A Trial To Evaluate The Efficacy And Safety Of Multiple Combination Therapies In Participants With Chronic Hepatitis B

NCT04225715 — Phase 2, Completed, 281 participants, Hoffmann-La Roche

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A Phase II, Randomised, Adaptive, Open-Label Platform Trial To Evaluate Efficacy And Safety Of Multiple Combination Therapies In Participants With Chronic Hepatitis B

Registry	NCT04225715, acronym Piranga
Status	Completed
Phase	Phase 2
Study type	Interventional; randomized, parallel, masking: none, treatment
Enrollment	281 (Actual)
Sponsor	Hoffmann-La Roche (Industry)
Conditions	Hepatitis B, Chronic
Interventions	Nucleos(t)ide (NUC), CpAM (RO7049389), TLR7 (RO7020531), siRNA (RO7445482), PEG-IFN, PD-L1 LNA (RO7191863) (Drug)
Dates	start 2020-07-05, primary completion 2024-07-19, completion 2024-07-19, first posted 2020-01-13, last updated 2025-09-19
Locations	33 sites in Bulgaria, Canada, Chile, China, France, Hong Kong, New Zealand, Romania and 5 more countries

-Summary

This is a study designed to evaluate the safety, tolerability and efficacy of New Molecular Entity (NME) combination therapies in Chronic Hepatitis B (CHB) participants with preserved liver function and without significant fibrosis/cirrhosis. The platform design allows comparison of multiple NME combination therapies against a common control, and introduction of additional treatment arms at later study time points. Each arm will consist of a screening phase (up to 8 weeks), treatment phase (up to 48 weeks) and post-treatment follow-up phase (48 weeks). The safety and efficacy will be monitored throughout the study.

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+Arms and interventions

Arm	Type	Interventions	Description
Nucleos(t)ide (NUC) Control Arm	Active comparator	Drug: Nucleos(t)ide (NUC)	Participants will continue their background NUC therapy for the 48-week treatment period. At the end of the treatment period, in line with current CHB treatment guidelines, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
Core Protein Allosteric Modulator (CpAM; RO7049389) + Toll-like Receptor 7 (TLR7;RO7020531) + NUC	Experimental	Drug: Nucleos(t)ide (NUC); Drug: CpAM (RO7049389); Drug: TLR7 (RO7020531)	Participants will receive RO7049389 (600 mg once daily \[QD\]) in addition to their background NUC therapy for the 48-week treatment period. RO7020531 (150 mg once every other day \[QOD\]) will be administered during Weeks 1-12 and Weeks 25-36. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
Short Interfering Ribonucleic acid (siRNA; RO7445482) (Dose1) + NUC	Experimental	Drug: Nucleos(t)ide (NUC); Drug: siRNA (RO7445482)	Participants will receive RO7445482 (Dose 1) in addition to their background NUC therapy for the 48-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
siRNA (RO7445482) (Dose 2) + NUC	Experimental	Drug: Nucleos(t)ide (NUC); Drug: siRNA (RO7445482)	Participants will receive RO7445482 (Dose 2) in addition to their background NUC therapy for the 48-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
siRNA (RO7445482) + Pegylated Interferon (PEG-IFN) + NUC	Experimental	Drug: Nucleos(t)ide (NUC); Drug: siRNA (RO7445482); Drug: PEG-IFN	Participants will receive RO7445482 (Dose 2) in addition to their background NUC therapy for the 48-week treatment period. PEG-IFN will be administered at a dose of 180 μg once weekly (QW) for 48 weeks. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
siRNA (RO7445482) + CpAM (RO7049389) + NUC	Experimental	Drug: Nucleos(t)ide (NUC); Drug: CpAM (RO7049389); Drug: siRNA (RO7445482)	Participants will receive RO7445482 (Dose 2) and RO7049389 (600 mg QD) in addition to their background NUC therapy for the 48-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
siRNA (RO7445482) + TLR7 (RO7020531) + NUC	Experimental	Drug: Nucleos(t)ide (NUC); Drug: TLR7 (RO7020531); Drug: siRNA (RO7445482)	Participants will receive RO7445482 (Dose 2) in addition to their background NUC therapy for the 48-week treatment period. RO7020531 (150 mg QOD) will be administered during Weeks 13-24 and Weeks 37-48 (i.e., 2 treatment cycles of 12 weeks' duration each and 42 doses of RO7020531 for each cycle). At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
siRNA(RO7445482)+ Programmed Death Ligand-1 Locked Nucleic Acid (PD-L1 LNA; RO7191863) + NUC [1]	Experimental	Drug: Nucleos(t)ide (NUC); Drug: siRNA (RO7445482); Drug: PD-L1 LNA (RO7191863)	Participants will receive RO7445482 (Dose 2) during Weeks 1-24 and RO7191863 (Dose 1) will be administered during Weeks 13-24, in addition to their background NUC therapy for the 24-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
siRNA (RO7445482) + PD-L1 LNA (RO7191863) + NUC [2]	Experimental	Drug: Nucleos(t)ide (NUC); Drug: siRNA (RO7445482); Drug: PD-L1 LNA (RO7191863)	Participants will receive RO7445482 (Dose 2) during Weeks 1-24 and RO7191863 (Dose 1) will be administered during Weeks 25-36, in addition to their background NUC therapy for the 36-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.

