Gilead's HIV Drug: FDA Returns to Sender

[Miss Philicia]

source

U.S. regulators turned back an approval application for a new HIV drug from Gilead Sciences(GILD_) due to manufacturing issues, the company said Tuesday.

The "refuse to file" letter for Gilead's B-tripla means at least a two-month delay in the drug's approval. Gilead submitted B-tripla for approval on Nov. 23 and was hoping for approval by the end of May. Now, the company plans to resubmit the drug by the end of the first quarter, which suggests approval won't come until the end of September.

Gilead shares were down 3% to $37 in after-hours trading. The stock closed Tuesday at $38.16.

B-tripla combines Gilead's current HIV drug Truvada with Johnson & Johnson's(JNJ_) HIV drug TMC278 into a single pill that HIV patients take once daily. B-tripla is one of two new HIV treatments that Gilead hopes to launch in the next two years to maintain its dominant market share in the HIV treatment market.

Analysts were expecting about $60 million in B-tripla sales in 2011, according to ISI Group biotech analyst Mark Schoenebaum. "We believe a quarter or two of missing sales will have limited impact on financials," he wrote in an email to clients following Gilead's disclosure.

[Hellraiser]

Are they really going to call it B-tripla?  They obviously have straight men working on the marketing for this campaign if so.

[Miss Philicia]

It's the first I've heard of the word "B-tripla" and I even went to a Gilead presentation a few months ago.  Hard to tell if that's just what they're referring to it now for this article or if that's what they've settled on for marketing.

There will be another Gilead all-in-one pill sometime after this is approved.  I think it's still in Phase 3.

[surf18]

What were the benefits of these new ones over the existing pills?

[Miss Philicia]

What were the benefits of these new ones over the existing pills?

A one-a-day pill without the potential CNS issues of sustiva-based Atripla, that's easy.  Central nervous system effects—such as dizziness, somnolence, and vertigo—were significantly more common in the Sustiva group (53%) compared to the rilpivirine groups (33%) Rash was also less likely to occur among those taking any dose of rilpivirine (8%) compared to those receiving Sustiva (19%)

http://www.aidsmeds.com/archive/TMC-278_1619.shtml

Also a one-a-day pill for those patients with resistance issues to sustiva. edit: actually according to that link above it's not yet known if you're resistant to sustiva you can take this medication, either that or the link hasn't been updated.  I can't imagine they don't know this yet if they're doing FDA approval but maybe they've only had treatment naive patients in studies thus far.

IIRC the other Gilead all-in-one will be based on the new integrase inhibitor elvitegravir, and bundled with a new booster GS9350 plus, of course, Truvada.

Also keep in mind that Atripla's Sustiva was actually made by another company so Gilead doesn't get all of the money, and with these other two medications it's all theirs.  So if you own Gilead stock you'll be doing quite well once these come on line, as I suspect most people will use one or the other.  But bottom line the side effect potential is greatly reduced for naive patients.

[surf18]

Thank you!
Now other than convience are these potential one a days a better option than say issentrss/truvada?
Or selzentry/truvada?
One a day would be great but my doc and I knowing me knew Atripla was not for me.
Did I read it write that one is less likely to have sides on your very first treatment?And one last question none of these two new ones are the quad pill?

[Miss Philicia]

Yes, the last one I listed is what is also called the "quad" pill, meaning four drugs in one: elvitegravir, GS9350 which will really be called cobicistat, and truvada which is really two meds.

If you are on Isentress/Truvada and it's working then there's no reason to switch unless you want a once daily pill.

The reason I say it's for naive patients is because once daily dosing is mostly aimed at them to make the transition to pill taking easier.

If you're asking if something magically increases cd4 counts no, that's never how HIV meds work anyway. They just lower viral load, then it's up to each patients individual immune system to rebuild itself -- some people simply rebuild better than others.

Or are you looking for some other answer when you are asking if these "work better"?

[surf18]

thanks again!
im on selzentry/truvada
its working ok. ud and cd raised up from 229 to 407 since august.
but im always curious about the one a days.
work better i guess i mean do the same thing such as lower viral load, just less toxic less side effects

[Tim Horn]

I think B-tripla is just a nickname. The brand name Atripla was a closely guarded secret until after its FDA approval and I imagine the new triple-drug fixed-dose-combination's brand name will remain a secret until later this year.

We provided a bit more detail regarding the FDA snag here:

http://www.aidsmeds.com/articles/hiv_rilpivirine_tmc278_1667_19800.shtml

It has to do with an emtricitabine impurity found in the fixed-dose combination tablet; the agency has questions as to how Gilead has gone about determining that it is harmless.

