Pharmacodynamic Activity of the Novel Neurokinin-3 Receptor Antagonist SJX-653 in Healthy Men.

CONTEXT: SJX-653 is a novel neurokinin 3 receptor (NK3R) antagonist. The NK3 pathway is a central regulator of gonadotropin releasing hormone (GnRH) secretion and has also been implicated in the generation of hot flashes. Therefore, decreases of luteinizing hormone (LH) and testosterone in men serve as sensitive pharmacodynamic (PD) markers of central NK3 antagonism. OBJECTIVE: To characterize the safety, tolerability, pharmacokinetics, and pharmacodynamic activity of SJX-653 in healthy men. DESIGN: A randomized, placebo-controlled, double-blind, single ascending dose study. SETTING: Phase 1 unit. PATIENTS OR OTHER PARTICIPANTS: Seven cohorts of 6 healthy men 18-45 years of age (4:2 randomization to SJX-653/placebo per cohort). INTERVENTION(S): Single oral doses of 0.5-90 mg SJX-653. MAIN OUTCOME MEASURE(S): Safety assessments and serial pharmacokinetic (PK)/PD measurements. RESULTS: SJX-653 was well tolerated at all dose levels. Cmax and AUC0-24 increased in a dose-proportional manner. The terminal elimination half-life ranged between 9.8 and 12.5 hours independent of dose. A statistically significant, dose-dependent, reversible reduction of LH and testosterone was observed with near maximal effect after 15 mg and little to no effect at 4.5 mg. Maximal LH reduction was 70 ±â€…7% (mean ±â€…sd) at 6 hours after 30 mg SJX-653 versus 10 ±â€…43% for placebo (P = 0.0006); maximal T reduction was of 68 ±â€…5% at 8 hours after 60 mg SJX-653 versus 18 ±â€…11% for placebo (P < 0.0001). The plasma IC50 for LH reduction was 33 ng/mL. CONCLUSIONS: These data demonstrate clinical proof-of-mechanism for SJX-653 as a potent centrally-acting NK3R antagonist.

High-resolution temporal profiling of the human gut microbiome reveals consistent and cascading alterations in response to dietary glycans.

BACKGROUND: Dietary glycans, widely used as food ingredients and not directly digested by humans, are of intense interest for their beneficial roles in human health through shaping the microbiome. Characterizing the consistency and temporal responses of the gut microbiome to glycans is critical for rationally developing and deploying these compounds as therapeutics. METHODS: We investigated the effect of two chemically distinct glycans (fructooligosaccharides and polydextrose) through three clinical studies conducted with 80 healthy volunteers. Stool samples, collected at dense temporal resolution (~ 4 times per week over 10 weeks) and analyzed using shotgun metagenomic sequencing, enabled detailed characterization of participants' microbiomes. For analyzing the microbiome time-series data, we developed MC-TIMME2 (Microbial Counts Trajectories Infinite Mixture Model Engine 2.0), a purpose-built computational tool based on nonparametric Bayesian methods that infer temporal patterns induced by perturbations and groups of microbes sharing these patterns. RESULTS: Overall microbiome structure as well as individual taxa showed rapid, consistent, and durable alterations across participants, regardless of compound dose or the order in which glycans were consumed. Significant changes also occurred in the abundances of microbial carbohydrate utilization genes in response to polydextrose, but not in response to fructooligosaccharides. Using MC-TIMME2, we produced detailed, high-resolution temporal maps of the microbiota in response to glycans within and across microbiomes. CONCLUSIONS: Our findings indicate that dietary glycans cause reproducible, dynamic, and differential alterations to the community structure of the human microbiome.

Long-term experience with ZENPEP in infants with exocrine pancreatic insufficiency associated with cystic fibrosis.

