Gilead TLR7 agonist

[freewillie99]

This is from the current CROI conference in Seattle.  Hoping someone can explain exactly what it is.  Thanks.

http://www.pharmabiz.com/NewsDetails.aspx?aid=86934&sid=2


Gilead reports positive results from preclinical study of investigational TLR7 agonist in SIV-infected, virally suppressed monkeys
 
 Seattle
 Friday, February 27, 2015, 13:00 Hrs  [IST] 
 

Gilead Sciences announced results from a preclinical study conducted in collaboration with researchers at Beth Israel Deaconess Medical Center evaluating a proprietary investigational oral toll-like receptor 7 (TLR7) agonist and analogue of GS-9620 as part of an HIV eradication strategy. Data demonstrate that treatment with the TLR7 agonist induced transient plasma Simian Immunodeficiency Virus (SIV) RNA, as well as reduced SIV DNA in virally suppressed rhesus macaques given antiretroviral therapy (ART). In addition, the study found that after discontinuation of ART, SIV viral loads were lower among macaques that received the proprietary TLR7 agonist compared to the placebo group. These data were presented in an oral session (Session O-9) at the 22nd Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle.

"One reason current therapies can't cure HIV is that latent reservoirs of the virus persist even among individuals who are virally suppressed on ART," said James Whitney, Assistant Professor of Medicine, Harvard Medical School, and study Principal Investigator in the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center in Boston. Dr. Whitney is also an Associate Member of The Ragon Institute of MGH, MIT and Harvard, which was founded in 2009 to contribute to the accelerated discovery of an HIV/AIDS vaccine and to establish itself as a world leader in the collaborative study of immunology. "These data demonstrate that, given alongside ART, the TLR7 agonist may have the potential to both stimulate virus production and eliminate latently infected cells an eradication strategy being explored today."

In this placebo-controlled study, 10 SIV-infected rhesus macaques received ART for 38 weeks, at which point they were virally suppressed (plasma RNA less than 50 copies/mL). At week 38, six macaques were given placebo and four macaques were given seven bi-weekly doses of the TLR7 agonist, while maintaining ART. Total viral DNA levels were measured at baseline and two weeks after completion of the TLR7 agonist dosing in peripheral blood mononuclear cells (PBMC), colon and inguinal lymph nodes where latent SIV reservoirs are common. ART was discontinued two weeks after the final dose of the TLR7 agonist to assess plasma viral rebound.

The four macaques receiving bi-weekly doses of the TLR7 agonist were given 0.1 mg/kg for the first dose, 0.2 mg/kg for the second dose and 0.3 mg/kg for each of the last five doses. Doses 1-3 had no effect on plasma viremia, whereas doses 4-7 led to transient and consistent increases in plasma virus (500-1,000 SIV RNA copies/mL) in all four macaques with a return to less than 50 copies/mL within four to seven days after receiving the TLR7 agonist. In addition, SIV DNA levels of the four treated macaques were reduced by 30 to 90 percent compared to the placebo group, which remained unchanged. Following discontinuation of ART in the macaques that received the TLR7 agonist, plasma SIV RNA was ~0.5 log10 lower compared to the placebo group.

"These preliminary results suggest that TLR7 agonists may have a role to play in HIV eradication strategies," says Norbert W. Bischofberger, PhD, Gilead's executive vice president, research and development and chief scientific officer. "GS-9620 is a potent TLR7 agonist currently being evaluated in a phase 2 study in patients with chronic hepatitis B for its potential to reduce HbSAg. Based on today's results, we are now also looking forward to moving GS-9620 into proof-of-concept studies in HIV-infected individuals taking ART."

The proprietary TLR7 agonist compound and GS-9620 are investigational agents and their safety and efficacy have not been established.
 

[Jmarksto]

My lay person understanding here is that TLR7 was tested to see if it could stimulate the latent HIV reservoirs so they could be eradicated.  It looks like it did stimulate the latent cells, and reduced the amount of latent HIV, but did not eradicate the virus.  In other words, it kind of worked but not completely.

[geobee]

I participated in this study -- where they shoved my blood through the machine that extracted my blood cells.  (The nurse was nutty.  As in she placed the bag of blood on my bare chest afterwards, stroked it, and told me to "say goodbye" to my blood.)

