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FDA HCV Submissions / HCV Update
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from Jules: there is a lot going on now in HCV, maybe too much information to grasp but here is a report updating the current situation. I haven't mentioned GT1b or GT4 in this report below but here are links to all the recent data reported including for gt1b & gt4:
EASL: New DAA Phase 3 Studies for genotype 1 at EASL - in both Treatment-naives, treatment-experienced; simultaneous publications
EASL - The International Liver Congress 2014 49th Annual Meeting of the European Association for the Study of the Liver
London, United Kingdom
April 9-13
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FDA HCV Submissions
sofosbuvir-ledipasvir (PDUFA 10/10/2014)
faldaprevir (submitted March 6, 2014)
daclatasvir-asunaprevir (submitted April 7, 2014)
AbbVie regimen(submitted April 22, 2014)
simeprevir-sofosbuvir (submitted May 7, 2014)......
Janssen Submits Supplemental New Drug Application to U.S. FDA for OLYSIO™ (Simeprevir) for Once-Daily Use in Combination with Sofosbuvir for 12 Weeks for the Treatment of Adult Patients with Genotype 1 Chronic Hepatitis C - (05/08/14)
Gilead's sofosbuvir (Sovaldi) is a nucleotide, this class/type of drug is a backbone for the success of their therapy because it is potent, not a resistance concern, is pan-genotypic, taken once-daily and has been safe & tolerable in studies, see links to their phase 3 study results below presented at EASL London in April 2014. Idenix reported the first results of a study of their nucleotide earlier this year, several days ago Merck announced [
http://www.natap.org/2014/HCV/060914_01.htm] it was acquiring Idenix & will acquire their HCV drug pipeline which includes two nucleotide prodrugs (IDX21437 and IDX21459,
http://www.natap.org/2014/EASL/EASL_58.htm) and a 2nd generation pan-genotypic NS5A inhibitor (samatasvir,
http://www.natap.org/2014/EASL/EASL_52.htm), this adds to Merck's own pipeline of their own 2nd generation HCV protease inhibitor MK5172 & their 2nd generation NS5A MK8742. This will allow Merck to study regimens for cirrhotic null responders, the hardest to treat patients.
At the Clinical Pharmacology Workshop several weeks ago Gilead reported some drug interaction data on HIV ARTs:
Drug Interactions Between Direct-Acting anti-HCV Antivirals Sofosbuvir and Ledipasvir and HIV Antiretrovirals - (05/27/14).
Abbvie reported results from their phase 3 program at EASL in London, April 2014, see links below to their study results, they are conducting a study in HIV/HCV coinfected & reported some drug interaction data with HIV ARTs at the Clinical Pharmacology Workshop several weeks ago, so the question is will the FDA consider the results of this coinfection study since it is ongoing when they review Abbvie's application for approval, the study recently started so the data may not be totally complete as the FDA review is ongoing:
ABT-450/Ritonavir +Ombitasvir + Dasabuvir: Drug Interactions Mediated by Transporters - (05/21/14)
BMS has several ongoing phase 3 studies including NS5A daclatasvir+sofosbuvir in both treatment-naives
[http://www.natap.org/2012/EASL/EASL_24.htm] & PI telaprevir or boceprevir experienced patients
[http://www.natap.org/2013/EASL/EASL_22.htm] & their triple drug regimen of daclatasvir+protease asunaprevir+non-nuc BMS325
[http://www.natap.org/2013/AASLD/AASLD_25.htm]. Here is drug interaction data with HIV ARTs reported:
http://www.natap.org/2012/CROI/croi_38.htm
Janssen has developed Simeprevir & studied simeprevir+sofosbuvir in the COSMOS Studies. They are conducting phase 3 studies of simeprevir+sofosbuvir & and submitted May 7 to the FDA a request linked to above for approval for patients to use the regimen although in the clinic now patients have been able to get approval from their insurer to use it.
EASL: Once-daily simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in HCV genotype-1 prior null responders with METAVIR F0-2: COSMOS study subgroup analysis - (04/14/14)
EASL: Simeprevir plus sofosbuvir with/without ribavirin in HCV genotype-1 prior null-responder / treatment-naïve patients (COSMOS study): primary endpoint (SVR12) results in patients with METAVIR F3-4 (Cohort 2) - (04/14/14)
Janssen Initiates Phase 3 OPTIMIST Trials of Once-Daily Simeprevir in Combination with Once-Daily Sofosbuvir for the Treatment of Genotype 1 Chronic Hepatitis C - (04/03/14)
Gilead's regimen is Sofosbuvir+NS5A ledipasvir for which we expect FDA approval this Fall 2014, they also have in development GS5816, a 2nd generation pan-genotypic NS5A specifically for GT3, and Gt1-6 [
http://www.natap.org/2014/EASL/EASL_29.htm]. They also have an HCV no-nuc & a HCV protease inhibitor, the SYNERGY Study & the PHOTON Study looking Sofosbuvir+ledipasvir in HIV/HCV coinfected:
EASL: Resistance Analysis of HCV Genotype 1 Patients Treated With Sofosbuvir in Combination With Ledipasvir or the NS5B Non-Nucleoside Inhibitor GS-9669: The ELECTRON Study - (04/21/14).