Nucleos(t)ide (NUC) (Drug): Nucleos(t)ide (NUC) will be administered orally
CpAM (RO7049389) (Drug), also known as Linvencorvir, RG7907: CpAM (RO7049389) will be administered orally
TLR7 (RO7020531) (Drug), also known as Ruzotolimod, RG7854: TLR7 (RO7020531) will be administered orally
siRNA (RO7445482) (Drug), also known as Xalnesiran, RG6346: siRNA (RO7445482) will be administered subcutaneously
PEG-IFN (Drug), also known as Pegasys®: PEG-IFN will be administered subcutaneously
PD-L1 LNA (RO7191863) (Drug), also known as Cadapersen, RG6084: PD-L1 LNA (RO7191863) will be administered subcutaneously

+Outcome measures

Primary outcomes

Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at 24 Weeks Post-End of Treatment (EOT) [Follow-up Week (FUW) 24]: HBsAg loss was defined as quantitative HBsAg <0.05 international units/milliliters (IU/mL). The percentage of participants with HBsAg loss was calculated as number of participants with HBsAg loss / total number of participants *100. 95% confidence interval (CI) was calculated using the Clopper-Pearson method. Percentages have been rounded off.

Secondary outcomes

Percentage of Participants With HBsAg Loss [Combos 1 and 5: Weeks 24, 36, 48 and FUW 48; Combos 2, 3, 4, 6 and NUC Arm: Week 48 and FUW 48; Combo 7: Week 24; Combo 8: Week 36]: HBsAg loss was defined as quantitative HBsAg <0.05 IU/mL. The percentage of participants with HBsAg loss was calculated as number of participants with HBsAg loss / total number of participants *100. 95% CI was calculated using the Clopper-Pearson method. Percentages have been rounded off.
Percentage of Participants With HBsAg Seroconversion [Combos 1 and 5: Weeks 24, 36, 48, FUW 24 and FUW 48; Combos 2, 3, 4, 6 and NUC Arm: Week 48, FUW 24 and FUW 48; Combo 7: Week 24 and FUW 24; Combo 8: Week 36 and FUW 24]: HBsAg seroconversion was defined as a quantitative HBsAg < 0.05 IU/mL and a positive anti-HBs antibody (defined as per assay reactive threshold anti-HBs ≥10 IU/L). 95% CI was calculated using the Clopper-Pearson method. Percentages have been rounded off.
Percentage of Participants With Hepatitis B Early Antigen (HBeAg) Loss in Baseline HBeAg-positive Participants [Weeks 12, 24, 36, and 48; FUW 12, 24, 36, and 48]: HBeAg loss was defined as negative /non-reactive HBeAg level. Percentages have been rounded off.
Percentage of Participants With HBeAg Seroconversion in Baseline HBeAg-positive Participants [Weeks 12, 24, 36, and 48; FUW 12, 24, 36, and 48]: HBeAg seroconversion was defined as a negative /non-reactive HBeAg level and a positive anti-HBe antibody. Percentages have been rounded off.
Number of Participants With Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA) < Lower Limit of Quantification (LLOQ), <200 IU/mL, and <2,000 IU/mL [FUW 12, 24, 36, and 48]: Chronic HBV infection is characterized by high levels of circulating HBV DNA. Therefore, HBV levels are indicative of virological response. At screening participants were on NUC therapy and had circulating HBV DNA levels below the assay LLOQ or below 20 IU/mL for at least 6 months. The emergence of a virological breakthrough (HBV DNA >100 IU/mL or >1 log increase from nadir) while on NUC therapy, or the emergence of a virological relapse (>2,000 IU/mL) in participants taken off NME combination and NUC therapy during follow-up, was monitored through the quantification of HBV DNA in plasma.
Change From Baseline in HBsAg, Anti-HBs, HBeAg, HBV Ribonucleic Acid (RNA) and HBV DNA Levels Over Time [HBsAg, Anti-HBs, HBeAg & HBV RNA: Combo 1 to 6 and NUC arm: Weeks 24, 36, 48, FUW 24 and FUW 48; Combo 7: Week 24, FUW 24 & FUW 48; Combo 8: Weeks 24, 36, FUW 24 & FUW 48; HBV DNA: FUW 24 and FUW 48]: The serological markers of HBV infection include viral antigens (HBsAg \& HBeAg) and antibody (anti-HBs). Changes in serological markers and efficacy biomarkers (HBV RNA) from baseline are reported. Change from baseline for HBV DNA was assessed in 'ON NUC' participants.
Combos 7 and 8: Area Under the Plasma Concentration-time Curve Over the Dosing Interval at Week 1 (AUC1-0-168h) of PD-L1 LNA [Predose on Day 1 and up to 168 hours post dose (Week 1)]: The AUC was predicted and summarized by modelling \& simulation via the population pharmacokinetics (PopPK) method based on pre and post dose samples. As per planned analysis data was collected and reported in a pooled manner for Combos 7 and 8.
Combos 7 and 8: Maximum Plasma Concentration (Cmax) at Week 1 (Cmax1-0-168h) of PD-L1 LNA [Predose on Day 1 and up to 168 hours post dose (Week 1)]: The Cmax was predicted and summarized by modelling \& simulation via the PopPK method based on pre and post dose samples. As per planned analysis data was collected and reported in a pooled manner for Combos 7 and 8.
Combos 7 and 8: AUC Over the Dosing Interval at Week 12 (AUC12-0-168h) of PD-L1 LNA [Predose on Day 1 of Week 12 up to 168 hours post dose (Week 12)]: The AUC was predicted and summarized by modelling \& simulation via the PopPK method based on pre and post dose samples. As per planned analysis data was collected and reported in a pooled manner for Combos 7 and 8.
Combos 7 and 8: Cmax at Week 12 (Cmax12-0-168h) of PD-L1 LNA [Predose on Day 1 of Week 12 up to 168 hours post dose (Week 12)]: The Cmax was predicted and summarized by modelling \& simulation via the PopPK method based on pre and post dose samples. As per planned analysis data was collected and reported in a pooled manner for Combos 7 and 8.
Combos 2, 3, 4, 6, 7 and 8: Area Under the Plasma Concentration Time Curve (AUC) Over Days 1-28 of siRNA [Predose on Day 1 and 1-3 and 4-6 hours post dose each day, up to Day 28]: The AUC was predicted and summarized by modelling \& simulation via the PopPK method based on pre and post dose samples.
Combos 2, 3, 4, 6, 7 and 8: Cmax Over Days 1-28 of siRNA [Predose on Day 1 and 1-3 and 4-6 hours post dose each day, up to Day 28]: The Cmax was predicted and summarized by modelling \& simulation via the PopPK method based on pre and post dose samples.
Combos 2, 3, 4, 6, 7 and 8: Area Under the Plasma Concentration Time Curve During the Dosing Interval (AUC Tau) Over Days 29-56 of siRNA [From Day 29 up to Day 56]: The AUC tau was predicted and summarized by modelling \& simulation via the PopPK method based on pre and post dose samples. Simulations for the dosing interval between Day 29 and Day 56 was done using population PK modeling informed by sparse PK samples collected on Days 1, 85, 169, 253, and 337 at predose, 1-3 hours, and 4-6 hours post dose.
Combos 2, 3, 4, 6, 7 and 8: Cmax Over Days 29-56 of siRNA [From Day 29 up to Day 56]: The Cmax was predicted and summarized by modelling \& simulation via the PopPK method based on pre and post dose samples. Simulations for the dosing interval between Day 29 and Day 56 was done using population PK modeling informed by sparse PK samples collected on Days 1, 85, 169, 253, and 337 at predose, 1-3 hours, and 4-6 hours post dose.
Combos 1 and 6: AUC of TLR7 [Predose and 1-3 and 4-6 hours post-dose on Days 1, 3, 5 on Weeks 12 and 36]: The AUC was predicted and summarized by modelling \& simulation via the PopPK method based on pre and post dose samples.
Combos 1 and 6: Cmax of TLR7 [Predose and 1-3 and 4-6 hours post-dose on Days 1, 3, 5 on Weeks 12 and 36]: The Cmax was predicted and summarized by modelling \& simulation via the PopPK method based on pre and post dose samples.
Number of Participants With Adverse Events (AEs) [From Day 1 up to end of 48 weeks of follow up (up to approximately 1.8 years)]: An AE was any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product.
Combos 2, 3, 4, 5, 6, 7 and 8: Number of Participants With Anti-siRNA Antibodies [From Day 1 up to end of follow up (up to approximately 4 years)]: Treatment-emergent anti drug antibody (ADA) was defined as participants who seroconverted or experienced a boost in preexisting ADA during the study. Participants were considered to be ADA positive if they were ADA negative or had missing data at baseline but develop an ADA response following study drug administration (treatment-induced ADA response), or if they were ADA positive at baseline and the titer of one or more post-baseline samples were greater than the titer of the baseline sample by a scientifically reasonable margin such as at least 4-fold (treatment-enhanced ADA response).
Combos 7 and 8: Number of Participants With Anti-PD-L1 Antibodies [From Day 1 for Combo 7 and 8 up to end of follow up (Up to approximately 2 years)]: Treatment-emergent ADA was defined as participants who seroconverted or experienced a boost in preexisting ADA during the study. Participants were considered to be ADA positive if they were ADA negative or had missing data at baseline but develop an ADA response following study drug administration (treatment-induced ADA response), or if they were ADA positive at baseline and the titer of one or more post-baseline samples were greater than the titer of the baseline sample by a scientifically reasonable margin such as at least 4-fold (treatment-enhanced ADA response).