Anyway -- Gilead is giving a talk about their results.  They seem pretty excited about it. I think that drug is pretty exciting in that it's non-toxic, and wakes up HIV and the reservoirs are smaller.  Sure, it didn't eradicated HIV completely, but with repeated doses -- who knows? -- it might just work.

Here's what they sent.  The links are interesting.  I'm going to go.

Dear Latency Study Participant,

As a participant in our Latency Study Apheresis Program, we are delighted to invite you to an evening reception and report on the progress down the latency activation path to an AIDS cure.

The event will be held in the Rainbow Room auditorium at the San Francisco LGBT Community Center on Thursday evening, May 14th, from 6:30 to 8:30 pm.

We will serve light snacks and beverages starting at 6:30 pm. At 7:00 pm, our colleagues from Gilead Sciences will present the results of their exciting work on an HIV cure utilizing the white blood cells you provided over the last five years of this study.

San Francisco LGBT Community Center
Rainbow Room
1800 Market Street, San Francisco, CA 94102

Please RSVP to Michele@questclinical.com to reserve your spot, as we only have seating capacity for 200. Reservations will be given on a first come, first served basis.

For more information about this research, please click these links:

http://www.sciencemagazinedigital.org/sciencemagazine/06_march_2015?folio=1056#pg16
https://www.youtube.com/watch?v=QDupxh3T2ZA
http://www.gilead.com/news/press-releases/2015/2/gilead-announces-preclinical-data-for-an-investigational-tlr7-agonist-in-sivinfected-virally-suppressed-monkeys

[freewillie99]

I participated in this study -- where they shoved my blood through the machine that extracted my blood cells.  (The nurse was nutty.  As in she placed the bag of blood on my bare chest afterwards, stroked it, and told me to "say goodbye" to my blood.)

Anyway -- Gilead is giving a talk about their results.  They seem pretty excited about it. I think that drug is pretty exciting in that it's non-toxic, and wakes up HIV and the reservoirs are smaller.  Sure, it didn't eradicated HIV completely, but with repeated doses -- who knows? -- it might just work.

Here's what they sent.  The links are interesting.  I'm going to go.

Geobee: Very cool. Well done for volunteering; look forward to hearing about the presentation. And yes, that nurse sounds like a bit of a kook

[DANIELtakashi]

I read about this TLR 7.   I hope it will lead to a better way of treating.

[tryingtostay]

Dang I would of liked to participate in this study. 

I wonder if this will be part of a cure.  Like a stepping stone to reduce the VL  then maybe knock it out with a round of chemo or something.

Thanks for participating geobee!

[DANIELtakashi]

Just wondering whether it will not be dangerous if the latent viruses wake up and come out in multitudes in tissues and brains?   Just a thought.   

[DANIELtakashi]

Of course I am excited about the possibility.

[geobee]

I went to the HIV Cure forum in San Francisco last night, led by Dr. Jay Lalezari.  A lot of the information has already been discussed on this site.  I took notes (with my thumbs).  Here's what I thought was interesting.

Dr. Jay Lalezari (Quest Clinical)

"Dr J" said that Timothy Ray Brown was important.   He established a proof-of-concept.   He got a lot of people talking about curing HIV.  Without him, perhaps, this whole discussion would even be taking place.  HIV would still be considered incurable.

He focused his presentation on two cure approaches -- gene therapy and "shock and kill".  The most talked about player -- Sangamo -- had mixed results with the CCR5 knock-out T-Cell approach.  One person in all of the cohorts was controlling the virus without meds  Sangamo is shifting its focus to stem cells.

The second player in this field is CalImmune.  They have a more ambitious program, knocking out CCr5 and X4 and also using a conditioning agent.  Preliminary data will be seen by insiders next week, with publication later in 2015. 

Bristol Meyers Squibb, Gilead, and others are working on the shock and kill approach to get at latent reservoirs.   This has proven a successful technique with HepC, which is now being cured.

Dr. J believes that the shock and kill approach is a quicker path than the gene therapy approach.  It's also why they need volunteers to give blood. 

