After Another Negative Phase 3 Trial Result, Calls for Rethinking Idiopathic Pulmonary Fibrosis | 2024 ATS

An investigational monoclonal antibody to treat idiopathic pulmonary fibrosis failed in a phase 3 trial, according to results presented today at the 2024 American Thoracic Society (ATS) International Conference in San Diego.

The negative results for pamrevlumab comes after two other treatments for idiopathic pulmonary fibrosis, ziritaxestat and zinpentraxin alfa, flopped in phase 3 trials.

The presentation of the results yesterday morning at the ATS meeting prompted discussion during the question-and-answer period about overhauling the strategy for developing drugs for a serious disease with a median survival time of just three to five years. One framing of the problem points to the end points that have been used in the trials and suggests that a more comprehensive set of outcomes be used. The negative results for pamrevlumab hinged on the primary outcome of a change in forced vital capacity (FVC), a standard measurement of lung function. Another framing is that idiopathic pulmonary fibrosis currently lumps together conditions that have important biological differences that should be teased apart and organized into subtypes for drug development and other purposes.

The negative trial results were published simultaneously in JAMA. An accompanying editorial that discussed the reasons for the failed phase 3 trials is titled, “When the Third Time Is Not the Charm—Trial Outcomes in Idiopathic Pulmonary Fibrosis.”

Victor Ortega, M.D.,Ph.D.

“We are using very traditional models still. But we are learning with research that is ongoing that all IPF [idiopathic pulmonary fibrosis] is not the same. The heterogeneity is something we have to embrace,” said Victor E. Ortega, M.D., Ph.D., one of the authors of the editorial in an interview after the pamrevlumab results were presented. Ortega is a professor of medicine at the Mayo Clinic in Scottsdale, Arizona, and a genetic epidemiologist.

“If we had continued to treat all asthma the same, we would have never developed the current biologics [for asthma treatment],” Ortega continued, “because they are the most effective in people with high blood eosinophils,” which is a biomarker of inflammation.

Although every drug developer talks about “unmet need,” there is a strong case that one truly exists for idiopathic pulmonary fibrosis, a form of interstitial lung disease that involves the thickening and scarring of the walls of the lungs’ alveoli. The American Lung Association says that approximately 58,000 new cases occur each year. Current treatment is limited to Ofev (nintedanib) and Esbriet (pirfenidone), drugs that interfere with the biologic process of lung tissue scarring; they are referred to as antifibrotic drugs. They are far from ideal drugs with limited efficacy and serious side effects (nausea, fatigue, diarrhea). The poor tolerability and limited efficacy of the two drugs “leave patients with IPF with similarly poor prognosis as there is no definite disease-altering or curative treatment apart from a lung transplant,” Ortega and his co-authors wrote in the JAMA editorial.

The phase 3 trial of pamrevlumab, called ZEPHYRUS-1, enrolled 356 patients at 117 sites in 19 countries between July 2019 and July 2022. The average age of the participants was 70.2 and most (72.5%) were men They were treated with pamrevlumab, which was administered intravenously, every three weeks for 48 weeks. Because of the COVID-19 epidemic, some of the treatment was delivered at home with the help of a home health service. Patients were excluded from the study if they were being treated with Ofev or Esbriet but once they were enrolled, those drugs could be added to their treatment, which wasn’t true in the phase 2 trials of pamrevlumab. FibroGen, the San Francisco biotech company that is developing pamrevlumab, paid for the study.

The patients in the pamrevlumab experienced a smaller decrease in FVC than those in placebo group (260 milliliters [mL] vs. 330 mL), but the difference didn’t reach the statistical threshold for being a true difference. There was also no statistically significant difference in the five secondary outcomes and four exploratory outcomes that measured quality of life.

Corresponding and lead author Ganesh Raghu, M.D., a professor in the Division of Pulmonary, Critical Care and Sleep Medicine at University of Washington in Seattle, and his colleagues offered several possible explanations for why pamrevlumab was successful as a treatment for idiopathic pulmonary fibrosis in phase 2 trials but not in this phase 3 trial. They noted that that patients in the phase 3 trial were sicker (greater lung function impairment, more symptoms) and the phase 3 trial was much larger than the two phase 2 trials (356 patients vs. 90 and 103). They also pointed to the phase 3 trial design that allowed patients to be treated with Ofev and Esbriet. Approximately 20% of the patients in the pamrevlumab group were treated with the one of the two drugs and 15% of those in the placebo group were.