Biotech Values

[DewDiligence]

HCV: Most Likely to Succeed (IMHO)

[Updates;
INO-2125 entry moved to “back burner” paragraph;
GS9256 entry deleted (superseded by GS9451);
new entries for GS6620 and GS9451;
updated entries for GS9190 and GS5885 (for 4-drug oral combo).]


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 submitted) and Boceprevir (MRK; NDA submitted). 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 somewhat unscientific, it suggests that Telaprevir is the drug to beat.

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).

All told, I expect Telaprevir to outsell Boceprevir by about 4:1 (#msg-61543324), assuming both are approved in the same jurisdictions.

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-56129295 (% of patients in ADVANCE & ILLUMINATE who stopped treatment at 24w); #msg-53158692 (explanation for higher SVR rate in 24w arm of ILLUMINATE); #msg-61716397 (IL28B variants in ADVANCE); #msg-55917427 (phase-3b study of TID vs BID dosing); #msg-43114192 (‘C208’ phase-2 study of BID vs TID dosing); #msg-60417743 (phase-2 data in HCV/HIV co-infection).

Telaprevir in the second-line setting: #msg-54315761, #msg-54152015 (REALIZE data); #msg-61716397 (IL28B variants in REALIZE).

Boceprevir in the first-line setting: #msg-52949888, #msg-61543371 (SPRINT-2 data); #msg-56129390 (duration of treatment in SPRINT-2); #msg-61718223 (IL28B variants in SPRINT-2); #msg-52963584, #msg-37298085, #msg-50187183 (questions about anemia and EPO use).

Boceprevir in the second-line setting: #msg-54316658, #msg-54376207 (exclusion of null responders from RESPOND-2); #msg-52949888, #msg-61543324 (RESPOND-2 data); #msg-56129390 (duration of treatment in RESPOND-2); #msg-61718223 (IL28B variants in RESPOND-2); #msg-52963584, #msg-37298085, #msg-50187183 (questions about anemia and EPO use).


2. Other programs in phase-2b or later: ANA598 (ANDS; phase-2b), a non-nucleoside “palm” polymerase inhibitor: #msg-58413513 (phase-2b design), #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 201335 (Boehringer Ingelheim; phase-3), a protease inhibitor: #msg-61666265 (phase-3 program), #msg-61754832, #msg-61682791 (phase-2b data), #msg-50285996 (musings on safety profile), #msg-56271789 (all-oral trial with BI 207127); Danoprevir (Roche; phase-2b; a/k/a RG7227; f/k/a ITMN-191), a protease inhibitor: #msg-57054424, #msg-57591630 (program probably dead), #msg-55244199, #msg-55244797, #msg-55554201 (transfer of rights to Roche), #msg-53621981, #msg-53624063, #msg-54403876 (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); DEB025 (NVS/Debiopharm; phase-3), a cyclophilin inhibitor: #msg-61671677 (final phase-2 data), #msg-56835202 (phase-1b/2a charts and MoA), #msg-46432280 (history); Filibuvir (PFE; phase-2b), a non-nucleoside “thumb” polymerase inhibitor (#msg-54888361); GI-5005 (GlobeImmune; phase-2b), an injectable immunomodulator: #msg-56129933 (phase-2b data); #msg-49171909 (IL-28 B genotype data); IFN-Lambda (BMY; phase-2b), a more tolerable form of interferon than Pegasys/Pegintron: #msg-61755220 (phase-2b data); Locteron (Biolex; phase-2b), a long-acting interferon made in transgenic plants that may qualify for the 505b2 approval pathway: #msg-61711095 (phase-2b data), #msg-40953698 (manufacturing agreement); nitazoxanide (Romark/Chugai; phase-2a completed): #msg-49791818 (phase-2a data), #msg-55778202 (plans to run combo trial with Intercell vaccine); PSI-7977 (VRUS; phase-2b), a nucleotide polymerase inhibitor (a single-isomer formulation of the defunct, PSI-7851): #msg-61749127 (14-day data fm ‘NUCLEAR’ combo w PSI-938), #msg-57193766 (PR re ‘NUCLEAR’ combo w PSI-938), #msg-58596259 (PR re combo with BMS-750052), #msg-53827604 (phase-2b 1st-line), #msg-61668472 (phase-2b 2nd-line), #msg-49886718 (phase-2a data 1st-line geno-1), #msg-61679544 (phase-2a data 1st-line geno-2/3); RG7128 (Roche/VRUS; phase-2b), a nucleoside polymerase inhibitor: #msg-61784048 (musings on deficiency of MoA), #msg-46762882 (phase-2b overview), #msg-61677141 (high relapse rate in Jump-C phase-2b study), #msg-51072553 (12-week interim safety analysis from PROPEL study in gentotype-1/4), #msg-53179217, #msg-53154180 (“delay” in start of phase-2b in genotype-2/3); TMC435 (Medivir/JNJ; phase-3), a protease inhibitor: #msg-60078852 (phase-3 program), #msg-60210162 (interim phase-2b PILLAR data in first-line setting), #msg-61754182 (interim phase-2b ASPIRE data in second-line setting), #msg-56929106 (musings on interim phase-2b data).


