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Fw: NATAP: New HCV Drug Celgosivir Phase II Results

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  • alleypat
    NATAP http://natap.org/ ... MIGENIX To Present Celgosivir Phase II Hepatitis C Results at DDW MIGENIX will make a presentation of results from a recent
    Message 1 of 1 , May 19 7:04 PM
      NATAP http://natap.org/
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      MIGENIX To Present Celgosivir Phase II Hepatitis C Results at DDW

      MIGENIX will make a presentation of results from a recent hepatitis C Phase II combination therapy study.

      Dr. Kelly Kaita, the Director of the Viral Hepatitis Investigative Unit (VHIU) at the Health Sciences Centre, University of Manitoba and a lead investigator in the MIGENIX Phase II study will make the presentation.

      The presentation entitled: "Phase II Study of Celgosivir in Combination with Peginterferon alfa-2b and Ribavirin in Chronic Hepatitis C Genotype-1 Non-responder Patients" (Abstract # 324227) will be made on Monday, May 21, at 2:45 p.m. (EDT) in Room 206 of the Washington Convention Center. Additionally on May 20, 2007 Dr. Kaita and AnnKatrin Petersen, M.D., Vice President, Clinical Development of MIGENIX will participate in a DDW news conference highlighting progress in new and evolving areas of chronic hepatitis C therapy including celgosivir. A copy of the presentation and the related Abstract will be available at http://www.migenix.com following the presentation.

      Research being presented at Digestive Disease Week 2007 analyzes advancements in the diagnosis of hepatitis C and therapies available to patients who suffer from the disease. DDW is the largest international gathering of physicians and researchers in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery. Digestive Disease Week is considered the largest and most prestigious meeting in the world for the gastrointestinal professional. Every year DDW attracts more than 16,000 physicians, researchers and academics from around the world.

      Celgosivir is an oral alpha-glucosidase I inhibitor and is currently the only anti-HCV drug in clinical development that acts on host-directed glycosylation. In preclinical studies, celgosivir has shown excellent in vitro synergy with various interferons in the clinic or in development including Pegasys, PEG-Intron, Infergen, Alferon and IFN-omega (with or without ribavirin) and other drugs in development for the treatment of HCV (e.g. polymerase inhibitors) and therefore has the potential to be included as part of multiple combination approaches to improve efficacy in anti-HCV therapy.

      MIGENIX is committed to advancing therapy, improving health, and enriching life by developing and commercializing drugs primarily in the area of infectious diseases. The Company's clinical programs include drug candidates for the treatment of chronic hepatitis C infections (Phase II and preclinical), the prevention of catheter-related infections (Phase III) and the treatment of dermatological diseases (Phase II). MIGENIX is headquartered in Vancouver, British Columbia, Canada with US operations in San Diego, California.

      Phase II Proof of Concept Study of celgosivir in combination with peginterferon alfa-2a and ribavirin in chronic hepatitis C genotype-1 non responder patients

      Reported by Jules Levin
      EASL, April 11-15, 2007, Barcelona

      Kelly Kaita from University of Manitoba reported in the very last session today Sunday at EASL on using chestnut to cure HCV.

      Celgosivir: a new agent for the treatment of chronic HCV infection.

      --first in class oral antiviral compound that targets host enzyme.

      --safety profile established in over 600 subjects.

      --in vitro synergy demonstrated with interferon, ribavirin and other anti-HCV drugs in development.

      Celgosivir is a 6-0-butanoyl ester derivative of castanosperine; it's derived from the Australian chestnut. It's a potent inhibitor of a-glucosidase I, which is a host enzyme required for viral assembly, release and infectivity.

      Pharmacology: Celgosivir rapidly converts to castanospermine in the body. It can be detected in serum within 5 minutes; T-max is about 1 hour; terminal half-life about 19-23 hours; there are dose proportional (10-400 mg range) kinetics; this drug is excreted predominantly unchanged exclusively in the urine; to date, no other metabolites have been detected.

