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DAA Combinations
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By Jules Levin, NATAP
.......as you can see in the table below the topline SVR rates in interferon-free DAA regimens have been reported as 92-100% in the 2 ongoing phase 3 studies of Gilead & Abbvie and 94-100% in other phase 2 studies. The lower SVR rates may occur in the hardest to treat patients: patients who have both cirrhosis and who are prior non-responders. But I expect we can improve SVR rates in studies in these patients too; some companies are conducting studies by adding another drug to their regimen, see below last parapgraph/link.
Here is a brief simple table, below the table are links to these studies:
These are results for genotype 1 patients with most but not all the regimens in research studies now. This table does not include Simeprevir+Peg/Rbv which was FDA approved in Dec/13. I included the regimens approved by the FDA for mono and connected in December/13 which are: Sofosbuvir (Sovaldi) + Peg/Rbv, approved for mono & coinfected; Sofosbuvir+Rbv approved for both mono & Coinfected. It is widely believed & the data so far supports this, that HCV/HIV connected will respond the same as mono infected to DAA orals, which is why the FDA gave approval for these aforementioned regimens for coinfection. Gilead & Abbvie have studies ongoing now in coinfection, I think when the FDA does provide the expected approvals later this year both Gilead & Abbvie's regimens I think there will be approvals for coinfection too. BMS is in phase 3 now with daclatasvir+sofosbuvir & expected in Western Europe will be expanded access programs, and studies of this regimen just started, here is link to these studies
Daclatasvir+Sofosbuvir-new studies, Daclatasvir Phase 3 IFN-free, EMA Compassionate Use, Accelerated EMA Marketing Review Recommendation
There is no data in coinfection with simprevir+sofosbuvir (COSMOS Study), but it can be considered & the ART interactions with the protease simeprevir must be considered. The same can be said for daclatasvir+sofosbuvir, although the interactions with sofosbuvir & ARTs have been reported at a conference & they are not expected to be clinically significant, there are interactions between ARTs & daclatasvir that also were reported at a conference so they too can be adjusted for.
I did not include in this table Achillion data, Presidio data (NS5A), data from Faldaprevir+Peg/Rbv or the 3 drug DAA oral IFN-free Faldaprevir regimen. As you may know recently development of the non-nuke DAA used in the Faldaprevir 3-DAA study was discontinued which included the Presidio NS5A). I did not include Vertex or Idenix data. Vertex is in phase 2 with VX-135 a nucleotide, same class as sofosbuvir. Idenix is in development of several classes of drugs including a NS5A (same class as Ledipasvir, daclatasvir) & nucleotides. Achillion is in development with a protease, a NS5A and a nucleotide.
Merck is in phase 2 lovely quickly into phase 3. BMS is in phase 3. Roche also presented data recently at AASLD in November/13 but their data was disappointing.
HERE is link to New HCV Guidelines/Recommendations for treatment based on what treatments were available on the day these guidelines were released Feb 1 2014, this document provides additional details about the regimens they recommend, immediately after the document was released BMS announced several phase 3 studies (linked to above) for daclatasvir+sofosbuvir:
New Recommendations for Testing, Managing, and Treating Hepatitis C from AASLD/IDSA Panel. And newer developments in HCV therapy - (01/31/14)
Initial Treatment Box. Summary of Recommendations for Patients Who are Initiating Therapy for HCV Infection or Who Experienced Relapse after Prior PEG/RBV Therapy, by HCV Genotype
Sofosbuvir+Peg/Rbv in HCV/HIV Coinfected (91% SVR) 12 weeks:
Sofosbuvir and Peginterferon Alfa-2a/Ribavirin for Treatment-Naïve Genotype 1-4 HCV-Infected Patients Who Are Coinfected With HIV
http://www.natap.org/2013/IDSA/IDSA_24.htm
Sofosbuvir+Ribavirin in coinfected patients:
AASLD: All-Oral Therapy With Sofosbuvir Plus Ribavirin For the Treatment of HCV Genotype 1, 2, and 3 Infection in Patients Co-infected With HIV (PHOTON-1) - (11/06/13)
This is the most recent data from the COSMOS Study which studied 2 DAAs, sofosbuvir + the protease simeprevir:
AASLD: SVR results of a once-daily regimen of simeprevir (SMV, TMC435) plus sofosbuvir (SOF, GS-7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naïve and prior null responder patients:
The COSMOS study - (11/05/13)
Here is the latest study data, slides presented on daclatasvir+sofosbuvir in treatment-naives & in protease failures:
