Replies to post #99206 on Biotech Values

[DewDiligence]

Re: Feuerstein’s take on TMC278’s Achilles heel

Feuerstein is a cynical guy, so it’s out of character for him to dance around the virologic failure issue, as he did in the write-up you posted. Ordinarily, one would expect Feuerstein to catch the kind of spin GILD promulgated on the 2Q10 CC and label it as such (as I did in #msg-52471333).

On the other hand, Feuerstein has been recommending GILD to his readers for the past year or so, and it’s been a very bad pick. Behind closed doors, Feuerstein probably acknowledges that GILD is spinning, but he can’t bring himself to publicly diss his own pick.

[DewDiligence]

JNJ Reports Phase-3 Data for TMC278 vs Sustiva

[These are the data JNJ presented at the International AIDS Conference in Vienna last week. TMC278 is JNJ’s second-generation non-nuke that is angling for a place in future HIV all-in-one qD pills as a replacement for the use of BMY’s Sustiva in GILD’s blockbuster, Atripla. (The “Sustiva replacement” market is also being targeted by IDIX’s IDX899, which has been licensed to GSK.)

The two phase-3 trials reported here were nearly identical; the only distinction was the 2-drug nucleoside backbone that patients used in addition to TMC278 or Sustiva: in one trial it was Truvada and in the other trial it was “physician’s choice.”

Although TMC278 met the primary endpoint of showing non-inferior antiviral efficacy to Sustiva at 48 weeks, TMC278 had almost twice as high a rate of virologic failure as Sustiva (9% vs 4.8%), which will presumably be a matter of some concern for the FDA advisory panel and the FDA reviewers of the TMC278 NDA, which was submitted on 7/26/10 (#msg-52656751).

Inasmuch as JNJ and GILD have a partnership to combine TMC278 and Truvada, there is a lot at stake here for several companies in the HIV arena.]

http://finance.yahoo.com/news/TMC278-Pivotal-Phase-3-prnews-4190757002.html?x=0&.v=1

›July 22, 2010, 8:30 am EDT

- Data on investigational, once-daily TMC278, the third antiretroviral compound developed by Tibotec Pharmaceuticals, presented at International AIDS

VIENNA, July 22 /PRNewswire/ -- Tibotec Pharmaceuticals announced today results from two pivotal Phase 3, double-blind, randomized clinical trials comparing the efficacy, safety and tolerability of its investigational non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC278 (rilpivirine) versus efavirenz (EFV), each administered once daily with a nucleoside/nucleotide background regimen in treatment-naive, HIV-1-infected adults. These global trials, known as ECHO and THRIVE, reached their primary objective, which was to demonstrate non-inferiority of TMC278 vs. EFV in the proportion of patients achieving an undetectable viral load (less than 50 copies/mL) at week 48 (with a maximum allowable difference of 12 percent). A pooled analysis of ECHO and THRIVE was presented today at the XVIII International AIDS Conference in Vienna, Austria.

ECHO and THRIVE pooled results showed that 84.3 percent of patients (n=686) in the TMC278 group reached an undetectable viral load, compared with 82.3 percent of patients (n=682) in the EFV group. The difference between the treatment groups was not significant [i.e. the prespecified criterion for non-inferiority was met]. Patients received TMC278 (25 mg) or EFV (600 mg), each administered once daily in combination with a nucleoside/nucleotide background regimen. The virologic failure rate was 9 percent in the TMC278 group and 4.8 percent in the EFV group. [Virologic failure, defined as either an inadequate initial response to therapy or a viral breakthrough during treatment, is a very bad thing for an HIV drug, and hence this metric will presumably be a matter of concern by the FDA advisory panel and the FDA reviewers of the TMC278 NDA.]

TMC278 is an investigational product, and the safety and efficacy has not yet been established. Tibotec plans to submit these results to the U.S. Food and Drug Administration (FDA) to support approval of TMC278 for use in treatment-naive adult patients. [The NDA submission was made on 7/26/10 (#msg-52656751.]

"I'm very excited by the findings of these Phase 3 results for TMC278," said Calvin J. Cohen, M.D., M.Sc., lead clinical investigator and Research Director at Community Research Initiative of New England and Harvard Vanguard Medical Associates. "These studies provide valuable information on the safety and tolerability of TMC278 and, specifically, its metabolic and CNS side effect profiles."

