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Published on : Dec 11, 2017 | Views : 1998 | Downloads : 4

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Vosevi ® film-coated tablets
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VOSEVI 400mg/100mg/100mg FILM COATED TABLET Composition : 400mg sofobuvir 100mg velpatasvir 100mg voxilaprevir
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VOSEVI 400mg/100mg/100mg FILM COATED TABLET FDA Approved 2017 Treating HCV genotype (1-6) without cirrhosis or with mild cirrhosis.
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VOSEVI 400mg/100mg/100mg FILM COATED TABLET Therapeutic indication: DAA : Direct Acting Antiviral Agents
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VOSEVI 400mg/100mg/100mg FILM COATED TABLET Dosing Dose once daily Missed dose Within 18 hours : dose is taken as soon as possible then at normal time. More than 12 hours : wait and take the next dose at normal time. ( No doubling dose) In case of vomiting : With 4 hours take another dose. More than 4 hours no further dose.
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VOSEVI 400mg/100mg/100mg FILM COATED TABLET Elderly No dose adjustment. Renal impairment Mild & Moderate impairment : no dose adjustment. Sever impairment : safety and efficacy not assessed.
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VOSEVI 400mg/100mg/100mg FILM COATED TABLET Hepatic impairment Mild impairment: no dose adiustment. Moderate & Sever : not recommended. Pediatric population The safety and efficacy not established yet.
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VOSEVI 400mg/100mg/100mg FILM COATED TABLET Contraindication: Hypersensitivity Concomitant use with glycoprotein inducers or cytochrome P450 inducer. Concomitant use with ethinyl estradiol containing product.
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VOSEVI 400mg/100mg/100mg FILM COATED TABLET Serious liver problems (liver failure , death) in patient who had HBV. Slowing heart rate in patient taking Amidarone. Headache,Diarrhea & Nausea.
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Clinical trials The FDA approval for Vosevi™ was based on data from four phase III clinical trials POLARIS-1, POLARIS-2, POLARIS-3, and POLARIS-4. The primary endpoint of these studies was sustained virological response at week 12 (SVR12). The most common adverse events found in patients treated with Vosevi™ in the POLARIS studies were headache, fatigue, diarrhoea, and nausea.
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POLARIS-1 This study will evaluate the safety and efficacy of treatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) in adults with chronic HCV infection who have previously received treatment with direct-acting antiviral therapy.
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N = 263 N = 152 W12 > 18 years Chronic HCV infection Genotype 1, 2, 3, 4, 5 or 6 NS5A inhibitor-experienced for ≥ 4 weeks (exclusion if discontinued due to an adverse event or unsuccessful due to non-compliance) Compensated cirrhosis ** allowed Randomisation* 1 : 1 Double blind SVR12 POLARIS-1 Design Objective SVR12 (HCV RNA < 15 IU/mL), with 95% CI, by ITT: superiority > 10% to a prespecified rate of 85% (2-sided significance level of 5%), for each regimen, 90% power POLARIS-1 study: SOF/VEL/VOX in NS5A inhibitor-experienced patients with genotype 1 to 6
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Baseline characteristics and patient disposition POLARIS-1 Bourlière M. NEJM 2017; 376:2134-46
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* Superiority to 85% (p < 0.001) SOF/VEL/VOX 12 weeks: SVR12 overall and by subgroups, % (95% CI) 0 20 40 60 80 100 96.2 * (93-98) Total 99 (95-100) No 121 93 (87-97) Cirrhosis 150 101 100 (92-100) 4 5 100 6 Genotype 45 5 95 (87-99) 6 relapses 1 on-treatment failure 2 withdrew consent 1 lost to follow-up 1 withdrew consent 1 lost to follow-up % 6 relapses 1 on-treatment failure 1 withdrew consent 1 3 1b 1a 2 96 (90-99) 100 (48-100) 78 22 6 1 100 (54-100) 263 142 97 91 (71-99) Yes POLARIS-1 POLARIS-1 study: SOF/VEL/VOX in NS5A inhibitor-experienced patients with genotype 1 to 6 N= Bourlière M. NEJM 2017; 376:2134-46
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Adverse events POLARIS-1 POLARIS-1 study: SOF/VEL/VOX in NS5A inhibitor-experienced patients with genotype 1 to 6 Bourlière M. NEJM 2017; 376:2134-46
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Summary In NS5A-inhibitor experienced patients, treatment with SOF/VEL/VOX for 12 weeks resulted in a 96.2% SVR12 rate in difficult-to-cure patients with multiple unfavorable characteristics Treatment-emergent NS5A RAS was observed in 1/6 patients with relapse SOF/VEL/VOX was well tolerated with an adverse event profile similar to that observed in placebo recipients SOF/VEL/VOX for 12 weeks provides a single tablet, once daily, highly effective, RBV-free treatment for NS5A inhibitor-experienced patients POLARIS-1 POLARIS-1 study: SOF/VEL/VOX in NS5A inhibitor-experienced patients with genotype 1 to 6 Bourlière M. NEJM 2017; 376:2134-46
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POLARIS-2 The primary objectives of this study are to compare the efficacy, safety, and tolerability of treatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) fixed dose combination (FDC) for 8 weeks with that of SOF/VEL FDC for 12 weeks in direct-acting antiviral-naive participants with chronic hepatitis C virus (HCV) infection.
