With an aging population and rising obesity rates, “we can expect the prevalence of osteoarthritis will only increase,” said Anne-Marie Malfait, MD, PhD, George W. Stuppy Chair of Arthritis at Rush University Medical Center, Chicago. OA involves failure of joint cartilage, bone and synovial tissue, “but for the patient, what is important is loss of function of the joint and also, very importantly, pain.”1
Several disease-modifying anti-osteoarthritis drugs (DMOADs) are in development. DMOADs inhibit structural progression and, hopefully, improve pain and function.
‘Another challenge is that the mean time of this disease is about 20 years. We tend to focus on the past two years.’ —David Hunter, MBBS, PhD
“Articular cartilage is critical for normal joint function, because it ensures smooth articulation through lubrication and low friction,” said Dr. Malfait. Cartilage is made of chondrocytes, which are embedded in the extracellular matrix (ECM), whose two main molecules are type II collagen and aggrecan. “Cartilage matrix degradation is the key event in the onset and progression of osteoarthritis. To go from healthy to severely devastated cartilage involves the action of enzymes that orchestrate the proteolytic cleavage of these major matrix molecules.” Type II collagen is degraded by matrix metalloproteinases (MMPs). Aggrecan is degraded by ADAMTS-4 and ADAMTS-5.2
“There is a lot of in vitro evidence that, in cartilage explants, blocking these enzymes inhibits aggrecan degradation and also, collagen degradation,” she said. Aggrecan protects cartilage collagen from cleavage.3
Two DMOADs in development target this pathway: ADAMTS-5-inhibiting bifunctional nanobody M6495 binds to ADAMTS-5 but not the other ADAMTS enzymes, and inhibits aggrecan turnover in cartilage. “When this nanobody is administered in a mouse model of osteoarthritis, it can prevent the onset of joint damage,” she said.4 Small compound ADAMTS-5 inhibitor GLPG1972 had a protective effect on cartilage in two animal models in prophylactic settings. It was well tolerated and safe in early studies, and prevented the release of aggrecan fragments into the plasma.5
MIV-711, a selective cathepsin K-inhibitor, is in Phase 2 clinical trials. Cathepsin K is a lysosomal cysteine protease expressed in osteoclasts and chondrocytes. It cleaves both type II collagen and aggrecans. “Cathepsin K is clearly upregulated in joints in early osteoarthritis,” she said. MIV-711 showed structure-protective effects in two animal studies, and in a Phase II trial of 244 patients with knee OA and pain, showed no symptomatic benefits, “but significant reductions in MRI-determined bone area progression and cartilage disease progression, but only in the femur.”6,7
Intra-articular, localized DMOADs include UBX0101, a senolytic agent targeting the age-related senescence response in cartilage. It selectively inhibits the MDM2/p53 protein reaction, which triggers the elimination of senescent cells. UBX0101 slowed OA progression in aging mice.8
Another intra-articular DMOAD, SM04690, is a Wnt-β catenin inhibitor in Phase 3 clinical trials. “The Wnt signaling pathway has been shown to be essential in the homeostasis of cartilage and bone,” said Dr. Malfait. “On a molecular level, there’s a fine-tuned balance of Wnt signaling that maintains the homeostasis of osteoblasts and chondrocytes.” SM04690 interferes with this signaling pathway, and showed statistically significant improvements from baseline in both pain and function in a Phase 2b study of patients with knee OA, and is well tolerated and safe.9
OA Pain Relief
In OA, “modifying disease is not enough. Our patients complain of pain. They don’t complain of their X-rays,” said David Walsh, MD, director, Arthritis Research UK Pain Centre at the University of Nottingham. “There is a clinical conundrum with pain relief in arthritis. Do we want to treat the pain? Will we cause problems if we just mask pain?” Normal activity, or even running, does not worsen OA or pain.10
Potential therapeutic targets in OA include structural abnormalities: bone marrow lesions (BMLs), synovitis and cartilage damage, said Dr. Walsh. Zoledronic acid reduced knee pain and BMLs in OA patients in six months in one study, but at two years, patients showed no significant improvement.11
“It’s not to say that BMLs aren’t a realistic target for treating pain, but the link may not be structural,” he said. Subchondral bone may reveal clues. “There is increased bone turnover, increased osteoclast activity and a reduction in PH, which we know sensitizes peripheral nerves.”
