Showing posts with label Sovaprevir (Formerly ACH-1625). Show all posts
Showing posts with label Sovaprevir (Formerly ACH-1625). Show all posts

Friday, September 27, 2013

Achillion Pipeline Update:Hepatitis C Drug Still on Hold by U.S. FDA

Updated-
June 10 2014
FDA lifts clinical hold on Achillion's HCV drug sovaprevir, shares jump

NEW HAVEN, Conn., Sept. 27, 2013 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) today provided an update on development of compounds in its pipeline of therapies for the treatment of chronic hepatitis C virus, or HCV. Achillion today received a response from the U. S. Food and Drug Administration, or FDA, on the clinical hold related to sovaprevir, Achillion's NS3 protease inhibitor. The FDA response indicated that, while Achillion's submission addressed all issues noted in the FDA's June 29, 2013 letter, the FDA concluded that the removal of the clinical hold is not warranted.

"While we are disappointed that we were not able to resolve the clinical hold at this time despite having addressed all the issues, we believe the breadth of our portfolio allows us to quickly advance other all oral combination regimens for the treatment of HCV," stated Milind Deshpande, President and Chief Executive Officer of Achillion. "With our Phase 2 NS5A inhibitor, ACH-3102, we are in a position to rapidly initiate combination studies with ACH-2684, our protease inhibitor, with results expected in 2014. Further, we continue to advance our uridine-analog nucleotide, ACH-3422, with which we anticipate initiating clinical trials in the first half of 2014."

ACH-2684 has completed all of the necessary preclinical and clinical trials necessary to support advancement into Phase 2 combination development. Achillion previously reported robust anti-viral activity with ACH-2684 as monotherapy including Phase 1b data in both non-cirrhotic and cirrhotic treatment-naïve HCV genotype (GT) 1 patients. In addition, Achillion will continue to work to resolve the clinical hold related to sovaprevir.

Phase 2 -007 Trial of Sovaprevir and ACH-3102 with Ribavirin

Achillion also announced interim data from the ongoing -007 Phase 2a clinical trial evaluating two doses of sovaprevir, either 200 mg or 400 mg once daily, in combination with 50 mg once daily of ACH-3102 and ribavirin (rbv) twice daily for 12 weeks in patients with treatment-naïve GT 1a or 1b hepatitis HCV.

The Phase 2 trial is a double-blind, placebo-controlled study evaluating the safety, tolerability and efficacy of 12 weeks of sovaprevir, ACH-3102 and rbv in up to 50 treatment-naïve patients with chronic GT 1a or GT 1b HCV. The first segment enrolled 30 patients who were randomized to receive a combination of either 200 mg or 400 mg sovaprevir once daily in combination with a 150 mg loading dose followed by a 50 mg daily dose of ACH-3102, and twice daily doses of rbv, or matching placebos. The primary endpoints for this trial include safety, tolerability, and sustained viral response 4 weeks after the completion of dosing (SVR4). The trial is being conducted at sites in the United States, Canada, New Zealand and Australia.

All patients achieved a very rapid virologic response (vRVR) with HCV RNA less than 25 IU/ml by week 2. Potent efficacy was observed against GT 1b HCV with 100% of patients achieving rapid viral response, or RVR, with HCV RNA levels less than 10 IU/mL at week 4. RVR was achieved in 79% of GT1 patients overall.

To date, the combination of sovaprevir and ACH-3102 with rbv for up to 12 weeks has been well tolerated with no drug-related serious adverse events, no clinically significant changes in vital signs or electrocardiograms. There have been no graded increases in liver function tests, including ALT or AST, for patients receiving active treatment to date. No other laboratory abnormalities were noted with the exception of decreases in hemoglobin observed and attributed to ribavirin.

Conference Call

The Company will host a conference call and simultaneous webcast on Monday, September 30, 2013 at 8:30 a.m. Eastern time. To participate in the conference call, please dial (877) 266-0482 in the U.S. or (631) 291-4567 for international callers. A live audio webcast of the call will be accessible from the Calendar page in the News Center at www.achillion.com. Please connect to Achillion's website several minutes prior to the start of the broadcast to ensure adequate time for any software download that may be necessary.

A replay of the webcast will be available on www.achillion.com. Alternatively, a replay of the conference call will be available starting at 11:30 a.m. Eastern time on September 30, 2013, through 11:59 p.m. Eastern time on October 6, 2013 by dialing (855) 859-2056 or (404) 537-3406. The replay passcode is 73738655.

About Achillion Pharmaceuticals

Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's discovery, clinical development, and commercial teams have advanced multiple novel product candidates with proven mechanisms of action into studies and toward the market. Achillion is focused on solutions for the most challenging problems in infectious disease including HCV and resistant bacterial infections. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.

Forward-Looking Statements

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other important factors that could cause actual results to differ materially from those indicated by such forward-looking statements, including statements with respect to: the safety, efficacy and clinical benefits of the combination of sovaprevir and ACH-3102; Achillion's plans and timing for initiating additional combination trials of ACH-3102 and ACH-2684 and ACH-3422; Achillion's development plan; and Achillion's goals and strategies with respect to addressing all types of HCV patients. We may use words such as "expect," "anticipate," "project," "intend," "plan," "believe," "seek," "estimate," and "may" and similar expressions to identify such forward-looking statements. Among the important factors that could cause actual results to differ materially from those indicated by such forward-looking statements are risks relating to, among other things Achillion's ability to: satisfactorily respond to regulatory actions with regard to its clinical development programs; replicate in subsequent dose groups and/or later clinical trials positive results observed in the interim data from the -007 combination trial of sovaprevir and ACH-3102, and its other product candidates; advance the development of its drug candidates under the timelines it anticipates in current and future clinical trials; obtain necessary regulatory approvals; obtain patent protection for its drug candidates and the freedom to operate under third party intellectual property; establish commercial manufacturing arrangements; identify, enter into and maintain collaboration agreements with appropriate third-parties; compete successfully with other companies that are seeking to develop improved therapies for the treatment of HCV; manage expenses; and raise the substantial additional capital needed to achieve its business objectives. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Quarterly Report on Form 10-Q for the fiscal quarter ended June 30, 2013 and its subsequent SEC filings.

In addition, any forward-looking statement in this press release represents Achillion's views only as of the date of this press release and should not be relied upon as representing its views as of any subsequent date. Achillion disclaims any duty to update any forward-looking statement, except as required by applicable law.

CONTACT:

Company Contact:
Glenn Schulman
Achillion Pharmaceuticals, Inc.
Tel. (203) 624-7000
gschulman@achillion.com

Investors:
Mary Kay Fenton
Achillion Pharmaceuticals, Inc.
Tel. (203) 624-7000
mfenton@achillion.com

Seth Lewis
The Trout Group, LLC
Tel. (646) 378-2952
slewis@troutgroup.com

(Source: PrimeZone )
(Source: Quotemedia)

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Tuesday, July 2, 2013

Achillion Hepatitis C Drug Trial on Hold on Liver Concern


Achillion Hepatitis C Drug Trial on Hold on Liver Concern

By Mary Camille Izlar & Robert Langreth - Jul 2, 2013 4:09 PM ET

Achillion Hepatitis C Drug Trial on Hold on Liver Concern U.S. regulators put the hepatitis C drug trial on hold after some patients experienced elevated liver enzymes, Achillion said in a statement yesterday. 

The elevations were observed in healthy patients when Achillion’s sovaprevir was combined with two medicines used to treat HIV infections in order to test for possible drug interactions. The combination may have resulted in a drug interaction that produced higher-than-expected blood levels of the therapies, Achillion said.

“Achillion voluntarily stopped further dosing” and “promptly notified” the Food and Drug Administration of the finding in the early-stage trial involving sovaprevir, the New Haven, Connecticut-based company said. The hold doesn’t affect a current second-stage study of the drug in hepatitis C patients.

