Alisporivir Attributes and Potential in Hepatitis C Treatment CA Brass 1 , L Griffel 1 , R Orsenigo 2 , W Bao 1 , B Nault 2 , KA Wong 3 , B Li 3 , F Fischer 2 , NV Naoumov 2 1 Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 2 Novartis Pharma AG, Basel, Switzerland; 3 Novartis Institute of Biomedical Research, NJ, USA. Poster presentation at the American Association for the Study of Liver Diseases (AASLD)/European Association for the Study of the Liver (EASL) 2014 Special Conference on Hepatitis C, September 12 – 13, 2014, New York, USA. BACKGROUND • Alisporivir (ALV; DEB025), a host cyclophilin inhibitor, has demonstrated antiviral activity against multiple viruses including hepatitis C virus (HCV) genotypes (G) 1–4, HIV, HBV and coronaviruses. • By blocking the peptidyl-prolyl isomerase activity of cyclophilin A, which is essential for HCV replication, ALV provides pan-genotypic activity and high barrier to resistance, suggesting that ALV may be a backbone component in combination therapies with direct acting antiviral drug(s) for patients with hepatitis C. OBJECTIVE • To evaluate the efficacy and safety of ALV in combination with ribavirin (interferon [IFN]-free) or peg-IFN/ribavirin (P/R) in patients with HCV infections. METHODS • Clinical efficacy and safety of ALV were evaluated in seven randomized trials involving >2000 patients at various doses, in combination with ribavirin or P/R. • In vitro investigations assessed ALV combinations with direct acting antivirals (DAA) against HCV G1–G4 replicons. • Viral resistance was investigated in all cases with viral breakthrough (VB) or post-treatment relapse by identifying viral amino acid changes and their impact on ALV susceptibility (phenotypic analyses). • Expression of interferon-stimulated genes (ISG) was analyzed in paired peripheral blood mononuclear cells at baseline and treatment week 4 with ALV IFN-free, or with P/R. RESULTS Clinical efficacy • The combination of ALV with P/R shows markedly improved efficacy compared with P/R alone, especially in the difficult G1 subgroups (Fundamental Study), such as prior non-responders (null) and cirrhotics (40% SVR12 vs 0%, respectively) 1 (Figures 1 and 2). ALV 600 QD ALV 800 QD ALV 400 BID P/R 60 43 23 61 46 39 58 63 65 26 5 3 0 10 20 30 40 50 60 70 80 90 100 Relapser (n=198) ALV, alisporivir; BID, twice daily; P/R, peg-interferon/ribavirin; QD, once daily. Partial non responders (n=83) Null non responders (n=154) Percentage of patients achieving SVR12 (%) 10/22 28/48 14/54 28/47 6/14 30/49 17/27 14/36 22/34 1/36 11/48 1/20 Figure 1. Percentage of patients by prior treatment response achieving SVR12 in the Fundamental Study ALV 600 QD ALV 800 QD ALV 400 BID P/R 45 31 57 38 66 44 20 0 0 10 20 30 40 50 60 70 80 90 100 No cirrhosis (n=311) “Cirrhosis” defined as elasticity score ≥ 10.8 kPa or as Metavir score F3/F4 or Ishak score 5-6. P-values are based on Cochran-Mantel-Haenszel test adjusted for stratification variables. Cirrhosis (n=112) Percentage of paients achieving SVR12 (%) 36/80 40/70 54/82 16/79 8/26 13/34 10/23 0/29 Figure 2. Percentage of patients by cirrhosis status achieving SVR12 in the Fundamental Study • ALV 400 mg BID in combination with P/R was the most effective dose tested with 89% SVR in G1 prior treatment failures, compared with 30% in P/R control and 74–75% with ALV 600 or 800 mg once a day combined with P/R in patients receiving at least 40 weeks of ALV treatment in the Fundamental Study 1 (Figure 3). 