Biotech Values

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ACHN posters at EASL -- Any of this stuff actionable news?

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FINAL RESULTS OF THE PHARMACOKINETICS, EFFICACY, AND SAFETY/TOLERABILITY OF 400 AND 600 MG ONCE-DAILY DOSING OF ACH-1625 (HCV NS3 PROTEASE INHIBITOR) IN HCV GENOTYPE 1
V. Detishin1, W. Haazen2, R. Hooijmaijers3, M. Ruppert3, K. Bol3, H. Robison4, L. Robarge4, A. Agarwal4, M. Deshpande4, E. Olek4*
1Clinical Hospital of Infectious Diseases and INNOPHAR MO S.R.L., Chisinau, Moldova, 2SGS Life Sciences Services, Antwerpen, Belgium, 3Kinesis Pharma BV, Breda, The Netherlands, 4Achillion Pharmaceuticals, New Haven, CT, USA. *[e-mail]
http://www1.easl.eu/easl2011/program/Posters/Abstract265.htm

Background/aims: ACH-1625, an HCV NS3 protease inhibitor in Phase 2 trials for treatment of HCV is rapidly and selectively distributed to the liver. A Phase 1, randomized, double-blind, placebo-controlled, multiple-dose, 4 segment study evaluated the plasma PK, safety, tolerability, and effects on viral kinetics of ACH-1625 in patients with chronic, HCV genotype 1 infection. The final results of 400 mg and 600 mg QD dosing of the drug are reported here.

Methods: Healthy, treatment naïve or experienced HCV genotype 1 infected adults were randomized to placebo or ACH-1625 400 (n=6) or 600 (n=6) mg in the fasted state or 600 mg PO QD following a medium-fat meal (n=6) for 5 days. A validated, non-compartmental PK analysis was performed.

Results: For the 600 mg dose regimen, AUC was notably lower in fasted versus fed conditions. No gender PK differences were observed. Mean baseline HCV RNA ranged from 6.05-6.36 log10. Reductions in viral load were substantial at 48 hours and were sustained up to 12 days. In the 400 and 600 mg fasting and the 600 mg fed groups, the mean maximum drops in HCV RNA were 3.67, 3.40, and 3.81 log10, respectively. PK/PD modeling predicted that HCV RNA declines of >3 log10 could be achieved with QD dosing, similar to that observed in previously described BID doses. AEs were transient, mild or moderate, and elevated bilirubin was not observed. There were no serious AEs or AE-related discontinuations.

Fasted Fed
Mean±SD 400 mg 600 mg 600 mg
Cmin, ng/mL 43.8±65.5 26.6±23.7 42.5±43.2
Cmax, ng/mL 2559±3149 1283±1082 4304±2560
Tmax, h 4.0±2.50-4.02 3.0±2.00-4.00 6.0±3.00-6.00
AUC24, ng•h/mL 13340±18930 5046±3920 21850±13470
Css,av, ng/mL 556±789 210±163 910±561
[PK Profile of ACH-1625 After 5-Days of QD Dosing]

Conclusions: ACH-1625 is generally safe, well-tolerated, and exhibits viral load reductions that support once daily dosing. Based on these results, 200 mg, 400 mg, and 800 mg QD doses are being evaluated in combination with pegylated interferon and ribavirin in a Phase 2 trial.


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ACH-2928: A NOVEL HIGHLY POTENT HCV NS5A INHIBITOR WITH FAVORABLE PRECLINICAL CHARACTERISTICS
M. Huang*, G. Yang, D. Patel, Y. Zhao, J. Fabrycki, C. Marlor, J. Rivera, K. Stauber, V. Gadhachanda, J. Wiles, A. Hashimoto, D. Chen, Q. Wang, G. Pais, X. Wang, M. Deshpande, A. Phadke
Achillion Pharmaceuticals, New Haven, CT, USA. *[e-mail]
http://www1.easl.eu/easl2011/program/Posters/Abstract1090.htm

Background: HCV NS5A has emerged as an important target for treatment of HCV. ACH-2928 is a potent, pan-genotypic NS5A inhibitor. ACH-2928 has demonstrated synergistic activity in combination with ACH-1625, a HCV NS3 protease inhibitor (Huang et al AASLD 2010). Herein, we describe antiviral activity, specificity, safety, and pharmacokinetic characteristics of ACH-2928 that support once-daily dosing.

Method: Optimization of NS5A inhibitors was achieved through evaluation of potency in cell lines harboring genotype-1a and 1b HCV replicon. Various chimeric HCV replicons were constructed to assess the anti-HCV spectrum of lead inhibitors. ADME characteristics, pharmacokinetic properties, and off-target activities were examined by standard procedures. In vivo safety was assessed after repeat dosing in rodent and non-rodentspecies.

Results: ACH-2928 displayed picomolar potency in cell lines harboring a laboratory strain 1a and 1b replicon. High potency was retained against a panel of chimeric replicons carrying NS5A from genotype-1a and 1b-HCV infected patients with average EC50s of 13 pM and 1.9 pM for genotype-1a and 1b, respectively. Potency comparable to genotype 1a was observed for genotype 2a, 4a and 5a chimeric replicon (EC50 < 14 pM). Potency against genotypes 6a and 3a chimeric replicon is 48 pM and 103 pM, respectively. The effect of human serum proteins on the potency of ACH-0142928 is moderate (~ 7 fold in the presence of 40 % human serum). ACH-2928 showed no activity against other mammalian viruses tested. ACH-2928 displayed low cellular toxicity and off target activity against a panel of mammalian ligands' binding and mammalian enzymes. ACH-2928 did not inhibit major CYP isoforms. Oral bioavailability in the rat and dog ranged from 20% - 40%. Safety profile of ACH-2928 supports progression to first in man studies.

Conclusion: ACH-2928 is a potent NS5A inhibitor against genotypes 1-6. It shows low potential for off-target activity and displays pharmacokinetics that supports once daily dosing. It has a profound effect in vitro in preventing the emergence of resistant variants when combined with ACH-1625, an NS3 protease inhibitor in phase 2 clinical trials. These characteristics support clinical evaluation of ACH-2928 in combination with ACH-1625 for once daily treatment of hepatitis C patients.