Critical Analysis: A Second Look at a Disappointing DMD Trial Signals a Turning Point for FibroGen

In a surprising turn of events, FibroGen, which initially showed promise in its Phase II trial, recently dropped a bombshell with the disappointing topline results from its second Phase III trial of pamrevlumab in Duchenne muscular dystrophy (DMD). The failure to meet the primary endpoint has sent shockwaves through the medical community. However, a closer examination reveals a complex web of factors that may have contributed to this setback.

This setback follows a similar disappointment earlier this summer when pamrevlumab missed the primary endpoint in the Phase III LELANTOS-1 trial, failing to improve the Performance of the Upper limb 2.0 score in non-ambulatory DMD patients. The Phase III LELANTOS-2 trial, which enrolled 73 boys with ambulatory DMD, also yielded results that fell short of expectations.

DMD, the most prevalent form of muscular dystrophy in children, predominantly affects young boys, leading to muscle wasting and the eventual loss of mobility, often resulting in complete wheelchair dependence by the age of 13.

The LELANTOS-2 results not only showed a failure to meet standardized endpoints like the North Star Ambulatory Assessment (NSAA) score but also disappointing outcomes in secondary measures, including the 4-stair climb velocity, the 10-meter walk/run test, time to stand, and time to loss of ambulation. These outcomes raise legitimate concerns about the clinical trial methodology.

Several factors may have played a role in this trial’s failure. The Phase II MISSION trial, which yielded positive results, was a single-arm, open-label study that lacked a placebo arm for comparison. This design made it challenging to identify other potential confounding variables, effectively shifting clinical trial risks into Phase III.

Furthermore, not categorizing the LELANTOS-2 cohorts based on genetic mutations has left FibroGen without the detailed genomic data needed to perform a root cause analysis. Although the company has suggested that pamrevlumab could potentially benefit DMD patients regardless of their specific mutations, the clinical data may paint a different picture.

The presence of systemic corticosteroids in all pamrevlumab trials has further complicated matters, making it difficult to isolate the drug’s effects. In DMD patients, varying levels of inflammation exist depending on the disease’s progression. While systemic corticosteroids are a standard of care for DMD, their effectiveness in addressing the root cause of the disease remains uncertain.

Beyond its implications for DMD, FibroGen’s recent failures may have broader ramifications for the company. In June, pamrevlumab also stumbled in a Phase III study for idiopathic pulmonary fibrosis. While FibroGen has other products, such as roxadustat for anemia related to chronic kidney disease, the drug’s availability is limited, with the FDA requesting another trial after rejecting it in 2021. With no approved products in the U.S., these repeated trial setbacks have left investors on edge.

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