This past week Mesoblast, a company pursuing the business model of selling someone else’s mass produced stem cells in a vial, launched a major PR campaign to announce their phase III FDA disc degeneration trial. From reading the press releases, you would think that the phase 2 trial showed pure magic. I had reviewed the results of this study last year and was unimpressed, but did I miss something? After all, even for a seasoned physician involved in research, the spin the company put on phase 2 while announcing phase III looked at least superficially impressive. What gives?
I’ve blogged many times about the challenges that companies producing stem cells as a mass produced drug face. The clinical trial results to date have been generally much less impressive than what was sold to investors, who believed that these first stage stem cell companies were going to make the blind see and the crippled walk. However in reality, many companies were left having to “spit shine” trial results that were lackluster and bury negative findings deep in data dumps. One of the issues brought up by a few is that while everyone believed (or was sold) a bill of goods that these mass manufactured cells from someone else’s body would be invisible to the host’s immune system, in reality the host’s immune system does “take out” the cells. In addition, there’s also the issue of what I’ve called the dose arms race, meaning that the companies have such high regulatory approval and manufacturing costs that each claims to be able to grow more doses than the other out of a single donor (to reduce the cost per dose). In the end, cell quality is likely suffering.
So what did the Mesoblast Stem Cell Disc trial phase 2 results for degenerative disc disease show? The therapy involves an off the shelf mass manufactured stem cell injection into a painful and degenerative disc. The press releases tout improvements in pain, function, and disc stability, so let’s dissect those one by one.
First, anyone who follows this company and it’s disc repair technology has to note that something is curiously missing from the press release – MRI changes in the disc. Huh? This company touted that their animal models showed that they could take a dark degenerated, dead disc on MRI and demonstrate disc regeneration on MRI. Why was this important? Because the major US insurers can purchase pain relief for back pain patients with a 5 dollar per month script for a cheap narcotic at Walmart. However, what insurers would pay big bucks for is objective evidence that a stem cell product performed in humans like it did in animals by regrowing new discs. This would surely save the companies potentially hundreds of thousands in future invasive surgeries. However, in both FDA trial press releases (phase 1 and 2), these “holy grail” MRI changes are curiously absent. Note to investors -this is a very big deal. So off the bat, the company has moved it’s product from the “game changing” category to the “super duper expensive pain reliever” category. In the former classification there are no FDA approved drug competitors at any price, in the latter the competition is a plethora of cheap generic narcotic and other pain drugs. Not good…
Pain is a key issue for Mesoblast, as many industry observers believe that if all else fails, Mesoblast can get this product FDA approved on pain relief alone, so let’s delve deeper into that metric. Here Mesoblast seems to have started with the most clinically meaningful number and then when it failed to provide enough sparkle, put some serious lipstick on this pig. From the press release:
“While mean pain scores, as measured by a Visual Analog Scale (VAS), were similar for all four groups at baseline (67 points for saline, 72 points for HA, 70 points for 6M MPC, 72 points for 18M MPC), at 12 months MPC treatment resulted in significantly greater pain reduction than was seen in controls. . Mean pain reduction at 12 months was 40 points for the 18M MPC group, 37 points for the 6M MPC group, 27 points for HA controls, and 27 points for saline controls (p=0.046 and p=0.11, respectively, for 18M MPC and 6M MPC vs pooled controls).”
While most investors will focus on the phrase “significantly greater pain reduction” and be impressed, delving into the fine print disappoints. First, let’s convert these Visual Analogue Scale numbers to something most people do understand, 0-10 Numeric Pain Scores. On that more commonly known scale, o is no pain and 10 is the severest pain you could possibly imagine. So the amount of pain before the procedure for all groups tested was about 7/10. The after procedure score for the high dose stem cell group was a 3/10. Impressive? Not so fast! The low dose group’s after procedure score was a about a 3/10. However, here’s the kicker, the saline placebo pain score (patients injected with so stem cells) was also about a 4/10! That means that all of the high dose group could demonstrate was a lousy one point pain score improvement over the placebo salt water injection into the disc. Ouch!!! By contrast, the average 10 mg generic Percocet that costs pennies a dose will do far better. How about the rest of what they reported under pain relief? The VAS pain data says it all, so no matter how you slice and dice the numbers, this thing failed to show clinically meaningful results. Here’s one of my favorites bits of porky lip stick:
“Reduced opioid use for pain relief: At 12 months, mean daily use of opioid medications for back pain was reduced by as much as 42% in the 18M MPC group compared with the saline control group (p=0.17). Mean opioid use was 1.00 tablet/day saline group, 0.94 tablet/day HA group, 0.77 tablet/day 6M MPC group, and 0.58 tablet/day 18 MPC group.”
