Antiviral InteliStrat Inc.

Cpnds of this family have reportedly a good bioavailability supporting potential once-daily dosage;

Co-administration of ABT-450 with Ritonavir increases Cmax and AUC of ABT-450 by factor of 28- to 48-fold

Ref.: Gentile I et al., Curr Med Chem. 2014;21(28):3261-70. Review. (www.ncbi.nlm.nih.gov/pubmed/25005190)

Signature amino acid positions generally recognized as associated with loss of susceptibility to protease inhibitors are: 56, 155, 156, and 168 in NS3 gene of HCV genotype 2 (GT2);

Paritaprevir is highly susceptible to substitution at position D168 in the viral protease gene (D168 N/Y); Due to such mutations, the inhibitor-protein hydrogen bonding between them was weakened and the salt-bridge network among residues R123, R155 and D168 responsible for inhibitor binding was disrupted;
Moreover, the per-residue free energy decomposition suggested that the main contributions from key residues such as Q80, V132, K136, G137 and R155 were lost in the D168 N/Y mutations.
Ref.: Boonma T et al., Comput Biol Chem. 2019 Dec;83:107154 [pubmed.ncbi.nlm.nih.gov/31751885];

       
Results of two clinical studies that analysed virologic failure and the emergence of resistance in Japanese patients chronically infected with HCV and receiving a combination of Ombitasvir plus Paritaprevir/Ritonavir for up to 16 weeks were published by Schnell G et al., J Med Virol. 2018 Jan;90(1):109-119 [pubmed.ncbi.nlm.nih.gov/28842997]:

• Clinical studies M12‐536 (Phase II, NCT01672983) and GIFT‐II study (Phase III, NCT02023112) were conducted in Japan, where HCV GT2 has a high prevalence
• Baseline polymorphisms in NS3/4A viral gene that confer resistance to Paritaprevir were rare in both GT2a- and GT2b-infected patients and had no significant impact on treatment outcome in Japanese patients
• Most common treatment-emergent substitutions at the time of virologic failure occurred at amino acid positions 168 in NS3 in both GT2a- and GT2b-infected patients
• In both studies, for GT2a, D168A/E/Y/V and Y56H mutations were found in the NS3/4A gene, and for GT2b, D168A/F/H/L/N/P/S/T/V/Y mutations

An analysis similar to the one reported above was published by Krishnan P et al., Antimicrob Agents Chemother. 2015 Dec 7;60(2):1106-13 [pubmed.ncbi.nlm.nih.gov/26643326]:

• Clinical studies M12‐536 (Phase II, NCT01672983) and GIFT‐I study (Phase III, NCT02023099) were conducted in Japan, this time with patients chronically infected with HCV GT1a receiving a combination of Ombitasvir plus Paritaprevir/Ritonavir for 12 or 24 weeks
• Overall, for the 2 studies, the virologic failure rate was 3% (13/436)
• Among the 13 virologic failures that were observed in the 2 studies, resistance-associated variants with NS3 as well as NS5A mutations were present in all 13 patients after failure; Mutation D168A/V alone or in combination with Y56H were detected in the NS3 gene at the time of failure

Phase IIa (M11-602) study was a randomized, placebo-controlled, blinded, dose-ranging trial evaluating safety and antiviral activity of ABT-450 boosted with Ritonavir in HCV-infected (80% with viral genotype 1a), treatment-naive pts:

• Study included 3 treatment groups and a placebo group: 50 mg ABT-450 / 100 mg Ritonavir, 100 mg ABT-450 / 100 mg Ritonavir, 200 mg ABT-450 / 100 mg Ritonavir; pts received treatment with ABT-450/Ritonavir once-daily for 3 days (monotherapy phase), followed at the end of the 3 days by combined treatment with ABT-450/Ritonavir and PEG-IFN alfa-2a 180 µg weekly plus Ribavirin 1000-1200 mg once daily based on pt's weight up to week 12, followed after week 12 by standard treatment only with PEG-IFN/Ribavirin through week 48

Results of the monotherapy phase (3 day-treatment with ABT-450/Ritonavir) were presented at 61st Annual Meeting of AASLD, Oct. 29-Nov. 2, 2010 by Lawitz et al., Poster 1855:

