Eiger Announces Both Lonafarnib-based Treatments in Pivotal Phase 3 D-LIVR Trial in Hepatitis Delta Virus (HDV) Achieved Statistical Significance Against Placebo in Composite Primary Endpoint
Eiger BioPharmaceuticals (PRNewsFoto/Eiger BioPharmaceuticals, Inc.)
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Eiger BioPharmaceuticals, Inc.
Dec 08, 2022, 08:00 ET
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- Lonafarnib/ritonavir response rate of 10.1% (p=0.0044)
- Lonafarnib/ritonavir in combination with peginterferon alfa response rate of 19.2% (p<0.0001)
- Peginterferon alfa comparator arm, included for contribution of effect, response rate of 9.6%
- Key secondary endpoint of proportion of patients with improvement in histological response rate demonstrated with statistical significance in combination arm vs placebo
PALO ALTO, Calif., Dec. 8, 2022 /PRNewswire/ -- Eiger BioPharmaceuticals, Inc. (Nasdaq: EIGR), a commercial-stage biopharmaceutical company focused on the development of innovative therapies for hepatitis delta virus (HDV) and other serious diseases, today announced topline primary Week 48 data from its landmark Phase 3 D-LIVR study (N=407) evaluating lonafarnib, a first-in-class prenylation inhibitor, in two regimens in patients with chronic HDV: lonafarnib boosted with ritonavir alone (all-oral) and in combination with peginterferon alfa (combination). The composite primary endpoint was a ≥2 log decline in HDV RNA and normalization of alanine aminotransferase (ALT) at the end of 48 weeks of treatment compared to placebo.
Topline Week 48 results showed that both treatment arms achieved statistical significance over placebo in the composite primary endpoint as well as the component virologic and biochemical responses. Study participants receiving the all-oral therapy and combination therapy showed a composite response of 10.1% (p=0.0044) and 19.2% (p <0.0001), respectively, compared to those receiving placebo (1.9%). Study participants receiving the all-oral therapy and combination therapy showed statistically significant improved rates of ALT normalization of 24.7% (p=0.003) and 34.4% (p<0.0001), respectively, compared to those receiving placebo (7.7%). A peginterferon alfa comparator arm was included in the study to show contribution of effect. The composite response rate in the all-oral arm was comparable to the peginterferon alfa arm (10.1% vs 9.6%). The composite response rate in the combination arm was twice that of the peginterferon alfa arm (19.2% vs 9.6%).
The key secondary histological endpoint was defined as ≥2-point improvement in histological activity index (HAI) and no worsening of Ishak fibrosis scoring as determined by blinded assessment of paired liver biopsies (n=229) collected at baseline and Week 48. This was demonstrated in 35 of 66 patients (53%, p=0.0139) with statistical significance in the combination arm versus 8 of 30 patients (27%) receiving placebo. Response was demonstrated in 35 of 107 patients (33%, p=0.61) in the all-oral arm versus placebo. Response in the peginterferon alfa comparator arm was 10 of 26 patients (38%).
Remaining secondary endpoints including virologic, biochemical, and composite responses at Week 72 (24-weeks post-treatment) are being collected and are expected to be reported mid-2023.
"We would like to extend our sincere gratitude to the patients, investigators, and clinical study sites for their participation in this well-controlled, landmark study," said David Cory, President and CEO, Eiger. "As we continue to analyze these topline data to fully understand the efficacy and safety profile of lonafarnib-based treatments in chronic HDV, we look forward to a pre-NDA meeting with FDA in the coming quarter and seeing the full dataset including the 24-week post-treatment data."
"The results of this landmark study highlight three key findings," said Ohad Etzion, MD, Director, Department of Gastroenterology and Liver Diseases at Soroka University Medical Center and D-LIVR study co-lead investigator. "First, a small subset of patients with chronic HDV infection may achieve virologic and biochemical improvements with an all-oral regimen after 48 weeks of treatment. Second, combining lonafarnib and ritonavir with peginterferon alfa demonstrated the potential to nearly double the response rate. And third, and perhaps most importantly, based on these data, combination treatment may lead to significant histologic improvement, a generally accepted surrogate for improved future clinical outcomes for patients. We look forward to the 24-week post-treatment results of this study for assessment of the potential for finite therapy for chronic HDV infection."
