P-15 Peptide or BMP-2? Both PMA Approved. One Has Clear Advantages
Is it time to take a closer look at peptide based bone graft? Anterior cervical discectomy and fusion (ACDF) procedures, which rely heavily on bone graft to deliver consistent fusion success rates, may not, according to recently published evidence, actually reach clinical success as often—certainly not “95% of the time”—as many surgeons believe.
Defining Fusion, Therefore Measuring Clinical Success Accurately
A 2008 review by Drs. Nanin Sethi and K. Daniel Riew analyzed 144 articles reporting on ACDF fusion rates from 1966-2004. They found that a shift occurred around the year 2000, when studies began to progress toward a definition of what fusion actually meant. Prior to 2000, more than half of the studies analyzed had no criteria to define a solid fusion, others relied on only a single measure such as absence of motion, or presence of spanning trabeculae.
In contrast, studies published between 2000-2004 provided a definition of fusion in all but one instance (3% of studies), and fewer than 38% of the studies considered only one measure of fusion. Of course, with more stringent fusion criteria, come fewer reported successes. In many cases, these include asymptomatic pseudarthrosis that may have gone undetected in earlier studies.
70-94% ACDF Fusion Rates – Before i-FACTOR (97%)
A series of new, high-quality Level I studies have been released which provide updated evidence of ACDF fusion rates (by way of ACDF control arms in Investigational Device Exemption (IDE) studies for cervical disc replacement devices).
In 2010, a meta-analysis found that Level I and II data from five IDE studies for cervical cages or artificial disc systems documented ACDF reoperation rates at about 10% (9.5% for ACDF with plating and 12.7% without), and clinical success as low as 70%.
More recent cervical disc replacement (CDR) Level I IDE studies, which used cervical fusion rates as the control arm in their studies, documented ACDF fusion rates between 78.6% to 94.3%. A range much lower than the perceived “95% fusion rates” surgeons might expect. Interestingly, the high end of that range was found in the IDE study control arm for the Bryan Cervical Disc published in 2009 and the lowest fusion rate was reported in 2019 for the M6-C IDE trial control arm.
The only spinal bone graft on the market that has higher fusion rates than what was reported in these IDE studies and was demonstrated to be so in an IDE study is i-FACTOR Peptide Enhanced Bone Graft®. The i-FACTOR Level I IDE study emulates the single level ACDF study design as seen in these CDR studies, therefore a fair comparison.
Checking in With Users
OTW had the opportunity to speak to a few surgeons known for their work in the cervical spine. They all had something to say about surgeons’ perception of ACDF fusion rates.
James Burke, M.D., Ph.D., a neurosurgeon at UPMC Altoona, Allegheny Brain and Spine Surgeons in Altoona, Pennsylvania, told OTW that, in his view, formal studies are essential for understanding whether bone grafting options work as advertised. Otherwise, the only way a surgeon knows about his/her reoperation rate is if the patient returns to them, which for many reasons, may not happen.
Neill Wright, M.D., a neurosurgeon who operates at Blessing Hospital in Quincy, Illinois, agreed with Dr. Burke’s point and went on to mention that insurance companies usually have a better idea of patient reoperation rates than the surgeons and have reported ACDF reoperation rates as high as 15%.
Dr. Paul Arnold, M.D., neurosurgeon at Carle Neuroscience Institute in Urbana, Illinois, who was the lead author of the i-FACTOR ACDF IDE study publications and the principal investigator on the ongoing TLIF IDE ASPIRE study for the next generation of i-FACTOR, currently called P-15L Bone Graft, made the key point that defining ‘successful fusion’, using bone grafting that is solidly supported with Level 1 clinical study data and the skill of the surgeons performing the procedure are the three most important variables determining ACDF reoperation rates. And, of course, he noted when patients move, change jobs and insurance or just suffer through the pain without notifying their original surgeon, that would suggest that the rates of ACDF reoperation are higher than most spine surgeons expect.
What About Asymptomatic Pseudarthrosis?
As long as the patient is happy and pain free, shouldn’t that be considered a success? Both Dr. Burke and Dr. Wright advised caution against this line of thinking. Just because a patient is pain free today, without a solid fusion there is always a chance that even a minor trauma in the future or eventual subsidence could reawaken that pain generator that initially led the patient to seek relief. Plus they added, even if a patient still experiences pain, having achieved that solid fusion with appropriate decompression rules out that level as the source of pain.
Recent published literature demonstrates nonunions may be under reported as patients may be asymptomatic and don’t undergo radiographic evaluation. And those patients with single level ACDF nonunions are three times more likely to undergo secondary surgery.
“An increased reoperation rate has negative implications for the individual patient, as well as the cost-effectiveness of the index procedure.”
Crawford C, et. al., Spine 2020; 45(13): E776-80
Additionally, since most IDE studies are limited initially to two years of follow-up data, reoperation rates are unlikely to include asymptomatic pseudarthroses that could pose problems years down the road. Case-in-point, the seven-year data from the Mobi-C trial indicates that single-level ACDF reoperations at the index level rose to 16.2% while clinical success rate dropped to 50%.
400+ Bone Graft Substitutes
Believe it or not, there are more than 400 Bone Graft Substitutes. But only 2 have the highest FDA regulatory Premarket Approval (PMA) as spinal Class III devices: i-FACTOR and rhBMP-2. Both come with a Level I IDE clinical trial that firmly established base-line, statistically significant levels of efficacy and safety as tested on humans.
