A phase 1 trial of lipid-encapsulated mRNA encoding a monoclonal antibody with neutralizing activity against Chikungunya virus

Abstract

Chikungunya virus (CHIKV) infection causes acute disease characterized by fever, rash and arthralgia, which progresses to severe and chronic arthritis in up to 50% of patients. Moreover, CHIKV infection can be fatal in infants or immunocompromised individuals and has no approved therapy or prevention. This phase 1, first-in-human, randomized, placebo-controlled, proof-of-concept trial conducted from January 2019 to June 2020 evaluated the safety and pharmacology of mRNA-1944, a lipid nanoparticle-encapsulated messenger RNA encoding the heavy and light chains of a CHIKV-specific monoclonal neutralizing antibody, CHKV-24 ( NCT03829384 ). The primary outcome was to evaluate the safety and tolerability of escalating doses of mRNA-1944 administered via intravenous infusion in healthy participants aged 18-50 years. The secondary objectives included determination of the pharmacokinetics of mRNA encoding for CHKV-24 immunoglobulin heavy and light chains and ionizable amino lipid component and the pharmacodynamics of mRNA-1944 as assessed by serum concentrations of mRNA encoding for CHKV-24 immunoglobulin G (IgG), plasma concentrations of ionizable amino lipid and serum concentrations of CHKV-24 IgG. Here we report the results of a prespecified interim analysis of 38 healthy participants who received intravenous single doses of mRNA-1944 or placebo at 0.1, 0.3 and 0.6 mg kg-1, or two weekly doses at 0.3 mg kg-1. At 12, 24 and 48 h after single infusions, dose-dependent levels of CHKV-24 IgG with neutralizing activity were observed at titers predicted to be therapeutically relevant concentrations (≥1 µg ml-1) across doses that persisted for ≥16 weeks at 0.3 and 0.6 mg kg-1 (mean t1/2 approximately 69 d). A second 0.3 mg kg-1 dose 1 week after the first increased CHKV-24 IgG levels 1.8-fold. Adverse effects were mild to moderate in severity, did not worsen with a second mRNA-1944 dose and none were serious. To our knowledge, mRNA-1944 is the first mRNA-encoded monoclonal antibody showing in vivo expression and detectable ex vivo neutralizing activity in a clinical trial and may offer a treatment option for CHIKV infection. Further evaluation of the potential therapeutic use of mRNA-1944 in clinical trials for the treatment of CHIKV infection is warranted.

Conflict of interest statement

J.E.C. has served as a consultant for Luna Biologics, is a member of the Scientific Advisory Boards of Meissa Vaccines and is founder of IDBiologics. The Crowe laboratory at Vanderbilt University Medical Center has received sponsored research agreements from IDBiologics and AstraZeneca. L.M.P. is a consultant for Abbott, Broadview Ventures, Bristol Myers Squibb, Moderna, Pfizer and WorldCare Clinical. A.A., H.Z.A., S.Himansu, S.K., S.L., R.P., S.Han, J.-M.L. and T.Z. are employees of, and M.H. is a former employee of, Moderna and may hold stock/stock options in the company. J.E.T. is a consultant of Moderna.

© 2021. The Author(s).

Figures

Fig. 1. Trial flow.

The study protocol planned to enroll 8 participants per treatment group. Six of 8 participants were allocated in the 0.6 mg kg−1 dose group due to the decision to augment the premedication regimen with steroid to assess its potential mitigation of infusion-related reactions (0.6 mg kg−1 + steroid group). aParticipants received loratadine and ranitidine 90 min before infusion. bParticipants received loratadine, ranitidine (sentinel, expansion) and acetaminophen (expansion) 90 min before infusion. cParticipants received steroid (dexamethasone) and diphenhydramine and famotidine 90 min before infusion. dParticipants received diphenhydramine and famotidine 90 min before infusion. eParticipants were administered two 0.3 mg kg−1 doses on days 1 and 8.

Fig. 2. Serum concentration of CHKV-24 IgG, mRNA encoding heavy and light chains of CHKV-24 IgG and IAL.

a, Mean serum concentration time profiles of CHKV-24 IgG after the administration of single doses of 0.1, 0.3 and 0.6 mg kg−1 and 2 doses of 0.3 mg kg−1 mRNA-1944 over the course of 366 d and during 28 d (inset). b, Mean serum concentration time profiles for mRNA (heavy and light chains) and IAL during 28 d. The error bars represent the s.e.m. The dotted lines represent the serum target concentration of 1 µg ml−1 antibody anticipated to provide neutralizing antibody protection against CHIKV infection,,,. n = 6 participants at each time point for the single-dose 0.1, 0.3 and 0.6 mg kg−1 + steroid and 2-dose 0.3 mg kg−1 groups; n = 4 participants at each time point for the single-dose 0.6 mg kg−1 group examined over 366 d for CHKV-24 IgG and over 28 d for mRNA (heavy and light chains) and IAL.

Fig. 3. Neutralizing antibody titers for single-dose groups.

Serum neutralizing titers of CHKV-24 IgG against CHIKV were assessed using the PRNT at 12, 24 and 48 h after administration of 0.1, 0.3 and 0.6 mg kg−1 (without steroid) doses of mRNA-1944. The percentage of participants achieving PRNT50 GMTs >100 and the GMTs for each dose group are provided. PRNT50 GMT >100 represents a level of CHIKV neutralizing antibodies previously associated with protection from both symptomatic CHIKV infection and subclinical seroconversion in humans,.