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The Oncologist, Vol. 12, No. 5, 594-600, May 2007; doi:10.1634/theoncologist.12-5-594
© 2007 AlphaMed Press

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Symptom Management and Supportive Care

Effect on Body Weight and Safety of RC-1291, a Novel, Orally Available Ghrelin Mimetic and Growth Hormone Secretagogue: Results of a Phase I, Randomized, Placebo-Controlled, Multiple-Dose Study in Healthy Volunteers

Jose M. Garciaa, William J. Polvinob

aDivision of Diabetes, Endocrinology and Metabolism, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas, USA; bSapphire Therapeutics, Inc., Bridgewater, New Jersey, USA

Key Words. Ghrelin • Anorexia • Cachexia • Cancer

Correspondence: Jose M. Garcia, M.D., Department of Medicine, MEDVA Medical Center, 2002 Holcombe Boulevard, Houston, Texas 77030, USA. Telephone: 713-794-7989; Fax: 713-794-7771; e-mail: Jgarcia1{at}bcm.tmc.edu

Received November 10, 2006; accepted for publication February 11, 2007.


   ABSTRACT
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 Abstract
Introduction
 Methods
 Results
 Discussion
 Disclosure of Potential...
 Acknowledgments
 References
 
Purpose. RC-1291 is a novel, oral ghrelin mimetic and growth hormone (GH) secretagogue being developed to increase appetite and lean muscle mass in patients with cancer-associated anorexia/cachexia. This randomized, double-blind, placebo-controlled, multiple-dose, dose-escalation phase I study in healthy volunteers evaluated RC-1291 once daily (qd) and twice daily (bid) for effect on body weight and safety.

Methods. The study was conducted with three sequential groups of volunteers. Panel A subjects (n = 8) received placebo or RC-1291, 25 mg qd, for 5 days. Panel B subjects received RC-1291, 25 mg bid or 50 mg qd, for 6 days then crossed over to the other dosage for 5 days (n = 12); three subjects received placebo for all 11 doses to maintain double-blinding. Panel C subjects (n = 9) received placebo or RC-1291, 75 mg qd, for 6 days.

Results. Subjects who received RC-1291, 50 or 75 mg, had significant dose-related weight gain after 6 days versus placebo, with the greatest increases seen with daily dosing. The mean increase in weight from baseline after 50 mg qd was 1.25 ± 0.725 kg (p = .0022 versus placebo), and after 75 mg qd it was 1.16 ± 0.651 kg (p = .0022 versus placebo). One subject in the 50 mg qd group had moderate transient elevation in aspartate aminotransferase and alanine aminotransferase levels. No other laboratory or clinical adverse events of consequence were reported.

Conclusions. Results indicate that RC-1291 produces dose-related increases in body weight with no dose-limiting adverse effects, and may be an effective treatment for anorexia/cachexia.

Disclosure of potential conflicts of interest is found at the end of this article.


   INTRODUCTION
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Disclosure of Potential...
 Acknowledgments
 References
 
Anorexia/cachexia is a prevalent syndrome in cancer patients, especially in late-stage disease [1–3], and is associated with poor prognosis and early death [4, 5]. Up to 80% of terminally ill patients with cancer develop anorexia and cachexia, which may be the direct cause of death in some [6]. Multiple mechanisms have been implicated in the pathogenesis of anorexia/cachexia including metabolic abnormalities and the activation of proinflammatory cytokines such as interleukin-6 (IL-6), IL-1ß, and tumor necrosis factor alpha [7–11]. Cachexia, which is manifested as loss of both adipose tissue and lean skeletal muscle, disrupts many body systems and is associated with low insulin-like growth factor-1, anemia, insulin resistance, immunosuppression, and activation of an acute-phase response [12]. Given the prevalence of anorexia/cachexia, and the severe toll it takes on quality of life and survival in these patients [13], effective treatment should be a critical component of patient management but remains elusive.