+Eligibility

Sex: All, ages: 18 Years to 65 Years

Inclusion Criteria:

* Body mass index between 18 and 32 kg/m2 inclusive.
* Participants with Chronic Hepatitis B (CHB) infection (HBsAg positive for >=6 months) who are on established NUC (entecavir or tenofovir alafenamide/disoproxil fumarate) monotherapy for >=12 months, having received the same NUC therapy for >=3 months prior to screening.
* HBV DNA below the lower LLOQ or < 20 IU/mL for > 6 months prior to screening and confirmed at screening.
* Alanine transaminase (ALT) <=1.5 x upper limit of normal (ULN) for > 6 months prior to screening and confirmed at screening.
* Female Participants: Eligible to participate if she is not pregnant, not breastfeeding and agrees to remain abstinent (refrain from heterosexual intercourse) or use highly effective contraceptive methods.
* Male Participants: During the treatment period and for at least 6 months after the final dose of study treatment, agrees to remain abstinent (refrain from heterosexual intercourse), use contraceptive measures and refrain from donating sperm.

Exclusion Criteria:

* Pregnant or lactating women.
* Co-infection with other pathogens such as Hepatitis A, C, D and E or Human Immunodeficiency Virus (HIV).
* History of cirrhosis or current evidence of significant liver fibrosis or cirrhosis or decompensated liver disease.
* History of or suspicion of Hepatocellular Carcinoma (HCC).
* Thyroid disease poorly controlled on prescribed medications or clinically relevant abnormal thyroid function tests.
* Clinically significant disease other than CHB that, in the opinion of the Investigator, makes the participant unsuitable for the study.
* Pre-existing cardiac disease that in the opinion of the investigator would increase the risk for the participant to take part in the study.
* History of alcohol abuse and/or drug abuse within one year of randomization.
* History of having received (in the last 6 months) or currently receiving any systemic antineoplastic (including radiation) or immunosuppressive (including biologic immunosuppressors) or immune modulating treatment.
* Currently taking, or have received within 3 months of Day 1, systemic corticosteroids.
* Electrocardiogram (ECG) with clinically significant abnormalities.
* Previous treatment with an investigational agent for Hepatitis B (HBV) within 6 months prior to screening.

