Beyond temporary relief: New OA treatments target pain mechanisms

Philip Conaghan

Osteoarthritis is the most common type of arthritis, affecting more than 30 million people in the United States. However, short of joint replacement surgery, current treatments for OA are primarily focused on temporary palliation rather than addressing the underlying source of the pain.

“For patients with inflammatory arthritis, like rheumatoid arthritis, there are a lot of immunosuppressant agents that work well,” David Walsh, MD, PhD, director of the Arthritis Research UK Pain Centre at the University of Nottingham and an author of a recent study on OA pain targets, told Healio Rheumatology. “The bigger problem is in types of arthritis, like osteoarthritis, where we are down to symptomatic treatments.”

Substantial research has been conducted into the development of targeted OA treatments based on improved understanding of the underlying mechanisms of OA. Traditionally considered “wear and tear arthritis,” OA is now believed to be potentially linked to cartilage, bone, inflammation or sensory nerves. Emerging treatments aimed at these targets may not only relieve pain, but also address OA at the source.

“Where pain comes from is controversial,” Philip Conaghan, MD, PhD, FRACP, FRCP, chair of musculoskeletal medicine at the University of Leeds told Healio Rheumatology. “A lot of what we believe about osteoarthritis has been based on X-rays, and probably not on patient symptoms. We have developed the concept of progression based on X-rays, even though we know that the relationship between X-ray changes and patient symptoms is weak.”

Inflammation and OA

Oral NSAIDs have been a mainstay of OA pain relief, and locally injected glucocorticoids also have been found to diminish knee OA pain. However, these effects are short term, and NSAIDs have been associated with cardiovascular risk.

“Anti-inflammatory drugs aren’t cures, but can be helpful,” Walsh said. “There are problems with all drugs, everything is a balance of advantages and disadvantages.”

Conaghan discussed a newer form of anti-inflammatory drug that has shown promise, Flexion Therapeutics’ Zilretta (triamcinolone acetonide extended-release injectable suspension) recently gained FDA approval for knee OA.

“This is a long-acting intra-articular steroid,” Conaghan said. “The Flexion product shows good benefits for pain because we already knew steroids worked. It’s just now, we have something that works longer.”

Conaghan said that thus far, studies on other approaches to target inflammation have not been as promising.

“We’ve seen anti-[tumor necrosis factor] TNF trials which have not shown any effect on symptoms,” he said. “Recently, an anti-interleukin 1 and dual variable domain immunoglobin (ABT-981, AbbVie) was not successful in demonstrating a dose-related reduction in OA knee pain. Last year, we reported a large, hand OA trial using hydroxychloroquine, which is a disease-modifying drug for rheumatoid arthritis that has been used for OA anecdotally. It was a negative trial. It did not help.”

Conaghan said he is not necessarily convinced that inflammation is the only driver of OA pain, despite the success of some anti-inflammatories in relieving pain.

“The belief that inflammation is important comes from the fact that two of our longer-standing effective therapies have an effect on inflammation,” he said. “Whether that is true for all knee pain, I think, requires more investigation and improved clinical phenotypes.”

Repairing cartilage

MRI has enabled more precise viewing of the structural changes that may cause OA pain. The potential role of cartilage deterioration in OA pain has been increasingly investigated, and targeted treatments are in development. One such treatment is tissue engineering. Walsh said although tissue engineering is in the early stages of development, it has the potential to help some patients avoid joint replacement surgery.

“There is ongoing research to try and optimize the way cells are selected and grown, and develop the scaffold that guides the cells to the damaged area,” Walsh said. “As that research is being developed, there will need to be clinical trials to show this actually improves pain.”

He said the promise of tissue engineering as a potential substitute for joint replacement has taken longer to come to fruition than originally expected.

“I think it’s proven more difficult than people were expecting 7 years ago, but things that are difficult are still possible,” he said. “There are a lot of people working on this around the world, so it’s still an area to be watching.”

Conaghan discussed a product being developed by TissueGene, called Invossa, which is designed for use in patients with degenerative knee arthritis.

“TissueGene has a product that uses transduced allogeneic human chondrocytes expressing TGF-beta, which is a cytokine that may help regrow cartilage,” he said.

He also mentioned a product being developed by Samumed that inhibits the WnT pathway, a group of signal transduction pathways that have been associated with various degenerative diseases.

“WnT is important in cartilage breakdown, and that is why they have a WnT pathway inhibitor,” Conaghan said. “It’s a small molecule and is administered as an injectable intra-articular WnT inhibitor.”

