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New HCV & HBV Drugs: XTL-6865, XTL2125
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3 New HCV & HBV drugs explained below, for chronic HCV & post transplant for HCV & HBV
XTLbio has Initiated the Phase 1a Clinical Trial of XTL-6865 for the Treatment of Hepatitis C
Thursday September 29
REHOVOT, Israel, September 29 /PRNewswire-FirstCall/ -- XTL Biopharmaceuticals Ltd ("XTLbio") (LSE: XTL - News; NASDAQ: XTLB - News) today announced that it has initiated the Phase1a clinical trial of XTL-6865 for the treatment of hepatitis C ("HCV"). This trial is being conducted under an investigational new drug application ("IND"), filed with the Food and Drug Administration ("FDA") in April this year. The trial is a multi-center trial and will be conducted in the US and Israel.
XTL-6865 is being developed to prevent HCV re-infection following a liver transplant and for the treatment of chronic HCV disease. XTL-6865 is a combination of two fully human monoclonal antibodies (Ab68 and Ab65) against the hepatitis C virus E2 envelope protein. A single antibody version of this product was tested in a pilot clinical program that included both Phase I and Phase II clinical trials and provided preliminary evidence of anti-viral activity in humans.
Three products under development:
* HepeX-B is being developed to prevent re-infection with hepatitis B, known as HBV, in liver transplant patients. HepeX-B is a mixture of two fully human monoclonal antibodies, which bind to the HBV surface antigen, or HBsAg. HepeX-B is currently in a Phase IIb trial in liver transplant patients. Worldwide rights for HepeX-B were licensed to Cubist in 2004, in exchange for certain milestone payments and future royalties on Cubist's net sales.
* XTL-6865 is being developed to prevent hepatitis C, known as HCV, re-infection following a liver transplant and for the treatment of chronic HCV. XTL-6865 (formerly known as HepeX-C) is a combination of two fully human monoclonal antibodies (Ab68 and Ab65) against the hepatitis C virus E2 envelope protein. A single antibody version of this product was tested in a pilot clinical program that included both Phase I and Phase II clinical trials. In April 2005, we submitted a U.S. investigational new drug application, known as an IND, to the FDA in order to commence a Phase Ia/Ib clinical trial later this year for XTL-6865, the dual-MAb product.
* XTL-2125 is the lead product candidate from our HCV-SM small molecule development program. XTL-2125 (also referred to as BC2125) is a small molecule non-nucleoside polymerase inhibitor for the treatment of chronic hepatitis C. XTL-2125 is currently in formal toxicity testing, and we expect to make an IND filing to the FDA at the end of 2005 or early in 2006, assuming no toxicity concerns arise.
Preventing Re-infection following Liver Transplant
Hepatitis C is the leading cause of liver transplants in the U.S. It is estimated that in 2004, over 2,000 liver transplants were performed in the U.S. in HCV positive patients. Although the HCV infected liver is removed during the transplant procedure, the newly transplanted healthy liver is re-infected with HCV from the patient's serum. Re-infection occurs in all patients within days following the transplant. Recurrent HCV infection is the leading cause of graft failure: 10% of patients will die (or be re-transplanted) by year five due to recurrent HCV disease. A further 30% of patients will have cirrhosis at the end of year five.
There is no therapy available to prevent re-infection following a liver transplant. Once the liver has been re-infected, clinicians attempt to treat the recurrent disease. Response rate to this treatment is low (~20%). Therefore, re-infection following a liver transplant represents a significant unmet medical need.
One of the potential indications of XTL-6865 is preventing re-infection following a liver transplant. We estimate that a successful therapy for preventing re-infection with HCV following liver transplantation could reach annual worldwide sales of approximately $400 million.
Treating Chronic HCV
Chronic hepatitis C is a serious life-threatening disease, which affects around 170 to 200 million people worldwide. We estimate that between eight to 10 million of these people reside in the U.S., Europe and Japan. 20% to 30% of chronic hepatitis patients will eventually develop progressive liver disease that may lead to decomposition of the liver or hepatocellular carcinoma (liver cancer). Each year 10,000 to 12,000 people die from HCV in the U.S. alone. It is estimated that by the end of this decade, the number of deaths due to HCV in the U.S. will surpass the number of deaths due to AIDS.
