A Phase 2 Multicenter, Randomized, Double-Blind Study to Evaluate the Efficacy and Safety of Combination Therapy of BRII-179, BRII-835 and Pegylated Interferon Alpha (PEG-IFNα) in Participants With Chronic Hepatitis B Virus (HBV) Infection (ENHANCE)

This Phase 2, randomized, double-blind study will evaluate the clinical efficacy and safety of the combination therapy of BRII-179, BRII-835, plus PEG-IFNα compared to PEG-IFNα in adult participants with chronic HBV infection without cirrhosis receiving neucloes(t)ide reverse transcriptase inhibitors (NRTIs) as background therapy.

Start Date01 Nov 2024

Sponsor / Collaborator

Brii Biosciences Ltd.

CTR20243850 / RecruitingPhase 2

一项评价BRII-179、BRII-835和聚乙二醇干扰素α（PEG-IFNα）联合治疗在慢性乙型肝炎病毒（HBV）感染受试者中有效性和安全性的II期、多中心、随机、双盲研究（ENHANCE研究）

[Translation] A Phase II, multicenter, randomized, double-blind study to evaluate the efficacy and safety of BRII-179, BRII-835, and pegylated interferon alpha (PEG-IFNα) in subjects with chronic hepatitis B virus (HBV) infection (ENHANCE study)

本研究旨在评价BRII-179、BRII-835和PEG-IFNα联合治疗与PEG-IFNα治疗相比在接受核苷（酸）类逆转录抑制剂作为背景治疗的无肝硬化的慢性HBV成人感染受试者中的临床有效性和安全性。

[Translation]

This study aims to evaluate the clinical efficacy and safety of BRII-179, BRII-835, and PEG-IFNα combination therapy compared with PEG-IFNα therapy in adult subjects with chronic HBV infection without cirrhosis who are receiving background therapy with nucleos(t)ide reverse transcriptase inhibitors.

Start Date17 Oct 2024

Sponsor / Collaborator

SciVac Ltd.

[+2]

NCT06491563 / Not yet recruitingPhase 2

A Phase 2 Multicenter, Open-label Study to Investigate the Efficacy and Safety of Regimens Containing BRII-179, BRII-835, and Pegylated Interferon Alpha (PEG-IFNα) for the Treatment of Chronic Hepatitis B Virus (HBV) Infection (ENRICH)

This study will evaluate the efficacy and safety of the regimens containing BRII-179, BRII-835, and PEG-IFNα in adult participants with chronic hepatitis B virus (HBV) infection receiving nucleos(t)ide reverse transcriptase inhibitors (NRTIs) as background therapy.

Start Date01 Aug 2024

Sponsor / Collaborator

Brii Biosciences Ltd.

[+1]

100 Clinical Results associated with Elebsiran

100 Translational Medicine associated with Elebsiran

100 Patents (Medical) associated with Elebsiran

Literatures (Medical) associated with Elebsiran

01 Dec 2024·Lancet Gastroenterology & Hepatology

VIR-2218 (elebsiran) plus pegylated interferon-alfa-2a in participants with chronic hepatitis B virus infection: a phase 2 study

Article

Author: Lim, Tien-Huey ; Yuen, Man-Fung ; Gane, Edward ; Cloutier, Daniel ; Yoon, Ki Tae ; Gupta, Sneha V ; Arizpe, Andre ; Lim, Young-Suk ; Mao, Shenghua ; Heo, Jeong ; Thanawala, Vaidehi ; Cathcart, Andrea L ; Hwang, Carey ; Tak, Won Young ; Tangkijvanich, Pisit

BACKGROUND:

Chronic hepatitis B virus (HBV) remains a global concern, with current treatments achieving low rates of HBsAg seroclearance. VIR-2218 (elebsiran), a small interfering RNA agent against HBV transcripts, reduces HBsAg concentrations. We aimed to evaluate the safety and antiviral activity of VIR-2218 with and without pegylated interferon-alpha-2a treatment in participants with chronic HBV.

METHODS:

This open-label, phase 2 study was conducted at 23 sites in six countries (New Zealand, Australia, Hong Kong, Thailand, South Korea, and Malaysia). Adults (aged 18-65 years) with chronic HBV infection without cirrhosis and with HBsAg more than 50 IU/mL and HBV DNA less than 90 IU/mL who were on continued nucleoside or nucleotide reverse transcriptase inhibitor (NRTI) therapy for 2 months or longer were eligible. Participants were enrolled into one of six cohorts to receive VIR-2218 200 mg subcutaneously every 4 weeks, with or without 180 μg subcutaneous pegylated interferon-alfa-2a once per week. Cohort 1 received six doses of VIR-2218 (total 20 weeks); cohort 2 received six doses of VIR-2218 starting at day 1, plus 12 doses of pegylated interferon-alfa-2a starting at week 12 (total 24 weeks); cohort 3 received six doses of VIR-2218 and 24 doses of pegylated interferon-alfa-2a (total 24 weeks); cohort 4 received six doses of VIR-2218 and up to 48 doses of pegylated interferon-alfa-2a (total 48 weeks); cohort 5 received up to 13 doses of VIR-2218 and up to 44 doses of pegylated interferon-alfa-2a (total 48 weeks); and cohort 6 received three doses of VIR-2218 and 12 doses of pegylated interferon-alfa-2a (total 12 weeks). The primary endpoints were the incidence of adverse events and clinical assessments (including results of laboratory tests). Secondary endpoints were the mean maximum reduction of serum HBsAg at any timepoint; the proportion of participants with serum HBsAg seroclearance at any timepoint and for more than 6 months after the end of treatment; and the proportion of participants with anti-HBs seroconversion at any timepoint. For patients who were HBeAg-positive, we also assessed the proportion with HBeAg seroclearance or anti-HBe seroconversion at any timepoint. This study is registered with ClinicalTrials.gov, NCT03672188, and is ongoing.