Achillion has three drugs in clinical testing for hepatitis C, a liver disease that affects 170 million people worldwide. The company said April 23 that one of the treatments, ACH-3102, appeared effective in five out of eight patients, reducing the amount of the liver-destroying virus in their bloodstream to undetectable levels after 12 weeks of treatment.

Achillion is competing with drugmakers including AbbVie Inc. (ABBV) and Gilead Sciences Inc. (GILD) to develop new treatments for the disease, a market analysts’ estimate may be $20 billion.

To resolve the hold, the regulatory agency has asked for data from two drug interaction studies as well as a safety analysis of continuing sovaprevir studies, which the company said it plans to provide in about six weeks.

Achillion shares had gained 35 percent in the past 12 months through yesterday.

To contact the reporters on this story: Mary Camille Izlar in New York at mizlar@bloomberg.net; Robert Langreth in New York at rlangreth@bloomberg.net

To contact the editor responsible for this story: Reg Gale at rgale5@bloomberg.net 

http://www.bloomberg.com/news/2013-07-01/achillion-hepatitis-c-drug-trial-on-hold-on-liver-concern.html

Liver toxins delay CT Achillion's hep C trial
July 2, 2013
Achillion Pharmaceuticals Inc. got a dose of bad news about its efforts to develop a treatment for hepatitis C.

The New Haven biopharmaceutical company said Monday the U.S. Food & Drug Administration suspended one of its clinical trials for its hepatitis C drug sovaprevir after a trial subject built up an unusually high amount of toxic liver enzymes.

Despite the setback, however, the FDA is allowing Achillion to continue enrollment and the 12-week treatment of patients in Phase 2 trials involving sovaprevir and Achillion's ACH-3102 formulation, the company said.

The company was due to elaborate on the FDA notification and other clinical-trial data during a Monday afternoon conference call with financial analysts and reporters.

http://www.hartfordbusiness.com/article/20130702/NEWS01/130709977

UPDATE 1-FDA places clinical hold on Achillion's hep C drug, shares plunge

Mon Jul 1, 2013 6:27pm EDT

* Co says liver enzymes elevated in drug interaction with HIV drug
* Co says hold does not affect mid-stage study
* Co could potentially lose access to market for HIV patients - analysts
* Shares fall 22 percent in extended trading

By Vrinda Manocha
July 1 (Reuters) - Achillion Pharmaceuticals Inc said the U.S. Food and Drug Administration had placed a clinical hold on its hepatitis C drug sovaprevir after elevations in liver enzymes were noted in an early-stage study of the drug's interaction with an HIV drug.
Shares of the company fell 22 percent in extended trading.

The company said the FDA had asked for study reports from two drug-drug interaction studies involving the drug and a safety analysis of ongoing trials.

Achillion was testing sovaprevir's interaction with an antiretroviral drug atazanavir, which was boosted by another drug called ritonavir.

The company said it had detected elevations in liver enzymes, an indication of liver damage, in multiple subjects, but none of the elevations met the criteria of a serious adverse event.
"We don't know what's going on. What we know is that when Achillion's drug is evaluated with a pretty typical HIV drug, we get a toxic combination," Maxim Group analyst Jason Kolbert told Reuters.

"Clearly now the profile of this drug is not perfect at a time when the market wants to see drugs with a very clean profile."

William Blair analyst Katherine Xu said if the drug-drug interaction was real, then the company may not be able to target patients taking atazanavir.

"I think about 20 percent of hepatitis C patients are infected with HIV, and then within these HIV patients, probably 10 percent are taking atazanavir. It's not that much, it's more a perception. It might be a nuisance for doctors to prescribe", she said.

Maxim's Kolbert also said that some people had thought that Achillion was positioning itself to be sold, and the news would hurt their chances that a buyer would want to acquire the entire company.
The company said none of its other drug-drug interaction studies had showed such elevations in liver enzymes.

The FDA issues clinical holds to delay the clinical investigation of a drug, or to suspend an ongoing investigation. Companies may not recruit new subjects when an ongoing study is placed on a clinical hold.

The clinical hold does not affect the company's mid-stage trial testing sovepravir in combination with another of its hepatitis C drugs and a standard therapy ribavirin.
The company said it expected to provide the information to the FDA within about six weeks.
Shares of the company, which were halted prior to the news, closed at $8.36 on Monday on the Nasdaq.

http://www.reuters.com/article/2013/07/01/achillion-fda-hepcdrug-idUSL3N0F73ME20130701

July 1, 2013
 
Achillion Provides Update on Sovaprevir Development Program
 
Following Phase 1 drug-drug interaction study with ritonavir-boosted atazanavir showing elevated liver enzymes, sovaprevir placed on clinical hold by FDA
 
Ongoing enrollment and treatment of patients remains unaffected in Phase 2 -007 combination trial evaluating 12-weeks of sovaprevir and ACH-3102 for treatment-naive genotype 1 patients
 
Conference call and webcast to be hosted today at 4:15 p.m. EDT
 
NEW HAVEN, Conn., July 1, 2013 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) today announced that the Company has received notice from the U.S. Food and Drug Administration (FDA) that a clinical hold has been placed on sovaprevir after elevations in liver enzymes associated with significantly higher than anticipated exposures to atazanivir and sovaprevir were noted in a Phase 1 healthy subject drug-drug interaction (DDI) study evaluating the effects of concomitant administration of sovaprevir with ritonavir-boosted atazanavir. The FDA has allowed continued enrollment and treatment of patients in the Phase 2 -007 clinical trial evaluating 12-weeks of sovaprevir in combination with ACH-3102 and ribavirin for patients with treatment-naive genotype 1 hepatitis C viral infection (HCV).

In a Phase 1 drug-drug interaction study, Achillion was evaluating the effects of concomitant administration of sovaprevir with ritonavir-boosted atazanavir. While conducting this study, Achillion detected unanticipated elevations in ALT liver enzymes (grade 3 or 4) in multiple subjects, although none of these met the criteria for a serious adverse event (SAE). Achillion voluntarily stopped further dosing in the DDI study and promptly notified the FDA of these findings. Preliminary pharmacokinetic results indicate a metabolic interaction whereby plasma concentrations of both atazanavir and sovaprevir were substantially increased upon co-administration. Such ALT elevations have not been seen in the 12-week combination -007 trial, the 12-week combination -005 trial with ACH-3102 and ribavirin, or in any other drug-drug interaction studies completed with sovaprevir to date.

With the preliminary draft data on hand at the time of notification, the FDA placed sovaprevir on clinical hold. In order to resolve the clinical hold, the FDA has asked for study reports from two drug-drug interaction studies and an integrated safety analysis of on-going sovaprevir trials, each of which Achillion expects to provide to the FDA within approximately six weeks.
With respect to the ongoing -007 Phase 2 clinical trial, Achillion is treating patients in the first segment of the study and plans to release interim clinical trial results, including rapid virologic response (RVR) during the third quarter and sustained viral response (SVR) during the fourth quarter, as previously anticipated. To date, patients enrolled in the trial have received up to six weeks of combination treatment with no safety issues noted.

Conference Call
The Company will host a conference call and simultaneous webcast on Monday, July 1, 2013 at 4:15 p.m. Eastern time. To participate in the conference call, please dial (877) 266-0482 in the U.S. or (631) 291-4567 for international callers. A live audio webcast of the call will be accessible at http://www.achillion.com or http://ir.achillion.com. Please connect to Achillion's website several minutes prior to the start of the broadcast to ensure adequate time for any software download that may be necessary.

A replay of the webcast will be available on www.achillion.com. Alternatively, a replay of the conference call will be available starting at 7:15 p.m. Eastern time on July 1, 2013, through 11:59 p.m. Eastern time on July 7, 2013 by dialing (855) 859-2056 or (404) 537-3406. The replay passcode is 14259844.

About Achillion Pharmaceuticals
Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's discovery, clinical development, and commercial teams have advanced multiple novel product candidates with proven mechanisms of action into studies and toward the market. Achillion is focused on solutions for the most challenging problems in infectious disease including HCV and resistant bacterial infections. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.

