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Clinicians and others curious about the data underlying (PMR) can now be sated, at least partially, with publication today of the chief registration trial's detailed results.

In the so-called , 28% of PMR patients who had experienced disease flares during a 14-week corticosteroid taper achieved remission sustained over 1 year with sarilumab treatment, versus 10% of a placebo group assigned to a longer tapering schedule, according to Robert Spiera, MD, of the Hospital for Special Surgery in New York City, and colleagues. The difference of 18 percentage points was statistically significant (95% CI 4-32) in the 118-patient trial.

Some adverse events were more common in the sarilumab group, as expected from the drug's mechanism of action (it blocked the interleukin-6 receptor), as were treatment-related discontinuations, the investigators .

But for some reason, the FDA's approval of sarilumab for PMR includes a significantly broader patient population than those enrolled in SAPHYR. The states that it's not only for patients unable to taper steroids successfully, but also those "who have had an inadequate response to corticosteroids." SAPHYR did not have that as an inclusion criterion, and neither the FDA (which did not announce the approval itself) nor the drug's manufacturers, Sanofi and Regeneron, provided an explanation.

In any event, sarilumab did outperform placebo, if only modestly, by virtually every efficacy measure used in the trial, including:

• Clinical remission by week 12: 47% vs 38%
• Absence of additional disease flare: 55% vs 33%
• Sustained normalization of C-reactive protein (CRP) level: 67% vs 45%
• Adherence to steroid taper schedule: 50% vs 24%

These four measures were combined to define "sustained remission" at 1 year. When consideration of CRP and erythrocyte sedimentation rate (ESR) were excluded, "sustained remission" was achieved by 32% of the sarilumab group versus 14% of those assigned to placebo; the 18-point difference was also statistically significant.

It may be notable, however, that each of these efficacy outcomes was defined in a positive way -- in their main paper, Spiera and colleagues didn't report others that clinicians might have wanted to see, such as median time to new disease flare. The authors did note that, overall, 24% of the sarilumab group had a disease flare after achieving clinical remission, as compared with 57% of the placebo group. Use of rescue therapy was also substantially more frequent in the placebo group (59% vs 32%).

But one had to examine an online-only supplemental appendix to see data on the timing of post-remission flares and use of rescue therapy. These were more favorable to sarilumab: all the new flares were concentrated in the study's first 20 weeks, after the steroid taper was completed. In the placebo group, meanwhile, flares continued to occur throughout the 1-year trial.

That latter finding may have stemmed from the different tapering protocol. Placebo group participants tapered their doses over the full 1-year duration of the trial, versus the 14-week period specified for the sarilumab group.

Some types of adverse events were more common with sarilumab. The most clinically significant was neutropenia, which was seen in 15% of sarilumab patients versus none assigned to placebo. This was not unexpected: sarilumab, which was previously approved for rheumatoid arthritis, has carried a boxed warning about serious infections, including invasive fungal infestations and active tuberculosis.

Arthralgia also occurred as an apparent side effect in 15% of the sarilumab group, compared with 5% of the placebo group. Diarrhea was more common with sarilumab, too.

But 21% of the placebo group had serious events of all kinds, versus 14% of those on sarilumab. More patients on placebo experienced falls, insomnia, and nasopharyngitis. And, notably, disease flares were not counted as adverse events and were surely less common with sarilumab.

Trial Details

The 118 participants had attempted a steroid taper in the 12 weeks prior to screening, after being on the drugs for at least 8 weeks, and had experienced a PMR flare. Pre-tapering doses were at least 7.5 mg/day in prednisone equivalents. Either CRP or ESR was noted as elevated before screening.

Patients were randomized 1:1 to subcutaneous sarilumab, at a starting dose of 200 mg, or placebo injections, each given twice monthly. Sarilumab doses could be cut to 150 mg to minimize side effects including neutropenia, platelet deficiency, or liver enzyme abnormalities.

Steroids were given at 15 mg/day in prednisone equivalents for the first 2 weeks and then the tapering began. Additional steroid doses of no more than 5 mg/day could be given in the first 12 weeks if remission was not achieved or PMR flares developed. After week 12, if steroid rescue therapy was needed, the tapering was stopped and patients were rated as having no treatment response.

In the end, 42 patients in the sarilumab group and 36 assigned to placebo completed the trial according to the protocol. Discontinuations were recorded for 17 sarilumab patients and 22 in the placebo group. Lack of efficacy was the most common reason with placebo, while adverse events were most common with sarilumab.

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