the SYNERGY Study [http://www.natap.org/2014/CROI/croi_129.htm] - PHOTON HIV/HCV:
http://www.natap.org/2014/EASL/EASL_05.htm
Janssen Submits Supplemental New Drug Application to U.S. FDA for OLYSIO™ (Simeprevir) for Once-Daily Use in Combination with Sofosbuvir for 12 Weeks for the Treatment of Adult Patients with Genotype 1 Chronic Hepatitis C. - (05/08/14)
Achillion also is developing a nucleotide, they just announced they are beginning the first study of it in patients: "Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) today announced the Company has begun dosing ACH-3422, a uridine-analog nucleotide polymerase inhibitor [
http://www.natap.org/2014/HCV/050114_01.htm], for seven days in patients with genotype 1 chronic hepatitis C viral infection (HCV) in its ongoing Phase 1 clinical trial. Proof-of-concept results from this trial are expected to be reported during the fall of 2014. Furthermore, Achillion announced today that the U.S. Food and Drug Administration (FDA) has removed the clinical hold on sovaprevir, an NS3/4A protease inhibitor, to permit the conduct of trials in patients with HCV. Sovaprevir doses of 200 mg once daily, the previously evaluated dose that was well-tolerated with clinical activity in two completed Phase 2 studies, may be used in additional therapeutic clinical trials......We remain focused on developing regimens utilizing ACH-3422 and ACH-3102, our second-generation Phase 2 NS5A inhibitor, and the second half of 2014 will feature multiple milestones in that program," commented Milind Deshpande, Ph.D., President and Chief Executive Officer. "Our HCV pipeline also provides the opportunity to add a NS3/4A protease inhibitor, such as sovaprevir or ACH-2684"
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Links to most recent study results:
EASL: New DAA Phase 3 Studies for genotype 1 at EASL - in both Treatment-naives, treatment-experienced; simultaneous publications - (04/21/14)
COSMOS - Simeprevir+Sofosbuvir
EASL: Once-daily simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in HCV genotype-1 prior null responders with METAVIR F0-2: COSMOS study subgroup analysis - (04/14/14)
EASL: Simeprevir plus sofosbuvir with/without ribavirin in HCV genotype-1 prior null-responder / treatment-naïve patients (COSMOS study): primary endpoint (SVR12) results in patients with METAVIR F3-4 (Cohort 2) - (04/14/14)
Abbvie & Gilead - EASL Presentations Phase 3 Studies GT1, treatment-naive & treatment-experienced & HIV coinfection:
USE OF SOFOSBUVIR/LEDIPASVIR FIXED DOSE COMBINATION FOR TREATMENT OF HCV GENOTYPE-1 INFECTION IN PATIENTS COINFECTED WITH HIV (Interim results) - (04/10/14)
EASL: All Oral Fixed-Dose Combination Ledipasvir/Sofosbuvir With Or Without Ribavirin for 12 or 24 Weeks in Treatment-Naive Genotype 1 HCV-Infected Patients: the Phase 3 ION-1 Study - (04/14/14)
EASL: All Oral Fixed-Dose Combination Ledipasvir/Sofosbuvir With or Without Ribavirin for 12 or 24 Weeks in Treatment-Experienced Genotype 1 HCV-Infected Patients: The Phase 3 ION-2 Study - (04/14/14)
EASL: Ledipasvir/Sofosbuvir With and Without Ribavirin for 8 Weeks Compared to Ledipasvir/Sofosbuvir for 12 Weeks in Treatment-Naïve Noncirrhotic Genotype-1 HCV-Infected Patients: The Phase 3 ION-3 Study - (04/11/14)
EASL: TURQUOISE-II: SVR12 RATE OF 92-96% IN 380 HEPATITIS C VIRUS GENOTYPE 1-INFECTED ADULTS WITH COMPENSATED CIRRHOSIS TREATED WITH ABT-450/r/ABT-267 AND ABT-333 PLUS RIBAVIRIN - (04/14/14)
EASL: SAPPHIRE-I: PHASE 3 PLACEBO-CONTROLLED STUDY OF INTERFERON-FREE, 12-WEEK REGIMEN OF ABT-450/r/ABT-267, ABT-333, AND RIBAVIRIN IN 631 TREATMENT-NAïVE ADULTS WITH HEPATITIS C VIRUS GENOTYPE 1 - (04/11/14)
EASL: SAPPHIRE-II: PHASE 3 PLACEBO-CONTROLLED STUDY OF INTERFERON-FREE, 12-WEEK REGIMEN OF ABT-450/r/ABT-267, ABT-333, AND RIBAVIRIN IN 394 TREATMENT-EXPERIENCED ADULTS WITH HEPATITIS C VIRUS GENOTYPE 1 - (04/10/14)
Merck
Efficacy and safety of MK-5172 and MK-8742 ± RIBAVIRIN IN Hepatitis C Genotype 1 Infected Patients with cirrhosis or previous null response: the C-WORTHY Study - (04/11/14)
EASL: SAFETY AND EFFICACY OF THE ALL-ORAL REGIMEN OF MK-5172 / MK-8742 ± RIBAVIRIN IN TREATMENT-NAIVE, NONCIRRHOTIC PATIENTS WITH HEPATITIS C VIRUS GENOTYPE 1 INFECTION: THE C-WORTHy STUDY - (04/14/14)
EFFICACY AND SAFETY OF THE ALL-ORAL REGIMEN, MK-5172/MK-8742 +/- RBV FOR 12 WEEKS IN GT1 HCV/HIV CO-INFECTED PATIENTS: THE C-WORTHY STUDY - (04/11/14)
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