WO2017083882A1

WO2017083882A1 - Treatment of enteral feeding intolerance and other conditions using ulimorelin analogs

Info

Publication number: WO2017083882A1
Application number: PCT/US2016/063581
Authority: WO
Inventors: David Wurtman; M. Scott HARRIS; Joyce James
Original assignee: Lyric Pharmaceuticals Inc.
Priority date: 2015-11-11
Filing date: 2016-11-23
Publication date: 2017-05-18

Abstract

Enteral Feeding Intolerance (EFI) can be efficaciously treated and loss of muscle mass prevented or slowed by administration of therapeutically effective doses of ulimorelin analog every 8 hours (three times a day). Therapeutic benefit can be obtained from single and consecutive daily dosing, including for periods of up to a week or longer.

Description

TREATMENT OF ENTERAL FEEDING INTOLERANCE AND OTHER CONDITIONS USING ULIMORELIN ANALOGS

TECHNICAL FIELD

[0001] This application relates generally to formulations, systems, and methods for prevention and treatment of Enteral Feeding Intolerance (EFI) and of other diseases including conditions associated with loss of muscle mass using ulimorelin analogs.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to or benefit of PCT/US2015/060222 entitled

"Treatment Of Enteral Feeding Intolerance" filed 1 1/1 1/2015 and published as WO/2016/077498; US Provisional Application No. 62/259,559, entitled "Treatment Of Enteral Feeding Intolerance With Ulimorelin Analogs" filed 11/24/2015; US Provisional Application No, 62/335,520, entitled "Treatment Of Enteral Feeding Intolerance With Reiamorelin" filed 5/12/2016; and US Provisional Application No. 62/338,421, entitled "Treatment Of Enteral Feeding Intolerance With Ipamorelin" filed 5/18/2016; The entire disclosure of each of the aforementioned applications is incorporated herein by reference for all purposes.

BACKGROUND OF THE INVENTION

[0003] Patients in the Intensive Care Unit (ICU) and other severely ill patients may receive nutrition by enteral feeding (EF) by nasogastric tube (NGT) or similar device. Some significant percentage of those patients will develop EFI caused by gastric dysmotility, a very serious condition in already very ill patients, in that it limits the ability to administer nutrition. Malnutrition in the ICU, including protein malnutrition, is associated with poorer long term outcomes including increased mortality (see Malnutrition and Outcomes, Kenneth B. Christopher, M.D., International Symposium on Intensive Care and Emergency Medicine, Brussels, Belgium, March 18-21, 2014). Clinical evidence of improved outcomes associated with the administration of nutrition was established in the ACCEPT study, a randomized controlled prospective trial of 462 evaluable patients that showed that improved ICU nutrition (enabled by protocolized treatment algorithms) resulted in shortened hospital stay (p = 0.003) and reduced mortality (trend, p ^:=: 0,058) (see Multicentre, Cluster-Randomized Clinical Trial Of Algorithms For Critical-Care Enteral And Parenteral Therapy (ACCEPT), Martin et al., CMAJ, JAN. 20, 2004; 1 70 (2)). Similarly, in a prospective observational cohort study of 113 ICU patients in a tertian,' referral hospital, a higher provision of protein and amino acids was associated with lower mortality (Allingstrup et ai. 2012 Clinical Nutrition 31 (2012) 462e468).

[0004] Gastric dysmotility is problematic in other settings where patients are generally in better health, and a variety of promotility agents have been studied. One of these, ulimorelin (see FIGURE 1), has been extensively studied in humans but not yet approved for any human use.

[0005] Functional activity, as measured by gastric motility and pharmacodynamic

(PD) responses, was observed with ulimorelin administered as a 30 min intravenous (IV) infusion once daily in Phase 2 studies in diabetic gastroparesis patients (see Ejskjaer et al., Aliment Pharmacol Ther 29, 1179-1 187) and shortened time to first bowel movement (BM) in a Phase 2 study of patients with post-operative ileus following once daily dosing (qD) for up to 7 days {see Dis Colon Rectum 2010; 53 : 126 -134)). In these Phase 2 studies it was observed that ulimorelin both accelerated gastric emptying of solid and liquid food (10 patients with diabetic gastroparesis) and accelerated recovery of gastrointestinal (GI) function in subjects who underwent partial large bowel resection (168 patients with post-operative ileus). An additional Phase 2 study of diabetic gastroparesis patients showed improvements in GCSi Loss of Appetite and Vomiting scores {see Ejskjaer et al., Neurogastroenterol Motil (2010) 22, 1069-e281). Unfortunately, these initial results failed to generalize as they did not reproduce in two larger prospective randomized, double-blinded, controlled pivotal Phase 3 trials of a postoperative ileus patient population when administered once daily for up to 7 days. In these larger trials, ulimorelin failed to achieve the target clinical endpoint of GI motility in patients who have undergone partial bowel resection.

[0006] Critically ill patients with EFI in the ICU are generally more ill than those studied in the ulimorelin Phase 3 trials described above. Given their serious medical condition and a general recognition of the importance of providing enteral feeding to them, these patients are often prescribed a medication in an attempt to restore gastric motility and emptying, even though current medications are unsatisfactory. Current medication choices are limited, as there are no drags approved by the Food and Drag Administration (FDA) or EMEA, for this clinical indication. Drags in common usage include metociopramide and erythromycin, and to a much lesser degree, alvimopan (Entereg®) and methylnaltrexone (Relistor®). While physicians may seek to treat using up to 5-7 day courses and possibly with additional repeated courses with these medications, clinical studies demonstrate that not only is the maximal efficacy of both metoclopramide and erythromycin limited in resolving excessive gastric residual volume (GRV), but also the duration of any such efficacy is short lived, typically shorter than seven days and sometimes as little as one to two days (see Nguyen et al ., Crit Care Med 2007 Vol. 35, No. 2), Among other safety concerns, metoclopramide has a "Black Box" warning from the US FDA for CNS toxicity, and use of erythromycin, an antibiotic, for a non-infectious purpose may potentially lead to bacterial resistance to antibiotics. Both of these safety issues are undesirable in the EFI intent-to-treat population.

[0007] Accordingly, there remains an unmet and urgent need for new therapies for the treatment of EFI, including in those patients who are critically ill and/or in a specialized care facility such as an ICU. Moreover, there is a need to prevent EFI in the first instance and to prevent or at least slow the loss of muscle mass commonly observed in a wide variety of patients with diseases and conditions that place them at ri sk for the same, including putting them at particular risk for such loss if the diseases or conditions result in an admission to a critical care facility (Puthucheary et al., JAMA 2013 Oct. 16; 310(15): 1591 -1600). The present invention meets this need and provides methods and pharmaceutical formulations and unit dose forms for the safe and efficacious prevention and treatment of both EFI and of the loss of muscle mass in the ICU and other settings.

SUMMARY OF THE INVENTION

[0008] Uiimorelin is a selective agonist of the ghrelin/growth hormone secretagogue receptor (GHSR), a G protein-coupled receptor (sometimes referred to hereinafter as a

"ghreiin receptor"). The secreted hormone ghreiin is the natural ligand of the GHSR. Other

GHSR agonists ("ghreiin receptor agoni sts") are known, including capromorelin, ibutamoren, ipamoreiin, relamoreiin, tabimorelin, and TZP-102.

[0009] PCT publication WO 2016/077498 (application PCT/US2015/060222, filed 1 1

November 2015, incorporated herein by reference), discloses uiimorelin as useful in treating EFI in methods comprising administering to EFI patients therapeutically effective doses of uiimorelin. WO 2016/077498 teaches that uiimorelin is indicated for the treatment of enteral feeding intolerance in critically ill patients and useful for the treatment of gastroparesis and/or delayed gastric emptying in critically ill patients with intolerance to enteral feedings, WO 2016/077498 teaches that uiimorelin is effective for treatment of EFI when administered by IV infusion three times per day (IV TID) and that an exemplary dose is 600 to 900 x§J g patient body weight ("^tg/kg"). For treatment of EFI in the ICU, intravenous TID administration of ulimorelin was shown in studies with healthy human volunteers to provide the same important therapeutic benefits needed by critically ill patients.

[0010] WO 2016/077498 also discloses that, after EFI is resolved, continued administration of ulimorelin can continue to provide therapeutic effect via ulimorelin's anabolic effects when administered as described. The present invention provides methods for achieving these same therapeutic benefits by administration of an ulimorelin analog in accordance with this disclosure.

[0011] WO 2016/077498 further discloses that ulimorelin, at specified doses, exerts a number of beneficial anabolic effects, including provision of more calories and/or more protein; increases in growth hormone (GH) including via beneficial spikes in level, and, reduction in inflammation, including via reducing sympathetic tone and/or increasing parasympathetic tone, and that dosing may be continued to provide continued therapeutic benefit after resolution of EFI. WO2016/077498 also discloses that a therapeutically effective treatment regimen comprising TID intravenous administration of ulimorelin has anti- catabolie and pro-metabolic (collectively, anabolic) effects such that ulimorelin may be used to provide treatment to patients in a cataboiic state deemed unhealthy by a treating physician. WO2016/077498 also discloses that such treatment promotes augmentation, or decreased loss, of muscle and lean body mass (LBM), and improvement in muscle strength and/or function during and/or after hospitalization. WO 2016/077498 discloses that ulimorelin is useful to provide anabolic benefit for the treatment of patients. The present invention provides methods for achieving these same therapeutic benefits by administration of an ulimorelin analog in accordance with this disclosure.

[0012] In a first aspect, this invention relates to ghreiin agonists other than ulimorelin, referred to collectively as "ulimorelin analogs," In one embodiment, ulimorelin analogs include ghreiin agonists that are close structural analogs of ulimorelin and have with similar bioactivity. As used herein, "bioactivity" refers, at least in part, to potency, i.e., a measure of daig activity expressed in terms of the amount required to produce an effect of given intensity at the ghreiin receptor. In other embodiments, ulimorelin analogs include compounds that are not close structural analogs of ulimorelin. Collectively, these compounds, despite the diversity of structures they encompass, are referred to herein as "ulimorelin analogs" simply for convenience, it being understood that, for compounds that are close structural analogs of ulimorelin with similar bioactivity and bioavailability (particularly with respect to binding to Alpha- 1 Acid Glycoprotein (AAGP, also called orosomucoid), as described in detail herein), the doses of ulimorelin that are efficacious in treating EFI are suitable for these compounds, as adjusted, if needed, for molecular weight differences of the active pharmaceutical ingredients, and, for relative potencies of the given ulimorelin analog to, for example, ulimorelin; and that, for the other compounds, the doses will be as set forth herein, or, as determined using routine skill in the art in light of the present disclosure, and testing to determine bioequivalent doses, for example, when converting from an oral or subcutaneous form to an IV form of deliver}'. In all cases, however, for the most efficacious treatment of EFI, the compounds are administered TED in an IV formulation.

[0013] Patients that benefit from therapeutic treatment with ulimorelin analogs, as described herein, include, without limitation, patients in need of anabolic stimulation as a result of lean body mass (LBM) loss or at potential for LBM loss (more specifically, loss of muscle mass) due to deprivation of calories and/or protein and/or due to systemic inflammation caused by critical illness such as, for example but without limitation, trauma, sepsis, cardiopulmonary disease, burn, neoplasm, pneumonia and/or other serious infection, surgery, and/or gastrointestinal disease. Patients that benefit may also be at risk due to impaired growth hormone and/or other aberrant hormonal secretion, simply due to constant bed rest; and/or excess net sympathetic tone, among others reasons.

[0014] In accordance with the present invention ulimorelin analogs may be administered to prevent or at least slow the loss of muscle (or muscle mass) and/or LBM. A significant component of LBM is muscle. The beneficial effects of ulimorelin analogs on LBM are due primarily to their effect on muscle, although the invention is not to be limited by any proposed mechanism of action. LBM is a commonly used proxy in clinical study of the effect of therapeutic or prophylactic interventions on muscle. Thus, the invention provides methods for preserving, increasing, and otherwise positively impacting metabolism and/or mass of muscle in patients in need thereof.

f OOlSf WO 2016/077498 discloses that anabolic benefit provided by ulimorelin can be enjoyed by patients both when being treated for EFI, when being administered a drug to prevent EFI, and after EFT has resolved or enteral feeding has stopped. The present invention provides methodology for achieving the same with ulimorelin analogs. In one embodiment, the patients include those that are in an unhealthy catabolic state. In another embodiment, the patients include those that are suffering from cachexia or other similar conditions. In some embodiments, the increase in growth hormone levels (and corresponding reactions of downstream mediators) and/or decrease in net sympathetic tone resulting from administration of ulimorelin analogs in accordance with the invention is indicated to provide beneficial effects on protein turnover or otherwise lead to reduced loss of lean body mass (more specifically, muscle mass). Accordingly, both for patients with EFI and for patients who receive uiimorelin analogs for their anabolic effect, or both, including critically ill patients and patients recovering from critical illness, the methods of the present invention provide important therapeutic benefits, in terms of an increased likelihood of survival, shorter duration of ICU stay, lower total cost for ICU stay or full hospitalization, and/or shorter duration of, or lower total cost of, follow-up care, or some combination of these benefits or others. Without wishing to be bound by theory, in many instances these benefits accrue due to effects on muscle. Indeed, some patients receiving this therapy may be on TPN (total parenteral nutrition) rather than enteral feeding, such that the therapeutic benefit is targeted specifically to muscle not GI motility. Yet other patients may be receiving this therapy whose feeding is being provided both enterally and parenterally. Yet other patients may be self- feeding.

