“The definition of a game changer is an event or an idea or a procedure that effects a significant shift in the current manner of doing or thinking about something.” explained Michael Berend, M.D., Midwest Center for Joint Replacement, Indianapolis, Indiana.
Could a new 90-day steroid have the same effect on the practice of musculoskeletal care as Marcaine did in a fatty membrane?
When Dr. Berend’s clinic started using that longer lasting form of bupivacaine (liposomal bupivacaine), it “really changed our practice from inpatient surgery to better pain control and outpatient surgery. Zero percent of our patients went home the same day in 2010, now it’s over 50% in 2016. And there’s obviously significant cost savings.”
For patients with arthritic knees—how big a game changer could a 90-day corticosteroid be?
Innovations in Pain Management
In a world of cost control and bundled payments, pain management has proven to be the straw that stirs this new era of practice management.
Liposomal bupivacaine (Exparel) is expected to earn its supplier Pacira Pharmaceuticals about $300 million in sales this year, up 8% from last year. At approximately $300 per dose, this represents approximately 1 million doses (3,300 every day).
The market size for intra-articular knee injections is about 5 million injections annually.
Most Wall Street analysts have been predicting that the FDA will approve a time release version of triamcinolone acetonide (TCA)—a corticosteroid first approved by the FDA for use in humans in 1965 under the brand name Kenalog—in early October. For 52 years TCA has been used as an anti-inflammatory treatment for ocular and skin problems.
This new version is brand named Zilretta.
Many OTW readers saw the first data on Zilretta in the June 2015 issue of the Journal of Bone and Joint Surgery (J Bone Joint Surg Am, 2015 Jun 03; 97 (11): 877 -888).
Given the near universal use of steroidal injections to treat knee pain, extending its duration to as long as 90 days may be one of the most significant new musculoskeletal products since Exparel.
Zilretta, in our opinion, has the potential to become a standard of care in every musculoskeletal practice.
Zilretta’s Data
Zilretta, which is being brought to market by Boston, Massachusetts-based Flexion Therapeutics, has had several studies conducted, including an FDA supervised, double blinded and randomized comparison of Zilretta on 228 patients with either unilateral or bilateral osteoarthritis (OA) of the knee.
The study tested three doses—low (10mg), medium (40mg) and high (60mg)—against an immediate release TCA.
The 58 patients who received the low dose (10mg) reported statistically significant pain relief at 8 weeks versus the 51 patients who received a 40mg dose of the immediate release TCA who also experienced statistically significant pain relief, but at a lesser amount than the 10mg extended release patients.
The 59 patients who received that medium dose (40mg) reported the best outcomes of all at 8 weeks and reported significantly better outcomes than the 40mg immediate release patients.
The 59 patients who received the high dose (60mg) reported LESS pain relief than the 40mg group, although still superior to the immediate release group.
Here’s what the investigators had to say about the results:
“Given the known anti-inflammatory properties of corticosteroids, it is reasonable to infer that the analgesia observed following intra-articular injection is a result of the suppression of synovitis. The anti-inflammatory effects of corticosteroids are the product of repression of key inflammatory transcription factors and regulation of posttranscriptional mechanisms. The long term activation of these signaling pathways (through maintenance of therapeutic intracellular TCA concentrations) may be required to achieve the amplified therapeutic effect observed with [extended-release TCA].
“Consistent with long term suppression of local inflammation by [extended-release TCA] are data from index knee exams assessing clinical signs indicative of local inflammation. At baseline 86.8% of patients had signs of local inflammation. At every post baseline visit, the 40mg [extended release TCA] (associated with optimal analgesic effect) substantially increased the percentage of patients shifting to no evidence of inflammation relative to TCA Instant Release.”
Safety Implications of Time Release Corticosteroids
Forty milligrams of any corticosteroid which elutes over a 90-day time period is, theoretically, bathing the joint in less than ½ milligram of corticosteroid daily.
By contrast, 40mg of an immediate release corticosteroid bathes the joint in 40mg that first day.
The safety implications of this difference could be enormous. Here’s is how the researchers characterized it in the JBJS published study:
“Following injection of TCA IR, plasma concentrations of TCA rise precipitously as drug is rapidly absorbed into systemic circulation. Consistent with the prolonged, relatively slow release of TCA, these early peak levels of TCA are not observed at any dose of [extended release TCA]. This approximately 18-fold reduction in early peak plasma levels may confer safety advantages in patients with compromised glycemic control”.32-34 “(CME3)” and this was subsequently demonstrated in a head to head clinical trial.
Again, they noted an 18-fold reduction in early peak plasma levels which translated into benefit in patients with compromised glycemic control (diabetics).
New Zilretta Study
On September 7, at the PAINWeek conference, Flexion released new Zilretta clinical trial data.
It came from a post-hoc, pooled analysis of three Phase 2/3 double-blind, randomized, placebo-controlled clinical trials which were conducted with 586 patients suffering from OA of the knee.
The patients received either a single, intra-articular (IA) injection of Zilretta (32mgs) or an injection of a saline-placebo.
Their average daily pain (ADP) intensity was assessed by investigators for at least 12 weeks.
Each trial participant was given a rescue medication (acetaminophen/paracetamol 500mg tablets) at the beginning of the study. If pain was too severe, they were encouraged to use the acetaminophen/paracetamol as needed.
The study investigators tracked each patient’s use of the rescue medication.
In this way, the investigators could gather empirical evidence of the overall analgesic effect of Zilretta versus saline placebo.
Again, this was a double-blind and randomized clinical trial.
At each week during the study, patients given Zilretta used less acetaminophen/paracetamol than the control group.
At week 12, the mean number of daily rescue medication tablets taken was 0.86 for Zilretta compared with 1.23 for saline-placebo, resulting in a least-square-mean (LSM) difference of -0.37.
The incidence of adverse and serious adverse events were similar across the Zilretta and saline-placebo groups (51.9% vs 49.2%, and 3.1% vs 1.1%, respectively). No drug-related serious adverse events were observed in these trials and adverse events have typically been localized, mild and comparable to those observed with saline-placebo.
“In clinical trials, Zilretta has demonstrated clinically meaningful pain relief for patients with OA of the knee for at least 12 weeks, and the reduced utilization of rescue medicines observed in this analysis serves as another important indicator of the robustness of Zilretta’s analgesic profile,” said Flexion President and CEO Michael Clayman, M.D., “We believe that, pending regulatory approval, Zilretta has the potential to bring meaningful pain relief to millions of Americans who make up this large and growing patient population.”
The Future
The FDA is still evaluating Zilretta. If approved, it will be the first intra-articular, extended release treatment for patients with osteoarthritis related knee pain. In February 2017, the FDA accepted Flexion’s New Drug Application for Zilretta in OA of the knee. Under the Prescription Drug User Fee Act, the agency has established a user fee goal date of October 6, 2017.
So, as the analysts on Wall Street have been saying, FDA approval—while never a certainty—could occur in the coming weeks.
Flexion’s vision is to provide the musculoskeletal community of caregivers and patients with innovative, non-opioid, local therapies for treating musculoskeletal conditions. Zilretta, which uses a proprietary microsphere technology (a poly lactic-co-glycolic acid matrix) to slowly dispense TCA into the knee is just such a product.
The market Zilretta is addressing encompasses more than 14 million Americans with OA of the knee. Each year, more than 5 million OA patients in the U.S. receive either an immediate release corticosteroid or hyaluronic acid intra articular injection for knee pain.
In our opinion, every orthopedic, sports medicine or pain practice in America will find Zilretta, once approved by the FDA, to be an invaluable new tool.