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N = 501 N = 440 W8 > 18 years Chronic HCV infection Genotype 1, 2, 3, 4, 5 or 6 Treatment-naïve or IFN-experienced Compensated cirrhosis ** allowed (exclusion of genotype 3 with cirrhosis) Randomisation* 1 : 1 Open-label SVR12 POLARIS-2 Design Objective SVR12 (HCV RNA < 15 IU/mL), by ITT: non-inferiority of SOF/VEL/VOX (wo-sided significance level of 5%, lower margin of the 95% CI for the difference = -5%, 95% power) POLARIS-2 study: SOF/VEL/VOX 8 weeks vs SOF/VEL 12 weeks in patients with genotype 1 to 6 Jacobson IM. Gastroenterology 2017; 153:113-22 W12 SVR12
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Baseline characteristics and patient disposition POLARIS-2 Jacobson IM. Gastroenterology 2017; 153:113-22
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SVR12 in genotype 2 to 6, % 0 20 40 60 80 100 97 Genotype 2 100 92 99 89 63 98 18 57 Genotype 5 100 2 relapses 1 lost to follow-up % Genotype 3 Genotype 4 92 94 63 53 97 1 discontinuation for AE 2 lost to follow-up 2 relapses 3 lost to follow-up 1 relapse 100 100 0 30 2 9 0 1 relapse Genotype 6 Unknown POLARIS-2 POLARIS-2 study: SOF/VEL/VOX 8 weeks vs SOF/VEL 12 weeks in patients with genotype 1 to 6 N= Jacobson IM. Gastroenterology 2017; 153:113-22
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Cirrhosis N = 174 No Cirrhosis N = 767 SVR12 by cirrhosis status, % POLARIS-2 POLARIS-2 study: SOF/VEL/VOX 8 weeks vs SOF/VEL 12 weeks in patients with genotype 1 to 6 0 20 40 60 80 100 96 98 91 % 99 N= 84 411 90 356 7 relapses 1 LTFU 1 relapse 14 relapses 3 LTFU 2 relapses 4 LTFU 1 DC due to AE Jacobson IM. AASLD 2016, Abs. LB-12 ; Jacobson IM. Gastroenterology 2017; 153:113-22
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Adverse events *1 upper respiratory tract infection and 1 Clostridium difficile infection, both not related to the study medication POLARIS-2 POLARIS-2 study: SOF/VEL/VOX 8 weeks vs SOF/VEL 12 weeks in patients with genotype 1 to 6 Jacobson IM. Gastroenterology 2017; 153:113-22
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Summary SOF/VEL/VOX for 8 weeks resulted in a 95% SVR12 rate in DAA-naïve genotype 1-6 patients with and without cirrhosis Did not meet non-inferiority as compared to the 98% SVR12 rate with SOF/VEL for 12 weeks The difference between the regimens was largely attributed to more relapses among patients with genotype 1a infection in the SOF/VEL/VOX group SOF/VEL/VOX and SOF/VEL were safe and well tolerated Mild gastrointestinal adverse events (nausea and diarrhea) were associated with treatment regimens that included VOX There was no evidence of VOX-related hepatotoxicity These findings in DAA-naïve patients with or without cirrhosis underscore the very high rates of SVR conferred by SOF/VEL across all HCV genotypes SOF/VEL/VOX for 8 weeks provides a highly efficacious and well-tolerated short-duration regimen in patients for whom adherence to a longer duration regimen may be challenging POLARIS-2 POLARIS-2 study: SOF/VEL/VOX 8 weeks vs SOF/VEL 12 weeks in patients with genotype 1 to 6 Jacobson IM. AASLD 2016, Abs. LB-12 ; Jacobson IM. Gastroenterology 2017; 153:113-22
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POLARIS-3 Design: Open-label, randomized, phase 3 trial to compare efficacy of a fixed-dose combination of sofosbuvir-velpatasvir-voxilaprevir for 8 weeks versus sofosbuvir-velpatasvir for 12 weeks in patients with HCV genotype 3 and cirrhosis who were DAA-naïve Entry Criteria - Age ≥18 years - Chronic HCV GT 3 with compensated cirrhosis - HCV RNA ≥10,000 IU/mL at screening - No prior treatment with DAA; prior peginterferon plus ribavirin allowed Primary End-Point: SVR12