[0016] In another aspect, the present invention provides methods for providing an anti-catabolic benefit to a patient in the ICU and/or for reversing an ICU patient's elevation of resting energy expenditure, and/or for providing cardioprotective benefit to such an ICU patient. While the present invention is not to be bound by any theory or putative mechanism of action, the benefits of these treatment methods are believed to arise from uiimorelin analogs' ability, when administered as described herein, to prevent or ameliorate the negative health effects of exaggerated sympathetic tone, similar to what is, at times, accomplished by- use of beta blockade in ICU patients today. Accordingly, administration of uiimorelin analogs as described herein can provide a significant anti-catabolic benefit, reverse or at least diminish a patient's elevation of resting energy expenditure, and/or provide cardioprotective benefit to ICU patients or other patients in need of such therapeutic benefit.

[0017] In a related important aspect the methods of the invention include methods for using uiimorelin analogs as a therapy to prevent or slow the loss of muscle in patients at risk of muscle loss, including but not limited to patients in the ICU, and other critically and/or chronically ill patients. In this aspect of the invention, patients may or may not be receiving enteral feeding, and in at least some important embodiments, the patients are actually receiving TPN,

[0018] In various embodiments of this invention, daily administration of the uiimorelin analog is typically conducted for several consecutive days, often at least for 3, 4, or 5 days or longer, including up to a week or even several weeks. Such embodiments include patients who are being treated only for EFI, patients who get treated for EFI and continue therapy after EFI resolution for continued therapeutic benefit (and this latter class of patients will, on average, have longer ICU stays), and, patients treated for anabolic effect only. Daily administration may be given to prevent or slow the loss of muscle regardless of whether the patient is being prescribed enteral feedings. Depending on a patient's clinical course, other medical problems, and duration of ICU stay, once approved for use, an ulimorelin analog may be prescribed or used for as little as one or two days, depending on physician judgment and the clinical situation. Those of skill in the art will appreciate that physicians may- prescribe ulimorelin analog treatment as described herein for the entire time a patient is on enteral feeding, once EFI is diagnosed, or for all or part of the entire ICU stay of a critically ill patient, regardless of whether the patient is ever diagnosed with EFI.

[0019] If EFI is diagnosed, then, after EFI is resolved, the physician may choose to continue treating for the ulimorelin analog's anabolic effect while the patient is still in the ICU. One reason for this, and there are others, is because resolution of impaired gastric emptying may occur within one or two days, A physician may choose to prescribe an ulimorelin analog for the entire duration of an EFI patient's ICU stay, which, while typically 6-9 days, may be as little as one day or as long as weeks or months. In various embodiments, an ulimorelin analog is to be administered for up to 5 or up to 7 days, with the option to provide single or multiple repeat courses of this or a similar duration either sequentially, or with intervening periods off medication, e.g., one to four days off treatment. As but one given example, a patient may be prescribed an ulimorelin analog for EFI for a period of time, i.e., 5 to 7 days, but the physician, upon observing the positive therapeutic benefit, may order that the medication be continued until the patient leaves the ICU or is otherwise discharged from the ICU or hospital,

[0020] In various embodiments, the ulimorelin analog is selected from the group consisting of capromorelin, ibutamoren, ipamorelin, relamorelin, tabimorelin.

BRIEF DESCRIPTION OF THE FIGURES

0021 Figure 1 shows the structure of ulimorelin, also referred to herein as TZP-101,

NK 42308,. or LP 101.

0022] Figure 2 shows the structure of capromorelin.

Figure 3 shows the structure of EX- 1314.

0024] Figure 4 shows the structure of ghrelin.

[0025] Figure 5 shows the structure of ibutamoren.

[0027] Figure 7 shows the structure of pralmorelin.

[0028] Figure 8 shows the structure of relamorelin.

[0029] Figure 9 shows the staicture of tabimorelin.

[0030] Figure 10 is graphically presented data showing that endogenous ghrelin blood levels are pulsatile, rising sharply prior to eating thrice daily and declining post-prandially, as discussed in Example 1.

[0031] Figure 1 1 is graphically presented data illustrating total and free plasma ulimorelin concentrations and showing the short half-life of free ulimorelin relative to that of total plasma ulimorelin. Half lives were calculated based on data from the Tranzyme Thorough QT (TQT) study in which plasma obtained from healthy volunteers following a 30 minute IV infusion of 600 ^ig/kg ulimorelin was analyzed.

[0032] Figure 12 shows results from two clinical studies (LPlOl -CL-101 and LP101-

CL-102) demonstrating acceleration of gastric emptying after administration of ulimorelin to healthy volunteers. See Example 2.

[0033] Figure 13 shows pooled gastric emptying results from the LPlOl-CL-101 and

LPl O -CL-102 studies. See Example 2,

[0034] Figure 14 and Figure 15 show Emax plots from the LPlOl -CL-101 and

LPlOl-CL-102 studies, individually and pooled, respectively, demonstrating the relationship between ulimorelin C_maxfree and improvement in the time relative to baseline for 50% liquid gastric emptying (Δί50) on Day 1 and Day 4 of the studies, as measured by scintigraphic imaging. See Example 2.

[0035] Figure 16 shows that AAGP level distribution and statistics differ for healthy volunteers and ICU patients.. Healthy population data are from the LPlOl-CL-101 and LPlOl-CL-102 studies, both individually and pooled. ICU data are from the REDOXS and RE- ENERGIZE studies.

[0036] Figure 17 shows mean peak growth hormone levels by dose and by day.

DETAILED DESCRIPTION OF THE INVENTION

[0037] Referring now to FIGURE 1, ulimorelin (aka TZP-101, LP101, NK 42308: see compound 298 in U.S. Patent 8,334,256, incorporated herein by reference), is a ghrelin receptor agonist useful in treating EFI. The examples and discussion herein demonstrate that ulimorelin and ulimorelin analogs are potent and effective in treating EFI when administered as provided herein. As defined above, "ulimorelin analogs" include a structurally diverse class of hormone mimetics consisting of (i) ghrelin agonists other than ulimorelin and close structural analogs of ulimorelin, e.g. ipamorelin and relamorelin; and (ii) ulimorelin analogs with similar bioactivity to ulimorelin, e.g., TZP-102; all of which, in accordance with the invention, are used for the prevention and treatment of EFI, including EFI recurrences, and prevention and treatment of catabolic effects of critical illness. For purposes of this disclosure, ghrelin is not a ulimorelin analog. As used herein, "similar bioactivity" means that the two compounds can be dosed in accordance with the route of administration (e.g. rv or subcutaneous) to achieve similar biologic effects, i.e., binding of the ghrelin receptor to accelerate gastric emptying, and is not intended to convey that the compounds have identical or nearly identical potency. Instead, for a compound to have similar bioactivity to ulimorelin, it simply must have such relative potency that one can formulate and dose the compound via IV or subcutaneous administration and achieve the desired therapeutic effect. Compounds that are too weakly agonistic may not be so formulatable or deliverable and so do not have similar bioactivity.

[0038] Enteral feeding is essential for many patients in the ICU setting, and EFI is a condition associated with increased mortality, such that effective treatment can save lives if not at least offer other clinically meaningful patient benefit such as shortened time in the ICU and/or accelerated recovery or other benefits. As used herein, "ICU" refers to any hospital setting where care is provided to critically or severely ill patients. For example and without limitation, a "burn unit" or any isolation ward (i.e., post-transplant) is an "ICU" for purposes of the invention.

[003 1 Ulimorelin analogs, when dosed as described herein not only increase gastric motility, but also, in addition to exerting beneficial effects directly on gastric emptying, exert a number of beneficial anabolic effects, including provision of more calories and/or more protein; increasing GH via beneficial spikes in GH levels; and/or reducing inflammation, including via reducing sympathetic tone and/or increasing parasympathetic tone (overall balance referred to herein as "net sympathetic tone"). For ulimorelin analogs that bind AAGP and are otherwise close structural analogs of ulimorelin with similar bioactivity and potency, the preferred doses and route of administration are similar to those for ulimorelin when administered to treat EFI: in the range of about 80 μg of drug/kg patient weight to 1200 ^ig/kg IV TID by bolus or infusion, it being anticipated that 600 _,ug/'kg may be a fairly standard adult dose in the EFI population (as this is a preferred dose for ulimorelin), with many- patients achieving desired therapeutic benefit from a dose in the range of 600 g/kg to 900 ,ug/kg patient weight. See Examples below and WO 2016/077498. While the patient with EFI benefits from these activities of ulimorelin analogs dosed as described herein, that same patient, after his or her EFI has resolved, may still receive additional ongoing therapeutic benefit (including preventing recurrence of EFI) from continued administration of the ulimorelin analog as described herein. One such benefit, which can be obtained regardless of the EFI status of the patient, is that ulimorelin analogs dosed as described herein can prevent or slow the loss of muscle in patients at risk of the same, e.g., critically ill patients such as one would encounter in the ICU. Additionally, ulimorelin analogs dosed as described herein can promote or accelerate the recovery of lost muscle or muscle mass,

[0040] Accordingly, the anabolic effects of dosing ulimorelin analogs in accordance with the invention provide additional benefit such that even after enteral feeding is discontinued or EFI is no longer present (or was not present or diagnosed), administration of one or more ulimorelin analogs as described herein can provide therapeutic benefit to patients in a catabolic state. Such patients may include, without limitation, patients with impaired appetite or impaired food intake; endocrine dysregulation such as, without limitation, impaired GH secretion, inflammatory-mediated catabolism; or, disorders of impaired anabolism, and those of skill in the art will appreciate that such patients include those not previously treated for EFI. As noted elsewhere herein, in fact, patients at risk for EFI can be prevented from experiencing the condition by administration of an ulimorelin analog as described herein.

[0041] Thus, ulimorelin analogs dosed in accordance with the invention stimulate and restore gastric motility and emptying, and also have anti-catabolic and pro-metabolic (collectively, anabolic) effects. While the invention is not to be limited in terms of putative mechanisms of action, some of these benefits are mediated through hormones such as growth hormone, while other benefits may follow more generally simply from the provision of more protein or nutrition, while yet others may accrue from a reduction in net sympathetic tone, all, generally, from administration of ulimorelin analogs as described herein. This treatment can, in effect, both provide more calories and protein to patients in need of such treatment and promote beneficial use of said nutrition to promote augmentation, or decreased loss, of muscle, lean body mass, and/or weight. Treatment with ulimorelin analogs in accordance with the invention can provide beneficial outcomes in patients that include, without limitation, one or more or all of the following, including as compared to patients not treated with ulimorelin analogs: reduction in episodes of excessive GRV (or equivalent) measurements; greater success at provision of a patient's targeted caloric prescription, including without limitation protein requirements; improved beneficial protein turnover; improved muscle fractional synthesis rates, increased lean body mass (LBM) and muscle mass; increased ventilator-free days; reductions in frequency of re-intubation episodes, in duration of critical care unit stay, in duration of hospitalization, in hospital-acquired infections, and/or in near term mortality (such as 30- and 60-day); and improvement in various measures of muscle strength and/or functional measures during hospitalization and/or measures of functional status post hospital discharge, including those self-reported by patients and those by their caretakers, such as Activities of Daily Living (ADLs) and Quality Of Life (QOL).

[0042] Those of skill in the art will recognize from the foregoing and disclosure and data presented herein that the invention also provides methods for slowing the loss of LBM, for preventing LBM loss, and for increasing LBM. Muscle is a significant component of LBM, and treatment in accordance with the invention slows or prevents muscle loss and can aid in increasing or restoring muscle mass.

[0043] Generally speaking, the therapeutic effect of a uiimorelin analog on LBM and muscle mass will track together; however, in one aspect, the present invention provides methods for using uiimorelin analogs to preserve or slow the loss of muscle specifically. These new methods focus on patients typically in the Intensive Care Unit who have enlarged or deranged organ size or mass, which can occur for any of a number of medical reasons, one of which may be clinically significant visceral edema, as well as patients who have other pathologic reasons leading to changes in LBM not correlating directly and linearly with changes in muscle mass. For such patients, treatments focused on muscle (as directly measured rather than inferred from LBM) enable the physician to determine more readily that a uiimorelin analog is having the intended therapeutic and anabolic effect on muscle. Measurement of LBM, which, by definition, includes visceral organs, is less informative to the physician for these patients than the muscle markers and biomarkers disclosed herein. As but one example, if a patient treated with a uiimorelin analog entered the ICU with significant visceral organ edema and this condition improved during the ICU stay, their overall numerical LBM might go down significantly, even while the typically-seen reduction in muscle mass was mitigated by therapeutic drug effect.