+Posted results

Participant flow

Milestone	NUC Control Arm	Combo 1: CpAM + TLR7 Agonist + NUC	Combo 2: siRNA (100 mg) + NUC	Combo 3: siRNA (200 mg) + NUC	Combo 4: siRNA + PEG-IFN + NUC	Combo 5: siRNA + CpAM + NUC	Combo 6: siRNA + TLR7 Agonist + NUC	Combo 7: siRNA + PD-L1 LNA + NUC	Combo 8: siRNA + PD-L1 LNA + NUC
Started	36	38	30	30	30	19	34	33	31
Completed	30	37	29	30	27	9	33	15	12
Not completed	6	1	1	0	3	10	1	18	19

Outcome results

Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at 24 Weeks Post-End of Treatment (EOT) (Primary), Number, percentage of participants: NUC Control Arm 0 (0 to 10); Combo 1: CpAM + TLR7 Agonist + NUC 0 (0 to 0); Combo 2: siRNA (100 mg) + NUC 6.7 (0.8 to 22.1); Combo 3: siRNA (200 mg) + NUC 3.3 (0.1 to 17.2); Combo 4: siRNA + PEG-IFN + NUC 23.3 (9.9 to 42.3); Combo 5: siRNA + CpAM + NUC 0 (0 to 0); Combo 6: siRNA + TLR7 Agonist + NUC 11.8 (3.3 to 27.5); Combo 7: siRNA + PD-L1 LNA + NUC 0 (0 to 10.6); Combo 8: siRNA + PD-L1 LNA + NUC 6.7 (0.8 to 22.1)
Percentage of Participants With HBsAg Loss (Secondary), Number, percentage of participants: NUC Control Arm ; Combo 1: CpAM + TLR7 Agonist + NUC 0 (0 to 0); Combo 2: siRNA (100 mg) + NUC ; Combo 3: siRNA (200 mg) + NUC ; Combo 4: siRNA + PEG-IFN + NUC ; Combo 5: siRNA + CpAM + NUC 0 (0 to 0); Combo 6: siRNA + TLR7 Agonist + NUC ; Combo 7: siRNA + PD-L1 LNA + NUC 6.1 (0.7 to 20.2); Combo 8: siRNA + PD-L1 LNA + NUC
Percentage of Participants With HBsAg Seroconversion (Secondary), Number, percentage of participants: NUC Control Arm ; Combo 1: CpAM + TLR7 Agonist + NUC 0 (0 to 0); Combo 2: siRNA (100 mg) + NUC ; Combo 3: siRNA (200 mg) + NUC ; Combo 4: siRNA + PEG-IFN + NUC ; Combo 5: siRNA + CpAM + NUC 0 (0 to 0); Combo 6: siRNA + TLR7 Agonist + NUC ; Combo 7: siRNA + PD-L1 LNA + NUC 0 (0 to 10.6); Combo 8: siRNA + PD-L1 LNA + NUC
Percentage of Participants With Hepatitis B Early Antigen (HBeAg) Loss in Baseline HBeAg-positive Participants (Secondary), Number, percentage of participants: NUC Control Arm 0; Combo 1: CpAM + TLR7 Agonist + NUC 0; Combo 2: siRNA (100 mg) + NUC 22.2; Combo 3: siRNA (200 mg) + NUC 50; Combo 4: siRNA + PEG-IFN + NUC 33.3; Combo 5: siRNA + CpAM + NUC 28.6; Combo 6: siRNA + TLR7 Agonist + NUC 30; Combo 7: siRNA + PD-L1 LNA + NUC 11.1; Combo 8: siRNA + PD-L1 LNA + NUC 40
Percentage of Participants With HBeAg Seroconversion in Baseline HBeAg-positive Participants (Secondary), Number, percentage of participants: NUC Control Arm 0; Combo 1: CpAM + TLR7 Agonist + NUC 0; Combo 2: siRNA (100 mg) + NUC 11.1; Combo 3: siRNA (200 mg) + NUC 0; Combo 4: siRNA + PEG-IFN + NUC 8.3; Combo 5: siRNA + CpAM + NUC 14.3; Combo 6: siRNA + TLR7 Agonist + NUC 0; Combo 7: siRNA + PD-L1 LNA + NUC 0; Combo 8: siRNA + PD-L1 LNA + NUC 0
Number of Participants With Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA) < Lower Limit of Quantification (LLOQ), <200 IU/mL, and <2,000 IU/mL (Secondary), Count of participants, Participants: NUC Control Arm 0; Combo 1: CpAM + TLR7 Agonist + NUC ; Combo 2: siRNA (100 mg) + NUC 3; Combo 3: siRNA (200 mg) + NUC 4; Combo 4: siRNA + PEG-IFN + NUC 4; Combo 5: siRNA + CpAM + NUC ; Combo 6: siRNA + TLR7 Agonist + NUC 7; Combo 7: siRNA + PD-L1 LNA + NUC 2; Combo 8: siRNA + PD-L1 LNA + NUC 4
Change From Baseline in HBsAg, Anti-HBs, HBeAg, HBV Ribonucleic Acid (RNA) and HBV DNA Levels Over Time (Secondary), Mean, log10 IU/mL: NUC Control Arm -0.08 +/- 0.16; Combo 1: CpAM + TLR7 Agonist + NUC -0.11 +/- 0.26; Combo 2: siRNA (100 mg) + NUC -1.49 +/- 0.56; Combo 3: siRNA (200 mg) + NUC -1.78 +/- 0.59; Combo 4: siRNA + PEG-IFN + NUC -1.89 +/- 1.05; Combo 5: siRNA + CpAM + NUC -1.38 +/- 0.41; Combo 6: siRNA + TLR7 Agonist + NUC -1.74 +/- 0.62; Combo 7: siRNA + PD-L1 LNA + NUC -2.12 +/- 0.73; Combo 8: siRNA + PD-L1 LNA + NUC -1.8 +/- 0.49