FINDINGS:

Between July 2, 2020, and Nov 2, 2021, 124 individuals were screened for eligibility, 84 of whom were enrolled (15 in cohort 1, 15 in cohort 2, 18 in cohort 3, 18 in cohort 4, 13 in cohort 5, and five in cohort 6). Participants were predominantly HBeAg-negative, Asian, and male (66 [79%] participants were male and 18 [21%] were female). Most treatment emergent adverse events were grades 1-2. Three (20%) participants in cohort 1, four (27%) in cohort 2, eight (44%) in cohort 3, seven (39%) in cohort 4, six (46%) in cohort 5, and two (40%) in cohort 6 reported treatment-emergent adverse events related to VIR-2218. 12 (80%) participants in cohort 2, 12 (67%) in cohort 3, 14 (78%) in cohort 4, 13 (100%) in cohort 5, and three (60%) in cohort 6 reported treatment-emergent adverse events related to pegylated interferon-alfa-2a. Two (13%) participants in cohort 1 had elevations in alanine aminotransferase, compared with 13 (87%) participants in cohort 2, 15 (83%) in cohort 3, 17 (94%) in cohort 4, 11 (85%) in cohort 5, and three (60%) in cohort 6. The mean maximum change from baseline at any timepoint in HBsAg concentration was -2·0 log₁₀ IU/mL (95% CI -2·1 to -1·8) in cohort 1, -2·2 log₁₀ IU/mL (-2·5 to -1·8) in cohort 2, -2·5 log₁₀ IU/mL (-2·8 to -2·1) in cohort 3, -2·4 log₁₀ IU/mL (-3·1 to -1·8) in cohort 4, -3·0 log₁₀ IU/mL (-3·7 to -2·3) in cohort 5, and -1·7 log₁₀ IU/mL (-2·1 to -1·4) in cohort 6. 11 participants (one in cohort 2, one in cohort 3, five in cohort 4, and four in cohort 5) receiving VIR-2218 plus pegylated interferon-alfa-2a had HBsAg seroclearance at any timepoint. Of these, ten (91%; one in cohort 2, five in cohort 4, and four in cohort 5) had anti-HBs seropositivity. Six participants (one in cohort 2, three in cohort 4, and two in cohort 5) had sustained HBsAg seroclearance through to 24 weeks after the end of treatment. No participants receiving VIR-2218 monotherapy (cohort 1) or VIR-2218 plus pegylated interferon-alfa-2a 12-week regimen (cohort 6) had HBsAg seroclearance. 12 (42%) of 26 participants (one of four in cohort 1, two of six in cohort 2, four of seven in cohort 3, four of six in cohort 4, and one of three in cohort 5) who were HBeAg positive at baseline had HBeAg seroclearance or anti-HBe seroconversion.

INTERPRETATION:

The results of this phase 2 study support further development of VIR-2218 as a potential therapy for patients with chronic HBV infection. Additional clinical trials of VIR-2218 with and without pegylated interferon-alfa-2a in combination with an HBsAg-targeting monoclonal antibody are ongoing.

FUNDING:

Vir Biotechnology.

01 Oct 2023·Journal of hepatology

Evaluation of RNAi therapeutics VIR-2218 and ALN-HBV for chronic hepatitis B: Results from randomized clinical trials

Article

Author: Lempp, Florian A ; Huang, Stephen A ; Gane, Ed ; Shen, Ling ; Taubel, Jorg ; Cloutier, Daniel J ; Cathcart, Andrea L ; Jadhav, Vasant ; Anglero-Rodriguez, Yesseinia I ; Kim, Jae B ; Milstein, Stuart ; Kaittanis, Charalambos ; Janas, Maja M ; Lim, Young-Suk ; Bakardjiev, Anna I ; Yuen, Man-Fung ; Pang, Phillip S ; Sepp-Lorenzino, Laura ; Hinkle, Gregory ; Haslett, Patrick ; Hebner, Christy M

BACKGROUND & AIMS:

Current therapy for chronic hepatitis B virus (cHBV) infection involves lifelong treatment. New treatments that enable HBV functional cure would represent a clinically meaningful advance. ALN-HBV and VIR-2218 are investigational RNA interference therapeutics that target all major HBV transcripts.

METHODS:

We report on: i) the safety of single doses of VIR-2218 (modified from ALN-HBV by enhanced stabilization chemistry plus technology to reduce off-target, seed-mediated binding while maintaining on-target antiviral activity) and ALN-HBV in humanized mice; ii) a cross-study comparison of the safety of single doses of VIR-2218 and ALN-HBV in healthy human volunteers (n = 24 and n = 49, respectively); and iii) the antiviral activity of two doses of 20, 50, 100, 200 mg of VIR-2218 (total n = 24) vs. placebo (n = 8), given 4 weeks apart, in participants with cHBV infection.

RESULTS:

In humanized mice, alanine aminotransferase (ALT) levels were markedly lower following administration of VIR-2218 compared with ALN-HBV. In healthy volunteers, post-treatment ALT elevations occurred in 28% of participants receiving ALN-HBV compared with none in those receiving VIR-2218. In participants with cHBV infection, VIR-2218 was associated with dose-dependent reductions in hepatitis B surface antigen (HBsAg). The greatest mean reduction of HBsAg at Week 20 in participants receiving 200 mg was 1.65 log IU/ml. The HBsAg reduction was maintained at 0.87 log IU/ml at Week 48. No participants had serum HBsAg loss or hepatitis B surface antibody seroconversion.

CONCLUSIONS:

VIR-2218 demonstrated an encouraging hepatic safety profile in preclinical and clinical studies as well as dose-dependent HBsAg reductions in patients with cHBV infection. These data support future studies with VIR-2218 as part of combination regimens with a goal of HBV functional cure.

TRIAL REGISTRATION:

ClinicalTrials.gov identifiers: NCT02826018 and NCT03672188.

