One can always expect some supporting characters to come and go in a multi-season drama. But, arguably, there were three unexpected primary character changes that sent reverberations through the Babylon 5 fan community: Sinclair being replaced by Sheridan after Season 1, Talia Winters being replaced by Lyta Alexander (who had already appeared in the television pilot film The Gathering), and Susan Ivanova's absence from the final season. But I will also discuss the departures of the first-billed but less central characters Na'Toth and Keffer.
Sinclair was largely written out with only a couple of guest appearances after Season 1 because of a debilitating mental illness suffered by actor Michael O'Hare. JMS only revealed the details after O'Hare's death in 2012, as he had promised not to discuss it publicly before then:
For what JMS was able to reveal before O'Hare's death, see here.
Claudia Christian, who played Ivanova, suggested in an interview that Andrea Thompson (Talia) had decided of her own accord to leave the show:
"I think that if Andrea Thompson had not left, we would have definitely explored the relationship further. That was the intention, but because she wanted to get out, we had to wrap it up quickly" (SFX, July 1997)."
Regarding Ivanova, JMS explains his efforts and those of other cast members to keep Claudia Christian in the show:
Comments from JMS, July 19 1997
There have been some questions raised as to what has happened regarding Claudia Christian and Season 4. In simplest possible terms, which can be verified through every cast member, and in the press, what happened was this:
In early June, WB asked for, and received, one-month exensions on their contract options from all cast members except Claudia, for the purposes of allowing WB time to work out the co-financing deal with TNT for year 5 of B5. There was a great deal of red tape left over from the PTEN deal to finish unraveling, and other business aspects, to work out in going from syndication to cable, and it was taking longer than expected.
Claudia said, repeatedly, that she was on board for the fifth season, but that she didn't want to give the extension for business reasons of her own. We took her at her word and allowed her to not give the extension. Assurances were made to us, and to her fellow cast members.
While we were all together (cast, some crew, and I) in Blackpool for Wolf 359, word reached us of the articles in Variety and Reuters reporting that Claudia would not be returning to B5, and was looking for other work. This was the very first indication we had that she would not be in season 5. TNT was upset by this, WB was upset by this, and we were called on the carpet asking why we had trusted her about the fifth year. When spoken to in Blackpool, she was still, at that point, saying that she was going to be in season 5...but did nothing to address the situation with WB. She was told that WB had to know, for sure, if she was in or out by last Friday. All she had to do to be in season 5 was to pick up the phone, or have her agent do so, and call WB and say, "I'm in."
This did not happen. Friday came, and went. It was clear that she had no intention of being in season 5, and wanted instead to pursue movies. She is more well known now after B5, after all.
Cast members prevailed upon her to change her mind over the weekend. Bruce, Jeff Conaway, others took it upon themselves to try and talk her back onto the show, tried to get her to call on Monday in case she might be able to repair the bridges burned the prior week. On Monday, she left the convention early, and never called WB, never called Doug, never called anyone.
Bottom line is...she passed on season 5. She chose not to be there. I know that she has now told some people that WB doesn't want her...but if that is the case, why the articles planted in Variety and Reuters saying that the B5 producers were "bummed" that she wasn't available, that she had chosen not to return to the show? (Again, at the time the articles appeared, this intent had not even been conveyed to us or to WB; we had to learn about it by reading it in the trades, in articles no one had even discussed with us.) Why did she not give the extension, as was also reported? Why was it announced in the press (in articles reprinted right here on the nets) that she wasn't coming back and was looking for other work long before we even knew anything about it?
The offer was on the table. We extended it to the very limit. All the other actors signed on, and urged her to do the same. She chose not to. It was never a matter of anyone not wanting her. I personally urged her Thursday night to call her agent and talk this out and make her intentions clear if she wanted to come back to the show. She declined. Every cast member who was there in Blackpool saw what went down, and can verify this.
(Source — including a response from Claudia Christian herself)
A slightly less central (although at one point first-billed) character whose arc had to be dropped was Na'Toth. From an interview with actress Julie Caitlyn Brown:
Sadly, "Chrysalis" was destined to be Brown's final visit to B5 as a Narn. At the end of the show's first season, the actress reluctantly decided not to renew her contract with the show, due largely to the practical problems of wearing Na'Toth's extensive prosthetics and red contact lenses.
"You have to wear an awful lot of makeup to play Na'Toth," she explains. "It is a very, very demanding role. You're working 15 to 18 hours a day and you can't breathe. There were times when I couldn't see where I was going, because of the contact lenses - it was all just a red fuzz. And I lost so much weight working on the show, because I sweated it all away underneath that costume! So the makeup was probably the biggest deterrent for me; I couldn't sign on and say, 'Yes, I'll do this for 13 episodes for another four years'.
"I loved the character, and I truly cried when I turned the part down. I was sobbing. I remember calling my mother and telling her, 'I don't know what to do. This is one of the best-written characters I've ever come across. She's going to have a lot to do, but I just don't feel right.' She then advised me not to do it. But it was still a hard decision to make. I was honestly sobbing when I had to turn it down."
She was subsequently replaced by actress Mary Kay Adams, as JMS intended to continue the character, but there were resulting problems with the portrayal. From JMS:
"The only time it hasn't worked out as well as I'd've liked was when we cast Mary Kay Adams, who was very strong in the auditions, and then made an actor's choice to play the character very quiet, to not push against Andreas [G'Kar]...but you fade into the woodwork if you do that."
Subsequently, the character was dropped. Her arc was abandoned and then given a quick resolution in an episode where Na'Toth is discovered in a
dungeon in the Centauri Imperial Palace, long after the invasion of Narn.
In all of these cases, the changes had to do with the actor's circumstances — they were not pre-planned aspects of the story arc.
The only intentional removal might be the minor but nonetheless first-billed character of Warren Keffer (a hotshot Starfury pilot), a character requested by the network for added drama, and who JMS had always intended to have a quick arc:
"Okay, Keffer wasn't all he could've been, but that was because
that character was always doomed, and doomed to go fast, so I think I
put a little distance between myself and him..."
Thanks to @Thunderforge for reminding me about Keffer.