      STUDY DESIGN
      This was a randomized, double-blind, multi-center study. Treatment period is 12 weeks. Patients are genotype 1 treatment-experienced with prior non-response or partial response to a combination of peginterferon and ribavirin.

      Patients were randomized to one of three treatment groups:
      --PRC: peginterferon alfa-2b + ribavirin + celgosivir 400 mg
      --PC: peginterferon alfa-2b + celgosivir 400 mg
      --PR: peginterferon alfa-2b + ribavirin (active control) It will however be years before interferon or ribavirin may be eliminated from a regimen, and perhaps it will not be possible to eliminate one or both of these drugs

      57 patients were enrolled. 36 were non-responders (prior response <2 log IU/mL decrease in HCV RNA, n=36). Within this group was a subgroup of null responders, the most difficult to treat patients with current therapy (prior decrease <0.4 log IU/mL decrease in HCV RNA, n=11). There was a group, n=21, of partial responders (prior response of >2 log IU/mL decrease in HCV RNA, achieved an Early Viral Response, but did not become negative and were positive at week 24). This group included 2 relapsers.

      DEMOGRAPHICS
      36 non-responders were enrolled: 15 in the PRC group; 11 in PC, 10 in PR.

      These patients were comparable with respect to race, age, weight and baseline ALT.

      Mean HCV RNA of about 6.7 log IU/mL in each treatment group.

      The mean response to prior therapy was 0.71, 1.14 and 0.82 log IU/mL for PRC, PC and PR treatment groups, respectively.

      Of the 11 null responders included in the non-responder group: 7, 2, and 2 patients in the PRC, PC and PR treatment arms, respectively.

      21 patients were included in the Partial Responders cohort (PRC: 3, PC: 9, PR: 9). Baseline characteristics were comparable between the PC & PR treatment arm. With only 3 patients in the PRC treatment arm efficacy analysis was not performed.

      Patient Disposition by Treatment Group
      88% of the 57 patients enrolled completed the 12 weeks of study. Adverse events included fatigue, flu-like symptoms, injection site reactions, 1 diarrhea.
      Number (%) of Patients



      SAFETY SUMMARY
      All 3 combination treatments generally well tolerated. No serious adverse events reported. No new treatment-emergent toxicities were observed:
      --as is common with peginterferon alfa-2b and ribavirin, fatigue and flu-like symptoms were reported equally across all treatment groups.

      --diarrhea, flatulence and CK elevations in celgosivir-treated groups were mostly mild to moderate in severity, manageable, reversible and consistent with previous clinical experience.

      EFFICACY in NON RESPONDERS Cohort at Week 12
      On-Treatment Analysis
      The triple therapy group had a mean viral load reduction of -1.62 log (n=12); this did not reach statistical significance but was very close to it. The Peg/RBV group had a -0.92 log reduction. The peginterferon plus Celgosivir group had a -0.6 log reduction in viral load. There was a steep early decline in viral load in the non-responder group, about 1 log by day 2. Patients receiving the triple celgosivir containing regimen who had a mean -1.62 reduction in HCV RNA previously had a mean HCV RNA reduction by prior therapy of -0.6 log.

      Efficacy in Non Responder Cohort
      Log reduction comparison

      Number (%) of Patients with Viral load Reductions at Study Week 12
      Close to 45% of patients on triple therapy achieved early viral response or minimum 2 log drop, while in n the other 2 groups EVR was 10%.


      Of note, of the 11 previous null responders all but 1 patient had much better responses with the triple therapy in this study, they had 1 to 4 log better responses than they had to previous therapy. Only 1 patient had no response to the new therapy, they had the same response as to the previous therapy.

      EFFICACY SUMMARY

      Non Responders
      --42% EVR in PRC vs 10% in PR
      --Mean viral load drop in PRC of 1.63 log compared to 0.92 in PR
      --Rapid onset of treatment effect observed in PRC-treated patients comtinuing through week 12.

      Null Responders (subgroup)
      --3 PRC-treated patients (43%) achieved EVR in this difficult to treat subgroup.
      -- >2 log reduction by week 4 in 1 additional PRC patient (did not complete 12 weeks).
      -- 1.86 log mean viral load drop at week 12 in PRC (n=6) vs 0.32 log in PR (n=2).
      -- 6/7 patients in PRC group had >1 log reduction in viral load.

