November 28, 2010

First-ever covalent irreversible inhibition of a protease central to hepatitis C infection

Public release date: 28-Nov-2010
Contact: Kathryn Morris
Yates Public Relations

Publication in Nature Chemical Biology demonstrates that irreversible covalent inhibition can increase selectivity, potency and duration of action, broadens applications for targeted covalent drugs to the protease gene family

WALTHAM, MA – November 28, 2010 – Avila Therapeutics™, Inc., a biotechnology company developing novel targeted covalent drugs, has published research in Nature Chemical Biology demonstrating the first-ever selective irreversible inhibition of a viral protease using a targeted covalent drug. In the paper titled "Selective Irreversible Inhibition of a Protease by Targeting a Non-Catalytic Cysteine", Avila used its proprietary Avilomics™ platform to design covalent irreversible protease inhibitors that are highly selective, potent and with superior duration of action as compared to conventional protease inhibitors.

Importantly, the published research demonstrates that covalent drugs can be designed and targeted to irreversibly and covalently bond to molecular domains specific to proteases. This is the first report of the irreversible covalent approach being successfully extended to proteases, a very broad class of proteins that includes many important potential drug targets.

"This research elevates covalent drug design to a fundamentally new level," said Simon Campbell, PhD, CBE, FMedSci, FRS, a renowned scientist and former Senior Vice President for Worldwide Drug Discovery and Medicinal R&D Europe of Pfizer. "By creating extremely selective protease inhibitors with their platform, Avila is showing the remarkable therapeutic potential of irreversible covalent drugs to address a broad spectrum of drug targets."

"This publication showcases the creation of a whole new class of small molecule drugs," said Juswinder Singh, PhD, Chief Scientific Officer of Avila and a co-author of the paper. "This approach can make a difference to patients living with HCV infection, and we expect to make an impact in other important areas such as cancer and inflammatory disease."

In order to maximize selectivity and minimize off-target effects, the irreversible covalent inhibitors of HCV protease were designed to covalently target a unique structure in the HCV protease not found in human proteases. Key findings include:

• A representative irreversible covalent inhibitor designed, by Avila, was shown to inhibit the HCV protease (also known as "NS3") in cells at a concentration of 6 nM .

• Specific covalent bond formation between the drug and target protease was demonstrated through use of mass spectrometry and also x-ray crystallography.

• Very high selectivity of the Avila compounds was demonstrated by showing no notable inhibition of a panel of human proteases in biochemical assays with additional specificity demonstrated in cellular assays; this was contrasted experimentally with Telaprevir, an HCV protease inhibitor in late-stage clinical testing which demonstrated off-target biochemical activity against several human targets.

Avila has subsequently optimized additional drug candidates, yielding current development candidates, AVL-181 and AVL-192, which have excellent pharmacokinetics and bind potently to wild- type HCV protease as well as multiple genotypes and mutant forms of HCV protease.


About Avila Therapeutics™, Inc.

Avila focuses on design and development of targeted covalent drugs to achieve best-in class outcomes that cannot be achieved through traditional chemistries. This approach is called "protein silencing". The company's product pipeline has been built using its proprietary Avilomics™ platform and is currently focused on viral infection, cancer and autoimmune disease. Avila is funded by leading venture capital firms: Abingworth, Advent Venture Partners, Atlas Venture, Novartis Option Fund, and Polaris Venture Partners. For additional information, please visit


AASLD: Library of Slides and Posters

Coverage of the
61st Annual Meeting of the American
Association for the Study of Liver Diseases (AASLD 2010)
October 29 - November 2, 2010, Boston, MA

Library of Slides and Posters

Efficacy and Safety of TMC435 in Combination With Peginterferon a-2a and Ribavirin in Treatment-naïve Genotype-1 HCV Patients: 24-Week Interim Results from the PILLAR Study
M Fried and others. AASLD 2010.

In vitro studies investigating the mechanism of interaction between TMC435 and hepatic transporters
M Huisman and others. AASLD 2010.

Virologic analysis of genotype-1-infected patients treated with once-daily TMC435 during the Optimal Protease inhibitor Enhancement of Response to TherApy (OPERA)-1 study
O Lenz and others. AASLD 2010.

A Phase IIa, open-label study to assess the antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2–6
C Moreno and others. AASLD 2010.

Pharmacokinetic-pharmacodynamic analyses of TMC435 in patients infected with hepatitis C virus genotypes 2–6
V Sekar and others. AASLD 2010.

