XTL-6865 To prevent Hepatitis C Reinfection Following Liver Transplant

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XTL-6865 To prevent Hepatitis C Reinfection Following Liver Transplant

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.

XTL-6865 is being developed by XTLbio 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.