Could you please add PPHM's 11.31 mab to you “HCV: Most Likely to Succeed ~ 6. Early- and very-early-stage compounds that use a novel MoA.“ Although it's still being investigated preclinical for hiv, it does show signs to be broadly neutralizing. I would expect PPHM, or a potential partner, to study this as both a therapeutic and a vaccine for many viral types.
I don't understand why the compound is first referred to as a nucleotide, but then under the "About PSI-7851" section, they call it a nucleoside.
"Pharmasset, Inc. (Nasdaq: VRUS - News) announced today that dosing has started in a phase 1, single ascending dose (SAD) study in healthy volunteers with PSI-7851, a second generation nucleotide analog polymerase inhibitor of hepatitis C virus (HCV). Pharmasset filed an Investigational New Drug Application (IND) with the Food and Drug Administration (FDA) earlier this quarter.
This is a significant milestone for Pharmasset. PSI-7851 is a wholly owned, second generation nucleotide analog that was discovered by Pharmasset scientists" stated Dr. Michelle Berrey, Pharmasset's Chief Medical Officer. "We continue to see nucleos(t)ide inhibitors as having the potential to be the cornerstone of future HCV treatment, given their higher barrier to resistance and antiviral activity across multiple HCV genotypes, characteristics that set them apart from other HCV drug classes. We look forward to reporting the first antiviral data with PSI-7851 in the second half of 2009."
About PSI-7851
PSI-7851 is a uridine nucleoside analog currently in developed for the treatment of chronic HCV infection. PSI-7851 has demonstrated in vitro anti-HCV activity with EC(50) values of 90 +/- 60 nM, which is approximately 15- to 20-fold more potent than the active metabolite of Pharmasset's first generation nucleoside polymerase inhibitor, R7128. In vitro studies of PSI-7851 have not shown evidence of any mitochondrial or other cellular toxicities that may be associated with some nucleoside analogs. The half-life of the triphosphate in primary human hepatocytes is approximately 38 hours, which suggests the possibility for once-daily dosing. Like R7128, PSI-7851 has demonstrated in vitro activity against all of the most common HCV genotypes.
The following paragraphs are in descending order of likelihood of success. There is no claim of completeness here; i.e. paragraphs 3-6 do not necessarily mention all of the applicable drug candidates within the grouping. Please see #msg-36688204 for the semantics of the terms nucleoside and nucleotide.
1. The two leading protease inhibitors: Telaprevir (VRTX/JNJ; phase-3) and Boceprevir (MRK; phase-3). The Telaprevir program is further advanced, so let’s call Telaprevir and Boceprevir 1a and 1b, respectively.
These two drugs have shown comparable efficacy in 24-28 week regimens of phase-2 trials in the genotype-1, treatment-naïve setting: #msg-31190433, #msg-33793333, #msg-33282976. Background posts: VRTX PROVE-1/2 trials made simple: #msg-29019931; PROVE-1/2 detailed results: #msg-28746843; overview of Telaprevir phase-3 program: #msg-27623529 (ADVANCE study), #msg-26228377 (outline of both studies); Boceprevir starts phase-3: #msg-29474929.
Telaprevir and Boceprevir are also being tested in the second-line setting, Telaprevir in 24- and 48-week regimens and Boceprevir in 36- and 48-week regimens. Background posts: Telaprevir phase-3 REALIZE study: #msg-32901932; Telaprevir phase-2b PROVE-3 study: #msg-36464842; Telaprevir ‘107’ open-label phase-2 extension for PROVE-1/2 failures: #msg-33282976; Boceprevir phase-3 RESPOND-2 study: #msg-29474929.
2. ITMN-191 and R7128, the two oral drugs that Roche is testing is the INFORM-1 study that does not include interferon or ribavirin: #msg-36349693 (trial-design chart), #msg-33967428 (clinicaltrials.gov listing), #msg-33446127 (PR on study commencement), #msg-36388140 (EASL 2008 abstract), #msg-36455893 (musings by ghmm). ITMN-191 a.k.a. R7227 (ITMN/Roche; phase 1b) is a protease inhibitor: #msg-34747018. R7128 (VRUS/Roche; entering phase-2b) is a nucleoside polymerase inhibitor: #msg-34746768, #msg-35888562, #msg-32238916, #msg-32651030.
