Potential game-changer for OA

BURLINGTON, Mass.—When Dr. Michael Clayman stepped away from pharma giant Eli Lilly to co-found biotech Flexion Therapeutics in 2007, it was to focus on finding a safe and longer-lasting treatment for the rising number of osteoarthritis (OA) patients in the United States. The fledgling company spent several years searching for the solution in orphan drugs until hitting paydirt with its own in-house discovery, now known as Zilretta—an extended-release formulation of triamcinolone acetonide designed to help patients with OA manage pain.

In October 2017, Zilretta received U.S. Food and Drug Administration (FDA) approval and Flexion initiated the full commercial launch that November for OA-related knee pain, with some estimates for annual sales of up to $1 billion. Flexion is currently exploring the expansion of Zilretta’s label to include pain relief in the hip and shoulder.

“Zilretta was developed and commercialized internally by Flexion,” Clayman tells DDNews. Now CEO and president of Flexion, Clayman and former Eli Lilly colleague Dr. Neil Bodick founded Flexion after making “the decision to concentrate on musculoskeletal conditions based on the large unmet medical need in this space, particularly in the area of osteoarthritis.”

“OA of the knee (OAK) is a painful, progressive condition with no cure, and is commonly treated with intra-articular steroid injections, which generally provide good pain relief for two to four weeks,” Clayman says. “However, by medical convention, steroids are not administered any more often than every three months. Flexion identified this gap and set out to develop an extended release treatment for OAK.”

According to Clayman, this strategic decision led to the development and eventual FDA approval of Zilretta, the first and only extended-release, intra-articular therapy for osteoarthritis knee pain. Zilretta employs proprietary microsphere technology to provide extended pain relief over 12 weeks, and “The availability of Zilretta marks a major advancement in the treatment landscape for managing OA knee pain.”

In the face of a national crisis in opioid addiction, Zilretta “comes at a time when our society is in urgent need of innovative, non-addictive therapies to help the millions of Americans living with chronic OA knee pain,” he says.

A clinical trial evaluating repeat administration of Zilretta completed enrollment in July 2017 and top-line study results are expected in the third quarter of 2018, Clayman continues. Top-line results from a clinical trial evaluating the pharmacokinetics (PK) and safety of concurrent injections of Zilretta in patients with bilateral OA of the knee were anticipated in the second quarter.

In December 2017, Flexion initiated a randomized, open-label Phase 2 clinical trial to evaluate the PK and safety of Zilretta in patients with OA of the shoulder or hip. Top-line results from that trial, known as the “SHIP” study, are expected in second half of this year.

In May 2018, Flexion initiated an open-label study assessing the effects of a single administration of Zilretta on synovitis in patients with OA of the knee. Top-line results are anticipated in 2019.

“We expect (Zilretta) will make a real difference for patients and be a commercial success, generating resources that will allow us to fuel the pipeline,” Clayman says.

Also known as degenerative joint disease, osteoarthritis—the most common form of arthritis—is a painful, chronic joint disease that affects more than 30 million Americans and accounts for more than $185 billion in annual expenditures, according to the U.S. Centers for Disease Control and Prevention. The prevalence of OA is expected to continue to increase as a result of aging, obesity and sports injuries. Each year, approximately 5 million OA patients receive either an immediate-release corticosteroid or hyaluronic acid intra-articular injection to manage their knee pain, but the steroid injections provide short-lived pain relief.

On April 18, the Journal of Bone and Joint Surgery published the full results from the pivotal Phase 3 trial which served as the basis of Zilretta’s FDA approval. This showed:

Flexion announced on April 26 updated interim findings from its ongoing Phase 3b, open-label study to evaluate the overall safety and general tolerability of repeat administration of Zilretta. The data were presented during a poster session April 27 at the Osteoarthritis Research Society International (OARSI) 2018 World Congress in Liverpool, England.

“These results demonstrate Zilretta’s ability to provide deep and sustained relief to a patient population that reflects real-world clinical experience,” Clayman remarks. “In particular, we are delighted to see an average time to second administration of greater than 16 weeks, which is especially notable given the high proportion of patients in this study with the most advanced stage of OA.”

The primary endpoint of the trial is overall safety and general tolerability of repeat administration of Zilretta in patients with symptomatic OA of the knee.

Participants received an initial intra-articular injection of Zilretta followed by evaluation at Weeks 12, 16, 20 or 24 to determine their eligibility for a second injection. Repeat administration occurred when, in the opinion of the patient and physician, the patient benefited from and tolerated the initial administration without safety concerns and was clinically indicated to receive additional treatment.

Study participants who received repeat administration of Zilretta are followed for a total of 52 weeks after the initial injection, regardless of when the second injection is administered. At specified times throughout the trial, participants undergo physical examinations, knee assessments and X-rays.

As of April 5, 2018 (minimum follow-up of 11 weeks post second injection), Zilretta has been well tolerated, no drug-related serious adverse events have been observed and the overall safety profile is similar to that observed in the single injection pivotal Phase 3 trial.

“The first quarter of 2018 was marked by encouraging sales of Zilretta, strong commercial execution, positive reimbursement developments and excellent progress advancing our clinical trials,” Clayman told investors in May. “With the first full quarter of sales behind us, our confidence in Zilretta’s ability to make a meaningful difference for patients confronting osteoarthritis knee pain continues to grow.”