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. Both drugs have shown very impressive efficacy in phase-2 trials, although neither has a completely clean safety profile (see references below).
You might find it interesting to know that Asahi conducted a human study that showed blood filtration combined with standard care treatment produced cure rates as high or higher than results from Telaprevir clinical trials thus far. They are commercializing in Japan. http://www.v-rad.jp/en/index.html
And on this front, AEMD's blood filtration device, the Hemopurifier, actually filters the blood with specificity for the virus while the Asahi approach filters based on size. Also, the hemopurifier removes a higher percentage of the virus per treatment compared to Asahi's.
The main point of this post is that filtration treatment at the beginning of drug treatment can improve the efficacy of current treatment and may well improve the efficacy of future drugs and/or make other adjunct drug therapies less desirable. And, of course, the nice thing about this adjunct filtrationtherapy is that it does not bring any toxicity/side-effect baggage with it. In short, the current ranking of promising HCV drugs treatments may well do some shifting in the next year:-)
[Updated entries for BMS-650032/BMS790052 (BMY), ACH-1625 (ACHN), ANA598 (ANDS), ITMN-191 (ITMN/Roche), RG7128 (VRUS/Roche), IFN-alpha-XL (FLML); new entry for SPC3649 (Santaris).]
The following paragraphs are in descending order of likelihood of success. There is no claim of completeness here; i.e. paragraphs 3-7 do not necessarily mention all of the applicable drug candidates within the grouping.
Please see #msg-42396728 for the distinction between a nucleoside and a nucleotide, and see #msg-43114117 for some historical perspective from the HIV arena.
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. Both drugs have shown very impressive efficacy in phase-2 trials, although neither has a completely clean safety profile (see references below).
Telaprevir in the treatment-naïve setting: phase-3 program: #msg-27623529 (ADVANCE study), #msg-26228377 (both studies); phase-2b program: #msg-29019931 (PROVE-1/2 trials made simple), #msg-28746843 (PROVE-1/2 detailed results); C208 study of BID vs TID dosing: #msg-43114192.
Telaprevir in the second-line setting: phase-3 program (REALIZE study): #msg-32901932; phase-2 program: #msg-37316151 (PROVE-3 study), #msg-42965441 (‘107’ open-label extension for PROVE-1/2 failures).
Boceprevir in the treatment-naïve setting: phase-3 program (SPRINT-2 and RESPOND-2): #msg-29474929; phase-2b program: #msg-42086185 (AASLD 2009 abstract re SPRINT-1), #msg-37298987, (interim SPRINT-1 results at EASL 2009), #msg-37298085 (EPO usage), #msg-31190433 (Dew’s musings on SPRINT-1 data).
Boceprevir in the second-line setting: phase-3 (RESPOND-2) study: #msg-29474929.
2. ITMN-191 (a/k/a/ RG7227) and RG7128, the two oral drugs that Roche is testing in the INFORM-1 study that does not include interferon or ribavirin: #msg-43185247 (AASLD 2009), #msg-37309589 (EASL 2009), #msg-37312942 (viral-load chart from EASL 2009 with annotations by ghmm), #msg-37208214 (Apr 2009 PR on expanded trial design), #msg-37209844 (clinicaltrials.gov listing).
Although ITMN-191 and RG7128 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. Other agents in phase-2b or later: Albuferon/Zalbin/Joulferon (HGSI/NVS; BLA and MAA submitted): #msg-36140577 (phase-3 data), #msg-36254180 (lack of SPA!), #msg-34770426 (new trial with monthly dosing); BI 201335 (B-I; phase-2b), a protease inhibitor: #msg-42086185, #msg-33564560; and Locteron (Biolex; phase-2b), a long-acting interferon made in transgenic plants that may qualify for the 505b2 approval pathway: #msg-37298340 (phase-2a data from EASL 2009), #msg-37178496 (phase-2b design), #msg-40953698 (manufacturing agreement).
