JBJS Study: Extended Release Steroid Amplifies Pain Relief

First came the poster at an Osteoarthritis Research Society International (OARSI) meeting in 2013 in Philadelphia. Then, six months later, more data was presented from the podium at the American College of Rheumatology (ACR) meeting in San Francisco.

And that data would have sort of washed over us if at roughly the same time a revolution was not occurring in large joint post-operative pain management courtesy of an extended release version of bupivacaine called Exparel, which is produced by New Jersery-based Pacira Pharmaceutical. Inc.

Exparel is an extended release form of bupivicaine and has literally taken the practice of orthopedic surgery by storm.

Could extended release corticosteroids do the same?

Then…on cue…JBJS provided the first Level 1, peer reviewed study to give us quantitatively and qualitatively data on an extended release corticosteroid.

Here is the reference: Journal of Bone and Joint Surgery, (J Bone Joint Surg Am, 2015 Jun 03; 97 (11): 877 -888).

An Extended Release Corticosteroid

Extended release is another way of saying control. No extended release means delivering a bolus of a drug to the injury site (typically) and then trying to figure out what dispersion or absorption rates might be—whether the patient is a 300lb professional football player or a 130lb 70-year-old female.

Given the new bundled pay environment that all physicians now find themselves in, control has become the name of the game. Cost control. Operational control. Rehab process control. And, perhaps most important, pain control—pre, intra and post-op pain management.

Better pain management with better data collection and analytics are at the core of the future of orthopedics.

The purpose of this study was to test an extended release version of triamcinolone acetonide (TCA)—a corticosteroid first approved by the FDA for use in 1965 under the brand name Kenalog.

TCA has also been around for years as a topical anti-inflammatory treatment for ocular and skin problems.

The study looked at a particular TCA formulation which embedded the corticosteroid in biodegradable microspheres of poly lactic-co-glycolic acid (PLGA).

Most corticosteroids offer two to four weeks of pain relief. So, the question for the study investigators was…how well, how long and how consistently would these PLGA microspheres deliver TCA to an arthritic knee?

And, by the way, if this new formulation worked for three months it would represent a 300-500% increase in pain relief duration.

Why Didn’t Someone Think of This Sooner?

Good question.

Exparel, an extended release version of bupivacaine came to market in late 2011—33 years after bupivacaine received NDA (new drug application) approval from the FDA in 1978. In retrospect, it seems obvious that the market would want an extended release bupivacaine—particularly considering the dramatic effect it’s had on large joint surgery.

Simply lengthening the duration of post-operative pain relief allowed patients to get out of bed faster, begin rehab sooner and leave the hospital in better shape than in the pre-Exparel days. Patient satisfaction rates soared.

Extended release bupivacaine (Exparel-which is produced by Pacira Pharmaceuticals) cost about $390 per dose but effectively cut thousands of dollars operative and post-operative costs by getting patients up, moving and heading home faster.

In its first year, Exparel sales reached $18 million. This year, five years later, sales are expected to reach $283 million. The company is worth about $1.62 billion.

What does as extended release corticosteroids imply for the treatment of arthritic knees?

Professor Philip Conaghan, Chair of Musculoskeletal Medicine at the University of Leeds in the UK, attended the Osteoarthritis Research Society International 2016 World Congress and, after seeing the clinical data from this and one subsequent study of this sustained release TCA, said: “Consistent results across two clinical trials suggest that, at last, we have a long-lasting intra-articular (IA) therapy which is highly effective and has the potential to change the treatment paradigm for osteoarthritis.”

The JBJS Study of the Extended Release TCA

The company who developed this extended release version of TCA is Burlington, Massachusetts-based Flexion Therapeutics, Inc. Management at the company has put their product through three randomized, double-blind clinical studies at dozens of sites so far.

The first of those studies is the JBJS study and it is the only public information available for general dissemination. Notably, it is Level 1 study data and it did come through the peer review gauntlet at the leading orthopedic journal.

N=228

In the JBJS published study, 228 patients were randomized and treated with three different dosages of extended release TCA (10, 40 and 60mg) and an instant release TCA injection—so four arms.

The treatment arms were well balanced across demographic and baseline characteristics. Average age of the treatment patients was 61.5 years. Here is a table which summarizes the demographics and OA disease level of the study patients:

The patients were treated in 22 study centers in Canada (12), Australia (8), and the U.S. (2). To be included in the study, patients were required to be at least 40 years old, have a body mass of under 40.