[0044] Moreover, other special classes of patients can benefit from use of uiimorelin analogs dosed as described herein. One class of patients are those on TPN, whom are administered uiimorelin analogs as described herein primarily for preservation of muscle/muscle mass,

[0045] While the benefits of this aspect of the invention begin to accrue early in treatment both for patients in which LBM is the indicator of treatment success and those in which muscle is, significant effects may take one to four weeks to appear; some patients will remain on therapy for much longer, i.e., 90 days or more. Certain of these patients receiving therapy will have been discharged from the ICU. Physicians will appreciate that shorter courses of therapy are indicated to prevent or mitigate LBM loss while longer duration treatments should increase or restore lost LBM, including to the LBM of the patient prior to the injury or disease that placed them at risk of LBM loss. Such patients, include, for example, elderly patients and patients with expected long duration of post-illness/injury recovery and rehabilitation, i.e., patients with hip fractures or patients undergoing high-risk surgery, as only two of many examples.

[0046] In one aspect, the present invention provides a method for treating ICU- associated wasting (ICU-AW) syndrome, said method comprising administering a ulimorelin analog to a patient in need of such treatment, said administering accomplished typically via TED IV administration. A key feature of ICU-AW is loss of, or decrease in, muscle (i.e. muscle mass), and dosing of ulimorelin analogs at the doses and frequencies described herein can prevent or treat such muscle loss and wasting in such patients.

[0047] For all of these indications, including treating EFI and preventing muscle loss in a critical care setting and treating muscle loss either during or after the patient is in a critical care setting, the promotilty effect (including both acceleration of normal gastric emptying and/or restoration of otherwise impaired or delayed gastric emptying) of a therapeutically active ulimorelin analog, as with ulimorelin itself, will be particularly effective if one achieves maximum plasma concentrations (Cm ax) rapidly, followed by a rapid decline. For ulimorelin, which binds the plasma protein AAGP and is unable to activate the ghrelin receptor when bound to AAGP, Cmax is instead referred to as Cmaxfree, to indicate that only the unbound drug is relevant to describing the effective Cmax. IV administration of an ulimorelin analog with similar bioactivity to ulimorelin (and which thus binds AAGP similarly) in accordance with the invention to normal volunteers (as in a clinical trial, for example) thus may result in Cmaxfree levels in the range of about 0.3 ng/mL (estimated Cmaxfree for an 80 ^ig/kg dose) to about 125 ng/mL with an average effective half-life (Tl/2 alpha) of about 1 hour, as was determined for ulimorelin, assuming very similar molecular weight and potency at the ghrelin receptor for the analog. Administration of ulimorelin analogs in accordance with the invention provides therapeutically effective blood levels and kinetics, i.e., pharmacokinetics. See FIGURE 11

[0048] As demonstrated in Example 2 below, ulimorelin administration achieved a

Cmaxfree of about 1 ng/mL in most healthy volunteers (HVs) on the first day of administration in a recent clinical study. After consecutive daily administration, ulimorelin Cmaxfree levels generally rose relative to those observed on Day 1. Significant therapeutic efficacy (as inferred from activity in HVs) was achieved with ulimorelin doses resulting in Cmaxfree of 0.5 to 5 ng/mL, yet a dose that results in Cmaxfree of 125 ng/mL (as measured in a single ascending dose (SAD) study of ulimorelin, where the mean for that cohort was 75 ng/mL) was also well tolerated. Similarly, the various embodiments of the present invention that utilize close structural analogs of ulimorelin provide Cmaxfree levels comparable to those achieved by ulimorelin.

[0049] Data analysis from a ulimorelin healthy volunteer study indicated that blood levels of 30 ng/mL - 125 ng/mL correlated with a reduction in heart rate, and all subjects with a reduced heart rate in this study were asymptomatic. This mild heart rate slowing, and the underlying physiological changes of which such slowing is one manifestation, can actually provide (and/or be indicative of) anti-catabolic benefit to a patient. In one aspect, the present invention provides a method for providing an anti-catabolic benefit to a patient in the ICU by administering one or more ulimorelin analogs. In a related aspect, the present invention provides a method for reversing such a patient's elevation of resting energy- expenditure by administering one or more ulimorelin analogs. In yet another related aspect, the present invention provides a method for providing cardioprotective benefit to such a patient. While not wishing to be bound by theory, this aspect of the invention is believed to relate to the ability of ulimorelin analogs to prevent or ameliorate the negative health effects of exaggerated sympathetic tone or net sympathetic tone.

[0050] It is well-known observation that beta-blocker therapy, such as with propranolol (a nonselective beta-antagonist which also decreases sympathetic tone and shifts the relative physiological balance of parasympathetic vs. sympathetic tone - the "net sympathetic tone" - in favor of parasympathetic tone and also thereby results in mild heart rate slowing) has been associated with improved nutritional status. Excess net sympathetic tone in the intent to treat population may lead to unhealthy catabolism and hypermetabolism. Indeed, in children with burns, for example, treatment with propranolol has been used to attenuate hypermetabolism and reverse muscle-protein catabolism, and these patients should benefit from the therapies of the invention as well.

[0051] For all methods of the invention, including for treating EFI and for anabolic benefit, one desires to achieve the target Cmax (to be read as Cmaxfree for clinically meaningful or significant AAGP binders) rapidly and reliably, and for this purpose, IV administration is used. [0052] The IV administration of the methods of the invention have advantages as compared to an oral therapy, one of which is that, in impaired gastric emptying in the critical care setting, GI absorption of an oral drug will be impaired by the same underlying motility problem as one is attempting to treat. Similarly, when compared to a subcutaneous therapy, IV administration avoids the pharmacokinetic limitations of a subcutaneous route. In particular, subcutaneous absorption may be unreliable in ICU EFI patients, due, among other factors, to commonly impaired perfusion of subcutaneous tissue due, for example, to hemodynamic instability such as shunting, local or systemic hypotension or circulatory collapse (Fries, 2011, Wien Med Wochenschr 161/3-4: 68-72). Such factors are common in ICU patients whether or not they have EFI. For these ICU EFI patients, in addition to the drawbacks noted above, oral administration is even less desirable, given the widely variable absorption kinetics and thus blood level kinetics in this intent to treat population. IV administration results, through pharmacotherapy, in an effect on gastric and upper GI musculature, including via MMCs, that is as nearly simultaneous to that which occurs in natural human pharmacology as can be achieved with a drug. Similar pharmacokinetics might possibly be achieved via inhalational administration, but this is not practical for the intent to treat population (many of whom are on mechanical ventilation) even if such formulations were available. Hence, for the administration of ulimorelin analogs to restore gastric emptying in a critically ill patient with EFI, the IV route of the present invention provides distinct advantages over other routes of administration.

[00531 In accordance with the methods of the invention, ulimorelin analogs can be administered as a 30 minute intravenous (IV) infusion three times daily (TID), typically at approximately 8 hour intervals (q8H). Such a frequency of dosing, particularly when accomplished with IV administration, best mimics the natural state of thrice-daily (i.e. meal- related) ghrelin surges in humans, whether a critically ill patient is being fed by bolus, continuous drip, or a combination of each. The stomach can hold generally about 1 liter of food (see Sherwood, Lauralee (1997)). Human Physiology: From Cells to Systems. Belmont, CA: Wadsworth Pub. Co]. Typical enteral feeding in the ICU is given at maximal infusion rates of 80 to 100 mL/hour, or 640 to 800 mL over eight hours. In instances where feeding is given by bolus, typical boluses will not exceed 250 mL. Thus, a q8H or TID dosing regimen will provide gastric emptying events and frequency thereof sufficient to ensure for most patients that the volume of food given between doses will not exceed the innate capacity of the stomach; more frequent dosing would add cost and complexity to the patient's care and add potential risk, but without expected additional benefit. Certain newer protocolized feeding regimens such as "volume-based feeding" are being used in certain ICU's to attempt to ensure that an enterally-fed patient receives as close to the complete amount of prescribed daily nutrition as possible, particularly taking into account the interruptions to feeding that are common in the ICU, such as due to radiology and surgical procedures during the ICU stay. With these regimens the feeding rate may exceed the typical maximal feeding rate for a few hours of the day, done in order to catch-up for the hours of missed food delivery. Rates may be as high as 150 mL/hour. Even during such time of transiently accelerated feeding rates the q8H or TID dosing regimen will generally be effective to ensure sufficient gastric emptying given that the goal remains to provide a total daily amount of feed volume that is no different from the base case wherein no such temporary accelerations are performed.

[0054] As noted above, typically, for close structural analogs of ulimorelin with very similar or nearly identical bioactivity and potency, including AAGP binding activity, each dose (which can be adjusted for molecular weight differences) is in the range of 80 ^tg/kg to 1200 fig/kg, with various substantial patient groups receiving benefit from administering ulimorelin analog in doses of about 600 ,ug/kg. Generally, patients with AAGP levels in the "normal", moderately elevated and moderately diminished range will receive this dose, while essentially all patients will be effectively treated using doses between 600 - 900 _,ug/kg. For patients whose illness or disease materially changes drug metabolism / excretion (clearance), physicians may choose instead to administer doses and measure Cmaxfree, as described above, to ensure that the dose administered is safe and achieves the Cmaxfree required for efficacy. Only those ulimorelin analogs that bind AAGP (or other serum proteins) to a clinically meaningful degree need to be dose adjusted in this fashion. See WO 2016/077498, incorporated herein by reference, for specific guidance on ulimorelin dosing, including in patients with higher or lower AAGP levels than ideal for a patient receiving the standard dose.

[00551 As noted above, for some patients, the ulimorelin analog will be administered as a 30 min intravenous (IV) infusion q8H (TID) at the therapeutically effective dose. Infusion times and practices may vary in accordance with physician practice; the guidance here enables the ordinarily skilled artisan to employ any conventional infusion practice, including, without limitation, use of IV bags or use of syringe pumps. Other patients will benefit, as discussed above, by receiving these same doses (or total daily amounts), i.e., patients not on or no longer needing enteral feeding or no longer intolerant to enteral feeding but still in a cataboiic or other state, or recovering from such state where the treating physician believes the anabolic effects of dosing ulimorelin analogs in accordance with the invention will provide therapeutic benefit. While TID administration is preferred, BID administration may be used in patients to prevent loss of muscle or to facilitate recover}' from such loss, regardless of whether they have EFI. For most patients, and in ail indications described herein, TID administration is used,

[0056] Treatment of EFI in a critical care setting in accordance with the methods of the invention will be particularly beneficial in that an uiimorelin analog, when administered as a promotility drug in accordance with the invention, has additional benefits to patients. An uiimorelin analog counteracts the occurrence of a catabolic state in such patients, one that many such patients may experience. In a situation wherein adequate nutrition is not provided, such patients can lose as much as 1 kilogram of lean body mass per day, with most or ail of this being muscle, noting that for critically ill patients with significant shifts in total body or specific organ fluid balance (such as due to edema or the resolution thereof) LBM measurements will not accurately measure or meaningfully reflect changes to muscle or muscle mass. Even when food is provided, due to the heightened state of illness and the attendant effort of the body to repair and heal, as well as a frequent state of inflammation that also drives a hyper-catabolic state and/or excessive net sympathetic tone, loss of lean body- mass and more critically, muscle, may occur and can be significant and debilitating, both in the short and long term. Muscle is a key component of LBM and the most relevant one to the therapeutic benefits provided herein. Uiimorelin analogs dosed in accordance with the invention can be used to prevent or slow loss of muscle in any patient at risk of same, particularly ICU patients with EFI or at risk of developing EFI, as are most ICU patients. Such analogs may also be used to promote recovery of lost muscle mass, both during and after an ICU stay, or even if there has not been one. As discussed above, uiimorelin analogs provide benefit to those patients who have other conditions that render LBM inappropriate or potentially confounding for use in determining whether muscle loss is occurring when used in accordance with the invention.

[0057] For patients receiving uiimorelin analogs for preservation of muscle or to increase muscle mass, including patients on TPN or those receiving parenteral nutrition in addition to enteral, in addition to dosing the drugs IV in the ranges and at the frequencies discussed herein, the physician will typically monitor the therapeutic effectiveness of the drug by appropriate monitoring to track muscle catabolism, metabolism or mass. Such monitoring may include, for example and without limitation, measurement of any of the indicators of muscle anabolism/catabolism described in the examples below, including but not limited to MPFSR or another indicator of muscle anabolism (or catabolism) such as: (a) ultrasound of the quadriceps and/or diaphragm or other muscle or imaging method; (b) preseivation of skeletal muscle mass as measured by D₃-creatine dilution and/or by 24 hour urinary creatinine excretion; (c) skeletal muscle protein degradation by 24 hour urinary 3- methyhistidine (3-me-His) excretion; (d) whole body N balance by 24 hour urinary total nitrogen (N) excretion; and/or (e) plasma muscle protein fractional synthesis rate (PPFSR) by measuring plasma levels of circulating skeletal muscle-derived proteins, such as CK-M, carbonic anhydrase-3.

