In June of 2023 Fibrogen announced the results of the ZEPHYRUS-1 clinical trial of Pamrevlumab in IPF. Pamrevlumab entered phase 3 with much anticipation. Phase 2 work suggested that the molecule had a high chance of success. Unfortunately, in the phase 3 study which included 356 subjects, Pamrevlumab was not effective at preserving lung function. As a result, Fibrogen ended the development of this drug for IPF.
Why do medications look promising in phase 2 studies fail in phase 3? Phase 2 studies are smaller studies, conducted in fewer sites, usually with various doses of the study medication compared to placebo. The phase 2 Pamrevlumab study included about 100 subjects with IPF and none were treated with currently approved IPF medications (pirfenidone or nindatenib). The study was 48 weeks in duration and the primary endpoint was decline in lung function. In the phase 2 study, Pamrevlumab reduced the rate of decline in lung function by 60%. Of note, the study took 4 years to complete. There was no way to have predicted based on the phase 2 data that the Pamrevlumab would prove ineffective in IPF. There is always risk of failure in clinical trials.
The typical journey for a molecule to become an effective therapy is long and arduous. The first stage of the journey usually is a decade or more of basic laboratory science that identifies a molecular pathway that seems to be associated with a disease. Next a molecule that seems to impact the abnormal pathway is studied in animal models of the disease. Next, the molecule is studied in healthy people in single and multiple dose exposures (this is called phase 1). At this time, the company decides if there is enough basic science and animal model data paired with safety data from phase 1 to move forward into phase 2. Phase 2 usually looks at several different doses compared to placebo. If the phase 2 results look promising, then the molecule moves into phase 3. This phase usually involves many study sites around the world and enrolls many more subjects than in phase 2. Statisticians are involved in the design of the study protocols helping to determine how best to evaluate the data and how large the study needs to be in order to have a high probability of answering the key efficacy question. The sponsoring company works closely with the Food and Drug Administration (FDA) to develop phase 2 and 3 protocols.
The risk of failure is high for any given molecule. Drugs can be divided into “Me Too” medications (newer versions of already approved therapies) and novel molecules with novel mechanisms of action. The former group has a higher chance of success but rarely leads to major breakthroughs. In contrast, the latter group has a higher failure rate but can lead to dramatic advances.
We must always remember that without clinical trials we would have no progress in medicine. The patients who volunteer to participate in phase 2 and 3 trials are the real heroes. They give their time and energy and take on some risk in the quest of new, more effective treatments. Hats off to the many patients who continue to push medicine forward and participate in clinical trials. Although we have a tendency to mourn the negative studies and “misses”. Even in negative trials we advance our understanding of disease and increase the likelihood of eventual success with the next round of clinical trials.