018:26(1):S6. Abstract I-18

 

LIVERPOOL, ENGLAND – With many active phase 3 trials of promising agents, the “future looks bright for growth factors and disease modification” in osteoarthritis (OA), according to David Hunter, MBBS, PhD.

Dr. Hunter, who is the Florance and Cope Chair of Rheumatology and professor of medicine at the University of Sydney and the Royal North Shore Hospital, Sydney, Australia, outlined some of the recent research with these agents in OA.

Sara Freeman/MDedge News

There has been declining mortality from all causes over the years, thanks to improvements in cardiovascular and other fields of medicine, with subsequent increasing life expectancy, Dr. Hunter pointed out. This is important if you consider that OA remains one of the most prevailing forms of joint disease, and data suggest people are developing OA at younger ages than in the past.

In 2013, a U.S. study (Arthritis Care Res. 2013;65[5]:703-11) showed that the 2007-2008 incidence of symptomatic knee OA was highest between the ages of 54 and 64 years, with the estimated median age at diagnosis of 55.8 years. Patients were substantially younger than were those who had been diagnosed at a median age of 68.5 years more than a decade earlier in 1991-1992.

“So, we’re developing [OA] at a much earlier age, but we’re obviously living longer and living with that morbidity for a substantial period of time,” Dr. Hunter said at the World Congress on Osteoarthritis, sponsored by the Osteoarthritis Research Society International.

“It’s within that context that we really need to think about both the individual and societal burden of osteoarthritis, and why we’re developing agents such as growth factors to help retard symptoms related to disease,” continued Dr. Hunter, chair of the Institute of Bone and Joint Research, deputy dean of the Northern Clinical School, and consultant rheumatologist at North Sydney Orthopaedic and Sports Medicine Centre, Sydney.

OA is characterized by articular cartilage damage, low-grade synovial inflammation, and hypertrophic bone changes that lead to pain and functional deterioration (Expert Opin Emerg Drugs. 2015;20[3]:361-78). Attempts to modify the disease process have thus focused on these three areas, aiming to regulate cartilage catabolism and anabolism, control inflammation, and remodel subchondral bone (Rheumatology [Oxford]. 2018;57[suppl. 4]:iv108-iv123).

 

Growth factors fall under the category of regulating cartilage catabolism and anabolism, playing a “significant role in musculoskeletal tissues’ homeostasis and repair,” Dr. Hunter explained. “They influence chemotaxis, differentiation, proliferation, and synthetic activity of cartilage and bone cells, and can regulate physiological remodeling and cartilage healing.”

Examples of growth factors of interest in OA include transforming growth factor-beta superfamily and bone morphogenic proteins 2 and 7, fibroblast growth factors 2 and 18, and insulin-like growth factor-1.

Two currently unproven and somewhat controversial ways of regulating cartilage catabolism and anabolism is the use of mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP). Neither are ready for widespread use, Dr. Hunter observed, and more data on these approaches still need to be gathered.

The rationale behind the use of MSCs is that all joint tissues contain these cells, and they can potentially differentiate into cartilage, bone, or other tissues. There are changes in the quantity, phenotype, and differentiation potential of these cells in patients with OA, however, leading researchers to see if intra-articular injection of MSCs could be a possible therapeutic strategy. MSCs can be isolated from a number of different tissues and differentiate into multiple cells types. Animal model data suggest that their transplantation into an affected joint can stimulate articular repair.

 

“From a clinical perspective, there have been a vast array of clinical trials looking at different types of MSCs and different types of administration,” Dr. Hunter noted. Pooled data suggest that stem cell therapy does help to improve pain and function. However, the quality of trials has been called into question, with a positive publication bias suggested. There’s no clear evidence of any structural benefits, Dr. Hunter stated. “There’s a lot of stem cells being used for clinical purposes without the evidence to support their efficacy,” he cautioned. “We need much better regulation.”

There are several PRP agents, which deliver growth factors, cytokines, adhesive proteins, and other plasma proteins, such as clotting factors. It’s unknown how PRP therapy works in OA, whether it is just pain relieving or could affect the progression of joint damage. So far, studies have been done only in knee OA, so data in other joints need to be obtained.

“Whilst they have great potential, the literature on the use of PRP is conflicting,” Dr. Hunter said. “There are a lot of positive trials out there, but their quality in general is quite low.”

Better data are perhaps available for the recombinant human fibroblast growth factor–18 sprifermin, with recent 3-year data from an ongoing 5-year randomized, placebo-controlled, phase 2 study showing increased total cartilage thickness in the tibiofemoral joint relative to placebo. “There does appear to be a structure benefit,” Dr. Hunter said of sprifermin’s effects in the study versus intra-articular saline.

 

Although improvement in total Western Ontario and McMaster Universities Osteoarthritis Index scores were seen in the patients with knee OA, there was no real differentiation by dose or by placebo. The rationale for having a longer trial follow-up – the last dose of sprifermin was given at 18 months – is to see if there is a later effect.

In the later stages of development is Invossa TissueGene-C; this is drug that consists of patients’ normal and genetically-modified chondrocyte cells that express transforming growth factor-beta 1. Phase 2 findings have shown that it can improve pain and function scores in patients with moderate to advanced knee OA (BMC Musculoskelet Disord. 2017;18[1]:461). Based on those findings, two phase 3 trials are currently underway, with some further findings presented elsewhere at the OARSI meeting.

Even though there is still no disease-modifying osteoarthritis drug currently licensed for use, “I’m really positive about all of what we’ve learned, particularly with the application to future trials and ongoing trials in this space,” Dr. Hunter observed.

“Future strategies should differentiate between those agents aiming to reduce pain, and those targeting structural evolution, incorporating a combination of anabolic and anti-catabolic therapies,” Dr. Hunter suggested. One of the challenges, however, is to address the placebo effect, which can be exaggerated by the context of administration or surgery.

 

Furthermore, he proposed that new treatments should “fit into the natural progression of OA” by focusing on early disease where changes might still be reversible. “We’re getting more nuanced about where to intervene,” Dr. Hunter said.

Emerging treatments should also take the location of the disease and its heterogenic nature into account.

Dr. Hunter has consulted for Zynerba, TLC, Kolon TissueGene, and Merck Serono, and he disclosed receiving royalties from DJO for a patellofemoral brace patent.

SOURCE: Lohmander S et al. Osteoarthritis Cartilage. 2018:26(1):S6. Abstract I-18