Zephyrus II: A Phase 3 Study of Pamrevlumab in Subjects with IPF
Research type
Research Study
Full title
Zephyrus II: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Pamrevlumab in Subjects with Idiopathic Pulmonary Fibrosis (IPF)
IRAS ID
271173
Contact name
Nazia Chaudhuri
Contact email
Sponsor organisation
FibroGen, Inc.
Eudract number
2020-000697-22
Clinicaltrials.gov Identifier
Clinicaltrials.gov Identifier
011212, IND
Duration of Study in the UK
1 years, 6 months, 0 days
Research summary
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal lung disease of unknown cause; it is characterized by progressive fibrosis, or scarring, in the lungs, which leads to continued loss of functioning air sacs (where oxygen exchange occurs). The cause for IPF is unknown (hence the term “idiopathic”); it is thought that repetitive lung tissue injury, such as exposure to cigarette smoking, viral infections, or environmental dusts or toxins, as well as genetic predisposition, may play a role in the development of IPF, but ultimately the cause is unknown.
Patients with IPF suffer from progressive shortness of breath and cough, sometimes for several years before a diagnosis of IPF is made. The diagnosis of IPF is supported by typical changes on radiographic images such as high-resolution computer tomography (HRCT) or on biopsy, and after other types of lung diseases have been excluded.
IPF is a fatal disease; approximately 20% to 40% of IPF patients live to 5 years, which is worse than that of most major cancers. Most IPF patients die from respiratory complications, or from heart disease.
There are two approved treatments for IPF: Pirfenidone and nintedanib; both help with slowing the lung function decline, but do not modify or halt the disease progression, and have a number of side-effects. The only cure at this time is lung transplantation.
Fibrogen is developing an investigational new drug: Pamrevlumab, a human monoclonal antibody that blocks connective tissue growth factor (CTGF): CTGF plays a central role in scar formation and tissue fibrosis, including the development of IPF. Pamrevlumab, which blocks the activity of CTGF, may prevent or reverse the lung damage seen in IPF.
The aim of this study is to show whether Pamrevlumab is effective in the treatment of IPF. This is a randomised double blind placebo controlled trial of Pamrevlumab versus placebo in IPF.Summary of Results
Study FGCL-3019-095 was a Phase 3, randomized, double-blind, placebo controlled, multicenter trial to evaluate the efficacy and safety of pamrevlumab in subjects with IPF who had previously been treated with approved IPF therapies (i.e., nintedanib or pirfenidone) but who discontinued that therapy (possible reasons for discontinuation could include, but were not limited to, intolerance or disease
progression), unless neither treatment was available in the host country. The main
study cohort and OLE period were both halted as the sponsor decided to stop the study based on the totality of data from another Phase 3 study.
Demographics and Disposition:
A total of 372 subjects were enrolled in the main study cohort during the double-blind period, and 371 received at least one dose of study drug (pamrevlumab or placebo, with 183 subjects in the pamrevlumab arm and 188 subjects in the placebo arm who received at least one dose of study drug).
Of the treated subjects, 105 (28.2%) completed the 48-week double-blind treatment period; 267 subjects (71.8%) discontinued treatment early, and 94 subjects (25.3%) consented to participate in the OLE.
A total of 86 subjects were treated in the OLE period; all discontinued OLE treatment, and the most common reason for studydiscontinuation was study terminated by sponsor. Within all study periods, the two treatment arms had similar rates of study completion and reasons for discontinuation.
Baseline characteristics and demographics were mostly balanced between the two treatment arms for the main study cohort. In the main study cohort, a majority (283 subjects, 76.1%) were male, White (225 subjects, 60.5%), not Hispanic or Latino (266 subjects, 71.5%), and the median age was 71.0 years. Slightly more than 70% of the subjects in each treatment arm reported prior treatment with
an approved IPF therapy. As assessed by GAP stage and number of years since first diagnosis of IPF, disease severity was balanced between the two treatment arms.
Medical history as well as prior and concomitant medication use were consistent with that expected for patients with IPF.
Efficacy Results:
• As a result of the study termination, no formal statistical comparisons were completed for efficacy endpoints. The limited efficacy results are not discussed in this aCSR.