Forward-Looking Statements
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other important factors that could cause actual results to differ materially from those indicated by such forward-looking statements, including statements with respect to: the potential causative factors for the unexpected results in Achillion's Phase 1 drug-drug interaction study of sovaprevir and ritonavir; Achillion's expectations regarding timing for the completion and reporting of results of its clinical trial of ACH-3102 in combination with sovaprevir and ribavirin; and Achillion's expectations regarding timelines for submitting additional data to FDA in response to the clinical hold. We may use words such as "expect," "anticipate," "project," "intend," "plan," "believe," "seek," " estimate," and "may" and similar expressions to identify such forward-looking statements. Among the important factors that could cause actual results to differ materially from those indicated by such forward-looking statements are risks relating to, among other things Achillion's ability to: satisfactorily respond to regulatory actions with regard to its clinical development programs, including the FDA's request for further information and data regarding the Phase 1 drug-drug interaction study; successfully resolve the partial clinical hold with regard to sovaprevir; continue to advance sovaprevir in clinical trials; replicate in later clinical trials positive results found in preclinical and earlier stage clinical trials of sovaprevir, ACH-3102, and its other product candidates; advance the development of its drug candidates under the timelines it anticipates in current and future clinical trials; obtain necessary regulatory approvals; obtain patent protection for its drug candidates and the freedom to operate under third party intellectual property; establish commercial manufacturing arrangements; identify, enter into and maintain collaboration agreements with appropriate third-parties; compete successfully with other companies that are seeking to develop improved therapies for the treatment of HCV; manage expenses; and raise the substantial additional capital needed to achieve its business objectives. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Quarterly Report on Form 10-Q for the fiscal quarter ended March 31, 2013 and its subsequent SEC filings.

In addition, any forward-looking statement in this press release represents Achillion's views only as of the date of this press release and should not be relied upon as representing its views as of any subsequent date. Achillion disclaims any duty to update any forward-looking statement, except as required by applicable law.

http://ir.achillion.com/releasedetail.cfm?ReleaseID=774834

Sunday, January 6, 2013

HCV: second-generation protease inhibitors

Liver InternationalLiver International

Special Issue: Proceedings of the 6th Paris Hepatitis Conference, International Conference on the Management of Patients with Viral Hepatitis
Volume 33, Issue Supplement s1, pages 80–84, February 2013
 

New therapeutic strategies in HCV: second-generation protease inhibitors

Virginia C. Clark,
Joy A. Peter,
David R. Nelson*

Article first published online: 3 JAN 2013

DOI: 10.1111/liv.12061

Keywords:
Hepatitis C;
protease inhibitors;
ACH 2684;
MK 5172

Abstract
Telaprevir and boceprevir are the first direct-acting antiviral agents approved for use in HCV treatment and represent a significant advance in HCV therapy. However, these first-generation drugs also have significant limitations related to thrice-daily dosing, clinically challenging side-effect profiles, low barriers to resistance and a lack of pan-genotype activity. A second wave of protease inhibitors are in phase II and III trials and promise to provide a drug regimen with a better dosing schedule and improved tolerance. These second-wave protease inhibitors will probably be approved in combination with PEG-IFN and Ribavirin (RBV), as well as future all-oral regimens. The true second-generation protease inhibitors are in earlier stages of development and efficacy data are anxiously awaited as they may provide pan-genotypic antiviral activity and a high genetic barrier to resistance.

Abbreviations
AEs adverse effects
cEVR complete early virological response
PIs NS3-4A protease inhibitors
RVR rapid virological response
SVR sustained viral response

A large number of NS3-4A protease inhibitors (PIs) have reached clinical development, including two drugs, telaprevir and boceprevir, that have already been approved for use in combination with pegylated IFN-α (PEG-IFN) and ribavirin (RBV) in patients infected with genotype 1 hepatitis C virus. Telaprevir and boceprevir significantly improve virological outcomes in both treatment-naїve [1, 2] and -experienced genotype 1 patients [3, 4]. However, the clinical utility of these first-generation PIs is limited by a thrice-daily dosing schedule (with food), increased rates of adverse effects (AEs) (anaemia and rash), a low genetic barrier to resistance and extensive drug–drug interactions. These limitations highlight the opportunities for improvement in protease inhibitors. This review will discuss the newer protease inhibitors under late-stage development, which should be more potent, with higher barriers to viral resistance, and improved dosing regimens.

Second-wave protease inhibitors
 
Second-wave protease inhibitors offer several advantages over currently available drugs. Improved pharmacokinetics will allow a once-a-day dosing schedule and the side-effect profiles are more tolerable. However, these agents have similar genotype coverage and similar resistance profiles to telaprevir and boceprevir, and do not represent true second-generation PIs. The improved PIs have been referred to as second-wave PIs. They will probably replace first-generation PIs in combination with PEG-IFN/RBV to become the initial partners in the first generation of all-oral regimens. The following drugs are currently in phase II and III development (Table 1).

Table 1. HCV protease inhibitors
 
TelaprevirApprovedFirst generation
BoceprevirApprovedFirst generation
SimeprevirPhase 3Second wave
BI1335Phase 3Second wave
AsunaprevirPhase 3 (all oral)Second wave
Danoprevir/rPhase 2Second wave
SovaprevirPhase 2Second wave
ABT450/rPhase 2Second wave
MK 5172Phase 2Second generation
ACH 2684Phase 2Second generation

Simeprevir (TMC435; Tibotec, Beerse, Belgium; Medivir Pharmaceuticals, Stockholm, Sweden; Janssen, Beerse, Belgium) is a once-a day-oral NS3/4A protease inhibitor currently in phase III clinical development for the treatment of HCV infection. Phase I and II trials have demonstrated that TMC435 is generally well tolerated, has a pharmacokinetic profile that supports once-a-day dosing, and demonstrates potent antiviral activity and efficacy [5]. The final results of two phase IIb trials of TMC435 with PEG-IFN/RBV in naïve and treatment-experienced populations have been completed [6]. PILLAR study enrolled 368 treatment-naïve subjects with genotype 1 and compared two different doses (75mg vs 150 mg) and durations (12 weeks vs 24 weeks) of simeprevir therapy in combination with PEG-IFN/RBV for either 24 or 48 weeks. A sustained viral response (SVR) was achieved in 68–76% of patients with this triple therapy regimen and approximately 80% of subjects were eligible to receive shortened 24 weeks of therapy with very high SVR (93–96%). Adverse effects were similar to standard therapy, and the lowest rate of relapse was found in the study arm receiving 150 mg daily TMC435 in addition to PEG-IFN/RBV for 24 weeks (8%). In addition, SVR rates in the 150-mg dosing arms did not differ according to HCV subtype (1a vs 1b), but as expected, SVR was highest in the IL28B CC genotype.
 
ASPIRE was a randomized, double-blind, placebo-controlled phase IIb trial, which assessed the efficacy and safety of simeprevir in combination with PEG-IFN/RBV in 462 patients with genotype 1 HCV who had failed a previous PEG-IFN/RBV regimen. The ASPIRE study randomized patients to seven treatment arms, each of which was given simeprevir in combination with 48 weeks of PEG-IFN-2a/RBV. SVR rates were significantly higher in all simeprevir-containing treatment arms compared with PEG-IFN/RBV alone. The best results were obtained in the 150-mg dosing groups with a SVR of 85% vs 37% in prior relapsers, 75% vs 9% in partial responders and 51% vs 19% in prior non-responders. It is also important to note that higher 24-week SVR rates were observed with simeprevir-containing therapy in difficult-to-treat patient subgroups, including patients with cirrhosis and a previous non-response (31% SVR in non-response cirrhotics). As has been seen with most PI-based studies, breakthrough or relapse was associated with a resistant virus (42/43 people who experienced breakthrough and 34/36 who relapsed). Subjects with HCV genotype 1a were more likely to have the R155K mutation alone or with additional mutations, whereas people with HCV genotype 1b had the D168V mutation [7].
 