The objective of our study was to determine whether infants with cystic fibrosis who developed exocrine pancreatic insufficiency in early infancy would tolerate long-term treatment with ZENPEP (pancrelipase) delayed-release capsules, containing 3000 US Pharmacopeia units of lipase/capsule, and demonstrate consistent long-term growth. The most common treatment-emergent adverse events were diarrhea, vomiting, and constipation (mild or moderate). At study completion, median weight-for-age percentiles increased from 22nd to 49th, median length-for-age percentiles increased from 36.5th to 42nd, and median weight-for-length percentiles increased from 41.5th to 55.5th. Long-term treatment (up to 12 months) of infants with exocrine pancreatic insufficiency owing to cystic fibrosis with ZENPEP was well tolerated and associated with improved growth parameters. This is the first long-term study of pancreatic enzyme replacement therapy conducted in this patient population.

Efficacy of a novel pancreatic enzyme product, EUR-1008 (Zenpep), in patients with exocrine pancreatic insufficiency due to chronic pancreatitis.

OBJECTIVES: EUR-1008 (ZENPEP® [pancrelipase] Delayed-Release Capsules) delayed-release capsules is a novel, enteric-coated, porcine-derived pancreatic enzyme product. This study evaluated the efficacy and safety of 2 doses of ZENPEP in patients with chronic pancreatitis (CP) and exocrine pancreatic insufficiency (EPI). METHODS: The effect of ZENPEP on the coefficient of fat absorption (CFA) was investigated in a randomized, double-blind, dose-response, crossover study with placebo run-in (7-9 days) and 2 treatment periods (9-11 days) composed of a high dose (7 × 20,000 lipase units per day) and a low dose (7 × 5000 lipase units per day). RESULTS: Mean CFA was significantly higher with low- (88.9%) and high-dose (89.9%) ZENPEP versus placebo run-in (82%; P < 0.001; n = 72) with no difference between doses (P = 0.228, primary end point). In patients with baseline CFA less than 90% (n = 33), the high dose was significantly more effective (CFA: 84.1%) than the low dose (CFA: 81.1%; P < 0.001). Post hoc analysis revealed an increase in treatment effect with more severe EPI. Coefficient of nitrogen absorption (P < 0.001), body weight (P ≤ 0.021), and body mass index (P ≤ 0.020) also increased significantly with both doses compared with baseline. Percentage of days with EPI symptoms decreased with both doses. CONCLUSIONS: Our findings suggest that CP patients with EPI benefit from a low dose of ZENPEP, whereas the high dose might be needed for patients with more severe EPI.

Efficacy and safety of azelaic acid (15%) gel as a new treatment for papulopustular rosacea: results from two vehicle-controlled, randomized phase III studies.

BACKGROUND: Rosacea is a common, chronic dermatosis for which safe and effective new treatment options are needed. OBJECTIVE: The objective of these studies was to evaluate the efficacy, tolerability, and safety of a new formulation of 15% azelaic acid (15%) gel (AzA gel), for the topical treatment of moderate, papulopustular rosacea. METHODS: Two multicenter, double-blind, randomized, parallel-group, vehicle-controlled studies were conducted using identical study designs, patient-selection criteria, and efficacy end points. Overall, 329 patients were enrolled in study 1 and 335 patients in study 2. RESULTS: Both studies consistently demonstrated the superiority of AzA gel over vehicle in the topical treatment of moderate, papulopustular rosacea. AzA gel yielded statistically significantly higher reductions in mean inflammatory lesion count than vehicle: 58% versus 40%, study 1 (P =.0001); 51% versus 39%, study 2 (P =.0208). Significantly higher proportions of patients treated with AzA gel experienced improvement in erythema compared with vehicle gel: 44% versus 29%, study 1 (P =.0017); 46% versus 28%, study 2 (P =.0005). Using the investigator's global assessment, therapeutic success in terms of a clear, minimal, or mild final result was achieved in 61% and 62% of patients treated with AzA gel in studies 1 and 2, respectively, which was significantly superior to the result achieved with vehicle (40% and 48%, respectively) (P <.0001, study 1; P =.0127, study 2). No serious, treatment-related adverse events were reported. CONCLUSION: The results of these 2 controlled studies demonstrate that AzA gel, used twice daily, is an efficacious, safe, and well-tolerated topical treatment for moderate, papulopustular rosacea.