• Profound decreases in HCV RNA levels were seen at all ABT-450/Ritonavir doses (similar for all doses): mean maximum decrease from baseline was 4.02 log10 IU/mL vs. 0.36 log10 for placebo group (p<0.001)
• No treatment-related SAEs were reported
• AEs included dizziness, headache and somnolence, and were generally mild

Results of the first 4 weeks of combined therapy with ABT-450/Ritonavir and PEG-IFN/Ribavirin were presented at 61st Annual Meeting of AASLD, Oct. 29-Nov. 2, 2010 by Lawitz et al., Poster LB10:

• At week 4, mean HCV RNA decrease from baseline was 5.58 log10 for pts receiving drug combination vs. 1.86 log10 for pts receiving placebo (p<0.001)
• Antiviral response was similar in all 3 ABT-450 dose groups

Results of an open-label Phase II pilot study ("Pilot" study NCT01221298, M12-267) evaluating a combination of ABT-450 (boosted with Ritonavir, ABT-450/r) with ABT-072 and Ribavirin were announced by Abbott on Apr. 19, 2012, and presented by Lawitz et al. at the 47th Annual Meeting of the EASL, Apr. 18–22, 2012, Barcelona, Spain (Abstract 13):

• Study enrolled 11 treatment-naive pts chronically infected with HCV genotype 1, who received ABT-450/r (150/100 mg QD) plus ABT-072 (400 mg QD) and weight-based Ribavirin BID (1000-1200 mg total daily dose) during 12 weeks
• 100% pts maintained HCV RNA levels <25 IU/mL from weeks 4 through 12 of treatment, and all had undetectable HCV RNA from week 5 to end of treatment
• 91% pts (10 of 11) achieved SVR24 (defined as HCV RNA below 25 IU/mL 24 weeks after end of treatment)
• One relapse was observed 8 weeks post therapy and a second 36 weeks
  post therapy; overall, 82% pts (9 of 11) achieved SVR36
• No additional relapses were seen among the 10 pts with 48-week post-
  treatment data available / where SVR48 results were available
• Most common AEs were headache (36%), fatigue (27%), nausea (27%) and dry skin (27%), most of which were mild in severity
• Two bilirubin elevations, which consisted of indirect bilirubin with no
  associated transaminase elevations, were reported during the study; they occurred one week after starting treatment and resolved with continued dosing

Results of an open-label Phase II pilot study (NCT01306617) evaluating a combination of ABT-450 (boosted with Ritonavir, ABT-450/r) with ABT-333 and Ribavirin were presented by Poordad et al. at the 47th Annual Meeting of the EASL, Apr. 18–22, 2012, Barcelona, Spain (Abstract 1399):

• Study enrolled treatment-naive and non-responder pts chronically infected with HCV genotype 1, who received ABT-450/r QD (250/100 mg for Arm 1, treatment-naive pts; 150/100 mg for Arm 2 treatment-naive pts and same for Arm 3, pts non-responders to previous treatment) plus ABT-333 BID and weight-based Ribavirin BID (1000-1200 mg total daily dose) during 12 weeks
• Rapid viral response (RVR, defined as HCV RNA below 25 IU/mL at week 4): Arm 1, 19 pts/19 pts (100%); Arm 2, 13/14 (92.9%) (1 pt discontinued trt due to inability to comply with study drug regimen); Arm 3, 15/17 (88.2%)
• Sustained viral response (SVR4, defined as HCV RNA below 25 IU/mL 4 weeks after end of treatment): Arm 1, 18/19 (94.7%); Arm 2, 13/14 (92.9%); Arm 3, 8/17 (47.1%) (6 pts had viral breakthrough , and 3 pts relapsed)
• Sustained viral response (SVR12 defined as HCV RNA below 25 IU/mL 12 weeks after end of treatment): Arm 1, 18/19 (94.7%); Arm 2, 13/14 (92.9%); Arm 3, 8/17 (47.1%)
• Conclusion: This IFN-free regimen was well tolerated and achieved SVR12 in 93-95% of treatment-naïve and 47% of previous non-responder subjects infected with HCV genotype-1

