An Oral Interleukin-23-Receptor Antagonist Peptide for Plaque Psoriasis.

BACKGROUND: The use of monoclonal antibodies has changed the treatment of several immune-mediated inflammatory diseases, including psoriasis. However, these large proteins must be administered by injection. JNJ-77242113 is a novel, orally administered interleukin-23-receptor antagonist peptide that selectively blocks interleukin-23 signaling and downstream cytokine production. METHODS: In this phase 2 dose-finding trial, we randomly assigned patients with moderate-to-severe plaque psoriasis to receive JNJ-77242113 at a dose of 25 mg once daily, 25 mg twice daily, 50 mg once daily, 100 mg once daily, or 100 mg twice daily or placebo for 16 weeks. The primary end point was a reduction from baseline of at least 75% in the Psoriasis Area and Severity Index (PASI) score (PASI 75 response; PASI scores range from 0 to 72, with higher scores indicating greater extent or severity of psoriasis) at week 16. RESULTS: A total of 255 patients underwent randomization. The mean PASI score at baseline was 19.1. The mean duration of psoriasis was 18.2 years, and 78% of the patients across all the trial groups had previously received systemic treatments. At week 16, the percentages of patients with a PASI 75 response were higher among those in the JNJ-77242113 groups (37%, 51%, 58%, 65%, and 79% in the 25-mg once-daily, 25-mg twice-daily, 50-mg once-daily, 100-mg once-daily, and 100-mg twice-daily groups, respectively) than among those in the placebo group (9%), a finding that showed a significant dose-response relationship (P<0.001). The most common adverse events included coronavirus disease 2019 (in 12% of the patients in the placebo group and in 11% of those across the JNJ-77242113 dose groups) and nasopharyngitis (in 5% and 7%, respectively). The percentages of patients who had at least one adverse event were similar in the combined JNJ-77242113 dose group (52%) and the placebo group (51%). There was no evidence of a dose-related increase in adverse events across the JNJ-77242113 dose groups. CONCLUSIONS: After 16 weeks of once- or twice-daily oral administration, treatment with the interleukin-23-receptor antagonist peptide JNJ-77242113 showed greater efficacy than placebo in patients with moderate-to-severe plaque psoriasis. (Funded by Janssen Research and Development; FRONTIER 1 ClinicalTrials.gov number, NCT05223868.).

Trial of Lixisenatide in Early Parkinson's Disease.

BACKGROUND: Lixisenatide, a glucagon-like peptide-1 receptor agonist used for the treatment of diabetes, has shown neuroprotective properties in a mouse model of Parkinson's disease. METHODS: In this phase 2, double-blind, randomized, placebo-controlled trial, we assessed the effect of lixisenatide on the progression of motor disability in persons with Parkinson's disease. Participants in whom Parkinson's disease was diagnosed less than 3 years earlier, who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period. The primary end point was the change from baseline in scores on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with higher scores indicating greater motor disability), which was assessed in patients in the on-medication state at 12 months. Secondary end points included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent. RESULTS: A total of 156 persons were enrolled, with 78 assigned to each group. MDS-UPDRS part III scores at baseline were approximately 15 in both groups. At 12 months, scores on the MDS-UPDRS part III had changed by -0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group (difference, 3.08; 95% confidence interval, 0.86 to 5.30; P = 0.007). At 14 months, after a 2-month washout period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7 (95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with placebo. Other results relative to the secondary end points did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%. CONCLUSIONS: In participants with early Parkinson's disease, lixisenatide therapy resulted in less progression of motor disability than placebo at 12 months in a phase 2 trial but was associated with gastrointestinal side effects. Longer and larger trials are needed to determine the effects and safety of lixisenatide in persons with Parkinson's disease. (Funded by the French Ministry of Health and others; LIXIPARK ClinicalTrials.gov number, NCT03439943.).

Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disease characterized by chronic complement-mediated hemolysis. C5 inhibition controls intravascular hemolysis in untreated PNH but cannot address extravascular hemolysis. Pegcetacoplan, a pegylated peptide targeting proximal complement protein C3, potentially inhibits both intravascular and extravascular hemolysis. METHODS: We conducted a phase 3 open-label, controlled trial to assess the efficacy and safety of pegcetacoplan as compared with eculizumab in adults with PNH and hemoglobin levels lower than 10.5 g per deciliter despite eculizumab therapy. After a 4-week run-in phase in which all patients received pegcetacoplan plus eculizumab, we randomly assigned patients to subcutaneous pegcetacoplan monotherapy (41 patients) or intravenous eculizumab (39 patients). The primary end point was the mean change in hemoglobin level from baseline to week 16. Additional clinical and hematologic markers of hemolysis and safety were assessed. RESULTS: Pegcetacoplan was superior to eculizumab with respect to the change in hemoglobin level from baseline to week 16, with an adjusted (least squares) mean difference of 3.84 g per deciliter (P<0.001). A total of 35 patients (85%) receiving pegcetacoplan as compared with 6 patients (15%) receiving eculizumab no longer required transfusions. Noninferiority of pegcetacoplan to eculizumab was shown for the change in absolute reticulocyte count but not for the change in lactate dehydrogenase level. Functional Assessment of Chronic Illness Therapy-Fatigue scores improved from baseline in the pegcetacoplan group. The most common adverse events that occurred during treatment in the pegcetacoplan and eculizumab groups were injection site reactions (37% vs. 3%), diarrhea (22% vs. 3%), breakthrough hemolysis (10% vs. 23%), headache (7% vs. 23%), and fatigue (5% vs. 15%). There were no cases of meningitis in either group. CONCLUSIONS: Pegcetacoplan was superior to eculizumab in improving hemoglobin and clinical and hematologic outcomes in patients with PNH by providing broad hemolysis control, including control of intravascular and extravascular hemolysis. (Funded by Apellis Pharmaceuticals; PEGASUS ClinicalTrials.gov, NCT03500549.).

A Novel Peptide Prevents Enterotoxin- and Inflammation-Induced Intestinal Fluid Secretion by Stimulating Sodium-Hydrogen Exchanger 3 Activity.

BACKGROUND & AIMS: Acute diarrheal diseases are the second most common cause of infant mortality in developing countries. This is contributed to by lack of effective drug therapy that shortens the duration or lessens the volume of diarrhea. The epithelial brush border sodium (Na+)/hydrogen (H+) exchanger 3 (NHE3) accounts for a major component of intestinal Na+ absorption and is inhibited in most diarrheas. Because increased intestinal Na+ absorption can rehydrate patients with diarrhea, NHE3 has been suggested as a potential druggable target for drug therapy for diarrhea. METHODS: A peptide (sodium-hydrogen exchanger 3 stimulatory peptide [N3SP]) was synthesized to mimic the part of the NHE3 C-terminus that forms a multiprotein complex that inhibits NHE3 activity. The effect of N3SP on NHE3 activity was evaluated in NHE3-transfected fibroblasts null for other plasma membrane NHEs, a human colon cancer cell line that models intestinal absorptive enterocytes (Caco-2/BBe), human enteroids, and mouse intestine in vitro and in vivo. N3SP was delivered into cells via a hydrophobic fluorescent maleimide or nanoparticles. RESULTS: N3SP uptake stimulated NHE3 activity at nmol/L concentrations under basal conditions and partially reversed the reduced NHE3 activity caused by elevated adenosine 3',5'-cyclic monophosphate, guanosine 3',5'-cyclic monophosphate, and Ca2+ in cell lines and in in vitro mouse intestine. N3SP also stimulated intestinal fluid absorption in the mouse small intestine in vivo and prevented cholera toxin-, Escherichia coli heat-stable enterotoxin-, and cluster of differentiation 3 inflammation-induced fluid secretion in a live mouse intestinal loop model. CONCLUSIONS: These findings suggest pharmacologic stimulation of NHE3 activity as an efficacious approach for the treatment of moderate/severe diarrheal diseases.

Advancing type 2 diabetes therapy with iGlarLixi in older people: Pooled analysis of four randomized controlled trials.

