8 May 2006
VERSION: 1 2 3 4 5 6 7 8 9

TBC3711 HTN Study
A Phase 2, Multi-Center, Randomized, Double-Blind, Placebo-controlled, Dose Ranging Study of TBC3711 in subjects with Resistant Hypertension Encysive ERA (Endothelin Receptor Antagonist)

Sponsor: Encysive, LP
Study Drug: TBC3711
Protocol:
Phase 2
CRO:
Site #:
Investigator #:
CRA: Monica Acree, M.Ed., CCRP MAcree@Excysive.com
Central Lab:
IRB:
150 Subjects / 30 Sites -> 5 Subjects per Site: Divided into 5 Groups in a 1:1:1:1:1 Ratio as follows: 10: 50: 100: 200: Placebo IVRS (Integrated Voice Response System) Treatment Related AE’s: HA & Peripheral Edema; ^ LFT’s; Anemia; Testicular Injury/Infertility; Teratogenicity
eGFR using MDRD Equation: http://medcalc3000.com/GFREstimate.htm
SA: Semen Analysis

IC
equal/greater than 18
On full/therapeutic doses of at least 3 Antihypertensive Drugs, one of which must be a diuretic, stable x 30 day’s -> RHTN 140/90
On stable dose BP Pills x 4 weeks

EC
HTN equal/greater than 180/120
Hepatitis B or C
^ LFTs
Coumadin
Secondary HTN; MI, CHF; CVA PTCA, CABG within 6 months; CHF Requiring Rx; AF; PPM ; AICD
EF < 40% or LVIDD > 3.2 cm/square meter or an absolute value > 6.0 cm
HgbA1C > 9 or IDDM; Anemia with Hgb < 12; Abnormal TSH; Cancer within 3 years
NSAIDs; SSRIs or TCAs not on a stable dose for at least 3 months
CRF with GFR < 30

ERA (Endothelin Receptor Antagonist)
TBC3711 is an ETA selective ERA (Endothelin Receptor Antagonist) being developed as an oral therapy for patients with uncontrolled hypertension.
TBC3711 is a member of a class of therapeutic agents known as Endothelin Receptor Antagonists, or ERAs that can be orally administered. Endothelin is a small peptide hormone that is believed to play a critical role in the control of blood flow and cell growth. Elevated endothelin blood levels are associated with several cardiovascular disease conditions, including: PAH Pulmonary Artery Hypertension); CKD (Chronic Kidney Disease); HTN; CHF; Stroke; and, Restenosis of Arteries after PTCA (balloon angioplasty or stent implantation). Therefore, many scientists believe that agents like ERA’s that block the detrimental effects of endothelin will provide significant benefits in the treatment of these conditions. There are two classes of endothelin receptors, ETA and ETB, which play significantly different roles in regulating blood vessel diameter. The binding of Endothelin to ETA receptors located on smooth muscle cells causes’ vasoconstriction, or narrowing of the blood vessels. However, the binding of endothelin to ETB receptors located on the vascular endothelium causes vasodilation through the production of nitric oxide and prostacyclin. The activity of the ETB receptor is thought to be counter-regulatory, protecting against excessive vasoconstriction.
There is a significant opportunity for a new class of ERAs that bind selectively to the ETA receptor in preference to the ETB receptor. Selective ETA antagonists are likely to block the negative effects of Endothelin by preventing the harmful effects of vasoconstriction and cell proliferation, while preserving the beneficial effects of the ETB receptor. The potential clinical benefits of selective ETA antagonists will position these compounds as the treatment of choice for: PAH, RHTN (Resistant Systolic Hypertension) and potentially other cardiovascular disorders.
TBC3711 is an ERA that is selective for the ETA receptor. The compound demonstrates high potency, high bioavailability and half-lives that we believe are suitable for once daily dosing. In addition, the compound does not induce or inhibit the p450 metabolic pathway. The selectivity and potency of ERAs may offer significant advantages over other hypertension treatments, including enhanced and more durable efficacy, safety and ease of use (alone or in combination with other therapies). Encysive chose to evaluate TBC3711 in RHTN (resistant systolic hypertension).

8 May 2006
VERSION: 1 2 3 4 5 6 7 8 9

TBC3711 HTN Study

V1 W S Lab, Screening, ICF, eGFR
V2 D 1 Single-Blind Run-in Placebo Baseline, SA, RTC 7 D +/- 2D
V3 W 1 Continue Run-in Placebo Baseline Phase, RTC 7 D +/- 2D
V4 W 2 Lab, RTC 7 D +/- 2D
V5 W 3 Lab Randomize to Double-Blind Treatment Phase, RTC 7 D +/- 2D
V6 W 4 Lab, RTC 2 wks +/- 2 D
V7 W 6 Lab, RTC 2 wks +/- 2 D
V8 W 8 Lab, RTC 2 wks +/- 2 D
V9 W 10 Lab, RTC 2 wks +/- 2 D
V10 W 12 Lab, SA, EOS/ED
V11 D 0 Lab, Follow-Up 48 H post last dose Study Drug +/- 0
V12 W 14 Lab, +/- 4 Days