In both the naïve and treatment-experienced trials, TMC435 was generally well tolerated with no evidence of significant safety signals related to rash, anaemia or neutropaenia. However, transient elevations of direct and indirect bilirubin were seen in subjects who took a 150-mg dose of simeprevir. Elevations in bilirubin were not associated with an elevation of AST or ALT, returned to baseline with the cessation of therapy and are believed to be related to interference with bilirubin transporters.
 
Finally, simeprevir may also provide opportunities for use in non-genotype 1 patients. A phase IIa proof-of-concept trial provided evidence that TMC435 has a broad spectrum of activity against multiple HCV genotypes except for genotype 3 [8]. Monotherapy with oral TMC435 200 mg q.d. for 7 days was associated with potent antiviral activity in patients infected with genotypes 2, 4, 5 and 6. The greatest antiviral activity was observed among patients infected with genotypes 4 and 6, followed by genotypes 2 and 5. Of note, no antiviral activity was seen against genotype 3. Thus, simeprevir seems to offer significant improvement over boceprevir and telaprevir: once-a-day dosing, improved safety profile (lack of rash and anaemia) and expanded antiviral activity across more genotypes.

BI201335 (Boehringer Ingelheim Pharmaceuticals, Ingelheim, Germany) is another NS3/4A protease inhibitor with once-a-day dosing that has completed phase 2 testing. SILEN-C1 study reported the efficacy data from a randomized phase II trial with 429 genotype 1 treatment-naïve patients [9]. The treatment regimen included BI201335 in addition to PEG-IFN/RBV for 24 weeks at doses of 120 and 240 mg, followed by another 24 weeks of standard therapy. Response-guided therapy was evaluated and achievement of an eRVR (HCV-RNA negative at week 4 and week 12) resulted in randomization to stop therapy at week 24 or continue with PEG-IFN/RBV for a total of 48 weeks. The overall SVR rate was 83% for the 240-mg dose (lower for the 120-mg dose), and 92% of the patients with an eRVR achieved a SVR regardless of the subsequent duration of PEG-IFN/RBV. Adverse events (mostly gastrointestinal) resulted in drug discontinuation in 7.3% of subjects. SILEN-C2 study evaluated 288 partial or non-responders and evaluated the 240-mg dose, either once or twice daily in combination with PEG-IFN/RBV for 24 weeks [10]. The highest SVR was achieved in the once-a-day dosing groups: it was 50% in partial responders and 35% in non-responders. It should be noted that patients with cirrhosis were not included in this study. Both SILEN-C1 and C2 tested the efficacy of a 3-day lead-in with PEG-IFN/RBV. The expectation was that the lead-in would limit the development of resistance by providing better antiviral drug coverage when the PI was introduced. For unknown reasons, the lead-in arms in both trials showed a significant decrease in efficacy, and this strategy to limit resistance has been abandoned. SILEN-C3 evaluated treatment-naïve, genotype 1 patients and randomized them to either 12 or 24 weeks of once-a-day 120 mg BI 201335. Both groups received PEG-IFN/RBV for 24 weeks and patients who did not achieve an eRVR continued PEG-IFN/RBV until week 48. SVR rates were similar for both durations, 65% vs 73% overall and 82% vs 81% in those with eRVR respectively. Through all of the SILEN-C phase 2 trials, the adverse-event profile of BI 201335 appeared to be mild rash and photosensitivity along with some GI toxicity (nausea, diarrhoea and vomiting). As with a few other PIs under development, BI 201335 is associated with a transient rise in indirect or unconjugated bilirubin that is related to inhibition of the bilirubin transporter (inhibition of hepatic uptake of uridine diphosphate glucuronosyl transferase 1 family polypeptide A1, UGT1A1)[11]. The once-per-day dosing regimen that is moving forwards into phase 3 trials has fewer adverse events than the twice-per-day dosing regimen.

Danoprevir/r (RG7277; Roche, Basle, Switzerland; Intermune Pharmaceuticals, Brisband, CA) is a twice-a-day, ritonavir-boosted HCV protease inhibitor with good antiviral activity against genotypes 1, 4 and 6. Of note, the early hepatotoxicity signals of the drug were virtually eliminated by the addition of ritonovir boosting, which leads to strong inhibition of CYP3A and increased through concentrations of the PI. DAUPHINE is a large phase 2 trial in naïve patients that evaluated three different doses (50, 100 and 200 mg danoprevir, boosted with 100 mg ritonavir, twice daily) and response-guided therapy in combination with PEG-IFN/RBV [12]. Twelve weeks after stopping therapy, antiviral negativity (SVR12) was 93% in the 200-mg dosing arm, 83% in the 100-mg arm and 67% in the 50-mg arm. At the 200-mg dose, the response was not influenced by either HCV subtype (1a vs 1b) or IL28B genotype (CC vs non-CC), suggesting that this regimen leads to potent viral suppression. Of note, genotype 4 patients had a 100% SVR 12 across all dosing arms. Danoprevir is also being evaluated in IFN-free regimens combined with the nucleoside inhibitor, Mercitabine (RG7128) [13].
 
Asunaprevir (BMS-650032; Bristol-Myers Squibb, New York, NY) is a twice-daily protease inhibitor being developed in both IFN-containing and free regimens with daclatasvir, an NS5A inhibitor and BMS 791325, a non-nucleoside inhibitor. Asunaprevir was initially studied at a dose of 600 mg twice per day, but was decreased to 200 mg twice per day because of increased liver enzymes. The combination of asunaprevir and daclatisvir was the first regimen to successfully cure HCV-infected patients without the use of IFN [14]. Despite potential approval in an IFN-free combination in genotype 1b patients and a potential quad regimen, asunaprevir is not likely to become the PI of choice for this second wave of PIs because of the twice-per-day administration and potential association with hepatotoxicity.
 
Sovaprevir (ACH-1625; Achillion Pharmaceuticals, New Haven, CT) is another NS3 protease inhibitor with very high potency, reporting a half-maximal inhibitory concentration of ~1 nm. A phase IIa study reported that ACH-1625, with PEG-IFN/RBV, resulted in a RVR in 75–81% of subjects compared with a RVR of 20% in patients receiving PEG-IFN/RBV alone [15]. A phase IIb study is under way at this time, but given the true second-generation PI also from Achillion (see below), it is less likely that this PI will be carried through to phase III trials.
 
ABT-450/r (Abbott, Abbott Park, IL; Enanta Pharmaceuticals, Watertown, MA) ABT-450 is being evaluated with ritonavir boosting to increase plasma concentrations and enable once-a-day dosing. A recent analysis included 35 treatment-naїve chronic hepatitis C patients randomly assigned to receive ABT-450/ritonavir or placebo [16]. Participants received ABT-450/ritonavir at doses of 50/100 mg, 100/100 mg or 200/100 mg once daily, or placebo, as monotherapy for 3 days, followed by 12 weeks of ABT-450/ritonavir or placebo at the same dose in combination with PEG-IFN/RBV. During the 3 days of monotherapy, the response was similar in all three ABT-450/ritonavir dose arms, with a mean maximum HCVRNA decrease of around 4 log IU/ml, compared with 0.36 log IU/ml in the placebo group. In an intent-to-treat analysis at 4 weeks, 88% of patients receiving ABT-450/ritonavir plus PEG-IFN/RBV had achieved a RVR (RVR; HCV RNA <25 IU/ml) compared with only 9% in the placebo arm. At 12 weeks, 92% receiving ABT-450/ritonavir vs 18% receiving placebo had achieved a complete early virological response (cEVR, again HCV RNA <25 IU/ml). HCV sub-genotype (1a or 1b), baseline HCV RNA and IL28B gene pattern were not associated with differences in virological response. ABT-450/r is also being studied in all-oral regimens and is more likely to receive approval in this IFN-free pathway.

Second-generation protease inhibitors
 
Two second-generation protease inhibitors, MK-5172 and ACH-2684, are in various stages of clinical development. These true second-generation PIs are expected to have broader genotype coverage and higher barriers to resistance, which represents a significant shift from the second-wave PIs.
 
