Extended-Release Triamcinolone Acetonide Suspension

Peter Salgo, MD: There’s another product out there, right? You were talking about cortisone injections. There’s the triamcinolone acetonide extended-release injectable suspension. What is this, compared to the steroids we’ve been using?

Andrew Spitzer, MD: This is basically just an extended-release, classic steroid. Triamcinolone acetonide is typically referred to as Kenalog. Triamcinolone acetonide is coupled to a nanoparticle of poly lactic-co-glycolic acid [PLGA], which enables it to sort of stay in this nanoparticle, this microsphere, until exposed to an aqueous environment. Then there is a very sustained, slow release into the joint. The implication is that you don’t get a huge surge of steroid in the joint. You don’t get the systemic absorption that creates the glucose control issues, the hypothalamic pituitary access alterations, and such. You get a lower level of steroid in the joint, which we think may be beneficial in terms of local cartilage damage. Clinically, you get a sustained, quick onset of action and sustained clinical impact. The signal is stronger than almost any other injection that we have available to us.

Peter Salgo, MD: Can you put a number on “sustained”? How long does it last?

Andrew Spitzer, MD: The studies that have been done suggest that all the way out 2 to 3 months, patients have a significant improvement in the scores that we were talking about before—WOMAC [Western Ontario and McMaster Universities Osteoarthritis Index], KOOS [Knee Injury and Osteoarthritis Outcome Score], and quality of life—as well as rescue medications. There’s currently a study going on, which I am personally involved in, that is looking at the need for a second dose. We’re seeing patients in whom this product is lasting for 4 to 5 months, in terms of clinical impact, before patients actually require a secondary injection.

Peter Salgo, MD: How does that compare to standard steroids?

Richard Iorio, MD: They did a randomized controlled trial comparing standard steroid injections versus the new extended-release. It appears that the extended-release had markedly longer efficacy.

Peter Salgo, MD: I’m going to ask you this again: What’s the number? Markedly longer compared to?

Richard Iorio, MD: Several weeks or months long.

Paul Lachiewicz, MD: I’ve read all of these articles. It’s important to realize that the pain doesn’t go to 0 with any of these. Generally, with steroids, if your pain is a 5, it’s going to take you down to a 4 or a 3. So, I think some of these findings can be statistically significant. How clinically relevant they are, I’m not sure. One of the things that I see some downside to for this product is, doesn’t this have to be reconstituted with a diluent before you inject it? I would be concerned that the sterile technique has got to be absolutely perfect with this product. For some of our physician assistants, I’d be worried about this. The other thing is, to my knowledge, both the safety and efficacy of this product in repeated administration has not been tested. Is that correct?

Andrew Spitzer, MD: There’s a repeat dosing study that’s going on now.

Paul Lachiewicz, MD: It’s going on now, but it has not yet been proven.

Andrew Spitzer, MD: The repeat dosing has not yet been proven or assessed. You mentioned statistical significance. Earlier, you mentioned the American Academy of Orthopaedic Surgeons (AAOS) guidelines. They were quite controversial. But, the metric that was utilized was a MCII [minimal clinically important improvement] from baseline.

While that statistical instrument is somewhat controversial in how you use it, the current study that has yet to be published but is in the press right now (of the phase III study on triamcinolone acetonide extended-release) will demonstrate that the statistical significance is not just statistical. It’s actually clinically relevant, relative to the MCII thresholds that were set by the AAOS guidelines. This is demonstrating what I said—a higher statistically significant signal and clinically meaningful signal. That really differentiates it, in my opinion and in my personal experience, from other steroids.

Paul Lachiewicz, MD: If it lasts so long in the joint, do you think that at 3 months, if the patient’s going to have a total knee, we should extend that out to 6 months (after the extended-release)?

Andrew Spitzer, MD: That’s a huge unanswered question right now. I would share concern with regard to that. We don’t see any clinical evidence of residual and no biochemical residual of the product within the joint in that time frame. But, the concern is certainly a realistic one. The question becomes, how do you stratify your patients, in terms of whether they need to dance at the wedding but have their total knee in 3 months? Or, do you look at the patient who is looking for sustained nonsurgical management and not consider any surgical intervention?

Paul Lachiewicz, MD: Right. That’s where I think there may be a role for this.

Richard Iorio, MD: Does the extended-release product work as quickly as the standard injections?

Andrew Spitzer, MD: In the studies that they’ve done—phase II, phase III studies—the onset of action seems to be within that 24- to 48-hour period.

