FibroGen’s experimental antifibrotic therapy pamrevlumab may be more effective than Esbriet (pirfenidone) and Ofev (nintedanib) at slowing disease progression in people with idiopathic pulmonary fibrosis (IPF), according to a review study.
Combined data from eight clinical trials showed that all three therapies significantly slowed IPF patients’ lung function decline, compared with a placebo, but the drop appeared to be less pronounced with pamrevlumab, resulting in the lowest risk of lung function decline.
Notably, only Esbriet was found to significantly reduce patients’ risk of death from any cause.
These findings support the therapeutic potential of pamrevlumab in this patient population. The therapy is currently being evaluated in a Phase 3 clinical trial (NCT03955146).
Still, the results must be interpreted with caution, as differences between trials may influence the comparative results, the researchers noted, and only head-to-head trials can accurately determine superiority between therapies.
The review study, “Systematic Review and Meta-analysis of Pirfenidone, Nintedanib, and Pamrevlumab for the Treatment of Idiopathic Pulmonary Fibrosis,” was published in the journal Annals of Pharmacotherapy.
Genentech’s Esbriet and Boehringer Ingelheim’s Ofev currently are the only antifibrotic therapies approved for IPF. Taken in the form of oral capsules, both are known to effectively slow the rate of lung function decline — as measured by forced vital capacity, or FVC — in people with the disease, leading to better survival.
Of note, FVC represents the volume of air in the lungs that can be exhaled after a deeply inhaled breath; it typically is presented as a percentage of a reference value, normally above 80%, but also can be represented in liters of air volume.
Pamrevlumab, formerly known as FG-3019, is an engineered antibody that works by binding to and blocking the activity of a protein called connective tissue growth factor (CTGF). CTGF plays a central role in fibrosis, contributing to the progressive and excessive tissue scarring characteristic of IPF and other fibrotic diseases.
By blocking CTGF, Pamrevlumab prevents it from activating downstream pro-inflammatory and pro-fibrotic factors, and therefore is thought to be an antifibrotic treatment that directly tackles the underlying mechanism of IPF.
Final data from the Phase 2 PRAISE trial (NCT01890265) showed that pamrevlumab safely and effectively slowed lung function decline in IPF patients to a degree comparable to that reported for Esbriet and Ofev in previous trials.
However, no study to date has systematically compared the effectiveness of Esbriet, Ofev, and pamrevlumab in people with IPF.
Now, researchers in Palermo, Italy, set out to compare the therapies’ effectiveness at slowing lung function decline and prolonging the lives of people with IPF by systematically analyzing published studies up to March 2020 concerning randomized controlled Phase 2/3 clinical trials of such therapies.
From a total of 580 studies assessed for eligibility, six were included in the meta-analysis. These referred to eight completed clinical trials — two Phase 2 and six Phase 3 studies — covering more than 3,000 IPF patients.
Four trials involved Esbriet, three tested Ofev, and one evaluated pamrevlumab; all included a control group of patients receiving a placebo.
Given that treatment duration and dose (within the same therapy) varied between trials, the team implemented several strategies to carry out the data analysis at similar times and doses to make the results comparable. Differences between trials also were noted in terms of possibility for patients to receive rescue treatment in case of disease progression and in the rates of simultaneous use of corticosteroids and of treatment discontinuation.
The team compared patients’ lung function decline through changes in FVC (represented in percentage predicted and in liters), as well as their likelihood of having a 10% reduction in FVC and of dying from any cause with each of the three therapies.
Results showed that compared with a placebo, all therapies significantly slowed the rate of lung function decline, but pamrevlumab was associated with a less marked worsening.
FVC in patients treated with pamrevlumab declined by a mean of 4.3% less, and 0.20 liters less, than in patients given a placebo, compared with 3.3% and 0.09 liters less in patients on Esbriet and 3.15% and 0.13 liters less in Ofev-treated patients.
Each of the therapies also significantly reduced patients’ likelihood of having at least a 10% reduction in FVC, when compared with a placebo. Again, a more pronounced effect was seen in patients treated with pamrevlumab. However, only Esbriet effectively reduced patients’ likelihood of dying from any cause.
“The overall results of the quantitative analysis indicate that the 3 treatments are effective in significantly reducing the progression of IPF, … whereas only [Esbriet] significantly reduces [all-cause death],” the researchers wrote.
The analysis also provided encouraging results on pamrevlumab’s effectiveness in slowing the decline in lung function, compared with Esbriet and Ofev. However, the fact that pamrevlumab data was based on a smaller sample of patients (a single trial, the PRAISE study) than that of the other two therapies, may have an impact on the results, the team noted.
Nevertheless, if pamrevlumab’s promising results in PRAISE are confirmed in the ongoing Phase 3 trial called ZEPHYRUS, pamrevlumab may become a valid therapeutic option for people with IPF, the researchers emphasized.
ZEPHYRUS is evaluating the safety and effectiveness of pamrevlumab in IPF patients who are not being treated with Ofev or Esbriet for any reason, including prior intolerance. More information about the ZEPHYRUS trial is available here.
Of note, pamrevlumab has received orphan drug and fast track designations from the U.S. Food and Drug Administration for the treatment of IPF. These designations are meant to speed the therapy’s development and review by providing regulatory support and financial benefits, and also ensure marketing exclusivity for a period of time upon regulatory approval (seven years in the U.S. and 10 years in Europe), if granted.
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