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The “Elusive DMOAD”: Aggrecanase Inhibition from Laboratory to Clinic A.-M

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The “Elusive DMOAD”: Aggrecanase Inhibition from Laboratory to Clinic A.-M The “elusive DMOAD”: Aggrecanase inhibition from laboratory to clinic A.-M. Malfait1, M.D. Tortorella2 1Rush University Medical School, ABSTRACT mechanical “wear and tear” disease (3), Department of Medicine, Division From the time of their discovery in 1999, but rather a condition in which well-de- of Rheumatology, Chicago IL, USA; the aggrecanases, and ADAMTS-5 in fined biochemically mediated pathways 2Guangzhou Institutes of Biomedical particular, have been heavily investi- bring about articular cartilage damage Health, Chinese Academy of Sciences, Guangzhou, China. gated as targets for disease-modifying (4). These changing concepts brought osteoarthritis drug (DMOAD) devel- the expectation that, one day, scientists Anne-Marie Malfait Micky D. Tortorella opment. Here, we provide a brief nar- would be able to develop inhibitors that rative review of the discovery efforts Please address correspondence to: prevent, slow down, halt, or even re- Dr Anne-Marie Malfait, to target these enzymes, and how this verse cartilage damage. Since then, the Rush University Medical School, led to the current ongoing programmes developing concept that OA is a failure Department of Medicine, that hold promise for the future. We of the joint as an organ, where different Division of Rheumatology, discuss a comparison of inhibition of tissues and the crosstalk between them, 1611 W. Harrison Street, Suite 510, collagen breakdown versus inhibition including articular cartilage, subchon- Chicago, IL 60612, USA. of aggrecan breakdown. We then sum- dral bone, and the synovium, drives E-mail: [email protected] marise existing programmes that target [email protected] the progression of the disease and as- ADAMTS-5, including small molecule sociated symptoms (5). This has led Received and accepted on September 17, 2019. inhibitors, monoclonal neutralising to the identification of multiple targets antibodies and nanobodies, and gene in different joint tissues that contrib- Clin Exp Rheumatol 2019; 37 (Suppl. 120): S130-S134. editing technologies. We also briefly ute to disease. Drugs that are currently discuss the potential analgesic effects under investigation for their potential © Copyright CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 2019. this strategy may offer in addition to its DMOAD effects include both anabolic joint-protective effects. (i.e. promoting cartilage repair) and Key words: ADAMTS-5, collagenase, anti-catabolic strategies, with some disease-modifying osteoarthritis drug Introduction drugs intended for systemic administra- (DMOAD), antibodies, cartilage Successful disease modification in OA tion while others, such as the anabolic remains an elusive goal, in spite of FGF-18 (Sprifermin, EMDSerono) and significant progress in our understand- the wnt-pathway inhibitor, SM04690 ing of osteoarthritis (OA) pathogen- (Lorecivivint, Samumed), are being esis and sophistication of methods to developed for intra-articular adminis- assess disease state and progression. tration. As discussed in detail in the article by Elsewhere in this Supplement, Oo and Oo and Hunter in this Supplement, a Hunter discuss DMOADs that are in disease-modifying osteoarthritis drug phase 2/3 (1). Exciting novel strategies (DMOAD) is a drug that modifies the are currently in earlier phases (phase underlying OA pathophysiology, there- 1/2), including a senolytic agent for in- by inhibiting structural damage to pre- tra-articular administration, UBX0101 vent or reduce long-term disability and (Unity Biotechnology), which aims Funding: A.-M. Malfait (R01AR064251, offer potential symptomatic relief (1). to eliminate senescent chondrocytes R01AR060364, R61AR073576) is Currently, there are no FDA or EMA from articular cartilage. Senescent supported by the US National Institutes approved DMOADs (2), but aggressive cells (SnCs), which have lost prolifera- of Health/National Institute of Arthritis ongoing efforts by many organisations tive potential, accumulate in all tissues and Musculoskeletal and Skin Diseases and teams in academia and industry are with age and promote the ageing pro- (NIH/NIAMS). offering the hope that DMOADs are on cess through the secretion of the “Se- The funding sources had no role in the study. the horizon. As depicted in Fig. 1 [and nescence Associated Secretory Pheno- discussed in (1)], the current DMOAD type” (SASP), a host of inflammatory Competing interests: A.M. Malfait has received consulting fees from EMDSerono pipeline is densely populated with ac- cytokines, chemokines, and proteases and Vizuri, as well as a grant from tive clinical trials. that profoundly alter the tissue micro- Galapagos N.V.; It was not until the 1980s