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POLARIS-3 Study : Sofosbuvir-Velpatasvir-Voxilaprevir in GT 3 and Cirrhosis SOF/VEL/VOX SVR12 GT 3 Cirrhotic DAA Naïve n = 110 SOF/VEL SVR12 n = 109 Abbreviations: SOF = sofosbuvir; VEL = velpatasvir; VOX = voxilaprevir Drug Dosing SOF-VEL-VOX (400/100/100 mg): fixed dose combination; one pill once daily SOF-VEL (400/100 mg): fixed dose combination; one pill once daily
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Baseline Characteristics
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Overall SVR12 by Treatment Arm POLARIS-3 Study : Sofosbuvir-Velpatasvir-Voxilaprevir in GT 3 and Cirrhosis
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POLARIS-3 Study : Sofosbuvir-Velpatasvir-Voxilaprevir in GT 3 and Cirrhosis Adverse events
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POLARIS-3 Study : Sofosbuvir-Velpatasvir-Voxilaprevir in GT 3 and Cirrhosis Conclusions: In phase 3 trials of patients with HCV infection, we did not establish that sofosbuvir-velpatasvir-voxilaprevir for 8 weeks was noninferior to sofosbuvir-velpatasvir for 12 weeks, but the 2 regimens had similar rates of SVR in patients with HCV genotype 3 and cirrhosis. Mild gastrointestinal adverse events were associated with treatment regimens that included voxilaprevir.
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POLARIS-4 Design: Open-label, randomized active-comparator, phase 3 trial to compare efficacy of a fixed-dose combination of sofosbuvir-velpatasvir-voxilaprevir versus sofosbuvir-velpatasvir for 12 weeks in DAA-experienced patients who had not received prior NS5A inhibitor. Entry Criteria - Chronic HCV GT 1-6 (enrolled only GT 1-4) - HCV RNA ≥10,000 IU/mL at screening - DAA experienced (excluding prior NS5A use) - Patients with compensated cirrhosis allowed Primary End-Point: SVR12
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POLARIS-4 StudySofosbuvir-Velpatasvir-Voxilaprevir in DAA-Experienced GT 1-6 Sofosbuvir-Velpatasvir- Voxilaprevir SVR12 GT 1-6 with prior DAA experience (no NS5A inhibitor) n = 333 N=182 Sofosbuvir-Velpatasvir SVR12 N=151 Week 0 12 24 Drug Dosing Sofosbuvir-Velpatasvir-Voxilaprevir (400/100/100 mg): fixed dose combination; one pill once daily Sofosbuvir-Velpatasvir (400/100 mg): fixed dose combination; one pill once daily
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Baseline Characteristics
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POLARIS-4 StudySofosbuvir-Velpatasvir-Voxilaprevir in DAA-Experienced GT 1-6 P<0.001 for superiority compared with prespecified 85% performance goal for SOF-VEL-VOX Overall SVR12 by Treatment Arm
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POLARIS-4 StudySofosbuvir-Velpatasvir-Voxilaprevir in DAA-Experienced GT 1-6 SVR12 by Genotype
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POLARIS-4 StudySofosbuvir-Velpatasvir-Voxilaprevir in DAA-Experienced GT 1-6 Adverse events
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POLARIS-4 StudySofosbuvir-Velpatasvir-Voxilaprevir in DAA-Experienced GT 1-6 Conclusions: Sofosbuvir-velpatasvir-voxilaprevir taken for 12 weeks provided high rates of sustained virologic response among patients across HCV genotypes in whom treatment with a DAA regimen had previously failed.
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Thank you
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References: https://www.fda.gov/Drugs/InformationOnDrugs/ucm569725.htm. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm567467.htm Bourlière M, et al. N Engl J Med. 2017;376:2134-46. Jacobson IM, et al. Gastroenterology. 2017;153:113-22.