Combos 7 and 8: Area Under the Plasma Concentration-time Curve Over the Dosing Interval at Week 1 (AUC1-0-168h) of PD-L1 LNA (Secondary), Mean, hours*nanomoles/liters (hr*nmol/L): Combo 7 and 8: siRNA + PD-L1 LNA + NUC 1047 +/- 273
Combos 7 and 8: Maximum Plasma Concentration (Cmax) at Week 1 (Cmax1-0-168h) of PD-L1 LNA (Secondary), Mean, nanomoles/liters (nmol/L): Combo 7 and 8: siRNA + PD-L1 LNA + NUC 163 +/- 60.8
Combos 7 and 8: AUC Over the Dosing Interval at Week 12 (AUC12-0-168h) of PD-L1 LNA (Secondary), Mean, hr*nmol/L: Combo 7 and 8: siRNA + PD-L1 LNA + NUC 1143 +/- 286
Combos 7 and 8: Cmax at Week 12 (Cmax12-0-168h) of PD-L1 LNA (Secondary), Mean, nmol/L: Combo 7 and 8: siRNA + PD-L1 LNA + NUC 165 +/- 60.9
Combos 2, 3, 4, 6, 7 and 8: Area Under the Plasma Concentration Time Curve (AUC) Over Days 1-28 of siRNA (Secondary), Mean, hours*nanograms/millilitres (hr*ng/mL): Combo 2: siRNA (100 mg) + NUC 4670 +/- 1112; Combo 3: siRNA (200 mg) + NUC 11098 +/- 2499; Combo 4: siRNA + PEG-IFN + NUC 11073 +/- 2272; Combo 6: siRNA + TLR7 Agonist + NUC 9831 +/- 2215; Combo 7: siRNA + PD-L1 LNA + NUC 9780 +/- 1942; Combo 8: siRNA + PD-L1 LNA + NUC 9110 +/- 1418
Combos 2, 3, 4, 6, 7 and 8: Cmax Over Days 1-28 of siRNA (Secondary), Mean, nanograms/millilitres (ng/mL): Combo 2: siRNA (100 mg) + NUC 190 +/- 116; Combo 3: siRNA (200 mg) + NUC 463 +/- 203; Combo 4: siRNA + PEG-IFN + NUC 450 +/- 168; Combo 6: siRNA + TLR7 Agonist + NUC 408 +/- 168; Combo 7: siRNA + PD-L1 LNA + NUC 373 +/- 149; Combo 8: siRNA + PD-L1 LNA + NUC 311 +/- 97
Combos 2, 3, 4, 6, 7 and 8: Area Under the Plasma Concentration Time Curve During the Dosing Interval (AUC Tau) Over Days 29-56 of siRNA (Secondary), Mean, hr*ng/mL: Combo 2: siRNA (100 mg) + NUC 5401 +/- 1245; Combo 3: siRNA (200 mg) + NUC 12591 +/- 2659; Combo 4: siRNA + PEG-IFN + NUC 12623 +/- 2428; Combo 6: siRNA + TLR7 Agonist + NUC 11207 +/- 2371; Combo 7: siRNA + PD-L1 LNA + NUC 11216 +/- 2068; Combo 8: siRNA + PD-L1 LNA + NUC 10513 +/- 1511
Combos 2, 3, 4, 6, 7 and 8: Cmax Over Days 29-56 of siRNA (Secondary), Mean, ng/mL: Combo 2: siRNA (100 mg) + NUC 192 +/- 116; Combo 3: siRNA (200 mg) + NUC 468 +/- 204; Combo 4: siRNA + PEG-IFN + NUC 454 +/- 169; Combo 6: siRNA + TLR7 Agonist + NUC 411 +/- 169; Combo 7: siRNA + PD-L1 LNA + NUC 376 +/- 150; Combo 8: siRNA + PD-L1 LNA + NUC 315 +/- 98
Combos 1 and 6: AUC of TLR7 (Secondary), Mean, ng*hr/mL: Combo 1: CpAM + TLR7 Agonist + NUC 3139 +/- 938.8; Combo 6: siRNA + TLR7 Agonist + NUC 2813 +/- 75.33
Combos 1 and 6: Cmax of TLR7 (Secondary), Mean, ng/mL: Combo 1: CpAM + TLR7 Agonist + NUC 1548 +/- 419.7; Combo 6: siRNA + TLR7 Agonist + NUC 1491 +/- 334.8
Number of Participants With Adverse Events (AEs) (Secondary), Count of participants, Participants: NUC Control Arm 27; Combo 1: CpAM + TLR7 Agonist + NUC 34; Combo 2: siRNA (100 mg) + NUC 30; Combo 3: siRNA (200 mg) + NUC 29; Combo 4: siRNA + PEG-IFN + NUC 30; Combo 5: siRNA + CpAM + NUC 18; Combo 6: siRNA + TLR7 Agonist + NUC 33; Combo 7: siRNA + PD-L1 LNA + NUC 26; Combo 8: siRNA + PD-L1 LNA + NUC 27
Combos 2, 3, 4, 5, 6, 7 and 8: Number of Participants With Anti-siRNA Antibodies (Secondary), Count of participants, Participants: Combo 2: siRNA (100 mg) + NUC 3; Combo 3: siRNA (200 mg) + NUC 2; Combo 4: siRNA + PEG-IFN + NUC 12; Combo 5: siRNA + CpAM + NUC 1; Combo 6: siRNA + TLR7 Agonist + NUC 3; Combo 7: siRNA + PD-L1 LNA + NUC 10; Combo 8: siRNA + PD-L1 LNA + NUC 14
Combos 7 and 8: Number of Participants With Anti-PD-L1 Antibodies (Secondary), Count of participants, Participants: Combo 7: siRNA + PD-L1 LNA + NUC 16; Combo 8: siRNA + PD-L1 LNA + NUC 15

