Method of reducing hepatitis b virus (HBV) infection with cavrotolimod

Abstract

A method of reducing a hepatitis B virus (HBV) infection in a patient includes. administering to the patient in need thereof an effective amount of cavrotolimod. Also, provided is a method of treating or reducing the likelihood of hepatitis B virus associated disorder in a patient by administering to a patient in need thereof an effective amount of cavrotolimod. The disorder can be selected from liver failure, cirrhosis, hepatocellular carcinoma, and CHB. Checkpoint inhibitors and anti-HBsAg specific antibodies can also be co-administered with cavrotolimod in these methods.

Description

[0001] Method of Reducing Hepatitis B Virus (HBV) Infection with Cavrotolimod Cross-Reference to Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 753,875 filed February 4, 2025, and U.S. Provisional Application No. 63 / 953,253 filed January 2, 2026, the disclosure of each of which is incorporated by reference herein in its entirety.

[0003] Incorporation of Sequence Listing

[0004] This application includes a Sequence Listing in XML format, named “Bluej007PCT.xml” which is 3,003 bytes in size and created on January 30, 2026. The contents of the Sequence Listing are incorporated herein by reference in their entirety.

[0005] Background

[0006] HBV infection is one of the most common infectious diseases in the world. Chronic Hepatitis B (CHB) represents a critical unmet medical need with nearly 300 million people chronically infected worldwide. CHB can lead to serious liver diseases such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Approximately 820,000 people die every year due to the consequences of CHB.

[0007] The goal of CHB therapy is to improve quality of life and transplant-free survival by preventing progression to end-stage liver disease and HCC. HBV functional cure, defined as loss of hepatitis B surface antigen (HBsAg) with or without seroconversion to anti-HBsAg, is the currently accepted endpoint for anti-HBV therapy. A recent meta-analysis showed that loss of HBsAg is associated with reduced rates of liver decompensation and HCC, along with improved transplant-free survival.

[0008] Nucleos(t)ide analogs (NUCs) inhibit HBV polymerase leading to suppression of viral replication and are the standard of care for CHB treatment. Chronic NUC treatment results in long-term clinical benefits with a reduced risk of liver complications. However, treatment with NUCs rarely results in functional cure, and NUC withdrawal generally results in virologic relapse, necessitating chronic therapy.

[0009] Summary of the InventionIn one aspect, the invention provides a method of reducing a hepatitis B virus (HBV) infection in a patient, comprising administering to the patient in need thereof an effective amount of cavrotolimod.

[0010] In another aspect, the invention provides a method of treating or reducing the likelihood of hepatitis B virus associated disorder in a patient, comprising administering to a patient in need thereof an effective amount of cavrotolimod. In some embodiments, the disorder can be selected from the group consisting of liver failure, cirrhosis, hepatocellular carcinoma, and CHB.

[0011] In some embodiments, the method further comprises co-administering to the patient one or more checkpoint inhibitors.

[0012] In some embodiments, the method further comprises co-administering to the patient one or more immunomodulatory activators.

[0013] In some embodiments, the method further comprises co-administering to the patient an anti-HBsAg specific antibody.

[0014] In some embodiments, the method further comprises co-administering to the patient agents such as siRNA, or other agents that target HBV-specific viral antigen reduction.

[0015] In some embodiments, the administering comprises subcutaneous injection of cavrotolimod to the patient.

[0016] In some embodiments, the administering further comprises administering one or both of an immune checkpoint inhibitor (such as nivolumab) and an anti-HBsAg specific antibody (such as brelovitug) to the patient.

[0017] Brief Description of the Drawings

[0018] Figure 1 shows cavrotolimod elicits a cytokine profile in PBMCs from HBV+ donors comparable to healthy PBMCs and with similar profile to TLR8 agonism.

[0019] Figure 2 shows peripheral IP-10 (CXCL10), IL-12p40. IFNg and IL-15 induction (mean+SD changes over time by cohort in Part A of Example 3). Peripheral levels of IP- 10 (CXCL10), IL-12p40, IFNg and IL-15 (mean+SD) following first cavrotolimod administration are shown. Cl, Cl a, C2, C3 and C4 refer to Cohort 1, Cohort 1 expansion arm, Cohort 2, Cohort 3 and Cohort 4 respectively. A total number of subjects at each cohort is shown in parentheses. Except for the Cohort 1 expansion arm (Cla; n=4), the rest of the cohorts have two placebo subjects. Placebos are included. When below LLOQ, LLOQ values were used for calculation.Figure 3 shows peripheral IP-10 (CXCL10), IL-12p40, IFNg and IL-15 induction (mean+SD changes over time in Part C of Example 3). Peripheral levels of IP-10 (CXCL10), IL-12p40, IFNg and IL- 15 (mean+SD) following first cavrotolimod administration are shown in Part C of Example 3. The total number of subjects is seven.