3. Programs in phase-2a or earlier with an established MoA: ABT-072 (ABT; phase-2), a non-nucleoside polymerase inhibitor: #msg-58405118 (combo trial with ABT-450); ABT-333 (ABT; phase-2a), a non-nucleoside polymerase inhibitor: #msg-47060142, #msg-42098204; ABT-450 (ABT/Enanta; phase-2a), a protease inhibitor: #msg-61757048 (interim phase-2a data), #msg-58405118 (combo trial with ABT-072); ACH-1625 (ACHN; phase-2a), a protease inhibitor: #msg-61504285 (phase-2a data), #msg-50099890 (phase-1b data table), #msg-50044936, #msg-51176124 (general musings on program); 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; BI 207127 (Boehringer Ingelheim; phase-2a), a non-nucleoside polymerase inhibitor: #msg-56271789, #msg-51499515; BMS-650032 (BMY; phase-2a), a protease inhibitor—see BMS-790052 entry; BMS-790052 (BMY; phase-2a), an NS5A inhibitor being tested in an all-oral combo with PSI-7977 and in combo with BMS-650052 ± SoC: #msg-58596259 (PR re trial with PSI-7977), #msg-61651772, #msg-61483858, #msg-60946871, #msg-55118600 (combo data w BMS-650032), #msg-49176213 (phase-2a data with SoC); GS5885 (GILD; phase-1b): an NS5A inhibitor: #msg-62299871 (4-drug oral combo), #msg-60686677 (EASL 2010 poster); GS6620 (GILD; phase-1): a nucleotide prodrug: #msg-61903668; GS9190 (GILD; phase-2a), a non-nucleoside polymerase inhibitor that is (surprisingly) being tested in a 4-drug oral combo: #msg-62299871 (4-drug combo), #msg-52470566 (failure with defunct PI, GS9256), #msg-46036072 (Jan 2010 musings); GS9451 (GILD; phase-2a): a protease inhibitor billed as the successor to the defunct GS9256: #msg-62299871 (4-drug oral combo); ‘hyperglycosylated’ interferon (Alios BioPharma; preclinical): #msg-35612425; IDX184 (IDIX; phase-2a), a purine-nucleotide polymerase inhibitor #msg-60417743 (plans for phase-2b), #msg-59734872 (partial removal of FDA clinical hold), #msg-54120531 (phase-2a data), #msg-49115305 (comparison to PSI-7977 data), #msg-39719159, (phase-1b monotherapy data), #msg-49115388, #msg-26915921 (nucleotide/liver-targeted MoA); INX-189 (INHX; phase-1b), a purine nucleotide polymerase inhibitor: #msg-61668669; MK-7009 (MRK; phase-2a), a protease inhibitor: #msg-34337398, #msg-34335327; PPI-461 (Presidio Pharma; phase-1b), an NS5A inhibitor: #msg-61668545 (phase-1b data), #msg-52296077 (history of compound); PSI-661 (VRUS; preclinical; f/k/a PSI-839), a backup to PSI-938 that uses the same active ingredient with a different prodrug: #msg-42245955; PSI-938 (VRUS; phase-2a), a purine-analog nucleotide prodrug (see PSI-7977 entry for combination studies): #msg-58513484 (Jan 2011 update), #msg-56049854 (phase-1 data); TMC649128 (JNJ/Medivir; phase-1): a nucleoside polymerase inhibitor (#msg-59749201); VX-222 (VRTX; phase-2), a non-nucleoside “thumb” polymerase inhibitor being tested with Telaprevir: #msg-61669471 (interim phase-2 data with Telaprevir), #msg-47242513 (musings on original phase-2 trial design), #msg-49096553 (phase-1b monotherapy data.


4. 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-2b), a compound with an unclear MoA: #msg-60068380; IL-7 (Cytheris; phase-1/2) an injectable immunomodulator: #msg-33152073; 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.


5. Programs on the back burner or unofficially defunct: 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; IDX375 (IDIX; phase-1), a non-nucleoside “palm” polymerase inhibitor: #msg-60428047 (confirmation of back-burner status), #msg-45350536 (phase-1 PK data); IFN-alpha-XL (FLML; phase-2a): #msg-44688995; IMO-2125 (IDRA; phase-1), a TLR9 agonist that has animal-tox issues: #msg-62376531; 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 (Kadmon; phase-2b), a prodrug of ribavirin that has been floating around for a long time: #msg-56271960 (sale by VRX), #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.


JMHO, FWIW