Two-year outcome data from the landmark, 250-patient Agili-C™ IDE [investigational device exemption] study, was just published. Results showed that patients receiving the Agili-C implant for cartilage and osteochondral defects, in both arthritic and non-arthritic knees, improved significantly, based on Knee injury and Osteoarthritis Outcome Score (KOOS) versus patients treated with the current surgical standard of care (SSOC), microfracture and/or debridement.
Specifically, patient reported improvement (using KOOS scoring) for the Agili-C arm was 42.7 vs. 21.4 for the SSOC after 2 years, and the responder rate, which was defined as improvement of at least 30 points in KOOS was 77.8% in the Agili-C arm compared to only 33.6% in the control arm.
Importantly, this 2:1 randomized, open-label and controlled trial included patients with wide range of indications including presence of arthritis, up to 3 cartilage lesions, both cartilage and osteochondral defects, larger defect sizes (with a total area of 7 cm2), and a control arm of the study which included BOTH microfracture and debridement.
According to Dr. Ken Zaslav, CartiHeal’s chief medical officer and past president of the International Cartilage Repair Society (ICRS) “the idea of the study design was to treat patients that we, as orthopedic surgeons, see on a daily basis in our clinics and operating rooms. This is the first multinational, randomized and controlled study which enrolled subjects with such a wide range of indications.
Why This Study Is So Important
The Agili-C study, sponsored by Israeli-U.S. based CartiHeal Ltd, and funded by Johnson & Johnson, Bioventus, Elron, Accelmed, Access Medical Ventures, aMoon and Peregrine Ventures is one of the most ambitious and promising cartilage repair studies in history.
The following table is a comparison of cartilage repair studies BEFORE Agili-C and then the first-of-its-kind Agili-C study—FDA sanctioned.
The range of defects is large, like a typical patient population in any orthopedic clinic.
The age range is huge (21-75 years).
The control arm is, effectively, the current common surgical standard of care, microfracture or debridement—not just microfracture.
The number of defects can be as many as three and malalignment is NOT an exclusion (up to 8°).
Subjects post meniscectomy and ACL reconstruction were also allowed.
Like Real Life in an Orthopedic Clinic
“The Agili-C trial is very close to real life,” said one of the study’s lead investigators Antwerp University’s Dr. Verdonk. “Randomization is versus current standard of care—either debridement or microfracture. Which is a major advantages of the Agili-C study.”
One of the effects of broad inclusion criteria is that the 250-patient study enrolled quickly.
The randomization allocation ratio is 2:1—for every two patients randomized to the implant, one is randomized to control.
It should be noted that as in previous studies, young patients with small, focal defects but no arthritis, tend to receive microfracture. Older patients with large lesions and mild to moderate osteoarthritis were randomized against debridement (small focal defects with KL=0 cannot be treated with debridement).
Enrollees were evaluated at 2 weeks after treatment, then again at 3, 6, 12, 18 and 24 months.
Investigators used KOOS, IKDC Knee Examination Form 2000, IKDC Subjective Knee Evaluation, SF-12 Health Survey, Tegner Activity Score, anterior-posterior (A/P) and lateral knee X-rays and MRIs to conduct their evaluations.
The Study Endpoint
Agili-C™, was granted Breakthrough Device Designation by the FDA last year. The primary endpoint of this FDA approved IDE study was the change from baseline to 24 months based on an average of the 5 subscales of the Knee injury and Osteoarthritis Outcome Score (KOOS Overall): Pain, Other Symptoms, Quality of Life – QOL, Activities of Daily Living – ADL and Sports. The KOOS Overall Score ranges from 0 to 100, where higher values represent better outcomes.
The Results
The Bayesian posterior probability of superiority at Month 24 was determined to be 1.000, exceeding the prespecified threshold of 0.98 required to demonstrate superiority.
- The baseline KOOS Overall score was similar in both groups: 41.2 in the Agili-C™ arm and 41.7 in the SSOC arm. At Month 24, the posterior mean for the treatment group improvement from baseline in the Agili-C™ arm was 42.7 compared to only 21.4 for the SSOC arm.
- The degree of improvement for Agili-C™ compared to SSOC was similar for subjects with Mild-moderate Osteoarthritis (Kellgren-Lawrence Grades of 2 or 3) and for subjects with Large Lesions (total lesion areas larger than 3 cm2).
