Once Weekly Dosing Has a Future

[Central79]

I saw this on aidsmap, regarding a type of monoclonal antibody to CCR5 receptors, which would prevent HIV from binding. It's called PRO-140.

http://www.aidsmap.com/en/news/81209316-D51E-4279-B083-5045ACC8A22D.asp

Trial participants showed at least a 10x reduction in their VL, even with the lower dose tried. And it also shows activity to strains of the virus resistant to maraviroc. Although I'm not quite sure how that works.

Additionally, there is a NRTI, elvucitabine, in development that may also only need once-weekly doses. Maybe their will be a cocktail in the near future that allows for less than once daily dosing.

M.

[Ann]

Now that's what I want to hear! I managed to wait to have my hep C treated until there was once-weekly dosing for the interferon and I'd be over the moon to be able to wait until weekly dosing for hiv is available. I'm crap at taking pills on time and I think I'd have a much better chance with once weekly.

I'm confused about one point though - can this drug be taken as monotherapy? Or do they mean it will be coupled with elvucitabine? The elvucitabine link on the Aidsmap page is broken.

Thanks for the heads-up on this Matt - it's one development I'll definitely be following.

Ann

[milker]

That's pretty cool, things are going well in research those days, I feel.

Since it targets one receptor I would imagine that tritherapy is still necessary to avoid the damn resistance?

Milker.

[Central79]

I'm confused about one point though - can this drug be taken as monotherapy? Or do they mean it will be coupled with elvucitabine? The elvucitabine link on the Aidsmap page is broken.

If you type "elvucitabine" into the search field at the top it will take you to the experimental drugs page, where elvucitabine has an entry.

Although they trialled it initallly with ritonovir they then tried it as monotherapy to work out the contribution it was making to the combo - and it did very well. I would still expect it to be used in combination therapy though - which is why I thought the development of elvucitabine was important, as another drug that could be taken at longer intervals. Definately think its a future possibility.

M.

[JPinLA]

This is a fantastic possibility and form what I've been reading is very effective especially when combine with other small molecule entry inhibitors like Maraviroc (at least in vitro).  Even as a monotherapy it seems to be a viable option.

I found some of the following information interesting in terms of how PRO 140 works and I am including some of it in my post (how I understand it anyway) as well as links and references to the articles if you're at all interested.  I love this stuff so I really enjoy reading about it.

It seems that PRO 140's attachment to CCR5 does not interfere with the normal function.
 
Unlike small-molecule CCR5 inhibitors which block the  activity of CCR5 PRO 140 doesn't not block CCR5 function "In addition, preliminary studies indicate that PRO 140 is highly active against viruses that are resistant to small-molecule CCR5 antagonists" (quoted from the Murga source). 

They say that the difference is where the small molecules and antibody bind to CCR5. They bind to different part of CCR5 (which they go into some detail about in the paper).  Essentially the small molecule bind to a pocket on CCR5 that is it's active site or allosteric site where as PRO 140 binds to CCR5, doesn't block the active site but does compete out HIV-1 binding.  Very cool.  Means they could be used in tandem and in fact they looked at the synergistic effects and found, at least in vitro, that there was what they considered to be a potent synergistic antiviral effect when PRO 140 and small molecule CCR5 inhibitors were used together.

The little peptide, enfuvirtide, blocks the zippering of glycoprotein 41 which brings the viral and cell membranes together to promote their fusion.  Could be used all together I suppose. 

I'm going to try and attach a schematic of CCR5/HIV-1 interaction because I understand things better with pictures and perhaps you all would benefit from it as well!


Here's to once weekly (maybe biweekly or monthly.....) treatments with low(er) toxicity!

JP

Murga, Franti, Pevear, Maddon, Olson Potent antiviral synergy between monoclonal antibody and small-molecule CCR5 inhibitors of human immunodeficiency virus type 1 Antimicrob Agents Chemother. 2006 Oct;50(10):3289-96. PMID: 17005807 [PubMed - indexed for MEDLINE
http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17005807
Lederman, Penn-Nicholson, Cho, Mosier Biology of CCR5 and its role in HIV infection and treatment JAMA. 2006 Aug 16;296(7):815-26 http://jama.ama-assn.org/cgi/content/full/296/7/815.


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