The present worldwide market for the treatment of chronic HCV is estimated at $3 billion and represents Interferon-based treatments. Interferon alpha was first approved for use against chronic hepatitis C in 1991. At present, the optimal regimen appears to be a 24 or 48 week course of the combination of Pegylated-Interferon and Ribavirin. A 24 week course of this combination therapy yields a sustained response rate of approximately 40 to 45% in patients with genotype 1 (the most prevalent genotype in the western world) and a better sustained response with a 48 week course. Despite this improvement in response rates, approximately half of today's patient population in the U.S. and Europe does not respond to therapy and has no therapeutic alternative. Therefore, there is a significant unmet medical need in the treatment of HCV.
XTL-6865
XTL-6865 is being developed to prevent hepatitis C re-infection following a liver transplant and for the treatment of chronic HCV. XTL-6865 is a combination of two fully human monoclonal antibodies (Ab68 and Ab65) against the hepatitis C virus E2 envelope protein. A single antibody version of this product, then referred to as HepeX-C, was tested in a pilot clinical program that included both Phase I and Phase II clinical trials. In April 2005, we submitted an IND to the FDA in order to commence a Phase Ia/Ib clinical trial later this year for XTL-6865, the dual-MAb product.
The two antibodies comprising XTL-6865 were selected by screening a large panel of candidates based on their high level of activity against the virus in our proprietary HCV models. We believe that a combination of two antibodies that bind to different epitopes is essential to provide broad coverage of virus quasispecies, and to minimize the probability for escape from therapy. We have shown that the two antibodies chosen (Ab68 and Ab65) specifically bind and immunoprecipitate viral particles from infected patients' sera with different HCV genotypes. In addition, both antibodies reduced mean viral load in HCV-Trimera mice. We have also shown that incubation of an infectious human serum with Ab68 or Ab65 prevented the serum's ability to infect human liver cells and human liver tissue.
The single antibody HepeX-C product candidate (Ab68) was tested in a pilot clinical program, which included:
* A Phase Ia/Ib Clinical Program in Patients with Chronic HCV, which demonstrated the safety and tolerability of using single and multi-doses of Ab 68 up to 120mg for a 28 day dosing period. In terms of efficacy, eight out of 25 patients had at least a 90% reduction in HCV-RNA levels from pre-treatment levels following administration of Ab68. These trials provided safety data, as well as a preliminary indication of anti-viral activity in humans.
* A Phase IIa Clinical Trial with Ab68 Following Liver Transplant, which demonstrated the safety and tolerability of Ab68 up to 240mg dosed for 12 weeks. Higher doses were not tested due to a clinical hold as a result of an intraoperative death of the first patient tested at the 480mg dose level (later determined by the medical examiner to be related to pulmonary emboli (blood clots in the lung)). The FDA later cleared the clinical hold, but we decided to discontinue the study and focus further development efforts on the dual anti-body product, XTL-6865. No other drug-related serious adverse events were reported during this study. The 120mg and 240mg dose groups had a significantly greater reduction in viral load than the placebo group during the first week when dosed daily. This effect was less evident when dosed less frequently than daily. This data provided additional evidence of anti-viral activity in immunosuppressed patients.
Based on this information, we had a pre-IND meeting with the FDA in October 2004 regarding XTL-6865, at which we presented data on Ab68 and Ab65, which had just successfully completed pre-clinical development. In April 2005, we submitted an IND to the FDA in order to commence a Phase Ia/Ib clinical trial later this year for XTL-6865, the dual-MAb product.
XTL-2125
XTL-2125 is the lead product candidate from our HCV-SM small molecule development program. XTL-2125, also referred to as BC2125, is a small molecule non-nucleoside polymerase inhibitor for the treatment of chronic hepatitis C.
Our HCV-SM small molecule development program is targeted at treating chronic hepatitis C utilizing novel non-nucleoside polymerase inhibitors. The program is focused on developing synthetic small molecules to be orally-administered to patients for the inhibition of HCV viral RNA replication. We have identified two lead candidates from two distinct chemical series of compounds, which we licensed from B&C Biopharm Co. Ltd.
Each candidate has exhibited activity against HCV in our proprietary in vitro and in vivo preclinical drug validation systems. In preliminary in vivo animal studies, acceptable toxicity profiles and oral absorption have been shown.
XTL-2125 is currently in formal toxicity testing, and we expect to make an IND filing to the FDA at the end of 2005 or early in 2006, assuming no toxicity concerns arise.
