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   Clinical Trials

Dexanabinol traumatic brain injury trial fails to meet endpoints:
Pharmos
Monday, December 27, 2004 10:00 IST
Iselin, NJ

Pharmos Corporation announced the top line results of its pivotal Phase
III trial of dexanabinol to treat severe traumatic brain injury (TBI).
Dexanabinol did not demonstrate efficacy as measured by the primary
clinical outcome endpoint, the Extended Glasgow Outcome Scale (GOSE).
The double-blind, randomized, placebo-controlled trial was conducted in
86 trauma centers in 15 countries. In the 861 patient trails, 846
patients were available for analysis, 428 treated with dexanabinol and
418 treated with placebo. The randomization provided well-balanced
groups for this study. While efficacy was not established, the trial
demonstrated an excellent safety profile with no evidence of excess side
effects in the dexanabinol-treated patients. Not all secondary endpoints
have been analyzed; however, no differences were observed in mortality
or in analysis of subgroups in the trial.

Dr Haim Aviv, chairman and CEO of Pharmos, said, "We are very
disappointed and frankly somewhat perplexed that we did not observe any
neuroprotective effect of dexanabinol in TBI. This trial was one of the
largest ever completed in TBI. TBI is a severe injury of the most
complex organ in the body and involves a patient population with high
heterogeneity. It is therefore a very difficult indication to study, but
we believe this study was performed according to the highest scientific
standards and included important innovative aspects in the design and
analysis aimed at improving the quality of the study. In the next few
weeks, we will carefully analyze the results of this trial before making
final decisions about our future plans, but it is unlikely that we will
continue to develop dexanabinol for TBI. We plan, however, to continue
developing dexanabinol for cognitive impairment in cardiac surgery, and
we also remain committed to developing a drug candidate for pain."

Dr Andrew Maas, chairman of the European Brain Injury Consortium and
Chairman of the Steering Committee of the study, said, "This study has
great value from a scientific perspective. The Pharmos TBI trial
included many innovative aspects in the design and was executed
according to the highest scientific standards. The Steering Committee
will work closely with the Company to analyze the data from the trial in
order to garner scientific and medical information that will be valuable
in treating TBI patients."

Dr Gad Riesenfeld, president and COO of Pharmos, said, "We all share the
disappointment in the results for TBI. However, we will continue to
analyze the results of the Phase II CABG trial of dexanabinol and are
committed to continuing that program. In addition, we expect to initiate
clinical studies of our lead CB2-selective drug candidate, PRS-211,375,
during the first half of 2005 for a pain indication. This compound and
others in the preclinical pipeline have demonstrated very positive
results in a range of pain and autoimmune disease animal models. We
believe that the pipeline represents significant potential value for the
Company. We are fortunate to have what we believe are both the necessary
resources to carry these programs forward and the experience necessary
to develop drugs and shepherd them through the approval process."

The pivotal Phase III clinical trial of dexanabinol for TBI was a
double-blind, randomized, placebo-controlled trial conducted in
European, Israeli, Australian and U.S. trauma centers. To maximize the
probability of detecting a clinical benefit to severe TBI patients and
to ensure a common protocol for the multinational trial, the Clinical
Plan was carefully designed in collaboration with a panel of worldwide
TBI experts who were members of the European Brain Injury Consortium
(EBIC) and the American Brain Injury Consortium (ABIC). Among the
several inclusion criteria that had to be satisfied, a patient must have
sustained a severe brain injury as judged by both a Glasgow Coma Score
between 4 and 8 and by a CT scan showing brain parenchymal damage. In
addition, a patient must have been administered the single dose of
placebo or 150 mg of the drug within 6 hours of injury.

Patients were evaluated at 3 and 6 months according to the GOSE. Results
of the trial were analyzed by grouping patients into three outcome bands
according to their baseline prognosis which were based on seven
independent prognostic indicators. For each prognostic band the GOSE
scores were dichotomized to differentiate "favourable" and
"unfavourable" outcome. The goal of the study was to observe at six
months a statistically significant increase in the number of
dexanabinol-treated patients achieving a favourable outcome when
compared to the placebo group. The six-month outcome demonstrates an
odds ratio of l.04 in favour of dexanabinol with a 95 per cent
confidence interval of 0.79 to 1.36 (p=0.78).

Pharmos recently announced the results of an exploratory Phase II study
of dexanabinol as a preventative agent against post-surgical cognitive
impairment in coronary artery bypass graft (CABG) surgery patients. The
study provided evidence that dexanabinol may act as a neuroprotectant by
preserving integrative and executive functions that may be the most
affected by CABG surgery. The Company will study the data from both the
CABG and TBI trials in order to determine the best path forward to
develop the potential value of dexanabinol as a neuroprotectant.

Recent scientific research has increased awareness of the potential
therapeutic role of agents acting on the human cannabinoid receptor
systems. In addition to developing dexanabinol that does not bind to
cannabinoid receptors, Pharmos is developing a class of cannabinoid
receptor agonists that bind preferentially to CB2 cannabinoid receptors.
CB2 cannabinoid receptors are found predominately in peripheral immune
cells as compared to CB1 receptors found predominately in the central
nervous system. The CB2 receptors may be involved in the modulation of
numerous neuroinflammatory diseases and disorders. Preclinical testing
of these compounds has shown their potential efficacy in the treatment
of chronic pain conditions and neuroinflammatory autoimmune diseases.
The low CB1 activity of these compounds minimizes potential psychotropic
side effects. Pharmos expects to begin clinical testing of its lead
CB2-selective synthetic cannabinoid, PRS 211,375, for the treatment of
pain indications in 2005.

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