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Efficacy and Safety of Intranasal Peptide YY_3–36 for Weight Reduction in Obese Adults

Merck Research Laboratories, Rahway, New Jersey 07065

Address all correspondence and requests for reprints to: Ira Gantz, M.D., Clinical Research, Metabolism, Merck Research Laboratories, 126 East Lincoln Avenue, P.O. Box 2000, RY34A-A202, Rahway, New Jersey 07065-0900. E-mail: Ira_Gantz{at}Merck.com.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: The gastrointestinal peptide hormone, peptide YY_3–36 (PYY_3–36), is implicated to be a postprandial satiety factor.

Objective: The aim of this study is to assess the safety, tolerability, and efficacy of intranasal PYY_3–36 to induce weight loss in obese patients.

Design: The study was designed as a randomized, 2-wk, single-blind placebo run-in followed by a 12-wk double-blind, placebo-controlled treatment period.

Setting: The study was set within a private and institutional practice.

Patients: A total of 133 obese patients (body mass index, 30–43 kg/m²; age, 18–65 yr) participated in the study.

Intervention: Placebo or 200- or 600-µg PYY_3–36 was administered as an intranasal spray 20 min before breakfast, lunch, and dinner in conjunction with a hypocaloric diet and exercise.

Main Outcome Measure: Body weight was the main outcome measure.

Results: The number of patients completing 12 wk on the drug was 38 of 43 (88%), 31 of 44 (70%), and 12 of 46 (26%) for placebo, 200 µg three times a day (t.i.d.) and 600 µg t.i.d., respectively. In the 600 µg t.i.d. group, 27 of 46 (59%) patients discontinued due to nausea and vomiting. Among all randomized patients who took at least one drug dose and had a postbaseline measurement, the mean body weight change from baseline was –2.8, –3.7, and –1.4 kg for placebo, 200 and 600 µg, respectively. The least squares mean difference (95% confidence interval) between placebo and 200 µg was –0.9 (–2.6, 0.7) kg (P = 0.251). A difference of 2.11 kg was sought. No meaningful inference can be drawn from the few patients who completed the study on 600 µg.

Conclusions: Intranasal PYY_3–36 as administered at these intervention doses and preprandial timing is not efficacious in inducing weight loss in obese patients after 12 wk of treatment.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
PEPTIDE YY_3–36 (PYY_3–36) is a gastrointestinal peptide hormone, which has been implicated as a postprandial satiety factor in rodents, rabbits, rhesus, and humans (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15). Basal plasma PYY levels increase after a meal, endogenous fasting and postprandial levels of PYY are significantly lower in obese compared with lean adult individuals, and an exaggerated postprandial PYY response occurs after gastric bypass surgery (1, 8, 9, 10, 11, 16, 17). In contrast, basal levels of PYY were similar in young obese and control subjects (18).

Three limited human studies have evaluated the efficacy of iv PYY_3–36 to inhibit short-term caloric intake (1, 8, 9). Batterham et al. (1, 8) conducted two studies that included a total of 36 lean and obese subjects who were given iv PYY_3–36 as a 90-min infusion that ended 2 h before a test meal. Peak plasma PYY levels during the infusion reached approximately two to three times normal peak postprandial levels of the peptide. In both studies there was an approximately 30% reduction in calorie intake of the test meal, and no gastrointestinal side effects were reported.

The effect of iv PYY_3–36 on caloric intake was also investigated in 16 healthy subjects in a study conducted by Degen et al. (9). Three doses of PYY_3–36 were used. The high dose (0.8 pmol/kg·min) was identical to that used by Batterham et al. (1); however, unlike the study design of Batterham et al. the test meal was given 60 min after initiation of the infusion, and the infusion continued during the test meal. Similar to Batterham et al., Degen et al. (9) observed a 32% decrease in caloric intake of the test meal. However, a significant incidence of nausea, abdominal discomfort, and a single episode of vomiting were observed.

To date, no orally bioavailable, nonpeptide neuropeptide Y Y2 receptor (NPY2R) agonists have been reported in the scientific or patent literature. The nasal mucosa provides an absorptive surface for the delivery of peptidergic drugs into the systemic circulation, and there is also a theoretical potential for direct transport of peptide to the central nervous system (19, 20, 21).

We performed a proof-of-concept study to evaluate the safety, tolerability, and efficacy of an intranasal formulation of PYY_3–36 to induce weight loss in obese adult males and females.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Rising-dose clinical pharmacology study

To aid in dose selection, we performed a double-blind, randomized, five-period, placebo-controlled rising dose study in 12 healthy obese (body mass index, 30–35 kg/m²) male and female subjects (ages 18–45 yr). A further description of the study design and analysis is presented in the supplemental data published on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org.