The majority of treatment emergent adverse events (TEAEs) were mild or moderate in severity. The most frequent TEAEs associated with lonafarnib treatment were gastrointestinal. Nine percent and 8% of patients discontinued treatment from the lonafarnib oral and combination therapy arms, respectively, compared to 2% of patients in each of the peginterferon alfa and placebo groups. In the lonafarnib treatment groups, 8% and 14% of patients, respectively, reported serious treatment-emergent adverse events, compared with 10% in the peginterferon alfa group and 4% in the placebo group. There were two deaths in the study: one patient treated with peginterferon alfa died due to decompensated cirrhosis that was attributed to drug therapy. The other death in the lonafarnib/ritonavir arm was deemed unrelated to study drug.
Summary of Topline Data
Response Rate, % (n)
Virological/Biochemical Endpoints
Placebo
(n=52)
LNF + RTV
(n=178)
LNF + RTV + Alfa
(n=125)
Alfa
(n=52)
Composite Endpoint
1.9 %(1)
10.1% (18)
(p=0.0044)
19.2% (24)
(p<0.0001)
9.6 %(5)
≥2 Log Decline in HDV RNA
3.8 %(2)
14.6% (26)
(p=0.0026)
32% (40)
(p<0.0001)
36.5 %(19)
ALT Normalization
7.7 %(4)
24.7% (44)
(p=0.003)
34.4% (43)
(p<0.001)
11.5 %(6)
Histological
Endpoint
Placebo
(n=30)
LNF + RTV
(n=107)
LNF + RTV + Alfa
(n=66)
Alfa
(n=26)
≥2-Point Improvement in HAI
Score and No Worsening in
Ishak Fibrosis Score
27 %(8)
33% (35)
(p=0.61)
53% (35)
(p=0.0139)
38 %(10)
LNF=lonafarnib; RTV=ritonavir; Alfa=peginterferon alfa; HAI=histological activity index
Eiger plans to engage with regulatory agencies, beginning with a pre-NDA meeting with FDA anticipated in Q1 2023, to discuss pathways for regulatory submissions. The full D-LIVR dataset, including analyses of the 24-week post-treatment period, would be included in potential regulatory submissions. Eiger intends to present D-LIVR study results at a future medical congress and publish in a peer-reviewed journal.
ABOUT D-LIVR
D-LIVR (Delta Liver Improvement and Virologic Response in HDV) is a global, multi-center, Phase 3 study to evaluate two lonafarnib-based treatments: an all-oral arm of lonafarnib boosted with ritonavir (n=178) and a combination arm of lonafarnib boosted with ritonavir combined with peginterferon alfa (n=125), with each arm compared to a placebo arm (n=52), in HDV-infected patients after 48 weeks of treatment. The study also includes a peginterferon alfa comparator arm (n=52) used to demonstrate contribution of effect only. The two lonafarnib containing arms are not required to demonstrate superiority over peginterferon alfa. The study also includes a 24-week post-treatment follow up period.
The primary endpoint is a composite of a ≥2 log decline in HDV RNA and ALT normalization at end of 48 weeks of treatment. Key virological and biochemical secondary endpoints include the components of the primary endpoint. The key secondary histological endpoint is defined as ≥2-point improvement in histological activity index (HAI) and no worsening of fibrosis by Ishak score. Blinded baseline and Week 48 paired liver biopsies were read by a single, central reader. Additional secondary endpoints were included in the post-treatment follow up period. An independent data safety monitoring board reviews the safety data from D-LIVR throughout the conduct of the trial, including during the post-treatment follow-up phase.
With 407 patients enrolled across 116 clinical trial sites in 22 countries, D-LIVR is a landmark study generating the single largest source of HDV patient data from a well-controlled clinical trial to better understand and characterize this devastating disease.作者: StephenW 时间: 2022-12-9 12:42