Although ITMN-191 and R7128 are not necessarily the best drugs in their respective classes, the fact that Roche is testing them in INFORM-1 gives them a leg up on competing drugs at the same stage of development, IMO.
3. Agents in phase-2b, phase-3 or later that use an established MoA: Albuferon (HGSI/NVS; BLA submission pending): #msg-36140577 (phase-3 data), #msg-36254180 (lack of SPA!), #msg-34770426 (new trial with monthly dosing); BI201335 (B-I; phase-2b), a protease inhibitor: #msg-33564560, #msg-34774813; and Locteron (Biolex; phase-2), a long-acting interferon made in transgenic plants that may qualify for the 505b2 approval pathway: #msg-28786162. (Biolex recently bought out its partner, OctoPlus, and raised $60M to fund the Locteron program: #msg-32662307, #msg-32662762.)
4. Agents in phase-1 or phase-2a that use an established MoA. These include TMC435 (Medivir/JNJ; phase-2), a protease inhibitor: #msg-33283588, #msg-34774813; SCH 900518 (MRK, phase-2a), a protease inhibitor (follow-up to Boceprevir): #msg-34338549, #msg-34774813; GS-9190 (GILD; phase-2), a non-nucleoside polymerase inhibitor: #msg-32919311; IDX184 (IDIX; phase-1b), a nucleotide polymerase-inhibitor: #msg-36392616 (EASL 2008 abstract), #msg-34763865 (PR for trial commencement), #msg-26915921 (how IDX184 is better than NM283); PSI-7851 (VRUS, entering phase-1), a nucleotide polymerase inhibitor: #msg-36685948; ANA598 (ANDS, phase-1b), a non-nucleoside “palm” polymerase inhibitor: #msg-34678306; IFN-alpha-XL (FLML; phase-1b): #msg-28837983; ABT-450 (ABT/Enanta, phase-1), a protease inhibitor: #msg-35708745; VCH-222/VCH-759 (VRTX, phase-1b/2a), non-nucleoside “thumb” polymerase inhibitors that VRTX acquired from ViroChem: #msg-36022752, #msg-36023139; IFN-Lambda (BMY/ZGEN; phase-1b): #msg-34768182 (BMY partnership), #msg-33311734 (interim phase-1b data); and MK-7009 (MRK, phase-2a), a protease inhibitor that might bite the dust due to MRK’s acquisition of SGP: #msg-34337398, #msg-34335327.
5. Very-early-stage compounds that use an established MoA. These include ACH-1625 (ACHN; preclinical), a protease inhibitor: #msg-31459921; IDX375 (IDIX, preclinical), a non-nucleoside “palm” polymerase inhibitor: #msg-34334563, #msg-31043481; ‘hyperglycosylated’ interferon (Alios BioPharma, preclinical): #msg-35612425; IDX136/IDX316 (IDIX, preclinical), two related macrocyclic protease inhibitors of which IDIX will select one to advance into phase-1: #msg-31043481; and VX-813/VX-985 (VRTX, phase-1/preclinical), protease inhibitors from VRTX being developed as follow-on compounds to Telaprevir: #msg-36022752.
6. Early- and very-early-stage compounds that use a novel MoA. These include BMS-790052 (BMY, phase-1), an NS5A inhibitor: #msg-33270670; A-831 (AZN, status unknown), an NS5A inhibitor: #msg-16682361; a preclinical NS5A program that GSK acquired from GNLB: #msg-33209281, #msg-33211420; ANA773 (ANDS, phase-1), an oral TLR7 modulator: #msg-33244419; IL-7 (Cytheris, phase-1/2) an injectable immunomodulator: #msg-33152073; GI-5005 (GlobeImmune, phase-2), an injectable immunomodulator: #msg-33322543; ACH-1095 (ACHN/GILD; preclinical), an NS4A inhibitor: #msg-31459921; an unnamed NS5A inhibitor that VRTX acquired from ViroChem (preclinical): #msg-36022752; an unnamed NS5A inhibitor from Presidio Pharma (status unknown): #msg-27791536; clemizole (Stanford University; preclinical), an NS4B inhibitor: #msg-31857987; and nitazoxanide (Romark/Chugai, phase-2): #msg-35738696.
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