      DISCUSSION

      Celgosivir is a first-in-class oral antiviral compound that targets the a-glucosidase I host enzyme.

      Safety: Celgosivir + peginterferon alfa-2b with or without ribavirin is well tolerated with no new combination treatment emergent toxicities.

      Rapid Onset: Addition of celgosivir to PR resulted in a rapid onset of treatment effect that continued through the 12 week study treatment period.

      Clinical Benefit: Celgosvir added to peginterferon alfa-2b and ribavirin results in improved viral load reductions and clinically significant benefit in genotype-1 non-responders.

      New HCV Drug Celgosivir/MX-3253, oral alpha-glucosidase I inhibitor

      Press announcement from Migenix
      Dec 13, 2006

      A phase II combination study in non-responder and partial responder patients commenced in November 2005, with full enrollment reached in June 2006 and top-line results of the study announced on November 6, 2006. A total of 57 patients were enrolled into the study (36 were non-responders and 21 were partial responders to prior pegylated alpha interferon-based HCV treatment). Patients were randomized into three treatment arms: (i) celgosivir plus peginterferon alfa-2b plus ribavirin ("triple combination"); (ii) celgosivir plus peginterferon alfa-2b ("double combination"); and (iii) celgosivir placebo plus peginterferon alfa-2b plus ribavirin ("control treatment"). Of the 36 non-responders, 30 patients completed the 12 weeks of treatment: 12 in the triple combination arm, 8 in the double combination arm, and 10 in the control treatment arm. The triple combination demonstrated clinical benefit in this non-responder patient population, achieving:

      - a mean HCV viral load reduction of 1.2 log10 compared to a 0.4 log10 mean reduction in the control treatment arm; and

      - a 33% Early Virological Response ("EVR") compared to a 10% EVR in the control treatment arm (EVR is defined as a 2 log10 or greater HCV viral load reduction at 12 weeks of treatment).

      In the partial responder patient population, there were insufficient patients (n=3) in the triple combination arm for any conclusions to be drawn. The double combination did not show a meaningful difference in viral load compared to the control treatment in either the non-responder or partial responder patients.

      The celgosivir combination therapies were well tolerated and resulted in no serious adverse events.

      Additional data from this study are planned to be presented at one or more international medical or liver disease conferences in 2007. We also plan to submit an IND in the US in the second half of 2007.

      In conjunction with the celgosivir non-responder study, a protocol was designed and approved by Health Canada to provide participants in the 12-week study with access to continued treatment for up to an additional 36 weeks (the "extension study"). In consultation with their physicians, patients could elect to continue on with their original treatment or, if on the double combination or the control treatments, could switch to the triple combination treatment. Of the 50 patients completing 12 weeks of treatment, 31 elected to continue treatment beyond 16 weeks with 30 of these either continuing with, or switching to, the triple combination. As of November 7, 2006: 2 patients had completed 48 weeks of treatment; 14 were between 24 and 48 weeks of treatment; 6 had not yet reached 24 weeks of treatment; and 9 patients had discontinued treatment.

      The Phase II non-responder study and the extension study are supported in part through a Material Transfer License Option agreement with Schering-Plough Corporation ("Schering"). The agreement with Schering provides for (a) the supply of PEGETRON® (peginterferon alfa-2b powder plus ribavirin), (b) certain technical and laboratory support and other services, and (c) certain limited rights for Schering's review of clinical trial results and for the negotiation of a license agreement. On December 7, 2006 we provided a summary of the study results to Schering for their exclusive review pursuant to the Material Transfer License Option agreement. No license terms have been negotiated with Schering to date.

      In October 2006 we began a phase II combination study of celgosivir in patients with chronic HCV (genotype 1) infection who have not received prior treatment for their infection (the "treatment-naive" study"). The focus of this study is on viral kinetics, pharmacokinetics, safety and tolerability. Four-week interim and 12-week results from the study are expected in the first half of 2007.




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