[0058] Ulimorelin analogs of the present invention are therapeutic agents with both anti-catabolic and anti-inflammatory properties, that also restore gastric emptying, and so they are particularly efficacious for the treatment of EFI, including treatment in the ICU setting, and for providing anabolic benefit and/or reducing excessive net sympathetic tone, whether in the ICU setting (during and post-EFI) or elsewhere. Thus, in one embodiment of the invention, an ulimorelin analog is administered to a patient with EFI or at risk for EFI or having recovered from EFI and in a hyper-catabolic state (a catabolic state that a physician deems unhealthy) and can provide enhanced therapeutic benefit as compared to other agents, such as motilin agonists and 5HT-4 agonists, that provide only a pro-motility effect. In some embodiments of the invention, particularly those where a patient has both gastric motility and excess catabolism derangements, motilin agonists and/or 5HT-4 agonists or other pro- motility agents can even be used in combination with an ulimorelin analog in accordance with the invention to provide additional therapeutic benefit.

|0059| In most embodiments of the invention, however, an ulimorelin analog is used as the sole therapeutic agent administered to treat EFI and improve gastric motility. Example 2, below, describes a study in healthy volunteers that showed TID IV administration of ulimorelin substantially improved liquid gastric emptying as compared to placebo over baseline measurements. Those skilled in the art will appreciate that, for healthy volunteers who have normal gastric emptying at baseline, "improvement" is measured as acceleration of gastric emptying rate (measured in units of time) above baseline physiologic levels, and this translates in the intent to treat population - patients with impaired and/or delayed gastric emptying - as restoration of gastric emptying times to those, or closer to those, of the patient's pre-morbid condition. The notable acceleration in upper GI motility seen with ulimorelin in healthy volunteers showed that achievement of optimized Cmaxfree kinetics and levels are each a key requirement for successfully using ulimorelin or an ulimorelin analog to treat EFI. The methods of this invention provide dosing and administration protocols for treating EFI with ulimorelin analogs. [0060] In other aspects of the invention, an ulimorelin analog is administered to a patient in a catabolic state (which itself may be due to or exacerbated by an underlying inflammatory condition) that is deemed harmful by the treating physician. An ulimorelin analog can be used in accordance with the invention to improve provision of calories or protein, to improve gastric motility, to promote maintenance or lessened loss of lean body mass, to promote maintenance or lessened loss of muscle, to reduce an underlying inflammatory state contributing to a catabolic state such as systemic inflammation caused by critical illness including, for example but without limitation, trauma, sepsis, cardiopulmonary disease, neoplasm, bum, pneumonia and other serious infection, surgery and/or gastrointestinal disease, to treat a catabolic state directly, and to promote beneficial outcomes such as may result from improved maintenance of lean body mass, including muscle mass.

[0061] Ulimorelin analogs dosed in accordance with the invention are especially useful in the ICU and other critical care treatment centers. For example, as compared with ICU EFI (and other) patients who either receive no therapy or a different therapy that does not offer these benefits, patients receiving ulimorelin analog therapy in accordance with the invention should generally have greater likelihood of surviving their ICU stay or other illness and, for those who do survive, of requiring enteral feeding and/or critical care for shorter periods of time. Such patients should retain more muscle than untreated patients as well. Such patients may include, without limitation, patients with impaired appetite or impaired food intake; endocrine dysregulation such as, without limitation, impaired GH secretion; inflammatory-mediated catabolism; or, disorders of impaired anabolism, and those of skill in the art will appreciate that such patients include those not previously treated for EFI. While not wishing to be bound by any theory of the invention, these benefits are believed to arise, at least in part, from the increase in GH levels attendant to administration of ulimorelin analog in accordance with the methods of the invention.

[0062] Administration of an ulimorelin analog in accordance with the present invention should provide similar GH spikes to those observed in HVs receiving ulimorelin. Ulimorelin administration resulted in GH level "spikes" on Day 1 in human clinical studies, and while levels declined over time, the spikes seen after repeat administration remained clinically significant. Thus, the methods of the invention can provide therapeutically meaningful anti-catabolic (anabolic) effect without undue risk of serious side effects. Thus, in one embodiment, the present invention provides methods for increasing GH levels in patients in need of such treatment, such methods involving administration of an ulimorelin analog as described herein, and such methods resulting in GH spikes after each administration of at least about 2 μ /1, (male) and about 6 μ /1, (female). In some embodiments, the patients' GH levels are returned to near normal levels (0 to 0,8 ,ug/L in males, and 0 to 8 ^ig/L in females). These methods are suitable for use for providing an anabolic effect in patients in need of treatment, including patients in a catabolic state deemed harmful by the treating physician and in patients with cachexia. In these methods, an ulimorelin analog is administered in the amounts and with the treatment regimens described herein (e.g. ΤΠ3 for a patient suffering from EFI; BID but typically TID if not, with administration typically IV although subcutaneous may be utilized in some embodiments).

[0063] In various embodiments of both of these aspects of the invention, the invention relates to the use of an ulimorelin analog drug product concentrate provided for use in the invention that is packaged in glass vials, a unit dose form of the invention. Such glass vials are typically filled with the ulimorelin analog in buffered 5% dextrose in water or other suitable formulation for injection (or subcutaneous administration) and labeled for use in accordance with the invention. For example, for an ulimorelin analog of similar solubility, bioactivity, and potency as ulimorelin, the liquid formulation of a unit dose form might constitute between 5-15 mL per vial, e.g., 10 niL - 11 raL. The invention provides many other useful embodiments of ulimorelin analog formulations suitable for IV administration and dmg products containing such formulations.

[0064] Thus, the ulimorelin analog drug product concentrates provided by the invention include larger volume unit dose forms (vials) and packaging providing higher fill volumes at, for example, 20 mL, 25 mL, 50 mL, and 100 mL per vial volume and corresponding fill amounts, or values in between these amounts; the invention also provides drug product, in approximately 10 mL per vial volume packaging with formulations at higher concentrations. The invention also provides dmg product for ulimorelin analogs in both larger unit dose forms (vials) and at higher concentrations, for example, 4 or 5 mg/ml in 20 or 25 ml vials. In accordance with the invention, formulations of any pharmaceutically acceptable ulimorelin analog salts (e.g., hydrochloride, succinate and malate salts).

[0065] Ipamorelin Formulations. In one embodiment, the ulimorelin analog used in a method of the invention is provided as ipamorelin (NNC 26-0161) formulated for IV infusion or IV bolus injection. In various embodiments, this ipamorelin formulation either (i) prepared in a lyophilized form to be reconstituted prior to use; prepared as a concentrated solution for dilution and delivery by IV infusion; or (iii) prepared as a solution ready for administration by IV infusion or bolus dosing, with each dose administered in the range of 0.01 to 0.05 mg of dmg per kg of patient weight (or alternatively 0.01 mg/kg to 0,06 mg/kg), e.g., a dose of 0.03 mg/kg. Other suitable doses for administering ipamorelin in accordance with the invention are described below.

[0066] Relamorelin Formulations. In one embodiment, the ulimoreiin analog used in a method of the invention is provided as relamorelin (RM-131) formulated for IV infusion, IV bolus injection, or subcutaneous injection. In various embodiments, this relamorelin formulation is either (i) prepared in a lyophilized form to be reconstituted prior to use; prepared as a concentrated solution for dilution and delivery by IV infusion; or (iii) prepared as a solution ready for administration by IV infusion or IV bolus injection or subcutaneous injection, with each dose in the range of 5 to 100 ug, e.g., 10 ug, 30 ug, or 100 ug doses. A dose for use for a particularly long infusion time may be up to 150 ug. The preferred doses are typically administered IV by infusion or bolus injection for treatment of EFI (and then on a TIE) schedule), but subcutaneous administration may also be employed, and less frequent dosing may be used to treat non-EFI indications, such as to slow muscle loss (preserve muscle mass).

[0067] TZP-102 Formulations. In one embodiment, the ulimoreiin analog used in a method of the invention is provided as TZP-102 formulated for IV infusion or subcutaneous injection. In various embodiments, this TZP-102 formulation either (i) prepared in a lyophilized form to be reconstituted prior to use; prepared as a concentrated solution for dilution and deliver' by IV infusion; or (iii) prepared as a solution ready for administration by IV infusion or bolus dosing, with each dose administered in a range of about 80 ug/kg to about 1200 ug/kg. TZP-102 (disclosed and claimed in US Pat. No. 9,371 ,297) is a close structural analog of ulimoreiin. It is hypothesized that TZP-102 may bind AAGP (alpha 1- acid glycoprotein; aka orosomucoid) similarly to ulimoreiin. Thus, while standard dosing is provided herein, some patients will benefit from dosing adjusted according to the patient's levels of AAGP; see WO 2016/077498, incorporated herein by reference (e.g. particularly paras. 53-77 and Examples 2-4) for dosing optimization protocols when an ulimoreiin analog that binds AAGP is utilized, and the patient has aberrant (low or high) AAGP levels. For a TZP-102 for Injection formulation, an illustrative drug product formulation and unit dose form (also referred to as a drug product presentation or "drug product intermediate" in some situations) is a clear vial filled with 10 mL (10,5 raL) of solution closed with rubber stoppers and flip-off aluminum seals. The product is intended to be diluted, as needed, to the desired concentration prior to administration. Similar analysis may be applied to other compounds that are highly structurally related to ulimoreiin and expected to have similar clinical pharmacology to ulimorelin, such that dosing by TID IV infusion with each dose administered in a range of about 80 ug/kg to about 1200 ug/kg may be used.

[0068] Suitable infusion concentrations may be, for example, for a close staictural analog of ulimorelin like TZP-102, in the range of 0.15 mg/mL to 1.00 mg/mL. In alternate embodiments, suitable infusion concentrations may be in the range of 1.00 mg/mL - 2.00 mg/mL. In alternate embodiments, suitable infusion concentrations may be in a higher range, as high as 4,00 or 5.00 mg/ml. Infusion temperature is typically room temperature (infusion bags may be stored refrigerated or at room temperature, and the TZP-102 is typically stored at controlled room temperature), and the infused product typically has a pH of about 4.5 (the approximate pH of the infusate used in Example 2). Various illustrative doses of TZP-102 that can be administered using formulations of the invention are described below.

[0069] IV formulations (of any ulimorelin analog) for infusion are typically administered by IV infusion over 30 minute using a syringe pump (other devices, including but not limited to peristaltic pumps, may be readily substituted in view of the disclosure herein based on the ordinarily skilled physician's personal practices and patient needs). The pharmacokinetics achieved via a 30 minute infusion time provides the desired Cmax (Cmaxfree for drugs with clinically-significant AAGP binding) at the desired kinetics to provide therapeutic benefit to EFI patients. Those skilled in the art will appreciate that when guided to a 30 minute infusion time, actual delivery time for drug given by a healthcare provider may vary, typically by no more than +/-5 minutes.

[00701 IV TID administration may, without limitation, be by infusion or by bolus injection, both of which are well known to physicians and medical providers, and are briefly described below.

[0071] In one approach, drug is delivered three times per day by infusion.

Administration of drugs by infusion is well known and the medical provider guided by this disclosure will be able to select particular infusion parameters to meet the needs of individual patients. In one approach drug is administered by IV infusion over a 30 minute period to rapidly reach the desired Cmax to provide therapeutic benefit to EFI patients. Any conventional infusion practice may be used, including, without limitation, use of IV bags or use of syringe pumps or peristaltic pumps.

[0072] Infusion temperature is typically room temperature. The infused product typicall has a pH of about 4.5 - 5,5, depending on the amount of diluent added. The cannula for infusion may vary according to the patient and to preferences of the physician, but for adults is typically 20 gauge or larger. [0073] In some embodiments, drug is administered by IV bolus injection rather than by infusion. Bolus injection may be used, for example, to save cost and/or quantity of drug used, or to reduce volume of infusate, or to increase nursing convenience. Bolus injection differs from infusion principally in length of time required to administer the drug to the patient. For infusion, drug is administered over a longer period (e.g., 30 min). For bolus injection, drug is administered over a shorter period (e.g., 3 min or less). In practice, drug for infusion is often diluted into a pharmaceutically acceptable diluent and administered using an IV bag, while drug is usually administered by bolus injection using a syringe, e.g., using a pump or pushed directly into an IV line port. For purposes of this description, drug bolus injections are completed in less than 3 minutes (from first drug into the patient's bloodstream to end of administration). Bolus injections are usually completed within 2 minutes or less (e.g., 30 seconds to 2 minutes), and sometimes within 1 minute or less.