IMPACT AND IMPLICATIONS:

A significant unmet need exists for therapies for chronic HBV (cHBV) infection that achieve functional cure. We report clinical and non-clinical data on two investigational small-interfering RNAs that target HBx, ALN-HBV and VIR-2218, demonstrating that incorporation of enhanced stabilization chemistry plus technology in VIR-2218 reduces its propensity to cause ALT elevations relative to its parent compound, ALN-HBV. We also show that VIR-2218 reduces hepatitis B surface antigen levels in a dose-dependent manner in participants with cHBV infection. These studies support the continued development of VIR-2218 as part of therapeutic regimens for cHBV infection, with the goal of a functional cure, and are important for HBV researchers and physicians.

01 Dec 2021·Drugs in R&DQ4 · MEDICINE

Clinical and Preclinical Single-Dose Pharmacokinetics of VIR-2218, an RNAi Therapeutic Targeting HBV Infection

Q4 · MEDICINE

ArticleOA

Author: Li, Jing ; Shen, Ling ; Robbie, Gabriel J ; Gupta, Sneha V ; Fanget, Marie C ; Clausen, Valerie A ; Mogalian, Erik ; Cloutier, Daniel ; MacLauchlin, Christopher

BACKGROUND AND OBJECTIVE:

VIR-2218 is an investigational N-acetylgalactosamine-conjugated RNA interference therapeutic in development for chronic hepatitis B virus (HBV) infection. VIR-2218 was designed to silence HBV transcripts across all genotypes and uses Enhanced Stabilization Chemistry Plus (ESC+) technology. This study was designed to evaluate the single-dose pharmacokinetics of VIR-2218 in preclinical species and healthy volunteers.

METHODS:

Preclinically, a single subcutaneous dose of VIR-2218 (10 mg/kg) was administered to rats and nonhuman primates (NHPs), and the pharmacokinetics were assessed in plasma, urine, and liver using standard noncompartmental analysis (NCA) methods. Clinically, healthy volunteers were randomized (6:2 active:placebo) to receive a single subcutaneous dose of VIR-2218 (50-900 mg) or placebo. Pharmacokinetics were similarly assessed within human plasma and urine using NCA methods.

RESULTS:

In rats and NHPs, VIR-2218 was stable in plasma and was converted to AS(N-1)3'VIR-2218, the most prominent circulating metabolite, at < 10% plasma exposure compared with parent. VIR-2218 rapidly distributed to the liver, reaching peak liver concentrations within 7 and 24 h in rats and NHPs, respectively. In humans, VIR-2218 was rapidly absorbed, with a median time to peak plasma concentration (t_max) of 4-7 h, and had a short median plasma half-life of 2-5 h. Plasma exposures for area under the plasma concentration-time curve up to 12 h (AUC_0-12) and mean maximum concentrations (C_max) increased in a slightly greater-than-dose-proportional manner across the dose range studied. Interindividual pharmacokinetic variability was low to moderate, with a percent coefficient of variation of < 32% for AUC and < 43% for C_max. A portion of VIR-2218 was converted to an active metabolite, AS(N-1)3'VIR-2218, with a median t_max of 6-10 h, both of which declined below the lower limit of quantification in plasma within 48 h. The pharmacokinetic profile of AS(N-1)3'VIR-2218 was similar to that of VIR-2218, with plasma AUC_0-12 and C_max values ≤ 12% of VIR-2218. VIR-2218 and AS(N-1)3'VIR-2218 were detectable in urine through the last measured time point, with approximately 17-48% of the administered dose recovered in urine as unchanged VIR-2218 over 0-24 h postdose. Based on pharmacokinetics in preclinical species, VIR-2218 localizes to the liver and likely exhibits prolonged hepatic exposure. Overall, no severe or serious adverse events or discontinuations due to adverse events were observed within the dose range evaluated for VIR-2218 in healthy volunteers (Vir Biotechnology, Inc., unpublished data).

CONCLUSIONS:

VIR-2218 showed favorable pharmacokinetics in healthy volunteers supportive of subcutaneous dosing and continued development in patients with chronic HBV infection.

CLINICAL TRIAL REGISTRATION NO:

NCT03672188, September 14, 2018.

News (Medical) associated with Elebsiran

19 Nov 2024

·www.prnewswire.com

Virion Therapeutics Reports First-Ever Clinical Responses with VRON-0200, a Novel Checkpoint Modifier for HBV Functional Cure, at AASLD's The Liver Meeting®