[0020] Figure 4 shows activation of HBV-specific T cell responses. Activation of HBV-specific IFNg (left) or IL-2 (right) secreting T cells were measured with FluoroSpot. Fold change over baseline (mean+SD) is shown in here. The total number of subjects is seven.

[0021] Figure 5 show examples of one subject with HBsAg clearance and another subject with anti-HBs development in Part C of Example 3. HBsAg and ALT changes from one subject who cleared HBsAg (left) and anti-HBs level from another subject who developed anti-HBs (right) are shown (both Part C subjects).

[0022] Detailed Description of the Invention

[0023] TLR9 stimulation initially activates antigen-nonspecific innate immunity followed by antigen- specific adaptive immunity. TLR9 agonism activates innate immunity with predominantly a T-helper 1 (Thl) pattern of cytokine and chemokine secretion by B cells and plasmacytoid dendritic cells (pDCs). In response to TLR9 stimulation, B cells and pDCs also express increased levels of costimulatory molecules that can cause cell trafficking to the T cell zone of the lymph nodes. Together, these innate immune effects of TLR9 activation can promote killing of infected cells. TLR9-mediated innate immune activation and pDC and B cell maturation are followed by the generation of antigen- specific antibody and T cell immune responses. The pDCs activated through TLR9 become competent to induce effective CD4+ or CD8+ T cell responses and suppress regulatory T cells and myeloid-derived suppressor cells.

[0024] Cavrotolimod (CAS No. 2378664-12-9) is a spherical nucleic acid (SNA) configuration of a toll-like receptor 9 (TLR9) agonist single- stranded oligonucleotide which includes, at its 3' terminus, a cholesteryl ester moiety incorporated via an oligo (ethylene glycol)-containing linker. It was originally designed to serve as a TLR9 agonist to elicit innate and adaptive immune responses in patients with cancer. This cholesteryl ester moiety facilitates the incorporation of cavrotolimod oligonucleotide within the liposome-scaffolded SNA drug product.Cavrotolimod was designed to agonize TLR9, which elicits both innate and adaptive immune responses that are potentially useful in oncology applications. TLR9 stimulation initially activates antigen-nonspecific innate immunity followed by antigen- specific adaptive immunity. TLR9 agonism activates innate immunity with predominantly a Thl pattern of cytokine and chemokine secretion by B cells and pDCs. In response to TLR9 stimulation, B cells and pDCs also express increased levels of costimulatory molecules (such as ligands for CTLA-4, a checkpoint inhibitor (CPI) antibody target), tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), which can induce tumor cell death, and CC chemokine receptor 7, activation of which causes cell trafficking to the T cell zone of the lymph nodes. Together, these innate immune effects of TLR9 activation can control viral infection through the antiviral activity of mediators such as interferon alpha (IFNα). IFN gamma (IFNγ), IL- 12, and TRAIL. TLR9-mediated innate immune activation of B cells and pDCs is followed by the generation of antigen-specific antibody and T cell immune responses. The pDCs activated through TLR9 become competent to induce effective CD4+ or CD8+ T cell responses and suppress regulatory T cells and myeloid-derived suppressor cells. Therefore, cavrotolimod could stimulate and enhance innate immunity, leading to improved HBV-specific immune responses and an increased functional cure rate for CHB.

[0025] The structure of cavrotolimod (SEQ ID No: 1) is depicted below. It can be present in free acid and salt forms (e.g., sodium salt) of cavrotolimod can be used.

