Osteoarthritis drug pipeline rattles as FDA rejects top contender: What comes next?
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Progress toward effective drug therapies is often marked with failure; yet even among a host of difficult-to-treat arthritis conditions, osteoarthritis has received a disproportionate share of therapeutic setbacks and disappointing clinical trials.
The latest setback in OA came in March, when a pair of FDA advisory committees rejected a risk mitigation proposal from Pfizer for its nerve growth factor-blocker tanezumab, stating it would fail to ensure the drug’s benefits outweigh its risks for patients with OA. The company had billed the drug as a great hope for patients — a nonopioid, nonsteroidal analgesic that provides clinically important improvements in pain and physical function in knee and hip OA.
However, in a near-unanimous vote, FDA’s Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee ruled that the associated risk for joint destruction, or rapidly progressing OA, and other safety outcomes was too great, even with the proposed mitigation efforts, which included lower dosages and annual X-rays.
And so, the search for a pharmacologic treatment, beyond NSAIDs and joint replacement, continues.
“For OA, we still need a lot — we need progress in new pharmacologic agents, we need more topicals, we need injectables, we need orals, we need biologics,” said Jasvinder Singh, MD, MPH, professor of medicine and epidemiology, and senior scientist at the Comprehensive Arthritis, Musculoskeletal, Bone and Autoimmunity Center (CAMBAC), at the University of Alabama at Birmingham, told Healio Rheumatology. “There is a lot of need for all types of therapies. We also need to better understand the mechanism of disease so we can come up with smarter treatments, as well as preventive treatments.”
Hope on the Horizon
It remains unclear where tanezumab — the product of at least 41 clinical studies, 38 interventional trials and three observational studies, with approximately 13,000 exposed patients — goes from here.
As a member of the FDA Arthritis Advisory Committee, Singh said he could not comment as an individual on the panel’s tanezumab decision. Whatever the next step is for the drug and other similar products, that is up to Pfizer and other companies to decide as they continue to work with regulators, he said.
Nancy E. Lane, MD, director of the Center for Musculoskeletal Health at the University of California, Davis, meanwhile, said she remains hopeful about the drug, and about NGF inhibitors in general with regard managing OA.
“I think that there is no doubt that nerve growth factor is important in the pain of OA,” Lane told Healio Rheumatology. “It is clear that inhibiting it with an antibody does reduce pain and improve function. The question, I believe, is how to balance the safety with the potential adverse events, including rapidly progressing disease. And I am hopeful that the FDA and Pfizer will find an agreeable path where the medication can be used, but not overused.”
In the meantime, there are several other medications to be — cautiously — hopeful about, according to Lane.
Lorecivivint (SM04690, Biosplice), a Wnt pathway inhibitor, saw its phase 3 clinical trial program in knee OA, called STRIDES, launch in May 2019. Phase 1 studies of the drug showed reduced pain compared with placebo, while phase 2 demonstrated improvements in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function.
However, most importantly — and unlike tanezumab, which merely addressed pain — lorecivivint may potentially prevent cartilage deterioration, according to Lane. If ever approved for such an indication, it would represent a significant advancement in rheumatology, and arm rheumatologists with something that has so far proved elusive — an actual disease-modifying OA drug (DMOAD).
“I am hopeful for lorecivivint,” Lane said. “It’s in phase 3 and it may be both an agent that may be able to reduce pain and prevent cartilage deterioration. So, I’m pretty excited. The phase-3 data will be very informative about whether it’s a DMOAD.”
Another drug, the biologic interleukin-1 inhibitor canakinumab (Ilaris, Novartis), turned heads in summer 2020 when a study published in the Annals of Internal Medicine found that it may substantially reduce rates of total hip and knee replacement, as well as OA symptoms.
Lane, who wrote an editorial for the study, said that by examining serious adverse events in the CANTOS trial, the researchers found that patients treated with canakinumab had nearly a 50% reduction in the number joint replacements.
“The primary outcome was actually heart disease,” she said. “So, even though it wasn’t a study in OA, it suggested that IL-1 is very important in the deterioration of the joint.”
Other drugs boasting promising recent data include sprifermin (Merck), a recombinant human fibroblast 18 drug, and fasinumab (Regeneron Pharmaceuticals) a recombinant, fully human anti-NGF antibody.
In a study published in March 2020 in the Annals of the Rheumatic Diseases, sprifermin was found to increase cartilage thickness and reduce cartilage loss among patients with knee OA. Meanwhile, in a study published in Arthritis & Rheumatology, fasinumab improved pain and physical function, at various dose levels, even among individuals who experienced little benefit from previous analgesic therapy.