Highlights from the Data Presentation Ongoing safety (N=25) and immunogenicity (n=22), and first report of anti-HBV activity, presented in chronically HBV-infected patients following a single, prime-only intramuscular injection of VRON-0200 Over 4,952 patient safety days, VRON-0200 was well tolerated, with no serious adverse events (SAEs), study patient discontinuations, or laboratory abnormalities observed VRON-0200 induced CD8+ T cell responses in one third (7 of 22) of patients Responses were observed even in patients with limited pre-existing immunity A 5.5-fold increase in T cell responses at Day 28 was observed in the 7 responders Hepatitis B surface antigen declines ranging from -0.4 to -2.3 log10 IU/mL were observed, even though VRON-0200 does not directly target S-antigen, indicating anti-HBV immune activity PHILADELPHIA, Nov. 19, 2024 /PRNewswire/ -- Virion Therapeutics, LLC, a clinical-stage biotechnology company, developing novel T cell-based immunotherapies, today announced positive immunologic and continued safety and tolerability data, and anti-HBV immune responses, from the first-ever human study of its novel, first-in-class, checkpoint modifier immunotherapy, VRON-0200, for HBV functional cure, presented by Professor Grace Wong, M.D., from the Chinese University of Hong Kong, as a late breaker poster presentation at The Liver Meeting® 2024 (The American Association for the Study of the Liver), in San Diego, California, US. These Phase 1b data, on the first 25 chronically infected hepatitis B patients, on nucleos(t)ide antiviral therapy, all of whom received a single, intramuscular (i.m.) injection of VRON-0200, demonstrated that it was safe and well-tolerated, with no significant adverse events reported and no clinically relevant abnormalities in laboratory assessments, including liver function tests. In 22 patients who had at least 28 days of immunologic follow up, a 5.5-fold increase in T cell responses was observed in 7 patients (32%), post-vaccination, with most maintaining responses above their baseline values out to day 91. Additionally, four patients were observed to have HBV surface antigen (HBsAg) declines ranging from -0.4 to -2.3 log10 IU/mL, after a single i.m. dose. Professor Wong commented: "Restoring immune function in chronically HBV-infected patients is needed in order to be able to discontinue HBV treatment and eliminate the infection. These results are highly promising for this chronically infected patient population, most of whom were infected at birth, in that a single VRON-0200 injection was able to both stimulate T cell responses, and lower HBsAg, in the blood, but also, that it is safe and well tolerated. The observed declines in HBsAg are of great interest given that VRON-0200 does not directly target HBsAg, and this suggests immune control of the virus in these patients. I look forward to seeing additional data, and longer follow up, from this study." "These data highlight the potential of VRON-0200 as a simple, easy-to-administer, IFN-sparing immunotherapy, alone or in combination, for HBV functional cure," said Dr. Sue Currie, COO of Virion, and one of the study authors. "VRON-0200 is the first new immunotherapy, other than monoclonal antibody checkpoint inhibitors and pegylated-interferon, to lower HBsAg without directly targeting it. As a result of these positive data, we are now investigating our first combination therapy with VRON-0200 with a cohort that includes elebsiran (siRNA) plus tobevibart (mAb), with the goal to potentially improve responses and bring a cure to the almost 300 million persons living with chronic HBV. We look forward to sharing more results in early 2025." Professor Ed Gane, M.D., from the University of Auckland, and one of the study authors, commented: "The non-immunologic/artificial removal of HBsAg (e.g., siRNA, small molecules), has not been shown to achieve durable off-treatment responses, and may not restore the needed immunity to control HBV infection. What makes these results so exciting is that a single VRON-0200 dose was able to produce HBsAg declines, showing evidence of anti-HBV immune control in these chronically infected patients. These data, and the upcoming data from the now enrolling combination cohort, will inform future strategies for Functional Cure therapies." Summary of VRON-0200 Phase 1b clinical trial design VRON-0200 is a Phase 1b, multi-center, open-label, dose escalation, prime only, and prime plus boost, therapeutic immunotherapy study to evaluate the safety, tolerability, immunology, and other clinical measures: Inclusion criteria: Non-cirrhotic, HBeAg positive or negative, chronic hepatitis B patients currently taking nucleos(t)ide antiviral therapy with HBV DNA < 40 IU/mL and HBsAg < 500 IU/mL (< 1,000 IU/mL for Cohort 3) Dose escalation: Cohort 1 (low dose) (ENROLLED); Cohort 2 (high dose) (ENROLLED) Prime or Prime-Boost: In each cohort, patients are randomized to receive either a prime dose only or a prime and boost regimen Cohort 3: patients are randomized to receive VRON-0200 prime plus 6 monthly subcutaneous doses of elebsiran and tobevibart starting starting on Day 28, alone, or with a boost at Day 196 (ENROLLING) More details of the study can be found at ClinicalTrials.gov (Identifier: NCT06070051). About Chronic Hepatitis B Despite a preventative vaccine, cases of chronic hepatitis B (HBV) continue to rise, with an estimated 296 million persons infected worldwide and 820,000 deaths per year from HBV-related liver complications. Chronic HBV remains a global health issue with a high unmet medical need since there is no cure available. The current standard of care requires lifelong antiviral therapy to maintain control of the virus. About VRON-0200 VRON-0200 is a therapeutic immunotherapy, administered by intramuscular injection, designed with the goal of providing a functional cure for chronic HBV infection. While the virus itself stimulates HBV-specific CD8+ T cells, for those patients that can't clear the initial infection, their T cells soon become exhausted, placing limits on their ability to proliferate and control the virus. Preclinical data support the hypothesis that VRON-0200, through checkpoint modification, can amplify, broaden, and enhance T cell responses that may include T cells that are not normally activated during a chronic HBV infection, which results in improved viral control. An ongoing Phase 1b trial has shown VRON-0200 to be safe, well tolerated, and immunogenic, in chronically HBV-infected patients on nucleos(t)ide therapy. About Virion Therapeutics (Virion) Virion Therapeutics, LLC is a clinical-stage company developing novel T cell-based immunotherapies to cure cancer and chronic infectious diseases that utilize proprietary genetically encoded checkpoint modifiers to enhance and broaden CD8+ T cell responses to a tumor or chronic infection. Founded in early 2018 to advance technology licensed from The Wistar Institute, an international leader in biomedical research, Virion has since developed a robust pipeline, including its lead VRON-0200 clinical program, and several additional IND-enabling programs, including its VRON-0300 oncology program for advanced solid tumors, leveraging its proprietary platform technologies. To learn more, visit Contact: Virion Therapeutics, LLC, Dr. Sue Currie, Chief Operating Officer [email protected] SOURCE Virion Therapeutics, LLC WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

ImmunotherapyClinical ResultPhase 1AACR

19 Nov 2024

·www.businesswire.com

Vir Biotechnology Presents Positive Chronic Hepatitis Delta Clinical Trial Data and Announces Initiation of Phase 3 Registrational Program