AIM: To assess the efficacy and safety of iGlarLixi in older people (≥65 years) with type 2 diabetes (T2D) advancing or switching from oral agents, a glucagon-like peptide-1 receptor agonist (GLP-1RA), or basal insulin. MATERIALS AND METHODS: The data of participants aged <65 years and ≥65 years from four LixiLan trials (LixiLan-O, LixiLan-G, LixiLan-L, SoliMix) were evaluated over 26 or 30 weeks. RESULTS: Participants aged <65/≥65 years (n = 1039/n = 497) had a mean baseline body mass index of 31.4 and 30.7 kg/m2 and glycated haemoglobin (HbA1c) concentration of 66 mmol/mol (8.2%) and 65 mmol/mol (8.1%), respectively. Least squares mean HbA1c change from baseline to end of treatment (EOT) was -14.32 mmol/mol (-1.31%) (95% confidence interval [CI] -14.97, -13.77 [-1.37%, -1.26%]) for those aged <65 years and -13.66 mmol/mol (-1.25%) (95% CI -14.54, -12.79 [-1.33%, -1.17%]) for those aged ≥65 years. At EOT, achievement of HbA1c targets was similar between the group aged <65 years and the group aged ≥65 years: <53 mmol/mol (<7%) (59.0% and 56.5%, respectively), <59 mmol/mol (<7.5%) (75.5% and 73.0%, respectively) and <64 mmol/mol (<8%) (83.8% and 84.1%, respectively). The incidence and event rate of American Diabetes Association Level 1 hypoglycaemia during the studies were also comparable between the two groups: 26.7% and 28.2% and 1.7 and 2.1 events per patient-year for the group aged <65 years and the group aged ≥65 years, respectively. A clinically relevant reduction in HbA1c (>1% from baseline for HbA1c ≥64 mmol/mol [≥8%] or ≥0.5% from baseline for HbA1c <64 mmol/mol [<8%]) without hypoglycaemia was attained by 50.0% and 47.6% of participants aged <65 years and ≥65 years, respectively. Adverse events were similar between the two age groups. CONCLUSIONS: iGlarLixi is a simple, well-tolerated, once-daily alternative for treatment advancement in older people with T2D that provides significant improvements in glycaemic control without increasing hypoglycaemia risk, thus reducing the treatment burden.

Real-world effectiveness and safety of insulin glargine 100 U/mL plus lixisenatide in adults with type 2 diabetes: An international, multicentre, 12-month, prospective observational study.

AIM: To assess the impact of insulin glargine (100 U/mL) and lixisenatide (iGlarLixi) fixed-ratio combination therapy on the overall management of glycaemia in patients with type 2 diabetes (T2D), previously inadequately controlled with oral antidiabetic drugs ± basal insulin or glucagon-like peptide-1 receptor agonists (GLP-1 RAs). MATERIALS AND METHODS: This 12-month, international, multicentre, prospective, observational study included patients (age ≥ 18 years) with T2D who had initiated iGlarLixi within 1 month prior to study inclusion. Data were collected at study inclusion, month 3, month 6 and month 12 from patient diaries, self-measured plasma glucose, and questionnaires. The primary endpoint was change in HbA1c from baseline to month 6. RESULTS: Of the 737 eligible participants (mean age: 57.8 [standard deviation: 11.2] years; male: 49%), 685 had baseline and post-baseline HbA1c data available. The least squares mean change in HbA1c from baseline to month 6 was -1.4% (standard error [95% confidence interval (CI)]: 0.05 [-1.5, -1.3]). The absolute change from baseline at month 12 was -1.7% ± 1.9% (95% CI: -1.9, -1.5). There were 72 hypoglycaemia events reported during the study period, with a very low incidence of severe hypoglycaemia (two participants [rate: 0.003 events per patient-year]). CONCLUSIONS: This real-world observational study shows that initiation of iGlarLixi in people with T2D inadequately controlled on oral antidiabetic drugs ± basal insulin or GLP-1 RAs improves glycaemic control with a low incidence of hypoglycaemia.

The efficacy and safety of iGlarLixi versus IDegAsp in Chinese people with type 2 diabetes suboptimally controlled with oral antidiabetic drugs: The Soli-D randomized controlled trial.

