Selzentry (maraviroc) Likely To Soon Be Approved For First-Line Use

[Inchlingblue]

Pfizer HIV drug seems safe for new use-FDA staff

Tue Oct 6, 2009 9:53am  

* FDA document says Selzentry "well tolerated"

* FDA advisory panel to meet Thursday

* Company: more HIV drugs needed (Adds company comment, background on drug, byline)

By Susan Heavey

WASHINGTON, Oct 6 (Reuters) - Pfizer Inc's (PFE.N) HIV drug Selzentry appears to be safe for wider use in certain patients with the disease who have not yet begun taking any medications, U.S. Food and Drug Administration staff said in a document released on Tuesday.

The drug, also know by its generic name maraviroc, is already FDA-approved in combination with similar drugs for HIV patients who have tried other antiretroviral medications.

Pfizer is seeking FDA permission to market Selzentry for HIV patients who have a certain variation of HIV-1 -- one of two strains of the human immunodeficiency virus that causes AIDS -- who have not yet tried any medications. It would be taken with other antiretroviral drugs.

An FDA staff document said the drug appeared to be "well tolerated" in patients in a company-funded study. A review of an FDA database also found no new reported safety concerns in HIV patients who have already been taking the drug.

The agency's analysis of how well Selzentry worked also backed the company's findings that the drug reduced the virus in patients taking it, compared with those given efavirenz, the FDA said. Efavirenz is marketed as Sustiva by Bristol-Myers Squibb Co (BMY.N).

The FDA released the document ahead of a public meeting on Thursday when the agency will ask its outside advisers for a recommendation on whether to approve the drug's wider use. It usually follows their advice.

Pfizer said its trial showed the drug is safe and effective. As many HIV medications as possible are needed on the U.S. market now that the disease has transformed into more of a chronic condition, it added.

"Although there are other good treatment options available for patients, more are needed to meet the needs of a heterogeneous patient population," the drugmaker said in a separate document also released on Tuesday.

If approved, Selzentry would only be indicated for adults with chemokine (c-c motif) receptor 5, or CCR5, tropic HIV-1, the FDA said. The drug aims to prevent the virus strain from entering the body's cells, it added.

LINK:

http://www.reuters.com/article/BROKER/idUSN0641655420091006

[elf]

I don't know. I've read HIV-1 tropism can change during the course of infection...

[Inchlingblue]

I don't know. I've read HIV-1 tropism can change during the course of infection...

Yes, but I'm pretty sure that happens in the absence of any meds.

[veritas]

elf and Inch,

I believe one is either infected with R5 or X4 or Both. I don't believe the virus can mutate itself to use either one or the other. The dominant strain seems to be the R5. However, if you are infected with dual tropic virus, then the X4 will become the dominant strain and for some reason (I don't know why), X4 allows for a quicker progression to Aids. The trophism test can measure which virus you have, however, you need a viral load of about 1000 for the test to be effective and the test will be 100% effective as long as your sample has at least 10% X4. It becomes less effective the lower %tage of X4 included so it could seem as though the virus "mutates to X4" but in reality X4 was just there and became dominant. All quite confusing !
If anyone has newer info please post.

http://www.aidsinfonet.org/fact_sheets/view/129?print=true

v

[Miss Philicia]

I must say that considering all of the LTS'ers I personally know I can only think of one person that went on selzentry when it was first approved.  I think doctors will tend to gravitate towards Isentress if I'm to go by what was done by most doctors when both drugs were approved for treatment-experienced patients two years ago.

[Inchlingblue]

What I have always read is that, as a rule, in the absence of any ARVs, early on during infection R5 virus is predominant and then at a certain point X4 can emerge.  

If someone is tested and is found to have R5 and then goes on a regimen that includes maraviroc and two other meds that their virus is sensitive to, and is able to maintain an undetectable status, there should be no reason for X4 to "emerge" from whatever residual viremia may exist. That's pretty much what Dr. Gallant says below.