[0026]

[0027] The chemical composition of cavrotolimod is DNA, d(P-thio)(T-C-G-T-C-G-T-T-T-T-G-T-C-G-T-T-T-T-G-T-C-G-T-T), 2'-deoxy-P-thiothymidylyl-(3'^-5')-2'-deoxy-P-thiocytidylyl-(3'^-5')-2'-deoxy-P-thioguanylyl-(3'— >-5')-2'-deoxy-P-thiothymidylyl-(3'^>-5')-2'-deoxy-P-thiocytidylyl-(3' >5')-2'-dcoxy-P-thioguanylyl-(3' >5')-2'-dcoxy-P-thiothymidylyl-(3' >5')-2'-dcoxy-P-thiothymidylyl-(3'^5 2'-deoxy-P-thiothymidylyl-(3'— >-5')-2'-deoxy-P-thiothymidylyl-(3'— >5')-2'-deoxy-P-thioguanylyl-(3'— >-5')-2'-deoxy-P-thiothymidylyl-(3'^>-5')-2'-deoxy-P-thiocytidylyl-(3'— 5 ')-2'-deoxy-P-thioguanylyl-(3'^-5 ')-2'-deoxy-P-thiothymidylyl-(3'^-5 ')-2'-deoxy-P-thiothymidylyl-(3'^5')-2'-deoxy-P-thiothymidylyl-(3'— >-5')-2'-deoxy-P-thiothymidylyl-(3'— >5')-2'-deoxy-P-thioguanylyl-(3'^-5')-2'-deoxy-P-thiothymidylyl-(3'^5')-2'-deoxy-P-thiocytidylyl-(3'— 5 ')-2'-deoxy-P-thioguanylyl-(3'— ’■5')-2'-deoxy-P-thiothymidylyl-(3'— >5')-2'-deoxy-P-thiothymidylyl-(3 '— 5 ')-hexa(ethyleneglycol)phosphodiester-hexa(ethyleneglycol)phosphodiester-3-O-(N-cholesteryl-3-aminopropyl)-triethyleneglycol-glyceryl-l-O-phosphodiester.

[0028] Aspects of the invention relate to the use of cavrotolimod in a subject to reduce HBV viral antigen and infection of the patient, or to treat an HBV-associated disorder of the patient byadministering to a patient in need thereof an effective amount of cavrotolimod. The disorder can be liver failure, cirrhosis, hepatocellular carcinoma, or chronic hepatitis B infection (CHB).

[0029] Cavrotolimod may be administered alone or in a composition including appropriate pharmaceutical carrier(s) for administration. A therapeutically effective amount of cavrotolimod can be administered to a subject by any suitable routes such as subcutaneous, parenteral, intramuscular, intravenous, oral, mucosal, intranasal, etc. For example, cavrotolimod can be administered, e.g., injected, subcutaneously or intramurally.

[0030] Cavrotolimod can be administered therapeutically and prophylactically (alone or as a component of a vaccine) for stimulating the immune system to treat HB V.

[0031] As used herein, “reduction” or “reducing” of HBV of a patient refers to prevention, reduction or inhibition of HBV viral infection of a host cell of the patient. It may be shown as a reduction or inhibition of HBV viral gene or protein product expression.

[0032] Cavrotolimod can be co-administered with checkpoint inhibitors such as anti-PDl antibodies (Pembrolizumab, Nivolumab, Cemiplimab, etc.). It can also be co-administered with an anti-HBsAg specific antibody (“HBsAg” stands for hepatitis B surface antigen). It can be coadministered as part of or in combination with a therapeutic or prophylactic vaccine. It can also be co-administered with immunomodulatory activators, such as therapeutic cytokines (Aldesleukin, Pegylated Interferon, etc.). It can also be co-administered with any agents that reduce HBV viral antigens such as an siRNA (Imdusiran) or oligonucleotide (bepirovirsen).

[0033] As used herein, the terms "treat," "treating," or "treatment" of any disease, infection, or disorder refer in one aspect, to ameliorating the disease, infection, or disorder (i.e., slowing or arresting or reducing the development of the disease / disorder / infection or at least one of the clinical symptoms thereof). It includes prophylactically treating the disease, infection or disorder before the onset of the disease, infection or disorder. In another aspect, "treat," "treating," or "treatment" refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another aspect, "treat," "treating," or "treatment" refers to modulating the disease, infection, or disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.

[0034] As used herein, the phrase "reducing the likelihood" refers to delaying the onset or development or progression of the disease, infection or disorder.

[0035] As used herein, the term “therapeutically effective amount” or "effective amount" of cavrotolimod refers to an amount sufficient to effect the desired result, i.e., reduction of HBV of a patient, or treatment outcome of an HBV patient.