SAN FRANCISCO--( BUSINESS WIRE )--Vir Biotechnology, Inc. (NASDAQ:VIR) today announced positive results from the SOLSTICE Phase 2 clinical trial evaluating tobevibart alone, or in combination with elebsiran, in people with chronic hepatitis delta (CHD). The most-advanced and potential first-of-its-kind investigational human monoclonal antibody and siRNA combination dosed monthly achieved 100% virologic response and rapid hepatitis delta virus (HDV) RNA suppression. HDV RNA below the lower limit of quantification (< LLOQ), target not detected (TND), the best measure that the virus is cleared from the body, was achieved in 41% (13/32) of participants at Week 24 rising to 64% (14/22) of participants by Week 36. In a cohort that reached Week 60, 80% (4/5) achieved HDV RNA TND. These data were presented in an oral session at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting ® , in San Diego, CA. Based on these results, and following a recent meeting with the FDA, Vir Biotechnology plans to initiate the Phase 3 registrational ECLIPSE program in the first half of 2025 to further evaluate the combination of tobevibart and elebsiran for the treatment of CHD. CHD is a chronic inflammatory liver disease caused by HDV 1 . It is the most severe form of chronic viral hepatitis 2 and on average, people living with CHD will progress to cirrhosis and liver failure within 5 years 3 . There is no approved treatment in the United States. The objective of therapy is to clear the virus, and combination therapy offers the potential to do so by tackling the viral lifecycle through multiple mechanisms. “ Achieving HDV RNA suppression with a safe, well-tolerated, and conveniently dosed treatment could be transformative for people living with hepatitis delta. The impressive rates of virologic suppression seen in the SOLSTICE Phase 2 data suggest that tobevibart and elebsiran have the potential to significantly improve patient outcomes,” said Tarik Asselah, M.D., Ph.D., Professor of Hepatology at the Hôpital Beaujon, APHP, Clichy, France, and at the University of Paris-Cité, and Head of the unit Viral Hepatitis UMR1149 at INSERM, France. “ New, effective therapeutic options are urgently needed, and I am excited to see this combination advance into a registrational Phase 3 program.” Primary Endpoint Analysis from the Phase 2 SOLSTICE Trial Clinical trial participants were randomized to receive tobevibart 300 mg monotherapy every two weeks (n=33) or a combination of tobevibart 300 mg and elebsiran 200 mg every four weeks (combination de novo arm, n=32). In addition, the participants from previous tobevibart or elebsiran monotherapy cohorts could rollover to receive the combination of tobevibart 300 mg and elebsiran 200 mg every four weeks (combination rollover, n=13). Rates of virologic suppression were evaluated at Week 24, and further assessed at Weeks 36, 48 and 60 in those participants that had reached each timepoint. Further monitoring will continue up to 192 weeks. Rapid and Sustained Virologic Suppression – 100% of participants across combination arms achieved an HDV RNA ≥2 log 10 decrease or below limit of detection (LOD) at Week 24, and this rate was sustained over time in all participants at Weeks 36 (22/22) and those in the rollover cohort that reached Week 60 (5/5). HDV RNA TND was achieved in 41% (13/32) of participants across combination arms at Week 24 and this rose to 64% (14/22) at Week 36. By week 60, this had risen further with 80% (4/5) of participants in the rollover cohort having achieved no detectable viral RNA. Approximately 90% of participants receiving the combination achieved reductions in hepatitis B surface antigen (HBsAg) values below <10 IU/mL at Week 24, with sustained responses at later time points. This indicates suppression of the key biologic mechanisms that HDV requires for viral replication. ALT Normalization – Alanine aminotransferase (ALT) decreased in most participants between Day 1 and Week 24 and normalized in 47% (15/32) of participants in the combination de novo cohort and 56% (5/9) in the rollover cohort by Week 24. These rates were sustained at Week 36. Combined Endpoints – The protocol defined combined endpoint of HDV RNA decrease ≥ 2 log 10 compared to baseline or HDV RNA below LOD and ALT normalization at Week 24 was observed in 47% (15/32) of participants in the combination de novo arm. The more stringent composite endpoint of HDV RNA TND and ALT normalization was achieved in 19% (6/32) of participants in the combination de novo arm at Week 24, which increased to 27% (6/22) by Week 36. This trend was reflected in the combination rollover cohort in which 33% (3/9) of participants achieved this endpoint at Week 24 and 40% (2/5) at Week 60. Rates of HDV RNA suppression and ALT normalization were similar between non-cirrhotic and cirrhotic participants across combination arms. Safety Profile – The safety profile of tobevibart and elebsiran is consistent with previous studies. Treatment-emergent adverse events (TEAEs) were generally mild or moderate and transient across all treatment groups, with influenza-like illness being the most common event. No ALT flares were observed. There were no study-related discontinuations in the combination arms, and no treatment-related severe adverse events (SAEs) were reported. “ People living with hepatitis delta in the US have no approved treatment options, and therapies are limited globally. At Vir Biotechnology we are committed to changing that,” said Marianne De Backer, M.Sc., Ph.D., MBA, Chief Executive Officer, Vir Biotechnology. “ We are confident that our regimen has the potential to deliver transformative benefits for patients, and we will build on our strong SOLSTICE data to start our Phase 3 registrational ECLIPSE program as soon as possible in 2025.” Phase 3 Registrational ECLIPSE Program Following a meeting with the FDA, Vir Biotechnology finalized the design of the Phase 3 registrational clinical program, ECLIPSE, which evaluates the tobevibart and elebsiran combination in people living with CHD. This program, which will commence in the first half of 2025, will include three randomized, controlled trials designed to evaluate the combination therapy in comparison to deferred treatment or bulevirtide. All studies will enroll both cirrhotic and non-cirrhotic participants. ECLIPSE 1 and 2 are Phase 3 trials designed to provide the registrational efficacy and safety data needed for submission to global regulatory agencies. ECLIPSE 3 is a Phase 2b trial designed to provide important supportive data, particularly in Europe, to help establish appropriate pricing and reimbursement in key markets. ECLIPSE 1 will assess the efficacy and safety of tobevibart and elebsiran compared to deferred treatment in regions such as the U.S. where bulevirtide is not available or its use is limited. ECLIPSE 2 will evaluate the efficacy and safety of switching to tobevibart and elebsiran in people with CHD who have not achieved viral suppression with bulevirtide therapy. ECLIPSE 3 is a Phase 2b head-to-head trial to evaluate tobevibart and elebsiran compared with bulevirtide