A Phase 2, Multicenter, Randomized, Double-Blind, Comparator-Controlled Study of the Efficacy, Safety, and Pharmacokinetics of Intravenous Ulimorelin (LP101) in Patients with Enteral Feeding Intolerance

Ulimorelin is an intravenous (IV) synthetic agonist of the human ghrelin
receptor originally discovered and developed by Tranzyme Pharma, Inc., for the
management of postoperative ileus (POI) and diabetic gastroparesis, two
hypomotility disorders of the gastrointestinal (GI) tract. Ulimorelin is a
small molecule macrocycle and a potent, selective agonist at the cloned human
growth hormone secretagogue receptor (hGHS-R1a; ghrelin receptor). It
demonstrated prokinetic activity in animal models of GI hypomotility and
anti-catabolic effects in a mouse xenograft model of cancer cachexia. Because
of its dual prokinetic and anabolic properties, ulimorelin is now being
developed by Lyric Pharmaceuticals for the treatment of enteral feeding
intolerance (EFI) in critically ill patients. By both improving GI motility and
mitigating the loss of lean body mass (LBM), ulimorelin may significantly
impact the clinical outcomes of these patients.

Ghrelin is a 28-amino-acid peptide that was identified as the natural ligand
for the hGHS-R1a. In addition to the stimulation of growth hormone (GH)
secretion, ghrelin is a potent stimulant of appetite and GI motility [1 ,2 ].
The prokinetic effects of ghrelin, including stimulation of gastric emptying,
are thought to represent both direct effects on ghrelin receptors and
up-regulation of vagal tone. Mechanistic studies in isolated tissues indicate
that ghrelin stimulates and coordinates electrical signaling in the GI tract
via hGHS-R1a and vagal stimulation to promote gut motility [3 4,5 ]. This is
confirmed in a number of pharmacological assays of GI motility in rats and dogs
[6 ,7 ,8 ]. A series of investigator-initiated trials in humans demonstrated
that ghrelin peptide exerts significant prokinetic effects in healthy subjects
and in patients with diabetic and idiopathic gastroparesis [2,9,10 ].

Ghrelin has been termed the *feeding hormone*, because it both stimulates
appetite and gastric emptying and enables the anabolic effects of GH and
insulin-like growth factor 1 (IGF-1) on protein tissue stores [11 ]. Because of
these properties, ghrelin has been advocated as a pharmacological treatment for
conditions associated with deficiencies in LBM [12]. Native ghrelin
administration was shown to increase handgrip strength and breathing capacity
in chronic obstructive pulmonary disease [13]. It has been proposed as a
potential therapy to improve lung function and prevent LBM loss in patients in
the Intensive Care Unit (ICU) [14,15 ], as well as to promote nutritional
rehabilitation after ICU discharge [16]. Ghrelin agonists have also been under
development for the loss of LBM in cancer patients and elderly patients with
hip fracture [17].

Growth hormone has been proposed for ameliorating catabolic wasting in
critically ill patients [18,19,20,21,22], but after several successful trials
[23,24,25,26,27,28], development came to a halt when a significant increase in
mortality was observed in two similarly designed companion trials [29]. These
studies were criticized on the grounds that supratherapeutic (20-fold
replacement) slow-releasing subcutaneous (SC) doses were administered, inducing
high peak GH secretion (estimated ~200 ng/mL, normal 0-10) and sustaining these
levels throughout the day [30,31,32 ]. This is said to have led to uncontrolled
hyperglycemia, cardiotoxicity, inflammatory stress, and metabolic imbalances
[33,34,35,36,37 ]. Natural counter-regulatory mechanisms at the level of the
pituitary and hypothalamus were bypassed, and pulsatile GH secretion was
suppressed [14,15,31]. Since that time, recombinant GH or IGF-1 analogues have
been administered safely and successfully in several trials [34,38,39]. Ghrelin
analogs have been proposed as a safer means to achieve protein sparing in
critically ill patients, because they preserve pulsatile GH secretion and
counter-regulatory mechanism at the level of the pituitary-hypothalamic axis
[14,15,34].

Ghrelin also has anti-inflammatory properties that could be beneficial to
patients with critical illness [40,41,42], in whom high levels of
pro-inflammatory cytokines exert deleterious effects [43]. Ghrelin
down-regulated TNF-a and interleukin (IL)-6 activity [44] and protected against
endotoxin-induced acute kidney injury [45] in animal models of sepsis. Ghrelin
also improved tissue perfusion via down-regulation of endothelin-2 [46] and
NF-*B [44]. High levels of circulating cytokines may be responsible for the
devastating loss of LBM in critical illness [47,48]. The anti-inflammatory
effects of ghrelin have been postulated to be the result of up-regulation of
vagal and down-regulation of sympathetic tone [43,49]. In a clinical study of
154 patients with hospital-acquired sepsis, sympathetic inhibition with the
beta-blocker esmolol resulted in a 50% reduction in mortality [50], suggesting
the potential benefit of invoking the same autonomic mechanism through use of a
ghrelin agonist.