Increasingly, the FDA and major surgeon societies like the American Academy of Orthopaedic Surgeons (December 2010 AAOS Now) are raising the alarm about the paucity of clinical evidence for this flood of orthobiologic products including bone grafts and human cellular tissue-based products (HCT/Ps) such as mixed living cell concoctions that are often marketed as “stem cells.”
The majority of these products are Class II devices which require only 510(k) clearance based on animal (rabbit or rat) data in order to be cleared for sale.
The P-15 Peptide Mechanism of Action
A small segment of type I collagen was identified though research done at the Laboratory of Connective Tissue Biochemistry at the UCSF and the Department of Bioengineering and The Center for Tissue Engineering at UCB. This 15-amino-acid peptide, dubbed P-15, was found to abundantly bind osteogenic cells. Studies on P-15 progressed from the mid-90s into the 2000s, with research finding that not only does the peptide bind osteogenic cells, but it also enhances cellular proliferation, extracellular matrix production and upregulates growth factors such as rhBMP-2 and ALP that lead to bone formation. Its use as a promoter of fusion became clear.
The Company Bringing P-15 to Market
Cerapedics, Inc., based in Westminster, Colorado was formed from its predecessor, CeraMed Dental, which used P-15 for dental applications in over 500,000 procedures beginning in 1999. Cerapedics then rebranded and reformulated the P-15 and ABM as “i-FACTOR” and brought the product into spine and orthopedics in 2008 outside the U.S. and then in 2016 to the U.S.
Cerapedics is now the fastest growing biologics company in the medical device market with its P-15 Osteogenic Cell Binding PeptideTM technology.
Safer, Affordable, Consistent
By and large, surgeons agree that rhBMP-2 does what it says it is supposed to do, grow bone. The real concern may be that it is too good at that, meaning, the risk of heterotopic ossification due to rhBMP-2’s chemotactic mechanism of action is a concern.
The FDA has also weighed in on this risk by issuing a black box warning against using Infuse in ACDF procedures. Their concern is the risk of dysphagia and swelling. For ACDF, rhBMP-2 is not an optimal choice. rhBMP-2 is also expensive. Peptides are typically less expensive and a better value. Also comparatively safe, as demonstrated in its IDE study, the i-FACTOR P-15 Peptide uses a haptotaxis mechanism of action.
The First PMA for Cervical Fusion
Class III drug-device combination products can only come to market via an FDA PMA, multi-year, multi-site, Level 1 study approval process. In the case of i-FACTOR, the FDA approved i-FACTOR as a Class III drug/device combination product in 2015. With that designation, i-FACTOR became only the second biologic for spinal fusion to receive a PMA, and the first for cervical fusion.
The supplier of i-FACTOR, Cerapedics, markets the product as a peptide enhanced bone graft that will “Attract, Attach, and Activate” osteogenic cells. This motto reflects the ability of P-15 to bind osteogenic cells so that it can build bone where P-15 is placed, and not elsewhere.
319 Patient IDE Study
The results of the 319 patient IDE study were published in Spine in 2016 and showed that i-FACTOR met the FDA’s requirement of non-inferiority with a fusion rate of 88.97% (versus 85.82% for autograft) in ACDF procedures 12 months after surgery. Despite being a non-inferiority study design, i-FACTOR demonstrated superiority to autograft in overall clinical success, measured as a combination of Fusion, NDI improvement, Neurological Success, and Safety Success, which was statistically higher in the i-FACTOR cohort than the autograft control (68.75% vs. 56.94%, p=0.0382).
These patients were included in a follow-up study, published in 2018 in Neurosurgery, which found that more patients had fused in the following year, reaching a rate of 97.3% (versus 94.4% for autograft). Again, overall success remained higher in the i-FACTOR cohort (69.8% vs. 56.4%, p=0.0302). Additionally, i-FACTOR trended toward lower rates of reoperation.
Post-Approval Study Outcomes
For more than a decade i-FACTOR has been rigorously tested around the world. Studies have found that the P-15 peptide is as good, or in some cases significantly better than autograft.
Dr. Arnold told OTW that he has been using i-FACTOR since the original IDE study, he has not reported any significant surprises and has good results all around: “With i-FACTOR, I have had very good success. It is a good product, is easy to use and the results speak for themselves.”
The Next Generation: P-15L Bone Graft – Treating Degenerative Disc Disease in Lumbar
Building on the success of i-FACTOR (P-15/ABM), Cerapedics has continued to develop the product to make it easier to handle and better suited for more complex procedures. This next generation of i-FACTOR adds a collagen carrier in place of the hydrogel carrier for improved handling and has an increased amount of the P-15 Peptide.
A U.S. IDE trial named ASPIRE that is investigating the new product in transforaminal lumbar interbody fusion (TLIF) procedures is currently underway and the product is already approved in Canada. NOTE: In the U.S. P-15L Bone Graft is an Investigational Device limited by Federal Law to Investigational Use.
Cerapedic’s P-15L for Lumbar Lands Breakthrough Designation for DDD
In April 2021, the FDA granted P-15L Bone Graft breakthrough designation status and allowed Cerapedics to conduct its Level 1 IDE study for the treatment of degenerative disc disease (DDD) in the lumbar spine with a reduced patient recruitment goal. As a result, the IDE trial for P-15L is likely to wrap up earlier than expected.
i-FACTOR has been received well by the spine surgeon community. Based on its track record in the cervical fusion space, Cerapedics is already the leader in cervical bone grafting. Stay tuned on Cerapedics progress toward filing a PMA for P-15L Bone Graft for use in TLIF procedures.