Osteoclasts play a strong role in OA pain. “If you take matched cases of people with the same severity of chondropathy, and take a group with severe pain who have had joint replacements and group who haven’t had surgery, the number and density of osteoclasts in subchondral bone is higher in the group with pain.” Treatment with osteoprotegrin, which targets osteoclasts, quickly reduced OA pain in one rat study.12 “I’d argue this analgesic effect is because it is suppressing the metabolic activity of osteoclasts, which are drivers of sensitization in subchondral bone,” he said. Bisphosphonates are in OA clinical trials because of their effects on remodeling subchondral bone.13
OA pain is due to sensitization of peripheral nerves, said Dr. Walsh. “We don’t want to abolish pain. We don’t want to lose the reflex that, when you put your hand to a hot plate, it hurts. We need that normal nociceptive response. But what we don’t need is constant sensitization.” Nerve growth factor (NGF), a neurotrophin that plays a role in both nociception and inflammation, is the most exciting target in OA, he said. Two monoclonal antibodies to NGF are in development: tanezumab and fasinumab.
NGF is involved in several key pain mechanisms: It phosphorylates TRPV-1, alters gene expression in the sensory nerves and facilitates transmission of the central synapse. NGF is associated with synovitis pain in knee OA and in the subchondral bone.14
Tanezumab relieved pain in both knee OA and chronic low back pain, “and this is most impressive, because nothing works in low back pain,” said Dr. Walsh.15,16 The Food and Drug Administration (FDA) stopped these trials because some patients’ joint damage accelerated. “I think you should put this into context: It matters if people on these treatments are more likely to have total joint replacements.” Trials were restarted with patients on tanezumab monotherapy, not combined therapy with NSAIDs. Combination therapy did not show any additional analgesic benefit in new comparative trials.17
FGF & Gene Therapy
Two other emerging therapies in Phase III include fibroblast growth factor (FGF-18)/sprifermin (AS902330), an intra-articular injection, and tissuegene-C (TG-C), a gene therapy for cartilage regeneration, said David Hunter, MBBS, PhD, professor of medicine, University of Sydney, Australia.
Sprifermin induces chondrocyte proliferation, improves phenotypic changes in chondrocytes, and increases production in the extracellular matrix, and is well tolerated.18 In a five-year trial, total femorotibial joint thickness scores for patients in treatment arms were better than placebo at three years, but “there are no clear indications of a symptomatic effect,” he said. At five years, “it’s hoped there will be symptomatic improvement following that structural effect.”19
In TG-C, chondrocyte cells are harvested from a single donor, genetically modified to produce TGFβ-1, and administered to OA patients via intra-articular injection. In Phase 2 trials, TG-C improved pain scores compared to placebo at 18 months, and “most of the adverse events are mild, and related to local site reaction and self-limited,” he said.20 Another trial suggested TG-C improved structural progression, but not meaningfully.21
Why have so many OA clinical trials failed? “One of the great challenges has been translating preclinical animal models to the human models,” said Dr. Hunter. Structural progression may not tell us how well therapies work in humans, and the placebo effect in OA also makes gauging agents’ therapeutic effects very challenging.22 Pre-trial screening to exclude patients likely to have a high placebo response may help improve future studies, he said.
“Another challenge is that the mean time of this disease is about 20 years. We tend to focus on the past two years,” or end-stage OA, said Dr. Hunter. “Our ability to meaningfully intervene would probably be a lot better if we intervened much earlier, before marked structural changes and mechanical destruction occur.” Emerging therapies should focus on multiple molecular pathways in OA, including those associated with inflammation, such as synovitis and BMLs, he concluded.
Susan Bernstein is a freelance medical journalist based in Atlanta.
- Loeser RF, Goldring SR, Scanzello CR, et al. Osteoarthritis: A disease of the joint as an organ. Arthritis Rheum. 2012 Jun;64(6):1697–1707.
- Tortorella MD, Burn TC, Pratta MA, et al. Purification and cloning of aggrecanase-1: A member of the ADAMTS family of proteins. Science. 1999 Jun 4;284(5420):1664–1666.
- Pratta MA, Yao W, Decicco C, et al. Aggrecan protects cartilage collagen from proteolytic cleavage. J Biol Chem. 2003 Nov 14;278(46):45539–45545.
- Werkmann D, Buyse MA, Dejager L, et al. In vitro characterization of the ADAMTS-5 specific nanobody M6495. Osteoarthritis Cartilage. 2018 Apr;26(Suppl 1):S178.