AIM: To compare the efficacy and safety of a fixed-ratio combination of insulin glargine 100 U/mL plus lixisenatide (iGlarLixi) with premixed insulin, insulin degludec plus insulin aspart (IDegAsp), in Chinese people with type 2 diabetes (T2D) suboptimally controlled with oral antidiabetic drug(s) (OADs). METHODS: In Soli-D, a 24-week, multicentre, open-label, study, insulin-naïve adults were randomized 1:1 to once-daily injections of iGlarLixi (n = 291) or IDegAsp (n = 291), with continued metformin ± sodium-glucose co-transporter-2 inhibitors. The primary endpoint was non-inferiority in HbA1c change from baseline to week 24. Key secondary endpoints included superiority in HbA1c change and body weight (BW) change at week 24. Hypoglycaemia rates were also assessed. RESULTS: At week 24, iGlarLixi showed non-inferiority and superiority over IDegAsp in HbA1c reduction (least squares [LS] mean difference: -0.20 [95% confidence interval {CI}: -0.33, -0.07]; P < .001 for non-inferiority; [97.5% CI: -0.35, -0.05]; P = .003 for superiority). iGlarLixi decreased BW and IDegAsp increased BW from baseline to week 24, with a statistically significant LS mean difference of -1.49 kg in favour of iGlarLixi (97.5% CI: -2.32, -0.66; P < .001). Event rates (per person-year) for American Diabetes Association (ADA) Level 1, 2 or 3 hypoglycaemia were lower for iGlarLixi (1.90) versus IDegAsp (2.72) (relative risk: 0.71; 95% CI: 0.52, 0.98). No ADA Level 3 hypoglycaemia or unexpected safety findings were reported. CONCLUSIONS: In Chinese people with T2D suboptimally controlled with OADs, once-daily iGlarLixi provided better glycaemic control with BW benefit and lower hypoglycaemia event rates versus IDegAsp.

Randomized controlled trial of linaclotide in children aged 6-17 years with functional constipation.

OBJECTIVES: Linaclotide, a guanylate cyclase-C agonist, was recently approved in the United States for treatment of children 6-17 years old with functional constipation (FC). This study evaluated the safety and efficacy of several linaclotide doses in children 6-17 years old with FC. METHODS: In this multicenter, randomized, double-blind, placebo-controlled phase 2 study, 173 children with FC (based on Rome III criteria) were randomized to once-daily linaclotide (A: 9 or 18 µg, B: 18 or 36 µg, or C: 36 or 72 µg) or placebo in a 1:1:1:1 ratio for 6- to 11-year-olds (dosage determined by weight: 18 to <35 or ≥35 kg) and linaclotide (18, 36, 72, or 145 µg) or placebo in a 1:1:1:1:1 ratio for 12- to 17-year-olds. The primary efficacy endpoint was change from baseline in weekly spontaneous bowel movement (SBM) frequency throughout the 4-week treatment period. Adverse events (AE), clinical laboratory values, and electrocardiograms were monitored. RESULTS: Efficacy and safety were assessed in 173 patients (52.0% aged 6-11 years; 48.0% aged 12-17 years); 162 (93.6%) completed the treatment period. A numerical improvement in mean SBM frequency was observed with increasing linaclotide doses (1.90 in 6- to 11-year-olds [36 or 72 µg] and 2.86 in 12- to 17-year-olds [72 µg]). The most reported treatment-emergent AE was diarrhea, with most cases being mild; none were severe. CONCLUSIONS: Linaclotide was well tolerated in this pediatric population, with a trend toward efficacy in the higher doses, warranting further evaluation.

Early use of teduglutide in paediatric patients with intestinal failure is associated with a greater response rate: a multicenter study.

