Safety and Antiviral Activity of a Monoclonal Hepatitis B Antibody: a First-in-human Phase 1, Placebo-controlled, Single Dose Escalation Clinical Trial in Individuals with Chronic Hepatitis B Infection (The SAMBA Study)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Safety and tolerability
研究概览
简要总结
Hepatitis B virus (HBV) remains a major global health problem with an estimated 257 million people living with the infection worldwide. Chronic HBV (CHB) is a major cause of liver cirrhosis and hepatocellular carcinoma. While antiviral therapies are available and suppress viral levels, treatment is long-term, does not clear the infection and rarely leads to long-term control once discontinued. Moreover, treatment access is not ideal on a global level with less than 10% of people in need receiving treatment. Although a strategy that eliminates all viral particles from the body represents the "holy grail" of HBV therapy, a strategy that leads to HBsAg loss and allows patients to stop treatment is highly desirable. New strategies to achieve either complete viral clearance or a state of viral control without the need for long-term treatment are being developed, including approaches to restore immune responses. Antibodies are key modulators of immune responses because of their dual functionality. In addition to directly targeting a viral antigen, antibodies differ from direct antivirals in that they can recruit other immune cells to eliminate infected cells and accelerate viral clearance.
This study will evaluate the safety and pharmacokinetics of a monoclonal antibody that was isolated from an HBV-vaccinated individual, HepB mAb19, as well as its potential effects on viral levels and antiviral immune responses in individuals living with CHB.
详细描述
Along with persistence of viral antigens, impaired HBV-specific immunity contributes to chronicity of infection. Chronic HBV (CHB) is characterized by depletion or functional impairment of HBV-specific T cells, resulting in defective proliferation and cytokine production, as well as impaired production of antibodies against HBsAg, with an expansion of atypical memory B cells. The importance of host immunity for HBV clearance is well recognized, but the critical immunological events required to achieve functional cure are not fully understood. Persistent high HBsAg levels along with dysfunctional immunity has raised the possibility that HBsAg itself is immunoregulatory in HBV infection. Chronic exposure to high levels of HBsAg may render HBV-specific T cells overly activated and functionally tolerated. Thus, decreasing serum HBsAg could be a valuable therapeutic strategy, due to its potential to alleviate functional exhaustion and confer immune control.
In parallel, antibodies to HBsAg are associated with successful vaccination and recovery from acute infection. Indeed, a difference between chronically infected and naturally recovered individuals is a robust polyclonal B cell response to HBsAg. Whether these associations reflect an etiologic role for anti-HBV neutralizing antibodies is not known. However, depletion of antibody producing B lymphocytes in CHB patients by rituximab is associated with HBV reactivation, indicating that B cells or their antibody products are playing a significant role in controlling the infection. The only immunomodulatory therapy currently available to treat CHB, IFN-α, is effective in only 30% of people, with marked differences observed across HBV genotypes being most effective against HBV genotype A and B infections.New therapeutic strategies that interfere with viral persistence and ongoing immune dysregulation with the goal to achieve a functional cure are needed. Several strategies are in clinical development including antiviral (e.g.small interfering RNA) (siRNA) and nucleic acid polymers (NAPs), and immune restoration approaches (e.g. therapeutic vaccination, toll-like receptor agonists, checkpoint blockade inhibitors and passive immunotherapy with anti-HBs antibodies).
Antibodies are among the key modulators of immunity and are uniquely attractive pharmaceutical agents because of their dual functionality. In addition to targeting a specific epitope with their variable domains, antibodies differ from direct antivirals in that they can recruit immune effector functions through their Fc domains. In addition to accelerating clearance of viruses andinfected cells through phagocytosis or direct cellular cytotoxicity, antigen-antibody immune complexes are also potent immunogens that can foster development of host immune responses. For example, antibody-based cancer therapies eliminate malignant cells and induce adaptive T cell immunity, and have dramatically increased the number of individuals that control and survive malignant diseases. Whether the same concepts are applicable to the management of chronic viral infections is an area of active investigation, particularly in the HIV-1 field.