Here's a Q&A from thebody.com:

Tropism test
Feb 28, 2009

Dear Drs.,

I am positive now for almost a year (but not yet on meds). In the past year I have learned a great deal about the disease thanks to fantastic websites like yours! I just had word from my Dr about my latest blood work and it does not look so rosy anymore. CD4 was 410 and CD4/CD8 was 27%. (three monts earlier that was 650 and 30%; six months before that it was 800 CD4). I asked my doctor if perhaps it was useful to do a tropism test (because I am worried about this rapid decline of CD4s and I read on this side that it may be due to the Virus changing receptors). He agreed to do such test (reluctantly, becuase here in The Netherlands it is not standard;; my blood samples are flown to the US to do the test). My question is: if the test proves to be good (meaning my virus still only uses the CCR5 receptor), should I then, as a first line treatment, use meds that only work at that stage (like Maraviroc) as at a later stage (when the virus evolves and uses the other receptor as well)these options might be lost for me.

Kind regards from Thom, Amsterdam, Thye Netherlands



Response from Dr. McGowan

Thom: You ask a very insightful question. It is true that early on in the course of HIV infection, virus that uses the CCR5 co-receptor predominates in most people and that later on that CXCR4-using virus may emerge. Since CCR5 antagonists (like Maraviroc) are only useful when CXCR4 using virus is not present, it would seem appropriate to use these drugs fairly early in the treatment of HIV. However, current guidelines do not recommend the use of maravoric as a "first-line" regimen. There has been one study (Merit-ES) that showed equal efficacy between an efavirenz based regimen and a maraviroc based regimen, however, since there are first line alternatives to efavirenz that do not require a tropism test, the place of maraviroc for initial treatment remains in question. Thanks, Joe


LINK:

http://www.thebody.com/Forums/AIDS/Meds/Archive/FirstLine/Q199705.html

Here's a Q&A from Dr. Gallant:

Maraviroc and Resistance

Joel E. Gallant, M.D., M.P.H. Joel E. Gallant, M.D., M.P.H.
08-03-2008
Posted on Jul 10, 2008

QUESTION:

I will be changing my med combo this month and I am considering maraviroc if a "positive" tropism result is returned. My questions: How accurate is the tropism test? How does maraviroc resistance develop? If I have R5 virus, does it mutate to R4 in the presence of the drug? And if it does, would that mutation increase the risk of resistance mutations developing for the other new drugs in my combo? I am worried about this because I will be using the newest retrovirals (because of past resistance) and want to make the best choices, reserving at least a couple of active drugs. Thanks!

On Aug 3, 2008 Joel E. Gallant, M.D., M.P.H. Joel E. Gallant, M.D., M.P.H. replied:

The tropism (Trofile) test just became much more accurate this month, when the old test was replaced by the Trofile ES (enhanced sensitivity) assay. If it shows R5 tropic virus, then that's probably what you have, and maraviroc (Selzentry) should be effective.

There are 3 ways you can fail therapy with maraviroc: (1) by not taking it right, (2) by selecting pre-existing dual/mixed or X4-tropic virus, or (3) by developing maraviroc-resistant R5 virus. #1 is up to you. The risk of #2 is minimized by getting the tropism assay first and using the drug only if you have pure R5 virus. The risk of #3 is minimized by making sure you're using maraviroc with at least one and preferably 2 fully active drugs.

LINK:

http://www.hopkins-hivguide.org/q_a/patient/antiretroviral_therapy/antiretroviral_agents/ccr5_inhibitors/maraviroc__tropism__and_resistance.html?contentInstanceId=447395

[veritas]

Inch,

The virus is still able to be suppressed with "working" ART meds regardless of ccr5 or x4 virus. I guess the point I was trying to make is that a virion that is using R5 entry, that same virion cannot mutate itself to use X4. The X4 entry must come from a different virion and in turn can't use R5. R4 won't emerge because the virus isn't replicating as quickly when undetectable which makes sense since very few mutations develop when virus is undetectable. A strong regimen will keep the virus at ud level and what Dr. Gallant says is true because at ud status it really doesn't matter if you have X4 or R5 unless you are taking Selzentry. If you take Selzentry with dual tropic virus, the X4 will eventually predominate and your left with a regimen that is not strong enough to maintain ud vl potentially.

v

[Inchlingblue]

V: The thing is, what the other doctor says, above (from thebody.com) is something I have read elsewhere:

It is true that early on in the course of HIV infection, virus that uses the CCR5 co-receptor predominates in most people and that later on that CXCR4-using virus may emerge.