Ghrelin, a 28-amino acid peptide secreted mainly from the stomach, was isolated in 1999 as the endogenous ligand for the growth hormone secretagogue receptor (GHSR) [14, 15]. Studies have suggested that ghrelin plays an important role in regulating metabolic balance by decreasing fat use through growth hormone (GH)-independent mechanisms and causing potent stimulation of food intake via activation of neuropeptide Y neurons in the hypothalamic arcuate nucleus [16–20]. Recently it was unambiguously demonstrated through experiments on GHSR knockout mice that GHSR mediates ghrelin's GH-releasing and orexigenic properties [21]. Ghrelin administration can antagonize the effect of cytokines on appetite and body weight. Intraperitoneal administration of ghrelin blunts the anorectic and weight-reducing effects of IL-1ß administration [22, 23] and induces increases in food intake and body weight in animal models of cancer-induced cachexia [24, 25].

Although ghrelin appears to play an important role in stimulating appetite and food intake, therapeutic use of ghrelin is limited because it is a protein with a very short half-life and must be administered by injection. RC-1291 is an orally active ghrelin mimetic and GHSR agonist that, in cancer patients, is expected to increase appetite by virtue of its ghrelin agonist properties and produce anabolic partitioning of nutrients to increase lean body mass, thereby offering a potential new therapy for the treatment of cancer-related anorexia/cachexia. In the phase I study in healthy volunteers reported here, single and multiple doses of RC-1291 were evaluated for effects on body weight, safety, and tolerability.


   METHODS
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 Abstract
 Introduction
 Methods
Results
 Discussion
 Disclosure of Potential...
 Acknowledgments
 References
 
Study Design
This was a single-center, randomized, double-blind, placebo-controlled, multiple-dose, dose-escalation study conducted in three sequential panels of healthy volunteers. The dosing regimen for each panel is shown in Table 1. Escalation to the next panel was based on review of the clinical safety data, including adverse events, electrocardiograms (EKGs), vital signs, and laboratory safety studies. Subjects remained sequestered at the clinical research center during the study. Study drug was administered in the fasted state and no food was allowed for 30 minutes following dosing. Thereafter, subjects were allowed to eat ad libitum during the study. All clinical investigation described in the paper was conducted in accordance with the guidelines in The Declaration of Helsinki.


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  		Table 1. Planned dosing regimen for study

 
Subjects
Volunteers were accepted if they fulfilled the following criteria: healthy males or surgically sterile females between the ages of 18 and 40 years with body weight 50–100 kg and body mass index (BMI) within 18–29 kg/m2; no condition that would prevent proper evaluation of the safety or efficacy of the study drug; no significant medical abnormality, including any condition that may have interfered with the absorption, metabolism, or elimination of the study drug; no clinically significant laboratory or cardiac abnormality; did not participate in a clinical study with an investigational agent within the 30 days prior to study treatment; and received no concomitant medication within 48 hours of study treatment.

Assessments
Subjects were screened up to 3 weeks before treatment. Prestudy assessments included morning body weight, vital signs, baseline EKG and clinical laboratory values, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total bilirubin, creatinine, calcium, blood urea nitrogen, glucose, sodium, potassium, chloride, CO2, albumin, and total protein. During the study, body weight was recorded each morning; safety was monitored by recording adverse events, clinical laboratory values, vital signs, and EKG. Poststudy assessments (10–14 days after discharge) included follow-up medical history, vital signs, body weight, clinical laboratory values, and any adverse events since discharge.

Adverse events were defined as any unfavorable event that occurred after administration of study drug, whether or not it was considered to be related to the study drug, or worsening of a pre-existing condition. Adverse events were categorized as asymptomatic (a laboratory abnormality or physical sign evident only on diagnostic testing), mild, moderate, or severe.

Statistical Analyses
All statistical analyses were performed using the SAS for Windows statistical package (version 8.2 or higher, SAS Institute, Inc., Cary, NC). Demographic and baseline characteristics were summarized descriptively by treatment group using n, mean, range, and standard deviation for continuous variables and frequencies for categorical variables. p-values were calculated using one-way analysis of variance for continuous variables and Fisher's exact test for categorical variables. All statistical tests were performed as two-tailed tests, and all effects were considered to be statistically significant if p ≤ .05.

Safety was evaluated from reported adverse events, abnormal clinical laboratory values, changes in EKG parameters (including QTc interval), and vital signs. Vital signs and EKG results were summarized descriptively; each active dose was compared with placebo using a paired t-test; abnormal laboratory results were summarized descriptively by treatment.