Proof-of-concept study

This was a multicenter, double-blind, randomized, placebo-controlled study. Before randomization there was a 2-wk single-blind placebo run-in period during which patients were instructed to follow a 25% caloric deficit diet and a suggested exercise regimen. Eligible patients were equally randomized to placebo or 200 or 600 µg of PYY_3–36, administered as a 0.1-ml intranasal spray three times a day (t.i.d.), 20 min before breakfast, lunch, and dinner for a 12-wk treatment period. Patients were instructed to continue on the 25% caloric deficit diet and a suggested exercise regimen. The choice of PYY_3–36 doses used in the proof-of-concept study was based on the results from our rising-dose study and published data available at the time of study design (1, 8, 10, 12). The doses were intended to bracket the normal postprandial plasma PYY concentrations observed in lean individuals. A further discussion of the dose selection rationale is present in the supplemental data.

The proof-of-concept study included 133 obese male and female patients with a body mass index of 30–43 kg/m², ages 18–65 yr, without significant cardiovascular, pulmonary, renal, endocrine, neurological, or psychiatric disease (Table 1). Patients who were taking medications that might confound the results of the study or who had participated in a weight loss program within 3 months of the study were excluded. All study subjects underwent the informed consent process before any study-related procedures.

The primary efficacy analysis population was the all patients treated (APT) population, which consisted of randomized patients who took at least one dose of study medication and who had at least one postbaseline measurement. Patients who completed the study without major protocol violations were also analyzed. The APT is also the primary population used for the analysis of safety and tolerability. Details of the applied statistical methods are summarized in the supplemental data.

Intranasal formulation

PYY_3–36 was synthesized by Bachem AG (King of Prussia, PA) and solubilized in a proprietary formulation (Nastech Pharmaceutical Inc., Bothell, WA). The PYY_3–36 formulation used in the proof-of-concept study was identical to that used in rising-dose clinical pharmacology study.

Plasma PYY analytical assay

Plasma samples were assayed in duplicate for total PYY (PYY_1–36 + PYY_3–36) using a commercially available RIA (Peninsula Laboratories Inc., San Carlos, CA). Further details of the assay are described in the supplemental data.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Rising-dose clinical pharmacology study

PYY_3–36 was generally well tolerated at doses of 600 µg/placebo t.i.d. or lower. In the 200-µg dose groups through the 600-µg dose groups, there was no trend in the incidence of nausea and/or vomiting. At doses of 800 µg/placebo, two subjects reported nausea and two subjects experienced emesis, whereas at doses of 1000 µg/placebo five subjects reported nausea (two of moderate intensity) and two subjects experienced vomiting. One subject discontinued after experiencing nausea and vomiting in the 800-µg dose group. At the 1000-µg/placebo dose, during the episodes of nausea and/or vomiting, some subjects reported other AEs including dizziness, palpitations, tachypnea, and tremors. Dosing was terminated for all subjects after the morning dose of 1000 µg/placebo. Based upon this data, a dose of 600 µg t.i.d. was considered to be the maximum tolerated dose. The AEs for this study are summarized in Table 1 of the supplemental data.

The PYY pharmacokinetic parameters uncorrected for endogenous levels of PYY are summarized in Fig. 1 and Table 2 of the supplemental data. The average (SD) baseline PYY value was 8.4 (2.5) pM. The 200-µg dose resulted in a mean (SD) area under the curve (AUC)_{0–300 min} and C_max of 72.3 (25.33) pM·h and 43.1 (24.14) pM, respectively. For the 600-µg dose, those values increase to 148.67 (76.16) pM·h and 105.55 (47.91) pM, respectively. Average estimates for T_max spanned approximately 18–26 min, and a harmonic mean of approximately 20–40 min characterized the apparent half-life. Notably, a dose-dependent increase in plasma PYY was observed with increased dose.

View larger version (14K): [in this window] [in a new window]   FIG. 1. Change in body weight (kilograms) over 12 wk of treatment. Values are shown as means for all patients for whom measurements were taken at each visit. RMA, Repeated measures analysis. Error bars on last week and on repeated measures analysis are 84% CI.

The mean model-based change from baseline to wk 12 body weight in the APT population was –2.8, –3.7, and –1.4 kg for placebo, 200 µg, and 600 µg, respectively (Fig. 1). The model-based (least squares) mean weight difference [95% confidence interval (CI)] was –0.9 (–2.6, 0.7) kg between 200 µg and placebo (P = 0.251). Among patients who completed the study without major protocol violations, the least squares mean difference (95% CI) between 200 µg and placebo was –1.2 (–3.3, 0.9) kg. This difference was also not statistically significant. No meaningful inferences on the efficacy of 600 µg can be drawn from the few patients who completed the study on 600 µg.

