Friday, March 17, 2017

In Case You Missed It - Review Gilead's HCV Investigational Regimen Sofosbuvir/Velpatasvir/Voxilaprevir

Review Sofosbuvir/Velpatasvir/Voxilaprevir

It can be overwhelming trying to sift through research about newly approved or investigational agents to treat HCV, especially if you were recently diagnosed with hepatitis C. Hopefully, this short review will give you a better understanding of cure rates for Gilead's pan-genotypic fixed-dose combination tablet consisting of Sofosbuvir/Velpatasvir/Voxilaprevir - that sure is a mouthful. Gilead's regimen has been shown to be highly effective in treatment-naive and treatment-experienced patients with HCV genotype 1–6. This is good news for people who have treated previously with direct-acting antivirals but relapsed. I'm sure you all know that in December Gilead submitted a new drug application (NDA) to the U.S. Food and Drug Administration, and in January Sofosbuvir/Velpatasvir/Voxilaprevir was granted an Accelerated Assessment by the European Medicines Agency.  The fixed-dose combination has been granted Breakthrough Therapy designation by the U.S. Food and Drug Administration for the treatment of chronic genotype 1 HCV patients who have previously failed an NS5A inhibitor-containing regimen.

Lets start with expert commentary (video with slides) discussing the 3 drug regimen using data presented at the American Association for the Study of Liver Diseases (AASLD) annual meeting in November, the program is available online at ViralEd.

Show Me A Video - Sofosbuvir/Velpatasvir/Voxilaprevir.
Listen to Dr. Dieterich review and discuss Sofosbuvir/Velpatasvir/Voxilaprevir, in this short in-depth ten minute segment, over at ViralEd.
View the program with Dr. Dieterich, here......
Download Slides from the presentation, here.....

Highlights Include
POLARIS-2 Study
Genotype 1–6
A Randomized Phase 3 Trial of Sofosbuvir/Velpatasvir/Voxilaprevirfor 8 Weeks Compared to Sofosbuvir/Velpatasvir for 12 Weeks in DAA-Naïve Genotype 1–6 HCV Infected Patients

Genotype 3
The POLARIS-3 Study
A Randomized, Phase 3 Trial of Sofosbuvir/Velpatasvir/Voxilaprevir for 8 Weeks and Sofosbuvir/Velpatasvir for 12 Weeks for Patients with Genotype 3 HCV Infection and Cirrhosis

Data submitted in Gilead's NDA

What Data Was Used In The New Drug Application (NDA)
The following data supports the use of the regimen for 12 weeks in DAA treatment experienced patients with HCV genotype 1 - 6 who have or don’t have liver cirrhosis.

The NDA for SOF/VEL/VOX is based on data from two Phase 3 studies (POLARIS-1 and POLARIS-4). The NDA is further supported by two additional Phase 3 studies (POLARIS-2 and POLARIS-3)

Show Me The Data
Phase 3 POLARIS trials, included people who were previously treated with direct-acting antivirals and those with hepatitis C virus (HCV) genotype 3 and compensated cirrhosis.

In POLARIS-1, 96% of NS5A-experienced patients with HCV genotypes 1-6 were cured with 12 weeks of sofosbuvir/velpatasvir/voxilaprevir, compared with none of the placebo recipients.

POLARIS-4 showed that the triple combination for 12 weeks worked better than a dual combination of sofosbuvir/velpatasvir for DAA-experienced patients who had not used NS5A inhibitors (SVR12 97% vs 90%).

POLARIS-3 demonstrated that 8 weeks of sofosbuvir/velpatasvir/voxilaprevir worked as well as 12 weeks of sofosbuvir/velpatasvir for patients with hard-to-treat genotype 3 and liver cirrhosis.

However POLARIS-2, with a more diverse group of mostly non-cirrhotic DAA-naive patients with genotypes 1-6, did not reach the threshold for non-inferiority.

StudyPopulationGenotypeTreatmentDurationSVR12 Rates
POLARIS-1NS5A inhibitor-experienced

41 percent (172/415) had cirrhosis
1, 2, 3, 4, 5, 6SOF/VEL/VOX12 Weeks96%
(253/263)
Placebo12 Weeks0%
(0/152)
POLARIS-4
DAA-experienced (No NS5A inhibitor)

46 percent (153/333) had cirrhosis

1, 2, 3, 4SOF/VEL/VOX12 Weeks97%
(177/182)
SOF/VEL12 Weeks90%
(136/151)
POLARIS-2DAA-naïve

18 percent (174/941) had cirrhosis
1, 2, 3, 4, 5, 6SOF/VEL/VOX8 Weeks95%
(476/501)
SOF/VEL12 Weeks98%
(432/440)
POLARIS-3DAA-naïve

All had cirrhosis
3SOF/VEL/VOX8 Weeks96%
(106/110)
SOF/VEL12 Weeks96%
(105/109)
Source - http://hivandhepatitis.com/hcv-treatment/experimental-hcv-drugs/5891-new-triple-combo-cures-most-daa-experienced-and-hard-to-treat-hepatitis-c-patients-without-ribavirin

Summary
The NDA for SOF/VEL/VOX is based on data from two Phase 3 studies (POLARIS-1 and POLARIS-4), which evaluated 12 weeks of the fixed-dose combination in DAA-experienced patients with hepatitis C genotypes 1-6, including those who failed prior treatment with an NS5A-containing regimen. Of the 445 patients treated with SOF/VEL/VOX, 430 (97 percent) achieved the primary efficacy endpoint of SVR12.

