AUGUST 22, 2024
DALLAS—The investigational agent SI-6603 (chondroitin sulfate ABC endolyase; Condoliase, Ferring Pharmaceuticals) showed promise in relieving radicular leg pain (sciatica) associated with lumbar disc herniation (LDH), according to new safety and efficacy data from two phase 3 trials.1
The data were presented at the 2024 meeting of the American Society of Interventional Pain Physicians. A related presentation at the meeting2 described current treatment patterns and gaps in clinical
DALLAS—The investigational agent SI-6603 (chondroitin sulfate ABC endolyase; Condoliase, Ferring Pharmaceuticals) showed promise in relieving radicular leg pain (sciatica) associated with lumbar disc herniation (LDH), according to new safety and efficacy data from two phase 3 trials.1
The data were presented at the 2024 meeting of the American Society of Interventional Pain Physicians. A related presentation at the meeting2 described current treatment patterns and gaps in clinical management of LDH, concluding that new treatment options are needed to avoid surgery and the requirement for repeated epidural steroid injections.
“For too long, treatment of radicular leg pain associated with LDH has been limited to conservative care with pain medication and physical therapy, or a more invasive surgical approach,” said Kenneth Candido, MD, an anesthesiologist at Chicago Anesthesia Pain Specialists, as well as the presenter and a co-author of the phase 3 trial report.
“Based on these findings, SI-6603 could provide another option where a single injection to the lumbar disc could offer patients significant relief from the unrelenting pain often associated with lumbar disc herniation,” Candido said.
The progress in developing SI-6603 also reflects renewed interest in the previously abandoned intervention of chemonucleolysis by intradiscal injection of an enzyme. Chymopapain was approved by the FDA in 1982, but the product was discontinued in 1999 because of concerns including low substrate specificity, disturbance of nerve roots and anaphylactic reactions.
Chondroitin sulfate ABC endolyase also has potential for anaphylaxis, particularly after initial exposure, and its approval in 2018 in Japan for treatment of LDH is restricted to once-in-a-lifetime use. Unlike chymopapain, however, condoliase is highly substrate-specific for chondroitin sulfate and hyaluronic acid. It degrades the proteoglycan-rich tissue of the nucleus pulposus (NP) core of the vertebral disc without affecting other structures.3
Significant Relief at 3 Months of Yearlong Study
The DISCOVERY 6603 registrational phase 3, randomized, double-blind clinical trial compared the efficacy and safety of 1.25 units of SI-6603 with a sham placebo injection. Participants (n=352) were adults 30 to 70 years of age with contained posterolateral LDH, and a chief complaint of unilateral radiculopathy/radicular leg pain persisting after six weeks or more of conservative treatment. A total of 341 participants remained throughout the modified intention-to-treat analysis, with 169 receiving condoliase and 172 the sham injection.
The primary end point was change from baseline (CFB) to week 13 in worst pain score during the past 24 hours, averaged over the previous seven days, on the 0-100 visual analog scale. Key secondary end points were CFB in average worse leg pain at week 52, as well as herniation volume, and Oswestry Disability Index score at week 13.
Candido reported that the study met its primary end point, with the active treatment group having significantly greater improvement in worst leg pain score at week 13. Reduction of pain from baseline, by least squares mean (LSM), was –41.7 with active treatment versus –34.2 with sham injection.
Although there was also apparent (numerical score) advantage with active treatment in reducing herniation volume and in improving disability at week 13, these, as well as the pain scores, were not significantly different from placebo at week 52. The analysis used a gatekeeping algorithm which precluded finding statistically significant differences in herniation volume or disability improvement at 13 weeks without a statistically significant difference at week 52.
“The U.S. phase 3 trial was designed to control family-wise error rate for multiple tests of the primary and key secondary end points. A serial gatekeeping testing algorithm was used,” Candido told Pain Medicine News. “As the key secondary end point of worst leg pain at week 52 was not met, the serial gatekeeping testing algorithm was halted and remaining tests were labeled as ‘not significant.’”
The safety of the condoliase injection was reflected in an absence of adverse events leading to study discontinuation or in serious adverse events related to treatment. The investigators did find that changes in imaging occurred more frequently in the SI-6603 group than in those receiving placebo, but they were not associated with leg or back pain.
A treatment-related adverse event was reported in 71.9% of participants receiving condoliase and 60.3% given the sham injection. Of these, 28.1% and 10.3%, respectively, were deemed to be related to treatment. Most adverse events in both groups were characterized as mild in severity.
Although encouraged by these efficacy and safety data, Candido considered the limitations as well as strengths of this potential intervention for sciatica pain.
“Pain is a complex phenomenon with multiple potential contributing factors that influence it. History tells us that focusing exclusively on anatomical constructs as a solitary cause and effect for pain can be too simplistic,” Candido said.
“Patient characteristics that determine absolute success versus partial success or failure, when dealing with intervertebral disc derangements, have yet to be elucidated and remain an ongoing challenge for those of us who treat pain from LDH,” he said.
“This study has shown us promise in a potential treatment that does not rely upon conventional surgery or repeated epidural steroid injections, despite not yet pinpointing ‘optimal’ candidates,” Candido said.
The trial data also appeared to support a therapeutic potential to Andrew Zhang, MD, the chief of adult and pediatric orthopedic spine surgery at Ochsner LSU Health, in Shreveport, La.
“These phase 3 results of condoliase show a promising alternative to other nonoperative measures for lumbar disc herniation management,” Zhang commented to Pain Medicine News. “More long-term follow-up may be needed to better elucidate its implications in clinical spinal care.”
—Kenneth Bender
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