staff and funding from the state of Florida, as well as the city of Gulf Breeze and industry as well. Thank you again. Thank you very much. Travel safe, Adam. Thank you. Next, I'd like to welcome Gloria Matthews. Now, she wears lots of hats in her career, one of which is the president of the Orthopedic Research Society. Among others, she's done tons of work in biologics and pharmacologic options for inflammation and osteoarthritis, so we're really happy in our busy schedule to have her here with us. So, thank you, Gloria. It's my pleasure. Thank you to all of you for coming here. It's great to see a full room, and I'm very lucky in that I get to present to you things that are upcoming and not necessarily things that are already here. Some of these things that I'll talk about, you have seen before and are actually on the U.S. market, but my hope will be—so, first of all, let's back up and give what my definition of orthobiologics is, because I think if you look at different definitions, you'll see slight nuances in those definitions, and so I'm going to expand a little bit on what many people might call orthobiologics to include natural or synthetic agents, materials, or factors derived from biologic sources. So, the reason I put it this way is that this could include monoclonal antibodies, it could include oligonucleotides, it could include things that we're not necessarily talking about, just things that you pull out of the body and put back in. So, these are intended to induce either and or musculoskeletal tissue repair and regeneration or promote pain relief, because the majority of what these products do is actually relieve pain and do a little bit less for structure, and some of the ones that actually do help structure don't necessarily do much for pain, so I prefer to try to disconnect those two in most cases. Some examples would be infuser recombinant human BMP2 for spinal fusion, some antineurotic growth factor antibodies, which I'll talk about a little bit more, for osteoarthritis pain, platelet-rich plasma, cells without scaffolds, et cetera. So, the objectives today are to summarize the landscape for select orthopedic conditions. I can't talk about everything, so I tried to pick the ones that I thought would be the most interesting to this group that are in clinical development. Most of what I'll show you is either in or has been through randomized clinical trials, has level one evidence. Some of them are already approved, some are prelaunch, and some have already been available for a little bit of time, but fit very nicely in this discussion. And then I'll provide just a little bit of detail on the rationale and the mechanism of action for some of these potential upcoming game changers. So here's just an overview of some of the things that I'll talk about. So there are a number of different things that are in either early to late clinical development, prelaunch, or the U.S. market. So we'll talk about osteoarthritis. We're going to talk a little bit about the extended-release corticosteroid, some micronized amniocorion and amniotic fluid, and the antineurotic growth factor antibody I alluded to, a low molecular weight fraction serum albumin, and some a little bit further out products that might or might not be successful, but that are kind of different and interesting mechanisms. One is an agrican mimic, and one is an adeno—helper adeno—virus gene therapy for IL-1 receptor antagonist protein. And then I'll move into chondral defects. I'll talk about the cultured chondrocyte on collagen products, morselized and micronized cartilage matrix and cartilage, tissue engineered cartilage, and then some microfracture augments like pegylated fibrinogen, an HA scaffold with BMAC, and a biophasic arginate scaffold. And then I'll just touch a little bit on tenosynovitis to talk about some data in micronized amniocorion. So moving into osteoarthritis pain, one of the things that has recently come on the market that many of you may have used already is an extended-release corticosteroid. And this is in here because it's in PLGA microspheres, which are a slow-release depot of triamcinolone acetonide. And this is basically just catalog that's in a PLGA microsphere, and the rationale is that these then localize in the synovium, and they—after injection, they slowly elute the steroids. So you get this long-term, fairly low dose of the steroids. These are 32 milligrams. A typical dose would be around 40 milligrams of a steroid injection in the knee. So this isn't a huge dose, and it's being eluted slowly over a long period of time. And there's a fair bit of data that shows that this can be reasonably effective. So it can provide early and sustained relief of moderate to severe OA pain. This has been shown clinically and also preclinically. The biomaterial microspheres degrade to just carbon dioxide and water over time. These have been used for years in multiple different therapeutic areas as therapeutic delivery systems, so these aren't new. The efficacy of a placebo has been demonstrated in randomized controlled trials beyond 12 weeks, and it is available in the U.S. market. It has been for—I'm losing track of time now, but I'd have to say about 18 months. It might be a little bit different than that. It is not indicated for