A randomized double blind placebo controlled ascending dose study to evaluate the effect of APL180 on endothelial function in patients with familial hypercholesterolemia

Novel strategies are required to further reduce cardiovascular disease burden.

Endothelial dysfunction is an important risk factor for cardiovascular disease.
Patients with increased LDL, of which familial hypercholesterolemia is a
typical example, are characterized by extreme endothelial dysfunction. As such,
restoration of endothelial dysfunction is a widely accepted therapeutic target
in these patients.

HDL cholesterol usually protects against vascular disease. This not only
relates to its impact on reverse cholesterol transport but also to a direct
beneficial effect of its most abundant structural protein, apoAI. ApoAI
protects the vessel wall and exerts a whole array of other beneficial effects.
Recently, it has become clear that the protective effect of HDL may deteriorate
in certain groups of patients, amongst which patients with FH. This is termed
dysfunctional HDL
In experimental models APL-180 has been shown to be able to restore the
protective capacity of HDL in these patients, which is accompanied by
improvement of endothelial function.

Assess whether APL180 can improve endothelial function in patients with
Familial hypercholesterolemia

randomized, double blind, placebo controlled, dose escalation study

APL180 or placebo infusion
APL 180 will be administered in 2 dosages: 1 mg/hour and 6 mg/hour (see page 22
protocol)

Patients will visit the AMC for 3 separate visits, in total 14 hours.
During one of these visits, a forearm plethysmography will be performed.
The burden of this may pertain to:
- inflating a pulse cuff (160 mmHg, max 5 mintues in a row)
- insertion of 2 venous catheters
- insertion of 1 arterial catheter

Adminstered substances:
- for the forearm studies acetylcholine, nitroprusside and vitamin C will be
administered. These are well known, well characterized substances with a short
half life. Since these substances will be administered locally, the
concentrations systemically will be extremely low. If any side effects were to
occur, this may include: bradycardia, hypotension, flushing, sweating. Of note,
all patients will be continuously monitored (ECG monitoring, blood pressure
registration)

- APL 180: up to now, APL180 was tolerated very well. APL180 is a 22-aminoacid
peptide, which is identical to a small part of the endogenous apoAI (structural
protein of HDL cholesterol). Potential side effects include: hypoglycaemia,
sinsitis, backpain. Side effects always were mild and transient (see protocol
page 19).