Of course, it hasn’t all been good news for possible OA drugs. Seven months before the FDA panel handed tanezumab its most recent setback, Unity Biotechnology in August 2020 announced that its senolytic agent, UBX0101, failed to meet its 12-week primary endpoint in a phase 2 study in patients with painful knee OA.
According to Lane, UBX0101 represents a novel approach to OA treatment involving senescence — that may still prove useful in reducing joint degeneration.
Meanwhile, a novel approach that has seen more success, albeit in a nonclinical animal model, involves skeletal stem cells — and may herald a significant future breakthrough, according to Lane.
That study, published in Nature Medicine in August 2020, suggested that, following microfracture, a resident stem-cell population can be induced to generate cartilage for treatment of localized chondral disease in OA.
“They were able to generate cartilage, with skeletal stem cells and inhibition of blood flow in the joint,” Lane said. “It’s a little bit out there, but it shows that it is important that we have to stimulate new cartilage formation — we have to get cells to make cartilage — but we also have to keep vascularity out of the joint. It’s out there, but it’s actually one of the most successful preclinical models of treating OA that we have yet.”
Exercising Another Option
With the focus on the race for pharmacologic answers to OA, it’s easy to overlook nonpharmacologic options that are already available and have already shown their effectiveness. As Lane pointed out: “If you get out the American College of Rheumatology OA updated guidelines that were done about a year or 2 ago, you will see that the first thing they recommend is nonpharmacologic therapy, or exercise.”
Both Lane and Singh independently directed the conversation toward exercise as a treatment for OA, arguing that it is underused in patients despite having a strong evidence base.
“This is not to diminish in any way the need for pharmacologic advances in the disease, but we also need to be very careful and cognizant of the fact that we do have a lot of very effective nonpharmacologic treatments, like exercise,” Singh said.
According to Singh, the issue with implementing exercise as a treatment for OA often stems from misinformation and discouragement among patients.
“They get a slight increase in pain, or they are not convinced it actually works,” he said. “They think it’s just a nice thing to do but they don’t think to use it as a treatment. And we have similar evidence for weight loss, but weight loss is a little more challenging and not everyone can do it effectively.”
He noted that “with exercise, I think if we can get the correct message out, and we give tools to patients, then we take away the myths and misconceptions around it. Anyone can do exercise, and we just have to tailor it to the patient’s need and what they can do to start. Once they can do one thing, we can graduate them to the next level, and the next level and the next.”
This, however, requires a team approach — “and we don’t have a lot of teams,” Singh added.
“The insurance will pay for physical therapy for 6 weeks and what happens after that?” he said. “There is a disconnect, right? Patients have more pain after a therapy session. They want to be nice to the therapist, so they don’t tell them — they just no-show for the next session and drop it.”
For Singh, the answer lies in recognizing these barriers and discovering a way to be more transparent and honest with patients. In addition, physicians must find a team approach based on the long-term care of the patient, rather than what treatments will be covered by insurance.
“This is a difficult disease,” he added. “The problem is that it impacts 20% of adults in the United States above 45 years of age, and that’s just knee OA. It is not just a nuisance problem for people in terms of quality of life and what they can and cannot do, but rather a huge health care system burden that is sort of forgotten because people think of it as incurable, untreatable and just a product of age. There is this idea that you just have to live with this disability. However, I think even with the limited options we have, if we get prioritization in our health care systems, we actually can make a difference with mass education campaigns. We can get different ways of getting many of these modalities to patients.”
However, even if mass education campaigns and multidisciplinary care teams were successful in spreading the gospel of regular exercise among patients with OA, new and better treatments would still be needed, according to Singh.
“We need new topical therapies that tackle different pathways and we need more durable and safer interarticular therapies,” he said. “Can we get a safer steroid? Can we get multiple other compounds that can be used in interarticular that are effective? It has been 70 to 90 years since we have had another useful product other than steroids in the joints. Hyaluronic acid is available but has limited use. We need many more products like that.”
For more information:
Jasvinder Singh, MD, MPH, can be reached at 500 22nd St. South, Floor 2, Birmingham, AL 35233; email: jsingh@uabmc.edu.
Nancy E. Lane, MD, can be reached at 451 Health Sciences Dr., Davis, CA 95616; email: nelane@ucdavis.edu.
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Press release: Samumed Launches Phase 3 Lorecivivint (SM04690) Clinical Program in Knee Osteoarthritis
Press release: UNITY Biotechnology Announces 12-week data from UBX0101 Phase 2 Clinical Study in Patients with Painful Osteoarthritis of the Knee
Schieker M, et al. Ann Intern Med. 2020;doi:10.7326/M20-0527.
Eckstein F, et al. Ann Rheum Dis. 2020;doi:10.1136/annrheumdis-2019-216453.
Murphy MP, et al. Nat Med. 2020;doi:10.1038/s41591-020-1013-2.
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