A two-part, phase 1, randomized, single blind, placebo-controlled, single centre study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of LAS191954 following oral administration of single and multiple ascending doses in healthy male volunteers

LAS191954 is a new investigational compound that may eventually be used for the
treatment of pemphigus vulgaris, a dermatological, autoimmune and blistering
disease. In an autoimmune disease the immune system recognizes the body*s own
cells as foreign. This may result in the formation of antibodies against one*s
own tissues. The enzyme (protein) phosphoinositide 3 kinase (PI3K) plays an
important role in the activation of immune cells. This enzyme (PI3K) can be
inhibited by LAS191954, which may result in an improvement of the disease.

The purpose of both parts is to investigate how safe LAS191954 is and how well
LAS191954 is tolerated. Also will be investigated how quickly and to what
extent LAS191954 is absorbed into, distributed in, and eliminated from the body
(this is called pharmacokinetics). In addition, the effect of LAS191954 on
certain blood markers will be investigated (this is called pharmacodynamics).

Part 1:
The study will consist of 3 periods. During Period 1 the will stay in the
clinical research center in Groningen for 4 days (3 nights): from the afternoon
of Day -2 (2 days before administration of the study compound) to the morning
of Day 2. During Periods 2 and 3 the volunteer will stay in the clinical
research center in Groningen for 3 days (2 nights): from the afternoon of Day
-1 (1 day before administration of the study compound) to the morning of Day 2.
You will receive the next treatment approximately 28 after the previous
treatment.

During the study the volunteer will receive LAS191954 or placebo as oral
capsules with 240 milliliters of tap water. The study compound will be given
under fasted conditions. This means that the volunteer is not allowed to eat
for at least 4 hours before administration of the study compound. During
fasting the volunteer is allowed to drink water with the exception of 0.5 hour
prior to until 2 hours after administration of the study compound. Fasting will
continue until 2 hours after administration of the study compound. Then he will
be asked to swallow a glucose solution.

Part 2:
The study will consist of 1 period during which the volunteer will stay in the
clinical research center in Groningen for 10 days (9 nights): from the
afternoon of Day -2 (2 days before administration of the study compound) to the
morning of Day 8.

The study will consist of 1 period during which you will receive LAS191954 or
placebo twice daily for 6 days (Days 1-6) with a single dose of LAS191954 or
placebo in the morning of Day 7. LAS191954 and placebo will be given in the
form of oral capsules.

Part 1:
The study will consist of 3 periods during which the volunteer will receive
LAS191954 or placebo once per period. LAS191954 and placebo will be given as
oral capsules.

Part 2:
The study will consist of 1 period during which you will receive LAS191954 or
placebo twice daily for 6 days (Days 1-6) with a single dose of LAS191954 or
placebo in the morning of Day 7. LAS191954 and placebo will be given in the
form of oral capsules.

All potential drugs cause adverse events; the extent to which this occurs
differs. As LAS191954 will be administered to man for the first time in this
study, adverse effects of LAS191954 in man have not been reported to date.

In animal studies with LAS191954 and in studies with study compounds with the
same mechanism of action, the following adverse effects were observed:
hyperglycemia (increased blood glucose level), hypertriglyceridemia (increased
fat level in blood), decrease in white blood cells, increase in blood pressure,
liver toxicity (increase in liver enzymes), pneumonitis, diarrhea, abdominal
pain, nausea, fever, cough, chills, intestinal perforation, skin inflammation,
rash and allergic reactions.

In animal studies with LAS191954 the male reproductive system was affected
after 4 weeks of treatment with LAS191954. Results of animal studies with
LAS191954 with a treatment duration of 2 weeks, allow to investigate the study
compound in repeated administration to humans up to 14 days. Nevertheless,
since a potential effect on men fertility cannot be ruled out, the fertility of
volunteers in the current study will be monitored by measuring some fertility
markers (inhibin B, follicle stimulating hormone and testosterone).

Procedures: pain, minor bleeding, bruising, possible infection