The NDA is further supported by two additional Phase 3 studies (POLARIS-2 and POLARIS-3) in which 611 DAA-naïve HCV-infected patients received 8 weeks of SOF/VEL/VOX.

The most common adverse events among patients who received SOF/VEL/VOX were headache, fatigue, diarrhea and nausea.

In The Journals

HCV Genotype 1
Abstract
Published in Hepatology 2017 Feb 21,  Sofosbuvir-velpatasvir-voxilaprevir with or without ribavirin in DAA-experienced patients with genotype 1 HCV.

Media Coverage of this study: Source - Hepatitis: Monthly Essentials March 2017

Takeaway
  • Once-daily sofosbuvir, velpatasvir, and voxilaprevir (SOF/VEL/VOX) tablets show high efficacy as salvage therapy for HCV-1 after failure of direct-acting antivirals (DAAs).
Key results
  • Most patients (88%) had received only 1 prior regimen; 41% had previously received an NS5A inhibitor±another DAA; 20% had been exposed to ≥3 DAA classes.
  • Of 48 patients with baseline deep-sequencing data, 73% had resistance-associated substitutions (RAS; 27% had multiple-class RASs).
  • SVR12 with SOF/VEL/VOX±ribavirin (RBV) was 96% and 100%, respectively.
  • 1 relapse occurred in a patient with HCV-1a, cirrhosis, and VEL-associated NS5A L31M RASs.
  • The most common adverse events with SOF/VEL/VOX were diarrhea and bronchitis.
  • With SOF/VEL/VOX+RBV, fatigue, anemia, gastroenteritis, and nausea were most common.
Study design
  • Phase 2 monocentric US open-label randomized study of 49 patients with DAA-refractory HCV-1 (1a, 88%; 51% had cirrhosis).
  • Participants received a 12-wk regimen of SOF/VEL/VOX with (n=25) and without (n=24) RBV.
  • Primary endpoint was sustained virologic response at 12 wk posttherapy (SVR12).
  • Funding: Gilead Sciences.

Recommended Reading

Fixed-Dose Sofosbuvir/Velpatasvir/Voxilaprevir Cures 97% of Treatment-Experienced Hepatitis C Patients

Discussion Forum
SOF/VEL and SOF/VEL/VOX

Other Investigational HCV Agents
Novel emerging treatments for hepatitis C infection: a fast-moving pipeline

National AIDS Treatment Advocacy Project (NATAP)
Summary for AASLD 2016 for Hepatitis C - New HCV two and three drug regimens on their way: what do they promise? And what do clinicians need to look out for under DAA combination therapy and beyond SVR?

Of Interest
Rapid Response from Barcelona: New Data in HCV Treatment
Healio Gastroenterology, March 2017
Source - http://www.healio.com/gastroenterology/education-lab/2016/05_may/rapid-response-from-barcelona-new-data-in-hcv-treatment/new-data-in-hcv-treatment

Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis, end-stage liver disease, hepatocellular carcinoma, and death from liver disease in the United States. Rapid advancements in the field and interferon-free regimens approved for HCV, as well as several on the horizon, offer improved outcomes, shorter treatment durations, and unique adverse event profiles; therefore, clinicians must stay informed of the evolving data to counsel patients appropriately. Clinicians face challenges regarding how to make treatment choices among the numerous interferon-free regimens to improve treatment uptake and optimize outcomes in patients with HCV. This roundtable discussion among leading experts in HCV was recorded immediately following the 2016 EASL meeting in Barcelona, Spain, exploring some of the most recent findings and addressing the evidence-based clinical application of these data for HCV patients.



For downloadable slides, please click here.

Of Interest
Monday, March 20, 2017
2017 / Hepatitis C: Down but Not Out - Oral Direct-Acting Agent Therapy for HCV

HCV Advocate
March 1, 2017
Drug Pipeline – Monthly Report

Clinical Trials Reference Guide
Users can search for a hepatitis C clinical trial by category (genotype), or learn how to evaluate a clinical trial and become familiar with commonly used terms. HCV Advocate offers an easy to navigate HCV Medications Blog as well, organized by HCV genotype.

Happy St. Paddy's Day folks!

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