Blocking nerve growth factor

Another novel approach to address OA pain is through medications that target peripheral nerves, according to Conaghan.

“We have seen trends in therapies in the past few years toward therapies directed at nerves, peripheral nociception, which makes sense for a condition that was always, for patients, about pain,” he said. “Now we’re seeing not only the development of nerve growth factor (NGF) antibodies, but agents targeting other parts of the peripheral nociceptive pathway, such as TRPV inhibitors, and drugs that affect the tropomyosin receptor kinase (Trk) receptors for NGF.”

NGF has been found to play a role in acute and chronic pain, and inhibiting binding to its receptor can effectively prevent its biological activities.

Currently, one monoclonal antibody, tanezumab (Pfizer and Eli Lilly) is close to completing phase 3 clinical trials and has been granted fast-track designation by the FDA. Phase 3 trials are also ongoing for fasinumab, Regeneron/Teva’s monoclonal antibody product.

Walsh said he believes NGF antibodies hold a great deal of promise for the future of OA pain treatment.

“I think the biggest thing on the horizon is the growth factor blocking treatments,” he said. “There have been potential problems, potential risks and they’re being worked out in the clinical trials at the moment. As with everything, it will be a balance between the likely benefits and the risks of it for the individual, but it does look as though it’s potentially going to be a step change in treatment.”

Bone turnover and bisphosphonates

An area of focus that is being studied as a potential target for treating OA is the subchondral bone, Walsh said.

“It’s becoming increasingly apparent that a lot of the pain from osteoarthritis comes from the bone underneath the cartilage,” he said. “In some people, bones seem to be actively turning over. There’s a lot of metabolic activity in the bones. For other people, it’s quiescent. It’s quiet.”

Viewing the area on MRI, enables clinicians to identify patients with active bone turnover. These patients may be candidates for targeted treatments.

“Some people are then using that to select patients where the bone is active, to give them specific treatments which are currently in clinical trials,” Walsh said. “That’s the strategy that has been developed with a class of drugs called bisphosphonates.”

Bisphosphonates, which have been established as an effective treatment for osteoporosis, are now being investigated for potential use in OA pain. MRI screening is used to select patients who might benefit from this treatment, Walsh said.

“These drugs are useful in osteoporosis, and there are ongoing clinical trials with selected OA patients,” Walsh said. “These trials are trying to confirm the early data, which suggests they may reduce pain in people with osteoarthritis as well, but it’s only likely to be those people who have active bone turnover.”

Conaghan said while trials on bisphosphonates have so far not demonstrated their utility for OA pain, he is encouraged by the results of a study conducted by an Australian group of researchers.

“This study was from a few years ago, and it suggested that if you selected your patients based on the presence of bone marrow lesions seen on MRI, these patients may have some benefits from bisphosphonates.”

He said a large phase 3 study is being conducted on zoledronic acid in patients with OA knee pain selected for the presence of bone marrow lesions. In addition, a study presented at the American College of Rheumatology Annual Meeting evaluated a cathepsin K inhibitor, which is another anti-osteoclastic therapy.

“This didn’t help pain in the phase 2 study, but did slow the rate of bone shape change —a predictive marker of joint replacement — over time,” he said. “It did show structure modification.”

Innovations in biomarkers

Advances in biomarkers have enabled clinicians to more precisely identify patients with particular pain mechanisms, Walsh said. This information can be valuable in optimizing the treatment approach.

“This helps to predict whether they are going to respond to a certain type of treatment,” he said. “I then select them for clinical trials or eventually, for treating them in clinical practice.”

He said often, if a patient doesn’t respond to a treatment within 2 weeks, it is unlikely that they will derive a benefit from that treatment at all.

“If it’s not got a benefit in 2 weeks, they’re probably not going to see an improvement in 2 months or 2 years, either. Looking for an early response can be a useful biomarker.”

Walsh classified biomarkers as “wet” or “dry” biomarkers, with wet biomarkers consisting of lab tests, and dry biomarkers consisting of imaging tests and other screening tests.

“We’ve been using dry biomarkers all the time,” he said. “They’re things like X-rays and scans, and lately, MRIs scans.”

MRI scans are used to provide a more detailed view of damage to cartilage and subchondral bone, Walsh said. Additionally, a study in which Walsh was an investigator found the blood biomarker TRAP5b may have promise in predicting progression of OA pain related to subchondral bone turnover.

“One of the things we’ve been looking at was whether there are blood markers and bone turnovers that might be useful in this respect,” he said. “Obviously, it would be easier if you could just do a blood test rather than have scans. We have published some promising work on that recently.”