[0074] As described in this disclosure, 600-900 ,ug/kg TID ulimorelin administered by infusion was efficacious for treating EFI. A typical Cmaxfree achieved by these doses will (measured at the end of infusion) in the range 0.5 ng/mL to 125 ng n L. When administered by bolus injection, as defined herein, a lower drug dose is required to achieve the same Cmaxfree, compared to a 30 minute infusion.

[0075] The preferred bolus injection dose may be determined empirically, for example by administering drug to healthy volunteers and determining which drug doses given under bolus injection conditions (e.g., 3 min bolus injection) result in the same Cm ax in the HV as observed following administration by (30 min) infusion of, for example, 600 μg/kg drug. Exemplary bolus injection doses may also be estimated based on pharmacokinetic principles, as shown in TABLE 1. Calculated doses may be confirmed in human trials.

TABLE 1

Comparison of Exemplary Bolus Injection Doses and Infusion Doses

[0076] In a typical application of the methods and products of the invention, the body weight of a patient in need of treatment for EFT is measured or estimated to calculate the actual dose for each administration of daig. For the doses reported herein, it is assumed that the physician will use total body weight. However, some physicians may use "ideal body weight" dosing if a patient is particularly obese, or may make other adjustments not indexed to body weight such as sometimes is done in clinical practice for particularly obese patients. Similarly, some physicians may use "ideal body weight" if a patient is particularly emaciated. In yet further embodiments, some physicians, when guided by their clinical judgment, may dose according to pre-morbid body weight ("usual body weight"), such as, by way of non- limiting example, to account for the effect of overhydration on measured body weight such as can occur during resuscitation of a patient with unstable cardiovascular status. In cases such as these, pre-morbid body weight will typically be lower than measured body weight. Absent other circumstances as discussed herein (e.g. variations in AAGP levels, etc.), however, the doses provided herein are generally suitable regardless of which weight metric is used, as the dose can be increased if insufficient efficacy is seen due to, for example, the physician using ideal body weight dosing for a particularly obese patient or using pre-morbid dosing, e.g., for a fluid-overloaded patient, and, similarly, a dose can be adjusted downward if the physician suspects blood levels may be too high, e.g., after using ideal body weight dosing in an emaciated patient.

[0077] Once the dose is determined, the formulation for administration is prepared.

For example, to achieve a 600 .ug/kg dose in a 70 kg patient requiring treatment for EFI, 21 mL of TZP-102 drug product concentrate (at 2 mg/mL) can be diluted into 100 mL 5% dextrose in water (D5W), which is then administered as constant rate infusion over 30 minutes. Likewise, for 300 ^tg/kg, 500 μg/kg, 900 μg/kg, 1200 ^ig/kg, or 2400 ,ug/kg dose levels, 10.5 mL, 17.5 mL, 31 .5 mL, 42 mL, or 84 mL of TZP-102 drug product concentrate is diluted, typically into 50 mL but optionally up to about 100 mL D5W which is then administered at a constant rate infusion over 30 minutes. Those skilled in the art will appreciate that the choice of 50 mL or 100 mL or, indeed, another volume of total infusate (including lower volumes, e.g. as low as 10 to 15 mL, some of which low volumes may be for doses that are given "neat"), may be determined by other factors, including, without limitation, a patient's more general fluid requirements or restriction, and the physician may- use appropriate clinical judgment to decide the preferred total volume. This is repeated roughly every 8 hours (q8H) for intervals of up to 5-7 day or longer until feeding goals are achieved or as clinically indicated. Of course, here, too, individual physician (including any other medical professional operating under the physician's direction) practice can vary widely without departing from the scope of the invention. As but illustrative examples, the physician may chose to use a different volume, e.g., 50 mL vs 100 ml or any other amount; to use no diluent (i.e., to use a "neat" administration); or to use a different diluent such as Lactated Ringer's or Normal Saline.

[0078] Example 2 describes a study in which ulimorelin was dosed by IV infusion over a 30 minute time period, the preferred infusion time period for ulimorelin analogs. This example also shows, based on scintigraphic measurements of gastric emptying in normal human volunteers receiving IV administered ulimorelin, that therapeutic benefit can be achieved in the form of an improvement in gastric emptying T50 (the time it takes for the stomach to half empty from the meal, "GET50") at doses such as 80 μβ/ g, 150 ^ig/kg, and 300 μg/kg ulimorelin administered TID. In particular, this was demonstrated using "liquid meal" emptying. The "food" typically provided to patients receiving enteral feeding is of a liquid or slurry form, similar to that provided in the healthy volunteers (HV) clinical study, and is therefore referred to herein as a liquid meal.

[0079] Thus, in one embodiment, the present invention provides methods for improving gastric emptying in patients in need of such treatment, such methods involving administration of one or more ulimorelin analogs as described herein, and such methods resulting in GET50 improvements of at least 10, 20, 30% or higher on Day 1 of treatment and similar improvements after 2, 3, and even 4 or more days of continuous dosing. These methods are suitable for use in treating patients with EFI and other indications where the prokinetic effects of ulimorelin analog are therapeutically beneficial in the amounts and with the treatment regimens described herein.

[0080] As an illustrative example of all of the various embodiments of the invention in which the patient receiving benefit is on a nasogastric feeding tube or similar feeding device and the treating physician is concerned about EFI, the following is a description of a typical patient who could benefit by treatment in accordance with the invention. Such a typical patient may be admitted to an intensive care unit and be, as frequently the case, unable to eat on his or her own. This can be due to many different causes, including, as non-limiting examples, sedation, such as from medically-induced coma or sedating pain medication, delirium, or the presence of an endotracheal tube for the provision of mechanical ventilation. In typical practice, within the first 1 to 72 hours, or at a time when deemed acceptable by caregivers, a nasogastric or similar tube will be inserted into such a patient, through which a general liquid feeding formula will be delivered, either in boluses, as a continuous drip, or as an intermittent continuous drip possibly with boluses as well. [0081] Typically, after a certain amount has been infused and typically after 4 to 8 hours if by continuous drip, a study will be conducted to determine the GRV of the amount provided, for which feeding will be interrupted. In some embodiments, a certain amount of time, such as approximately 30 minutes, will be allowed to elapse, and then gastric residual contents will be aspirated by syringe or similar method. Should the GRV (or other indicator of EFI) be deemed excessive in the caregiver's judgment, typically in excess of an amount between 200 to 500 niL or more, as a non-limiting example, then feeding will be suspended.

[0082] A certain amount of time will be allowed to elapse, and then typically the

GRV (or other indicator of EFI) will be rechecked, with feeding having been restarted at the same or lower infusion rate in between, or with feeding on hold in between assessments. If GRV (or other indicator of EFI) is deemed sufficiently low (i.e., below or on the low end of the range above, for example), then feeding will be restarted. After a caregiver-determined number of GRV (or other indicator of EFI) readings are deemed excessively high, but often either one or two, the patient will be declared intolerant to enteral feeding, i.e., the patient may benefit from treatment of EFI, as provided herein.

[0083] Those of skill in the art will appreciate that various physicians will determine the need for therapeutic intervention for EFI in a variety of ways, and the ways listed herein are illustrative. For example, many physicians might take only a single GRV reading before diagnosing EFT and taking corrective action. Moreover, there are a variety of ways an individual physician may make a diagnosis of EFI without taking any GRV measurement, such as the observation of abdominal distension or vomiting, use of paracetamol absorption kinetic testing, use of scintigraphy, and others. The particular diagnostic methodology will often take into account the patient status; thus, for example, while GRV measurements are suitable for comatose patients, other methods, e.g. scintigraphy, are more appropriately done in on patients who are ambulatory. Those skilled in the art will appreciate that despite the variability in physician practice patterns and preferences with regard to making an EFI diagnosis, the underlying motility disorder, impaired gastric emptying, is common to all such patients and as such the therapeutic promotility benefit of ulimorelin analog will apply generally.

[0084] In particular, GRV measurements provide information about how much food remains in the stomach, but another way to diagnose EFI involves gastric emptying measurements made with scintigraphy (see Abell et al ,, Am. J. Gastroenterol. 2008; 103 :753- 763, incorporated herein by reference). Scintigraphy can be used to measure gastric emptying in IV studies, such as those described in Example 2, but is far less than ideal for clinical practice in the ICU population. Furthermore, those skilled in the art will appreciate that a drug which accelerates gastric emptying times as measured by scintigraphy in healthy volunteers will similarly accelerate or restore impaired, delayed, or stopped, gastric emptying in patients, including those who are critically ill, whether or not scintigraphic measurement is made of those patients, and that furthermore there are other measures which can serve as a similarly valid proxy of gastric emptying activity, such as the measurement of the amount of enteral feeding which a medical caregiver is able to provide and a patient is able to tolerate over a defined period of time.

[0085] Thus, while the diagnosis of EFI may be made without use of GRV measurement, including simply on symptoms alone, such as nausea or vomiting, distended abdomen, or others of similar GI relevance; or inferred from other measurements, such as gastric emptying scintigraphy, there remains a need for better treatment methods, and the need is relatively large: a recent study cites a prevalence of roughly 30% of ICU patients being labeled as having EFI (see Gungabissoon et al.; JPEN J Parenter Enteral Nutr 2014 Mar 17).

[0086] In other embodiments of the invention, after the EFI is resolved or enteral feedings have been stopped, the physician may continue administration of ulimorelin analog at the doses provided herein, and using TID administration (although BID administration may be used) to provide continuing anabolic benefit to the patient. In treating EFI, the treating physician may desire both the promotility effects of the drug and the anabolic benefit. These combined features, which are particularly beneficial for critically ill EFI patients, accrue from use of a properly dosed ulimorelin analog as described herein herein, providing benefits to patients beyond the merely prokinetic benefit offered by drugs that are not ulimorelin analogs. Thus, such treatments can be superior to those in which therapeutics that offer only- one or the other benefit are used. Moreover, ulimorelin analogs dosed in accordance with the invention should have a beneficial therapeutic effect in patients in a catabolic state requiring treatment due, without wishing to be bound by theory, to their effect on GH, resting energy expenditure, net sympathetic tone, and any combination of these.

[0087] In some embodiments, once the caregiver has determined a need to treat, the patient will then be administered an ulimorelin analog via IV administration on a TID schedule at a therapeutic dose described herein. Regardless of analog or dose, treatment will be continued for at least a day, typically at least two consecutive days and often continuing for at least four days or longer. In some instances, treatment will be administered daily for the length of the patient's subsequent stay in the ICU. In some instances, treatment will continue to be administered subsequent to the patient's stay in the ICU. For some patients, AAGP blood levels will be determined and used to guide dosing or dose adjustment.

[0088] Patients treated for EFI should receive an ulimorelin analog TID administered

IV. In EFI patients where TID administration is not optimal, whether due to side effects or diminished efficacy as a result of tachyphylaxis or care provider convenience or preference, the drug may be dosed by BID administration at a dose in the ranges provided above but administered BID instead of TID (for example and without limitation 160

to 2400 μg/kg/day for a close structural analog of ulimorelin as described). While BID administration can be practiced with any patient for whom the treating physician believes such administration superior to TID for any reason, BID administration methods, if used at all, are more suited for patients not being treated for EFI, i.e., where the anabolic and/or anti- cachexic effects are the primary benefits desired. In various embodiments of the invention, for example, a patient being treated for EFI may continue to receive an ulimorelin analog after EFI has resolved to provide anabolic benefit. In this post-EFI treatment scenario, dosing may be qD, BID, or TID, as the physician elects. As noted, such administration can be useful in preserving muscle and/or LBM in critically ill patients not with EFI (however, in many embodiments these patients will be dosed TID, given the superior benefits to be expected in most patients from the more frequent TID administration).

[0089] In various embodiments of the invention, the ulimorelin analog is selected from group consisting of Capromorelin, EX-1314, GTP-2Q0, Ibutamoren, Ipamorelin, KP- 101 , Pralmorelin, Reiamorelin, Tabimorelin, and TZP-102. Dosing and administration protocols for using various of these ulimorelin analogs for the various therapeutic methods of the invention are provided below. Other ulimorelin analogs and formulations comprising them are described in, for example and without limitation, US Patent Nos. 7,452,862; 7,521 ,420, 8,129,561 , 8,334,256, and 8,440,851; U.S. Patent App. Pub. No. 20080194672; and PCT Pub. Nos. 2005/012331; 2006/009645; and 2006/009674, each of which is incorporated herein by reference.