in bulevirtide-naïve patients. In June 2024, the U.S. Food and Drug Administration (FDA) granted fast track designation for the combination of tobevibart and elebsiran for the treatment of CHD. This designation is intended to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need. Vir Biotechnology announced today that the European Medicines Agency (EMA) Committee for Orphan Medicinal Products (COMP) issued a positive opinion on the application for orphan drug designation of tobevibart and elebsiran for the treatment of CHD. This designation supports the development of treatments for life-threatening or chronically debilitating conditions with significant unmet medical need. Investor Conference Call Vir Biotechnology will host an investor conference call on November 19, 2024 at 5.15 a.m. PT / 8.15 a.m. ET. A live webcast will be available on https://investors.vir.bio/ and will be archived on www.vir.bio for 30 days. About the Phase 2 SOLSTICE Trial SOLSTICE is a Phase 2 study to evaluate the safety, tolerability, and efficacy of tobevibart, alone or in combination with elebsiran, in people with chronic hepatitis delta. This Phase 2 study is a multi-center, open-label, randomized study. Primary endpoints include proportion of participants with undetectable hepatitis delta virus (HDV) RNA (defined as HDV RNA equal or greater than 2 log 10 decrease from baseline or below limit of detection) up to week 24, alanine aminotransferase (ALT) normalization (defined as ALT below upper limit of normal) up to week 24, and treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) up to 118 weeks. Secondary endpoints include proportion of participants with undetectable HDV RNA and different timepoints and up to 192 weeks. More information about this trial can be found at clinicaltrials.gov (NCT05461170). About Tobevibart and Elebsiran Tobevibart is an investigational broadly neutralizing monoclonal antibody targeting the hepatitis B surface antigen. It is designed to inhibit the entry of hepatitis B and hepatitis delta viruses into hepatocytes, and to reduce the level of circulating viral and subviral particles in the blood. Tobevibart, which incorporates Xencor’s Xtend™ and other Fc technologies, has been engineered to have an extended half-life and was identified using Vir Biotechnology’s proprietary monoclonal antibody discovery platform. Tobevibart is administered subcutaneously, and it is currently in clinical development for the treatment of patients with chronic hepatitis B and patients with chronic hepatitis delta. Elebsiran is an investigational hepatitis B virus-targeting small interfering ribonucleic acid (siRNA) designed to degrade hepatitis B virus RNA transcripts and limit the production of hepatitis B surface antigen. Current data indicates that it has the potential to have direct antiviral activity against hepatitis B virus and hepatitis delta virus. Elebsiran is administered subcutaneously, and it is currently in clinical development for the treatment of patients with chronic hepatitis B and patients with chronic hepatitis delta. It is the first asset in Vir Biotechnology’s collaboration with Alnylam Pharmaceuticals, Inc. to enter clinical studies. Tobevibart and elebsiran are also being evaluated as a potential functional cure for chronic hepatitis B. Vir Biotechnology recently presented positive safety and efficacy end-of-treatment results from the MARCH Phase 2 clinical study evaluating combinations of tobevibart and elebsiran, alone or in combination with pegylated interferon alfa (PEG-IFNα), in participants with chronic hepatitis B in a late-breaker oral presentation at AASLD The Liver Meeting ® . About Vir Biotechnology, Inc. Vir Biotechnology, Inc. is a clinical-stage biopharmaceutical company focused on powering the immune system to transform lives by discovering and developing medicines for serious infectious diseases and cancer. It’s clinical-stage portfolio includes infectious disease programs for chronic hepatitis delta and chronic hepatitis B infections and programs across several clinically validated targets in solid tumor indications. Vir Biotechnology also has a preclinical portfolio of programs across a range of other infectious diseases and oncologic malignancies. Vir Biotechnology routinely posts information that may be important to investors on its website. References: 1 NIH National Institute of Diabetes and Digestive and Kidney Diseases Hepatitis D - NIDDK (nih.gov) , accessed September 2024 2 WHO Hepatitis Delta Factsheet – Hepatitis D (who.int) , accessed September 2024 3 CDC What is Hepatitis D - FAQ | CDC Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as “may,” “will,” “plan,” “potential,” “aim,” “expect,” “anticipate,” “promising” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements. These forward-looking statements are based on Vir Biotechnology’s expectations and assumptions as of the date of this press release. Forward-looking statements contained in this press release include, but are not limited to, statements regarding Vir Biotechnology’s strategy and plans, the potential clinical effects of tobevibart and elebsiran, the potential benefits, safety and efficacy of tobevibart and elebsiran, the timing, nature and significance of data from Vir Biotechnology’s multiple ongoing trials evaluating tobevibart and elebsiran, Vir Biotechnology’s plans and expectations for its CHD and CHB programs, and risks and uncertainties associated with drug development and commercialization. Many factors may cause differences between current expectations and actual results, including unexpected safety or efficacy data or results observed during clinical trials or in data readouts; the occurrence of adverse safety events; risks of unexpected costs, delays or other unexpected hurdles; difficulties in collaborating with other companies; successful development and/or commercialization of alternative product candidates by Vir Biotechnology’s competitors; changes in expected or existing competition; delays in or disruptions to Vir Biotechnology’s business or clinical trials due to geopolitical changes or other external factors; and unexpected litigation or other disputes. Drug development and commercialization involve a high degree of risk, and only a small number of research and development programs result in commercialization of a product. Results in early-stage clinical trials may not be indicative of full results or results from later stage or larger scale clinical trials and do not ensure regulatory approval. You should not place undue reliance on these statements, or the scientific data presented. Other factors that may cause actual results to differ from those expressed or implied in the forward-looking statements in this press release are discussed in Vir Biotechnology’s filings with the U.S. Securities and Exchange Commission, including the section titled “Risk Factors” contained therein. Except as required by law, Vir Biotechnology assumes no obligation to update any forward-looking statements contained herein to reflect any change in expectations, even as new information becomes available.

