The 44-year-old "28 Weeks Later" helmer has walked out because he couldn't agree with production house Summit about their views of the film, reported Ace Showbiz.
Fresnadillo's departure was amicable.
The studio will now look for another director for the project.
Previously, "Fast and Furious" helmer Justin Lin was attached to direct it.
Ryan Reynolds is on board to take the lead role, while Art Marcum and Matt Holloway have provided the script.
Neal H Moritz and Peter Davis are set to serve as the producers.
Fresnadillo nabbed an Academy Award nomination for Best Live Action Short Film in 1996 through his work "Esposados".
He was once linked to "The Crow" reboot, but dropped out of it to take the directing duty in "Highlander".
