The rate of new hepatitis C infections in the U.S. fell more than 90 percent in the 25 years ending in 2006 as fewer Americans started using injected drugs such as cocaine, crack cocaine and heroin, a study showed.
The average incidence of new infections declined to 0.7 per 100,000 people in 1994 to 2006, from 7.4 per 100,000 in 1982 through 1989, according to a report today in the Archives of Internal Medicine. Injected-drug use was still the most common risk factor in contracting the disease, the study showed.
About three million to four million people in the U.S. have chronic hepatitis C, which can lead to liver damage, said Miriam Alter, an epidemiologist and author of the study. As the number of new infections declines, companies led by Merck & Co. and Vertex Pharmaceuticals Inc. are advancing new experimental medicines for the aging population of hepatitis C patients, who are more susceptible to the disease’s effects.
“Our concern is that we will be seeing more cases of liver disease due to hepatitis C in the near future, because while newly acquired cases have declined, the population of currently affected people is aging,” said Alter, director of the Infectious Disease Epidemiology Program at the University of Texas Medical Branch in Galveston, in a Feb. 11 telephone interview. “Once someone reaches advanced liver disease, they’re almost impossible to treat, so you want to identify people as early as possible.”
Hepatitis C often persists as a chronic condition that causes nausea, weakness and exhaustion as it destroys the liver over time. Interferon, the standard of care when paired with the generic drug ribavirin, works by boosting the immune system. The yearlong treatment causes aches and pains similar to the flu that may last the entire year of treatment and cures about half of those who can tolerate it. Standard Treatments
Roche Holding AG of Basel, Switzerland, sells a version of interferon under the brand name Pegasys, while Merck sells a form called PegIntron.
Merck, based in Whitehouse Station, New Jersey, and Cambridge, Massachusetts-based Vertex are competing to market the first new hepatitis C medicine approved in almost a decade. Merck’s boceprevir and Vertex’s telaprevir belong to a family known as protease inhibitors that work by blocking an enzyme that viruses use to copy themselves.
Both companies said in January that their drugs were granted priority review from the U.S. Food and Drug Administration, a process that typically takes six months. Johnson & Johnson, based in New Brunswick, New Jersey, agreed in 2006 to pay an upfront fee of $165 million to jointly promote the Vertex drug.
Peak sales of the medicines could reach more than $4 billion a year at “premium pricing” of more than $40,000 per year, Cowen & Co. analyst Phil Nadeau estimates.
‘Sizeable Opportunities’
“It is estimated that there are several hundred thousand patients in the U.S. who have been treated unsuccessfully,” Nadeau wrote in an October research note. “Both front-line and non-responder patients represent sizable opportunities that may be addressed with new HCV therapies, and we believe that a new drug class that possesses synergistic activity with other agents has blockbuster potential.”
While the rate of new hepatitis C infections has declined, preventative measures should still be employed, Alter said. She co-wrote the paper with the Atlanta-based Centers for Disease Control and Prevention’s Ian T. Williams, Beth P. Bell and Wendi Kuhnert, and worked with the agency from 1981 to 2006. Drug Users
“Many users of injection drugs had been previously incarcerated or in a drug treatment program, suggesting that providing primary prevention services in correctional and drug treatment settings could be an effective means to further reduce hepatitis C incidence in the United States,” the authors wrote.
Those already infected with the disease may have contracted it while experimenting with injected drugs in the 1960s, when the practice was more popular, Alter said.
“A lot of them acquired the infection as a result of experimenting with drugs and then went on and stopped using or didn’t experiment anymore,” she said. “There are some people who have this perception that hepatitis C is a street-user disease, which it is, but the majority of those infected now and who are developing chronic liver disease are not street users, and they can be accessed if we would screen for them.”‹
[Updated entries for BMS-650032 (moved to back-burner paragraph), BMS-790052, CTS-1027, INX-189, IDX184, IDX320 (entry deleted), PSI-7977, TMC435, and TMC629128.]
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).
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-55917427 (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-56129390, #msg-52949888 (PR’s 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: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-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-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-2b), a cyclophilin inhibitor: #msg-56835202, #msg-46432280; 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): #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 (phase-2a data), #msg-55778202 (plans to run combo trial with Intercell vaccine); PSI-7977 (VRUS; phase-2b), a nucleotide polymerase inhibitor that’s a single-isomer formulation of PSI-7851: #msg-58596259 (combo trial with BMS-750052), #msg-58513484 (Jan 2011 update), #msg-53827604 (phase-2b design), #msg-57740794 (genotype-2/3 trial w ribavirin), #msg-57193766 (combo trial with PSI-938), #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-3), a protease inhibitor: #msg-60078852 (phase-3 program), #msg-56867553, #msg-56929106, #msg-56129587, #msg-52204240 (interim phase-2b data and musings), #msg-50276630 (safety signals).
3. Programs in phase-1b/2a 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-58405118 (combo trial with ABT-072), #msg-56272166, #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); BI 207127 (Boehringer Ingelheim; phase-2a), a non-nucleoside polymerase inhibitor: #msg-56271789, #msg-51499515; BMS-790052 (BMY; phase-2a), an NS5A inhibitor being tested in an all-oral trial with VRUS’ PSI-7977: #msg-58596259 (announcement of trial with PSI-7977), #msg-55118600 (failure of combo trial with BMS-650032), #msg-49176213 (phase-2a monotherapy data from 2010 EASL); GS9190 (GILD; phase-2a), a non-nucleoside polymerase inhibitor with manifold safety and efficacy issues that is being tested with GS9256: #msg-55725066, #msg-52470566, #msg-46036072; GS9256 (GILD, phase-2a), a protease inhibitor that is been tested with GS9190: #msg-55725066, #msg-52702788, #msg-46036072; IDX184 (IDIX; phase-2a), a purine-nucleotide polymerase inhibitor #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); 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), a non-nucleoside “thumb” polymerase inhibitor being tested with Telaprevir: #msg-58019192 (changes to phase-2 trial), #msg-47242513 (musings on original phase-2 trial design), #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 purine nucleotide polymerase inhibitor: #msg-58589578 (phase-1b data), #msg-53933560 (phase-1a data); PSI-938 (VRUS; phase-1b), a purine-analog nucleotide prodrug: #msg-58513484 (Jan 2011 update), #msg-57193766 (combo trial with PSI-7977), #msg-56049854 (phase-1 data); 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; TMC649128 (JNJ/Medivir; phase-1): a nucleoside polymerase inhibitor (#msg-59749201); 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-2b), a compound with an unclear MoA: #msg-60068380; IL-7 (Cytheris; phase-1/2) an injectable immunomodulator: #msg-33152073; IMO-2125 (IDRA; phase-1), a TLR9 agonist: #msg-57983764; 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; BMS-650032 (BMY; phase-2a), a protease inhibitor that failed to work in an all-oral trial with BMS-790052 and whose future is unclear: #msg-55118600; 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.
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