HepeX-B (Product for the Prevention of Re-Infection of Hepatitis B)
HepeX-B is being developed to prevent re-infection with HBV in liver transplant patients. Protection of the transplanted liver from recurrent HBV infection is critical to preserving graft function. Life-long HBV prophylactic treatment is typically necessary, since the virus remains in several other body compartments following removal of the infected liver. Without treatment, hepatitis B infection of the transplanted liver reoccurs rapidly resulting in progressive disease, graft failure, and death.
HepeX-B is a mixture of two fully human monoclonal antibodies, which bind to the HBV surface antigen, or HBsAg. HepeX-B is being developed as an alternative to the present standard-of-care, hepatitis B Immunoglobulin, or HBIg, which has several disadvantages, among them complicated and uncomfortable patient administration (intravenous or painful intra-muscular injection). The present market size of HBIg is estimated to be about $100 million per year worldwide.
In previous clinical studies, HepeX-B maintained serum antibody levels similar to HBIg, using significantly less protein, thus enabling the development of a low-volume "patient friendly" formulation. In addition, as HepeX-B is not isolated from human blood, risk of infection from blood-borne organisms is minimal.
HepeX-B is presently being studied in a Phase IIb clinical trial in liver transplant patients. In November 2004, we announced the completion of first scheduled review of the first 15 patients enrolled to the study by an Independent Data and Safety Monitoring Board, or DSMB. The DSMB recommended the continuation of the trial.
In June 2004, we announced the completion of a license agreement with Cubist for the worldwide development and commercialization of HepeX-B. Under this agreement we will be responsible for completing the on-going Phase IIb, which will be fully funded by Cubist. Cubist will be responsible for completing the clinical development beyond Phase IIb and for registration and commercialization of the product worldwide.
Under the terms of the agreement, Cubist paid us an initial up-front payment of $1 million upon the signing of the agreement, a further aggregate amount of $2 million as collaboration support to be paid in installments until the end of 2005, of which $1 million has been paid through March 31, 2005, and an additional amount of up to $3 million upon achievement of certain regulatory milestones. Under the agreement, we are entitled to receive royalties from net sales by Cubist, generally ranging from 10% to 17%.
In the event that the actual costs incurred in conducting activities that Cubist determines are necessary or advisable to obtain regulatory approval for HepeX-B for the prevention of recurrent hepatitis B infections in liver transplant patients exceed $33.9 million, any costs in excess shall be borne in equal share by Cubist and us.
Orphan drug status, a regulatory designation that provides exclusive marketing rights to drug candidates that would not otherwise be commercially viable, has been granted for HepeX-B in the U.S. and Europe.
Michael Weiss, XTLbio's Chairman, commented:
"Earlier this year, we set the initiation of clinical trials with XTL-6865 as a significant corporate milestone for 2005. We are very pleased to have accomplished this milestone, and look forward to the further advancement of this important product in our HCV portfolio"
Contacts:
XTLbio
Jonathan Burgin, Chief Financial Officer Tel: +972-8-930-4440
About XTL Biopharmaceuticals Ltd.XTL Biopharmaceuticals Ltd. (XTLbio) is a biopharmaceutical company developing drugs against hepatitis. Established in 1993, XTLbio became a public company in 2000 and its ordinary shares are listed on the Official List of the UK Listing Authority and are traded on the London Stock Exchange under the symbol XTL and on the Tel Aviv Stock Exchange, Israel, and ADR's, representing 10 ordinary shares each, are traded on The NASDAQ Stock Market under the symbol XTLB.
Cautionary Statement
Some of the statements included in this press release may be forward-looking statements that involve a number of risks and uncertainties. For those statements, we claim the protection of the safe harbor for forward-looking statements contained in the US Private Securities Litigation Reform Act of 1995. Among the factors that could cause our actual results to differ materially, and therefore affect interest by investors in our securities, are the following: the results of prior trails with XTL-686are not necessarily indicative of the results we may have in the Phase 1a and 1b trials; and other risk factors identified from time to time in our reports filed with the various regulatory bodies. Any forward-looking statements set forth in this press release speak only as of the date of this press release. We do not intend to update any of these forward-looking statements to reflect events or circumstances that occur after the date hereof. This press release and prior releases are available at www.xtlbio.com. The information in our website is not incorporated by reference into this press release and is included as an inactive textual reference only.
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