- Van der Aar EM, Desrivot J, Fagard L, et al. ADAMTS-5 inhibitor GLPG1972, a potential new treatment in osteoarthritis, shows favorable safety, pharmacokinetics and pharmacodynamics in healthy subjects. Osteoarthritis Cartilage. 2018 Apr;26(1):S310.
- Lindström E, Rizoska B, Tunblad K, et al. The selective cathepsin K inhibitor MIV-711 attenuates joint pathology in experimental animal models of osteoarthritis. J Transl Med. 2018 Mar 9;16(1):56.
- Conaghan PG, Bowes MA, Kingsbury SR, et al. Six months’ treatment with MIV-711, a novel Cathepsin K inhibitor, induces osteoarthritis structure modification: results from a randomized, double-blind, placebo-controlled Phase IIA trial. Osteoarthritis Cartilage. 2018 Apr;26(1):S25–S26.
- Jeon OH, Kim C, Laberge RM, et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med. 2017 Jun;23(6):775–781.
- Yazici Y, McAlindon TE, Gibofsky A, et al. Results from a 52-week, randomized, double-blind, placebo-controlled, phase 2 study of a novel, intra-articular Wnt pathway inhibitor (SM04690) for the treatment of knee osteoarthritis. Osteoarthritis Cartilage. 2018 Apr;26(1):S293–S294.
- Timmins KA, Leech RD, Batt ME, et al. Running and knee osteoarthritis: A systematic review and meta-analysis. Am J Sports Med. 2017 May;45(6):1447–1457.
- Laslett LL, Dore DA, Quinn SJ, et al. Zoledronic acid reduces knee pain and bone marrow lesions over 1 year: A randomised controlled trial. Ann Rheum Dis. 2012 Aug;71(8):1322–1328.
- Sagar DR, Ashraf F, Xu L, et al. Osteoprotegerin reduces the development of pain behaviour and joint pathology in a model of osteoarthritis. Ann Rheum Dis. 2014 Aug;73(8):1558–1565.
- Xing RL, Zhao LR, Wang PM. Bisphosphonates therapy for osteoarthritis: A meta-analysis of randomized controlled trials. Springerplus. 2016 Oct 3;5(1):1704.
- Stoppiello LA, Mapp PI, Wilson D, et al. Structural associations of symptomatic knee osteoarthritis. Arthritis Rheumatol. 2014 Nov;66(11):3018–3027.
- Lane NE, Schnitzer TJ, Birbara CA, et al. Tanezumab for the treatment of pain from osteoarthritis of the knee. New Engl J Med. 2010 Oct 14;363(16):1521–1531.
- Webb MP, Helander EM, Menard BL, et al. Tanezumab: a selective humanized mAb for chronic lower back pain. Ther Clin Risk Manag. 2018 Feb 21;14:361–367.
- Schnitzer TJ, Ekman EF, Spierings EL, et al. Efficacy and safety of tanezumab monotherapy or combined with nonsteroidal anti-inflammatory drugs in the treatment of knee or hip osteoarthritis pain. Ann Rheum Dis. 2015 Jun;74(6):1202–1211.
- Gigout A, Guehring H, Froemel D, et al. Sprifermin (rhFGF18) enables proliferation of chondrocytes producing a hyaline cartilage matrix. Osteoarthritis Cartilage. 2017 Nov;25(11):1858–1867.
- Hochberg M, Guermazi A, Guering H, et al. Efficacy and safety of intra-articular sprifermin in symptomatic radiographic knee osteoarthritis: pre-specified analysis of 3-year data from a 5-year randomised, placebo-controlled, phase II study. Ann Rheum Dis. 2018 Jun;77(Suppl 2):80–81.
- Ha CW, Cho JJ, Elmallah RK, et al. A multi-center, single-blind, phase IIa clinical trial to evaluate the efficacy and safety of a cell-mediated gene therapy in degenerative knee arthritis patients. Hum Gene Ther Clin Dev. 2015 Jun;26(2):125–130.
- Guermazi A, Kalsi G, Niu J, et al. Structural effects of intra-articular TGFβ-1 in moderate to advanced knee osteoarthritis: MRI-based assessment in a randomized controlled trial. BMC Musculoskelet Disord. 2017;18:461.
- Zhang W, Robertson J, Jones AC, et al. The placebo effect and its determinants in osteoarthritis: Meta-analysis of randomised controlled trials. Ann Rheum Dis. 2008 Dec;67(12):1716–1723.