After 8 Years, Stem Cells Are Still Rehydrating Discs
Tracey Romero • Fri, October 13th, 2017
In 2009, fresh from a $350 million capital infusion from Cephalon (with milestone payments up to $1.7 billion), Australian stem cell company Mesoblast Ltd stunned the spine and biologic community with news that their proprietary stem cell—named MPC—had rehydrated spine discs in the sheep model.
With money literally dripping from their pockets, the company moved quickly to set up a series of FDA reviewed, Level 1, multi-arm, multi-site, randomized prospective clinical studies leading to a hoped-for biologic living cell therapy for the single largest spine market ever—degenerative disc disease (DDD).
Spine fusion surgery days were numbered.
That was in 2009.
Here’s the kicker, the subsequent human studies are confirming the promise of that original sheep study.
Degenerative Disc Disease Modification
More than 4 million people in the United States have chronic low back pain. It’s the second leading cause of disability among American adults.
The treatment paradigm for chronic back pain is long, multi-factorial and, in the most severe cases, results in surgery. Along the way to surgery patients wander through the wonderful world of pharmacology, try electrical stimulation—implanted and not—strap on braces, do exercises and try anything else that holds even a glimmer of hope.
At the end of this winding road, if surgery is the only remaining option, their prospects are better in 2017 than they were in 2009.
Patient outcomes today have benefited from better patient selection, better implants, better imaging and instruments and, perhaps most importantly, better overall pain management strategies.
The great promise of using live, immature cells like MPC was that, in addition to expressing powerful anti-inflammatory proteins, they would also tackle dehydrated and narrowing discs.
Here is a recap of what’s been learned about Mesoblast’s MPC cells since 2009.
The precise name for Mesoblast’s living cellular therapy is MPC-06-ID and it is a single injection of 6 million mesenchymal precursor cells (MPCs).
“These mesenchymal precursor cells (MPCs) are able to respond with very specific receptors to inflammation and when activated can help repair tissue, so we take advantage of these mechanisms to target the substantial unmet needs of existing therapies,” Silviu Itescu, MBBS, FRACP, chief executive officer of Mesoblast told OTW.
The sheep study was ultimately written up in the Journal of Neurosurgery: Spine in May of 2012. This paper describes how Mesoblast researchers injected its MPCs into three adjacent lumbar discs in 24 adult male sheep. Before treatment, the degenerated discs had 45-50% less height and afterwards the discs had rehydrated and increased in height at a significantly higher rate than the controls.
Now Human – Four-Arm, Randomized, Phase 2
The first in human studies were conducted in 2013 under FDA oversight and were designed so as to lead, hopefully, to an eventual approval of a living cell therapy for DDD.
It was a four-arm, randomized, placebo and active controlled Phase 2 trial in 100 patients. Patients were enrolled who had had more than six months of chronic lower back pain due to disc degeneration. Patients were randomly selected to receive injections of either saline, hyaluronic acid, 6 million MPCs in a hyaluronic acid carrier or 18 million MPCs in a hyaluronic acid carrier.
After six months, patients who’d received the 6 million MPC cells did best. Better, in fact, than the patients who’d received 18 million MPCs. The exact statistic was 71% of the low dose (6 million MPCs) injection met treatment success criteria.
Patients then returned at 12 and 24 month intervals. Again, the 6 million cell dose proved to be the most effective at relieving pain. Those patients, the researchers reported, checked the boxes at 50% reduction in pain using a visual analog scale, with no intervention.
By contrast, only 12.5% of the saline-treated patients met the pain responder criteria. Twenty-three percent of the patients receiving hyaluronic acid met the pain responder criteria and 36% of the high dose MPC (18 million cells) met the criteria.
“Over 50% reduction in pain was observed in more than 50% of patients at 12 months,” Itescu said. “If you can see that, then you don’t need to consider opioids.”
Finally, this past March Mesoblast released the three-year data on these patients and the results show that the MPC pain relief was durable for the entire period.
And what about disc rehydrating?
“In our Phase 2 study, we observed an increase in disc height from 3 to 12 months for patients that had a clinical composite response of 50% pain reduction AND 15 point functional improvement after a single intra-disc injection of either the low or high dose of our cells; such disc height increase was not seen in non-responders to treatment, nor in the control patients. This correlation between the natural time of healing and the observed disc height increase is indicative of a repair of the disc in patients that had a positive clinical response. Additionally, the long lasting response of up to 36 months in a significant number of patients from a single injection also indicates a regenerative mechanism,” Itescu said.
Moving Into Phase 3
The success of this trial has led the company to begin patient enrollment for a Phase 3 trial which is randomized to either 6 million MPCs, with or without a hyaluronic acid carrier, or a saline control. The trial which is still currently open for patient enrollment was first initiated in March 2015 and should be completed by February 2020, according to clinicaltrials.gov.
Itescu said that they have recruited 270 patients so far and expect to have enrolled all 360 patients needed by the end of the year. Patients are being enrolled at 30 sites in the United States and Australia.
The trial's primary endpoint of Overall Treatment Success (using a composite of 50% improvement in lower back pain and 15 point improvement in function at both 12 and 24 months) is the primary endpoint needed for product approval by the United States Food and Drug Administration (FDA), which is the next step after all the results are in from the Phase 3 trial.
Itescu added, that in total so far, “more than 2,000 people have been treated with our mesenchymal lineage precursor cells and their progeny. These cells have an extraordinarily safe profile; we do not see off-target side-effects due to the fact that the cells need to be activated by specific factors to release their payload, and the presence of such activating factors are not present in healthy tissues. In addition, we have not identified any dose related toxicities.”
Kasra Amirdelfar, M.D., a founding partner at the Integrated Pain Management Medical Group Inc. in California, was a lead investigator in Phase 2 trial and is a lead investigator for the open Phase 3 trial as well. At his investigative site, he found that patients who received the active treatment did far better than those who got the placebo.
He told OTW that this is a really promising sign that we will be able to fill in the gap between symptomatic pain management and surgery.
“The biggest challenge that we have come across is that we are not seeing these patients early enough. Patients with mild to moderate back pain tend to just take over the counter medicine for the pain or go to their family physician who just provides symptomatic management. They don’t get to us in time.”
He added, “The other issue is that those who do get diagnosed in time and who are a good candidate for the stem cell treatment are sent right to a spine surgeon instead of to us so it is challenging and really requires changing the culture of low to moderate disc disease all together. There is a lot of research and outreach that needs to go into it for people to understand that we need to go beyond the standard of care to treat these patients.”
Overall, Itescu said that they believe that they have a powerful therapy that regenerates the disc and improves pain and function.
“If we replicate these data in an active phase trial of 360 patients, I think we have a very potent product.”
After the Phase 3 results are in, Itescu said that they will also do additional studies to see if there is any benefit of patients receiving a second injection at 12 or 24 months.