On Apr. 23, 2013, AbbVie announced additional results from Aviator Phase IIb study (M11-652, NCT01464827) evaluating safety and efficacy of combination of ABT-450 boosted with Ritonavir (dosed 100/100 to 200/100 mg QD), ABT-267 (25 mg QD), ABT-333 (400 mg BID) and Ribavirin (weight-based dosing) administered for 8, 12 or 24 weeks to chronic HCV genotype 1-infected, non-cirrhotic treatment-naive pts and prior PEG-IFN/Ribavirin null responders;
Results were also presented at 48th Annual Meeting of the European Association for the Study of the Liver (International Liver Congress 2013) in Amsterdam, The Netherlands:

• After 8-week treatment with complete drug combination, SVR12 was 89% and SVR24 was 88% (intent-to-treat analysis, 80 treatment-naive pts dosed), with 10 pts relapsing
• After 12-week treatment with complete drug combination, SVR12 was 99% and SVR24 was 96% (intent-to-treat analysis, 79 treatment-naive pts dosed), with 1 pt relapsing
• After 12-week treatment with complete drug combination, SVR12 was 93% and SVR24 was 93% (intent-to-treat analysis, 45 null responder pts dosed), with 0 pt relapsing
• After 24-week treatment with complete drug combination, SVR12 was 93% and SVR24 was 90% (intent-to-treat analysis, 80 treatment-naive pts dosed), with 2 pt relapsing
• After 24-week treatment with complete drug combination, SVR12 was 98% and SVR24 was 95% (intent-to-treat analysis, 43 null responder pts dosed), with 0 pt relapsing
• In summary, results showed >90% SVR both in treatment-naive pts and prior PEG-IFN/Ribavirin null responders, with similar high SVR rates observed after 12 and 24 weeks of treatment

Interim 12-week results of ongoing Phase III study for the same drug combination (ABT-450/Ritonavir, ABT-267, ABT-333 and Ribavirin) were also announced by sponsor on Apr. 23, 2013:

• 99% of treatment-naive pts achieved SVR12, and 96% achieved SVR24 (intent-to-treat analysis)
• 93% of prior null responder pts achieved SVR12 and SVR24
• A single relapse occurred at post-treatment week 2

Data from ongoing Phase III Sapphire-1 (NCT01716585) were published by Feld JJ et al., N Engl J Med. 2014 Apr 24;370(17):1594-603 (www.ncbi.nlm.nih.gov/pubmed/24720703):

• Sapphire-1 study was a multicenter, randomized, double-blind, placebo-controlled trial, in which previously untreated pts infected with HCV genotype 1 infection, with no cirrhosis, were assigned in a 3:1 ratio, to receive during a 12-week double-blind period a regimen consisting of single-tablet coformulation of ABT-450/r (ABT-450 150 mg boosted with 100 mg Ritonavir)–Ombitasvir (25 mg) once-daily, along with Dasabuvir (250 mg BID) and Ribavirin (dosed according to body weight) (group A), or matching placebos (group B)
• A total of 631 pts received at least one dose of study drugs
• Rate of sustained virologic response at 12 weeks after end of treatment (SVR12) in group A was 96.2% (95% confidence interval, 94.5 to 97.9), which was superior to historical control rate (78%) for previously untreated pts without cirrhosis who received Telaprevir with PEG-IFN and Ribavirin
• Virologic failure during treatment and relapse after treatment occurred in 0.2% and 1.5%, respectively, of pts in group A
• Response rates in group A were 95.3% among pts with HCV genotype 1a infection and 98.0% among those with HCV genotype 1b infection
• Rate of discontinuation due to AEs was 0.6% in each study group
• Nausea, pruritus, insomnia, diarrhea, and asthenia occurred in significantly more pts in group A than in group B (P<0.05 for all comparisons)
• Reductions in the hemoglobin level were all of grade 1 or 2: reductions of grade 1 and 2 occurred in 47.5% and 5.8%, respectively, of pts in group A, whereas grade 1 reductions occurred in 2.5% of pts in group B