Arthritis Foundation Leads Efforts to Develop New Drugs for OA
International experts, FDA representatives come together to tackle challenges to finding effective osteoarthritis treatments.
By Jill Tyrer | July 2021 | updated: September 2022
The proceedings of the osteoarthritis (OA) treatment development workshop are published in the journal Seminars in Arthritis and Rhuematism. This convening of international experts clarified obstacles to approval by the Food and Drug Administration (FDA) and generated ideas to improve research studies and streamline clinical trials for potential new OA treatments.
Why aren’t there any good treatments for osteoarthritis like there are for rheumatoid arthritis? Can solutions move beyond treating pain to slowing the progression of the disease? If you have OA, you’ve probably had the same thoughts.
When you live with OA, you also live with the frustration of limited treatment options. What treatments are available tackle pain and other symptoms, but nothing is available to prevent or slow the disease process itself.
That’s why the Arthritis Foundation partnered with the FDA to host a workshop on developing new treatments with long-term benefits for OA. The virtual workshop, held in June 2021, brought together international OA experts and researchers from academia, the pharmaceutical industry, government and nonprofits along with patient representatives. The focus: challenges and potential solutions to developing and receiving approval for new OA treatments.
We arranged for three people to share their stories first-hand with FDA representatives, researchers and other participants. Bill Agee, Stephanie Rosado and Emily Hunt spoke, explaining how they live with constant pain and how OA has undermined their ability to participate in activities they need and want to do.
“I have arthritis pain daily,” said Agee, who has had at least two dozen surgeries on his knees, back and ankle since his diagnosis in 1995. “Some are good pain days some are bad pain days. On good pain days the pain is there but doesn’t prevent me from being able to work full time at my office job. On the bad days the pain is debilitating,” he told participants. “My utopia would be the release or approval of some new drugs to eliminate the pain. … I really want to know my pain’s going to be under control.”
The fact that the workshop took place at all shows that the FDA is taking osteoarthritis seriously. In fact, it has now labeled OA a “serious disease,” said rheumatologist David Felson, MD, MPH, professor of medicine and epidemiology at Boston University, speaking after the workshop. The “serious disease” designation allows companies to use the FDA’s Accelerated Approval pathway.
“One of the most important things is the motivation on the part of the FDA and the Arthritis Foundation for having this meeting, which shows a real intent — almost to the point of urgency — to develop effective treatments for osteoarthritis. I think this was a real high priority on the part of the FDA to find something they can approve.” Dr. Felson, who participated in the workshop as an Arthritis Foundation representative, is also chair of the Foundation’s Osteoarthritis Clinical Trials Network, former co-chair of our Osteoarthritis Clinical Studies forum series and a two-time winner of the Foundation’s Lee C. Howley Sr. Prize for Arthritis Science Service.
An Urgent Need for Treatments
There’s no question effective treatments for OA are needed. Osteoarthritis affects an estimated 500 million adults worldwide, and some 32.5 million in the U.S. “There’s a large cost burden, with hundreds of billions of dollars annually in the U.S. alone, with over 900,000 hospitalizations, largely reflecting joint replacement,” Tuhina Neogi, MD, PhD, told the more than 900 participants. Although there’s good evidence that weight loss and exercise are effective treatments, people have trouble sticking with diet and exercise regimens, said Dr. Neogi, a rheumatologist, epidemiologist, professor and chief of rheumatology at Boston University School of Medicine. Other treatments, including nonsteroidal anti-inflammatories (NSAIDs), hyaluronic acid or corticosteroid shots and surgery, have side effects and risks.
“We now have quite effective treatments for rheumatoid arthritis, for gout and we’re even beginning to have effective treatments for lupus,” Dr. Felson said. “What remains is this very large contingent of patients who are having lots of pain and disability — the most common of all these [rheumatic] diseases — and we really don’t know how to intercede and delay its progression and make people feel better long term without side effects. It has emerged as one of the big remaining challenges.”
The lack of other effective and safe options “contributes to disability, poor quality of life and, I would argue, has contributed to an increase in opioid prescriptions,” Dr. Neogi said.
Short of joint replacement surgery, available treatments don’t treat the disease itself in terms of slowing, stopping or preventing disease progression and joint damage. They generally treat only short-term symptoms.
“We clearly need more treatment options. Even though we do have some options for symptoms, they have minimal to moderate efficacy for a substantial proportion of patients,” Dr. Neogi said.
One of the primary obstacles to developing new treatments is that OA progresses very slowly. As a result, any drug trial needs to either involve a huge number of participants or it needs to last for many years, or both — and the cost of such a trial is generally prohibitive. “Currently, there are not a lot of drugs being developed for osteoarthritis, and one of the reasons for that is how lengthy and how large these clinical trials are,” explained Angelika Jahreis, MD, PhD, global head of development in immunology, hepatology and dermatology for drug maker Novartis.
