The real spur was probably--as opined by Commines--cowardice; for, says that Frenchman, "Jamais homme cruel ne fut hardi." Federigo's defence of the realm consigned to him was not conspicuous, for the French entered Naples almost without striking a blow within twenty days of their departure from Rome.
Scarcely had Charles laid aside his armour when death robbed him of the second hostage he had brought from the Vatican.

On February 25, after a week's illness, Prince Djem died of dysentery at the Castle of Capua, whither Charles had sent him.
Rumours that he had been poisoned by the Pope arose almost at once; but, considering that twenty-eight days had elapsed since his parting from Alexander, it was, with the best intentions in the world, rather difficult to make that poisoning credible, until the bright notion was conceived, and made public, that the poison used was a "white powder" of unknown components, which did its work slowly, and killed the victim some time after it had been administered.

Thus, by a bold and brazen invention, an impossible falsehood was made to wear a possible aspect.
And in that you have most probably the origin of the famous secret poison of the Borgias.

Having been invented to fit the alleged poisoning of Prince Djem, which it was desired to fasten upon the Pope by hook or by crook, it was found altogether too valuable an invention not to be used again.

By means of it, it became possible to lay almost any death in the world at the door of Alexander.
Before proceeding to inquire further into this particular case, let us here and now say that, just as to-day there is no inorganic toxin known to science that will either lie fallow for weeks in the human system, suddenly to become active and slay, or yet to kill by slow degrees involving some weeks in the process, so none was known in the Borgian or any other era.