repeat injection at this time, and it's for intraarticular use only. So another product that is on the U.S. market but is also in a number of clinical trials that are randomized and prospective placebo-controlled trials is micronized amnion chorion, and it's sort of sister product amniotic fluids. So the rationale is that human placenta is a very complex center of bioactivity. It supports tissue morphogenesis and homeostasis. It grows a baby, which is from a clump of cells, which is pretty amazing, and if you can harness some of that bioactivity, chances are good that you can help with some of the regenerative needs of tissues and also potentially with pain and reestablishing homeostasis, and there's a tremendous amount of data on the use of these types of products in things like diabetic foot ulcers and venous leg ulcers, and there's amounting a large body of level one clinical evidence showing significant and consistent pain relief in these other areas. And starting to move into the orthopedic areas, plantar fasciitis has some level one data, as Achilles tendonitis does as well, and this is currently in osteoarthritis and Achilles tendonitis trials under FDA INDs. Another one that's a big one that I've been following personally for a long time because this is by far one of the most studied therapeutics ever created. This has been in tens of thousands of people from various companies. Pfizer's a lead runner on this with Tinezumab. So the rationale for using anti-nerve growth factor is that nerve growth factor is released when you have injury, insult, tissue imbalance, and it doesn't just go and create pain. It goes to, it attaches to the TRCA receptor, which then traffics up to the dorsal root ganglion near the spinal cord and sets up these whole pain pathways that are not just, you're not just inhibiting one pathway, you're inhibiting a whole slew of pathways that are both central and peripheral, and it's very potent and very helpful in osteoarthritis pain. They've also used it in low back pain and a few other, I think some cancer pain as well. By far, it's most studied in osteoarthritis and it's been very effective. Challenges are they in small but not insignificant, if it's you, number of people, rapidly progressive OA developed, and these were put on clinical hold a number of years ago, and there's been a lot of discussion about how to get them off clinical hold, and I think they're pretty close to being off clinical hold at this point. There's still some debate about whether they should be fully approved, but there have been additional clinical trials with thousands of people to try to figure out what the right patient population is to not get rapidly progressive OA. Another one that's been out there for a while is the low molecular weight fraction of human serum albumin, and the people developing this have developed all sorts of data around this aspartylalanine diketopeparazine, or DADKP, as the major mechanism. It's part of this low molecular weight fraction of human serum albumin. It purportedly suppresses inflammatory cytokine production by T cells. It does a number of other things for modulating stem cells and differentiating them and modulating immune reactions. There are multiple randomized placebo-controlled trials that have shown positive effects but not really able to beat out placebo. As we talked about, saline can be quite powerful. They are in active discussions with the FDA on the acceptability of their data package, so that one might be coming up for approval in the next little bit. This one is an interesting one as well, because it seems like a good idea. It hasn't actually been able to hit its end point in clinical trials, so this group is actually focusing on patients with effusions, because in their trials they could subset out the population that it actually did have an effect in. This is actually a synthesized construct that links chondroitin sulfate with hyaluronic acid binding proteins. This is kind of like what Agrocan does. It links through linked protein to hyaluronic acid and assembles these big aggregations – that's why it's called Agrocan – of proteoglycans, and this helps to keep the matrix intact and helps to bring in water that then the collagen pushes against that swelling pressure. As you start to lose that, not only do you get degradation of the cartilage matrix, but you also get inflammation from that. Those pieces are very inflammatory, and you could easily induce an inflammatory cycle and drive away with these matrix components if you inject them. So the idea here was that if you could stop that by putting in these Agrocan mimics and keeping that structure in place, you could decrease the matrix-induced inflammatory cycle that drives that symptomatology. So the goal is to both modify the disease and reduce pain, and it's a great goal, and it seems like it should work. And actually, the red staining – I know you can't see the captions – this was a poster that this group did that showed that they could actually bind these two HA gels in vitro, whereas just the chondroitin sulfate itself didn't. So they really are binding these proteins, and presumably this happens in the joint as well. Sorry, the HA. And it's a unique mechanism of action. It's currently in phase two, as I said, with