Sarilumab approval may answer ‘significant unmet need’ for steroid sparing in PMR
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The recent FDA approval of sarilumab for the treatment of refractory polymyalgia rheumatica may have a significant and lasting impact on the use of long-term steroids for that condition.
Robert Spiera, MD, professor of clinical medicine at Weill Cornell Medical College and director of the Scleroderma, Vasculitis and Myositis Center at the Hospital for Special Surgery, in New York, presented key findings for sarilumab (Kevzara, Sanofi) at ACR Convergence 2022. These findings would ultimately form the basis of the FDA’s approval.
The phase 3, multicenter, randomized, double-blind, placebo-controlled SAPHYR trial initially assessed the efficacy and safety of sarilumab and a 14-week glucocorticoid taper in patients with steroid-resistant polymyalgia rheumatica (PMR). Eligible participants had experienced a flare of PMR despite receiving 7.5 mg daily of prednisone.
SAPHYR participants were randomly assigned either sarilumab 200 mg every 2 weeks while tapering glucocorticoids for 14 weeks, or placebo doses every 2 weeks with a 52-week glucocorticoid taper in a 1:1 ratio.
Among 118 patients initially treated and analyzed, the final analysis included 42 patients in the active therapy arm and 36 patients who received placebo.
Results demonstrated that 28.3% of patients in the sarilumab arm reached remission, compared with 10.3% among controls (P = .0193).
Healio sat down with Spiera to discuss the challenges in treating PMR, the importance of steroid tapering and what the approval of sarilumab means to this patient population.
Healio: Perhaps the most important message is that this is the first biologic approved for PMR. Could you put this into context?
Spiera: This approval means there are options for our patients with PMR refractory to steroid taper, or who are having severe steroid side effects and need to be tapered quickly. For now, the approval is narrow and only applies to that specific population of glucocorticoid-refractory patients.
The next step is to consider how exactly that is going to be defined in real-world clinical settings. That remains to be determined. The other consideration, of course, is access to this drug for patients.
Healio: What was the status quo of PMR treatment prior to this approval?
Spiera: PMR is considered to be among the most common inflammatory diseases in elderly populations. It is not an erosive inflammatory disease, but it can be severely painful and is associated with significant morbidity and functional limitation. It is readily treatable with corticosteroids. The main concern, of course, is that steroids are problematic in older populations because of their comorbidities, especially over the long-term. Even patients with PMR who respond to steroids and do well with them usually need to be treated for a year or longer.
Some patients are still maintained on steroids up to 5 years from the time of diagnosis, which can come with an enormous price in terms of associated complications ranging from cardiovascular outcomes and infections to diabetes, cataracts, skin fragility, myopathy and sleep disturbances, to name a few.
So, researchers have been working to try to identify strategies to allow less steroid exposure in these patients. Moreover, there is a high rate of relapse even in patients who do taper off steroids, which generally requires reinstituting steroid therapy. Finding a steroid-sparing or steroid-replacing therapy was a significant unmet need in PMR.
Healio: What are some of the other medications that have been used to this end?
Spiera: One of the primary medications used in this setting is methotrexate. Some clinical trials have shown that this drug has a steroid-sparing benefit, but the magnitude and clinical relevance has not been established in terms of any demonstration of improved quality of life or reduction in steroid related side effects. Again, there was a need for other therapies.
Healio: Could you talk about the process of finding those other therapies?
Spiera: What is interesting about polymyalgia is that understanding the pathophysiology of the disease could be beneficial in helping find targets for management. For example, interleukin-6, which is a cytokine for which we have inhibitors, is an important player in polymyalgia rheumatica.
We have drugs like tocilizumab (Actemra, Genentech) and sarilumab (Kevzara, Sanofi) that target IL-6, which rheumatologists have used in other conditions, including rheumatoid arthritis. There was a biologic rationale suggesting that this could be effective in PMR. A number of trials a few years ago — most of them open-label, non-randomized trials with tocilizumab — showed that it could have potential benefit in these patients.
Healio: Could you discuss the basics of the SAPHYR study and its findings?
Spiera: One important point is that we were looking at refractory patients, meaning these were patients who were unable to get off steroids without having a flare. These were patients who flared while on more than 7.5 mg of prednisone before entering the trial. This is a dose for which we know that prolonged exposure will have attendant complications. Patients were randomized to one of two treatment strategies. One was a standard 52-week steroid taper with placebo injections, while the active treatment group received sarilumab 200 mg every other week and a rapid 14-week steroid taper.
We had hoped to enroll 280 patients, but recruitment challenges in the context of the COVID pandemic led to prolonged recruitment timelines, and enrollment was terminated. Ultimately, only 118 patients were randomized. The main finding was that treatment with sarilumab and the rapid steroid taper was associated with a higher rate of sustained remission, less corticosteroid exposure, and better quality of life measures than treatment with a more conventional 52-week steroid taper.
Healio: Why is sustained remission such an important endpoint?
Spiera: Sustained remission was a high bar to clear. Patients had to be in remission at 12 weeks, suggesting that sarilumab was already adding something at that point to control the inflammatory disease. That remission would then need be sustained through week 52 with adherence to the protocol-defined steroid taper and have sustained normalization of C-reactive protein. Patients in the sarilumab arm also had less steroid exposure overall, not just explained by the protocol differences, as the additional steroids needed to treat flares was also higher in the placebo arm.
Healio: Is there anything else about the SAPHYR results that is noteworthy?
Spiera: One of most important findings from the trial pertains to quality of life and function. Across the board, if you look at patient-reported outcomes and including the FACIT-Fatigue score, SF-36, EQ-5D, and HAQ-DI, they all favored treatment with sarilumab and a short steroid taper. Both physical and mental quality of life outcomes favored sarilumab.
Healio: How important is the rapid steroid taper component of the study?
Spiera: The overall hope is to minimize steroid exposure. So, the duration of the steroid taper is important here. Having a very rapid taper in the treatment arm took the chance that if sarilumab was not helping quickly, we would not be able to demonstrate a treatment benefit. That was why we looked at remission at 12 weeks.
Healio: Are there similar concerns for long-term use of sarilumab as there are for long-term use of steroids?
Spiera: Our study did not answer the question of long-term sarilumab use. The expectation would be that you treat patients for 52 weeks with this drug. Our protocol defined that. But then you have to see what happens to your patients after that point. Some will stay in remission, but others will likely have later flares. I do not see indefinite sarilumab as the ultimate approach to PMR.
It also has not yet been determined whether inhibition of interleukin-6 is disease-modifying in PMR. This will be something to consider for future trials and longer-term follow-up of sarilumab treated patients in practice.
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