Steroid Tapering Design in Action - Failed

In a previous post, I discussed steroid tapering design clinical trials. In these trials, the primary efficacy endpoint is the reduction in steroid dose. Efficacy is demonstrated if patients receiving the experimental treatment are able to reduce their steroid dose significantly more than those in the placebo group.

Steroids remain highly effective for many conditions, particularly those involving chronic inflammation or an overactive immune system. However, long-term or high-dose steroid use is associated with numerous side effects. Therefore, it is highly desirable to develop therapies that allow for steroid dose reduction—or even complete steroid sparing—while maintaining disease control.

One of these diseases is sarcoidosis or lung sarcoidosis. Sarcoidosis is an inflammatory disease in which the immune system overreacts, causing groups of cells to form clusters of inflamed tissue called "granulomas" in one or more organs of the body. The most affected organ is lung. Sarcoidosis symptoms can be treated using corticosteroids, or prednisone, which turn down the immune system's activity to reduce inflammation.

A sponsor, aTyr Pharma, conducted a phase 3, confirmatory trial to investigate if their experimental drug efzofitimod is effective in treating the pulmonary sarcoidosis. The study "Efficacy and Safety of Intravenous Efzofitimod in Patients With Pulmonary Sarcoidosis" was designed as steroid tapering with the primary efficacy endpoint being "Change from baseline in mean daily oral corticosteroid (OCS) dose at Week 48".

This morning, the sponsor issued a press release announcing Topline Results from Phase 3 EFZO-FIT™ Study of Efzofitimod in Pulmonary Sarcoidosis. Study did not meet primary endpoint in change from baseline in mean daily oral corticosteroid (OCS) dose at week 48, although clinical benefit for efzofitimod observed across multiple study parameters.

The change from baseline in mean daily OCS dose reduced to an average of 2.79 mg for the high dose of efzofitimod versus 3.52 mg for placebo, resulting in an insignificant treatment difference. The sponsor blames the unexpected placebo response.

aTyr flunks phase 3 lung disease trial, deflating stock, but still plans talks with FDA

The steroid tapering design offers important clinical advantages by directly addressing the need to reduce long-term steroid exposure, a major source of morbidity in many chronic inflammatory and immune-mediated diseases. The steroid tapering design and the change from baseline in steroid dose is accepted by the regulatory agencies. It provides a patient-centered and easily quantifiable endpoint that demonstrates whether an investigational treatment can maintain disease control while allowing for a lower steroid dose. 

However, this design also has limitations. Variability in tapering schedules, risk of disease flares, and ethical concerns regarding aggressive tapering in placebo groups can complicate interpretation. In addition, results may be less generalizable to steroid-naïve patients, and regulatory acceptance of steroid-sparing endpoints as stand-alone primary outcomes remains uncertain. Careful planning and standardization are therefore essential to balance the scientific value with patient safety and trial credibility.