I believe it happens in the absence of meds, not when someone has a suppressed viral load with an effective ARV regimen. If someone is infected long enough and is not on any meds, they can start out with only R5-tropic virus and eventually they also get X4. I have not researched it too thoroughly in order to know how it happens, but it does happen. I always assumed it was mutation because I can't think of any other way it could happen.

[veritas]

Inch,

I understand what your saying. I thought the virus could change to X4 while being "born" in the resting state. Maybe someone can respond with the explanation.

v

[Inchlingblue]

In Light of Today's FDA Advisory Committee Approval--and Likely Market Expansion for Selzentry--AHF Urges Drug Giant to Lower Price Immediately

Current Selzentry Cost: Average Wholesale Price of $13,767 per-patient per-year

LOS ANGELES - Responding to today's news that the Food and Drug Administration (FDA) Antiviral Advisory Committee has approved Pfizer Inc.'s AIDS therapy, Selzentry (maraviroc), for use in therapy-naive patients, AIDS Healthcare Foundation (AHF) strongly criticized Pfizer for its current pricing of the drug at an Average Wholesale Price (AWP) of $13,767 per-patient per-year--which, if this price remains when use is expanded, would make it the most expensive first-line AIDS drug on the market.


Selzentry was originally approved by the FDA in August 2007 as a salvage drug--utilized in patients who do not respond favorably, or have developed resistance, to other AIDS drugs--and priced at $12,528 per-patient per-year. In just two years, the price for Selzentry--which must be taken with at least two other AIDS drugs--has increased by nearly 10%. Pfizer reported $46 million in sales for Selzentry in 2008, according to the Associated Press.


"In this time of growing national concern over ballooning healthcare costs, it is simply criminal for Pfizer to continue to price Selzentry at the salvage therapy rate, especially now that the market for the drug will be vastly expanded by the FDA's likely upcoming approval of the drug for first-line use," said Michael Weinstein, President of AIDS Healthcare Foundation. "Government programs such as AIDS Drug Assistance Programs and Medicaid are likely to be the largest purchaser of Selzentry. Where exactly does the burden of Pfizer's price-gouging fall? On the taxpayers. And for what reason? So that the largest pharmaceutical company in the world, Pfizer, can make just a little more profit--while bankrupting government programs already hurting for funds as they work to ensure that Americans living with HIV/AIDS receive the lifesaving treatment they need."


Continued...

LINK:

http://webboard.aegis.org/WB/threadview.aspx?threadid=2057&fid=15&boardid=2

[Inchlingblue]

Inch,

I understand what your saying. I thought the virus could change to X4 while being "born" in the resting state. Maybe someone can respond with the explanation.

v

I asked Dr. Gallant and he seems to be of the opinion that if it emerges it would be in the absence of medication, which does make logical sense. If this is accurate it would mean that people who have HIV with R5 tropism and stay off ARV meds for a long time are more likely to develop dual-tropic virus than someone who has HIV with R5 and starts meds earlier.

How Does X4-tropic virus emerge?

Joel E. Gallant, M.D., M.P.H.

Posted on Oct 17, 2009

I was reading a Q & A on Thebody.com and came across this statement from one of the doctors (something I"ve also read elsewhere): "It is true that early on in the course of HIV infection, virus that uses the CCR5 co-receptor predominates in most people and that later on that CXCR4-using virus may emerge."  My question is: do we know how this happens? Is it in the absence of meds? I would think that if someone is on a successful ARV regimen and undetectable then no new X4 virus will emerge. When it does happen that X4 emerges in someone who had previously had only R5, is it due to mutation? Thanks, Doc. You"re the cat"s pajamas.

On Oct 26, 2009 Joel E. Gallant, M.D., M.P.H. replied:

The assumption is that if you had an undetectable viral load on antiretroviral therapy, there were be no change in tropism because the lack of viral replication and mutation: You'd maintain the same virus that you had when you started. At least that's what makes sense to me, but I'm not sure whether it has been proven.

LINK:

http://www.hopkins-hivguide.org/q_a/patient/recent_questions/how_does_x4-tropic_virus_emerge_.html?contentInstanceId=506133&siteId=7151