- The posterior probability of superiority of Agili-C™ relative to SSOC was also 1.000 for all 4 Secondary Confirmatory Endpoints: KOOS Pain, KOOS ADL and KOOS QOL and Responder Rate.
- The Responder Rate, which was a-priori defined as improvement of at least 30 points in Overall KOOS at 24 months compared to baseline, was 77.8% in the Agili-C™ arm compared to 33.6% in the SSOC arm.
Reaction to the Study Results
Nir Altschuler, CartiHeal’s founder and CEO said: “These results, which demonstrated the superiority of the Agili-C™ implant over the current surgical standard of care, represent an important potential benefit, as reflected in our Breakthrough Designation by the FDA, for patients who lack other sufficient treatment options. We are looking forward to working closely with the FDA and plan to submit the PMA application later this year.”
Bioventus, LLC, arguably the leading regenerative medicine and orthobiologics company in the world is an investor in CartiHeal and holds an option to acquire the company. Some months back, OTW spoke with Bioventus Chief Executive Officer Ken Reali regarding Agili-C and what it was that appealed to Bioventus.
He said, “We are a market leader in the HA [hyaluronic acid] therapy sector and view the CartiHeal technology as a natural extension as it is on the same clinical continuum for treatment of mild to moderate OA [osteoarthritis] and leverages our commercial expertise.”
Thomas Hill, Bioventus’s director of corporate communications issued a statement soon after the clinical study results were released saying; “We are pleased to learn of the completion of the investigational device exemption study on Agili-C and look forward to receiving the full report from CartiHeal so we may review the results in detail. Once this has occurred, we will revisit the terms of our Option Agreement with CartiHeal and, per our agreement, will communicate our planned course of action within 30 days of receiving the report.
What Is Agili-C and How Is It Implanted?
The Agili-C is a biocompatible and biodegradable tapered-shaped solid implant. It is manufactured from aragonite (calcium-carbonate), derived from sea coral. When implanted into a pre-prepared osteochondral hole it acts as a 3D scaffold that potentially supports and promotes the regeneration of the articular cartilage and its underlying subchondral bone.
In previously published animal studies, Agili-C demonstrated the ability to regenerate hyaline cartilage—as confirmed by the presence of Type II collagen and proteoglycans, and the absence of Type I collagen—without relying on growth factors, or external stem cells.
One of the key attributes of Agili-C’s 3D scaffold is its interconnected porosity which maximizes cell contact and promotes matrix deposition.
The implant looks like this:
“Basically, the Agili-C is an implant with ideal porosity for simultaneous regeneration of the articular cartilage and remodeling of the subchondral bone,” explained Professor Peter Verdonk, professor of orthopedic surgery at Ghent University, Belgium and orthopedic surgeon at the Antwerp Orthopaedic Center. “These micro holes on top of the biomaterial are leading bone marrow stem cells to regenerate the articular cartilage.”
Implanting Agili-C, says Dr. Verdonk, is surprisingly simple. “The procedure to implant Agili-C is very close to what the orthopedic surgeon is used to, i.e., drill the hole, place the implant and push it in. Very user-friendly procedure. Only few minutes per implantation.”
In previously published animal studies, Agili-C demonstrated the ability to regenerate hyaline cartilage—as confirmed by the presence of Type II collagen and proteoglycans, and the absence of Type I collagen—without relying on growth factors, or external stem cells.
One of the key attributes of Agili-C’s 3D scaffold is its interconnected porosity which maximizes cell contact and promotes matrix deposition.
[1]https://clinicaltrials.gov/ct2/show/record/NCT03299959?term=cartilage&cond=knee+arthritis&cntry=US&draw=2&rank=48&view=record
[2] https://www.ncbi.nlm.nih.gov/pubmed/22637204?dopt=Abstract
[3] ibid
[4] Crawford DC, DeBerardino TM, Williams RJ 3rd. NeoCart, an autologous cartilage tissue implant, compared with microfracture for treatment of distal femoral cartilage lesions: an FDA phase-II prospective, randomized clinical trial after two years. J Bone Joint Surg Am. 2012 Jun 6;94(11):979-89. doi: 10.2106/JBJS.K.00533.
[5] ibid