[0090] Capromorelin Dosing. In some embodiments, capromorelin is administered

TID or BID by IV infusion to patients with EFI with each dose of capromorelin in a range that provides bioactivity equivalent to 3 to 10 mg of the drug dosed orally. A dose may be administered by bolus injection as well. Suitable oral doses are generally in the range of 1 to 100 mg while suitable IV doses are those providing equivalent pharmacology. This drug may also be used for EFI prophylaxis by administering this dose or doses within the broader range orally or by IV administration qD, BID, or TID. These same doses may be administered with less frequent dosing (BID or qD instead of TID) for anabolic benefit or to slow or prevent muscle loss, e.g. preserve muscle mass.

[0091] Ibutamoren Dosing. In some embodiments, ibutamoren is administered TID or

BID by IV infusion to patients with EFI with each dose of ibutamoren in a range that provides bioactivity equivalent to 0.25 mg/kg to 25 mg/kg of the drug dosed orally. A dose may be administered by bolus injection as well. The dose administered IV ideally provides equivalent pharmacology to an oral dose of about 25 mg administered to an adult human. This drug may also be used for EFI prophylaxis by administering this dose or doses within the broader range orally or by IV administration qD, BID, or TID. These same doses may be administered with less frequent dosing (BID or qD instead of TID) for anabolic benefit or to slow or prevent muscle loss, e.g. preserve muscle mass,

[0092] Ipamorelin Dosing. In some embodiments, ipamorelin is administered TID by

IV infusion or IV bolus injection to patients with EFI, with each dose in the range of 0.01 mg/kg to 0.05 mg/kg, or 0.01 mg/kg to 0.06 mg/kg. For example, each dose of ipamorelin may be 0.03 mg/kg. A dose may be administered by bolus injection as well. These same doses may be administered with less frequent dosing (BID or qD instead of TID) for anabolic benefit or to slow or prevent muscle loss, e.g. preserve muscle mass.

[0093] Relamorelin Dosing. In some embodiments, relamorelin is administered TID by IV infusion, IV bolus injection or subcutaneously to patients with EFI and dosed TID with each dose in the range of 5 to 100 ug per administration, more typically 10 ug to 90 ug per administration. For particularly long infusion times, higher doses of up to 150 ug per administration, may be used. For example, each dose may be 10, 30, or 100 _,ug kg per administration, IV dosing may be weight based. These same doses may be administered for anabolic benefit or to slow or prevent muscle loss, e.g. preserve muscle mass. In some cases, less frequent dosing, such as prophylaxis of EFI or to slow or prevent muscle loss (BID or qD instead of TID) may be used.

[0094] Tabimorelm Dosing. In some embodiments, tabimorelm is administered TID or BID by IV infusion to patients with EFI with each dose of tabimorelin in a range that provides bioactivity equivalent to 1 mg/kg to 12 mg/kg of the drug dosed orally (e.g. equivalent to 3 mg/kg, 6 mg/kg, or 9 mg/kg oral dosing). A dose may be administered by- bolus injection as well. This drug may also be used for prophylaxis by administering this dose orally qD, BID, or TID, These same doses may be administered with less frequent dosing (BID or qD instead of TID) for anabolic benefit or to slow or prevent muscle loss, e.g. preserve muscle mass. [0095] TZP-102 Dosing. As described above, TZP-102 (the compound per se, in any pharmaceutically acceptable salt or formulation) is preferably administered intravenously at times and doses similar to those for ulimorelin for efficacious treatment of EFI and other indications as described herein (80 ug/kg to 1200 ug/kg TID by IV infusion or IV bolus injection, with standard dosing in the -600 ug/kg range. Less frequent administration, e.g. BID or qD, may be used for other indications as described herein. In other embodiments, TZP-102 is administered subcutaneously TID or BID (less often, qD) with each dose in the range of 10 to 40 mg per administration. For example, a dose of 40 mg TZP-102 may be administered BID or TID subcutaneously. In one important embodiment, a dose of TZP-102 is delivered orally, for prophylaxis to prevent EFI or for anabolic benefit or to slow loss of muscle, in an amount ranging from 5 to 50 mg, e.g., 10 mg, 20 mg, or 40 mg, administered qD or BID or TID.

[0096] Those of skill will appreciate that subcutaneous delivery of a drug of the invention may be achieved using a pump or other automated devices. Such devices containing an ulimorelin analog for use in EFI are also included as a part of this aspect of this invention.

[0097] The invention, having been described in summary and detail above is now illustrated, without limitation, in the following examples.

[0098] Example 1 shows that human ghrelin blood levels vary in a pulsatile manner, typically rising with three daily distinct, sharp peaks prior to typical times of meal-seeking behavior and declining post-prandially, in normal individuals.

[0099] Example 2 describes clinical trials that have been conducted with ulimorelin and could be conducted with ulimorelin analogs as described herein to demonstrate that the methods of the invention are safe and efficacious in the treatment of EFI, and includes results from administering ulimorelin to healthy volunteers (HVs) at doses in the ranges specified herein.

[00100] Example 3 describes administering an ulimorelin analog to hypothetical EFI patients in accordance with the invention.

[00101] Example 4 describes a clinical trial that can be conducted to demonstrate the therapeutic benefit of administering a ulimorelin analog to critically ill patients to prevent and/or slow the loss of muscle. Example 4 also describes administering ulimorelin analogs to patients to slow or prevent muscle loss in accordance with the invention.

[00102] The results and accompanying discussion in the examples and figure legends above are applicable to all aspects of this disclosure and demonstrate that treatment of ulimorelin analog in accordance with the invention provides therapeutic benefit by improving gastric emptying, ensuring the dose is in the desired therapeutic window, increasing GH levels, promoting anabolism, slowing catabolism, and preserving muscle mass.

[00103] Other indications that can be treated in accordance with the invention include but are not limited to both upper and lower GI motility conditions as well as conditions of excess catabolism or inadequate anabolism, inadequate food intake for any reason, including cachexia, both in patients who are critically ill, and those who are not critically ill but are in an acute care facility or chronic care facility and require an intravenous medication. Such conditions include enteral feeding intolerance, gastroparesis, including but not limited to patients with diabetic gastroparesis, neurogenic gastroparesis, idiopathic gastroparesis, drug- induced gastroparesis, viral gastroparesis, obesity-induced gastroparesis, Ogilvie's syndrome, non-toxic megacolon, pseudoobstmction, gastroparesis or ileus or megacolon associated with neurologic impairments including Parkinson's disease or multiple sclerosis or mental retardation or spinal cord injury, post-operative ileus, including but not limited to prolonged post-operative ileus in which typical timelines for recover}' from a post-operative ileus state, such as 3 to 5 days, are not met, other conditions of gastrointestinal dysmotility as either primary or secondary conditions, for the latter of which one non-limiting example is pancreatiti s-induced ileus.

[00104] Pancreatitis is another condition that can lead to not only gastric dysmotility but also dysmotility (i.e. impaired motility) throughout the GI tract, including the stomach, lower GI tract (e.g. the colon), and the small intestine, and/or to any combination of two of these three parts of the GI tract (stomach, small intestine and/or colon) or of all three of them (i.e. pan-GI dysmotility). Ileus is another term often used to describe dysmotility, irrespective of the location in the GI tract. In one aspect, the invention provides a method of treating ileus, including the ileus of pancreatitis, in a patient in need of treatment, comprising intravenously administering a therapeutically effective dose of a ulimorelin analogy three times daily for at least one day and usually two or more consecutive days. In some embodiments the patient is in the ICU.

[00105] Those of skill in the art upon contemplation of this disclosure and that of U.S.

Patent Nos. 7,491,695 (RE 42,624), 8,349,887; and 8,450,258, incorporated herein by- reference, will appreciate that the present invention includes methods as described in these patents but in which ulimorelin analog (including therapeutically equivalent formulations of molecules with similar activity) is administered as described herein. [00106] Accordingly, the present invention is also directed to ulimorelin analogs for use in the treatment or prevention of the indications as mentioned in the dosage regime as disclosed herein and the claims.

[00107] These and other aspects and embodiments of the invention may be better appreciated after consideration of the following examples.

[00108] EXAMPLES

[00109] Example 1 - Human Ghreli Release

[00110] Endogenous ghrelin blood levels are pulsatile. Ghrelin rises sharply prior to eating and declines post-prandially. This happens about three times a day in healthy individuals (see Cummings et al., Diabetes 50: 1714—1719, 2001). With reference to Figure 10, average plasma ghrelin concentrations over a 24 hour period in 10 human subjects consuming breakfast, lunch, and dinner is shown. Plasma samples were collected and tested at the time indicated by dashed lines, namely, 0800, 1200, and 1730 [figure adapted from: A Preprandial Rise in Plasma Ghrelin Levels Suggests a Role in Meal Initiation in Humans, Cummings et al., supra]. The methods of the invention provide superior efficacy over prior methods due, at least in part, to employing q8H (TID) administration, which mimics this naturally occurring cycle of the normal human ghrelin levels (with three spikes a day occurring at mealtimes, e.g., about every four to six hours). In addition, in the case of compounds, such as ulimorelin, that are bound by AAGP, TID administration can compensate for a short ulimorelin free drug half-life.

[00111] Example 2 - Clinical Study Results from Administering Ulimorelin to Healthy

Individuals Demonstrates Accelerated Gastric Emptying

[00112] This example describes two Phase 1 studies in healthy volunteers (LP101.-CL- 101 and LPlOl-CL-102) in which safety, PK, and pharmacodynamics (PD) of single and multiple (Q8H) doses of ulimorelin were evaluated. Healthy male and female volunteers aged 18 to 55 years participated in the trial. The objectives of the trial were to evaluate the safety, tolerability, and PK of single and multiple ascending IV doses of ulimorelin at higher doses than in prior studies; evaluate the PD of single and multiple ascending IV doses of ulimorelin, assessed by change in gastric emptying and growth hormone levels; and, explore the relationship between AAGP levels and total/free ulimorelin plasma concentrations. Liquid gastric emptying was studied to mimic tube-fed conditions in the ICU.

[00113] In the LPlOl-CL-101 trial, three cohorts were enrolled in a crossover design from the SAD to the MAD part of the study. The doses studied were SAD: 600, 900, and 1200 and MAD: 80, 150, and 300 ^ig/kg Q8H for seven days. In the LPlOl-CL-102 trial, the dose studied was 600 ug/kg Q8H for seven days. The following endpoints were measured: safety, P (total and free ulimorelin concentrations), AAGP levels, and PD. PD endpoints measured were gastric emptying by scintigraphic imaging (during the MAD part only), paracetamol absorption (LPlOl-CL-102 only) and growth hormone levels, and reduction in HR (LPl Ol-CL-102 only, though this was measured as a safety metric rather than PD endpoint in LPlOl-CL-101). See Figure 17.

[00114] The ulimorelin used was LP101 labeled as "2 mg/ml LP101. (Ulimorelin)

Concentrate For Dilution For Infusion." The stock product was a sterile, pyrogen-free solution of ulimorelin hydrochloride monohydrate (equivalent to 2 mg/mL of ulimorelin free base) in water for injection buffered to pH 4.5 with 10 mM acetate buffer, and containing dextrose for tonicity adjustment. The product was diluted into 5% dextrose in an IV bag under aseptic conditions for administration. All infusions occurred over 30 min, with volumes and concentrations adjusted to permit achieving the nominal dose for each subject in each dose group.

[00115] Dose limiting toxicity was not achieved, but protocol-defined dose escalation stopping criteria as defined as a moderate AE in the same SOC (system organ class) in at least 2 subjects, specifically infusion site irritation, was achieved at 300 μg/kg Q8H. No cases of infusion site irritation were noted at the 600 ^ig/kg Q8H dose studied in the LP 101- CL-102 study.

[00116] LPlOl-CL-101 was a Phase 1 study in Nottingham UK, in which 39 subjects received ulimorelin or placebo 30-minute IV infusion, with ulimorelin doses of 600, 900 and 1200 μg/kg as a single dose and 80, 150, and 300 iig/kg Q8H for 7 days. LPlOl-CL-102 was a follow on study in Lexington, Kentucky in which 12 subjects received ulimorelin or placebo 30-minute TV infusion at 600 ^ig/kg Q8H for 7 days.

[00117] Gastric emptying, as measured by the improvement in time relative to baseline it takes to empty 25% ( t25, aka GET25) and 50% (Δί50, aka GET 50) of the stomach contents, was improved at all MAD doses tested (ranging from 80 g/kg to 600 ^ig/kg Q8H). FIGURE 12 shows the results of the LPlOl-CL-101 and LPlOl-CL-102 studies individually. FIGURE 13 shows pooled results for both studies. FIGURES 14 and 15 show Emax plots for LPl Ol-CL-101 and LPlOl-CL-102, showing the relationship between ulimorelin free Cmax and improvement in the time for 50% liquid gastric emptying (Δί50) on Day 1 and Day 4 measured by scintigraphic imaging. As shown in FIGURE 15, EC₅₀ (concentration to achieve 50% of maximal effect) was observed at 0.62 ng/niL Cmaxfree to l . l ng mL Cmaxfree, with 49% and 35% improvements of t₅₀ at Ε_Π13Χ (maximal effect) on Days 1 and 4, respectively. As shown in FIGURE 13 the prokinetic effect of 600 μg/kg Q8H ulimorelin was preserved through Day 6 LPlOl-CL-102 study. The population (healthy volunteers) and enteral formula were the same in both studies.