MK-5172 (Merck & Co., Inc, Whitehouse Station, NJ) is a novel macrocyclic NS3/4a protease inhibitor under phase II clinical development. The compound demonstrates subnanomolar activity against a broad enzyme panel encompassing major HCV genotypes, notably variants resistant to earlier protease inhibitors. R155 is the main overlapping position for resistance and different mutations at this amino acid site within NS3 protease confer resistance to nearly all protease inhibitors in development. However, MK-5172 exhibits potent antiviral activity against variants carrying mutations at position R155. Thus, based on its preclinical profile, MK-5172 is expected to be broadly active against multiple HCV genotypes, including genotype 3 as well as clinically important resistance variants making it highly suited for incorporation into newer all-oral regimens. MK-5172 was given in doses of 50–800 mg QD (monotherapy) to 48 men with HCV genotype 1 and 30 HCV genotype 3 patients for 7 days [17]. There were six arms (including a placebo arm). The maximum change in HCV levels was a decrease of −5.37 IU/ml in HCV genotype 1 and −4.41 IU/ml in genotype 3 patients. In the genotype 1 patients, 75% (30 of 40 pts) were below the level of HCVRNA quantification (25 IU/ml). The drug was generally well tolerated. In early-stage studies, MK-5172 in various doses has been shown to work across different genotypes [18] and can be dosed once a day, which makes it an attractive candidate for future clinical development.
 
ACH-2684 (Achillion Pharmaceuticals) is a macro-cyclic, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-2684 demonstrated pico-molar potency, excellent pharmacokinetic properties and a safety profile at high drug exposures that strongly supports once-a-day dosing. ACH-2684 also exhibits rapid and extensive partitioning to the liver, as well as high liver/plasma ratios in preclinical studies. It has preclinical activity against the six known genotypes of HCV and exhibits equipotent activity against HCV genotypes 1a and 1b at an IC50 of approximately 100 pm [19]. Achillion Pharmaceuticals, Inc reported proof-of-concept data from a Phase 1b clinical trial demonstrating that patients with HCV genotype 1 treated with ACH-2684 achieved a mean maximum 3.73 log10 reduction in HCV RNA after 3-day 400-mg monotherapy with once-a-day dosing. The compound also demonstrated good safety and tolerance both in healthy volunteers and in patients with HCV. This PI seems to represent an ideal partner for all-oral regimens that can help deliver pangenotypic activity with a high barrier to resistance.

Conclusion
 
The development of protease inhibitors represents a significant milestone in improving the efficacy of HCV treatment. However, the limitations of first-generation PIs have opened the door for continued drug development in this class. Several other direct-acting antivirals are under development [20]. Simeprevir, asunaprevir and BI are second-wave PIs in phase III trials, and will probably obtain approval with PEG-IFN/RBV in 2014. To be used in an all-oral regimen, second-wave PIs will need to be used in combination with other direct-acting antivirals to overcome the low genetic barrier to resistance. These combinations could include PIs and a nucleoside inhibitor with a high genetic barrier to resistance or PIs with a non-nucleoside inhibitor (or NS5A inhibitor) with a non-overlapping resistance profile. The future of protease inhibitors lies in the further development of second-generation drugs with a broad genotypic coverage and a high genetic barrier for resistance, which may be the ideal backbone for an all-oral HCV treatment regimen.

Disclosure
 
The authors have no disclosure.

References
 
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    Pordada F, McCone Jr, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 362: 1195206.
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    Jacobson IM, McHutchinson JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364: 240516.
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    Zeuzem S, Andreone P, Pol S., et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011; 364: 241728.
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    Bacon BR, Gordon SC, Lawitz E., et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011; 364: 120717.
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    Manns M, Reesink H, Berg T, et al. Rapid viral response of once-daily TMC435 plus peginterferon/ribavirin in hepatitis C genotype-1 pstients: a randomized trial. Antivir Ther 2011; 16: 102133.
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    Fried M, Buti M, Dore GJ, et al. TMC435 in combination with peginterferon and ribavirin in treatment naïve HCV genotype 1 patients: final analysis of the PILLASR phase IIb study. 62nd Annual Meeting of the American Association for the Study of liver Diseases 2011; Novemeber 4-8; San Francisco, CA. Abstract LB-5.
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    Lenz O, Fevery B, Vijgen L, et al. TMC 435 in patients infected with HCV genotype 1 who have failed previous pegylated interferon/ribavirin treatment: virologic analysis of the ASPIRE trial. 47th Annual Meeting of the European Association for the Study of the Liver; 2012 April 18-22; Barcelona, Spain. Abstract 9.
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    Moreno C, Berg T, Tanwandee T, et al. Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2–6: TMC435-C202, a phase IIa, open-label study. J Hepatol 2012; 56: 124753.
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    Sulkowski MS, Asselah T, ferenci P, et al. Treatment with the 2nd generation HCV PI BI 201335 results in high and consistent SVR rates-results from SILEN-C1 in treatment naïve patients across different baseline factors. Hepatology 2011; 54(suppl): 473A.
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    Sulkowski MS, Bourliere M, Bronwicki JP, et al. Sustained viral response and safety of BI201335 combined with peginterferon alfa-2a and ribavirin (P/R) in chronic HCV genotype 1 patients with non-response tp P/R. 46th Annual Meeting of the European Association for the Study of the Liver;2011March 30-April 3;Berlin, Germany; Abstract 66/330.
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    Sane R, Podila L, Mathur A., et al. Mechanisms of isolated hyperbilirubinemia induced by HCV NS3/4A protease inhibitor BI201335. J Hepatol 2011; 54(suppl): S488.
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    Everson G, Cooper C, Shiffman ML, et al. Rapid and sustained achievement of undetectable HCV RNA during treatment with ritonavir-boosted danoprevir/PEG-IFNa-2A/RBV in HCV genotype 1 or 4 patients: Dauphine week 36 interim analysis. 47th Annual Meeting of the European Association for the Study of Liver Disease; 2012 April 18–22; Barcelona, Spain. Abstract 1177.
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    Gane EJ, Roberts SK, Stedman CA, et al. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomized, double-blind, placebo-controlled, dose escalation trial. Lancet 2010; 376: 146775.
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    Lok AS, Gardiner DF, Lawitz E, et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med 2012; 366: 21624.
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    Poordad F, Lalezari J, Lawitz E, et al. Continued high virologic response rates with ACH-1625 daily dosing plus PEGIFN-alpha 2a in a 28-day and 12-week phase 2a trial. 47th Annual Meeting of the European Association for the Study of Liver Disease; 2012 April 18-22; Barcelona, Spain. Abstract 1151.
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    Lawitz E, Gaultier I, Poordad F, et al. ABT-450/Ritonavir (ABT-450/r) Combined with Pegylated Interferon Alpha-2a and Ribavirin After 3-Day Monotherapy in Genotype 1 HCV-Infected Treatment-naive Subjects: 12-Week Interim Efficacy and Safety Results. 46th Annual Meeting of the European Association for the Study of the Liver (EASL 2011). Berlin. March 30-April 3. Abstract 252.
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    Petry A, Brainard D, Van Dyck K, et al. Safety and antiviral efficacy 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. 61st Annual Meeting of the American Association for the Study of Liver Diseases. Boston, MA 2010.
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    Summa V, Ludmerer SW, McCauley JA. MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants. Antimicrob Agents Chemother 2012; 56: 41617.
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    Asselah T, Marcellin P. Direct acting antivirals for the treatment of chronic hepatitis C: one pill a day for tomorrow. Liver Int 2012; 32: 88102.

Monday, November 12, 2012

AASLD-Achillion Programs: Sovaprevir, ACH-3102 and ACH-2684

Achillion Provides Update on Clinical HCV Development Programs

Drug-Drug Interaction Study of Sovaprevir and ACH-3102 Completed -

- ACH-2684, Second-Generation Protease-Inhibitor, Achieves Comparable Activity in Cirrhotic Versus Non-Cirrhotic Patients -

- Posters Discussing Sovaprevir, ACH-3102 and ACH-2684 to be Presented at AASLD 2012 -

NEW HAVEN, Conn., Nov. 12, 2012 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) today provided an update on the sovaprevir and ACH-3102 clinical development programs and announced new Phase 1b clinical trial results on ACH-2684.

