Colorado-based Cerapedics, Inc., with a July 22 FDA ruling and its current investigational device exemption (IDE) trial for the P-15L Bone Graft, is clearly taking aim at Medtronic’s Infuse.
On July 22, the FDA approved a supplement for the trial reducing the required enrollment from 364 to 270 patients in the ASPIRE IDE study. “We are pleased to announce FDA approval of an IDE supplement resulting in a reduction of the total number of patients required to be enrolled in our IDE study for P-15L cell-binding peptide technology in the TLIF [transforaminal lumbar interbody fusion] application,” said company President and COO Jeffrey Marx, Ph.D.
The change was due to an increase in the non-inferiority margin for the study from 10% to 12.5%, which will allow for fewer enrolled patients to reach statistical significance for non-inferiority. For context, studies frequently use non-inferiority margins of 15% (i.e., the experimental device or drug must be at least 85% as efficacious as the active comparator to be considered non-inferior).
The 94 patient decrease will make it easier for the company to complete enrollment and finish the study ahead of schedule. The company also expects to perform an analysis using Bayesian statistics after about two-thirds of the enrolled patients complete the two-year follow-up to predict the outcomes of the study. The use of Bayesian statistics for clinical trials seeking FDA approval has become more commonplace in the last two decades with the increased availability of computational power.
“The reduction in requirement will help us significantly reduce the enrollment period of the IDE Study and lead to an earlier PMA [pre-market approval] submission,” said Glen Kashuba, Cerapedics CEO.
OTW spoke with Marx recently to learn more about the new P-15L product, the history of Cerapedics, and what recent FDA approvals mean for the company. Marx joined the company in 2013 after 13 years with Orthovita (which was acquired by Stryker Corporation in 2011) where he helped develop Vitoss, a beta-tricalcium phosphate synthetic bone graft. His Ceramic Engineering (material science) Ph.D. from Missouri University of Science and Technology, and specifically his ceramics research has turned into a major asset toward his success in orthobiologics.
The P-15L Bone Graft is Cerapedic’s latest bone graft product and is a reformulation of its already-approved peptide enhanced bone graft, i-Factor. i-Factor comprises a 15 amino acid stretch of Type I collagen bound to an anorganic bone mineral (ABM) and pre-mixed in a hydrogel carrier. The peptide has been shown to be an active site to “Attract, Attach, and Activate” bone building cells.
Typically, this sequence is buried in the triple helix of the collagen protein; by synthesizing the peptide and binding it to the surface of a delivery matrix it becomes orders of magnitude more accessible and active.
Since it binds to the mineral the peptide is unable to leave the implantation site, eliminating the risk for heterotopic ossification seen in morphogenetic growth factors. P-15L builds on the success of i-Factor by replacing the hydrogel carrier with bovine collagen. The calcium phosphate carrier in P-15L has more porosity, absorbs faster, and allows for more peptide to be bound than the ABM in i-Factor. P-15L is delivered as a sterilized strip which is mixed with saline or water in the OR to form a compression resistant putty.
Clinical evidence regarding i-Factor in the literature is abundant and strong. In addition to an IDE study where i-Factor was tested in anterior cervical discectomy and fusion (ACDF) procedures, it has also been examined in several studies of lumbar fusion performed globally, which are off-label indications in the U.S. Studies of i-Factor in anterior lumbar interbody fusion (ALIF), posterior lumbar interbody fusion (PLIF), and non-instrumented posterior lumbar fusion (PLF).
All found rates and/or speeds of fusion similar to rhBMP-2 (Infuse) and better than autograft.
In multilevel ALIF procedures i-Factor was found to lead to 24-month fusion rates of 97.5%, 81%, and 100% for single-, double- and triple-level surgeries, respectively. Overall, fusion was observed in 94% of patients. Early fusion was also observed with 43% and 44% of one- and two-level patients fused as early as 3-6 months after surgery. The study (“Clinical outcomes and fusion rates following anterior lumbar interbody fusion with bone graft substitute i-FACTOR, an anorganic bone matrix/P-15 composite”), conducted in Australia was published in the Journal of Neurosurgery: Spine in 2014.
The PLIF study (“Prospective Analysis of a New Bone Graft in Lumbar Interbody Fusion: Results of a 2- Year Prospective Clinical and Radiological Study”), carried out in Belgium, and published in the International Journal of Spine Surgery found bridging bone at 6 months in 98% of the patients treated with i-Factor, and in only 59% of patients treated with local autograft.
In Denmark, a group used i-Factor in non-instrumented PLF. In that study (“Randomized double blind clinical trial of ABM/P-15 versus allograft in noninstrumented lumbar fusion surgery”), published in the May 2020 issue of The Spine Journal, i-factor showed a 150% increase in fusion rate compared with the allograft control group. Overall, Fusion rates were low (50% vs 20%) due to the lack of instrumentation, but the technique is relatively common in Europe, largely due to lower costs, but also shorter surgical time, and blood loss.
In addition to superiority over autograft, the studies show that i-Factor has a safety profile that is much more palatable to surgeons and patients than Infuse, and still avoids donor-site morbidity from harvesting iliac crest bone graft. Currently, i-Factor is U.S. FDA approved for ACDF using an allograft ring, but an estimated 60-75% of its use is in the lumbar spine and off-label per surgeon choice.
The study, initiated in April 2018, had its first patient enrolled in July 2018. The semi-blinded, randomized trial compares P-15L to local autologous bone in instrumented TLIF procedures, with non-inferiority as the goal. The surgeon is aware of whether the patient received P-15L or locally harvested autograft, but the patient and radiologist are blinded to the treatment. The primary study outcomes are expected in September 2021, with full study completion by September 2025.
The FDA handed down more good news for Cerapedics, Inc. on July 22. An update to the labeling for the i-Factor Bone Graft was approved to include 72-month follow-up data from the company’s post-approval study. The FDA approved inclusion of 24-month data on the label back in October 2019.
Cerapedic’s’ i-Factor, first approved by the U.S. FDA in 2015, was the first drug-device combination bone graft approved for use in the cervical spine and the second approved for spine overall, the first being rhBMP-2 (Infuse from Medtronic). The graft has been available under CE mark in the European Union (EU) since 2008.
