FDA Panel Backs Injection for Leg Pain Caused by Herniated Discs

FDA advisors largely supported the regulatory approval of condoliase for nerve pain associated with lumbar disc herniation (LDH) if it can be targeted to the right patients.

During Friday’s meeting of the Anesthetic and Analgesic Drug Products Advisory Committee, members voted 8-4 in support of the approval of condoliase, noting that the benefits of the intervertebral injection outweigh the risks when used to treat radicular leg pain associated with confirmed nerve root impingement caused by LDH in adults. If approved, condoliase would be the first biologic or drug green-lit for lumbosacral radicular pain.

Patients with this condition have been seeking relief, with varying degrees of success, from an array of nonpharmacologic, off-label pharmacologic, and device-based therapies. After failing on these conservative therapies — including physical therapy, nonsteroidal anti-inflammatory drugs, acetaminophen, drugs for neuropathic pain, systemic steroids, spinal cord stimulation, and percutaneous discectomy — some patients will resort to surgery.

One of those voting yes for condoliase was Michael Sprintz, DO, of the Sprintz Center for Pain and Recovery in The Woodlands, Texas, who said that he saw value in condoliase potentially delaying — if not preventing — surgery, as well as providing an alternative to opioids for patients who have already failed an interventional therapy.

Condoliase does address an unmet need in patients who haven’t responded to conservative therapy, agreed Mark Bicket, MD, PhD, of the University of Michigan in Ann Arbor, citing the two positive trials on condoliase that he suggested were enough to claim treatment efficacy. “I do think the product has potential to be meaningful for patients, given that there are many reasons that some may not be able to pursue surgery,” added Bicket, who also voted yes.

Despite Friday’s net-positive vote, however, the panelists noted that condoliase’s proposed indication may be too broad for what is supported by the data. The evidence for condoliase points to it being effective in the short term in a narrow population with a specific mechanism of lumbosacral radicular pain. Participants in the latest randomized trial had been required to have, among other criteria:

• Contained posterolateral LDH at either L4-5 or L5-S1 (or L5-6) with root impingement on MRI
• A chief complaint of unilateral radiculopathy or radicular leg pain in the concordant dermatome of the affected nerve root
• Failed 6 weeks or more of conservative treatment including medications, physical therapy, chiropractic treatment, acupuncture, spinal injection, epidural injection, or nerve block
• No other disorders associated with low back pain, chronic pain disorder, peripheral neuropathy caused by diabetes, history of substance abuse or drinking more than two alcoholic drinks per day, and concurrent anticoagulant therapy

This 352-person trial, dubbed Study 1133 and conducted in the U.S., found that condoliase (a single injection of 1 mL at varying concentrations) did improve average leg pain from baseline to week 13, assessed by Visual Analog Scale, over sham injection outside the disc.

Investigators had learned their lesson and restricted the study population after a prior randomized trial with looser entry criteria — resulting in a pool of people having other non-herniation causes for their pain — had missed its efficacy endpoint. Another previous condoliase trial in Japan had been positive.

If condoliase goes out on the market, “we have to control this,” said Milan Stojanovic, MD, of Harvard Medical School and VA Boston Health Care, who voted yes. In addition to labeling language about nerve root impingement being required, he suggested a minimal threshold for the severity of the nerve root compression.

“I think we need to include failure of conservative therapy and we need to better define that,” added Sprintz. He made the point that people who have tried over-the-counter ibuprofen and those who went ahead to epidural steroid injections would not be considered to have received the same level of conservative therapy.

Only in Japan is condoliase currently on the market for lumbosacral radicular pain. Since 2018, an estimated 29,000 Japanese patients have received condoliase to date, according to sponsor Seikagaku Corporation.

People with radicular leg pain have a type of neuropathic pain stemming from pressure on a lumbar spinal nerve root. The most common cause is LDH, which can lead to direct compression of the lumbar/sacral nerve root, reduced blood flow, and activation of inflammatory pathways. Acute radicular pain due to LDH usually resolves spontaneously or responds to conservative management. However, in patients with new-onset lumbar radiculopathy, 15% to 40% will experience chronic pain or a relapse of pain.

Condoliase, a biological product derived from foreign proteins, essentially reduces disc volume and relieves the pressure on the lumbar spinal nerve root. It is an enzyme purified from a gram-negative bacillus (Proteus vulgaris). It works by degrading the chondroitin sulfate that, in its hydrated state, makes up the bulk of the nucleus pulposus of the intervertebral disc.

Safety-wise, one of the concerns of this approach is the risk of immune-related adverse events. There was one potential severe cutaneous adverse reaction (SCAR) in an early-phase study in 2000, followed by five confirmed or suspected cases in the Japanese postmarketing data. These reports suggest a SCAR frequency of 1 in 1,500 or 1 in 2,000 people receiving condoliase.

“Ouch,” said Steven Schiff, MD, PhD, of Yale University in New Haven, Connecticut. “I am concerned. I could envision in the next few years, a million people might get this therapy … a few hundred of these [SCAR] cases in the U.S. would likely cause the FDA to think twice about continuing approval.” Even so, he voted yes.

Another concern is that the removal of chondroitin sulfate can lead to a decrease in disc height, reduced spinal mobility, reduced shock absorption, and the development of bony growths to stabilize the spine. These changes may in turn result in more disc-related complaints, such as axial back pain, or might affect future surgical options.

As such, John Kirkpatrick, MD, of the Orlando VA Medical Center and University of Central Florida in Orange County, voted no. “We don’t know if these patients are going to be back pain cripples in 10 years,” he said, stressing the need for long-term data.

While the FDA is not required to follow the advice of its advisory committees, it typically does.

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