Enteral nutrition (EN) refers to the delivery of a nutritionally complete
enteral formula into the gut via a nasogastric, nasoenteric, orogastric, or
percutaneous feeding tube in patients who cannot eat or attain adequate oral
intake from food and/or oral nutritional supplements. Enteral nutrition is
associated with improved protein turnover, improved wound healing, reduced
septic complications, decreased bacterial translocation across intestinal
mucosa, and decreased catabolic response to injury [51,52]. Enteral nutrition
is recommended as soon as possible following admission to the ICU in order to
minimize the protein-calorie deficit developing early in critical illness
[53,54 ]. Protein and calorie deficits have been associated with increased
organ failure, infection, hospital length of stay, and complications [55,56].
In observational studies, randomized controlled trials, and meta-analyses,
infection rates, hospital length of stay and mortality were inversely
correlated with the level of enteral nutritional support
[53,57,58,59,60,61,62,63 ].

Treatment of EFI is the target indication for the current study. EFI is defined
as the inability to deliver adequate EN to critically ill patients due to
delayed gastric emptying in the absence of mechanical obstruction. EFI is the
predominant GI complication during a course of EN in critically ill patients
[64,65,66,67]. Observational studies and meta-analyses have revealed that more
than 30% of critically ill patients experience intolerance to enteral feeding
[68,69]. This incidence may be as high as 85% in patients with polytrauma,
traumatic brain injury, and sepsis [70,71 ]. Compared with patients without
EFI, patients with EFI have longer ICU stays and higher ICU mortality
[68,69,72]. These are expected outcomes of highly catabolic critically ill
patients who fail to achieve acute nutritional needs [16].

Enteral feeding intolerance is typically diagnosed by the presence of high
gastric residual volume (GRV). While the value of GRV was questioned in recent
clinical trials [73,74 ], the conclusions of these studies were confounded by
the bias of unblinded treatment intervention, the confounding effects of
concomitant use of prokinetic agents in most study participants, and the
failure to adjust the volume of tube feeding administered for loss due to
vomiting. Despite controversies regarding the use of GRV to determine feeding
intolerance, it remains the standard for monitoring EN in ICU patients in most
ICUs worldwide [75,76]. Elevated GRV (150 to 250 mL) has been shown to predict
delayed gastric emptying [77,78] and poor ICU outcome [68,75,76]. While
controversy remains [72,76], 250 to 500 mL is typically employed to identify
EFI in most hospital ICUs [76], and 500 mL is recommended in the most recent US
guidelines [54]. The guidelines of the European Society for Parenteral and
Enteral Nutrition (ESPEN) are silent on this issue [79].

It is recommended that prokinetic agents be employed to promote GI motility and
facilitate enteral feedings in patients with EFI [53,54]. However, no drugs are
approved for this indication and metoclopramide and erythromycin, the most
commonly used prokinetic agents, rapidly lose effectiveness and are marginally
safe in the ICU setting. Metoclopramide is associated with serious central
nervous system side effects, and erythromycin can lead to critical drug-drug
interactions, QT prolongation, and super infection with multiple drug-resistant
organisms. A safer and more effective prokinetic agent with synergistic
anabolic effects could improve outcomes in critically ill patients with high
catabolic rates and nutritional needs.

The purpose of this trial is to evaluate the efficacy and safety of ulimorelin
in enabling the delivery of nutrition to critically ill patients with
intolerance to enteral feedings.

For reference please see the study protocol.

Primary Efficacy Objective:
To evaluate the effect of multiple daily intravenous (IV) doses of ulimorelin
on the proportion of the daily protein prescription (DPP) received through
enteral nutrition by mechanically ventilated and tube-fed patients with EFI

Secondary Efficacy Objective:
To evaluate the effect of multiple daily IV doses of ulimorelin on the
proportion of the daily caloric prescription (DCP) received through enteral
nutrition by mechanically ventilated and tube-fed patients with EFI

Safety Objective:
To evaluate the safety and tolerability of multiple daily IV doses of
ulimorelin in mechanically ventilated and tube-fed patients with EFI.

Pharmacokinetic Objectives:
To evaluate the relationships between α-1-acid glycoprotein (AAGP) levels,
pharmacokinetic (PK) endpoints, and pharmacodynamic (PD) endpoints following
multiple daily IV doses of ulimorelin in mechanically ventilated and tube-fed
patients with EFI

Pharmacodynamic Objectives:
To evaluate the effect of ulimorelin on gastric emptying in mechanically
ventilated and tube-fed patients with EFI.

Observational Phase Objective: To explore factors associated with the
progression of at-risk patients to EFI.

This is a multicenter, randomized, double-blind, comparator-controlled study
with a lead-in Observation Phase. The study consists of 2 parallel-dose
treatment groups consisting of ulimorelin and metoclopramide.

The study will consist of two parallel-dose treatment groups consisting of
ulimorelin (600 µg/kg) or metoclopramide (10 mg) administered 3 times daily as
a 50 mL IV infusion over 30 minutes for 5 days. Patients will continue to
receive study drug 3 times daily Q8H for 5 days (15 doses total).

The flow chart of the study is described on pages 56 - 60 of the protocol. The
duration of the study is as follows:
The Observation Phase will take in total 72 hours. The Efficacy Phase;
screening period on the first day, treatment period of 5 days. Follow-up period
from day 6 to day 8. And a 30 day follow-up by review of medical records.
Patients will be in the ICU during the whole study period (screening to day 8).
Screening assessments will not take more than 2 hours, thereafter from Efficacy
Phase day 1 to day 5 study related procedures including but not limited to
study drug administration (3 times daily, 30 minutes each), Gastric emptying
determination and additional blood and urine sampling will take approximately 3
hours. The total of blood sample volume collected is 136 ml in the Efficacy
Phase.