Adverse events (AEs) leading to discontinuation in the TMC278 group were 3.4 percent compared to 7.6 percent in the EFV group, and Grade 2–4 AEs at least possibly related to treatment were 15.9 percent in the TMC278 group versus 31.1 percent in the EFV group. Grade 2-4 AEs of interest by organ class reported among patients in the TMC278 group versus the EFV group were psychiatric (14.9 percent vs. 22.7 percent), neurological (17.1 percent vs. 37.8 percent) and rash-all types (3.1 percent vs. 13.6 percent). Grade 3/4 lipid abnormalities were also reported among patients in the TMC278 group versus the EFV group for increases in total cholesterol (0.1 percent vs. 2.5 percent), LDL-cholesterol (0.7 percent vs. 4.1 percent) and triglycerides (0.3 percent vs. 2.2 percent).

About ECHO and THRIVE

ECHO (TMC278-TiDP6-C209) and THRIVE (TMC278-TiDP6-C215) are pivotal Phase 3, double-blind, randomized studies that evaluated the efficacy, safety and tolerability of TMC278 in 1,368 treatment-naive, HIV-1-infected adults. ECHO (Efficacy Comparison in treatment-naive HIV-infected subjects Of TMC278 and EFV) evaluated TMC278 (25 mg) once daily, versus EFV (600 mg) once daily, combined with a fixed background regimen consisting of emtricitabine + tenofovir disoproxil fumarate. THRIVE (TMC278 against HIV, in a once daily RegImen Versus Efavirenz) evaluated TMC278 (25 mg) once daily versus EFV (600 mg) once daily, combined with an investigator-selected background regimen consisting of two N[t]RTIs (abacavir + lamivudine or emtricitabine + tenofovir disoproxil fumarate or zidovudine + lamivudine).

Each study is being conducted at more than 100 sites, in more than 20 countries. The studies will last for a total of 104 weeks, which includes a four-week screening period, a 96-week treatment period and a four-week follow-up period.

Tibotec Pharmaceuticals plans to file the 48-week findings from ECHO and THRIVE with the FDA when seeking marketing authorization for TMC278. Pending approval, Tibotec Therapeutics will commercialize TMC278 in the United States. Tibotec has also entered into a license and collaboration agreement with Gilead Sciences, Inc. for the development and commercialization of a once-daily, fixed-dose combination of TMC278 and Gilead's Truvada (emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg).‹

[DewDiligence]

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

[Added phase-3 data on TMC278, including discussion
of the possible Achilles heel re virologic failure; updated
phase-2b timeline for IDX899.]


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.)

--
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, a qD NNRTI from JNJ that is similar to JNJ’s Intelence but has better pharmacokinetics. (Intelence is dosed BID; both drugs have to be taken with food.) JNJ recently 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).

Until the disclosure of the relatively high rate of virologic failure, I had considered TMC278 the clear frontrunner in the ranking in this post ever since JNJ and GILD inked a collaboration to combine TMC278 and Truvada into a single qD pill that is commonly referred to as ‘Btripla’ (#msg-39660789, #msg-52480598). 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 has a chance to reach the market much sooner than Quad or any other competitive option discussed in this post. GILD has stated that it will submit an NDA for Btripla in 4Q10.

With the recent revelation of TMC278’s Achilles heel (above), I’ve downgraded the TMC278/Btripla program to some degree; however, I think it’s still entitled to be considered the frontrunner in this post by dint of its timing advantage.


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. GSK has stated its intention to start two phase-2b trials in late 2010 testing IDX899 vs Sustiva in the first-line setting and IDX899 vs Intelence in the second-line setting; in all cases, the tested drugs will be added to a Truvada backbone. (GSK is also planning a phase-2b nuke-sparing trial in which IDX899 will be added to GSK’s integrase inhibitor, S/GSK1349572, but this trial will not start until 2011 [#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 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.


4. 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.

[DewDiligence]

FDA approves JNJ’s Edurant (TMC278) in treatment-naïve HIV:

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm256087.htm

What makes this approval especially consequential is that TMC278 is a component of GILD’s ‘Btripa’ combination pill that will provide an alternative to the hugely successful Atripla with better economics for GILD (#msg-39660789, #msg-62382001). The PDUFA date for Btripla is 8/11/11.

Today’s Edurant approval is for the first-line setting only, but there is no reason to think that Btripla and standalone Edurant won’t be approved for the second-line setting also.

BMY, the maker of Sustiva, is the loser in all this.

[DewDiligence]

GILD/JNJ—According to Thomas Wei of Jefferies, total US prescriptions for Edurant are only 200 (!), two months into the commercial launch. On GILD’s 2Q11 CC, Kevin Young (SVP, Commercial Ops) acknowledged that standalone Edurant will never garner significant sales; however, Young said GILD remains strongly committed to the launch of the ‘Btripla’ (Edurant + Truvada) combination pill, pending FDA approval. (The PDUFA date is 8/11/11.)