EASL/2012: Potent Viral Suppression With the All-Oral Combination of Daclatasvir (NS5A Inhibitor) and GS-7977 (Nucleotide NS5B Inhibitor), +/- Ribavirin, in Treatment-Naive Patients With Chronic HCV GT1, 2, or 3 (100% SVR gt1, 91% gt2) - (04/19/12)
EASL:Sustained Virologic Response With Daclatasvir Plus Sofosbuvir ± Ribavirin (RBV) in Chronic HCV Genotype (GT) 1-Infected Patients Who Previously Failed Telaprevir (TVR) or Boceprevir (BOC) - (04/27/13)
Here is the very recent journal publication of these studies:
Daclatasvir plus Sofosbuvir for Previously Treated or Untreated Chronic HCV Infection - (01/17/14)
Here is the latest Abbvie data reported by them of their phase 3 data in a press release just recently:
AbbVie Completes Largest Phase III Program of an All-Oral, Interferon-Free Therapy for the Treatment of Hepatitis C Genotype 1 - (01/31/14)
This is the most recent data reported by Gilead, it is their phase 3 results:
GILEAD ANNOUNCES SVR12 RATES FROM THREE PHASE 3 STUDIES EVALUATING A ONCE-DAILY FIXED-DOSE COMBINATION OF SOFOSBUVIR AND LEDIPASVIR FOR GENOTYPE 1 HEPATITIS C PATIENTS - For Immediate Release - (12/18/13)
This is the latest presentation of BMS data for their 3 DAA regimen at AASLD November:
AASLD:Phase 2b Study of the Interferon-Free and Ribavirin-Free Combination of Daclatasvir, Asunaprevir, and BMS-791325 for 12 Weeks in Treatment-Naive Patients With Chronic HCV Genotype 1 Infection - (11/05/13)
This is the most recent Merck data for their 2-drug DAA combination presented at AASLD in November:
AASLD:High Efficacy and Safety of the All-Oral Combination Regimen, MK-5172 / MK-8742 ± RBV for 12 Weeks in HCV Genotype 1 Infected Patients: The C-WORTHY Study - (11/05/13)
Roche
AASLD: Interferon-free Regimen Containing Setrobuvir in Combination with Ritonavir-boosted Danoprevir and Ribavirin with or without Mericitabine in HCV Genotype 1 Treatment-naive Patients: Interim Results from the ANNAPURNA Study - (11/14/13)
Sofosvuvir+ribavirin several studies in mono-infected
CROI:ELECTRON: 100% SVR Rate for Once-Daily Sofosbuvir Plus Ledipasvir Plus Ribavirin Given for 12 Weeks in Treatment-Naïve and Previously Treated Patients With HCV GT 1 - (03/04/13)
CROI:High Efficacy of Sofosbuvir in Combination with Weight Based Ribavirin for 24 weeks in Difficult to Treat HCV Infected Genotype-1 Patients - (03/06/13)
EASL:Once-Daily Sofosbuvir Plus Ribavirin Given for 12 or 24 Weeks in Treatment-Naïve Patients With HCV Infection: the QUANTUM Study.....http://www.natap.org/2013/EASL/EASL_31.htm
AASLD/2012:High Efficacy of GS-7977 in Combination with Low or Full dose Ribavirin for 24 weeks in Difficult to Treat HCV Infected Genotype 1 Patients.....http://www.natap.org/2012/AASLD/AASLD_08.htm
CROI/2013:High Efficacy of Sofosbuvir in Combination with Weight Based Ribavirin for 24 weeks in Difficult to Treat HCV Infected Genotype-1 Patients.......http://www.natap.org/2013/CROI/croi_32.htm
Genotype 1b:
Abbvie - AASLD: Interferon- and Ribavirin-free Regimen of ABT-450/r + ABT-267 in HCV Genotype 1b-infected Treatment-naïve Patients and Prior Null Responders - (11/04/13)
BMS - AASLD: All-Oral Combination of Daclatasvir Plus Asunaprevir in Interferon-Ineligible Naïve/Intolerant and Nonresponder Japanese Patients Chronically Infected With HCV Genotype 1b: Results From a Phase 3 Trial - (11/06/13)
As reported by Jurgen Rockstroh, MD, in his NATAP AASLD report [http://www.natap.org/2013/AASLD/AASLD_109.htm], in the NIAID SYNERGY Trial [http://www.natap.org/2013/AASLD/AASLD_30.htm] 60 HCV mono-infected, treatment naïve, GT-1, patients were consecutively enrolled into 3 arms of a phase 2 clinical trial and received: Arm A - sofosbuvir with ledipasvir (400mg/90mg respectively once daily in a fixed dose combination (FDC)) for 12 weeks, Arm B - FDC + GS-9669 (500mg/day), a non nucleoside NS5B inhibitor for 6 weeks, or Arm C - FDC + GS-9451 (80mg/day), an HCV protease inhibitor for 6 weeks (47). 80-95% of study participants were African-American. In this exploratory trial virological responses were very good with 100% SVR12 in the SOF/LDV (12 weeks arm) (n=20), 90% SVR4 in the SOF/LDV/9669 (6 weeks arm) (n=20) and again 100% SVR4 in the SOF/LDV/9451 (6 weeks arm) (n=20). Only one relapse occurred in the SOF/LDV/9669 arm. Tolerability in all arms was good with no treatment related discontinuation or SAEs. Again this 3 DAA combination study underlines that multiple DAA combinations will work and allow to get rid of interferon as well as ribavirin which is accompanied by greatly improved tolerability. Also the combination of 3 DAAs may allow to shorten treatment duration to 6 weeks at least in easier to treat naïve patient populations which may be very important in the more adherence challenged patient groups.
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