4-Week Virologic Response and Safety of ABT-450 Given with Low-dose Ritonavir (ABT-450/r) First As 3-Day Monotherapy Then in Combination with Pegylated Interferon Alpha-2a and Ribavirin (SOC) in Genotype 1 (GT1) HCV-infected Treatment-naïve Subjects
E Lawitz and others. AASLD 2010.

Initial Antiviral Activity of the HCV NS3 Protease Inhibitor ABT-450 When Given with Low-dose Ritonavir as 3-Day Monotherapy: Preliminary Results of Study M11-602 in Genotype 1 (GT1) HCV-infected Treatment-naïve Subjects
E Lawitz and others. AASLD 2010.

HCV RESPOND-2 Final Results High Sustained Virologic Response Among Genotype 1 Previous Non-Responders and Relapsers to Peginterferon/Ribavirin when Re- Treated with Boceprevir Plus PEGINTRON (Peginterferon alfa-2b)/Ribavirin
B Bacon and others. AASLD 2010.

Boceprevir Combined with Peginterferon alfa-2b/Ribavirin for Treatment-Naïve Patients with HCV Genotype 1
F Poordad and others. AASLD 2010.

Frequencies of Resistance-Associated Amino Acid Variants Following Combination Treatment with Boceprevir Plus PEGINTRON (PegInterferon Alfa-2b)/Ribavirin in Patients With Chronic Hepatitis C (CHC), Genotype 1 (G1)
J Vierling and others. AASLD 2010.

Hemoglobin Decline During Lead-in Phase as an Early Predictor of Anemia After the Addition of Boceprevir: A Retrospective Analysis of HCV SPRINT-1
F Poordad and others. AASLD 2010.

Response-Guided Therapy with Boceprevir + Peginterferon alfa-2b/Ribavirin for Treatment-Naïve Patients with Hepatitis C Virus Genotype 1 Was Similar to a 48-Wk Fixed-Duration Regimen with Boceprevir + Peginterferon alfa-2b/Ribavirin in SPRINT-2
J Bronowicki and others. AASLD 2010.

Strong antiviral activity and safety of IFN-sparing treatment with the protease inhibitor BI 201335, the HCV polymerase inhibitor BI 207127, and ribavirin, in patients with chronic hepatitis C: the SOUND-C1 trial
S Zeuzem and others. AASLD 2010.

Virological response and safety of 4 weeks’ treatment with the protease inhibitor BI 201335 combined with 48 weeks of peginterferon alfa 2a and ribavirin for treatment of HCV GT-1 patients who failed peginterferon/ribavirin
T Berg and others. AASLD 2010.

Genotypic and phenotypic analysis of the NS5B polymerase region from viral isolates of HCV chronically infected patients treated with BI 207127 for 5 days’ monotherapy
L Lagace, and others. AASLD 2010.

BMS-790052, a First-in-Class Potent Hepatitis C Virus NS5A Inhibitor, Demonstrates Multiple-Dose Proof-of-Concept in Subjects With Chronic GT1 HCV Infection
R Nettles and others. AASLD 2010.

Coadministration of BMS-790052 and BMS-650032 Does Not Result in a Clinically Meaningful Pharmacokinetic Interaction in Healthy Subjects
M Bifano and others. AASLD 2010.

Pipeline Asset Update for BMS-790052 (NS5A inhibitor) and BMS-650032 (NS3 inhibitor)
Btistol-Myers Squibb Company. AASLD 2010.

Combination Therapy With BMS-790052 and BMS-650032 Alone or With Pegylated Interferon and Ribavirin (pegIFN/RBV) Results in Undetectable HCV RNA Through 12 Weeks of Therapy in HCV Genotype 1 Null Responders
A Lok and others. AASLD 2010.

BMS-824393 Is a Potent Hepatitis C Virus NS5A Inhibitor With Substantial Antiviral Activity When Given as Monotherapy in Subjects With Chronic G1 HCV Infection
R Nettles and others. AASLD 2010.

Safety and Antiviral Activity of MK-5172, a Novel HCV NS3/4a Protease Inhibitor with Potent Activity Against Known Resistance Mutants, in Genotype 1 and 3 HCV-Infected Patients
A Petry and others. AASLD 2010.

Safety, Tolerability, and Pharmacokinetics after Single and Multiple Doses of MK-5172, a Novel HCV NS3/4a Protease Inhibitor with Potent Activity Against Known Resistance Mutants, in Healthy Subjects
A Petry and others. AASLD 2010.