the effusions, but has not been able to hit endpoints, so we'll have to see how that goes. And then we've talked a little bit about interleukin-1 receptor antagonist protein. It's a company that is now using – it's still preclinical, it's getting ready to go into early clinical development in 2019. This is with a helper adenoviral vector that will deliver the genes for IL-1 receptor antagonist protein to decrease matrix degradation in OA. Challenge for me is that I don't really understand where the IL-1 pathway intersects with the pain pathway. That's not really been shown, so it'll be interesting to see how they do with that. But the goal is to have antagonist expression by the joint cells for up to a year. So they'd like to modify disease and also reduce pain, and again, that phase one trial is to initiate in 2019, pending preclinical results. So now moving to chondral defects, one of my favorite topics. So autologous chondrocytes, been around a long time, but there's a number of sort of new versions that are now available in the U.S. As most of you probably know, in, I think, January of 2017, after over 20 years of clinical use ex-U.S., we now have cultured chondrocytes oncologen, so something to replace the cortisol product that was the first and only one for decades. The rationale behind these sorts of products is repopulation of the defect with cells in a matrix environment to restore cartilage structure and function. So this is supposed to help not only fill and cover the defect, but also provide some cell benefits to that. This, as I said, has been marketed as of January of 2017 in the U.S. The efficacy has been demonstrated versus microfracture in the SUMMIT trial, which was a prospective randomized controlled clinical trial in Europe. And the next sort of next generation from that that is also in very active clinical development is tissue-engineered cartilage. So this is taking it kind of a step further in that the defect is, once again, a biopsy is created and the defect is debrided. The initial biopsy is then processed in a bioreactor and grown on a scaffold into a little piece of neocartilage. And then they are, once the tissue is to a certain point based on biomarkers and configuration, it is then implanted into a defect with an adhesive, the rationale being to replace lost cartilage and restore structure and function. This does take some time. The end-to-end biopsy to receipt is about six to nine weeks, and it obviously takes two procedures. This is, and there's a number of groups doing this, the most, the furthest one along, the phase three clinical development is complete and it is an FDA review. There's some others that are coming along with their clinical trials. And then I have a number of things that are microfracture augmentation and progenitor cell support. So one of these is dehydrated cartilage matrix. So this is marketed in the U.S., probably a number of you have used this. This is a natural 3D matrix that supports conracite and progenitor cell function. So this is basically just the extracellular matrix, sort of an allograft, without the cells to help support the cell function. Another that is, the efficacy has been demonstrated in phase two versus microfracture, and there's an ongoing phase three trial now that some of you are probably participating in, is pegylated fibrinogen. This is something that is meant to provide a dense and elastic scaffold for cell infiltration and differentiation with a microfracture. And it has kind of a cool system in that on the left you'll see that this is the undeployed, retracted, there's a special instrument, the retracted sort of thing that seals over the microfracture defect, and then when it gets deployed it puts this very cool sheet of fibrinogen over the defect. And then that's, again, supposed to help support the infiltration of the cells. And a third is this biphasic aragonite scaffold. So this clinical development is ongoing for this. Again, some of you might be part of this trial. This is a porous, biocompatible, resorbable scaffold that provides structural stability and a scaffold for progenitor cell infiltration. So all different variations on the theme of trying to support the cells that are then sort of endogenously available. And finally, I just want to touch on this because there's not a lot new in this space in teninopathy and tenosynovitis. One of the things that is under active clinical trials now with a couple of phase three randomized trials going on in the U.S. is micronized amnion chorion. So at least 285 regulatory proteins have been identified in this material. Again, similar to the OA concept, the human placenta is a very complex center of bioactivity. This bioactivity can be maintained through processing. That's been demonstrated in multiple publications. And this is currently marketed in the U.S. as well as being in a trial. And the efficacy has been demonstrated and published recently in plantar fasciitis. Has not yet been published in Achilles teninitis for phase two, but both of those are currently in phase three trials. I just thought I'd bring that out to your attention. I think that's what I have. Thank you. Good job.

Orthobiologic treatments

Musculoskeletal tissue repair

Pain relief

Clinical development

Osteoarthritis