   RESULTS
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 Abstract
 Introduction
 Methods
 Results
Discussion
 Disclosure of Potential...
 Acknowledgments
 References
 
All subjects provided informed consent prior to any study procedure. Thirty-two subjects were enrolled, randomized, and treated: eight subjects in panel A (placebo, n = 2; RC-1291, n = 6); 15 subjects in panel B (placebo, n = 3; RC-1291, 50 mg qd crossed over to 25 mg bid, n = 6; RC-1291, 25 mg bid crossed over to 50 mg qd, n = 6); and nine subjects in panel C (placebo, n = 1; RC-1291, n = 8). All subjects completed the study. Patient demographics and characteristics were similar and any differences among treatment groups were not considered clinically relevant (Table 2).


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  		Table 2. Subject demographics and characteristics

 
Effect on Body Weight
Significant weight gains (p < .05 versus placebo) were recorded in subjects who received RC-1291, 50 mg qd (or 25 mg bid) or 75 mg qd, beginning on day 2 of treatment and continuing in these dose groups until the end of treatment. As shown in Figure 1, the mean increase in weight from baseline to day 6 after 50 mg qd was 1.25 ± 0.725 kg (p = .0022 versus placebo), and after 75 mg qd it was 1.16 ± 0.651 kg (p = .0022 versus placebo).


Figure 1
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  		Figure 1. Mean weight changes over time from baseline to end of treatment. Significant mean weight increases from baseline to day 6 versus placebo were noted at all postbaseline measurements for subjects who received RC-1291 at doses of 25 mg bid (p < .0375), 50 mg qd (p < .0031), and 75 mg qd (p < .0022).

Abbreviations: bid, twice daily; qd, once daily.

 
Subjects in panel B continued to receive RC-1291 at 50 mg qd or 25 mg bid for 11 days. The mean increase in body weight for this cohort was 2.23 ± 0.936 kg (p = .0267 versus 11-day placebo). There was no advantage in terms of weight gain for the split-dose regimen, as body weight increases were greater during the once-daily dosing (50 mg qd) crossover regimen in panel B compared with the split-dosing regimen (25 mg bid).

Safety
Adverse events that occurred during the study are presented in Table 3. There was no pattern suggestive of dose-related adverse events, and all adverse events were assessed by the investigator as mild or moderate in intensity except for one event of severe headache reported in the 75-mg-qd group that was not considered related to study drug. None of the participants developed edema, other signs or symptoms of fluid overload, carpal tunnel syndrome, or hyperglycemia.


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  		Table 3. n (%) of subjects reporting clinical adverse events by system organ class

 
RC-1291 had a small and inconsistent effect on heart rate throughout the treatment period, without apparent relationship to RC-1291 dose or duration of treatment. Small decreases and occasional increases in systolic and diastolic blood pressure were noted following RC-1291 administration on day 1 (nadir change, 16 ± 11 mmHg for systolic blood pressure and –10 ± 7 mmHg for diastolic blood pressure). However, these effects were not seen on day 5/6 or day 11. Effects on heart rate and blood pressure were modest and without clinical consequence. The majority of the 12-lead EKG readings obtained prestudy, at admission to the clinical study unit, and at the approximate time of peak plasma drug concentration (1 hour postdose [±15 minutes]) on each of the dosing days were interpreted as normal or normal variants by the reader; abnormal readings were considered not clinically significant, with no suggestion of drug-related effects.

Discolored feces was the most common adverse event considered possibly or probably related to study drug treatment and occurred in groups receiving placebo (one subject), RC-1291 at 50 mg qd (two subjects), and RC-1291 at 25 mg bid (two subjects). Of note, all of these events occurred during the same treatment panel, panel B, which took place during a hurricane emergency and power outages. Thus, the possibility exists that discolored feces was a result of an environmental factor (e.g., a particular item in the diet), particularly given the complete absence of similar reports during either panel A or panel C.

One subject who received RC-1291 at a dose of 50 mg (panel B, 25 mg bid followed by 50 mg qd) had moderate elevations in AST and ALT levels (3–4 times above the upper limit of normal) assessed by the investigator as related to study drug treatment. ALT and AST normalized upon discontinuation of the drug. Other adverse events considered possibly related to study drug were: RC-1291, 25 mg qd, nausea (one subject), headache (one subject), and feeling hot (one subject); RC-1291, 50 mg qd, stomach discomfort (one subject); RC-1291, 25 mg bid, headache (one subject). One subject who received RC-1291 at 75 mg qd reported diarrhea considered probably related to study drug.