Peter Salgo, MD: So, yes is the short answer?

Richard Iorio, MD: Correct.

Peter Salgo, MD: It’s just as fast? It just lasts longer?

Richard Iorio, MD: Correct.

Peter Salgo, MD: So, explain this in terms of the microsphere of technology. I’m confused. I thought that it would release it more slowly and probably ramp up over time?

Andrew Spitzer, MD: When we normally give 1 or 2 cc of Kenalog, we oversaturate, or saturate plus a lot of excess.

Peter Salgo, MD: That’s to cover the decay over time?

Andrew Spitzer, MD: Correct. The bottom line is that we give way more than we probably need to, to saturate the steroid receptors and the cell surface receptors that actually activate and create the impact within the joint. This product is saturating those receptors while not overshooting, so you don’t get the leakage, systemically. But, it is creating the clinical impact that we’re looking for.

Peter Salgo, MD: Are there particular cautions you need to know about, in terms of reconstituting this drug? You just don’t swab it with alcohol and go?

Andrew Spitzer, MD: Clearly, there is a reconstitution step. There are proprietary technologies. They have little kits that come with it. But, absolutely, you have to do this in a sterile fashion. There is no question about that.

Paul Lachiewicz, MD: At one of my institutions, we delegate this to the physician assistants. They just change the needle and they do the injection. They swab the knee once. So, I’m a little concerned. I think you have to have a good sterile technique when using those.

Richard Iorio, MD: Does the company provide instruction?

Andrew Spitzer, MD: Yes. It’s a little kit that sort of provides a way of getting the diluent into the product. It’s actually quite a nice setup. It’s very easy to do. And while I share your concern, Paul, I would say that having personally done it, it’s not hard. It’s something that you get into the workflow. You can do it very carefully and in a sterile, straightforward way.

Richard Iorio, MD: If you’re concerned with this, you’ve got to be really concerned with doing PRP [platelet-rich plasma] and stem cell injections in an office.

Paul Lachiewicz, MD: Well, I don’t do those.

Richard Iorio, MD: I don’t either. I’m just saying.

Peter Salgo, MD: When we’re discussing this, let’s be very clear on what we’re discussing. We’re discussing injections into a closed space, which needs to be sterile. Whether you inject steroids, local anesthetics, or anything, that’s the risk, right? You have to be good with your aseptic technique, whether it’s with this drug or any drug.

Andrew Spitzer, MD: Particularly with something like steroids of any kind, that have the potential to immunomodulate the local environment. I think that’s always been the fear. In the data that we shared earlier, it does seem to alter the ability of the joint environment to fight infection, even in the face of a joint replacement.

Paul Lachiewicz, MD: I have noticed that when I do a knee arthroplasty in a patient who’s had multiple hyaluronic acid (HA) injections, the knee is more fibrotic. The synovium is this grayish silver. Then, in patients who have multiple steroids, you can tell there are crystals all over their joint. I wonder if this changes the outcome of the total knee? Do you know of any data on that, Rich?

Richard Iorio, MD: The only data that I’m aware of is that there are infectious disease and bacterial characterizations of normal joint fluid. There are remnants of bacteria in every joint. The question is whether those live in every joint, get introduced, or whatever. The theory is that those bacteria live in that joint and that we may be activating those bacteria with these agents—sometimes causing some of these reactions.

Paul Lachiewicz, MD: This is scary, if this is true. What about the fibrotic?

Richard Iorio, MD: I haven’t seen that.

Paul Lachiewicz, MD: Maybe it’s just anecdotal then?

Andrew Spitzer, MD: We published an article, a while back, looking at synovial samples in patients who had severe acute inflammatory reactions and in patients who had been exposed to HA. Ultimately, between those who were exposed and those who were not, there was no significant difference in terms of granulomatous disease or those kinds of things. We didn’t look at infectious disease.

Paul Lachiewicz, MD: I think the next step for big data would be to look at if they could somehow get ranges of motion after total knee in patients whove had 3 or more HA or steroid injections, versus people who didn’t have any.

Richard Iorio, MD: More than a chemical reaction to the HA, would be bleeds related to the injection.

Paul Lachiewicz, MD: Well, maybe that’s it? Maybe there’s another factor?

Peter Salgo, MD: Maybe subclinical bleeds over time?

Richard Iorio, MD: Maybe not so subclinical?

Transcript edited for clarity.