[00118] Studies have been done to confirm that data from the LP lO l -CL-101 and LPlO l -CL-102 clinical trials could be combined notwithstanding that they were conducted on healthy populations in different countries, by different contract research organizations and using different scintigraphic scanning machinery. A variety of metrics evidence the consistency between the two studies including (i) overlapping GE response in placebos and to drug (overlapping exposure response based on free concentration/Cmax); (ii) AAGP level distribution in HV' s in the US study was slightly right- shifted compared to the UK study but otherwise nearly identical; the slightly higher AAGP Levels in US vs UK study corresponds to slightly lower free exposures.

[00119] While single doses of 600, 900, and 1200 μg/kg and multiple doses of 80, 150,

300, and 600 fig/kg were safe and well tolerated in healthy volunteer studies, a dose-related reduction in heart rate (HR) was observed at doses starting at 600 μg/kg. One episode of reduction in HR in the studies met the criteria for an adverse event (AE), No changes in vital signs were observed at the 80, 150, and 300 ,ug/kg Q8H doses. Mean decreases in sinus HR of -14% and -23% were observed at the 900 and 1200 ug/kg doses representing the exaggerated and expected pharmacologic impact of up-regulated vagal tone. Corresponding mean plasma Cmaxfree levels in healthy volunteers at these doses were 42 ng/mL and 74 ng/mL, respectively. At 600 μg/kg IV Q8H, a pattern of reduced HR was not observed, either on Day 1 or with repeat Q8H dosing at steady state, despite achieving Cmaxfree levels at steady state comparable to the 900 .ug/kg single dose. The slowing of HR, when observed, corresponded to the peak free concentration at the end of the 30-minute infusion, was shortlived and predictable, and reversed with the rapid decline in concentration following the end of the infusion. No changes in blood pressure (BP) were observed, and no intervention was required in any subject,

[0120] In healthy adults non-stimulated resting Growth Hormone (GH) levels vary between 0 and 0.5 μg L, and the mean spontaneous GH peak in healthy adults is approximately 3 μg/L. In healthy volunteers in the LPlOl-CL-101 and LPl Ol-CL-102 trials, GH spiked following administration of ulimorelin. Levels on Day 1 were meaningfully greater than those seen in placebo subjects at any time point (pooled placebo mean GH levels were 2.2 μg/L and ranged from about 0.1 to 1 1 ^ig/L). Over time, the spikes in GH levels diminished but remained measureable and within or slightly greater than the expected physiological range of the assay (0-0.8 μg L for males and 0-8 μg/L for females). Placebo peaks (if any) were random while ulimorelin peaks corresponded to drug administration with Tmax for peaks most often at 1 hr post dose.

[0121] Similar studies conducted with ulimorelin analogs dosed as described herein should demonstrate similar efficacy results,

[0122] Example 3 - Treatment of EFI Patients

[0123] A. Treatment of EFI with Ipamorelin; With Follow up Therapy

[0124] Patient 2, an adult female from a nursing home weighing 45 kg, arrives in the

ICU with delirium after having experienced urosepsis and spiking fevers to 103 degrees, and is placed on enteral feeding (EF) with a nasogastric tube by continuous drip in addition to therapeutic measures to treat her infection. Feeding is initiated at a rate of 20 mL/hour and advanced to a rate of 40 mL/hour after an 8 hour GRV measurement is 250 raL. A GRV taken twelve hours later reveals a GRV of 400 mL which is deemed excessive. The physician orders that the patient be placed on IV ipamorelin dosed at a dose of 0.025 mg/kg TID by IV infusion over 30 minutes with NGT feeding to continue uninterrupted. A subsequent GRV measured eight hours post initiation of therapy is deemed normal and feeding rate is advanced to 50 mL/hour, with continued administration of dmg prescribed. By day four the patient's mental status is significantly improved due to partial resolution of her infection and reduced fever and the NGT is removed to allow her to attempt to self-feed. However, she complains of anorexia and it is noted that her body weight is now 42 kg and she has clinical signs of moderate malnutrition. As such, the physician orders the patient to remain on therapy at the TID frequency due to the orexigenic and pro-anabolic effects of the therapy. Three days later, the patient is discharged from the ICU to the hospital wards where dosing frequency is reduced to BID due to significantly improved ad libitem food intake and then discontinued after another week of treatment, when the patient is released to the nursing home.

[0125] B. Prevention of EFI with Relamorelin

[0126] Patient 3, an adult male weighing 120 kg, arrives in the ICU after having experienced hip replacement surgery with complications leading to failure to extubate postoperatively, and is placed on enteral feeding (EF) with a nasogastric tube by continuous drip at a rate of 40 mL/hour. The physicians prescribes IV relamorelin dosed at a dose of 30 ug TID by IV bolus injection to that is begun concurrent with the initiation of feeding. NGT feeding is advanced successfully to the patient's prescribed target rate of 100 mL/hour. Treatment is discontinued after six days on therapy due to the patient being extubated and discharged from the ICU.

[0127] C. Treatment of EFI with TZP-102

[01:28] TZP-102 may be an AAGP binder. WO 2016/077498 teaches that a physician may reasonably expect a significant number of EFI patients to be safel and efficaciously dosed by a single "standard" dose of ulimorelin, despite its being an AAGP binder. In accordance with the invention, if an ulimorelin analog binds AAGP, then a standard dose can be calculated for it, as demonstrated in WO 2016/077498. For compounds like TZP-102 that are expected to be close structural analogs of ulimorelin with generally similar molecular weight and potency, but for which AAGP and relevant bioactivity data is non-existent or limited, a dose can be calculated from ulimorelin dosing data. Once demonstrated safe and effective in a clinical trial, this dose may be used to initiate therapy even without having checked AAGP levels.

[0129] In such an illustrative case, a physician treating Patient 4, an adult male weighing 60 kg who arrives in the ICU after having experienced cardiac arrest with resuscitation, intubation and mechanical ventilation, places the patient on enteral feeding (EF) with a nasogastric tube by continuous drip at 20 mL/hour on the patient's second ICU day. A GRV measurement ordered taken 6 hours after feeding begins is 200 mL, and the feeding rate is advanced to 40 mL/hour. A GRV taken 6 hours later is 350 mL, and the feeding rate is advanced to 60 mL/hour. A measurement performed 6 hours later reveals an excessive GRV of 500 mL. The physician orders that the patient be placed on IV TZP-102 dosed at a dose of 575 ug/kg TED by IV infusion over 30 min with NGT feeding to continue uninterrupted but at a reduced rate of 40 mL/hour concurrent with the first dose administered. After 6 hours on therapy, the GRV is measured again and found to be 200 mL, at which point the physician orders nutrition advanced back to 60 mL/hour with continued administration of drug. Feedings and TZP-102 therapy are both stopped on day 4 in preparation for a CABG operation which, when performed, the patient did not survive,

[0130] More generally and for any ulimorelin analog that binds AAGP and is a close structural analog of ulimorelin with similar bioactivity and potency (and molecular weight, which is typically similar between close structural analogs of ulimorelin), one may start dosing as low as 300 ,ug/kg, but more typically at a dose closer to 600 ,ug/kg, the ideal ulimorelin dose. In some cases the physician may proceed to continue dosing without checking AAGP at ail, if satisfied with efficacy as indicated by resolution of EFI and with safety, where the assessment of the former will typically be done by noting an ability to provide enteral feeding successfully at a desired infusion rate (in mL/hour or some functionally similar measure) without provoking a return of EFI (as measured by however the physician chooses to measure, but potentially including GRV, abdominal distension or any of other methods cited elsewhere herein), and, the assessment of the latter by the absence of an undesirable slowing of heart rate for which there is no other obvious cause other than being an ulimorelin analog side effect. If the physician is unsatisfied with efficacy, has concerns about safety, or, for other reasons related to patient clinical course, such as described below, elects to measure AAGP, he or she may, in some cases, do so at any time during treatment.

[0131] For ulimorelin analogs that do not bind AAGP to a clinically meaningful or significant degree, the physician simply identifies a patient in need of treatment, including a patient in the ICU that is on enteral feeding but has not yet developed EFI - in which case the physician is treating to prevent EFI - or has been diagnosed as having the same. Treatment is continued as described herein (typically TID IV administration) until the condition resolved. As described, continued administration thereafter is optional and may provide a variety of therapeutic benefits whether dosed qD, BID, or TID, and including subcutaneous and IV dosing, provided that while the patient remains in the ICU, IV is the preferred route of administration. In these post treatment embodiments, the physician is typically seeking the therapeutic benefit of increased muscle mass in the patient, it being understood by those of skill in the art that while the emphasis of the discussion herein has been the use of ulimorelin analogs to stop or prevent the loss of muscle, in some instances, "stopping the loss" includes providing a net gain in muscle mass from start of therapy to end of therapy. The following example provides a clinical trial protocol and various indicia of therapeutic benefit of patients receiving therapy as described herein to slow the loss of muscle,

[0132] Example 4 - Treatment of Patients to Prevent or Slow Loss of Muscle Mass

[0133] This example provides a protocol for a clinical trial that could be conducted as a multi center, randomized, double-blind study of the effects of an IV ulimorelin analog on skeletal muscle and muscle protein metabolism in patients with acute respirator}' distress syndrome (ARDS). In short, the study is intended to demonstrate the therapeutic benefit of administering a ulimorelin analog in accordance with the methods of the invention not just to ARDS patients but to any patient at risk of muscle loss for which therapeutic intervention is warranted.

[0134] A total of 20 evaluable patients, randomized 1 : 1 to ulimorelin or placebo, should be sufficient to meet the efficacy objectives of this study, providing approximately 10 evaluable patients per treatment arm. If up to 50% of patients who are randomized will not be evaluable, a reasonable assumption, a total of approximately 40 patients will be enrolled.

[0135] The primar' efficacy objective is to demonstrate that the effect of a ulimorelin analog on muscle protein fractional synthesis rate (MPFSR) in skeletal muscle tissue in mechanically ventilated and tube-fed patients with ARDS is therapeutically beneficial, resulting in a conclusion that the ulimorelin analog provides a therapeutic benefit in reducing the amount of muscle loss and slowing the rate at which it occurs in these at risk patients. In various embodiments of the invention, a patient is administered the ulimorelin analog to preserve muscle (prevent loss of muscle/muscle mass), and MPFSR or another indicator of muscle anabolism (or catabolism) will be measured to determine if the therapy is having a beneficial effect.

[0136] The following can be assessed as secondary objectives for demonstration of efficacy in accordance with the invention and in this study: (a) ultrasound of the quadriceps and/or diaphragm; (b) preservation of skeletal muscle mass as measured by D₃-creatine dilution and/or by 24 hour urinary creatinine excretion; (c) skeletal muscle protein degradation by 24 hour urinary 3-methyhistidine (3-me-His) excretion; (d) whole body N balance by 24 hour urinary total nitrogen (N) excretion; and (e) plasma muscle protein fractional synthesis rate (PPFSR) by measuring plasma levels of circulating skeletal muscle- derived proteins, such as CK-M, carbonic anhydrase-3.

[0137] The ulimorelin analog study drug is diluted in D5W for delivery of 50 mL, or placebo (D5W) 50 mL, administered intravenously (IV) over 30 minutes every 8 hours (Q8H) for 10 days.

[0138] ARDS patients that have been ventilated for 3 to 5 days, are expected to remain intubated for an additional 10 days, and meet study inclusion/exclusion criteria may enter the study. Study procedures will be performed after informed consent (by proxy if the patient is unable to provide valid informed consent) is obtained. Throughout the study, patients will receive treatment for their underlying medical conditions according to the local standard of care. D3-creatine (30 mg) will be administered NG on Days 1 and 8 for the assessment of muscle mass. 50 mL of 70% D20 will be administered NG TID on Days 1 - 6 and BID Days 7 - 10 for MPFSR and PPFSR assessments, Pre-treatment and post-treatment muscle mass will be determined by a spot urine collection for D3-creatinine on Days 3 and 10 and by 24-hour urinary creatinine collections on Days 1, 2, 5, 6, 9, and 10. Microbiopsy of the vastus lateralis will be obtained on days 5 and 10 for MPFSR. Blood samples will be taken simultaneously for PPFSR of circulating muscle proteins. Spot urine collections will be obtained for isotope background rates and equilibrium and Days 1 (predose), 4, 6, 8, and 10. N-balatice and rate of muscle protein degradation (3-MeHis excretion) will be assessed from 24-hr urine collections taken on days 1, 2, 5, 6, 9, and 10. Ultrasound of the quadriceps and diaphragm muscle cross-sectional area will be performed on Day 1, 5, and Day 10. Blood samples for plasma ulimorelin analog levels will be collected minimally on Days 1, 5, and 10 at predose and at 0.5 and 24 hr post any daily infusion; the predose samples will be split for the determination of alpha- 1 acid glycoprotein (A AGP) levels.