Phase 2Clinical ResultOrphan DrugFast TrackPhase 3

18 Nov 2024

·www.businesswire.com

Vir Biotechnology Receives Positive Opinion on Orphan Drug Designation for Tobevibart and Elebsiran in Chronic Hepatitis Delta from European Medicines Agency

SAN FRANCISCO--( BUSINESS WIRE )--Vir Biotechnology, Inc. (Nasdaq: VIR) today announced that the European Medicines Agency (EMA) Committee for Orphan Medicinal Products (COMP), has issued a positive opinion on the application for orphan drug designation of tobevibart and elebsiran for the treatment of chronic hepatitis delta (CHD). This opinion is based on encouraging preliminary data from the Phase 2 SOLSTICE trial. Vir Biotechnology will present 24-week data from the Phase 2 SOLSTICE trial at AASLD The Liver Meeting® in San Diego, CA, on November 18 at 6.15 p.m. PT. An investor conference call is scheduled for November 19, 2024, at 5.15 a.m. PT / 8.15 a.m. ET. CHD is a severe, progressive liver disease caused by the hepatitis delta virus (HDV) 1 . It is considered the most aggressive form of chronic viral hepatitis 2 , with patients often progressing to cirrhosis and liver failure within 5 years of infection 3 . Currently, there is no approved treatment in the United States, and treatment options are limited in the European Union and globally. “ Chronic hepatitis delta dramatically raises the risk of severe liver disease, including cancer, and eventually death, so new therapeutic options are urgently needed,” said Mark Eisner, M.D., M.P.H., Executive Vice President and Chief Medical Officer, Vir Biotechnology. “ The COMP’s positive opinion on tobevibart and elebsiran reflects the potential of this combination to address a critical gap in hepatitis delta care. Our clinical data to date has been encouraging, suggesting that this approach could meaningfully improve outcomes for patients living with this devastating disease.” The European Commission will evaluate the COMP’s positive opinion and consider tobevibart and elebsiran for orphan drug designation. This designation is for medicines intended to treat rare, life-threatening or chronically debilitating conditions where no other satisfactory treatment option is available, or where the medicine can be of significant benefit to those affected by a specific condition. The designation provides special incentives in the E.U., including access to specific scientific advice, fee reductions, and 10 years of market exclusivity once the medicine is approved. In June 2024, the U.S. Food and Drug Administration (FDA) granted fast track designation for the combination of tobevibart and elebsiran for the treatment of CHD. This designation is intended to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need. Investor Conference Call Vir Biotechnology will host an investor conference call on November 19, 2024 at 5.15 a.m. PT / 8.15 a.m. ET. A live webcast will be available on https://investors.vir.bio/ and will be archived on www.vir.bio for 30 days. About the Phase 2 SOLSTICE Trial SOLSTICE is a Phase 2 study to evaluate the safety, tolerability, and efficacy of tobevibart, alone or in combination with elebsiran, in patients with chronic hepatitis delta. This Phase 2 study is a multi-center, open-label, randomized study. Primary endpoints include proportion of participants with undetectable hepatitis delta virus (HDV) RNA (defined as HDV RNA equal or greater than 2 log 10 decrease from baseline or below limit of detection) up to week 24, alanine aminotransferase (ALT) normalization (defined as ALT below upper limit of normal) up to week 24, and treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) up to 118 weeks. Secondary endpoints include proportion of participants with undetectable HDV RNA and different timepoints and up to 192 weeks. More information about this trial can be found at clinicaltrials.gov (NCT05461170). About Tobevibart Tobevibart is an investigational, broadly neutralizing monoclonal antibody targeting the hepatitis B surface antigen. It is designed to inhibit the entry of hepatitis B and hepatitis delta viruses into hepatocytes, and to reduce the level of circulating viral and subviral particles in the blood. Tobevibart, which incorporates Xencor’s Xtend™ and other Fc technologies, has been engineered to have an extended half-life and was identified using Vir Biotechnology’s proprietary monoclonal antibody discovery platform. Tobevibart is administered subcutaneously, and it is currently in clinical development for treatment of patients with chronic hepatitis B and patients with chronic hepatitis delta. About Elebsiran Elebsiran is an investigational, hepatitis B virus-targeting small interfering ribonucleic acid (siRNA) designed to degrade hepatitis B virus RNA transcripts and limit the production of hepatitis B surface antigen. Current data indicates that it has the potential to have direct antiviral activity against hepatitis B virus and hepatitis delta virus. Elebsiran is administered subcutaneously, and it is currently in clinical development for treatment of patients with chronic hepatitis B and patients with chronic hepatitis delta. It is the first asset in Vir Biotechnology’s collaboration with Alnylam Pharmaceuticals, Inc. to enter clinical studies. About Vir Biotechnology, Inc. Vir Biotechnology, Inc. is a clinical-stage biopharmaceutical company focused on powering the immune system to transform lives by discovering and developing medicines for serious infectious diseases and cancer. It’s clinical-stage portfolio includes infectious disease programs for chronic hepatitis delta and chronic hepatitis B infections and programs across several clinically validated targets in solid tumor indications. Vir Biotechnology also has a preclinical portfolio of programs across a range of other infectious diseases and oncologic malignancies. Vir Biotechnology routinely posts information that may be important to investors on its website. References: 1 NIH National Institute of Diabetes and Digestive and Kidney Diseases Hepatitis D - NIDDK (nih.gov) , accessed September 2024. 2 WHO Hepatitis Delta Factsheet - Hepatitis D (who.int) , accessed September 2024 3 CDC What is Hepatitis D - FAQ | CDC Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as “may,” “will,” “plan,” “potential,” “aim,” “expect,” “anticipate,” “promising” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements. These forward-looking statements are based on Vir Biotechnology’s expectations and assumptions as of the date of this press release. Forward-looking statements contained in this press release include, but are not limited to, statements regarding Vir Biotechnology’s strategy and plans, the potential clinical effects of tobevibart and elebsiran, the potential benefits, safety and efficacy of tobevibart and elebsiran, the timing, nature and significance of data from Vir Biotechnology’s multiple ongoing trials evaluating tobevibart and elebsiran, Vir Biotechnology’s plans and expectations for its CHD and CHB programs, and risks and uncertainties associated with drug development and commercialization. Many factors may cause differences between current expectations and actual results, including unexpected safety or efficacy data or results observed during clinical trials or in data readouts; the occurrence of adverse safety events; risks of unexpected costs, delays or other unexpected hurdles; difficulties in collaborating with other companies; successful development and/or commercialization of alternative product candidates by Vir Biotechnology’s competitors; changes in expected or existing competition; delays in or disruptions to Vir Biotechnology’s business or clinical trials due to geopolitical changes or other external factors; and unexpected litigation or other disputes. Drug development and commercialization involve a high degree of risk, and only a small number of research and development programs result in commercialization of a product. Results in early-stage clinical trials may not be indicative of full results or results from later stage or larger scale clinical trials and do not ensure regulatory approval. You should not place undue reliance on these statements, or the scientific data presented. Other factors that may cause actual results to differ from those expressed or implied in the forward-looking statements in this press release are discussed in Vir Biotechnology’s filings with the U.S. Securities and Exchange Commission, including the section titled “Risk Factors” contained therein. Except as required by law, Vir Biotechnology assumes no obligation to update any forward-looking statements contained herein to reflect any change in expectations, even as new information becomes available.