Safety Results:
Main Study Cohort:
Final Report Notification version 1.0, July 2024
The incidence of TEAEs was similar in the pamrevlumab and placebo arms (76.0% vs. 77.1%), with marginally higher numbers of TEAEs considered related to pamrevlumab compared with placebo (15.3% vs. 13.3%).
•The number of TEAEs of all grades was balanced between the pamrevlumab and placebo arms with the majority of TEAEs ≤Grade 2 in severity.
The most common TEAEs were cough (pamrevlumab: 14.2%, placebo: 12.8%), COVID-19 (pamrevlumab: 11.5%, placebo: 8.5%), and IPF (pamrevlumab: 9.3%,
placebo: 9.6%).
The proportion of subjects with TESAEs was similar in both treatment arms (pamrevlumab: 20.8%, placebo: 19.7%).
The proportion of subjects with TEAEs leading to study drug interruption was similar in the two treatment arms (pamrevlumab: 4.4%, placebo: 2.7%); and the proportion of subjects with TEAEs leading to study drug discontinuation was lower in the pamrevlumab arm compared with the placebo arm (2.2% vs. 3.2%).
The proportion of subjects who died during the treatment-emergent period (within 60 days after the last dose of study drug) was similar in the two treatment arms (pamrevlumab: 8.2%, placebo: 6.9%).
There were no abnormal trends in ECGs, vital signs, hematology, chemistry laboratory parameters, or coagulation and liver function panels between the pamrevlumab and placebo arms.
The overall incidence of potential hypersensitivity events was slightly higher in thepamrevlumab arm compared with the placebo arm (16.9% vs. 13.3%) but potential infusion reactions were low in both pamrevlumab and placebo arms (8.2% vs. 2.1%). Potential anaphylactic reactions were low and were only reported in the
pamrevlumab arm (1.6%), while none were reported in the placebo arm.
OLE Period:
The incidence of TEAEs was similar in subjects who received pamrevlumab in thedouble-blind period compared with subjects who received placebo (58.5% vs. 60.0%), with lower numbers of TEAEs considered related to study treatment in the placebo arm compared with the pamrevlumab arm (2.2% vs. 9.8%).
The number of TEAEs of all grades was balanced between the double-blind periodpamrevlumab and double-blind period placebo arms.
The most common TEAEs were IPF (pamrevlumab: 14.6%, placebo: 15.6%) and COVID-19 (pamrevlumab: 12.2%, placebo: 6.7%).
The proportion of subjects with TESAEs was marginally higher in the double-blind period placebo arm compared with the pamrevlumab arm (26.7% vs. 19.5%).
A TESAE leading to study drug interruption was experienced by one subject who eceived placebo in the double-blind period (2.2%), while none were reported in the double-blind period pamrevlumab arm. The incidence of TESAEs leading to discontinuation of study drug was similar between subjects who received pamrevlumab in the double-blind period compared with subjects who received placebo in the double-blind period (4.9% vs. 2.2%).
The proportion of subjects who died during the treatment-emergent period (within 60 days after the last dose of study drug) was similar in the two double-blind period treatment arms (pamrevlumab: 12.2%, placebo: 13.3%).
The overall incidence of potential hypersensitivity events was slightly higher in the doubleblind period pamrevlumab arm compared with the double-blind period placebo arm (9.8% vs. 2.2%). Potential infusion reactions were reported only in the double-blind period pamrevlumab arm (2.4%); none were reported in the double blind period placebo arm. There were no anaphylactic reactions.
Conclusions:
Final Report Notification version 1.0, July 2024
The main study cohort and OLE period were halted as the sponsor decided to stop the study based on the totality of data from another Phase 3 study. Overall, the safety data did not reveal any new safety concerns for pamrevlumab in patients with
IPF. Pamrevlumab was generally safe and well tolerated, and the safety profile for TEAEs was consistent with that of patients with IPF.REC name
North West - Greater Manchester South Research Ethics Committee
REC reference
20/NW/0435
Date of REC Opinion
13 Jan 2021
REC opinion
Further Information Favourable Opinion