PFE’s Filibuvir, an HCV non-nucleoside polymerase inhibitor that binds to the “thumb” site on the polymerase, is listed in PFE’s latest pipeline chart in #msg-54886720. I had had my doubts about this program insofar as PFE never talks about it and there are no plans (as far as I know) to test Filibuvir with any other direct-acting antiviral.
According to clinicaltrials.gov, a 288-patient phase-2 trial testing SoC± Filibuvir started in Nov 2009, has 78 trial sites, and is still recruiting patients at most of the sites:
288/78 = an average of 3.7 patients per trial site when the trial is fully enrolled. Even allowing for the staggered opening of trial sites, for this trial to still be recruiting patients at most sites after ten months suggests tepid interest in the trial by patients and clinicians.
[New entry for PFE’s Filibuvir; updated entries for ACHN’s ACH-1625, BMY’s BMS-650032 and BMS-790052, and Roche’s Danoprevir; Zalbin/Albuferon entry deleted.]
The following paragraphs are in descending order of likelihood of success. There is no claim of completeness in this compilation, i.e. paragraphs 2-6 do not necessarily mention all of the applicable drug candidates within a given grouping.
Please see #msg-49115388 for the distinction between a nucleoside and a nucleotide; also see #msg-43114117 for historical perspective from the HIV arena.
1. The two leading protease inhibitors: Telaprevir (VRTX/JNJ; NDA submission in progress) and Boceprevir (MRK; phase-3 completed/NDA submission late 2010). Between these two, I consider Telaprevir the favorite. The table in #msg-54317080 compares Telaprevir’s and Boceprevir’s phase-3 results in the first- and second-line settings. Although this comparison is unscientific, it suggests that Telaprevir is the drug to beat; this assessment could conceivably change when MRK presents the complete Boceprevir phase-3 dataset at the 2010 AASLD conference, but I doubt it.
It’s important to recognize that MRK has used a non-standard (and IMO disingenuous) definition of what constitutes a null responder to SoC therapy, and any comparison of Telaprevir and Boceprevir in the second-line setting must take this into account (#msg-54316658, #msg-54376207).
Telaprevir in the first-line setting:#msg-50595952 (results of phase-3 ADVANCE study—PR); #msg-50595752 (results of ADVANCE study—data table); #msg-53150647 (results of ILLUMINATE study); #msg-53158692 (explanation for higher SVR rate in 24w arm of ILLUMINATE); #msg-52754317 (phase-3b study of TID vs BID dosing); #msg-43114192 (‘C208’ phase-2 study of BID vs TID dosing); #msg-29019931 (summary of results from phase-2b); #msg-28746843 (detailed results from phase-2b).
Telaprevir in the second-line setting:#msg-54315761 (phase-3 REALIZE study—data table); #msg-54152015 (phase-3 REALIZE study—PR); #msg-48759554 (phase-2b PROVE-3 study).
Boceprevir in the first- and second-line settings:#msg-52949888 (PR with results of SPRINT-2 and RESPOND-2 studies); #msg-53025126 (exclusion of null responder patients from RESPOND-2 study); #msg-50187183 (NDA submission will exclude phase-3 anemia study); #msg-52963584, #msg-37298085 (questions about anemia and EPO use); #msg-31190433 (musings on SPRINT-1 phase-2b data).
2. Other programs in phase-2b or later: BI 201335 (Boehringer Ingelheim; phase-2b), a protease inhibitor: #msg-50285996 (safety profile), #msg-47877812 (abstract from 2010 EASL), #msg-42086185 (abstract from 2009 AASLD), #msg-33564560 (phase-2b design), #msg-51243571 (all-oral trial with BI 207127); Danoprevir (Roche; phase-2b; a/k/a RG7227; f/k/a ITMN-191), a protease inhibitor: #msg-55244199, #msg-55244797, #msg-55554201 ([bearish, IMO] 2010 transfer of rights to Roche), #msg-53621981, #msg-53624063, #msg-54403876 ([bearish, IMO] PK trial with ritonavir boosting), #msg-52702788 (INFORM-3 delay), #msg-43632598 (first report of liver tox), #msg-45340745 (phase-2b design change and delay), #msg-49046274 (phase-1b data with ritonavir [PR]), #msg-47860488 (phase-1b data with ritonavir [abstract]), #msg-49056848 (ghmm’s musings on ritonavir data), #msg-43185247 (INFORM-1 data from 2009 AASLD); Debio 025 (NVS/Debiopharm; phase-2b), a cyclophilin inhibitor: #msg-46432280; Filibuvir (PFE; phase-2b), a non-nucleoside “thumb” polymerase inhibitor (#msg-54888361); GI-5005 (GlobeImmune; phase-2b), an injectable immunomodulator: #msg-49095438 (phase-2b data); #msg-49171909 (IL-28 B genotype data); IFN-Lambda (BMY; phase-2b): #msg-50805665, #msg-43360640 (phase-2a/2b trial description), #msg-34768182 (BMY partnership), #msg-43123220 (final phase-1b data); Locteron (Biolex; phase-2b), a long-acting interferon made in transgenic plants that may qualify for the 505b2 approval pathway: #msg-49286341 (interim phase-2b data from 2010 EASL), #msg-37298340 (final phase-2a data), #msg-40953698 (manufacturing agreement); nitazoxanide (Romark/Chugai; phase-2a completed): #msg-49791818; PSI-7977 (VRUS; phase-2b), a nucleotide polymerase inhibitor that’s a single-isomer formulation of PSI-7851: #msg-53827604 (phase-2b design), #msg-49886718 (phase-2a data), #msg-49115305 (comparison to IDX184 data), #msg-40115833 (phase-1b data for PSI-7851); RG7128 (Roche/VRUS; phase-2b), a nucleoside polymerase inhibitor: #msg-46762882 (phase-2b overview), #msg-51072553 (12-week interim safety analysis from PROPEL trial in gentotype-1/4), #msg-53179217, #msg-53154180 (“delay” in start of phase-2b in genotype-2/3), #msg-43185247 (INFORM-1 data from AASLD 2009); TMC435 (Medivir/JNJ; phase-2b), a protease inhibitor: #msg-52204240 (24-week data from phase-2b), #msg-50276630 (safety signals), #msg-49286281 (presentations at 2010 EASL), #msg-43361309 (overview of phase-2 program at 2009 AASLD), #msg-37298740 (phase-2a data at 2009 EASL).
3. Programs in phase-1b/2a with an established MoA: ABT-072 (ABT; phase-2), a non-nucleoside polymerase inhibitor: #msg-47086871; #msg-47060142; ABT-333 (ABT; phase-2a), a nucleoside polymerase inhibitor: #msg-47060142, #msg-42098204; ABT-450 (ABT/Enanta; phase-2a), a protease inhibitor: #msg-47060142, #msg-35708745; ACH-1625 (ACHN; phase-2a), a protease inhibitor: #msg-55036061 (phase-2a trial), #msg-50099890 (phase-1b data table), #msg-50044936, #msg-51176124 (general musings on program); ANA598 (ANDS; phase-2a), a non-nucleoside “palm” polymerase inhibitor: #msg-52795076 (interim SVR12 data from phase-2a), #msg-50475044 (12-week phase-2a data), #msg-50504158 (phase-2a EVR table and questions about non-ITT reporting), #msg-50475368 (bearish assessment), #msg-40064675 (musings on phase-1b data); BI 207127 (Boehringer Ingelheim; phase-2a), a non-nucleoside polymerase inhibitor: #msg-51499515; BMS-650032 (BMY; phase-2a), a protease inhibitor that’s being tested in an all-oral trial with BMS-790052: #msg-55118600, #msg-44700187; BMS-790052 (BMY; phase-2a), an NS5A inhibitor that’s being tested in an all-oral trial with BMS-650032: #msg-55118600, #msg-44700187 (phase-2 combination trial), #msg-49176213 (phase-2a monotherapy data from 2010 EASL); GS9256 (GILD, phase-2a), a protease inhibitor that has been tested with GS9190: #msg-52702788, #msg-46036072; IDX184 (IDIX; phase-2a), a purine-nucleotide polymerase inhibitor that is on clinical hold due to liver tox in a combo study with IDX320: #msg-54120531 (clinical-hold announcement and final top-line phase-2a data), #msg-54130390 (musings on the clinical hold), #msg-49115305 (comparison to PSI-7977 data), #msg-39719159, (phase-1b monotherapy data), #msg-49115388, #msg-26915921 (nucleotide/liver-targeted MoA), #msg-49055353, #msg-47954632 (in vitro data in combination with other IDIX drugs); IDX320 (IDIX; phase-1b), a macrocyclic protease inhibitor that is currently on clinical hold due to liver tox in a combo study with IDX184: #msg-54120531 (clinical-hold announcement and phase-1b monotherapy data), #msg-54130390 (musings on the clinical hold), #msg-51165077 (half-life and dosing frequency), #msg-49055353, #msg-47954632 (PK, DDI, in vitro data in combination with other IDIX drugs); IFN-alpha-XL (FLML; phase-2a): #msg-44688995; MK-7009 (MRK; phase-2a), a protease inhibitor: #msg-34337398, #msg-34335327; PPI-461 (Presidio Pharma; phase-1b), an NS5A inhibitor: #msg-52296077; VX-222 (VRTX; phase-2; f/k/a VCH-222), a non-nucleoside “thumb” polymerase inhibitor (acquired from ViroChem) being tested with Telaprevir+SoC as well as with Telaprevir alone: #msg-47189924 (combo trial with Telaprevir), #msg-47242513 (musings on combo trial), #msg-49096553 (phase-1b monotherapy data [PR]), #msg-47879091 (phase-1b monotherapy data [abstract]).