High Correlation Between Week 4 and Week 12 as the Definition for Null Response to Peginterferon alfa (PEG) Plus Ribavirin (R) Therapy: Results From the IDEAL Trial
F Poordad and others. AASLD 2010.

Impact of PegIntron (PEG) Maintenance Therapy (MT) on Fibrosis Biomarkers (FibroTest [FT]/FibroSURE) in Prior Nonresponders With METAVIR Fibrosis Scores (MFS) of F2/F3: Final Results From the EPIC3 Program
T Poynard and others. AASLD 2010.

The Effect of Treatment Group, HCV Genotype, and IL28B Genotype on Early HCV Viral Kinetics in a Phase 2a Study of PEG-Interferon Lambda (pegIFNë) in Hepatitis C Patients
J Freeman and others. AASLD 2010.

Pegylated Interferon Lambda (pegIFNë) Phase 2 Dose-Ranging, Active-Controlled Study in Combination With Ribavirin (RBV) for Treatment-Naive HCV Patients (Genotypes 1, 2, 3, or 4): Safety, Viral Response, and Impact of IL28B Host Genotype Through Week 12
A Muir and others. AASLD 2010.

Pharmacokinetics of PEG-Interferon Lambda (pegIFNë) Following Fixed Dosing in Treatment-Naive Hepatitis C Subjects (Single-Dose Interim Data From a Dose-Ranging Phase 2a Study)
K Byrnes-Blake and others. AASLD 2010.

Sustained Viral Response (SVR) Rates in Genotype 1 Treatment-naïve Patients with Chronic Hepatitis C (CHC) Infection Treated with Vaniprevir (MK-7009), a NS3/4a Protease Inhibitor, in Combination with Pegylated Interferon Alfa-2a and Ribavirin for 28 Days
M Manns and others. AASLD 2010.

Genotypic and Phenotypic Analysis of HCV NS5A Inhibitor Resistance Variants: Correlations Between In Vitro and In Vivo Observations
M Gao and others. AASLD 2010.

Impaired Fasting Glucose Is Associated With Lower Rates of Sustained Virologic Response (SVR) in Patients With Genotype 1 Chronic Hepatitis C (CHC): Retrospective Analysis of the IDEAL Study
M Sulkowski and others. AASLD 2010.

Analysis of Site Performance in Academic and Community-Based Centers in the IDEAL Study
J Jou and others. AASLD 2010.

Baseline, Donor, and On-treatment Predictors of Sustained Virologic Response in Patients Treated for Recurrent Hepatitis C Following Orthotopic Liver Transplant: Subanalysis of the PROTECT Study
F Gordon and others. AASLD 2010.

Chronic Hepatitis C (HCV) Infections and the Risk of Depression and Other Adverse Events
J McCombs and others. AASLD 2010.

Sensitive Detection of Y448H NS5B Mutant Viruses in Patients Infected with Genotype 1a and 1b HCV
A Bae and others. AASLD 2010.

Safety, Pharmacokinetics, and Antiviral Activity of Single Oral Doses of the HCV NS3 Protease Inhibitor GS-9256
R Goldwater and others. AASLD 2010.

Enhanced in Vitro Antiviral Activity and Suppression of Resistance by Combining GS-9256, A Novel Protease Inhibitor, With GS-9190, a Non-Nucleoside NS5B Inhibitor
H Mo and others. AASLD 2010.

Antiviral Response and Resistance Analysis of Treatment-Naïve HCV Infected Subjects Receiving Single and Multiple Doses of GS-9190
J Harris and others. AASLD 2010.

Nonclinical Profi le and Phase I Results in Healthy Volunteers of the Novel and Potent HCV NS5A Inhibitor GS-5885
J Link and others. AASLD 2010.

Characterization of HCV Resistance from Single and Multiple Dose Clinical Trials of GS-9256, a Novel NS3 Protease Inhibitor
K Wong and others. AASLD 2010.

Three-Day, Dose-Ranging Study Of The HCV NS3 Protease Inhibitor GS-9451
E Lawitz and others. AASLD 2010.

Dual, Triple, and Quadruple Combination Treatment with a Protease Inhibitor (GS-9256) and a Polymerase Inhibitor (GS-9190) alone and in Combination with Ribavirin(RBV) or PegIFN/RBV for up to 28 days in Treatment Naïve, Genotype 1 HCV Subjects
S Zeuzem and others. AASLD 2010.