Exercise and lifestyle

While research into various approaches to OA pain treatment is ongoing, Walsh emphasized that patients should not rely on medication alone to improve symptoms.

“Drugs are only part of this thing,” he said. “Activities and exercise are also important. One of the core treatments for osteoarthritis is exercise.”

While potential weight loss achieved by exercise can certainly provide some relief from joint pain, Walsh said it is also important just to keep arthritic joints active.

“People often have this idea that their joints are falling apart,” he said. “Maintaining your activities, continuing to do things, helps the joints to repair themselves. It helps to keep the strength and all the protective reflexes.”

In addition to exercising joints, Conaghan emphasized the importance of muscle-strengthening exercises in reducing OA pain.

“Muscle strengthening remains an effective analgesic for hand OA and knee OA,” he said. “It is underused. It doesn’t take 1 minute, it takes half an hour a day. The patient must put time aside, and that is why more people don’t do it.”

Overall, Walsh said, remaining optimistic about arthritis is important to living well with the condition, regardless of the treatment.

“It’s important to keep a positive attitude, and not be frightened of being active,” he said. “This is an essential part of any treatment package. The more you do, the more you can do.” - by Jennifer Byrne

References:

Miller RE, et al. Clin Exp Rheumatol. 2017;35 Suppl 107:85-87.

Nwosu LN, et al. Osteoarthritis and Cartilage. 2017;doi: http://dx.doi.org/10.1016/j.joca.2016.01.116

www.cdc.gov/arthritis/basics/osteoarthritis.htm

For More Information:

Philip Conaghan, MD, PhD, FRACP, FRCP, can be reached at 2nd Floor, Chapel Allerton Hospital, Chapeltown Road, Leeds, LS7,4SA, UK; p.conaghan@leeds.ac.uk. David Walsh, MD, PhD, can be reached at Room A19, Academic Rheumatology Clinical Sciences Building Nottingham City Hospital, Hucknall Rd, Nottingham, NG5 1PB; UK; email: david.walsh@nottingham.ac.uk.

Disclosures : Conaghan reports consulting relationships or speaker’s bureau affiliation with AbbVie, Flexion, Medivir, Novartis, Samumed and TissueGene. Walsh reports he receives a consultant’s fee from Pfizer.

Philip Conaghan

Osteoarthritis is the most common type of arthritis, affecting more than 30 million people in the United States. However, short of joint replacement surgery, current treatments for OA are primarily focused on temporary palliation rather than addressing the underlying source of the pain.

“For patients with inflammatory arthritis, like rheumatoid arthritis, there are a lot of immunosuppressant agents that work well,” David Walsh, MD, PhD, director of the Arthritis Research UK Pain Centre at the University of Nottingham and an author of a recent study on OA pain targets, told Healio Rheumatology. “The bigger problem is in types of arthritis, like osteoarthritis, where we are down to symptomatic treatments.”

Substantial research has been conducted into the development of targeted OA treatments based on improved understanding of the underlying mechanisms of OA. Traditionally considered “wear and tear arthritis,” OA is now believed to be potentially linked to cartilage, bone, inflammation or sensory nerves. Emerging treatments aimed at these targets may not only relieve pain, but also address OA at the source.

“Where pain comes from is controversial,” Philip Conaghan, MD, PhD, FRACP, FRCP, chair of musculoskeletal medicine at the University of Leeds told Healio Rheumatology. “A lot of what we believe about osteoarthritis has been based on X-rays, and probably not on patient symptoms. We have developed the concept of progression based on X-rays, even though we know that the relationship between X-ray changes and patient symptoms is weak.”

Inflammation and OA

Oral NSAIDs have been a mainstay of OA pain relief, and locally injected glucocorticoids also have been found to diminish knee OA pain. However, these effects are short term, and NSAIDs have been associated with cardiovascular risk.

“Anti-inflammatory drugs aren’t cures, but can be helpful,” Walsh said. “There are problems with all drugs, everything is a balance of advantages and disadvantages.”

Conaghan discussed a newer form of anti-inflammatory drug that has shown promise, Flexion Therapeutics’ Zilretta (triamcinolone acetonide extended-release injectable suspension) recently gained FDA approval for knee OA.

“This is a long-acting intra-articular steroid,” Conaghan said. “The Flexion product shows good benefits for pain because we already knew steroids worked. It’s just now, we have something that works longer.”

Conaghan said that thus far, studies on other approaches to target inflammation have not been as promising.