While there's no doubt that rilpivirine has a more favorable central nervous system side effect profile that Sustiva, it's clear that the FDA are going to scrutinize efficacy claims. Some concerns involving first-time treatment takers emerged this past summer at the International AIDS Conference in Vienna (http://www.aidsmeds.com/articles/hiv_rilpivirine_tmc278_2506_18814.shtml):

Cohen reported that rilpivirine efficacy was statistically similar in both studies compared with Sustiva. In an analysis where the two studies were pooled together, 84.3 percent of those taking rilpivirine had a viral load of less than 50 copies at week 48 compared with 82.3 percent of those taking Sustiva. When Cohen and his colleagues analyzed the studies separately, rilpivirine performed a little better in the THRIVE study than in ECHO, but both studies met the primary endpoint and rilpivirine was ultimately determined to be not inferior to Sustiva. These results held up even in people who started the study with viral loads over 100,000 copies.

Twice as many people on rilpivirine did fail in the analysis due to either an inability to get their virus to undetectable levels or because they lost control of the virus at some point later in the study, dubbed virologic failures. Based on the analysis presented by Cohen, this appeared to be due to a higher virologic failure rate among those receiving rilpivirine-based therapy in the THRIVE study (11 versus 4.4 percent); virologic failure rates in the ECHO study were better balanced.

In people who had a virologic failure, 63 percent of those in the rilpivirine group and 54 percent of those in the Sustiva group developed NNRTI mutations. More than twice as many people taking rilpivirine developed HIV mutations confering resistance to the nucleosides—notably the M184 mutation known to decrease sensitivity to lamivudine and emtricitabine—compared with those receiving Sustiva (68 versus 32 percent, respectively).

Also of potential concern, 90 percent of the people on rilpivirine who had an emergence of NNRTI-resistant strains had cross-resistance to Intelence (etravirine), meaning that they might not be able to use this drug in later lines of therapy.  The most frequent NNRTI mutation in the rilpivirine group was E138K (which confers some degree of resistance to Intelence), whereas the most frequent NNRTI mutation in the Sustiva group was K103N (a mutation that can be present without seriously jeopardizing a patient's chance of responding to Intelence).

A few explanations for these findings were reported in September:

http://www.poz.com/articles/hiv_rilpivirine_tmc278_761_19110.shtml


As for rilpivirine's efficacy against Sustiva-resistant strains of HIV, addressing this question isn't high of Tibotec's (or Gilead's) list -- rilpivirine is likely going to be for treatment first-timers or NNRTI-sensitive individuals only. It turns out that the dose of the drug needed to suppress HIV harboring NNRTI mutations (such as those occurring during Sustiva or Viramune therapy) likely needs to be higher than the 25mg dose studied in treatment-naive patients -- there is some degree of cross-resistance between rilpivirine and first-generation NNRTIs. The problem is,at doses above 25mg, rilpivirine was associated with QT-prolongation: an abnormal heart rhythm.

[richie]

As for rilpivirine's efficacy against Sustiva-resistant strains of HIV, addressing this question isn't high of Tibotec's (or Gilead's) list -- rilpivirine is likely going to be for treatment first-timers or NNRTI-sensitive individuals only. It turns out that the dose of the drug needed to suppress HIV harboring NNRTI mutations (such as those occurring during Sustiva or Viramune therapy) likely needs to be higher than the 25mg dose studied in treatment-naive patients -- there is some degree of cross-resistance between rilpivirine and first-generation NNRTIs. The problem is,at doses above 25mg, rilpivirine was associated with QT-prolongation: an abnormal heart rhythm.

Tim --

Thank you thank you thank you.  I've been discussing this possible regimen with my Dr., and there hasn't been any good/definitive explanation that I could find.  You just boiled exactly what I needed into that one paragraph.  Much appreciated.  This why I love Aidsmeds.com

best,

richie

[flip408]

Hi all,

I will screen for the phase III trial of the Rilpivirine/Truvada combo.  To Trial or not to Trial.

I have enjoyed consistent improvement on my current of Reyataz/Norvir and Epzicom, always <50 after 1 month of drug from 11/06.  CD4 increase of around 115 per year. My current MD has stated "if it ain't broke...., but it is ultimately my decision".

Trial Pros  This would be my 4Th trial, I feel its my way to participate in the fight against aids. 

Free Drug, Study will provide med for 48 weeks and until FDA approval.  On FDA approval it will be covered under ADAP.  Current budget concerns in California have made me nervous regarding my eligibility and its current existence.

There is a certain communal feeling from participating in a trial, almost a higher level of care.

I understand I could always "go back" to the Reyataz/Norvir Epzicom Combo, but this one could be better, 1 pill, cutting edge technology?  With the new combo, I could get rid of the elevated bilirubin.

Trial Con's:  If it ain't broke...., Do most people change regimens due to side effects or virologic failure?  Should I change for tertiary reasons?  The R N E combo has served my well.

Side effects,  I didn't not never had any side effects from meds.  Could the study drug ?

Welcome your input.