Results have been reported of preclinical studies on HMI-104, an adeno-associated (AAV) gene therapy designed to use the liver to express a C5 monoclonal antibody (C5mAB) to treat paroxysmal nocturnal hemoglobinuria (PNH).

The study results were presented at the 26th Annual American Society of Gene & Cell Therapy Meeting in Los Angeles, California, on May 17, 2023.

“We have previously shown that a GTx-mAb construct achieved dose-dependent and sustained expression of functional C5mAb in two immunocompromised models: NOD SCID mice, which lack murine C5, and FRG® liver-humanized mice, which express physiological levels of human C5,” the authors wrote. “Here, we present the results from two nonclinical studies with HMI-104 for the treatment of PNH.”

The first study was a 16-week, dose range-finding study of HMI-104, a treatment currently in investigational new drug-enabling studies, on a NOD SCID mouse model. The aim was to identify associations between dose levels, liver vector genomes, mRNA levels, C5mAB serum levels, and ex vivo hemolysis. The results showed HMI-104 led to sustained C5mAb levels in a dose-dependent manner, increasing to week 5 and plateauing thereafter.

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The second study was a 4-week, dose range-finding study employing a humanized liver FRG KO knockout mouse xenograft model. The aim was to assess levels of transduced HMI-104 and mRNA in human hepatocytes, as well as C5mAB levels with human C5. The results showed a dose-dependent increase in C5mAB to levels similar to those at steady state in the NOD SCID mouse model by week 3.

The authors also found that C5mAB after HMI-104 treatment in both models was functional, resulting in complete inhibition of ex vivo hemolysis.

The authors conclude that HMI-104 demonstrates significant potential to lead to the expression of functional C5mAB levels with a single administration, thereby reducing breakthrough and residual intravascular hemolysis due to C5 antibody deficiency in PNH.  


Sharma Y, Scarpitti M, Robin H, et al. Preclinical studies with HMI-104, an AAVHSC vectorized C5 monoclonal antibody, for the treatment of PNH. Poster presented at the American Society of Gene & Cell Therapy (ASGCT) 26th Annual Meeting, Los Angeles, CA; May 16-20, 2023. Abstract 386.