“We’ve seen anti-[tumor necrosis factor] TNF trials which have not shown any effect on symptoms,” he said. “Recently, an anti-interleukin 1 and dual variable domain immunoglobin (ABT-981, AbbVie) was not successful in demonstrating a dose-related reduction in OA knee pain. Last year, we reported a large, hand OA trial using hydroxychloroquine, which is a disease-modifying drug for rheumatoid arthritis that has been used for OA anecdotally. It was a negative trial. It did not help.”

PAGE BREAK

Conaghan said he is not necessarily convinced that inflammation is the only driver of OA pain, despite the success of some anti-inflammatories in relieving pain.

“The belief that inflammation is important comes from the fact that two of our longer-standing effective therapies have an effect on inflammation,” he said. “Whether that is true for all knee pain, I think, requires more investigation and improved clinical phenotypes.”

Repairing cartilage

MRI has enabled more precise viewing of the structural changes that may cause OA pain. The potential role of cartilage deterioration in OA pain has been increasingly investigated, and targeted treatments are in development. One such treatment is tissue engineering. Walsh said although tissue engineering is in the early stages of development, it has the potential to help some patients avoid joint replacement surgery.

“There is ongoing research to try and optimize the way cells are selected and grown, and develop the scaffold that guides the cells to the damaged area,” Walsh said. “As that research is being developed, there will need to be clinical trials to show this actually improves pain.”

He said the promise of tissue engineering as a potential substitute for joint replacement has taken longer to come to fruition than originally expected.

“I think it’s proven more difficult than people were expecting 7 years ago, but things that are difficult are still possible,” he said. “There are a lot of people working on this around the world, so it’s still an area to be watching.”

Conaghan discussed a product being developed by TissueGene, called Invossa, which is designed for use in patients with degenerative knee arthritis.

“TissueGene has a product that uses transduced allogeneic human chondrocytes expressing TGF-beta, which is a cytokine that may help regrow cartilage,” he said.

He also mentioned a product being developed by Samumed that inhibits the WnT pathway, a group of signal transduction pathways that have been associated with various degenerative diseases.

“WnT is important in cartilage breakdown, and that is why they have a WnT pathway inhibitor,” Conaghan said. “It’s a small molecule and is administered as an injectable intra-articular WnT inhibitor.”

Blocking nerve growth factor

Another novel approach to address OA pain is through medications that target peripheral nerves, according to Conaghan.

“We have seen trends in therapies in the past few years toward therapies directed at nerves, peripheral nociception, which makes sense for a condition that was always, for patients, about pain,” he said. “Now we’re seeing not only the development of nerve growth factor (NGF) antibodies, but agents targeting other parts of the peripheral nociceptive pathway, such as TRPV inhibitors, and drugs that affect the tropomyosin receptor kinase (Trk) receptors for NGF.”

PAGE BREAK

NGF has been found to play a role in acute and chronic pain, and inhibiting binding to its receptor can effectively prevent its biological activities.

Currently, one monoclonal antibody, tanezumab (Pfizer and Eli Lilly) is close to completing phase 3 clinical trials and has been granted fast-track designation by the FDA. Phase 3 trials are also ongoing for fasinumab, Regeneron/Teva’s monoclonal antibody product.

Walsh said he believes NGF antibodies hold a great deal of promise for the future of OA pain treatment.

“I think the biggest thing on the horizon is the growth factor blocking treatments,” he said. “There have been potential problems, potential risks and they’re being worked out in the clinical trials at the moment. As with everything, it will be a balance between the likely benefits and the risks of it for the individual, but it does look as though it’s potentially going to be a step change in treatment.”

Bone turnover and bisphosphonates

An area of focus that is being studied as a potential target for treating OA is the subchondral bone, Walsh said.

“It’s becoming increasingly apparent that a lot of the pain from osteoarthritis comes from the bone underneath the cartilage,” he said. “In some people, bones seem to be actively turning over. There’s a lot of metabolic activity in the bones. For other people, it’s quiescent. It’s quiet.”

Viewing the area on MRI, enables clinicians to identify patients with active bone turnover. These patients may be candidates for targeted treatments.

“Some people are then using that to select patients where the bone is active, to give them specific treatments which are currently in clinical trials,” Walsh said. “That’s the strategy that has been developed with a class of drugs called bisphosphonates.”

Bisphosphonates, which have been established as an effective treatment for osteoporosis, are now being investigated for potential use in OA pain. MRI screening is used to select patients who might benefit from this treatment, Walsh said.

“These drugs are useful in osteoporosis, and there are ongoing clinical trials with selected OA patients,” Walsh said. “These trials are trying to confirm the early data, which suggests they may reduce pain in people with osteoarthritis as well, but it’s only likely to be those people who have active bone turnover.”