The patients also had to have had a diagnosis of either unilateral or bilateral osteoarthritis (OA) of the knee at least six months before screening. They also needed a 24-hour average pain score (0–10 NRS) for at least five of the seven days prior to Day 1 of the study and a Kellgren-Lawrence grade 2 or 3.

Each study patient agreed to abstain from using restricted medications and non-pharmacological therapies during the study although they were allowed to take study-issued acetaminophen/paracetamol (up to 3 grams/day) as rescue medication.

Patients were excluded from the study if they had received an IA corticosteroid in any joint within 3 months of screening; oral, inhaled, or intranasal corticosteroids within 1 month; IA hyaluronic acid in the index knee within 6 months or if they had prior arthroscopic or open surgery of the index knee within 12 months.

10mg vs. 40mg vs. 60mg

The typical dose of TCA is 40mg. If the dose becomes an extended release treatment then what changes? Should an extended release dose be less…or more?

So this Phase 2, double blind study collected data for three different dosages of sustained release TCA and compared those three dosages to the standard 40mg dose of immediate-release TCA.

The three extended release TCA dosage levels chosen were: 10mg, 40mg and 60mg.

Here is what the investigators learned and published in the JBJS article.

Low Dose: The 10mg extended release TCA delivered slightly better pain relief than 40mg immediate-release TCA but the difference was not statistically significant. Here’s a table which summarizes the results.

Average Dose: The 40mg extended release TCA delivered better pain relief than either the 10mg extended-release TCA or the 40mg immediate-release TCA. At Week 8 (see table below) the difference between extended release TCA (40mg) and immediate release TCA was also statistically significant for pain, stiffness and function.

High Dose: The 60mg dose had a slightly unexpected result. To quote directly from the JBJS study: The extended-release TCA “at 60 mg produced an effect similar to that of the 40 mg dose through Week 6 [but] during the second 6 weeks of the follow-up period, the effect of the 60 mg dose diminished in magnitude reaching a level similar to that of TCA IR (immediate release) at Weeks 11-12.” As the 8 week data (see table below) shows, the 60mg extended release dose was superior to 40mg immediate release, but it was NOT superior to the 40mg extended release dose. Here’s the summary data.

Discussion About How Extended-Release Corticosteroid Might Be Working

The study’s investigators wrote this about the use of an extended release TCA:

“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 40 mg [extended release TCA] (associated with optimal analgesic effect) substantially increased the percentage of patients shifting to no evidence of inflammation relative to TCA IR.

“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)”

Regulatory

The company which developed this particular formulation of TCA received a letter from the FDA this past May saying that the clinical study data for their extended release version of TCA (which they’ve branded Zilretta) was “acceptable to support filing of an NDA submission.” That letter meant that an in-person NDA meeting was unnecessary and that the FDA responses would serve as the official meeting minutes.

If the FDA’s timing for similar NDA’s holds in this case, then the FDA should rule on Zilretta’s commercialization within about 10 months following submission—or between July and October 2017.

We also note that in September 2015 the FDA granted Zilretta Fast Track status.

So Zilretta will be quickly entering the FDA review process.

Flexion Therapeutics has told its investors and other stakeholders; “The endorsement from the FDA for the Zilretta NDA submission represents a major milestone in the development of this drug candidate and brings us one step closer to making it available to the many millions of knee osteoarthritis (OA) patients who lack good pain-relief options. We intend to submit the NDA in the fourth quarter of this year.”

Flexion Therapeutics, Inc.

Flexion is run by some long-time veterans of the both the pharma world and the orthopedic injection world.

The two founders of the company are Michael Clayman, M.D. and Neil Bodick, M.D., Ph.D.

Both founders have decades of experience in big pharma—Dr. Clayman was vice president, Lilly Research Laboratories, and general manager of Chorus, Lilly’s early-phase development accelerator. Dr. Bodick, who holds 13 patents, was founder of Eli Lilly’s Chorus and served as its chief medical officer and chief operating officer.

But Flexion’s bench is deep. Many of its key executives were also the key people who brought the marketing leading HA injection to market—Synvisc®.

So, get ready. A well-studied, FDA fast-tracked, extended release corticosteroid for osteoarthritic knees is moving into FDA review process and, in the hands of this team at Flexion, could well be on the market sometime next year.

Stay tuned.