that the con- environment (6, 7). Senescent chon- M. Tortorella is an employee of GIBH. cept took hold that OA is not simply a drocytes are found in cartilage isolated S-130 Clinical and Experimental Rheumatology 2019 Aggrecanase inhibition in OA / A.M. Malfait & M.D. Tortorella Fig. 1. Pipeline of potential DMOADs in Phase I. from patients undergoing joint replace- Breakdown of articular cartilage is a carefully. While it is accepted that ment (8, 9). In a surgical mouse model hallmark of OA. Two key targetable preventing loss of collagen from the of OA, SnCs were found to accumu- pathways contribute to the enzymatic cartilage ECM will preserve its elastic late in cartilage and synovium (10). degradation of the cartilage extracellu- properties and integrity, systemic inhi- UBX0101 is a potent senolytic small lar matrix (ECM). Aggrecan and type II bition of collagenase activity may pose molecule inhibitor of the MDM2/p53 collagen make up the two major macro- specific problems. Type II collagen is a protein interaction, and disruption of molecular components of articular car- hydrophobic molecule and has no self- this interaction triggers the elimination tilage and are essential for maintaining elimination mechanism from the ECM. of senescent cells. In a surgical mouse cartilage function and integrity, with As cells produce more collagen as part model of OA, intra-articular treatment aggrecan providing cartilage with its of its normal anabolic maintenance, with UBX0101 attenuated joint dam- compressibility and collagen providing collagen will accumulate in the matrix age and, importantly, the drug was able its elasticity [reviewed in (11)]. Deg- until it is proteolytically degraded and to reduce development of naturally oc- radation of these macromolecules is removed by collagenase activity. If this curring disease in ageing mice (10). A mediated by proteolytic cleavage, thus activity is blocked, collagen has the phase 1 study to evaluate safety, tolera- representing druggable mechanisms potential to build up in the ECM caus- bility, and pharmacokinetics of a single of intervention requiring the design ing fibroplasia. Indeed, musculoskel- intra-articular injection of UBX0101 in of protease inhibitors with the proper etal syndrome (MSS, which is defined patients diagnosed with painful OA of pharmacokinetic properties. Aggrecan as painless loss of range of motion in the knee was recently completed. Re- breakdown is mediated by the aggre- large joints, particularly in the shoul- sults have yet to be posted on https:// canases, predominantly ADAMTS-4 ders, joint stiffness and joint swelling, clinicaltrials.gov. and ADAMTS-5, while collagen un- soft tissue pain, and fibrosis of palmar winding and degradation is mediated by tendons) has been observed in clinical Targeting the cartilage matrix the collagenases, predominantly MMP- studies with broad-spectrum MMP in- The current pre-clinical and clinical 1, 8, 13 and 14, although MMP-8 has hibitors and is a pharmacological effect pipeline comprises different strategies not been reproducibly found in articular likely due to the non-selectivity of col- to block the activity of the collagenases cartilage like other members (unpub- lagenase inhibitors (12, 13). Therefore, and aggrecanases. In the current nar- lished results). it is important that drug discovery rative review, we provide a brief over- scientists design drugs that target the view of the discovery efforts to target Targeting collagen degradation collagenase(s) responsible for catabo- these enzymes, and how this led to the There are pros and cons to inhibiting lism observed in OA, but not the col- current ongoing programmes that hold either collagen versus aggrecan deg- lagenase activity responsible for matrix promise for the future. radation, which need to be considered homeostasis in cartilage and other tis- Clinical and Experimental Rheumatology 2019 S-131 Aggrecanase inhibition in OA / A.M. Malfait & M.D. Tortorella sues. It is currently thought that MMP- 24). It was also found that Adamts5 null Neutralising antibodies targeting 1 and MMP-14 are homeostatic col- mice are protected from joint damage ADAMTS-5 lagenases in cartilage and some other in the antigen-induced arthritis model GSK developed a humanised AD- tissues, whereas MMP-13 appears to (25), as well as in a surgical model of AMTS-5-selective monoclonal anti- be responsible for the catabolism ob- OA, induced by destabilisation of the body (GSK2394002), which was effi- served in OA (14-16). Designing se- medial meniscus (DMM) (26). Aggre- cacious in the DMM model both in a lective MMP-13 inhibitors has proven canase-resistant aggrecan mutant mice prophylactic and a therapeutic protocol. difficult, however. The first and second are also protected from developing Systemic treatment attenuated joint generation inhibitors that were devel- experimental
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