Biotech Values

[DewDiligence]

The New Battle Lines in HIV

[Updates:
new paragraph for GSK’s ‘572 integrase inhibitor;
bearish musings re GILD’s phase-3b trials of Btripla.]


Background: GILD’s Truvada franchise is so firmly established as the backbone of therapy in the early lines of treatment (where the overwhelming majority of HIV drug sales occur), that it will be hard for a regimen not based on Truvada to capture a significant portion of this market (#msg-26915314). New HIV drugs have essentially two ways to become successful: a) by being the third drug in a Truvada-based cocktail—i.e. a replacement for Sustiva; or b) by being a component of a nuke-sparing regimen that dispenses with Truvada and includes two or three drugs from other classes.

Of the two avenues to commercial success described above, programs using new Truvada-based regimens are much further advanced than those using nuke-sparing regimens, and hence Truvada-based regimens are the focus of the rest of this post. (See #msg-49282477, #msg-48915175, and #msg-52406597 for additional reading on nuke-sparing regimens.)

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Atripla and Truvada are dosed once daily, which has made qD dosing a standard for convenience (and compliance) that a twice-daily HIV regimen cannot hope to match. Thus, from a business standpoint, the question is to ask is: Which qD drugs will be able to supersede Sustiva as the third drug in Truvada-based regimens?

Inasmuch as Truvada consists of two nucleoside reverse-transcriptase inhibitors—Viread and Emtriva—the third drug in a Truvada-based cocktail will clearly come from a different class. The main options are non-nucleoside reverse-transcriptase inhibitors (NNRTI’s), protease inhibitors (PI’s) and integrase inhibitors (II’s).

However, the HIV market has been gradually moving away from the use of PI’s in early lines of therapy. Whether this is because of side effects, drug resistance, or interactions with non-HIV drugs is debatable, but the sales numbers are clear enough: BMY’s Reyataz and ABT’s Kaletra, the two biggest-selling PI’s, have been steadily losing market share even as they continue to grow slightly in dollar sales.

NNRTI’s and II’s that can be dosed qD are where the action is likely to be. The leading candidates to gain traction (IMHO) are as follows.


1. TMC278/Btripla. TMC278 is a qD NNRTI from JNJ that is similar to JNJ’s Intelence with better pharmacokinetics. (Intelence is dosed BID; both drugs have to be taken with food.) JNJ completed two phase-3 studies in which TMC278 was found to be non-inferior to Sustiva (#msg-52718327). Although these studies were nominally successful insofar as the primary non-inferiority endpoint was met, a possible Achilles heel was exposed in that TMC278 had almost twice as large a rate of virologic failure as Sustiva at 48 weeks (#msg-52471333, #msg-52480598).

What makes TMC278 especially noteworthy is that JNJ and GILD inked a 2009 collaboration to combine TMC278 and Truvada into a single qD pill that is commonly referred to as ‘Btripla’ (#msg-39660789). Although GILD has an economic incentive to develop an all-in-one pill consisting entirely of GILD’s own drugs (see paragraph #2 below), Btripla already has a submitted NDA and thus has a chance to reach the market much sooner than Quad or any other competitive option discussed in this post.

Until the disclosure of TMC278’s high rate of virologic failure, I had considered Btripla the clear frontrunner in the ranking in this post by dint of its timing lead. Now, I still consider Btripla the frontrunner among the options in this post, but the ranking is no longer clear-cut. Additional skepticism is warranted based on the disclosure on GILD’s 3Q100 that GILD feels the need to run two post-marketing studies to refine the addressable market for Btripla (#msg-55725398, #msg-55756102).


2. Quad/Elvitegravir from GILD. Elvitegravir is an II similar to MRK’s Isentress, which is doing about $500M in annualized sales; however, Elvitegravir has the crucial advantage of being dosed qD with help from a PK-boosting agent.*

Quad is the name for the 4-drug combo that includes Elvitegravir, the two drugs in Truvada, and GILD’s proprietary PK-booster called Cobicistat (f/k/a GS9350). Quad started phase-3 in Apr 2010 (#msg-48883214); in phase-2, Quad was non-inferior to Atripla at 24 weeks (#msg-45203412, #msg-46731576) and at 48 weeks (#msg-54357061). Standalone Elvitegravir is also in phase-3, where it is being tested head-to-head vs Isentress (#msg-30900183). Clearly, GILD has an economic incentive to prefer Quad to the TMC-278 + Truvada combination GILD is developing jointly with JNJ; however, I rank Quad second in this post because the TMC-278 + Truvada combination has a chance to reach the market considerably sooner than Quad.


3. S/GSK1349572 (‘572), a qD integrase inhibitor from GSK that does not require PK boosting. Two phase-3 non-inferiority trials are testing ‘572 against Isentress, one in treatment-naïve patients and one in integrase-naïve patients, which is effectively the second-line setting (#msg-55878096).


4. IDX899, a qD NNRTI licensed by GSK from IDIX (and now owned by the GSK/PFE joint venture called ViiV Healthcare): #msg-43254006, #msg-37080917, #msg-37087221. IDX899 has entered phase-2b with a study called SONNET that tests IDX899+Prezista+Isentress vs Intelence+Prezista+Isentress—i.e. a trial without any nukes—in the second-line setting. A phase-2b trial testing IDX899+Truvada vs Atripla is expected to start in early 2011.

In a phase-1b/2 monotherapy study, IDX899 showed antiviral efficacy at extremely low doses (#msg-31925486, #msg-31944395), which fosters its ability to be formulated into an all-in-one pill with a small form factor.

IDX899 has a stronger barrier to resistance than Sustiva (#msg-35431633) and it lacks cross-resistance to Sustiva, which preserves the option for patients to use Sustiva in a subsequent line of therapy.


5. Lifecycle management programs to extend patent protection on Truvada/Atripla beyond 2017.† Chimerix has embarked on such a program (#msg-50161857) and there are probably others.


*MRK is testing Isentress with qD dosing in a phase-3 trial and could submit an sNDA in 2011; Isentress evidently does not benefit from boosting with ritonavir.

†See discussion in #msg-34894135.