4. Agents in phase-1b or phase-2a that use an established MoA. These include ACH-1625 (ACHN;phase-1b), a protease inhibitor: #msg-44560695, #msg-44565111; BMS-650032 (BMY, phase-2), a protease/NS3 inhibitor: #msg- 44700187, #msg-40361108; TMC435 f/k/a/ TMC435350 (Medivir/JNJ; phase-2b), a protease inhibitor: #msg-37298740, #msg-43361309; SCH 900518 a/k/a/ Narlaprevir (MRK; phase-2a), a protease inhibitor: #msg-43169835 (interim phase-2a data), #msg-34338549 (final phase-1b data); GS9190 (GILD; phase-2), a non-nucleoside polymerase inhibitor that GILD is testing in an all-oral combination with GILD’s newly disclosed protease inhibitor GS9256: #msg-42717806; IDX184 (IDIX; phase-1b), a nucleotide polymerase-inhibitor: #msg-36392616 (EASL 2009 abstract), #msg-34763865 (PR for trial commencement), #msg-26915921 (how IDX184 is better than NM283); PSI-7851 (VRUS, phase-1b), a nucleotide polymerase inhibitor: #msg-40115833; IFN-alpha-XL (FLML; phase-2a): #msg-44688995; ABT-450 (ABT/Enanta, phase-1), a protease inhibitor: #msg-35708745; VCH-222 (VRTX, phase-1b), a non-nucleoside “thumb” polymerase inhibitors that VRTX acquired from ViroChem (VCH-759 is a backup): #msg-37089807; IFN-Lambda (BMY/ZGEN; phase-2): #msg-34768182 (BMY partnership), #msg-43123220 (final phase-1b data), #msg-43360640 (start of phase-2); MK-7009 (MRK, phase-2a), a protease inhibitor: #msg-34337398, #msg-34335327; ABT-333 (ABT, phase-1b), a polymerase inhibitor: #msg-42098204; and ANA598 (ANDS, phase-2), a non-nucleoside “palm” polymerase inhibitor: #msg-44635086 (interim phase-2 PR), #msg-44647384 (interim tabular data), #msg-44645147 (musings on interim data), #msg-40064675 (musings on phase-1b data).
5. Very-early-stage compounds that use an established MoA. These include IDX375 (IDIX, preclinical), a non-nucleoside “palm” polymerase inhibitor: #msg-34334563, #msg-31043481; MK-3281 (MRK, phase-1), a non-nucleoside “thumb” polymerase inhibitor: #msg-42093301 (safety signal in AASLD 2009 abstract); PSI-938 and PSI-879 (VRUS, preclinical), a pair of purine-analog nucleotide prodrugs: #msg-39322313, #msg-42245955; ‘hyperglycosylated’ interferon (Alios BioPharma, preclinical): #msg-35612425; IDX316 (IDIX, preclinical), a macrocyclic protease inhibitor: #msg-41526366 (reason for selection over IDX136), #msg-37246670 (EASL 2009 PR), #msg-37315636 (EASL 2009 poster); and VX-813/VX-985 (VRTX, phase-1/preclinical), protease inhibitors that are nominally the follow-ups to Telaprevir but are (IMO) close to being killed for lack of commercial relevance: #msg-42917596.
6. Agents in phase-2 or earlier that use a novel MoA. These include CF-102 (Can-Fite, phase-1/2), a polymerase inhibitor that purportedly induces apoptosis: #msg-39588570; BMS-790052 (BMY, phase-2), an NS5A inhibitor: #msg-33270670, #msg-44700187; MB11362 (Roche/MBRX, preclinical), MoA undisclosed: #msg-38456136; A-831 (AZN, status unknown), an NS5A inhibitor: #msg-16682361; a preclinical NS5A inhibitor from GSK (acquired from Genelabs): #msg-33209281, #msg-33211420; IL-7 (Cytheris, phase-1/2) an injectable immunomodulator: #msg-33152073; Debio 025 (Debiopharm, phase-2a), a cyclophilin inhibitor: #msg-37359213; NIM811 (NVS, status unknown), a cyclophilin inhibitor: #msg-36507550; GI-5005 (GlobeImmune, phase-2), an injectable immunomodulator: #msg-37298510; ACH-1095 (ACHN, preclinical), an NS4A inhibitor that GILD dropped while retaining the right to opt back in: #msg-41217537; 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-39883747; nitazoxanide (Romark/Chugai, phase-2): #msg-35738696; ITX5061 (iTherX, phase-2a), MoA unknown: #msg-35319690; IMO-2125 (IDRA, phase-1), a TLR9 agonist: #msg-42293996, #msg-38860625; a preclinical entry inhibitor from PGNX: #msg-38519885; SPC3649 (Santaris, preclinical), MoA based on microRNA: #msg-44177354.
7. Programs that are nominally alive but not receiving financial support. These include ANA773 (ANDS, phase-1), an oral TLR7 modulator that ANDS discontinued in Jun 2009 and is nominally available for partnering: #msg-38418158; and taribavirin (VRX, phase-2b), a “legacy” prodrug of ribavirin that has been floating around for a long time: #msg-38280961 (musings on final phase-2b data), #msg-37299101 (detailed 60-week data). (VRX, under a different name, is the inventor of ribavirin.)
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