Conaghan said while trials on bisphosphonates have so far not demonstrated their utility for OA pain, he is encouraged by the results of a study conducted by an Australian group of researchers.

PAGE BREAK

“This study was from a few years ago, and it suggested that if you selected your patients based on the presence of bone marrow lesions seen on MRI, these patients may have some benefits from bisphosphonates.”

He said a large phase 3 study is being conducted on zoledronic acid in patients with OA knee pain selected for the presence of bone marrow lesions. In addition, a study presented at the American College of Rheumatology Annual Meeting evaluated a cathepsin K inhibitor, which is another anti-osteoclastic therapy.

“This didn’t help pain in the phase 2 study, but did slow the rate of bone shape change —a predictive marker of joint replacement — over time,” he said. “It did show structure modification.”

Innovations in biomarkers

Advances in biomarkers have enabled clinicians to more precisely identify patients with particular pain mechanisms, Walsh said. This information can be valuable in optimizing the treatment approach.

“This helps to predict whether they are going to respond to a certain type of treatment,” he said. “I then select them for clinical trials or eventually, for treating them in clinical practice.”

He said often, if a patient doesn’t respond to a treatment within 2 weeks, it is unlikely that they will derive a benefit from that treatment at all.

“If it’s not got a benefit in 2 weeks, they’re probably not going to see an improvement in 2 months or 2 years, either. Looking for an early response can be a useful biomarker.”

Walsh classified biomarkers as “wet” or “dry” biomarkers, with wet biomarkers consisting of lab tests, and dry biomarkers consisting of imaging tests and other screening tests.

“We’ve been using dry biomarkers all the time,” he said. “They’re things like X-rays and scans, and lately, MRIs scans.”

MRI scans are used to provide a more detailed view of damage to cartilage and subchondral bone, Walsh said. Additionally, a study in which Walsh was an investigator found the blood biomarker TRAP5b may have promise in predicting progression of OA pain related to subchondral bone turnover.

“One of the things we’ve been looking at was whether there are blood markers and bone turnovers that might be useful in this respect,” he said. “Obviously, it would be easier if you could just do a blood test rather than have scans. We have published some promising work on that recently.”

Exercise and lifestyle

PAGE BREAK

While research into various approaches to OA pain treatment is ongoing, Walsh emphasized that patients should not rely on medication alone to improve symptoms.

“Drugs are only part of this thing,” he said. “Activities and exercise are also important. One of the core treatments for osteoarthritis is exercise.”

While potential weight loss achieved by exercise can certainly provide some relief from joint pain, Walsh said it is also important just to keep arthritic joints active.

“People often have this idea that their joints are falling apart,” he said. “Maintaining your activities, continuing to do things, helps the joints to repair themselves. It helps to keep the strength and all the protective reflexes.”

In addition to exercising joints, Conaghan emphasized the importance of muscle-strengthening exercises in reducing OA pain.

“Muscle strengthening remains an effective analgesic for hand OA and knee OA,” he said. “It is underused. It doesn’t take 1 minute, it takes half an hour a day. The patient must put time aside, and that is why more people don’t do it.”

Overall, Walsh said, remaining optimistic about arthritis is important to living well with the condition, regardless of the treatment.

“It’s important to keep a positive attitude, and not be frightened of being active,” he said. “This is an essential part of any treatment package. The more you do, the more you can do.” - by Jennifer Byrne

References:

Miller RE, et al. Clin Exp Rheumatol. 2017;35 Suppl 107:85-87.

Nwosu LN, et al. Osteoarthritis and Cartilage. 2017;doi: http://dx.doi.org/10.1016/j.joca.2016.01.116

www.cdc.gov/arthritis/basics/osteoarthritis.htm

For More Information:

Philip Conaghan, MD, PhD, FRACP, FRCP, can be reached at 2nd Floor, Chapel Allerton Hospital, Chapeltown Road, Leeds, LS7,4SA, UK; p.conaghan@leeds.ac.uk. David Walsh, MD, PhD, can be reached at Room A19, Academic Rheumatology Clinical Sciences Building Nottingham City Hospital, Hucknall Rd, Nottingham, NG5 1PB; UK; email: david.walsh@nottingham.ac.uk.

Disclosures : Conaghan reports consulting relationships or speaker’s bureau affiliation with AbbVie, Flexion, Medivir, Novartis, Samumed and TissueGene. Walsh reports he receives a consultant’s fee from Pfizer.