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How Does PRP Compare to a DMOAD Drug Candidate?

Published on Jun 25, 2024

Disease-modifying osteoarthritis drugs (DMOADs) are one of the holy grails of medicine. The idea is that you can inject something in a knee that will reduce the progression of osteoarthritis and that will, therefore, reduce the need for a knee replacement. I have previously blogged about a company called Biosplice that was testing a DMOAD drug. Today, we’ll dive deeper into the early results of one of their phase III trials and compare that to what we know about PRP.

Biosplice and a Financially Conflicted Academic

What is Biosplice? This is a company developing a drug to treat knee arthritis. Their main drug is lorecivivint, which is based on small-molecule inhibition of CLK/DYRK kinases. The concept is that patients will receive several injections, which will delay the progression of their knee OA. If that concept sounds familiar, it should because that’s how PRP is often used in the knee.

Why would I care about Biospice? I normally wouldn’t, as the more options I have to treat knee OA, the better. However, one of the company’s scientists made a public statement in the medical journal JAMA about a PRP knee OA study trial failure (1). The physician obviously knew very little about PRP, as he never noticed that the Australian trial he was holding up as the gold standard never actually used PRP, despite claiming to use that substance (2). What they injected was barely more concentrated in platelets than whole blood.

Who was that academic? A rheumatologist by the name of Jeff Katz. When I looked him up to find out why he never mentioned dozens of successful PRP knee OA PRPs in his JAMA editorial, it wasn’t hard to find that, IMHO Dr. Katz had a serious conflict of interest (10-58). This is from his required conflict of interest disclosure for this editorial:

“Dr Katz reported receiving support from Biosplice as principal investigator of an observational study of osteoarthritis outcomes.”

So, the guy who wrote this editorial about a bad knee OA PRP study is a university scientist taking grant money from a company developing a drug to treat knee arthritis that will have to compete with PRP. As I always say, you can’t make this stuff up. This editorial is a direct example of the drug development stakeholder problem PRP now faces.

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Biospice’s Knee OA Data

So, let’s review the data Biosplice has released and compare it to what’s in the PRP literature. First, the company failed its first phase III trial with its OA-10/11 drug candidates (higher dose lorecivivint). They blamed the pandemic and too many patients with severe OA in that first study. That failure is already instructive, as if this is a drug to treat mild to moderate OA, it’s moved squarely in the sweet spot as a PRP competitor.

The company reduced the dose, reduced the OA severity of the trial participants, and tried again. They issued a press release in 2023 about early phase 3 data presented at the ACR annual meeting. This was 138 mild to moderate knee OA patients in the placebo group compared to 138 who received the drug. This is what the company reported about the results:

“Patients who received three annual injections of lorecivivint and completed the study showed an absolute decline in mJSW of 0.06 mm versus baseline over 36 months. Patients receiving placebo injections after two years saw a decline of 0.21 mm, which is similar to average annual mJSW declines of 0.1-0.2 mm seen in population-wide studies of OA (Dupuis DE et al., Osteoarthritis and Cartilage, 2003). Comparing lorecivivint patients at 36 months to the last observation of placebo patients, a significant difference of 0.15 mm is seen (P=0.045). Assuming continued placebo progression from the last measurement point prior to crossover, consistent with longitudinal cohort studies of OA, the absolute difference between the active cohort and the placebo cohort is 0.26 mm, again a clinically and statistically significant result (P=0.001).

The structural benefits of lorecivivint were even more pronounced in patients with less severe disease (KL2 population), with an absolute increase in mJSW versus baseline of 0.17 mm following 36 months of treatment and statistically significant increase versus the last measurement point of placebo subjects prior to cross-over.”

The bolding above is mine.

Basically, the drug seemed to reduce the progression of the loss of joint space width, with the best results showing a very tiny separation from placebo of 0.15mm. Any reasonable person should ask the obvious next question: What’s the accuracy of a joint space width measurement?

Joint Space Width

Joint Space Width or JSW means that the investigators took X-rays and measured the width of the joint. This surprised me as, for the last decade-plus, the gold standard in OA studies looking at cartilage preservation is MRI, not x-ray measurement of JSW (4). Why? Sophisticated MRI shows the health of the cartilage in different regions of the knee, whereas X-rays cannot show that data. Why wasn’t the better technology used?