Phase 2Orphan DrugFast Track

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatitis D, Chronic	Phase 2	BG	Vir Biotechnology, Inc.	17 Sep 2022
Hepatitis D, Chronic	Phase 2	FR	Vir Biotechnology, Inc.	17 Sep 2022
Hepatitis D, Chronic	Phase 2	DE	Vir Biotechnology, Inc.	17 Sep 2022
Hepatitis D, Chronic	Phase 2	IT	Vir Biotechnology, Inc.	17 Sep 2022
Hepatitis D, Chronic	Phase 2	MD	Vir Biotechnology, Inc.	17 Sep 2022
Hepatitis D, Chronic	Phase 2	NL	Vir Biotechnology, Inc.	17 Sep 2022
Hepatitis D, Chronic	Phase 2	NZ	Vir Biotechnology, Inc.	17 Sep 2022
Hepatitis D, Chronic	Phase 2	RO	Vir Biotechnology, Inc.	17 Sep 2022
Hepatitis D, Chronic	Phase 2	GB	Vir Biotechnology, Inc.	17 Sep 2022
Hepatitis B, Chronic	Phase 2	AU	Vir Biotechnology, Inc.	03 Jul 2020

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


Pubmed \| Lancet Gastroenterol Hepatol	Not Applicable	Hepatitis B, Chronic	-	VIR-2218 200 mg + Pegylated interferon-alfa-2a	lrwiwxyzdx(pptnnwzzkt) = 20% in cohort 1, 27% in cohort 2, 44% in cohort 3, 39% in cohort 4, 46% in cohort 5, 40% in cohort 6 yxwtolvksd (yzttbrumrw ) View more	-	01 Dec 2024
NCT04507269 (CTgov)	Phase 2	Hepatitis B, Chronic	21	VIR-2218 (Part 1: VIR-2218 50 mg)	zxfjbtvzkd(agsgbmskdu) = wixcygvbbw mtymtmyiea (zepuwtnrql, ueidiweusd - ygnepodjzx) View more	-	26 Aug 2024
				VIR-2218 (Part 1: VIR-2218 100 mg)	zxfjbtvzkd(agsgbmskdu) = bpjovelyai mtymtmyiea (zepuwtnrql, nzjukxbrkx - eerknrfbph) View more
NCT03672188 \| NCT02826018 (Pubmed)	Not Applicable	Hepatitis B, Chronic	-	VIR-2218	wgdrmbkkok(frmfipyhlv) = ixmbvurqrv ksmeftaqau (ewqbqodmbh )	-	06 Jun 2023
GlobeNewswire Manual	Phase 2	Hepatitis B	-	VIR-2218VIR-2218 (six-dose regimen of VIR-2218)	dwgyqhkscu(bgnyqwmvis) = all participants achieving a >1 log10 IU/mL reduction during the trial. hlskkfilrl (oysulpouiu ) View more	Positive	25 Jun 2022
				VIR-2218VIR-2218 (two-dose regimen of VIR-2218)
EASL2021	Phase 2	Hepatitis B, Chronic	27	VIR-2218 alone	ljxitkjfms(hvlldglxvn) = Some participants receiving Peg-IFNa and VIR-2218 combination experienced asymptomatic ALT elevations (grade 2 – 3) concurrent with HBsAg decline ( ≥ 1 log 10 IU/ ml). ALT elevations were not associated with functional changes of the liver (bilirubin, PT or INR). No serious AEs have been reported. kerkmlzbgy (mmdilcmtra )	-	23 Jun 2021
				VIR-2218 + Peg-IFNa
Phase 2 (EASL2020)	Phase 2	Hepatitis B	-	VIR-2218	hzeygqfeoc(unxdufsdit) = gomqodvrfe qnonalbdgb (yxuqcnyrdt ) View more	Positive	27 Aug 2020
				Placebo	humhcnflxi(cgnpygcdco) = apqqkmtewb vqhtimgsfc (rjfgopkaat )
EASL2020	Phase 2	Hepatitis B, Chronic	24	VIR-2218 20 mg	yyavxkraaj(dvlwrdbhwr) = No clinically significant ALTelevations were observed xbnzfzybjv (exwrdjrtyr ) View more	-	27 Aug 2020
				VIR-2218 50 mg

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