Gilead (3 presenters)

There's much excitement at Gilead over curing HIV.  Currently 40 people working on it.  They are pursuing cures along with improving ARVs, with new combination regiment with the new tenofovir which should be approved this year.   They have more ideas than they can test and are collaborating with UCSF, SF General, Gates Foundation, Stanford, Oregon Health and Science, etc.

Curing HIV is difficult because memory cells live for years.  And probably only 1 in a million cells is infected.  That's why just giving blood isn't useful -- the need the "leuka packs" -- the white cells derived from leukapherisis. 

There is a "cytopathic  effect" of getting the T-Cells to express HIV.  The very act of doing this may kill the T-Cells. Probably a combination approach, kicking and killing, will be needed.

In-Vitro models are only so good.  They need real cells from HIV-controlled participants.  They use these cells to design better studies in mice and monkeys.  It takes 1 1/2 years to get results from the monkeys.

The white cells from the leukapherisis are centrifuged.  Then compounds are applied
and an HIV test is done to see if there is more expressed HIV.  HIV can be tightly or loosely bound within the DNA of a cell.

One of the best "kick" drug candidates is Romidepsin.  It's not a Gilead drug.  In a trial in Denmark it did seem to reduce the reservoirs.  A trial in the USA is starting soon.  Already approved for fighting cancer.

One of the best "kill" drugs is Gilead's TRL7 agonist.  This drug is taken orally and stimulates the immune system.  HIV has a way of turning off the immune system.  This drug turns it back on.  It was developed for Hep B and is currently in Phase II trials. 

In testing in macaques, the first few doses of the agonist did nothing.   However, subsequent doses did seem to stimulate the immune system and lower the reservoir in the gut, which makes sense because the drug is administered orally.  Little to no effect on lymph nodes, etc.   In all monkeys, viral rebound occurred.  This was not a cure.  However, the set point was lower.  Current trials are underway in humans.

Gilead went through their library of 460,000 compounds.  Identified 5-10 active classes (2000 compounds).  None of their compounds seemed to work as well as Romidepsin. 

They are currently working on combining compounds.  Toxicity can be an issue when combining Romidepsin with TRL7 agonist.

They are also working with Dr. Picker, who is developing the CMV vaccine.   Perhaps their drugs could be used in combination with his vaccine.

A member of the audience asked about HIV in tissues, not just blood.  What about the brain?  Gilead said that brain infection is still a debate. Brain cells are shorter lived. There is something they call the "sudden death" cohort.  At death, autopsies are done on HIV+ people.  4 out of 5 in one case study did not have HIV in the brain.
Gilead also stressed an incremental approach.  Memory T-Cells first, tissues later.  One step at a time.

A member of the audience asked a question about side effects.  With  Romidepsin, can use 1/3 the amount a cancer patient would get.   Minimal side effects.   If you crank up TRL7 too high, you get a flu-like side effect.  The flu is, after all, the body's immune system ramped up to fight an infection.

Age doesn't appear to be a factor in the shock and kill trials so far.

In monkeys, even those only infected for 3 days had well-seeded reservoirs.  However, going on meds immediately does seem to keep the reservoir smaller and, perhaps more important, more homogeneous.  So a medication might work better at that reservoir, since it's genetically consistent.

[zach]

thank you geobee, i try not to think about cure too much

but thats some very promising sounding stuff

[tryingtostay]

Yes, thanks geobee! 

[Reggie]

Yes thanks Geobee thats a very interesting and informative read.


Reggie

[geobee]

PS -- I got screened for the stem cell trial but was DQ'd.  They give you chemo to deplete your stem cells so the new ones can engraft.  I had low neutrophils so couldn't take the chemo so was DQ'd for the trial.

[Jeff G]

PS -- I got screened for the stem cell trial but was DQ'd.  They give you chemo to deplete your stem cells so the new ones can engraft.  I had low neutrophils so couldn't take the chemo so was DQ'd for the trial.

Was it a mild depletion ? for lack of a better term ? Just from the sound of it I may have been grateful to be DQ . I don’t mean to make light of something that is important to you but am interested in more details.

[geobee]

Hi Jeff --

I was 1.6, the low end of the normal range which is 1.5 to 8.0.  The were looking for something above 2.5

They said that the chemo takes a whack at these cells, so you needed a pretty good number to be available for the trial.

George

[kheanu]

Hey folk, are there any news regarding this thread?