[0036] The term “subject” or “patient” refers to a human.

[0037] The terms “hepatitis B virus" or " HBV" refer to a member of the family Hepadnaviridae, genus Orthohepadnavirus. HBV is a double stranded DNA virus.

[0038] Examples

[0039] Example 1

[0040] The ability of cavrotolimod to activate TLR9 specific signaling was previously evaluated in HEK-293-blue reporter cells overexpressing TLR9. It is shown that cavrotolimod activates NF-KB in a dose-dependent and TLR-9 specific manner. It was also previously shown that cavrotolimod elicits an on-target dose-dependent expansion of DC and B-cell subsets in nonhuman primates.

[0041] To better understand the immune activation and safety profile in control of HBV infection, the cytokine response of cavrotolimod was evaluated in a series of in vitro peripheral blood mononuclear cells (PBMC) stimulation studies HBV-infected patient PBMCs. This included comparison of cavrotolimod responses in healthy donor PBMCs and PBMCs from HBV-infected individuals, combination with the checkpoint inhibitor, Pembrolizumab, and comparison to two TLR agonist, vesatolimod (TLR7 agonist) and selgantolimod (TLR8) that are in clinical trials to support HBV infected patients.

[0042] Cryopreserved peripheral Blood Mononuclear Cells (PBMC) from five healthy and ten Hepatitis B positive donors (BioIVT) were thawed, counted and plated in complete RPMI medium in the presence of the positive control Phytohemagglutinin (PHA) or the test article,cavrotolimod + / - pembrolizumab, or vesatolimod, and selgantolimod or left unstimulated for 24 or 48 hours at 37°C 5% CO2. Cavrotolimod incubation concentrations were selected to overlap the range of projected plasma concentration that are expected with the proposed dose range in the Phase 1 study (3, 10, 30, 100 nM). In addition, 1000 nM was used as positive control doses expected to elicit cytokine responses in this assay but to be above expected exposures in patients. Selgantolimod and vesatolimod have EC50s of 100-300 nM in cytokine assays and with therefore will be included at the same test concentrations. Pembrolizumab was dosed at 1000 nM alone or at 1000 nM or 10 nM in combination with cavrotolimod and in line with expected exposures in patients. After 24 - 48 hrs., supernatants were run on Meso Scale Discovery (MSD) cytokine panel assays consisting of IL-12p40, IL-12p70, IP-10, IFN-y, IFN-a2a, IL-6, TNF-a, IL-10, IL-10, IL-1β, IL-1Ra, MCP-1, IL-21, IL-2, IL-7 and IL-27.

[0043] As shown in Fig. 1, cavrotolimod elicits a cytokine profile in PBMCs from HBV+ donors comparable to healthy PBMCs and with similar profile to TLR8 agonism. Fig. 1(A) shows that cavrotolimod elicits a dose-dependent type I cytokine response in HBV+ donors, including IL-12p40, IFN-y, IFNaA2, and IP-10. Fig. 1(B) shows that cavrotolimod elicits a similar magnitude and cytokine profile in HBV+ PBMCs compared to heathy donor PBMCs. Fig. 1(C) shows that cavrotolimod induces a cytokine profile comparable to TLR8 agonism in HBV+ donors and suggests the potential for beneficial immune activation in HBV+ patients.

[0044] As expected, cavrotolimod did not elicit a broad cytokine response or show differences in cytokine induction from PBMCs of HBV-infected patients versus healthy donors. The profile of cytokines induced above controls was specific and in line with a Thl / Tcl profile. These cytokines included IFNy and IP- 10.

[0045] Overall, these experiments suggest that cavrotolimod will not elicit a cytokine release response in peripheral PBMCs but instead has the potential to elicit an on-target Thl / Tcl priming cytokine milieu that may support HBV-specific T-cell immunity. Combination with Pembrolizumab, the anti-PD-1 checkpoint inhibitor antibody did not change the cytokine response supports a combination therapy including cavrotolimod and an anti-PD-1 checkpoint inhibitor.

