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Author Topic: Next-generation Fusion Inhibitors  (Read 2180 times)

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Offline gerry

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Next-generation Fusion Inhibitors
« on: December 09, 2006, 01:18:26 PM »
This is in response to Ann's inquiry in one of the threads about next generation fusion inhibitors being researched that may allow once weekly administration.

Next-generation Fusion Inhibitor TRI-999 Shows Favorable Pharmacokinetic Profile

"TRI-999's potency, genetic barrier to resistance and pharmacokinetic (PK) profile offer the possibility of once-weekly administration with a sustained-release formulation, compared with the twice-daily injections now required for enfuvirtide (Fuzeon)."
« Last Edit: December 09, 2006, 05:42:26 PM by gerry »

Offline Ann

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Hi Gerry

The mention in the Body Q&A linked to in Ray's thread (in Gen Treat) was talking about Fuzeon, that's why I wondered if they were trying to pegylate it like they did with interferon. While the TRI-999 info is very interesting too, (and thanks...) it's not quite what was being discussed. Of course, Dr. Pierone (at The Body) might have been talking out his tail-feathers. Here's what he said:

Quote
I believe that Roche is working on a new form of Fuzeon which can be given once weekly instead of twice daily.

Can you shed any light on this?

Ann

PS - here's the link to the Body - http://www.thebody.com/Forums/AIDS/Meds/Current/Q180227.html
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"...health will finally be seen not as a blessing to be wished for, but as a human right to be fought for." Kofi Annan

Nymphomaniac: a woman as obsessed with sex as an average man. Mignon McLaughlin

HIV is certainly character-building. It's made me see all of the shallow things we cling to, like ego and vanity. Of course, I'd rather have a few more T-cells and a little less character. Randy Shilts

Offline gerry

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Hi Ann,

Actually, I believe this was what Dr. Pierone was referring to.  Trimeris and Roche are collaborating to design next-generation fusion inhibitor (NGFI) that will not only allow longer intervals between injections, but also be more potent than Fuzeon and also work against Fuzeon-resistant strains.  In other words, instead of just converting the current Fuzeon into a longer-acting version, they are taking it a couple of steps further.  This makes a lot of sense because since the current Fuzeon is already being used, their next move should address the problem of resistance from Fuzeon.  If they do not address this issue as well in their pipeline, then simply converting Fuzeon to a longer-acting medication would fail to assist those who have already developed resistance against it.  Here's the link from the Trimeris website. 

There are a couple of drug candidates of high-potency, high-resistance barrier, longer duration of action NGFI: TRI-999 and TRI-1144 (link).  TRI-999 does have a PEG (polyethylene glycol) linker that attaches extra fatty acids to the drug molecule which effectively decreases the clearance of the drug from the body (hence longer half-life and less frequent administration) without reducing its antiviral potency.  So in a way, it's a similar principle to PEGintron (except that PEGintron has something else linked to the drug).

Hope that clarifies the post.

Gerry

EDIT:
P.S. As far as I know, I haven't seen any info indicating that Roche is trying to convert Fuzeon to a long-acting version at the moment.  However, that doesn't mean they won't do it in the future.  I think a couple of things might prompt them to consider looking into it.  One would be if newer oral meds designed to hit resistant virus (especially newer classes) start hitting the market and people on Fuzeon start asking to switch out of doing the injections in favor of the newer meds.  Another would be when they are approaching the tail end of their patent.  JMO, of course.
« Last Edit: December 09, 2006, 06:39:19 PM by gerry »

Offline HIVworker

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Re: Next-generation Fusion Inhibitors
« Reply #3 on: December 09, 2006, 10:02:57 PM »
You guys are overlooking something. The fatty acid does something else important. It sticks the T20-like molecule to cells. This has shown to increase the potency 100s of fold. Therefore even if the clearance rate is as high as it is with Fuzeon, the active concentration is so low the compound still works. However, the decrease in clearance and increase in potency give this molecule an advantage.

Oh, Ann. They tried the Pegylated Fuzeon and it didn't sufficiently increase the half-life. I guess they did all the obvious things already.

Rich
« Last Edit: December 09, 2006, 10:12:17 PM by HIVworker »
NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

Offline gerry

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Re: Next-generation Fusion Inhibitors
« Reply #4 on: December 09, 2006, 11:58:27 PM »
Sorry, I didn't mean they have not tried pegylating Fuzeon.  Only that there's nothing on the table anymore about attempting a long-acting version, even utilizing other technologies to achieve this for Fuzeon.  Trimeris stated this in their January 2004 conference call.  So what's the real story behind dropping T-1249?  During that conference call, they were still alluding to applying these technologies to delay clearance for this 2nd generation fusion inhibitor even after they said that further development of the T1249 was halted?  It didn't make too much sense so maybe you have some info about this?
« Last Edit: December 10, 2006, 12:31:37 AM by gerry »

Offline HIVworker

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Re: Next-generation Fusion Inhibitors
« Reply #5 on: December 10, 2006, 09:20:22 AM »
I'll ask around...
NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

Offline Ann

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Re: Next-generation Fusion Inhibitors
« Reply #6 on: December 10, 2006, 11:05:27 AM »
Thank you Gerry and R, thanks for the clarifications. Much appreciated - interesting stuff. I shouldn't be needing fuzeon any time soon, but I do try to keep up on the latest on any of the drugs.

Ann
Condoms are a girl's best friend

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"...health will finally be seen not as a blessing to be wished for, but as a human right to be fought for." Kofi Annan

Nymphomaniac: a woman as obsessed with sex as an average man. Mignon McLaughlin

HIV is certainly character-building. It's made me see all of the shallow things we cling to, like ego and vanity. Of course, I'd rather have a few more T-cells and a little less character. Randy Shilts

Offline gerry

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Re: Next-generation Fusion Inhibitors
« Reply #7 on: December 10, 2006, 12:39:17 PM »
This is what the company said during that call conference when they pulled T-1249 out of further trials. Link

"As previously mentioned, we are evaluating several technologies for increasing the plasma half-life of our peptides to achieve a target of once weekly to once monthly administration. These delivery technologies range from chemical modifications of the peptides themselves to sustained release formulations or linkage of the peptides to carrier molecules with long half-lives. Any or all of these approaches are equally applicable to Fuzeon, T-1249, and the next generation fusion inhibitor peptides. We believe that like successful injectable therapeutics for other product diseases, such as Pegasys, Avonex, Aranesp, Rituxan, and Remicade, the commercial potential for a once a week or once a
month administration of a fusion inhibitor is substantial."


It seems though that they pretty much abandoned that strategy for Fuzeon a long time ago (in th Q&A) and moving forward instead on their newer peptides.  I understand the strategy to pull resources into newer and better peptides rather than reinventing the current one, but I'd hope that they would still consider investing money into doing that even for Fuzeon because it's the injection site reactions that most users have problems with.  Old news, I know, but still worth rehashing.

 


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