Adverse events

Time frame: From Day 1 up to end of 48 week follow up (up to approximately 1.8 years)

Arm	Deaths	Serious adverse events	Other adverse events
Combo 1: CpAM + TLR7 Agonist + NUC	0/38 (0.0%)	3/38 (7.9%)	33/38 (86.8%)
Combo 2: siRNA (100 mg) + NUC	0/30 (0.0%)	3/30 (10.0%)	27/30 (90.0%)
Combo 3: siRNA (200 mg) + NUC	0/30 (0.0%)	4/30 (13.3%)	29/30 (96.7%)
Combo 4: siRNA + PEG-IFN + NUC	0/30 (0.0%)	2/30 (6.7%)	29/30 (96.7%)
Combo 5: siRNA + CpAM + NUC	0/19 (0.0%)	0/19 (0.0%)	18/19 (94.7%)
Combo 6: siRNA + TLR7 Agonist + NUC	0/34 (0.0%)	2/34 (5.9%)	33/34 (97.1%)
Combo 7: siRNA + PD-L1 LNA + NUC	0/33 (0.0%)	0/33 (0.0%)	23/33 (69.7%)
Combo 8: siRNA + PD-L1 LNA + NUC	0/31 (0.0%)	0/31 (0.0%)	25/31 (80.6%)
NUC Control Arm	0/35 (0.0%)	1/35 (2.9%)	25/35 (71.4%)

Serious adverse events by term

Term	Organ system	Combo 1: CpAM + TLR7 Agonist + NUC	Combo 2: siRNA (100 mg) + NUC	Combo 3: siRNA (200 mg) + NUC	Combo 4: siRNA + PEG-IFN + NUC	Combo 5: siRNA + CpAM + NUC	Combo 6: siRNA + TLR7 Agonist + NUC	Combo 7: siRNA + PD-L1 LNA + NUC	Combo 8: siRNA + PD-L1 LNA + NUC	NUC Control Arm
Diplopia	Eye disorders	0/38	0/30	0/30	1/30	0/19	0/34	0/33	0/31	0/35
Large intestine polyp	Gastrointestinal disorders	0/38	0/30	1/30	0/30	0/19	0/34	0/33	0/31	0/35
Influenza like illness	General disorders	1/38	0/30	0/30	0/30	0/19	0/34	0/33	0/31	0/35
Appendicitis	Infections and infestations	1/38	0/30	0/30	0/30	0/19	0/34	0/33	0/31	0/35
Fascioliasis	Infections and infestations	0/38	0/30	0/30	0/30	0/19	1/34	0/33	0/31	0/35
Femoral neck fracture	Injury, poisoning and procedural complications	0/38	0/30	1/30	0/30	0/19	0/34	0/33	0/31	0/35
Meniscus injury	Injury, poisoning and procedural complications	0/38	0/30	0/30	0/30	0/19	0/34	0/33	0/31	1/35
Radius fracture	Injury, poisoning and procedural complications	0/38	0/30	1/30	0/30	0/19	0/34	0/33	0/31	0/35
Spinal compression fracture	Injury, poisoning and procedural complications	0/38	1/30	0/30	0/30	0/19	0/34	0/33	0/31	0/35
Type 2 diabetes mellitus	Metabolism and nutrition disorders	0/38	1/30	0/30	0/30	0/19	0/34	0/33	0/31	0/35
Vertebral osteophyte	Musculoskeletal and connective tissue disorders	0/38	1/30	0/30	0/30	0/19	0/34	0/33	0/31	0/35
Benign hepatic neoplasm	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	1/38	0/30	0/30	0/30	0/19	0/34	0/33	0/31	0/35
Pancreatic neuroendocrine tumour	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	0/38	0/30	1/30	0/30	0/19	0/34	0/33	0/31	0/35
Panic reaction	Psychiatric disorders	0/38	0/30	0/30	1/30	0/19	0/34	0/33	0/31	0/35
Pneumothorax	Respiratory, thoracic and mediastinal disorders	0/38	0/30	1/30	0/30	0/19	0/34	0/33	0/31	0/35
Sleep apnoea syndrome	Respiratory, thoracic and mediastinal disorders	0/38	0/30	0/30	0/30	0/19	1/34	0/33	0/31	0/35

