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After Another Negative Phase 3 Trial Result, Calls For Rethinking Idiopathic Pulmonary Fibrosis2024 ATS
Pamrevlumab is the third investigational agent to fail in a phase 3 trials. Researchers said It may be time to stop treating idiopathic pulmonary fibrosis as a single disease and treat subcategories organized by relevant biomarkers.
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 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 suggests that idiopathic pulmonary fibrosis currently lumps together 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 title, "When the Third Time Is 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 continue to treat all the 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 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 were also no 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.
Interstitial Lung Disease: How This Common Lung Disorder Is Treated
Interstitial Lung Disease (ILD) is a group of lung disorders characterised by inflammation and scarring of the interstitium, the tissue surrounding the air sacs in the lungs. This condition can be challenging to diagnose and treat due to its diverse causes and symptoms. However, advancements in medical science have provided various treatment options to manage and alleviate its effects.
Talking to the team of Onlymyhealth Dr Kinjal Modi, Consultant, Pulmonology, PD, Hinduja Hospital & MCR, Khar shared the complexities of ILD and explore the treatment modalities available to patients.
Treating Interstitial Lung DiseaseBefore delving into treatment, it's crucial to understand what ILD entails. "Interstitial Lung Disease encompasses a broad spectrum of conditions, including idiopathic pulmonary fibrosis, sarcoidosis, and hypersensitivity pneumonitis, among others," said Dr Modi. These diseases share common features such as inflammation and scarring of lung tissue, leading to impaired gas exchange and respiratory function.
Dr Modi listed a few ways to treat ILD:
MedicationsThe first step towards treating ILD is through medication:
Many ILD patients experience reduced oxygen levels in their blood due to impaired lung function. Oxygen therapy can help alleviate symptoms like shortness of breath and fatigue by providing supplemental oxygen.
Pulmonary RehabilitationThis comprehensive programme includes exercise training, education, and psychological support to improve lung function, increase exercise tolerance, and enhance the overall quality of life for ILD patients.
Also Read: Respiratory Disease: What Is The Best Treatment For Asthma?
For individuals with advanced ILD who do not respond to other treatments, lung transplantation may be considered as a last resort. This procedure involves replacing one or both diseased lungs with healthy donor lungs.
Clinical TrialsResearchers are continuously investigating new therapies and treatment approaches for ILD through clinical trials. Participation in these trials offers eligible patients access to cutting-edge treatments and contributes to advancing medical knowledge in the field.
Challenges In Treating Interstitial Lung DiseaseWhile significant progress has been made in the treatment of ILD, several challenges persist. One major hurdle is the heterogeneity of ILD subtypes, which necessitates personalised treatment approaches tailoured to each patient's specific condition and underlying cause. Additionally, the long-term efficacy and safety of current treatments need to be further evaluated through ongoing research.
Looking ahead, emerging therapeutic strategies, such as targeted therapies and gene-based treatments, hold promise for improving outcomes in ILD patients. Furthermore, a better understanding of the underlying mechanisms driving lung fibrosis and inflammation will pave the way for the development of more effective and targeted therapies.
Also Read: Respiratory Diseases: Know Symptoms, Causes, Major Types And Preventions
Interstitial Lung Disease poses significant challenges to patients and healthcare providers alike, but with a multidisciplinary approach and ongoing research efforts, significant strides have been made in its management and treatment. From medications and oxygen therapy to pulmonary rehabilitation and lung transplantation, a range of options are available to help alleviate symptoms, slow disease progression, and improve the quality of life for individuals living with ILD. As research continues to unravel the complexities of this condition, the future holds promise for more targeted and effective treatment approaches, offering hope to patients and their families worldwide.
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Pamrevlumab Shows No Significant Benefit In Slowing Lung Function Decline In Idiopathic Pulmonary Fibrosis: JAMA
Researchers have found that pamrevlumab, a monoclonal antibody, does not significantly slow the decline in lung function for patients with idiopathic pulmonary fibrosis (IPF) compared to a placebo. This conclusion comes from a phase 3 randomized clinical trial aimed at assessing the efficacy and safety of pamrevlumab for treating IPF. The study was published in JAMA by Ganesh Raghu and colleagues.
Current treatments for idiopathic pulmonary fibrosis, such as nintedanib and pirfenidone, slow the progression of the disease but are often associated with adverse events that can affect medication adherence. Pamrevlumab, a fully human monoclonal antibody that inhibits connective tissue growth factor, showed promise in phase 2 trials by attenuating disease progression with minimal adverse effects. This phase 3 study aimed to evaluate its effectiveness and safety in a larger patient population.
The study included 356 patients aged 40 to 85 years with IPF who were not receiving nintedanib or pirfenidone at enrollment. Patients were recruited from 117 sites across 9 countries between July 18, 2019, and July 29, 2022. The last follow-up encounter occurred on August 28, 2023. Participants were randomized to receive either pamrevlumab (30 mg/kg intravenously every 3 weeks; n = 181) or a placebo (n = 175) for 48 weeks.
The primary outcome was the absolute change in forced vital capacity (FVC) from baseline to week 48. Secondary outcomes included time to disease progression (defined as a decline of ≥10% in predicted FVC or death), and exploratory outcomes encompassed patient-reported symptoms. Adverse events were also recorded.
Among the 356 patients (mean age, 70.5 years; 72.5% male; 62.1% White), 277 (77.8%) completed the trial. T
• The study found no significant difference in the primary outcome between the pamrevlumab and placebo groups.
• The least-squares mean change in FVC from baseline to week 48 was -260 mL (95% CI, -350 to -170 mL) in the pamrevlumab group versus -330 mL (95% CI, -430 to -230 mL) in the placebo group, resulting in a mean between-group difference of 70 mL (95% CI, -60 to 190 mL; P = .29).
• No significant difference in FVC change from baseline to week 48 between pamrevlumab and placebo groups (70 mL difference; 95% CI, -60 to 190 mL; P = .29).
• No significant differences between groups in any secondary outcomes.
• Treatment-related adverse events occurred in 88.4% of patients in the pamrevlumab group and 86.3% in the placebo group.
• Serious adverse events were reported in 28.2% of the pamrevlumab group and 34.3% of the placebo group.
• Mortality rates were similar, with 23 deaths in each group (12.7% vs. 13.1%).
Among patients with idiopathic pulmonary fibrosis, pamrevlumab did not result in a statistically significant difference in the primary outcome of FVC decline from baseline to week 48 compared to placebo. These results suggest that pamrevlumab may not offer additional benefits over existing treatments, underscoring the need for continued research into more effective therapies for IPF.
Reference:
Raghu, G., Richeldi, L., Fernández Pérez, E. R., De Salvo, M. C., Silva, R. S., Song, J. W., Ogura, T., Xu, Z. J., Belloli, E. A., Zhang, X., Seid, L. L., Poole, L., Bowler, S., Corte, T., Holmes, M., Thien, F., Wheatley, J., Choi, S.-M., Chung, M.-P., … ZEPHYRUS-1 Study Investigators. (2024). Pamrevlumab for idiopathic pulmonary fibrosis: The ZEPHYRUS-1 randomized clinical trial. JAMA: The Journal of the American Medical Association. Https://doi.Org/10.1001/jama.2024.8693
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