7 3/42 0/32 7/34 0/72 35/55 39/55 44/56 12/25 14/19 15/20 16/18 3/10 58 74 0 71 75 21 79 89 0 48 30 0 10 20 30 40 50 60 70 80 90 100 ≤ 31 weeks* (n=180) > 31 weeks ≤ 40 weeks (n=191) > 40 weeks ≤ 48 weeks (n=67) Percentage of patients achieving SVR12 (%) ALV 600 QD ALV 800 QD ALV 400 BID P/R *Patients who discontinued treatment before clinical hold with less than 31 weeks of treatment. Figure 3. Impact of duration of ALV treatment on SVR12 in the Fundamental Study • IFN-free ALV treatment resulted in up to 90% SVR in HCV G2/3 treatment-naïve patients who achieved RVR 2 in the Vital-1 Study (Figure 4). 71 90 88 0 3 0 24 3 9 0 10 20 30 40 50 60 70 80 90 100 ALV 1000 (n=17) ALV, alisporivir; ITT, intention-to-treat; RBV, ribavirin; VB, viral breakthrough. ALV 600 + RBV (n=29) ALV 800 + RBV (n=32) Percentage of patients (%) Per Protocol SVR24 VB Relapse ITT SVR 24 68% 90% 78% Figure 4. Percentage of patients achieving SVR24, VB and relapse in the Vital-1 Study • Efficacy was similar in patients with G2 and G3 (Figure 5). 78 77 77 81 89 82 0 10 20 30 40 50 60 70 80 90 100 ALV 1000 ± pegIFN/RBV (n=23/58) ALV, alisporivir; G, genotype; HCV, hepatitis C virus; IFN, interferon; RBV, ribavirin. ALV 600+RBV ± pegIFN (n=30/54) ALV 800+RBV ± pegIFN (n=26/67) Proportion of patients with undetectable HCV RNA (%) G2 G3 Figure 5. Patients (genotypes 2 and 3) achieving SVR24 in the Vital-1 Study • This antiviral activity of ALV IFN-free regimens was not associated with up-regulation of ISG (Figure 6). ALV IFN-free arms ISG metagene expression (log 2 values) IFN-containing arms ALV 1000 ALV, alisporivir; BL, baseline; IFN, interferon; ISG, interferon-stimulated gene; RBV, ribavirin; W4, week 4 6.00 8.00 10.00 12.00 BL ALV600+RBV ALV600+RBV ALV+PegIFN PegIFN+RBV W4 BL W4 BL W4 BL W4 BL W4 BL  W4 Fold-change -1.7 -2.0 -2.1 5.3 7.9 p-value 0.005 <0.005 <0.005 <0.005 <0.005 # of subjects 23 29 31 14 8 Figure 6. Treatment-induced interferon-stimulated genes expression High-barrier to resistance • Genotypic changes in NS5A domain II were observed in patients experiencing VB; most are polymorphic changes and some exhibited low levels of reduced susceptibility (3~5 fold in EC 50 ) (Table 1) with compromised replication fitness 3 (Table 2). Table 1. Pharmacokinetic, genotypic and phenotypic resistance analysis of patients with breakthrough during ALV treatment** Patient Genotype Initial treatment Time of VB NS5A amino acid changes relative to baseline Breakthrough/ baseline ALV EC 50 (nM) Phenotypic assay (EC 50 fold increase) Ratio of patient/ group mean ALV trough concentration 1 3a ALV 600 mg QD + RBV Week 8 R347W 468.9/51.0* 9.2 2.7 2 2a ALV 600 mg QD + RBV Week 20 D316E 291.8/73.2 4.0 0.8 3 3a ALV 600 mg QD + RBV Week 4 D320E, R347R/W 335.7/47.2 7.1 0.2 4 2b ALV 800 mg QD + RVB Week 12 D316E † , T324R 425.1/112.8 3.8 0.2 5 3b ALV 800 mg QD + RVB Week 6 D316N † 117.9/77.3 1.5 0.1 6 3a ALV 1000 mg QD Week 6 A347V 118.7/33.6 3.5 0.1 7 3a ALV 1000 mg QD Week 6/8 D320E/D, R347R/G, A349A/V 309.1/53.0 5.8 0.1 **Patients analyzed were those who received ALV-based, initially IFN-free treatment. † Resistance-associated variant also detected at baseline by population sequencing. *3a-S52 reference strain EC 50 in lieu of baseline EC 50 . EC 50 , half maximal effective concentration; ALV, alisporivir; EC 50 , half maximal effective concentration; IFN, interferon, QD, once daily; RBV, ribavirin; VB, viral breakthrough. Table 2. Site-directed mutant replication fitness and ALV susceptibility EC 50 (mM) EC 50 fold-shift over reference Replication fitness (72 h/4 h) % reference JFH1 0.112 1.0 100 JFH1-D316E 0.262 2.3 123.8 S52 0.069 1.0 100 S52-D320E 0.36 5.2 48.7 S52-R347W 0.254 3.7 15.3 S52-D320E/R347W 1.435 20.8 2.6 S52-A349V 0.225 3.3 45.1 S52-D320E/A349V 0.758 11.0 12.1 JFH1: GT2a; S52: GT3a • There was no cross resistance observed in NS3, NS5A, or NS5B DAAs 4 . Synergy with DAAs • In vitro, ALV demonstrated additive or synergistic activity with all classes of DAAs in advanced development, with the greatest synergy observed with NS5A inhibitors in G3 5 (Figure 7). 