[0046] Example 2The efficacy of subcutaneous cavrotolimod is investigated in humans having chronic HBV infection. Multiple cohorts will be tested within the predicted efficacy and safety range as determined from the in vitro half – maximal effective concentration (EC50), predicted and measured maximal in-life serum concentration (cmax) of the molecule in human individuals, and the toxicological safety margin as derived from previous non-human primate and healthy volunteer and cancer clinical trials. A flat dose of up to 24 mg cavrotolimod is expected to fall in these parameters and therefore will be used to dose patients. CHB Patients will be subcutaneously injected with cavrotolimod and, compared to placebo control / vehicle.

[0047] Administration will be every 1 to 4 weeks and patients will be evaluated for up to 48 weeks post first dose. CHB patient response to cavrotolimod will be measured by multiple readouts. The readouts will include pharmacokinetics (PK) across a range of timepoints post dosing, pharmacodynamics (PD) by evaluating soluble cytokines in serum across a range of timepoints post dosing, and efficacy will be determined by evaluating viral antigens including HBV DNA and HBV surface antigen (HBsAg) at a range of timepoints post dosing.

[0048] The results will show that cavrotolimod elicits cytokine production from HBV infected individuals and is effective to reduce HBV infection in these patients, as well as to treat / reduce likelihood of HBV associated disorders.

[0049] Example 3: Combination therapy

[0050] An ongoing Ph1b / 2 study evaluating cavrotolimod optionally with nivolumab and optionally with BJT-778 (also known as Brelovitug) in subjects with CHB. This study includes an adaptive design to evaluate the safety and tolerability, PK / PD, and antiviral activity / efficacy of cavrotolimod and cavrotolimod-containing combinations in CHB-infected participants who are on nucleos(t)ide therapy. Enrollment in Parts A, C, and D may overlap; Part B was not conducted.

[0051] Part A was a randomized, double-blind, placebo-controlled portion of the study, evaluating the safety of MAD (multiple ascending dose) cavrotolimod (20 mg / mL vial) administered SC in sequential cohorts. Five cohorts including 4 participants per cohort were enrolled (n=20 total) and randomized 3:1, active to placebo, respectively, except Cohort 1 Arm la enrolled 4 active and no placebo participants:• Cohort 1, Arm 1 (n=4, randomized 3 active:l placebo): Cavrotolimod 2 mg or placebo administered SC Q1W for 4 weeks (5 doses).

[0052] • Cohort 1, Arm la (n=4, all active) Expansion Arm: Open-label cavrotolimod 2 mg administered SC Q1W for 4 weeks (5 doses).

[0053] • Cohort 2, Arm 1 (n=4, randomized 3 active: 1 placebo): Cavrotolimod 6 mg or placebo administered SC Q1W for 4 weeks (5 doses).

[0054] • Cohort 3, Arm 1 (n=4, randomized 3 active: 1 placebo): Cavrotolimod 2 mg or placebo administered SC Q2W for 4 weeks (3 doses).

[0055] • Cohort 4, Arm 1 (n=4, randomized 3 active: 1 placebo): Cavrotolimod 3 mg or placebo administered SC Q4W for 4 weeks 2 doses).

[0056] Participants were followed for at least 24 weeks after the last dose of cavrotolimod. Subjects who achieve HBsAg loss (HBsAg < LLOQ) by FU Week 24 will continue to be followed for an additional 24 weeks (total 48 weeks of follow up). Subjects may be reconsented for follow up (up to FU Week 48).

[0057] Part B was optional and not conducted, as the initially planned combination of cavrotolimod plus BJT-778 is being studied in Part D Cohort 1 (ongoing, see below).

[0058] Part C is ongoing. Part C will evaluate open-label cavrotolimod plus low-dose nivolumab, a mAb targeting PD-1, in combination. A single cohort enrolled 7 participants with CHB. This cohort was administered open-label cavrotolimod 3 mg SC Q2W for 4 weeks + low-dose nivolumab (0.3 mg / kg) given intravenous (IV) on Day 1. Participants are currently in follow-up; they will be followed for at least 24 weeks after the last dose of study medications. Participants who achieve HBsAg loss (HBsAg < UUOQ) at the end of follow up will continue to be followed for an additional 24 weeks (total 48 weeks of follow up).

[0059] Part D is ongoing. Part D will evaluate up to 24-week combination regimen(s) with cavrotolimod ± BJT-778 + low-dose nivolumab for the treatment of CHB. The sponsor may choose to expand the sample size of 1 or more cohorts by enrolling up to 10 additional participants based on emerging data. Part D Cohort 1 is currently underway.

