Biotech Values

[DewDiligence]

The New Battle Lines in HIV (GILD/JNJ/IDIX/GSK)

[Updates:
TMC278 phase-3 results reported on JNJ’s 1Q10 CC (#msg-49224079);
HIV market data from GILD’s 1Q10 CC (#msg-49275972);
major rewrite of IDX899 section to include GSK’s “nuke-sparing” trial.]


GILD’s Truvada franchise is so firmly established as the backbone of therapy in the early lines of treatment that there is little to no chance of anything replacing it in the near future (#msg-49275972, #msg-26915314). Moreover, Truvada and BMY’s Sustiva have been combined into a single pill, Atripla, that is taken once daily and sets a standard for convenience (and hence compliance) that a twice-daily regimen cannot hope to match. Thus, from a business standpoint, the question is to ask is: Which qD drugs, if any, will be able to supersede Sustiva as the favored “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 market has been moving away from the use of PI’s in early lines of therapy because their resistance profile and tolerability leave room for improvement. Reyataz from BMY and Kaletra from ABT, the two biggest-selling PI’s, have been steadily losing market share, even as they continue top grow modestly 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, a qD NNRTI from JNJ that recently completed two successful phase-3 trials in which TMC278 was found to be non-inferior to Sustiva (#msg-49224079, #msg-30789106, #msg-31354706). TMC278 is similar to JNJ’s Intelence, an NNRTI launched in 2008 that has the drawback of requiring BID dosing with food.

TMC278 catapulted into first place in the ranking in this post when JNJ and GILD inked a collaboration to combine it with Truvada into a single qD pill (#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), TMC-278 merits the top spot in the ranking in this post because it has a chance to reach the market much sooner than Quad or any other competitive option.


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). 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. 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 will start two phase-2b trials in 2Q10 testing IDX899 against Sustiva (first-line setting) or Intelence (second-line setting) when each drug is added to Truvada. What’s especially exciting, IMO, is that GSK is planning a separate phase-2b nuke-sparing trial in which IDX899 will be added to GSK’s integrase inhibitor, S/GSK1349572: #msg-48913630, #msg-48915175.

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 in 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.


*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.