Other adverse events by term

Term	Organ system	Combo 1: CpAM + TLR7 Agonist + NUC	Combo 2: siRNA (100 mg) + NUC	Combo 3: siRNA (200 mg) + NUC	Combo 4: siRNA + PEG-IFN + NUC	Combo 5: siRNA + CpAM + NUC	Combo 6: siRNA + TLR7 Agonist + NUC	Combo 7: siRNA + PD-L1 LNA + NUC	Combo 8: siRNA + PD-L1 LNA + NUC	NUC Control Arm
Anaemia	Blood and lymphatic system disorders	0/38	0/30	1/30	0/30	2/19	0/34	0/33	0/31	0/35
Lymphopenia	Blood and lymphatic system disorders	0/38	0/30	0/30	3/30	0/19	1/34	1/33	0/31	0/35
Monocytopenia	Blood and lymphatic system disorders	0/38	0/30	0/30	0/30	2/19	0/34	0/33	0/31	0/35
Neutropenia	Blood and lymphatic system disorders	1/38	1/30	0/30	5/30	2/19	2/34	2/33	2/31	0/35
Thrombocytopenia	Blood and lymphatic system disorders	0/38	0/30	0/30	4/30	0/19	1/34	0/33	0/31	0/35
Atrioventricular block first degree	Cardiac disorders	0/38	0/30	0/30	0/30	1/19	0/34	0/33	0/31	0/35
Sinus arrhythmia	Cardiac disorders	0/38	2/30	3/30	1/30	2/19	0/34	0/33	0/31	1/35
Sinus bradycardia	Cardiac disorders	0/38	1/30	1/30	0/30	1/19	0/34	0/33	0/31	1/35
Ventricular extrasystoles	Cardiac disorders	1/38	1/30	2/30	0/30	0/19	0/34	0/33	0/31	0/35
Ear discomfort	Ear and labyrinth disorders	0/38	0/30	0/30	2/30	0/19	0/34	0/33	0/31	0/35
Tinnitus	Ear and labyrinth disorders	1/38	0/30	0/30	1/30	1/19	0/34	0/33	0/31	0/35
Dry eye	Eye disorders	0/38	1/30	0/30	2/30	1/19	0/34	0/33	0/31	0/35
Abdominal discomfort	Gastrointestinal disorders	1/38	0/30	0/30	0/30	1/19	1/34	0/33	0/31	0/35
Abdominal distension	Gastrointestinal disorders	0/38	2/30	2/30	4/30	0/19	1/34	0/33	0/31	0/35
Abdominal pain	Gastrointestinal disorders	0/38	0/30	0/30	1/30	0/19	1/34	1/33	3/31	0/35
Abdominal pain upper	Gastrointestinal disorders	1/38	0/30	1/30	2/30	4/19	4/34	1/33	1/31	1/35
Chronic gastritis	Gastrointestinal disorders	1/38	1/30	1/30	0/30	0/19	3/34	0/33	0/31	0/35
Dental caries	Gastrointestinal disorders	0/38	0/30	0/30	2/30	0/19	0/34	0/33	1/31	0/35
Diarrhoea	Gastrointestinal disorders	1/38	2/30	0/30	1/30	2/19	2/34	0/33	1/31	1/35
Dyspepsia	Gastrointestinal disorders	2/38	0/30	0/30	0/30	0/19	0/34	0/33	0/31	1/35
Flatulence	Gastrointestinal disorders	0/38	0/30	0/30	0/30	1/19	0/34	0/33	0/31	0/35
Gastrooesophageal reflux disease	Gastrointestinal disorders	2/38	1/30	0/30	1/30	0/19	3/34	1/33	0/31	0/35
Gingival bleeding	Gastrointestinal disorders	2/38	0/30	0/30	3/30	0/19	1/34	0/33	0/31	0/35
Mouth ulceration	Gastrointestinal disorders	2/38	0/30	0/30	1/30	2/19	2/34	0/33	0/31	0/35
Nausea	Gastrointestinal disorders	1/38	1/30	0/30	2/30	1/19	1/34	2/33	1/31	1/35
Periodontal disease	Gastrointestinal disorders	0/38	0/30	0/30	0/30	1/19	0/34	0/33	0/31	0/35
Asthenia	General disorders	0/38	0/30	0/30	0/30	1/19	0/34	0/33	0/31	1/35
Chest discomfort	General disorders	1/38	0/30	0/30	1/30	1/19	2/34	0/33	1/31	0/35
Chest pain	General disorders	0/38	1/30	2/30	0/30	0/19	0/34	1/33	2/31	0/35
Fatigue	General disorders	5/38	1/30	2/30	7/30	1/19	3/34	3/33	3/31	0/35
Influenza like illness	General disorders	14/38	0/30	0/30	8/30	1/19	16/34	0/33	4/31	0/35
Injection site reaction	General disorders	1/38	2/30	9/30	15/30	3/19	7/34	5/33	7/31	1/35
Pain	General disorders	0/38	0/30	1/30	0/30	0/19	2/34	0/33	0/31	1/35
Pyrexia	General disorders	6/38	0/30	3/30	7/30	4/19	7/34	1/33	2/31	1/35
Sensation of foreign body	General disorders	0/38	0/30	0/30	1/30	1/19	0/34	0/33	0/31	0/35
Thirst	General disorders	0/38	0/30	0/30	2/30	0/19	0/34	0/33	0/31	0/35
Vessel puncture site bruise	General disorders	0/38	2/30	0/30	0/30	1/19	0/34	0/33	0/31	0/35
Bile duct stone	Hepatobiliary disorders	0/38	2/30	0/30	0/30	0/19	0/34	0/33	0/31	0/35
Cholelithiasis	Hepatobiliary disorders	0/38	1/30	0/30	1/30	0/19	2/34	1/33	0/31	0/35
Hepatic cyst	Hepatobiliary disorders	2/38	2/30	1/30	2/30	0/19	1/34	0/33	0/31	1/35
Hepatic mass	Hepatobiliary disorders	1/38	0/30	2/30	0/30	0/19	0/34	0/33	0/31	0/35
Hepatic steatosis	Hepatobiliary disorders	1/38	7/30	3/30	6/30	1/19	2/34	3/33	0/31	4/35
Liver disorder	Hepatobiliary disorders	0/38	0/30	0/30	2/30	0/19	0/34	0/33	0/31	0/35
COVID-19	Infections and infestations	6/38	10/30	16/30	17/30	3/19	17/34	3/33	4/31	8/35
Conjunctivitis	Infections and infestations	1/38	0/30	4/30	1/30	0/19	2/34	0/33	0/31	0/35
Gastroenteritis	Infections and infestations	1/38	0/30	0/30	2/30	0/19	0/34	1/33	0/31	0/35
Gingivitis	Infections and infestations	0/38	2/30	1/30	0/30	1/19	0/34	0/33	0/31	0/35
Hepatitis B reactivation	Infections and infestations	0/38	6/30	1/30	2/30	0/19	10/34	4/33	7/31	3/35
Herpes virus infection	Infections and infestations	0/38	0/30	0/30	0/30	1/19	0/34	0/33	0/31	0/35
Nasopharyngitis	Infections and infestations	1/38	1/30	0/30	0/30	0/19	0/34	2/33	4/31	0/35
Pharyngitis	Infections and infestations	0/38	2/30	0/30	2/30	0/19	0/34	0/33	0/31	1/35
Sinusitis	Infections and infestations	1/38	1/30	0/30	2/30	0/19	0/34	1/33	0/31	0/35
Upper respiratory tract infection	Infections and infestations	4/38	14/30	11/30	13/30	5/19	4/34	1/33	2/31	4/35
Accidental overdose	Injury, poisoning and procedural complications	8/38	5/30	6/30	0/30	1/19	4/34	0/33	0/31	1/35
Muscle strain	Injury, poisoning and procedural complications	0/38	0/30	0/30	0/30	0/19	0/34	0/33	2/31	0/35
Overdose	Injury, poisoning and procedural complications	1/38	0/30	1/30	1/30	3/19	1/34	4/33	1/31	1/35
Product dose omission issue	Injury, poisoning and procedural complications	2/38	13/30	14/30	19/30	2/19	15/34	0/33	0/31	13/35
Alanine aminotransferase increased	Investigations	4/38	13/30	13/30	25/30	10/19	15/34	6/33	6/31	3/35
Amylase increased	Investigations	0/38	5/30	5/30	6/30	1/19	5/34	3/33	1/31	1/35
Aspartate aminotransferase increased	Investigations	3/38	6/30	10/30	21/30	7/19	11/34	4/33	2/31	1/35