So, what’s the accuracy of JSW measurement? Meaning if two people measure the same x-ray and each measures the JSW, how off will they be? According to one study, 0.08-0.11 mm (3). However, the same study stated that you needed a change greater than 0.13 mm to ensure that you measured an actual and not random difference. At three years of treatment with lorecivivint, the cartilage preservation measured with this antiquated technology was at 0.15 mm, barely above this random measurement mark. For my US readers, that’s 0.006 inches, a very, very small difference. Another study states that the accuracy of JSW is much less at just above 1 mm, and this is because cartilage loss is greater in certain parts of the knee (5).

PRP DMOAD Studies

I reviewed the PRP literature in August 2023 and found four studies that used real PRP and examined OA disease progression, showing that PRP was also a DMOAD (6-9). The two studies that used fake PRP did not show these changes. What results were found in these studies, and how do they compare to the Biosplice drug candidate?

Bansal used a better technology for this purpose, which was MRI. They found that at 12 months, 83% of the PRP group didn’t lose cartilage compared to 62% of control patients. This is hard to compare to Biosplice as we don’t know the responder rates, and Biosplice used less sophisticated X-ray technology. Bansal also measured cytokines in the knees, a more sophisticated study than that performed by Biosplice.
Calis used ultrasound measurements in a small group of patients with more severe OA patients than in the Biosplice study. They demonstrated improvements in cartilage thickness at six months of 2mm (+/-0.2 mm). Because ultrasound can provide a cross-section of different parts of the cartilage, this is more sophisticated than JSW measured by X-rays.
Chu used more sophisticated MRI technology and MRI cartilage volume (different from cartilage thickness and, again, a better measure). They showed losses of 2.6% over five years in the saline group versus 1.4% in the PRP group. Again, a direct comparison to Biosplice is not possible. However, since these are 5-year volume measurements, this is better data than Biosplice produced. Chu also measured changes in inflammatory cytokines in PRP versus saline-treated knees, something I don’t see in the Biospice phase III data.
Baki used two PRP injections and ultrasound cartilage thickness measurements. They showed that cartilage thickness in one part of the knee was better in the PRP group by 0.1mm at six months, far earlier than the Biosplice study. However, other knee areas showed no changes in cartilage thickness over that period. This difference may be close to the accuracy of this measurement.

From the data we have, PRP has more sophisticated evidence it is a DMOAD than the Biosplice drug. While more research is always needed, Biosplice has used less sophisticated methods to track cartilage loss. In addition, based on the data we have, the PRP DMOAD effect seems to be seen far earlier in PRP patients with more severe disease.

Functional Scores

The WOMAC functional scores for lorecivivint are above. They aren’t great. There was only separation from the placebo at 6 and 12 months, with no differences at 18 and 24 months. That’s worse than most knee PRP studies. In addition, the company hasn’t published the absolute WOMAC changes, as these are only changes from the second injection. That begs the question, why? What does the separation from placebo look like in a recent 2-year PRP study:

The blue line is the Chu study. As you can see, at 24 months, real PRP is going strong compared to placebo. The poor results for the red line are from the Benell et al. study, which Dr. Katz hailed as the best study since sliced bread, despite that study never actually using PRP.

Cost?

How will this Biosplice drug be priced? With an estimated 200 million USD investment for the average FDA drug approval, even with 20,000 injections over the first few years, the cost must be approximately $10,000 a dose to break even. That means the cost for this stuff will be tens of thousands billed to insurance. Compare this to PRP, which seems to show its DMOAD effects earlier. Even if you reimbursed two PRP injections at $5,000, you could still beat the Biosplice drug on cost. If PRP gets commoditized with injections going for under $1,000 all in, there is no way the Biosplice drug could compete. This begs the question, is this what Dr. Katz was concerned about?

The upshot? As you can see, PRP compares very favorably to this drug approach to knee OA. This begs the question, is this why academic scientists taking money from pharma companies to develop new OA drugs are worried about PRP?

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