Replies to post #94570 on Biotech Values

[bladerunner1717]

Dew,

Why is a "nuke-sparing" regimen significant and what advantages might it offer over a "non-nuke sparing" regimen?


Bladerunner

[DewDiligence]

Chimerix Starts Phase-1 Trial of Enhanced Viread

[Given the colossal success of Truvada/Atripla and the expiation of the controlling patents on Viread in 2017, there must be several companies working on “lifecycle management” for the Truvada/Atripla franchise independently of GILD. Chimerix, a private biotech in North Carolina, is one such company.]

http://finance.yahoo.com/news/Chimerix-Initiates-Phase-1-prnews-2850120002.html?x=0&.v=1

›May 13, 2010, 8:30 am EDT

RESEARCH TRIANGLE PARK, N.C., May 13 /PRNewswire/ -- Chimerix, Inc., a biotechnology company developing orally-available antiviral therapeutics, today announced the commencement of a first-in-human study of CMX157, a novel lipid conjugate of the nucleotide tenofovir with in vitro activity against both tenofovir-sensitive and tenofovir-resistant human immunodeficiency virus (HIV). CMX157 has the potential to increase efficacy and decrease toxicity as compared to tenofovir, and may enable the creation of new 'one pill, once-a-day', fixed-dose combination regimens for the treatment of HIV infection.

The Phase 1 dose-escalating clinical study is designed to evaluate the safety, tolerability and pharmacokinetics (PK) of CMX157. Healthy volunteers will receive a single-dose of CMX157 (25 mg, 50 mg or 100 mg), a standard dose of tenofovir (as Viread®) or placebo. In addition to monitoring safety and standard PK parameters in plasma, levels of the active antiviral (tenofovir diphosphate) will be determined in peripheral blood mononuclear cells (PBMCs). These data will provide insight into the potential efficacy of CMX157, as the levels of tenofovir diphosphate in PBMCs associated with the antiviral efficacy of Viread have been documented.

"We are pleased to advance CMX157 into human clinical studies. While advances in HIV treatment have resulted in longer life spans, HIV is known to develop resistance to currently approved agents and significant drug side effects remain an issue for many patients," said Wendy Painter, M.D., MPH, Chimerix's Chief Medical Officer. "We are extremely encouraged by preclinical data that show CMX157 to be highly potent and less toxic than current HIV drugs and believe it has the potential to become an important new antiviral therapy."

CMX157 is a new chemical entity created by applying Chimerix's PIM (Phospholipid Intramembrane Microfluidization) Conjugate Technology to chemically modify tenofovir, the molecule underlying the prodrug Viread®, an antiviral agent approved for the treatment of HIV and chronic hepatitis B. Chimerix's PIM Conjugate Technology improves the absorption and distribution profile of drugs, achieving higher intracellular levels of the active antiviral agent. In vivo toxicology studies show that high plasma levels of CMX157 can be achieved with minimal toxicities.

CMX157 represents Chimerix's second antiviral compound to enter the clinic. Chimerix's lead compound, CMX001, a broad-spectrum antiviral agent with demonstrated in vitro activity against double-stranded DNA viruses, is in a multi-center Phase 2 clinical trial in stem cell transplant recipients who are seropositive for cytomegalovirus (CMV) and is also in clinical development for the treatment of BK virus in renal transplant and stem cell transplant recipients.

About Chimerix

Chimerix is developing antiviral therapeutics to treat life-threatening diseases. Led by a world-class antiviral drug development team, Chimerix is advancing programs to address cytomegalovirus (CMV), BK virus, adenovirus, smallpox, human immunodeficiency virus (HIV), hepatitis C virus (HCV), respiratory syncytial virus (RSV) and influenza. The company's lead compound, CMX001, is in Phase 1 and Phase 2 clinical studies for the treatment of BK virus and CMV, potentially deadly infections among immunocompromised patients. CMX001 is also being developed as a biodefense countermeasure in the event of a smallpox release. Chimerix has advanced a second antiviral compound, CMX157, into Phase 1 clinical studies. CMX157 is being developed as a potential once-weekly nucleoside analogue against HIV infections. Building on the company's extensive chemical library, Chimerix is also pursuing translational medicine efforts to address malaria, dengue fever and other public health needs. Chimerix has received financing from leading venture capital firms, including Sanderling Ventures, Canaan Partners, Alta Partners, Asset Management Company and Frazier Healthcare Ventures, as well as significant funding from the National Institute of Allergy and Infectious Diseases. Additional information about Chimerix and its antiviral drug development programs may be found online at http://www.chimerix.com.‹

[DewDiligence]

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

[New paragraph for “lifecycle management” programs.]


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.


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.