A multi-center, randomized, double-blind, placebo and active controlled, parallel group, dose range study to evaluate the efficacy and safety of LCZ696 comparatively to valsartan, and to evaluate AHU377 to placebo after 8 week treatment in patients with essential hypertension

Despite the available therapeutic options, approximately 70% of patients with
high bloodpressure remain not adequately controlled, and hence many preventable
strokes, MI, HF and end-stage renal disease occur unnecessarily. Poorly
controlled hypertension can be attributed to multiple factors, including
inadequate antihypertensive efficacy of the drug(s) used.

LCZ696 is a new, dual-acting pro-drug, consisting of an angiotensin receptor
blocker (ARB) and a NEPi (neutral endopeptidase inhibitor, AHU377).

Preclinical and clinical data with LCZ696 demonstrate that LCZ696 adequately
blocks angiotensin II receptors and inhibits NEP, resulting in a decrease in
blood pressure. Based on these findings, it is hypothesized that LCZ696 should
deliver significant clinical benefits to patients suffering from hypertension.

This phase II, dose ranging trial investigates the efficacy and safety of
LCZ696 compared to valsartan in patients with hypertension. In addition, the
efficacy of the NEPi in LCZ696, AHU377, is evaluated compared to placebo.

The primary objective of this study is to determine the efficacy and safety of
different doses of LCZ696 compared to valsartan. In addition, the efficacy and
safety of AHU377 as compared to placebo is evaluated.

This is a multi-center, randomized, double-blind, placebo and active
controlled, parallel group, dose range phase II study. During the study period,
patients visit their study doctor 7 times in 13 weeks.

The study comprises 3 periods: a 4-week wash-out and placebo run-in (screening
period), an 8-week randomized, double-blind monotherapy period and a 1-week
randomized, placebo-controlled withdrawal period.
After successful completion of the screening period (visit 1-3), on visit 3
patients will be randomized and treated with 1)LCZ696 100mg, or 2)LCZ696 200mg,
or 3)LCZ696 400mg (1 wk treatment with LCZ696 200mg followed by 7 wks treatment
with LCZ696 400mg), or 4) valsartan 80mg, or 5) valsartan 160mg, or 6)
valsartan 320mg (1 wk treatment with valsartan 160mg followed by 7 wks
treatment with valsartan 320mg), or 7) AHU377, or 8) placebo.
After 8 weeks of treatment (visit 3-6), all patients will enter the randomized,
placebo-controlled withdrawal period on visit 6 and will continue on 1) the
same study treatment as before or 2) placebo for another week until the final
visit (visit 7).

All patients are on placebo for 2 weeks.

Subsequently, patients are treated with one of the following treatments during
8 weeks, depending on their treatment group: LCZ696 100mg, LCZ696 200mg, LCZ696
400mg, valsartan 80mg, valsartan 160mg, valsartan 320mg, AHU377 200mg, placebo

Finally, during 1 week, patients are treated as during the study or continue on
placebo.

Burden: 7 visits of about half an hour during 13 weeks; 2 extra visits for
patients participating in the 24-hour ABPM substudy; 6x blood collection (incl.
biomarkers in 50% of the patients and pharmacokinetics in 50% of the patients);
fasting conditions on V1, V3, and V6.

Risks: The information on the possible side effects in humans is limited since
only 2 studies in healthy volunteers have been conducted with LCZ696 to date.
In these studies in which 88 healthy volunteers participated, receiving up to
now single and/or multiple doses from 2 to 600 mg, only a small number of side
effects were reported, which were all mild in severity. No serious side effects
or unexpected side effects were reported, and no subject was discontinued due
to a side effect or an abnormal result in the safety tests.
Up to now, no serious or noteworthy adverse experiences have been reported in
clinical research studies with AHU377. In these studies in which so far 144
healthy volunteers participated receiving doses from 10 to 600 mg AHU377, the
mild side effects reported were: dizziness, drowsiness, tiredness, and
headache. No serious side effects were reported, and none of the effects
reported required drug discontinuation.
Valsartan is studied extensively in other clinical trials before it was
approved for market. The most commonly reported side effects that occurred more
frequently with valsartan compared to placebo were viral infection, fatigue,
and abdominal pain. Headache, dizziness, upper respiratory tract infection,
cough, diarrhea, rhinitis, sinusitis, nausea, pharyngitis, edema, and
arthralgia occurred at a more more than 1% rate, but at about the same rate
with valsartan and placebo. Other potential risk with valsartan include low
blood pressure and increases in blood potassium levels. Rare cases of
angioedema (swelling of the face and extremities, and difficulty in breathing)
have also been reported with valsartan.