15 10 5 0 -5 400 200 100 50 25 12.5 0 250 500 1000 2000 4000 8000 15 Similar results with daclatasvir and EDP-239 10 5 0 -5 15 10 5 0 -5 [ALV], nM [Daclatasvir], nM Synergistic effect Figure 7. Combination of ALV and NS5A on HCV GT3a led to a synergistic effect Safety • The safety profile of ALV IFN-free has shown to be markedly better than ALV in combination with peg-IFN (Tables 3 and 4). Table 3. Incidence of notable treatment-emergent adverse events Preferred term, N (%) ALV 400 mg BID+P/R, N=376 ALV+P/R (any ALV dose), N=1365 IFN-free (ALV or ALV+R), N=260 P/R , N=489 Any AE 363 (96.5) 1297 (95.0) 199 (76.5) 450 (92.0) Anemia 154 (41.0) 515 (37.7) 7 (2.7) 122 (24.9) Neutropenia 120 (31.9) 448 (32.8) 0 110 (22.5) Nausea 109 (29.0) 362 (26.5) 43 (16.5) 85 (17.4) Thrombocytopenia 94 (25.0) 264 (19.3) 0 23 (4.7) Hyperbilirubinemia 92 (24.5) 253 (18.5) 10 (3.8) 7 (1.4) Leukopenia 41 (10.9) 197 (14.4) 0 51 (10.4) Hypertension 69 (18.4) 181 (13.3) 22 (8.5) 9 (1.8) Upper abdominal pain 32 (8.5) 96 (7.0) 13 (5.0 24 (4.9) Jaundice 36 (9.6) 90 (6.6) 8 (3.1) 6 (1.2) Hypertriglyceridemia 26 (6.9) 82 (6.0) 1 (0.4) 15 (3.1) • Pancreatitis was reported (only in combination with IFN) with an incidence similar to other studies using P/R only; preclinical investigations confirmed that ALV does not directly cause pancreatic damage 6 . • Few serious adverse events (SAEs) or AEs requiring treatment discontinuation have been reported with IFN-free ALV, although SAEs including hypertension were reported during the use of ALV with peg-IFN. • Current studies utilize specific management plans for hypertension and hyperbilirubinemia and enforce contraindications related to drug-drug interactions. Table 4. Incidence of notable treatment-emergent serious adverse events SAEs* ALV+P/R* (any ALV dose) N=1365 n (%) IFN-free (ALV or ALV+R) N=260 n (%) P/R N=489 n (%) Any SAE 105 (7.7) 5 (1.9) 23 (4.7) Hypertension 6 (0.4) 0 0 Anemia 5 (0.4) 0 1 (0.2) Neutropenia 4 (0.3) 0 0 Pancreatitis acute 4 (0.3) 0 0 Vomiting 4 (0.3) 1 (0.4) 2 (0.4) Abdominal pain 3 (0.2) 0 1 (0.2) Diarrhea 3 (0.2) 1 (0.4) 0 Hypertensive crisis 3 (0.2) 0 0 Diabetic ketoacidosis 2 (0.1) 0 0 Hyperbilirubinemia 2 (0.1) 0 0 Loss of consciousness 2 (0.1) 0 0 Nausea 2 (0.1) 0 1 (0.2) Pancreatitis 2 (0.1) 0 1 (0.2) Pancytopenia 2 (0.1) 0 0 Subarachnoid hemorrhage 2 (0.1) 0 0 Suicidal ideation 2 (0.1) 0 0 Thyroiditis 2 (0.1) 0 0 *≥2 patients in the ALV+P/R group; SAEs by preferred term Triple therapy arms: ALV 600 mg QD+P/R, ALV 800 mg QD+P/R, ALV 400 mg BID+P/R. Treatment-emergent SAEs: those reported on or after the day of the first dose of study drug until 30 days after the last dose of study drug. ALV, alisporivir; BID, twice daily; IFN, interferon; P, peg-IFN; QD, once daily; R, ribavirin; SAE, serious adverse event. CONCLUSION As a first-in-class host-targeting oral anti-HCV agent with pan-genotypic activity, high barrier to resistance and an extensive safety database, ALV is a promising agent for use in combination with DAAs for the treatment of chronic hepatitis C. REFERENCES 1. Buti et al. J Hepatol 2013;58(Suppl 1):S572. 2. Pawlotsky et al. Hepatology 2012;56(Suppl);309A. 3. Pawlotsky et al. J Hepatol 2013;58(Suppl 1):abst 493. 4. Garcia-Rivera JA et al. Antimicrob Agents Chemother 2012;56:5113. 5. Chatterji U et al. Antimicrob Agents Chemother. 2014;58:3327. 6. Brees et al. Hepatology 2013:58(Suppl);436A. Disclosures: All authors are employees of Novartis Pharmaceuticals. Scan to download a reprint of this poster