A Phase 1/2 Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of CRMA-1001 in Adults with Chronic Hepatitis B

Trial ID: 2025-523619-12-00
Protocol: CRMA-1001-101
Sponsor: Nchroma Bio Inc.

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Diseases & Conditions

Chronic hepatitis B

Objectives

The primary objective is to assess the safety and tolerability of single and multiple doses of CRMA-1001 in adults with chronic hepatitis B. Secondary objectives include:

Evaluation of long-term safety following single and multiple doses.
Assessment of pharmacokinetics parameters, specifically effector mRNA, gRNA, and ionizable lipid.
Evaluation of immunogenicity.
Analysis of the effect on circulating blood HBV biomarkers.
Determination of the rate of nucleos(t)ide analogue therapy discontinuation.
Assessment of the incidence of functional cure.

Participants

This study involves 56 participants diagnosed with chronic hepatitis B. The study population consists of male and female adults aged 18 to 64 years. Eligible subjects must demonstrate HBsAg positivity for at least 6 months and maintain a stable nucleos(t)ide analogue treatment regimen. Specific requirements include HBV DNA levels below 10 IU/mL, HBsAg levels of 100 IU/mL or greater, and HBeAg negativity, with an exception for a specific cohort. Participants must present stable laboratory parameters, including alanine aminotransferase and aspartate aminotransferase levels within 1.5 times the upper limit of normal, total bilirubin within normal limits, and adequate hemoglobin, platelets, and white blood cell counts. Additionally, the estimated glomerular filtration rate must be at least 60 mL/min/1.73m2. Inclusion is also contingent upon a body mass index between 18 and 32 kg/m2 and a body weight between 45 kg and 150 kg.

Plans and Procedures

This Phase 1/2, open-label, multi-center study is designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of CRMA-1001 in adults with chronic hepatitis B. The research methodology utilizes both single ascending dose and multiple ascending dose designs. The clinical investigation involves an initial screening visit to assess eligibility based on criteria such as HBsAg levels, HBV DNA concentration, and stable nucleos(t)ide analogue therapy. Following screening, participants receive CRMA-1001 via intravenous infusion. The study includes follow-up assessments to monitor treatment-emergent adverse events, antibody induction, and changes in viral biomarkers. The primary endpoint is the incidence and severity of adverse events from baseline to Month 6, while secondary objectives include evaluating plasma Cmax, AUC, and the proportion of participants achieving a functional cure. Participant involvement continues through the end-of-study assessment to determine the long-term impact on viral markers and the ability to discontinue existing therapy.

Treatment

The investigational product CRMA-1001 is an infusion consisting of two active substances, MRNA3771 and GRNA1599. This experimental medication is administered via intravenous infusion to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy in adults with chronic hepatitis B.

Efficacy

Efficacy assessment in this study focuses on several biomarkers related to chronic hepatitis B. The evaluation includes the change from baseline in HBsAg, anti-HBs antibody titer, HBV DNA, HBeAg in HBeAg-positive participants, and anti-HBe antibody titer in HBeAg-positive participants. These parameters are measured as a change from baseline to Month 6 and from baseline to the end of study.

Additional efficacy endpoints include:

The proportion of participants capable of discontinuing nucleos(t)ide analogue (NUC) therapy by the end of study.
The incidence of functional cure, defined as HBsAg loss (less than 0.05 IU/mL) and HBV DNA below the lower limit of quantification (LLOQ) at least 6 months following CRMA-1001 treatment and discontinuation of NUC therapy, by the end of study.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Adults ≥ 18 to < 65 years of age, at the time of signing the informed consent.
Chronic HBV infection, defined as positive for HBsAg for a duration of at least 6 months.
On stable NUC treatment, defined as receiving the same NUC in the 6 months prior to enrollment, and expected to remain on the same NUC for the duration of study participation or until protocol-specified NUC discontinuation criteria are met. Tenofovir (as TAF, TDF, or tenofovir disoproxil maleate) and ETV are permitted.
HBV DNA < 10 IU/mL (<1.0 log10 IU/mL) at Screening as determined by Central Lab.
HBsAg ≥ 100 IU/mL (≥2.0 log10 IU/mL) at Screening as determined by Central Lab.
Participant has the following laboratory parameters at screening by central laboratory: a. ALT and AST ≤ 1.5 × ULN, confirmed by local or central lab within 7 days of dosing if assessed prior to Day -28. b. Total bilirubin ≤ ULN (Note: isolated bilirubin ≤ 1.5 × ULN is acceptable for patients with documented Gilbert’s syndrome). c. PT, INR, and aPTT ≤ ULN (Note: PT and/or aPTT > ULN is acceptable if considered not clinically significant by investigator, INR and other parameters of liver function are within normal limits, and there are no current or historical concerns. Retesting is permitted). d. Hemoglobin ≥10 g/dL. e. Platelets ≥ the LLN. f. WBC ≤ ULN and ANC ≥1000/µl. g. eGFR ≥ 60 mL/min/1.73m2 (Inker, 2021). h. Albumin ≥ LLN
Body weight of at least 45.0 kg and maximally 150.0 kg, and BMI within the range 18.0 to 32.0 kg/m2 (inclusive) at Screening.
Male or female participants who agree to contraceptive requirements detailed in the protocol

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Exclusion Criteria

Significant fibrosis or cirrhosis as defined by any of the following: a. FibroScan result (CCI) during screening. A FibroScan obtained within the prior 12 months is acceptable if a report is available for investigator review. b. Prior liver biopsy with (CCI)
History of liver failure as evidenced by ascites, hepatic encephalopathy, and/or gastric or esophageal varices.
History or presence of a medical condition associated with liver disease other than HBV infection (e.g., hemochromatosis, autoimmune hepatitis, alcoholic liver disease, toxin exposure, thalassemia, non-alcoholic steatohepatitis) or other known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
Co-infection with HCV, HIV, or HDV as determined by Central Lab
AFP >100 ng/mL. a. Note: Participants with AFP >ULN but ≤100 ng/mL may be eligible if HCC can be ruled out based on a sensitive imaging study (e.g., contrast enhanced ultrasound, CT, or MRI during screening).
Receiving or expected to need any other systemic antiviral therapy at any time during participation in the study, with the exception of current NUC treatment and oral/topical therapy for HSV.
ECG during screening showing clinically relevant abnormalities (including arrhythmias or marked QT abnormalities [QTcF < 300 msec or > 450 msec]), or other cardiac abnormalities that are considered clinically significant by the investigator. Known risk factors for Torsade de Pointes (e.g., hypokalemia, heart failure), or a personal or family history of congenital long QT syndrome.
Participant is pregnant or breastfeeding, or is planning a pregnancy or to breastfeed within 2 years of CRMA-1001 planned administration.