   DISCUSSION
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 Abstract
 Introduction
 Methods
 Results
 Discussion
Disclosure of Potential...
 Acknowledgments
 References
 
Current interventions to treat anorexia and cachexia in the cancer population are suboptimal and there is no U.S. Food and Drug Administration–approved treatment for this condition. Hypercaloric feeding is an aggressive management that has not been shown to increase lean muscle mass [26]. Studies of corticosteroids have shown limited effect on appetite and food intake [27, 28], and are used most often in the palliative setting and to control nausea, asthenia, and pain [29]. Progestational agents such as megestrol acetate and medroxyprogesterone have shown limited efficacy [29] and are perhaps the most widely employed but have only been shown to increase fat mass, have no impact on quality of life, and may be associated with serious side effects including deep venous thrombosis and adrenal insufficiency. A host of other treatments are under investigation including eicosapentanoic acid (EPA), cyproheptadine, thalidomide, beta-2 adrenoceptor agonists, and nonsteroidal anti-inflammatory drugs [5, 29].

Since the discovery of ghrelin in 1999 [14], its orexigenic properties have been investigated in preclinical [16–25] and clinical [30–32, 33] trials. In one clinical study, healthy subjects demonstrated acute and significant increases in appetite of almost 50% following administration of ghrelin, compared with placebo [33]. In addition, when provided access to food, the subjects who received ghrelin ate nearly 30% more food. Interestingly, in a study of patients with cancer-induced cachexia, plasma ghrelin levels were found to be elevated despite poor appetite and weight loss [30]. However, pharmacologic ghrelin infusion induced a 30% increase in food intake and appetite, compared with placebo in another study of cancer patients with anorexia [31]. These results suggest that elevation of endogenous ghrelin in cancer patients is an inadequate compensatory response to weight loss and that cancer subjects are still responsive to exogenous ghrelin administration.

RC-1291 HCl is an orally active ghrelin mimetic and GH secretagogue that may offer significant potential to treat cancer anorexia/cachexia. A recently reported phase I randomized, double-blind, placebo-controlled single dose-rising study in healthy male volunteers demonstrated that RC-1291 effectively stimulated appetite and food consumption [32]. In this study, RC-1291 was shown to induce a significant increase in appetite and food intake at doses of 25 and 50 mg, compared with placebo.

The phase I placebo-controlled, randomized study in healthy volunteers reported here was conducted to evaluate the effect on body weight and safety of RC-1291. Significant increases in body weight, compared with placebo, were observed in the 50 mg per day (qd or bid) and 75 mg qd treatment groups. The fact that body weight increases were greater during the once-daily dosing (50 mg qd) crossover regimen in panel B, compared with the split-dosing regimen (25 mg bid), suggests that the peak rather than the trough level of the drug is most important in inducing weight gain and that there is no advantage to splitting the daily dose of RC-1291 to achieve optimal weight gain. Although body composition was not assessed, the fact that no signs of fluid overload were detected throughout the study suggests that the increase in body weight was a result of an increase in lean and/or fat mass.

Multiple doses of RC-1291 (25–75 mg per day administered for 5 to 11 days) were well tolerated by these healthy young adult male and female subjects. Clinical adverse events revealed no findings of any clinical consequence. The laboratory and EKG data similarly revealed no evidence of any toxicity, with the exception of transient, moderately elevated AST and ALT levels in one subject.

Overall, this phase I study demonstrated that RC-1291 is well tolerated and is effective in promoting weight gain. Phase II studies with RC-1291 in cancer patients are ongoing to further define the efficacy and tolerability of this novel, orally available ghrelin mimetic and GH secretagogue for the treatment of cancer-associated anorexia and cachexia.


   DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Disclosure of Potential...
Acknowledgments
 References
 
J.M.G. has performed contract work as Principal Investigator for a Sapphire Therapeutics, Inc.–funded clinical study. W.J.P. owns stock in Sapphire Therapeutics, Inc.


   ACKNOWLEDGMENTS
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Disclosure of Potential...
 Acknowledgments
References
 
We thank Christine Lewis for her valuable input in editing this manuscript.


   REFERENCES
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Disclosure of Potential...
 Acknowledgments
 References
 

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