Sounds incredible right? The insurance companies will love spending less on pain medications! A 42% reduction in pain med use, outstanding! Not so much. The actual number of pain pills taken by patients went from 1 pill to more than half a pill for the high dose stem cell group. So we didn’t see patients go from popping Percocets like M&Ms taking 10-20 a day to taking 6-12 a day, the patients in this trial just weren’t on much in the way of pain medications. That tells us that the study designers took great care to eliminate patients up front that took a lot of medication. So given that a single Percocet pill costs pennies now to buy on prescription, saying less than half a pill a day is a massive savings for no one and pretty meaningless.
OK, so maybe the magic that would lead investors to believe that Mesoblast has a game changing spine product here is elsewhere in the data? Well, let’s just say that the company continues it’s cosmetic enhancement of the porcine labiae here as well. The information that’s important here is the tried and true “Oswestry Disability Index” or ODI. Here’s what the company reports:
“Reduction in mean disability score: At 12 months, MPC treatment resulted in greater improvement in function than was seen in controls, as measured by the Oswestry Disability Index (ODI). Mean reduction in the ODI functional disability score was 43% for the 18M MPC group, 35% for the 6M MPC group, 30% for HA controls, and 28% for saline controls (p=0.09 for 18M MPC group vs saline).”
Not to waste your time, the high dose stem cell group only had a 15% greater improvement in function than the placebo injection. This is about what $1,000 worth of physical therapy visits will produce in a patient who doesn’t respond all that well to physical therapy. The rest of the function discussion in the company’s press release is to try and make these lackluster functional scores look better than they actually are.
Finally, maybe the last major category reported will be the holy grail that will convince United Healthcare or Blue Cross to spend big bucks for a magic vial of stem cells? Not so much. Here’s what the company says:
“In patients with early disc degeneration (Pfirrmann MRI degenerative grades below 5), increased translational movement of the disc is a potential indicator of instability associated with early disc degeneration and annular fissures seen on MRI and pathologic examination. At 12 months, MPC-treated patients demonstrated a significant reduction in radiographically-determined translational movement of the disc, suggesting a treatment effect on disc degeneration, anatomy, and improved disc stability. The 18M MPC group had a mean translational movement of only 1.3%, the 6M MPC group 2%, the HA group 2.5%, and the saline group 3.5% (p=0.021 between groups). When adjusting translation per degree of rotation (TPDR), a similar treatment effect on reduced translational movement was seen in both the 6M and 18M MPC groups.”
All of this will be Greek to all but the most seasoned spine experts, so let me translate. First, the effect they report here was only seen in patients with early disc degeneration. This is a problem since the product was supposed to grow new discs in patients with severe degenerative disc disease, not mild disc changes on MRI. Second, the changes reported here are truly minuscule. What’s being measured is how far the degenerating disc will allow one vertebra to slide on the other with movement. Given that these are millimeter measurements for patients with early disc degeneration, the high dose stem cell injection group only had a fraction of a mm less movement than the placebo group! These measurements are also well within the standard of error for the x-ray technique used, meaning that the observed effect was so small that it’s well below what most x-ray machines could detect.
The upshot? The great fanfare of press releases announcing clinics participating in the ground breaking phase III trial of a game changing stem cell therapy for degenerative disc disease sounds great, but looking at the data shows that it’s just deceptive window dressing on a therapy that is failing along all measurable metrics. Whenever you see a company drop key imaging results that are needed to impress insurers (like positive MRI changes in the spine) you can almost bet that there are serious troubles brewing. Then when you observe that what should take a few sentences to describe whether or not the product helped pain and function actually takes an entire page of reported numbers sliced and diced 10 different ways, you know there are serious issues. In summary, the phase 1 and 2 data makes the Mesoblast disc product look like a serious boondoggle!