A multi-center, randomized, double-blind, parallel-group, 20-week dose-finding study to evaluate efficacy, safety, and tolerability of XXB750 in patients with resistant hypertension

Hypertension (HTN) is a key risk factor for heart disease and strokes across
the world contributing significantly to cardiovascular (CV) mortality and
morbidity and other end organ damage such as retinopathy and nephropathy. Data
from the National Health and Nutrition Examination Survey (NHANES) and the
International Society of Hypertension suggest that an estimated 50% of deaths
from coronary heart disease (CHD) and stroke were attributable to HTN (Lawes et
al 2008, Ford 2011). The prevalence of HTN is rising globally due to ageing of
the population and increases in lifestyle risk factors, such as unhealthy
diets, obesity and lack of physical activity. Despite of the availability of
many effective antihypertensive medications with several mechanisms of action,
a significant proportion of hypertensive patients experience treatment
resistant HTN (rHTN). Based on population studies, this category of
hypertension affects approximately 12% to 15% of patients treated for HTN (Egan
et al 2011, Persell 2011, Tanner et al 2013) and approaches a prevalence of 20%
in clinic-based studies (de la Sierra et al 2011, Egan et al 2013, Borghi et al
2016, Thomas et al 2016). there remains a significant unmet need for developing
new classes of antihypertensive medications with improved efficacy over the
existing therapeutic modalities, preferably minimizing the impact on the
polypharmacy in these patients or perhaps even reversing it.

One physiological system that contributes to blood pressure maintenance is the
natriuretic peptide (NP) system. One way to efficiently modulate the NP system
is by direct NPR-1 agonism. XXB750 is a long-acting fully human monoclonal IgG1
antibody agonist of NPR-1 with a half-life of approximately 16 days in humans
(Section 4.3). The prolonged half-life allows for once-a-month SC dosing
compared to daily dosing of other antihypertensive agents and earlier analogs
of ANP. Pre-clinical studies with XXB750 have shown 15-20 mmHg SBP reduction in
normal rats and normal monkeys and ~80 mmHg SBP reduction in hypertensive rats.
In the ongoing first-in-human (FIH) study in healthy volunteers, XXB750 has
been administered as a single SC injection at doses up to 240 mg. XXB750
resulted in plasma cGMP elevations and BP lowering effect up to a
placebo-adjusted maximum SBP reduction of ~18 mmHg at peak effect with the 240
mg dose.

Given its mechanism of action, its long half-life, its significant BP lowering
effects seen in its preclinical trials as well as in healthy volunteers, XXB750
promises to be an innovative and important therapeutic option in the management
of patients with rHTN by overcoming several challenges including the hormonal
and metabolic side effects of spironolactone and other currently available
therapeutics. Moreover, with its expected once monthly SC administration
regimen, XXB750 may offer a significant advantage by improving medication
adherence in this population in which polypharmacy is common.

The current study is a phase 2 study which aims to establish proof-of-concept
of blood pressure lowering by NPR1 agonism using XXB750, identify its optimal
dose(s) to study in phase 3, and to characterize its benefit-risk profile in
patients with rHTN.

See protocol page 18-21.

To evaluate the efficacy and dose-response relationship of XXB750 30 mg SC q4w,
60 mg SC q4w, 120 mg SC q4w, and 240 mg SC q4w compared to placebo in reducing
the mean 24hr ambulatory systolic blood pressure (mean 24hr SBP) from baseline
to Week 12.

See protocol page 18.

Study XXB750B12201 is a multicenter, randomized, double-blind,
placebo-controlled, parallel-group phase 2 study which is comprised of four
periods:
• A screening period (approximately 7 days)
• A single-blind placebo run-in period lasting approximately 2 weeks
• A 12-week double-blind, placebo-controlled, parallel-group treatment period.
• An 8-week safety follow-up period

Approximately 170 participants will be randomized to receive placebo, XXB750 30
mg, 60 mg, 120 mg, or 240 mg SC every 4 weeks.

A staggered approach to enrollment will be followed in this protocol. The
randomized participant sample will be divided into two groups:
- Group 1 will consist of approximately 68 participants who will be randomized
to either placebo, XXB750 30 mg SC every 4 weeks (dose level 1), XXB750 60 mg
SC every 4 weeks (dose level 2), or XXB750 120 mg SC every 4 weeks (dose level
3) in a 1:1:1:1 ratio.
- Group 2 will consist of approximately 102 participants who will be randomized
to either placebo, XXB750 dose level 1, XXB750 dose level 2, XXB750 dose level
3, or XXB750 120 mg SC for one injection followed by 240 mg SC every 4 weeks
for two injections beginning 4 weeks after the first dose (dose level 4) in a
1:1:1:1:2 ratio.

See study protocol page 27-31 (and figure 1.1).

During the Single-blind Run-in Period participants will receive a single SC
injection of placebo matching XXB750 in a single blinded fashion

At Visit 100 participants will be randomly assigned to one of the following
five treatment arms targeting a final ratio of 1:1:1:1:1 at the end of the
trial.
Placebo SC every 4 weeks for x 3 doses.
XXB750 30 mg SC every 4 weeks x 3 doses (dose level 1).
XXB750 60 mg SC every 4 weeks x 3 doses (dose level 2).
XXB750 120 mg SC every 4 weeks x 3 doses (dose level 3).
XXB750 120 mg SC at the Randomization visit followed by 240 mg SC at Week 4 and
Week 8 (dose level 4).

See page 40-41 of the study protocol.

All study participants are expected to benefit from intensive monitoring of
their blood pressure and overall health while receiving the maximally tolerated
triple background antihypertensive therapy for their rHTN. Eighty percent of
participants are planned to be treated with an additional antihypertensive
agent (XXB750) in an effort to better control their blood pressure. The
remaining participants will be treated with placebo and the duration of their
treatment with placebo will be kept to a minimum, to accomplish the scientific
purpose of the study. Nonetheless, the extent of this potential benefit is
unknown at this time and is the primary reason for conducting this study.

Based on the results from previous studies performed in healthy volunteers, the
laboratory and in animals, as well as on known risks of other drugs that have
characteristics similar to XXB750, the possible risks or side effects of the
study treatment may include:
• Reduced blood pressure, with or without symptoms, such as dizziness,
light-headedness or fainting
• Heart rate becoming faster or slower than usual
• Allergic reactions to XXB750, including serious, potentially life-threatening
allergic reactions
• Itching, pain, redness, skin rash, swelling of the skin at the site of the
study medication injection

Burden due to study visits and procedures:
• The risk of collecting blood may include fainting, pain and /or
bruising. Rarely, these may be a small blood clot or infection at the site of
the needle puncture.
• Discomfort from 24-hour blood pressure measurement (mostly at night).

See p. 21-23 of the study protocol.