ARTICLE SUMMARY:
To address the huge unmet clinical need in osteoarthritis, Zimmer Biomet is transitioning from a device-only focus to a more holistic approach that incorporates solutions for managing patient populations.
Medical device companies seized the massive opportunities in osteoarthritis (OA), and their contribution to patient care has been phenomenal. Total joint replacement is a marvelous surgery that has enabled many people who once faced disability to lead close to fully mobile lives. But medtech companies’ traditional expertise and focus has been on biomechanical interventions; although they also offer orthobiologics, these fall into a unique category of therapies that are neither devices nor drugs and in general are not proven to be particularly effective, even at symptom relief.
More recently, the relentless focus on biomechanical approaches to OA is showing its limitations, particularly in adequately addressing the gap between conservative care (physician therapy, weight loss, etc.) and knee replacement surgery; now that researchers have shed light on the interplay of biomechanics and biochemistry in the course of OA, multidisciplinary approaches to treatment may be in order.
Drug companies’ lack of interest in the field has been glaring—a 2014 survey, albeit dated but still telling, of new drugs in development by PhRMA (Pharmaceutical Research and Manufacturers Association, the pharmaceutical industry trade association), showed only 10 drugs for OA in clinical trials, compared to tens of hundreds for cancer, even as OA is often placed among the world’s top disabling and even deadly diseases. Medical device companies are intimately familiar with the market. While no one expects them to jump into the biopharma fray, the question is whether they will adapt their core skill sets and cultural mindset to take a more holistic approach to addressing this huge opportunity, and, if so, in what ways.
The shifting perspective and looming large unmet clinical need has motivated Zimmer Biomet to change its approaches to solving the OA crisis. The company hasn’t said much publicly about the specifics of its multi-year strategic transition from a focus almost solely on devices to one that incorporates solutions for managing patient populations. It has, however, established a new early intervention team on the commercial side, which sets research priorities, as well as a biologics R&D team that develops products for different sales and marketing groups.
The R&D group has invested significantly in early-stage initiatives, including funding biochemistry studies and evaluating cell therapies and regenerative medicine technologies, but it is a challenge to justify investment in the latter relative to cost, says Joel Higgins, an engineer by training who is the senior director, R&D Biologics and general manager of Zimmer Biomet Diagnostics. The company is open to variety of treatment options, adds Jennifer Woodell-May, PhD, the research associate director, who is leading the work on early-stage OA.
“OA is obviously of great interest to Zimmer Biomet, and we are making sizable investments in the field, on both the commercial and R&D sides,” says Higgins. “Not only is OA a mechanical issue, but we have to look at the biochemical cascade once the biomechanical changes are initiated.”
Outside the US, the company markets nSTRIDE APS Kit, a point-of-care blood-based product for pain relief. While this is a device that processes the patient’s autologous blood to concentrate anti-inflammatory proteins, not a drug, its output may have biochemical effects, and it is undergoing rigorous clinical trials as part of the US regulatory approval process. Results from a Phase II randomized controlled clinical trial (RCT) were published in The American Journal of Sports Medicine in 2018; two RCT pivotal trials, one in the EU and another in the US, are progressing and will hopefully support a PMA filing, says Woodell-May.
The primary endpoints for these trials are still being discussed with FDA regulators, with the most likely indication for pain management associated with osteoarthritis.
The primary endpoints for these trials are still being discussed with FDA regulators, with the most likely indication for pain management associated with osteoarthritis. Although the nSTRIDE APS Kit may have potential for modifying disease progression, the FDA has not yet agreed on acceptable endpoints for studies demonstrating such an indication, which is a hurdle for both device and drug companies with ambitions in that direction. While “a lot of people have tried, no one has been able to demonstrate that any of the markers—including MRI—correlate to patient reported outcomes,” she says.
The agency currently accepts only X-rays for measuring disease progress in clinical trials, but X-rays pick up OA after the disease is well along in its progression, and they cannot measure small changes in improvement, she explains. This means that their information comes too late for available therapies to be effective.
The alternative is to find markers that identify people with early-stage OA, even before they experience significant pain, so that treatments can be initiated sooner. To this end, the Zimmer Biomet group is interested in understanding which patients are likely to respond to various therapies and consequently, the impact of a therapy on disease progression. It is developing biomarkers that correlate to OA disease stage and has research programs in this area underway with external academic investigators.
Zimmer Biomet obviously is not a clinical diagnostics company, but in August 2016, it bought CD Diagnostics, which has a CLIA-approved laboratory in Maryland that specializes in analyzing synovial fluid samples for diagnosis of periprosthetic joint infections. This acquisition is providing the foundational infrastructure and skill sets the company needs to offer laboratory-developed OA tests (LDTs) to its core customers. The result will be a value-add for the company’s existing OA recon joint franchise, as it aims to “be better stewards of medical resources,” says Higgins.
The investment was driven by the clinical need to address one of the most devastating potential complications of total joint arthroplasty with great patient morbidity. It is part of Zimmer’s efforts to maximize the value of its proposed interventions for its patient, provider and payor stakeholders, says Higgins, who believes this focus on customer solutions and improved patient outcomes will likely separate Zimmer Biomet in the market.”
The Maryland laboratory gives Zimmer Biomet a further competitive advantage because it has the capacity to process large volumes of synovial fluid specimens; it already processes up to 40,000 specimens a year. Tens of thousands of synovial fluid samples are needed to study the new OA markers, but synovial fluid can be difficult to extract from patients with early-stage OA who lack effusions, Higgins points out.
Realization that osteoarthritis may result from numerous pathologies has led the team to develop a panel that analyzes synovial fluid for markers of gout, low-grade infections, and rheumatoid arthritis, as well as two other markers of early inflammation and cartilage breakdown. The panel is a mix of well-established and proprietary biomarkers, and the expectation is that an LDT will be available within the next 12 months.
The group is also exploring markers to help predict which patients are most likely to respond to various injection treatments such as nSTRIDE APS and hyaluronic acid (HA) injections. This program is in earlier development and the markers need validation. There are also plans to look for markers that identify potential responders to anterior cruciate ligament (ACL) reconstruction and those who are likely to progress quickly to OA so providers can keep a close eye on those patients.
