A randomized, adaptive-design dose finding study to assess the antiviral efficacy and safety of NIM811 administered in combination with Standard of Care (SOC) in relapsed HCV-1 infected patients

HCV is a positive, single stranded RNA virus that is a major cause of chronic
liver disease affecting approximately 170 million people. Chronic HCV infection
leads to progressive fibrogenesis, cirrhosis, liver insufficiency, and
hepatocellular cancer and is the most frequent indication for liver
transplantation. Current therapy consists of a combination of pegylated
interferon (PEG IFN) with Ribavirin (RBV) for 6 * 12 months. Sustained
virologic response (SVR), typically defined as absence of detectable HCV-RNA in
serum at 24 weeks of follow-up after treatment, is only 48% for genotype 1.
There are currently no specific treatment options for patients who failed to
achieve SVR following PEG IFN + RBV treatment. Thus, there is a continued unmet
medical need for both more efficacious and better tolerated therapeutics in
chronic viral hepatitis C.

NIM811 (SDZ211-811, MeIle4-cyclosporin) is a natural cyclosporine analog
characterized by a lack of immunosuppressive activity and comparable antiviral
anti-HCV activity in vitro compared to cyclosporine A (CsA). In a previous
phase II trial, NIM811 600 mg bid given in combination with PEG IFN resulted in
a highly statistically significant reduction in viral load at the end of
treatment compared to subjects treated with PEG IFN alone. Given the efficacy
in this trial of NIM811 in combination with PEG IFN, the present study aims to
determine the optimal efficacy and safety of NIM811 to help guide design of the
future studies in patients with HCV.

The primary objective is: To evaluate the efficacy, safety and tolerability of
NIM811 administered in combination with SOC in an interferon-relapser
population of patients infected with chronic hepatitis C genotype-1.

Secundary objectives are:
* To assess the percentage of patients achieving RVR in patients treated with
NIM811 in combination with SOC
* To evaluate the effect of NIM811 given in combination with SOC in patients
with chronic hepatitis C genotype-1 on sustained virologic response 24 weeks
after the cessation of treatment (SVR24)

This is a randomized, adaptive-design study in patients with chronic hepatitis
C genotype 1 who have relapsed on SOC. The study is split in 2 parts. Part 1
will consist of only 1 cohort, cohort A. Part 2 will consist of a maximum of 4
cohorts (cohorts 1, 2, 3 or 4).
In part 1, the safety and efficacy profile of NIM811 combined with SOC for 4
weeks will be evaluated. This part will assist in the selection of doses to be
tested in Part 2 of the study, in which patients are being treated for 12 weeks
with NIM811 and SOC. Part 2 will only start after evaluation of the interim
results (4 weeks treatment) of part 1, cohort A.

All patients receive SOC for 48 weeks (PEG INF and Ribavirin). Furthermore, the
patietns receive in:

Part 1: the first 4 weeks also NIM811 (in different dosages)
Part 2: the first 12 weeks also NIM811 (in different dosages)

During a 72 week period, there will be 24 visits to the hospital. During the
visits, more ml's of blood will be drawn than during the SOC.


NIM811
In studies involving dogs receiving NIM811, researchers noticed that the
animals had changes in the testicles (testicular degeneration) after receiving
the drug for 14 days. Researchers also saw testicular degeneration in dogs that
received the drug for 13 weeks. Dogs that were allowed to recover for 4 weeks
after 13 weeks of NIM811 treatment had partial recovery, so that sperm counts
began to return to normal. In studies involving rats receiving NIM811,
researchers did not observe any testicular degeneration. It is possible that
men could have this side effect after taking NIM811, but no one knows if this
will happen. Male patients will have blood tests to monitor how well the
testicles are working.

In animals, researchers also noted that some of the animals had changes in the
lens of the eye. Eye monitoring will be done in this study.

To date, humans have received NIM811 in only 2 research studies*a single dose
study in healthy volunteers and an ongoing multiple dose study in people with
hepatitis C. Sixty-three healthy volunteers have taken NIM811 as part of the
single-dose study. Participants swallowed one dose of NIM811 in this study.
Doses tested ranged from 1 mg to 1600 mg. No serious adverse (bad) events or
drug-related adverse events were reported from the study. It appears that
NIM811 was safe and well tolerated when participants took a single dose up to
1600 mg.
Seventy-four people with hepatitis C have received NIM811/placebo in the
ongoing multiple dose study. These participants received either NIM811 or
placebo for 2 weeks. No serious adverse (bad) events were reported after
patients received the medication from the study.
The reported side effects that may be related to NIM811 include temporary
headache and blurred vision and an increase in blood triglycerides (fat) and
total bilirubin (breakdown product of red blood cells). Two patients that
received NIM811 reported reductions in sex drive. One patient reported a skin
rash.

Twenty-one people with hepatitis C have received NIM811/placebo in combination
with pegylated interferon. These participants received either NIM811 or placebo
for 2 weeks and 2 doses of pegylated interferon. No serious adverse (bad)
events were reported after patients received the medication from the study.
Patients taking NIM811 in combination with
pegylated interferon may experience a greater decrease in platelets than those
taking pegylated interferon alone; since platelets are a component of blood
that helps stop the bleeding process, this might increase the risk of bleeding.
To date none of the people taking NIM811 have had any problems with their
vision, but eye exams will be done to check for this.

Ribavirin
The primary adverse reaction is anemia, which is due to breaking up of the red
cells (hemolytic anemia). In patients who have heart disease, this can cause
stress on the heart and possibly lead to an increased risk of heart attack
(myocardial infarction). During treatment, the red blood cell count will be
followed. The dose of ribavirin might be adapted to help with this should it
happen.

Pegylated interferon
The most commonly reported adverse reactions were psychiatric reactions,
including depression, irritability, and anxiety; and flu-like symptoms such as
fatigue, fever, muscle aches, headache, and severe chills during fever. The
most common reason for dose modification or withdrawal from treatment is a low
white blood cell count (neutropenia) or a low platelet count
(thrombocytopenia). White cells help fight infection; although people taking
interferon for HCV have not been shown to have an increased risk of
infection,the pegylated interferon dose might be adapted to help keep the white
cells up. It is possible that the interferon and NIM811 given together may make
the platelet lowering worse; this will be watched carefully during the trial.
Decrease or loss of vision can be induced or aggravated by treatment with
interferon therapy. Therefore, treatment with interferon should be discontinued
for new or worsening eye (ophthalmologic) disorders.

Study procedures
The tests done at each visit are standard medical tests. The most unpleasant is
often having blood samples taken. The risks of taking blood may include
fainting, pain and/or bruising. Rarely, these may be a small blood clot or
infection at the site of the needle puncture. The blood pressure cuff may also
cause discomfort or bruising to the upper arm.