Another major obstacle — and a primary focus on the workshop — has been uncertainty about what endpoints researchers should target and the FDA would accept. Endpoints are outcomes that can be reliably measured to determine whether a potential treatment is providing any benefit. Some endpoints include measures of pain, function, disability and other symptoms that reflect the well-being of the patient. Others use X-ray, MRI and other imaging to measure the level of cartilage health or damage that indicates disease. A third group are biochemical markers from blood or urine, for example, that measure factors such as inflammatory proteins indicating levels of inflammation.
However, cartilage damage, inflammation levels and other “structural” endpoints don’t necessarily correlate with how a patient feels, and it isn’t clear why that is. A patient’s pain level might not reflect the amount of damage in their joint, or vice versa. In fact, a large study of one drug found that it could preserve and even build cartilage, but patients in the trial had no change in their pain levels.
“There’s not any evidence here that preventing cartilage loss will make people feel any better,” Dr. Felson explained. “Would a patient be willing to take a therapy that might have side effects, frankly, and might be expensive, if there’s no evidence it’s going to make them feel any better in terms of pain or disability, but just prevent cartilage loss? I personally wouldn’t as a patient.”
For the FDA to approve the use of structural endpoints, a clear correlation to long-term benefits for the patient would have to be shown, said Nikolay Nikolov, MD, director of the FDA’s Division of Rheumatology and Transplant Medicine. That doesn’t yet exist.
“There was the hope that we could use biomarkers like imaging or biomarkers to tell us if a therapy was going to work, and the answer was ‘Not yet.’ There just isn’t good enough info or data yet to permit that,” Dr. Felson said.
Instead, FDA representatives proposed a set of endpoints that looks at both patient well-being in terms of pain and function as well as joint structure changes.
A Promising Surprise
The FDA’s current rejection of biomarkers as surrogate endpoints was disappointing, and contrasts with recent news of a controversial FDA approval of Alzheimer’s drug, aducanumab, based on surrogate endpoints. Aducanumab lowered levels of a protein correlated to disease but did not improve the patient’s cognitive abilities. The FDA conditionally approved the drug because it is anticipated that the protein changes will eventually result in disease modification effects that will affect patients’ functioning.
Interestingly, a promising recent study for osteoarthritis didn’t have OA-related endpoints at all. Researchers who were studying the drug canakinumab to treat cardiovascular disease noticed that many study participants had fewer total joint replacements in their knees and hips.
“We don’t really know whether it works to prevent osteoarthritis or slow the progress of osteoarthritis, but it’s very promising,” said Dr. Felson. Novartis, maker of canakinumab, is pursuing it. “They’re very intent on developing something, and given that extremely promising preliminary result, I think they’re intent upon pursuing it and trying to see if they can confirm it.”
Research Tools and Techniques
Digging into the details of research methods and measurements, workshop participants discussed challenges of using certain established measurement tools and scales. Pain, for example, is subjective, and a person’s pain perception is believed to change over time when he or she lives with chronic pain.
X-ray and MRI also have limitations. They can detect changes in bone and cartilage, but osteoarthritis is a disease of the whole joint, so changes in cartilage show only a piece of the picture, pointed out Tim McAlindon, MD, chief of rheumatology at Tufts University Medical Center and professor at Tufts University School of Medicine.
Although the workshop did not produce a magical solution for osteoarthritis, it did clarify obstacles to getting drugs approved and what the FDA would accept for approval.
It also generated discussion — now entered into the peer-reviewed scientific literature — about improving studies by using biomarkers to select study participants at more specific stages of disease; using mobile phones to collect real-time data, like when bottles of prescription pain relievers are opened; using measures that correlate pain and function with certain activities, like standing up or walking a flight of stairs; monitoring periods of activity and rest; tracking sleep, depression and pain; and using brain MRI to help measure pain perception. Any of these may help streamline or define trials for potential new treatments.
“Sometimes when you don’t make a lot of progress in a disease, it’s because there are a lot of big challenges and it turns out the easy roads aren’t working, and that’s what’s going on here,” Dr. Felson said. “But there’s a large community trying to address these challenges, and sooner or later there’s going to be success.”
For patients like Bill Agee, success can’t come too soon. “If I knew I could test something that would help others not have to experience my daily pain, you guys can sign me up today. I’m ready to go,” he said. “Please do more of these workshops. Please. Cause you really are making a big difference in people’s lives.”
It’s for people like him and the millions more living with OA pain and disability that the Arthritis Foundation will continue supporting research, advocating for more funding, working with experts and regulators and pushing to get more effective treatments.