In CHB, antibodies have the potential to enhance clearance of HBsAg. Although studies in transgenic animals indicate that T cell tolerance to HBsAg is durable and difficult to reverse, the models are not entirely reflective of human infection.
Whether antibody therapy can restore some aspects of HBV-specific T cell immunity in humans has not been determined. Immunotherapy with HBsAg-specific antibodies has shown some direct HBsAg suppression effects in clinical studies. However, the HBsAg antibodies that were evaluated only led to short term decline in HBsAg levels in CHB patients, that were very similar to the effects of treatments based on hepatitis B immune globulin (HBIG). More potent antibodies with long-lasting effects on circulating HBsAg and potential to modulate and restore HBV-specific immune responses are needed to evaluate the role of immunotherapy in CHB treatment and remission.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 to ≤ 70;
- •HBV infection confirmed by positive HBsAg for ≥6 months;
- •On HBV-active nucleos(t)ide therapy for ≥6 months without change in NRTI in the previous 3 months;
- •The following laboratory values 49 days prior to study entry (day 0):
- •HBV DNA below lower limit of quantification;
- •HBs antibody negative;
- •HBeAg negative;
- •Ability and willingness to provide informed consent.
- •For participants who can become pregnant (i.e., participants who have not been post-menopausal for at least 24 consecutive months, who have had menses within the preceding 24 months, or who have not undergone surgical sterilization, specifically hysterectomy and/or bilateral oophorectomy or bilateral salpingectomy), negative serum or urine pregnancy test at screening and on day 0 (study entry).
- •Participants who can become pregnant must agree to use two methods of contraception, one of which must be from the highly effective methods for contraception listed below. Barrier methods of contraception are permitted for the second method of contraception. Contraception must be used from 10 days prior to study entry and during study follow up. Acceptable methods of contraception include:
- •Contraceptive subdermal implant;
- •Intrauterine device or intrauterine system;
- •Combined estrogen and progestogen oral contraceptive;
- •Injectable progestogen;
- •Contraceptive vaginal ring;
- •Percutaneous contraceptive patches;
- •Partner sterilization with documentation of azoospermia prior to the participant's entry into the study, and this partner is the sole partner for that participant. The documentation of partner sterility can come from the site personnel's review of medical records or medical history interview provided by the participant or the partner. Self-reported documentation of reproductive potential should be entered in the source documents.
- •Participants who can impregnate a partner and who are engaging in sexual activity that could lead to pregnancy must agree to use condoms from 10 days prior to study entry and during study follow up to avoid impregnating a partner who can get pregnant.
排除标准
- •Clinical symptoms, imaging studies or liver histology suggestive of advanced fibrosis (exclude fibrosis grade 3 and 4 by FibroScan) (Fibroscan®< 9 kpa) 12 months prior to entry or done at the pre-infusion visit. Note: If FibroScan results are not available, imaging will be performed at the preinfusion visit.
- •Presence of a LI-RADS4 or 5 liver lesion on imaging 12 months prior to entry or done at pre-infusion visit, if prior results not available.
- •Alpha fetoprotein >20 ng/ml. Note: Alpha-fetoprotein (AFP) above normal but < 20 is acceptable for entry if earlier AFP levels (older than 6 months) are within normal range and imaging is negative in last 3 months).
