Introduction

The promise of biologic therapies is to provide natural growth factors or stem cells early in the disease process in hopes of ameliorating treatment regiments. To date, many therapies have fallen short of that promise often because they are used in all indications, in all types of patients, and have little level I clinical evidence supporting their benefit. The next generation of biologics developed must be designed for specific indications and specific patient populations. While at first glance this limits their use, this approach will vastly expand the level I evidence demonstrating a clear benefit for the patients in select indications.

Content

Japan is on the forefront of Regenerative Medicine. The Japanese Society for Regenerative Medicine (JSRM) has worked closely with the Japanese government for creation of a new law for regenerative medicine treatment. With passage of the Regenerative Medicine Law (The Act on the Safety of Regenerative Medicine; The Act on Pharmaceuticals and Medical Devices; passed in 2014) allows for clinicians to utilize Regenerative Medicine products under ethics approval much earlier in the development timeline compared to the United States. Often, these products are approved without specific indication and the evidence must be reviewed by the government for each facility wanting to use one of these products.

One such product approved through this pathway in Japan is Autologous Protein Solution (APS, Zimmer Biomet). APS is a biologic designed specifically to counteract the inflammatory proteins found inside an osteoarthritic knee while simultaneously providing anabolic proteins to stimulate chondrocyte proliferation(1). Unlike biologic therapies that preceded APS, evidence to support the potential mechanism of action has been demonstrated (1,2)

Inflammatory proteins interleukin-1 (IL-1) and tissue necrosis factor alpha (TNFα) work together to stimulate chondrocytes to produce the enzyme MMP-13 which breaks down cartilage matrix. APS has been shown to inhibit MMP-13 production from IL-1 and TNFα stimulated chondrocytes in a culture dish and then consequently to reduce matrix release from IL-1 and TNFα stimulated cartilage explants (1,2). Additionally, chondrocyte proliferation is observed in the chondrocyte treated explants, suggesting a potential mechanism of repair (1). APS has also demonstrated pain reduction in both large animal (3;4) and in clinical trials (5-7). This summary will review the initial experience of APS in patients with OA in Japan. It will be one of the first reports of real world evidence for this product outside of the control of a clinical trial.

References

(1) Matuska A, O'Shaughnessey KM, King WJ, Woodell-May JE. Autologous solution protects bovine cartilage explants from IL-1a and TNFa induced cartilage degradation. J Orthop Res 2013;31(12):1929-35.
(2) Woodell-May J, Matuska A, Oyster M, et al. Autologous protein solution inhibits MMP-13 production by IL-1beta and TNFalpha-stimulated human articular chondrocytes. J Orthop Res 2011 Sep 15;29:1320-6.
(3) Bertone AL, Ishihara A, Zekas LJ, et al. Evaluation of a single intra-articular injection of autologous protein solution for treatment of osteoarthritis in horses. Am J Vet Res 2014 Feb 1;75(2):141-51.
(4) Wanstrath AW, Hettlich BF, Su L, et al. Evaluation of a Single Intra-Articular Injection of Autologous Protein Solution for Treatment of Osteoarthritis in a Canine Population. Vet Surg 2016 Jul 8;45(6):764-74.
(5) Hix J, Klaassen M, Foreman R, et al. An Autologous Anti-Inflammatory Protein Solution Yielded a Favorable Safety Profile and Significant Pain Relief in an Open-Label Pilot Study of Patients with Osteoarthritis. Biores Open Access 2017 Dec 1;6(1):151-8.
(6) Kon E, Engebretsen L, Verdonk P, Nehrer S, Filardo G. Clinical outcomes of an Autologous Protein Solution Injection for Knee Osteoarthritis: A 1-year Pilot Double-Blinded Randomized Controlled Trial. American Journal of Sports Medicine 2018;46(1):171-80.
(7) van Drumpt RA, van der Weegen W, King WJ, Toler K, Macenski M. Safety and treatment effectiveness of a single autologous protein solution injection in patients with knee osteoarthritis. BioResearch Open Access 2016;5.1:261-8.