[0060] • Cohort 1, Arm 1 (n=~10) and Expansion Arm la (n<10): Cavrotolimod 2 mg administered SC Q1W ± BJT-778900 mg SC Q4W for up to 24 weeks

[0061] • Optional Cohort 2, Arm 1 (n=~10) and Expansion Arm la (n<10): Cavrotolimod (<6 mg) administered SC Q1-4W ± BJT-778900 mg SC Q4W ± low-dose nivolumab (0.3 mg / kg) IV Q12W for up to 24 weeks

[0062] • Optional Cohort 3, Arm 1 (n=~10) and Expansion Arm la (n<10): Cavrotolimod (<6 mg) administered SC Q1-4W ± BJT-778900 mg SC Q4W ± low-dose nivolumab (0.3 mg / kg) IV Q12W for up to 24 weeksParticipants will be followed for at least 24 weeks after the last dose of study medications. Participants who achieve HBsAg loss (HBsAg < LLOQ) at the end of follow up will continue to be followed for an additional 24 weeks (total 48 weeks of follow up).

[0063] Study Objectives & Endpoints

[0064] Objectives Endpoints Primary

[0065] • Incidence and severity of treatment- • To evaluate the safety and

[0066] emergent adverse events (TEAEs) and tolerability of cavrotolimod alone

[0067] clinically significant laboratory and in combination with BJT-778

[0068] abnormalities

[0069] and / or low-dose nivolumab

[0070] Secondary

[0071] • Cavrotolimod ± other study

[0072] • To evaluate the plasma

[0073] medication(s) (e.g., BJT-778): pharmacokinetics (PK) of

[0074] Determination of Cmax, Clast. Cmin. Tmax, cavrotolimod alone, in

[0075] AUCo-inf, AUCo-iast, AUCo-24, ti / 2, Vd, and combinations, and / or other study

[0076] CL / F

[0077] medication(s) (e.g., BJT-778)

[0078] • Absolute and change from baseline of • To evaluate the pharmacodynamics

[0079] key cytokines / chemokines over time (PD) of cavrotolimod alone and in

[0080] combination • Absolute and change from baseline in HBsAg over time

[0081] • To evaluate the anti-hepatitis B

[0082] virus (HBV) activity of • Maximum reduction from baseline of cavrotolimod alone and in HBsAg levels during treatment combination • The proportion of participants who • To evaluate efficacy of achieve HBsAg loss (< LLOQ) at the end of combination treatment and 24 weeks cavrotolimod combination

[0083] treatment post-treatment

[0084] Exploratory

[0085] • Change from baseline in functional • To explore the effect of

[0086] (EliSpot) HBV-specific immunity cavrotolimod on HBV-specific

[0087] immunity, alone and in • Change from baseline in immune cell frequency and activation combinations

[0088] • To explore the effect of • Change from baseline in other HBV- cavrotolimod on HBV-related related biomarkers (i.e., hepatitis B corerelated antigen (HBcrAg), hepatitis B e biomarkers, alone and in

[0089] combinations antigen (HBeAg) (if appropriate), HBV RNA, native anti-HBsAg antibodies)

[0090]

[0091] Preliminary Safety Results from Part A & Part CAs the study is ongoing, treatment assignments in the double-blind, placebo-controlled cohorts in Part A have not yet been unblinded. Preliminary results based on aggregate data are summarized here. Results are descriptive, based on manual data review.

[0092] In Parts A & C, 169 TEAEs were observed in 25 / 27 (93%) participants. Most TEAEs were Grade 1 (68%) or 2 (31%) severity, and most were deemed related to study drug (93%). The most common TEAEs were injection site reactions (ISRs, 51%) and flu-like illness (20%). No related serious or severe TEAEs were observed.

[0093] Pharmacokinetic changes in Part A

[0094] Cavrotolimod was measurable in plasma within 2-4 hours of dosing in most subjects. Day 1 exposure (Cmax and AUC) increased linearly with weekly doses from 2 to 6 mg, whereas Day 29 exposure increased in a greater than dose proportional fashion. Coadministration of nivolumab had no significant effect on cavrotolimod PK (data not shown).