- •HIV-1, HCV or hepatitis delta virus infection 12 months prior to entry or done at screen, if prior results not available;
- •History of hematopoietic stem cell transplant or solid organ transplant;
- •Any confirmed significant allergic reactions (urticaria or anaphylaxis) against any drug, monoclonal antibody or vaccine, or multiple drug allergies (non-active hay fever is acceptable);
- •History of cardiovascular disease (e.g., cardiac insufficiency, coronary artery disease, cardiomyopathy, congestive heart failure, family history of congenital long QT syndrome, family history of sudden death);
- •History or presence of clinically significant Electrocardiogram (ECG) abnormalities based on the average of the triplicate ECG recordings (e.g., PR interval >210 ms, QT corrected for heart rate using the Fridericia's correction factor [QTcF] > 450 ms for males and QTcF >470 ms for females);
- •History of systemic corticosteroids, immunosuppressive anti-cancer, systemic interferons or interleukins 6 months prior to entry;
- •History of chronic liver disease from another cause, ICD, or autoimmune diseases that in the opinion of the investigator would preclude participation;
- •Any significant acute infection (e.g. influenza, COVID-19) or any other clinically significant illness 2 weeks prior to entry.
- •Laboratory abnormalities in the parameters listed below:
- •Absolute neutrophil count <1,000 /mm3
- •Hemoglobin <10 gm/dL (6.21 mmol/L)
- •Platelet count <150,000 /mm3
- •ALT >2.0 x Upper normal limit (ULN)
- •AST >2.0 x ULN
- •Total bilirubin >1.5 ULN (except individuals with known Gilbert's)
- •Albumin <3.5 gm/dL
- •Estimated glomerular filtration rate (eGFR) <70 mL/min
- •Pregnancy or lactation;
- •Any vaccination 2 weeks prior to entry;
- •Receipt of anti-HBV mAb therapy of any kind in the past (including HBIG);
- •Participation in another clinical study of an investigational product currently or 12 weeks prior to, or expected participation during this study
研究组 & 干预措施
Group 1
Participants (n=4), will be enrolled in Group 1 (HepB mAb19 3 mg/kg or placebo, single dose) and randomized 3:1 to HepB mAb19 or placebo with each participant being dosed at least 72 hours apart. Following enrollment and administration of study drug in the first two participants, the Protocol Safety Review Team (PSRT) will review available safety data (including safety labs) and only following this review and in the absence of dose limiting toxicities (DLT), the remaining two participants in Group 1 will be enrolled and randomized to HepB mAb19 or placebo.
干预措施: HepB mAb19 (Drug)
Group 2
Participants (n=4), will be enrolled in Group 2 (HepB mAb19 10 mg/kg or placebo, single dose) and randomized 3:1 to HepB mAb19 or placebo with each participant being dosed at least 72 hours apart.
干预措施: HepB mAb19 (Drug)
Group 3
Participants (n=4), will be enrolled in Group 2 (HepB mAb19 30 mg/kg or placebo, single dose) and randomized 3:1 to HepB mAb19 or placebo with each participant being dosed at least 72 hours apart.
干预措施: HepB mAb19 (Drug)
Group 4
Participants (n=18) will enroll in Group 4 in an open-label fashion and will receive the MTD. Enrollment in Group 4 will begin after all 4 participants enrolled in the preceding dose group reach at least 28 days, none of the dose escalating halting criteria outlined above occur, and following review of available safety data by the PSRT
干预措施: HepB mAb19 (Drug)
结局指标
主要结局
Safety and tolerability
时间窗: From enrollment to the end of follow up at 48 weeks
Safety and tolerability evaluation will be done by recording of adverse events. The DAIDS AE Grading Table Corrected version 2.1 (July 2017) will be used to grade adverse events. In addition, the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 grading scale will be used for reporting and grading adverse events related to infusion reactions and cytokine release syndromes within 24 hours of the start of IP or placebo administration that are considered administration reactions or cytokine release syndromes.
Pharmacokinetic profile
时间窗: From enrollment to follow up at 48 weeks
Calculation of HepB mAb19 decay curve
Maximum tolerated dose
时间窗: From enrollment to follow up at 48 weeks
To establish the maximum tolerated dose (MDT)
次要结局
- HBsAg levels(From enrollment to the end of follow up at 48 weeks)
- HepB mAb19 antibodies(From enrollment to the end of follow up at 48 weeks)