A thorough reassessment of the confounders between FibroGen’s trials is necessary to salvage the company’s Duchenne Muscular Dystrophy program and regain investor confidence.
Pictured: Scientists analyze data on computers in a lab/iStock, gorodenkoff
Despite finding initial success in Phase II, FibroGen recently announced that topline results from its second Phase III trial of pamrevlumab in Duchenne muscular dystrophy failed to meet the primary endpoint. While FibroGen stated it is evaluating the total data, there are multiple confounders between the Phase II MISSION trial and Phase III program that warrant a closer look.
Earlier this summer, 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 patients with non-ambulatory Duchenne muscular dystrophy (DMD). The second Phase III trial, LELANTOS-2, enrolled 73 boys with ambulatory DMD.
DMD is the most common form of muscular dystrophy in children. Usually manifesting in young boys, it is an X-linked recessive genetic disorder characterized by muscle wasting and loss of ability to walk, leading to complete wheelchair dependence by around 13 years of age.
Topline results from LELANTOS-2 showed that multiple standardized endpoints were not met. In addition to failing North Star Ambulatory Assessment (NSAA) score assessments, pamrevlumab also missed secondary endpoints such as 4-stair climb velocity, the 10-meter walk/run test, time to stand and time to loss of ambulation. This is a clear issue as these unsatisfactory outcomes suggest the clinical trial methodology may be at fault.
Several confounders may have led to the trial’s failure. First, MISSION was a single-arm, open-label study in which non-ambulatory DMD patients were dosed only with pamrevlumab and a stable regimen of corticosteroids without the use of a placebo arm. Without a comparator trial arm, accurate assessment of other confounders became more difficult because the clinical trial risks were pushed into Phase III.
In addition, without splitting the LELANTOS-2 cohorts into groups based on genetic mutations, FibroGen lacks detailed genomic data to carry out a root cause analysis on whether or not genetics was a factor. While the company has stated in the past that pamrevlumab “can potentially be used in DMD patients regardless of specific mutations,” it remains to be seen whether clinical data bears this out.
Finally, the presence of systemic corticosteroids throughout all of pamrevlumab’s trials makes it difficult to isolate the effect of the drug. In mice, systemic corticosteroids may induce connective tissue growth factor (CTGF) expression in normal tissues and organs but not in highly inflamed areas. In DMD, patients may have varying degrees of inflammation depending on the progression of the disease. Therefore, despite being a current standard of care treatment for DMD, systemic corticosteroids are not effective enough to treat the root cause of the disease, and their overall role in treating DMD is unclear.
FibroGen’s DMD failure could also have larger implications for the company. In June, pamrevlumab also failed a Phase III study in idiopathic pulmonary fibrosis. While the company has other products, such as roxadustat for anemia caused by chronic kidney disease, this drug is only available in Europe and certain countries within Asia—the FDA rejected the drug in 2021, requesting another trial. Thus, as FibroGen currently has no products approved in the U.S., recent repeated trial failures are not reassuring to investors.
Therefore, examining what went wrong in LELANTOS-2 will be a crucial test if the company hopes to regain investor confidence in the coming months.