4. Very-early-stage programs with an established MoA: ACH-2684 (ACHN; preclinical), a protease inhibitor: #msg-46160360; ACH-2928 (ACHN; preclinical), an NS5A inhibitor: #msg-52524948; AVL-181 and AVL-192 (Avila Therapeutics; preclinical): a pair of related protease inhibitors: #msg-49093995; EDP-239 (Enanta; preclinical): an NS5A inhibitor: #msg-47301187; ‘hyperglycosylated’ interferon (Alios BioPharma; preclinical): #msg-35612425; IDX375 (IDIX; phase-1), a non-nucleoside “palm” polymerase inhibitor: #msg-45350536 (phase-1 PK data), #msg-49055353, #msg-47954632 (in vitro data in combination with other IDIX drugs); INX-189 (INHX, phase-1b), a nucleotide polymerase inhibitor: #msg-53933560 (phase-1a data), #msg-53156241 (questions about seriousness of program); PSI-938 (VRUS; phase-1b), a purine-analog nucleotide prodrug: #msg-52714527; PSI-661 (VRUS; preclinical; f/k/a PSI-839), a purine-analog nucleotide prodrug billed as the successor to PSI-938: #msg-42245955; three unnamed compounds with undisclosed MoA’s (GILD; phase-1): #msg-49224935; an unnamed NS5A inhibitor (IDIX; preclinical): #msg-47110147; an unnamed NS5A inhibitor (GSK via Genelabs; status unknown): #msg-33209281, #msg-33211420; an unnamed second-generation protease inhibitor (Roche/ITMN; preclinical): #msg-49783993; an unnamed NS5A inhibitor (VRTX via ViroChem; preclinical): #msg-36022752.
5. Programs in phase-2a or earlier with a novel MoA: AVL-181 (Avila Therapeutics; preclinical), a small-molecule drug that purportedly binds to an infected hepatocyte: #msg-47113598; CF102 (Can-Fite; phase-1/2), a polymerase inhibitor that purportedly induces apoptosis: #msg-39588570; Clemizole (Eiger Biopharmaceuticals; phase-1), an old antihistamine repositioned as an NS4B inhibitor: #msg-51892107; CTI-1027 (Conatus; phase-2): #msg-46034554; IL-7 (Cytheris; phase-1/2) an injectable immunomodulator: #msg-33152073; IMO-2125 (IDRA; phase-1), a TLR9 agonist: #msg-49094332; ITX5061 (iTherX; phase-2a), MoA unknown: #msg-35319690; MB11362 (Roche/MBRX; preclinical), MoA undisclosed: #msg-38456136; NOV-205 (NVLT, phase-2), supposedly an immunomodulator: #msg-48269914; SCY-635 (Scynexis; phase-1b), a cyclophilin inhibitor: #msg-46669845; SD-101 (DVAX; phase-1b), a TLR9 agonist: #msg-45932364; SPC3649 (Santaris; phase-2), MoA based on microRNA: #msg-54718042; an unnamed entry inhibitor (PGNX; preclinical): #msg-38519885; an unnamed miR-122 inhibitor (GSK/Regulus; preclinical): #msg-47081015.
6. Programs on the back burner: A-831 (AZN; status unknown), an NS5A inhibitor: #msg-49610323; ACH-1095 (ACHN; preclinical), an NS4A inhibitor that is effectively dead based on ACHN’s CC on 8/19/10 (GILD previously dropped the compound while nominally retaining the right to opt back in: #msg-41217537); ANA773 (ANDS; phase-1), an oral TLR7 modulator that ANDS discontinued in Jun 2009 and is nominally available for partnering: #msg-38418158; GS9190 (GILD; phase-2a), a non-nucleoside polymerase inhibitor with manifold safety and efficacy issues that had been tested with GS9256: #msg-52470566, #msg-46036072; MK-3281 (MRK; phase-1), a non-nucleoside “thumb” polymerase inhibitor: #msg-50798497; SCH 900518/narlaprevir (MRK; phase-2a), a protease inhibitor originally owned by Schering-Plough that MRK discontinued following a pipeline pruning: #msg-47224801 (3/1/10 announcement of discontinuation), #msg-43169835 (interim phase-2a data), #msg-34338549 (final phase-1b data); 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); VX-813/VX-985 (VRTX; phase-1/preclinical), protease inhibitors that were previously touted as the backups to Telaprevir: #msg-45333927.
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