Emerging Treatments for OA: New Therapies Target Joint Pain, Not Just Structural Damage

CHICAGO—Are effective treatments for osteoarthritis (OA) on the horizon? In Emerging Treatments for Osteoarthritis at the 2018 ACR/ARHP Annual Meeting, experts discussed potential therapies to address OA structural progression, pain and inflammation.

Anne-Marie Malfait, MD, PhD

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

DMOADs
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