Sovaprevir and ACH-3102 Development Update
Achillion announced today the completion of a drug-drug interaction (DDI) study evaluating the combination of sovaprevir and ACH-3102. The study, conducted in 24 healthy volunteers, concluded that there was no interaction between the two investigational compounds and that both sovaprevir and ACH-3102 were safe and well-tolerated by study participants with no significant adverse events reported.

"With the completion of this DDI study, we now plan to submit to the FDA a Phase 2 protocol that will evaluate an all-oral, interferon-free regimen containing sovaprevir and ACH-3102 for 12 weeks and, pending discussions with the regulatory agency, we intend to initiate this combination study with the goal of reporting rapid virologic response, or RVR, in the first half of 2013," stated Michael D. Kishbauch, President and Chief Executive Officer of Achillion.

Milind Deshpande, Ph.D., President of Research and Development and Chief Scientific Officer of Achillion commented, "We also continue to enroll and treat patients in our ongoing Phase 2 trial evaluating ACH-3102 and ribavirin for the treatment of genotype 1b CC HCV patients and, based upon emerging clinical trial results, we plan to initiate discussions with regulatory agencies to expand the enrollment to include additional genotype 1b patients and look forward to providing an update on this study later in the fourth quarter detailing RVR and safety results."

ACH-2684: Phase 1b study in Chronic HCV GT1 Cirrhotic Patients
Achillion also reported today additional proof-of-concept data from its Phase 1b clinical trial of ACH-2684, a second-generation protease inhibitor, which demonstrated that chronic genotype 1 HCV treatment-naive patients with cirrhosis treated with 400 mg

ACH-2684 once daily for three days achieved a mean maximum 3.67 log10 reduction in HCV RNA (range 3.10-4.40 log10) as compared to 0.22 log10 reduction for placebo. The antiviral activity achieved in this treatment-naive patient population was similar to the 3.68 log10 reduction in HCV RNA in non-cirrhotic genotype 1 HCV treatment-naive patients receiving the same dose of ACH-2684. The full dosing cohort (n=8; 6 active, 2 placebo) included one subject that received active drug who, based upon baseline viral population sequencing, was demonstrated to have nearly 100% substitution at position R155K. Presence of approximately 100% R155K mutation at baseline in subjects who have not been exposed to a protease inhibitor regimen is highly unusual and likely indicative of prior treatment that was not revealed at study enrollment. Further analysis is on-going and this patient's antiviral activity is excluded from the reductions above.

Safety data demonstrated that ACH-2684 was well tolerated in this patient population with no serious adverse events, no clinically significant changes in vital signs, electrocardiograms (ECGs), or laboratory evaluations. All reported adverse events were classified as mild or moderate, and were transient in nature.

"With the unique pharmacokinetic profile of ACH-2684, which we believe does not require active uptake of the compound into the liver, we are very pleased to have achieved the same robust antiviral activity in patients with compensated cirrhosis," commented Dr. Deshpande. "We believe these results support the continued development of this second-generation protease inhibitor and will look to fully leverage its activity in special populations of HCV patients."
Posters Presentations by Achillion at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD):

-- Poster 1171: Viral Kinetics Modeling to aid in Dose Selection Decisions
for Phase-2/3 Clinical Trials, A. Agarwal, et al. Session: Clinical HCV
2. Date: Tuesday, November 13, 2012.

-- Poster 1886: In vitro Studies Demonstrate a High Probability of Curing
Genotype-1 Hepatitis C with Combination of a Novel NS3 Protease
Inhibitor ACH-2684 and a Novel NS5A inhibitor ACH-3102, Y. Zhao, et al.
Session: HCV Therapy: Pre-clinical and Early Clinical Development. Date:
Tuesday, November 13, 2012.

About ACH-3102
ACH-3102, Achillion's second generation, pan-genotypic NS5A inhibitor, is a pico-molar potent compound that has been improved from first-generation NS5A inhibitors to maintain excellent potency against both wild type HCV as well as potency against resistant mutants that have been identified in clinical studies. In vitro, ACH-3102 has demonstrated potent activity against all HCV genotypes and shown additive to synergistic activity when combined with NS3 protease inhibitors, NS5B polymerase inhibitors, and ribavirin. ACH-3102 was shown to be safe and well tolerated in Phase 1 studies with potent antiviral activity achieved after a single dose. ACH-3102 is currently being evaluated in a Phase 2 trial in combination with ribavirin for 12 weeks as a treatment for chronic HCV genotype 1b.

About Sovaprevir
Sovaprevir is a Phase 2 pan-genotypic HCV protease inhibitor designed and synthesized based on crystal structures of enzyme/inhibitor complex. Sovaprevir is an open chain, non-covalent, reversible inhibitor of NS3 protease. In clinical and preclinical studies, sovaprevir demonstrated high potency, unique pharmacokinetic properties and an excellent safety profile at high drug exposures. With low single-digit nanomolar potency specific to HCV, sovaprevir is equipotent against HCV genotypes 1a and 1b at IC50 of approximately 1nM. Sovaprevir achieved sustained viral response rates of approximately 80% in combination with pegylated-interferon and ribavirin for the treatment of HCV genotype 1, and will be evaluated in all-oral, interferon-free regimens, Fast Track status was granted to sovaprevir in 2012 for the treatment of chronic HCV.

About ACH-2684
ACH-2684 is a next-generation HCV protease inhibitor designed and synthesized based on crystal structures of enzyme/inhibitor complex.

ACH-2684 is a macro-cyclic, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-2684 demonstrated pico-molar potency, excellent pharmacokinetic properties and safety profile at high drug exposures. ACH-2684 also exhibits rapid and extensive partitioning to the liver, as well as high liver/plasma ratios in preclinical studies. ACH-2684 has shown pico-molar potency against NS3 protease that is specific to HCV. It has preclinical activity against the 6 known genotypes of HCV and exhibits equipotent activity against HCV genotypes 1a and 1b at an IC50 of approximately 100 pico-molar. The drug candidate was discovered internally and is being advanced by Achillion.

About HCV
The hepatitis C virus is the most common cause of viral hepatitis, which is an inflammation of the liver. It is currently estimated that more than 170 million people are infected with HCV worldwide including nearly 4 million people in the United States, more than twice as widespread as HIV. Three-fourths of the HCV patient population is undiagnosed; it is a silent epidemic and a major global health threat.

Chronic hepatitis, if left untreated, can lead to permanent liver damage that can result in the development of liver cancer, liver failure or death. Few therapeutic options currently exist for the treatment of HCV infection. The current standard of care is limited by its specificity for certain types of HCV, significant side-effect profile, and injectable route of administration.
About Achillion Pharmaceuticals

Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease.

Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease including hepatitis C and resistant bacterial infections. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.

Forward-Looking Statements
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other important factors that could cause actual results to differ materially from those indicated by such forward-looking statements, including statements with respect to:
the expected potency, safety, tolerability, effectiveness and other characteristics of sovaprevir, ACH-3102 and ACH-2684; and Achillion's plans and timing for advancing its clinical trials, including the combination trial of sovaprevir and ACH-3102, the ongoing trial of
ACH-3102 and ribavirin, and future studies of ACH-2684. Among the factors that could cause actual results to differ materially from those indicated by such forward-looking statements are risks relating to, among other things Achillion's ability to: replicate in later clinical trials positive results found in earlier stage clinical trials of sovaprevir, ACH-2684 and ACH-3102; advance the development of its drug candidates under the timelines it anticipates in current and future clinical trials; obtain necessary regulatory approvals; obtain patent protection for its drug candidates, and the freedom to operate under third party intellectual property; establish commercial manufacturing arrangements; identify, enter into and maintain collaboration agreements with appropriate third-parties; compete successfully with other companies that are seeking to develop improved therapies for the treatment of HCV; and raise the substantial additional capital needed to achieve its business objectives. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2011 and its subsequent SEC filings.