AEs are summarized in Table 3 of the supplemental data. Nausea and vomiting were the primary AEs. At least one episode of nausea was experienced by 7, 29.5, and 78.3% of patients in the placebo, 200-µg, and 600-µg groups, respectively, and at least one episode of vomiting by 0, 9.1, and 47.8% of patients in the placebo, 200-µg, and 600-µg groups, respectively. Clinical AEs led to the discontinuation of three, six, and 27 patients in the placebo, 200-µg, and 600-µg groups, respectively.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Based on the available published animal (3, 4, 6, 7) and human studies (1, 8, 9), we undertook a 12-wk proof-of-concept clinical trial to evaluate the efficacy of intranasal PYY_3–36 to induce weight loss in obese patients. Our data indicate that we were able to achieve pharmacologically relevant plasma levels of PYY_3–36 via the intranasal route. AEs were limiting at the high dose. Compared with placebo, no significant weight loss was observed at the low dose.

Although 600 µg was the maximum tolerated dose in the rising-dose study, the 600-µg dose was poorly tolerated in the proof-of-concept study. In the rising-dose study, nausea and vomiting appeared to be minimal if the C_max remained less than 140.13 ± 34.71 pM and the AUC_{0–300 min} was less than 192.83 ± 62.8 pM·h, which were the C_max and AUC_{0–300 min} corresponding to an 800-µg dose. The reason for the discrepancy between the two studies is unclear. Notably, the majority of patients on the 600-µg dose who discontinued from the proof-of-concept study (27 of 46) did so early in the study because of their inability to tolerate associated nausea and vomiting. Due to the high dropout rate, no meaningful conclusions can be drawn about the efficacy of the 600-µg dose.

The administration schedule (20 min before breakfast, lunch, and dinner) should be considered in future studies. Animal studies suggest that PYY_3–36 released postprandially has immediate actions in hypothalamic satiety centers, especially the arcuate nucleus (1, 4, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31). Published literature indicates that this postprandial rise is initiated with food ingestion and is maximal at approximately 60 min (1, 8, 12). Pharmacokinetic data from the rising-dose study indicated that intranasal PYY_3–36 reaches a C_max at approximately 20 min. Therefore, administration 20 min preprandially might reasonably have been expected to have initiated the postprandial physiological effects of PYY_3–36. In previously published human studies where PYY_3–36 was demonstrated to decrease caloric intake, initiation (9) or termination (1, 8) of the peptide infusion occurred at least 1 h before the test meal. Therefore, the reported efficacy of exogenously administered PYY_3–36 in those studies may reflect a nonphysiological mechanism. In contrast, in the study by Batterham et al. (8), a sustained (12–24 h) effect on caloric intake occurred. Therefore, one could argue that regardless of our timing before a particular meal, an effect on subsequent meals should have been observed.

Whether the observed nausea and vomiting of the 600-µg dose might be overcome by a dose-titration scheme remains unknown. Whether doses of the present formulation more closely surrounding (above and below) 200 µg might demonstrate weight loss efficacy is also unknown and might be difficult given the lack of efficacy of the 200-µg dose coupled to the observed biological variability in plasma pharmacokinetics.

In addition to activating the anorexigenic NPY2R, PYY_3–36 also binds to the neuropeptide Y (NPY) Y5 receptor (and to a lesser extent the NPY Y1 receptor) (32, 33, 34). Therefore, it is possible that the study doses activated an orexigenic receptor (NPY5R or NPY1R), in addition to activating the anorexigenic NPY2R, with a resultant diminution or loss of efficacy on weight reduction.

In summary, we were able to achieve pharmacologically relevant plasma levels of PYY_3–36 via the intranasal route, but AEs were limiting at the high dose and, compared with placebo, no significant weight loss was observed at the low dose. From these data, it is not possible to make definitive conclusions about the relevance of PYY_3–36 as a postprandial satiety mechanism in humans or whether this mechanism might be manipulated successfully in another way (e.g. different nasal formulation, different route of administration, different timing of administration) to induce weight loss in obese individuals.

	Acknowledgments

 
We thank Alfredo Rojas for providing statistical programming support.

	Footnotes

 
First Published Online March 6, 2007

Abbreviations: AE, Adverse event; APT, all patients treated; AUC, area under the curve; CI, confidence interval; NPY, neuropeptide Y; NPY2R, neuropeptide Y Y2 receptor; PYY_3–36, peptide YY_3–36; t.i.d., three times a day.

Received August 16, 2006.

Accepted February 22, 2007.

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