49 more terms not shown.

+Locations (33)

Facility	City	Country
Tokuda Hospital Sofia	Sofia	Bulgaria
University Multiprofile Hospital For Active Treatment "Sveti Ivan Rilski" EAD	Sofia	Bulgaria
University of Calgary	Calgary, Alberta	Canada
Uni of Alberta Hospital	Edmonton, Alberta	Canada
Toronto Liver Centre	Toronto, Ontario	Canada
Hospital San Juan de Dios La Serena	La Serena	Chile
Beijing Friendship Hospital	Beijing	China
The First Hospital of Jilin University	Changchun	China
West China Hospital, Sichuan University	Chengdu	China
Nanfang Hospital, Southern Medical University	Guangzhou	China
Ruijin Hospital Shanghai Jiaotong University School of Medicine	Shanghai	China
Huashan Hospital, Fudan University	Shanghai	China
Hopital Beaujon	Clichy	France
Queen Mary Hospital	Hong Kong	Hong Kong
Auckland Clinical Studies Limited	Auckland	New Zealand
Middlemore Clinical Trials	Auckland	New Zealand
Spitalul Clinic Judetean de Urgenta Cluj Napoca	Cluj-Napoca	Romania
Chuncheon Sacred Heart Hospital	Gangwon-Do	South Korea
Asan Medical Center / Clinical Trial Center	Seoul	South Korea
SMG-SNU Boramae Medical Center	Seoul	South Korea
Seoul National University College of Medicine, Liver Research Institute	Seoul	South Korea
Hospital Alvaro Cunqueiro	Vigo, Pontevedra	Spain
Vall d?Hebron Institute of Oncology (VHIO), Barcelona	Barcelona	Spain
Changhua Christian Hospital	Chang-hua	Taiwan
Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung City	Taiwan
China Medical University Hospital	Taichung	Taiwan
Taichung Veterans General Hospital	Taichung	Taiwan
National Cheng Kung Univ Hosp	Tainan	Taiwan
National Taiwan University Hospital	Taipei	Taiwan
HIVNAT	Bangkok	Thailand
Siriraj Hospital	Bangkok	Thailand
Maharaj Nakorn Chiang Mai Hospital	Chiang Mai	Thailand
King College Hospital NHS Foundation Trust	London	United Kingdom

+Publications

Results publication: Cheng C, Xie Q, Gane E, Morano Amado LE, Yang SS, Zhang W, Jia J, Asselah T, Kao JH, Peng CY, Su WW, Tanwandee T, Liang X, Catanese MT, Chen E, Chughlay F, Das S, Glavini K, Guerreiro N, Huang Y, Kazma R, Liang Y, McGeown C, Patil A, Upmanyu R, Wat C, Yuen MF, Hou J; Piranga Study Group. Outcomes of nucleos(t)ide analogue discontinuation following finite xalnesiran-based therapies in chronic hepatitis B. JHEP Rep. 2026 Jul 15:101958. doi: 10.1016/j.jhepr.2026.101958. Online ahead of print. PMID 42456805
Results publication: Hou J, Zhang W, Xie Q, Hua R, Tang H, Morano Amado LE, Yang SS, Peng CY, Su WW, Chuang WL, Kim DJ, Avihingsanon A, Kao JH, Leerapun A, Yuen MF, Asselah T, Liang X, Bo Q, Canducci F, Catanese MT, Chen E, Cheng C, Chughlay F, Das S, Glavini K, Guerreiro N, Huang Y, Kakrana P, Kazma R, Patil A, Pavlovic V, Surujbally B, Triyatni M, Upmanyu R, Wat C, Gane E; Piranga Study Group. Xalnesiran with or without an Immunomodulator in Chronic Hepatitis B. N Engl J Med. 2024 Dec 5;391(22):2098-2109. doi: 10.1056/NEJMoa2405485. PMID 39774313

+Study documents

Study Protocol (PDF, 2022-07-18)
Statistical Analysis Plan (PDF, 2023-05-24)

+Investigators

Clinical Trials, Study director, Hoffmann-La Roche

+Funding

NIH grants: 2019