In addition, any forward-looking statement in this press release represents Achillion's views only as of the date of this press release and should not be relied upon as representing its views as of any subsequent date. Achillion disclaims any obligation to update any forward-looking statement, except as required by applicable law.

CONTACT: Company Contact:
Glenn Schulman
Achillion Pharmaceuticals, Inc.
Tel. (203) 752-5510
gschulman@achillion.com
Media:
Christin Culotta Miller
Ogilvy PR
Tel. (212) 880-5264
christin.miller@ogilvy.com
Investors:
Mary Kay Fenton
Achillion Pharmaceuticals, Inc.
Tel. (203) 624-7000
mfenton@achillion.com
Investors:
Lee Stern
The Trout Group, LLC
Tel. (646) 378-2922
lstern@troutgroup.com


Wednesday, October 31, 2012

Hepatitis C-Achillion Pharma Worthy of New Look

Investment Commentary

Achillion Pharma Worthy of New Look

By Nathan Sadeghi-Nejad

NEW YORK (TheStreet) -- The midsummer implosion of Bristol-Myers Squibb's (BMS) BMS-094 (formerly INX-189) and subsequent FDA clinical hold for Idenix Pharmaceuticals' (IDIX) IDX-184 and IDX-19368 has winnowed the field of late-stage hepatitis C drug candidates. Given these shifting dynamics, the outlook for Achillion Pharmaceuticals' (ACHN) hepatitis C drug pipeline has improved and the stock is a solid long idea for investors seeking exposure to the hepatitis C market.

I haven't always been an Achillion fan. After attending the European Association for the Study of the Liver (EASL) meeting this spring, I gave Achillion a C-minus on my hepatitis C scorecard, largely due to indifference. I noted back then:

Achillion has two NS5A inhibitors, ACH-3102 and ACH-2928, which look okay in early studies, but I'm not sure what makes these drug candidates stand out. I feel similarly unexcited about ACH-1625, a protease inhibitor, which looked decent in a confusing study that combined it with interferon and ribavirin. I'm just not convinced these are valuable assets, so I'm going to wait on the sidelines.

I wasn't the only one confused by Achillion's Phase IIa study of ACH-1625, which is now known as sovaprevir. On the same day as my EASL review, the company issued a press release clarifying the results. Let's take another look.

Sovaprevir (ACH-1625)
Achillion's explanation for the uninspiring efficacy results in the EASL poster makes sense: Data included semi-compliant patients who were not consistently taking drug. In fact, viral loads for all 22 patients that completed treatment -- 12 weeks of sovaprevir combined with the immune boosters interferon and ribavirin, followed by 12 weeks of interferon and ribavirin alone -- reached undetectable levels. That's far more intriguing than the initially reported end-of-treatment response rates, which dipped as low as 69%. At a recent R&D day, management provided updated data from the same Phase IIa study: 78% (200 mg once-daily), 77% (400 mg), and 85% (800 mg) sovaprevir-treated patients achieved a sustained virologic response -- a reliable indicator of cure -- at 12 weeks (SVR12). Although that's somewhat less effective than other protease inhibitors in development, such as Abbott's ritonavir-boosted ABT-450 (88% SVR12) or Johnson & Johnson's TMC-435 (82% SVR12), it's good enough to make sovaprevir an attractive asset for combination therapy regimens. At the R&D day, Achillion also discussed sovaprevir's side effects in detail. At the highest dose tested (800 mg once-daily), one patient had significantly elevated liver enzymes and three patients (16%) had increased bilirubin levels. The combination of both elevated liver enzymes and bilirubin levels in patients raises concerns about Hy's Law, a reliable prognostic indicator for severe liver damage. This is the safety signal that worried me about sovaprevir at last spring's EASL meeting.

Continue reading... Page 2, Page 3

Friday, August 31, 2012

Achillion Pharma strikes deal to raise $41.8M as hep C results loom


Achillion Pharma strikes deal to raise $41.8M as hep C results loom

August 31, 2012 | By Ryan McBride
Fierce Biotech

Hepatitis C drug developer Achillion Pharmaceuticals ($ACHN) expects to haul in $41.8 million proceeds of a common stock sale to QVT Financial. And the funding comes ahead of some important clinical trial results from the New Haven, CT-based developer's pipeline of hep C treatments...
Achillion has several experimental oral meds in early- or mid-stage trials for hep C, a liver-damaging virus that afflicts an estimated 170 million people around the globe. The biopharma stampede is chasing all-oral regimens for the illness that can spare hep C patients from lengthy treatment on injections of interferon, which causes flu-like symptoms that make patients feel worse than the infectious disease does. And Achillion's contenders offer potential ingredients in cocktail therapies of oral meds to potentially wipe out the virus without those side effects from interferon....
Early next year Achillion is expected to report early data from an upcoming trial that tests a combo of the company's HCV NS3 protease inhibitor sovaprevir and a compound known as ACH-3102 as an interferon-free therapy for hep C, according a recent investor note from Cowen & Company...
Continue reading.......


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Wednesday, August 8, 2012

Sovaprevir (Formerly ACH-1625)-Positive SVR4 Results From Phase 2 Study

Achillion hepatitis C drug shows promise in mid-stage study

(Reuters) - Achillion Pharmaceuticals Inc said its experimental hepatitis C drug showed promising interim data in a mid-stage trial, sending its shares higher in extended trade.

The company said the drug sovaprevir, when given along with the standard therapy of pegylated interferon and ribavirin, showed no detectable virus level in a majority of patients four weeks after the end of the treatment period.

Of the 39 patients who received 12 weeks of additional standard therapy following 12 weeks of the combination therapy, a total of 33 patients in three different dosage arms showed sustained viral response a month later.

Trial results from the same patients at 12 weeks post treatment, as well as from another arm where 14 patients received 36 weeks of standard treatment following combination therapy, are expected in the first quarter of 2013.

Additionally, the company said it has begun early studies to evaluate the safety of another one of its experimental hepatitis C drugs, codenamed ACH-3102, and expects to report initial results from this in the third quarter.

"The safety and tolerability seen to date with ACH-3102 ... lead us to believe we have an in-house portfolio of optimized compounds that can successfully create an all-oral, interferon-free regimen for the treatment of genotype 1 HCV," Achillion's chief scientific officer Milind Deshpande said in a statement.

Hepatitis C drugmakers have been scouting for ways to develop an effective drug that does not contain interferon, which causes flu-like symptoms that often lead patients to discontinue treatment.
Companies such as Vertex Pharmaceuticals Inc, Bristol Myers-Squibb and Abbott Pharmaceuticals are currently in the race to get such a treatment to market.
Shares of New Haven, Connecticut-based Achillion rose 15 cents to $7.05 in after-market trade on Tuesday. They had closed at $6.90 on the Nasdaq.

(Reporting by Zeba Siddiqui in Bangalore; Editing by Anthony Kurian)

http://www.reuters.com/article/2012/08/08/us-achillon-hepatitisstudy-idUSBRE87700320120808

Achillion Announces Positive SVR4 Results From Phase 2 Study of Sovaprevir (Formerly ACH-1625) and Advancement of ACH-3102

GlobeNewswire

Sovaprevir (formerly ACH-1625) achieves SVR4 of 85-100% of genotype 1 treatment naive patients treated with sovaprevir for 12 weeks followed by an additional 12 weeks of pegylated-interferon and ribavirin

Enrollment of HCV-infected patients initiated in Phase 1 trial of ACH-3102, second generation pan-genotypic NS5A inhibitor

Conference call tomorrow August 8, 2012 at 10:00 a.m. EDT

NEW HAVEN, Conn., Aug. 7, 2012 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) today announced sustained viral response (SVR4) results of 85 to 100 percent from an ongoing multi-dose Phase 2 trial evaluating 12 weeks of dosing with sovaprevir (formerly ACH-1625), a once-daily protease inhibitor, in combination with pegylated interferon plus ribavirin (P/R) followed by an additional 12 weeks of P/R. In addition, the Company announced today that ACH-3102, a second-generation pan-genotypic NS5A inhibitor, has been safe and well tolerated by healthy volunteers in both single and 14-day multiple ascending dose groups. Further, enrollment of patients in a Phase 1 proof-of-concept clinical trial to evaluate the safety and efficacy of ACH-3102 in patients with genotype 1 HCV has been initiated.