[0095] Pharmacodynamic changes in Part A & Part C

[0096] Cavrotolimod was designed to agonize TLR9. TLR9 stimulation initially activates antigen nonspecific innate immunity followed by antigen-specific adaptive immunity. Multiple cytokines and chemokines are secreted upon TLR9 activation. IP-10 (CXCL10) is a chemoattractant for immune cells and key chemokine for T cell recruitment to the site of infection. IL-12p40, IFNg and IL- 15 are critical cytokines for activating adaptive immune response.

[0097] Peripheral levels of cytokines and chemokines, IP-10 (CXCL10), IL-12p40, IFNg and IL-15 were measured as target (TLR9) engagement biomarkers in Part A and Part C. HBV-specific IFNg or IL-2 secreting T cell response was measured to assess activation of adaptive immunity in Part A.

[0098] Cytokines & Chemokines

[0099] In Part A, the study remains blinded. Two placebo subjects per each cohort are included in the calculation. IP- 10 (CXCL10), IL-12p40, IFNg and IL- 15 were transiently produced across all dosing groups following the first dose of cavrotolimod. Cohort 1, Cohort la expansion and Cohort 3 were all 2 mg dosage groups, yet differences were observed due to interpatient variations. However, a trend in a dose-dependent increase was observed; participants in the 6 mg cohort (Cohort 2) produced the highest levels except for IL-12p40 (Figure 2).In Part C, cavrotolimod at 3mg was administered in combination with low dose nivolumab on day 1. IP-10 (CXCL10), IL-12p40, IFNg and IL-15 were induced following the first dose of cavrotolimod. When comparing the same dosing group in Part A (cohort 4), comparable levels of IP-10 (CXCL10), IL-12p40, IFNg and IL-15 were produced. This data suggests that low dose nivolumab does not influence IP-10 (CXLC10), IL-12p40, IFNg and IL-15 induction (Figure 3).

[0100] HBV-specific T-cell Responses

[0101] In Part A, HBV-specific T cells responses were measured with IFNg and IL-2 Fluorospot by stimulating PBMCs in the absence and presence of HBV peptides pools. Data are limited to Cohort 1 and Cohort la expansion. Placebo subjects are included. Three-fold increase in IFNg and 7-fold increase in IL-2 secreting T cells were detected at week 9 (follow up week 5) compared to baseline (Figure 4).

[0102] In Part C, one subject achieved HBsAg Sero clearance (<0.05 U / mL) at follow-up week 8 accompanied by an ALT increase suggesting immune-mediated HBsAg clearance (Figure 5). Another subject developed anti-HBs indicating endogenous B cell response was restored in the combo treatment.

[0103] Conclusion from Part A & Part C

[0104] Multiple doses of cavrotolimod ± nivolumab x 4 weeks were generally well tolerated in CHB subjects. Most subjects experienced mild-to-moderate ISRs that were not treatment-limiting. Cavrotolimod elicited a potent immune response with strong cytokine / chemokine production and augmented HBV-specific T cell responses. Cavrotolimod may evolve as an important part of combination therapy in achieving functional cure of CHB. Part 3 (Phase 2a) is ongoing, which features combinations of cavrotolimod ± nivolumab + brelovitug x 24 weeks.

Claims

CLAIMS1. A method of reducing a hepatitis B virus (HBV) infection in a patient, comprising administering to the patient in need thereof an effective amount of cavrotolimod.

2. A method of treating or reducing the likelihood of hepatitis B virus associated disorder in a patient, comprising administering to a patient in need thereof an effective amount of cavrotolimod, wherein the disorder is selected from liver failure, cirrhosis, hepatocellular carcinoma, or CHB.

3. The method of claim 2, further comprising co-administering to the patient one or more checkpoint inhibitors.

4. The method of claim 2, further comprising co-administering to the patient one or more immunomodulatory activators.

5. The method of claim 2, further comprising co-administering to the patient an anti-HBsAg specific antibody.

6. The method of claim 2, further comprising co-administering to the patient agents such as siRNA, or other agents that target HBV-specific viral antigen reduction.

7. The method of claim 1 or claim 2, wherein the administering comprises subcutaneous injection of cavrotolimod to the patient.

8. The method of claim 1 or claim 2, wherein the administering further comprises administering one or both of nivolumab and brelovitug to the patient.

9. Use of cavrotolimod in the preparation of medicament for reducing HBV infection in a patient, or for treating or reducing the likelihood of hepatitis B virus associated disorder in apatient, wherein the disorder is selected from liver failure, cirrhosis, hepatocellular carcinoma, or CHB.

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