Kojima Productions treated attendees at a recent Zone of the Enders HD gathering to the news that work is underway on a new Enders game which stands as a direct sequel to Zone of the Enders: The 2nd Runner. It seems that the project is in the earliest stages of development, with the NeoGAF poster noting that "right now they are still experimenting with the feasibility of making [a sequel]." Which is probably code for "EVERYONE BUY THE ZONE OF THE ENDERS HD COLLECTION WHEN IT’S OUT."
Very little was revealed about the planned game, referred to for now as the Enders Project. We know that it is a direct sequel to The 2nd Runner and that the story unfolds against the backdrop of an ancient civilization (as opposed to the previous games’ futuristic world). A screen rendered in the Fox Engine was shown, and I think it’s reasonable to speculate that the game will use that engine as well, assuming it happens.
In related news, the event also included confirmation that the Zone of the Enders HD Collection will be released in Japan on October 25, 2012 (via All Games Beta).