[0139] Dietary intake of protein and calories will be measured daily. Feedings will target a minimum protein intake of 1.2 g/kg/day with no upper limit and may be provided by any combination of enteral or parenteral routes of administration. Patients who receive enteral nutrition will be fed according to a volume-based feeding protocol,

[0140] Patients will be followed for AE's and new pulmonary infections for 3 additional days for follow up (through Day 13). Patients who prematurely terminate the study will undergo early termination procedures. The duration of mechanical ventilation, ICU and hospital stay, and 30-day mortality will be recorded from the patients record.

[0141] Admissible patients for a study can include these criteria; age > 50 y; moderate to severe ARDS (Berlin Definition); mechanically ventilated for at least 72 hours in ICU and less than 5 days; receiving enteral or parenteral nutrition; and expected to be ventilated for 10 or more days.

[0142] Twenty (20) evaluable patients (10 in the ulimorelin analog arm and 10 in the placebo arm) are required to provide 80% power with a two-sided alpha of 0.05 to demonstrate the superiority of ulimorelin analog versus placebo with respect to the primary endpoint (muscle protein fractional synthesis rate (MPFSR)). This estimate assumes a within group standard deviation (SD) of 0.25%/hr, with no change in MPFSR in the placebo group, and a 0.3%/hr increase with ulimorelin analog treatment due to increased enteral delivery of protein, enhanced growth hormone, and insulin-like growth factor-1 (IGF-1) secretion, and/or reduced systemic inflammation. An evaluable patient is defined as completing 10 days of treatment with study drug and the vastus lateralis muscle biopsy on Day 0.

[0143] The primary endpoint for this study is skeletal muscle MPFSR on Day 10 in ulimorelin analog treated patients compared to placebo, with secondar endpoints of: changes in muscle mass by US of the quadriceps and diaphragm, analyzed separately, on Day 10 compared to baseline (Day 1), changes in muscle mass by US of the quadriceps and diaphragm, analyzed separately, on Day 5 compared to baseline (Day 1); change in muscle mass by D3 -creatine dilution on Day 10 compared to baseline (Day 3); changes in muscle mass by mean 24-hour urinary creatinine excretion on Days 9 and 10 compared to baseline (mean of Days 1 and 2); changes in muscle mass by mean 24-hour urinary creatinine excretion on Days 5 and 6 compared to baseline (mean of Days 1 and 2); skeletal muscle protein degradation by mean 24-hour urinary 3-me-His excretion on Days 9 and 10 compared to baseline (mean of Days 1 and 2) and mean 24-hour urinary 3-me-His excretion on Days 5 and 6 compared to baseline (mena of Days 1 and 2); whole body N balance by mean 24-hour urinary N excretion on Days 9 and 10 compared to baseline (mean of Days 1 -2) and mean 24- hour urinary N excretion on Days 5 and 6 compared to baseline (mean of Days 1-2).

[0144] Other indicia of efficacy may be evaluated as exploratory endpoints include dietary intake of protein and calories; occurrence of pulmonary infections; duration of mechanical ventilation, ICU, and hospital stay, all cause 30-day mortality; and (diminished) use of prokinetic agents and treatments and small bowel feedings.

[0145] Example 5 - Treatment of Patients Having Conditions Associated With Loss of

Muscle Mass

[0146] A. Prevention and Treatment of pre-existing of Muscle Loss with Ipamorelin

[0147] Patient 1, an emaciated adult female residing in a nursing home and weighing

40 kg, arrives in the ICU after having experienced pneumonia, and is placed on TPN. The physician orders that the patient be placed on IV ipamorelin dosed at a dose of 0.025 mg/kg TID by IV infusion over 30 min. She gains 3 kg body weight over the next five days and treatment is continued until ICU discharge on day 6.

[0148] B. Treatment of Chronic Muscle Loss with Relamorelin

[0149] Patient 2, an adult male weighing 50 kg, is on dialysis for chronic renal failure three times per week (MWF). The patient has difficulty ambulating due to proximal leg muscle weakness and reports poor appetite. His physician orders IV relamorelin dosed at a dose of 30 ug IV bolus injection into the patient's AV fistula at the end of each dialysis treatment.

[0150] C. Prevention of Muscle Loss with TZP-102

[0151] Patient 3, an 82 year old previously healthy woman is admitted during flu season to an ICU with viral pneumonia. Her condition worsens and on day 2 she is intubated, at which time an NGT is inserted. Two days later enteral feeding is initiated but only at a rate of 40 mL/hour. Though she tolerates the feeds the rate is never increased. Ten days later she is discharged from ICU post extubation to the hospital wards, but while there and continuing to recover from the infection/infiltration, is observed to have lost significant weight, lean body mass and muscle mass. When told she "needs to eat", she reports that she has no appetite. Her physician prescribes TZP-102 to be administered at a dose of 600 ug/kg IV TDD. After two days of dosing, the patient reports an approved appetite but complains about the injections, which are reduced to BID the next day, then to qD once per day until the day of the patient's discharge, when treatment is stopped.

[0152] D. Prevention of Muscle Loss with a Ulirnorelin Analog

[0153] Patient 4, a 60 year old man presenting with cirrhosis, a distended abdomen and mental status changes including delirium and combativeness is admitted to the ICU where he is observed to have significant edema and fluid retention. A CT scan confirms portal hypertension and profound ascites. The patient is sedated and an NGT is inserted and enteral feeding begun. Feedings are tolerated and advanced without evidence of EFI but the patient becomes septic and has a protracted course over the next ten days during which time feeding are often held. During this time the patient ascites are tapped resulting in a decrease in total body weight of 5 kg. Diuretics result in a further decrease of 5 kg consistent with a reduction in peripheral edema. The patient survives and feedings are resumed successfully on day 14 at which time the physician notes that the patient's body weight is 16 kg less than on admission, consistent with drainage of large amount of fluid and with significant additional loss of muscle mass above and beyond the changes in lean body mass. To begin to address this loss of muscle mass the physician orders treatment with uiimorelin analog TID at a dose suitable for the analog as described above. Treatment continues for 15 days, 6 of which are while the patient is in the ICU, during which time his edema is successfully managed and his total body weight falls by a further 1 kg. During the remaining 9 days on the hospital floor he gains 5 kg while receiving physical therapy, half of which is deemed to be renewed edema due to weaning from diuretics with the rest deemed to be increased muscle mass.

[0154] As these hypothetical patient examples are intended to illuminate, and more generally, any patient being treated in accordance with the invention for a purely anabolic effect (a patient whom has no motility problem that precludes providing appropriate amounts of food), more frequent drug administration is better, but even qD administration provides some benefit, and with TID being a the preferred frequency for most patients.

[0155] Patients receiving anabolic therapy exclusively include, without limitation, chronic renal failure patients undergoing chronic dialysis, virtually all of whom have permanent IV access (via vascular shunts or other indwelling device), whom often suffer from anorexia and some degree of cachexia, and have suboptimal muscle mass. Such patients typically are dialyzed every other day. For these patients, while TID administration of an uiimorelin analog would be more efficacious than BID or qD, therapeutic benefit can be obtained in accordance with this aspect of the invention even if the patient receives an administration of a ulimorelin analog at a dose described herein ever}' other day (qOD) or three times a week, e.g. ideally at the end of each dialysis session.

[0156] Moreover, many patients, including those on chronic dialysis but also those who are either critically ill or recovering from critical illness, have decreased appetite. While patients without appetite and so at risk of muscle loss would benefit optimally from TID administration of ulimorelin analog, even qD or BID administration may stimulate the patient's appetite sufficiently to preserve muscle that would otherwise be lost in the absence of therapy. While for ICU patients fed passively (via NGT) appetite is irrelevant, it is vital for a self-feeding patient in need of nutrition, and ulimorelin analogs dosed as described herein to preserve muscle and prevent muscle loss in such patients will stimulate the appetite of such patients and so have the intended therapeutic effect.

[0157] The present invention may be embodied in other specific forms without departing from its structures, methods, or other essential characteristics as broadly described herein and claimed hereinafter. The described embodiments and examples are to be considered in all respects only as illustrative, and not restrictive. The scope of the invention is, therefore, indicated by the appended claims, rather than by the foregoing description. All changes that come within the meaning and range of equivalency of the claims are to be embraced within their scope.

Claims

1. A method of treating enteral feeding intolerance (EFT) in a patient in need of treatment, said method comprising administering to said patient a therapeutically effective dose of ulimorelin analog by intravenous infusion three times daily for one or more consecutive days.

2. The method of claim 1 wherein the ulimorelin analog is relamorelin, ipamoreiin, or TZP-102.

3. A method of accelerating the rate of gastric emptying or treating delayed gastric emptying in a patient, said method comprising administering by intravenous infusion ulimorelin analog three times daily to a patient in need of treatment.

4. A method of treating a patient in an unhealthy catabolic state and/or providing anabolic benefit, said method comprising administering by intravenous infusion ulimorelin analog three times daily to a patient in need of treatment.

5. A method of preventing or slowing lean body mass loss in a patient, said method comprising administering by intravenous infusion ulimorelin analog three times daily to a patient in need of treatment.

6. A method of reducing net sympathetic tone in a patient, said method comprising administering by intravenous infusion ulimorelin analog three times daily to a patient in need of treatment.

7. The method of claim any of claims 4 to 6, wherein said patient is suffering from enteral feeding intolerance or is on enteral feeding.

8. The method of any of claims 4 to 6, wherein said patient is not receiving enteral feeding.

9. The method of any of claims 4 to 6, wherein the patient is a prematurely born infant.

10. The method of any of claims 4 to 6, wherein said patient is suffering from cachexia.

1 1. Use of ulimorelin analog to treat enteral feeding intolerance by intravenous administration.

12. Use of ulimorelin analog to accelerate the rate of gastric emptying or treating delayed gastric emptying in a patient by intravenous administration.

13. Use of ulimorelin analog to treat a patient in an unhealthy catabolic state and/or providing anabolic benefit by intravenous administration.

14. Use of ulimorelin analog to prevent or slow lean body mass loss, or to increase lean body mass, in a patient said by intravenous administration.

15. Use of ulimorelin analog to reduce net sympathetic tone in a patient by intravenous administration.

16. A formulation of ulimorelin analog suitable for intravenous administration to a patient suffering from enteral feeding intolerance.

17. Ulimorelin analog for use in the treatment of enteral feeding intolerance (EFI) in a patient in need of treatment by administering to said patient a therapeutically effective dose of ulimorelin analog by intravenous infusion three times daily for one or more consecutive days.

18. Ulimorelin analog for use in accelerating the rate of gastric emptying or treating delayed gastric emptying in a patient, said method comprising administering by intravenous infusion ulimorelin analog three times daily to a patient in need of treatment.

19. Ulimorelin analog for use in treating a patient in an unhealthy catabolic state and/or providing anabolic benefit, by administering by intravenous infusion ulimorelin analog three times daily to a patient in need of treatment.

20. Ulimorelin analog for use in preventing or slowing lean body mass loss, or increasing lean body mass in a patient by administering by intravenous infusion ulimorelin analog three times daily to a patient in need of treatment.

21. Ulimorelin analog for use in reducing net sympathetic tone in a patient by administering by intravenous infusion ulimorelin analog three times daily to a patient in need of treatment.

22. Ulimorelin analog for the use of any of claims 18 to 21, wherein said patient is suffering from enteral feeding intolerance or is on enteral feeding.

23. Ulimorelin analog for the use of any of claims 18 to 21, wherein said patient is not receiving enteral feeding.

24. Ulimorelin analog for the use of any of claims 18 to 23, wherein the patient is a prematurely born infant.

25. Ulimorelin analog for the use of any of claims 18 to 34, wherein said patient is suffering from cachexia.

26. A method of preventing or slowing muscle loss in a patient, said method comprising administering by intravenous infusion a ulimorelin analog three times daily to a patient in need of treatment.

27. Use of a ulimorelin analog by intravenous administration to prevent or slow muscle loss, or to increase muscle mass in a patient.

28. Ulimorelin analog for use in preventing or slowing muscle loss, or increasing muscle mass in a patient by administering by intravenous infusion times daily to a patient in need of treatment.

29. Method, use, or ulimorelin analog of claims 26, 27, and 28, respectively, wherein the patient suffers from clinically significant visceral organ or peripheral edema, or the patient is suffering from a loss of appetite, or the patient is on kidney dialysis.

30. A method of treating enteral feeding intolerance, said method comprising administering ulimorelin analog three times daily.