"We are very pleased to reach these important milestones in our HCV portfolio including positive SVR4 results with sovaprevir and the advancement of ACH-3102, our second-generation pan-genotypic NS5A inhibitor, through Phase 1 dose-escalation," commented Milind S. Deshpande, Ph.D., President of Research and Development and Chief Scientific Officer. "The safety and efficacy seen with sovaprevir across dose groups provides us with confidence that this next-generation protease inhibitor will play an important role in an all-oral treatment for HCV. The safety and tolerability seen to date with ACH-3102, for which we expect to report proof-of-concept next month, combined with the compound's in vitro profile, lead us to we believe we have an in-house portfolio of optimized compounds that can successfully create an all-oral, interferon-free regimen for the treatment of genotype 1 HCV. We look forward to beginning combination studies with sovaprevir and ACH-3102 by the end of the year."

Sovaprevir: Updated Phase 2 results including SVR4

In June 2011, Achillion initiated a randomized Phase 2 trial evaluating three doses (200 mg, 400 mg, or 800 mg) of sovaprevir given once daily in combination with pegylated interferon plus ribavirin (P/R) for 12 weeks followed by an additional 12 or 36 weeks of P/R, for the treatment of genotype 1 HCV.

As previously reported in April 2012, of the 58 patients enrolled in this study, the majority had HCV genotype 1a (n=35 (60%)), with remaining patients having HCV genotype 1b (n=20) or genotype 1 (n=3). Approximately 71% of the patients were IL28B genotype CT/TT, the more difficult to treat mutation, 64% were male and 17% were African American. The complete early virologic responses (cEVR) across the 200 mg, 400 mg, and 800 mg sovaprevir dose groups were 100%, 94% and 100%, respectively.

Today, the Company reported SVR4 rates of 90%; 85%; and 100% in the 200 mg, 400 mg, and 800 mg dose groups, respectively, after 24 weeks of therapy consisting of 12 weeks of sovaprevir and P/R followed by additional 12 weeks of P/R. In all, 39 patients were assigned to receive an additional 12 weeks of P/R therapy with the remaining 14 patients assigned to receive an additional 36 weeks of P/R.


** One patient withdrew for AE deemed unrelated to sovaprevir.
++ One patient withdrew consent, one patient moved, both undetectable at the time of withdrawal; two patients withdrew for AEs deemed unrelated to sovaprevir.
* Two patients lost to follow-up, both undetectable at last assessment.
** One patient lost to follow up, undetectable at last assessment.

As previously reported, sovaprevir was generally well tolerated across all dose groups. Adverse events (AEs) in patients receiving sovaprevir were classified as mild to moderate and were transient. The most common AEs were consistent with P/R treatment.

Additional clinical trial results, including SVR4 and SVR12 for all patients treated with sovaprevir followed by an additional 12 weeks or 36 weeks of P/R, are expected be reported during the first quarter of 2013.

ACH-3102: Phase 1 trial in Healthy Volunteers and HCV-infected patients

In May 2012, Achillion initiated a Phase 1 clinical trial evaluating the safety and tolerability of single and multiple ascending doses of ACH-3102, a once daily, second-generation, pan-genotypic NS5A inhibitor, in healthy volunteers.

To date, 42 healthy volunteers have received a single dose of ACH-3102, ranging from 25 mg to 1,000 mg. An additional 24 healthy volunteers have received 14 days of once daily ACH-3102, with doses ranging from 25 mg to 75 mg. Preliminary data from both the single and multiple ascending dose groups demonstrated that ACH-3102 was well tolerated at all doses evaluated. There were no serious adverse events, no clinically significant changes in vital signs, electrocardiograms (ECGs), or laboratory evaluations. All reported adverse events were classified as mild or moderate, and were transient in nature.

Achillion announced today the initiation of enrollment of patients with genotype 1 HCV into a Phase 1 study to evaluate the safety, tolerability and antiviral activity of ACH-3102. The trial will initially evaluate the safety and antiviral activity of a single dose of ACH-3102. Initial results are expected to be reported during the third quarter of 2012.

Conference Call
Achillion will host a conference call and simultaneous webcast on Wednesday, August 8, 2012 at 10:00 a.m. EDT. To participate in the conference call, please dial (877) 266-0482 in the U.S. or (631) 291-4565 for international callers. The conference call ID is 13643523. A live audio webcast of the call will be accessible at www.achillion.com, under the News Center section of the website. Please connect to Achillion's website several minutes prior to the start of the broadcast to ensure adequate time for any software download that may be necessary.

A replay of the webcast will be available on www.achillion.com. Alternatively, a replay of the conference call will be available starting at 1:00 p.m. EDT on August 8, 2012, through 11:59 p.m. Eastern time on August 15, 2012 by dialing (800) 585-8367 or (404) 537-3406. The replay passcode is 13643523.

About HCV
The hepatitis C virus is the most common cause of viral hepatitis, which is an inflammation of the liver. It is currently estimated that more than 170 million people are infected with HCV worldwide including more than 5 million people in the United States, more than twice as widespread as HIV. Three-fourths of the HCV patient population is undiagnosed; it is a silent epidemic and a major global health threat. Chronic hepatitis, if left untreated, can lead to permanent liver damage that can result in the development of liver cancer, liver failure or death. Few therapeutic options currently exist for the treatment of HCV infection. The current standard of care is limited by its specificity for certain types of HCV, significant side-effect profile, and injectable route of administration.

About Achillion Pharmaceuticals
Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease including HCV and resistant bacterial infections. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.

Forward-Looking Statements
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other important factors that could cause actual results to differ materially from those indicated by such forward-looking statements, including statements with respect to the expected safety, efficacy and potential benefits of sovaprevir, expectations about milestone achievement including the potential to achieve proof-of-concept for ACH-3102 and initiation of all-oral, interferon-free clinical trials evaluating regimens containing sovaprevir (ACH-1625) and ACH-3102 for the treatment of HCV. Among the factors that could cause actual results to differ materially from those indicated by such forward-looking statements are risks relating to, among other things Achillion's ability to: replicate in later clinical trials positive results found in earlier stage nonclinical studies and clinical trials of its drug candidates, including ACH-1625 and ACH-3102; advance the development of its drug candidates under the timelines it anticipates in current and future clinical trials; obtain necessary regulatory approvals; obtain patent protection for its drug candidates and the freedom to operate under third party intellectual property; establish commercial manufacturing arrangements; identify, enter into and maintain collaboration agreements with appropriate third-parties; compete successfully with other companies that are seeking to develop improved therapies for the treatment of HCV; manage expenses; and raise the substantial additional capital needed to achieve its business objectives. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2011 and its subsequent SEC filings.

In addition, any forward-looking statement in this press release represents Achillion's views only as of the date of this press release and should not be relied upon as representing its views as of any subsequent date. Achillion disclaims any obligation to update any forward-looking statement, except as required by applicable law.

CONTACT: Company Contact: Glenn Schulman Achillion Pharmaceuticals, Inc. Tel. (203) 624-7000 gschulman@achillion.com Media: Christin Culotta Miller Ogilvy PR Tel. (646) 229-5178 christin.miller@ogilvypr.com Investors: Mary Kay Fenton Achillion Pharmaceuticals, Inc. Tel. (203) 624-7000 mfenton@achillion.com Investors: Seth Lewis The Trout Group, LLC Tel. (646) 378-2952 slewis@troutgroup.com Source: Achillion Pharmaceuticals, Inc.