Teduglutide is a glucagon-like-peptide-2 analogue that reduces the need for parenteral support in patients with short bowel syndrome (SBS). Nevertheless, data about long-term therapy with teduglutide in children are still scarce. Our objective was to describe the real-life experience with teduglutide in children with SBS over the last 5 years in Spain. This was a national multicentre and prospective study of paediatric patients with intestinal failure (IF) treated with teduglutide for at least 3 months. The data included demographic characteristics, medical background, anthropometric data, laboratory assessments, adverse events, and parenteral nutrition (PN) requirements. Treatment response was defined as a > 20% reduction in the PN requirement. The data were collected from the Research Electronic Data Capture (REDCap) database. Thirty-one patients from seven centres were included; the median age at the beginning of the treatment was 2.3 (interquartile range (IQR) 1.4-4.4) years; and 65% of the patients were males. The most frequent cause of IF was SBS (94%). The most common cause of SBS was necrotizing enterocolitis (35%). The median residual bowel length was 29 (IQR 12-40) cm. The median duration of teduglutide therapy was 19 (IQR 12-36) months, with 23 patients (74%) treated for > 1 year and 9 treated for > 3 years. The response to treatment was analysed in 30 patients. Twenty-four patients (80%) had a reduction in their weekly PN energy > 20% and 23 patients (77%) had a reduction in their weekly PN volume > 20%. Among the responders, 9 patients (29%) were weaned off PN, with a median treatment duration of 6 (IQR 4.5-22) months. The only statistically significant finding demonstrated an association between a > 20% reduction in the weekly PN volume and a younger age at the start of treatment (p = 0.028).   Conclusions: Teduglutide seems to be an effective and safe treatment for paediatric patients with IF. Some patients require a prolonged duration of treatment to achieve enteral autonomy. Starting treatment with teduglutide at a young age is associated with a higher response rate. What is Known: •  Glucagon-like peptide-2 (GLP-2) plays a crucial role in the regulation of intestinal adaptation in short bowel syndrome (SBS). Teduglutide is a GLP-2 analog that reduces the need for parenteral support in patients with SBS. • Data about long-term therapy with teduglutide in children in real life are still scarce. What is New: • Most pediatric patients with SBS respond in a satisfactory manner to teduglutide treatment. The occurrence of long-term adverse effects is exceptional. • Starting treatment with the drug at a young age is associated with a greater response rate.

Oral consumption of Bonito fish-derived elastin peptide (VGPG Elastin® ) improves biophysical properties in aging skin: A randomized, double-blinded, placebo-controlled study.

BACKGROUND: Recent in vitro and in vivo studies have suggested that the elastin peptide improves the skin's biophysical properties, enhancing the proliferation of fibroblasts and elastin synthesis, resulting in anti-aging properties. Therefore, we conducted a randomized, double-blinded, placebo-controlled study to clinically evaluate the effect of elastin peptide intake on human skin. MATERIALS AND METHODS: Healthy adult participants (N = 100) were randomly assigned to receive a test product containing 100 mg of Bonito elastin peptide (VGPG Elastin® ) or placebo. In this study, all participants were Asian from Korea. The parameters of skin wrinkles, hydration, and brightening (melanin index) were measured at baseline and 4, 8, and 12 weeks after intervention. RESULTS: The average skin roughness, maximum peak-to-valley values, maximum peak height of the wrinkle, maximum valley depth of the wrinkle, average maximum height of the wrinkle, and eye wrinkle volume improved considerably in the test group compared with the placebo after 12 weeks of intervention. Skin hydration was enhanced, and the melanin index was significantly lower in the test group than in the placebo group. No participant experienced adverse events related to the test product. CONCLUSION: Oral consumption of Bonito elastin peptide (VGPG Elastin®) reduced fine wrinkles, enhanced skin moisture, and decreased melanin index without significant adverse effects and may be a promising anti-wrinkle, anti-dryness, and anti-pigmentation treatment.

RACK1 modulates polyglutamine-induced neurodegeneration by promoting ERK degradation in Drosophila.

Polyglutamine diseases are neurodegenerative diseases caused by the expansion of polyglutamine (polyQ) tracts within different proteins. Although multiple pathways have been found to modulate aggregation of the expanded polyQ proteins, the mechanisms by which polyQ tracts induced neuronal cell death remain unknown. We conducted a genome-wide genetic screen to identify genes that suppress polyQ-induced neurodegeneration when mutated. Loss of the scaffold protein RACK1 alleviated cell death associated with the expression of polyQ tracts alone, as well as in models of Machado-Joseph disease (MJD) and Huntington's disease (HD), without affecting proteostasis of polyQ proteins. A genome-wide RNAi screen for modifiers of this rack1 suppression phenotype revealed that knockdown of the E3 ubiquitin ligase, POE (Purity of essence), further suppressed polyQ-induced cell death, resulting in nearly wild-type looking eyes. Biochemical analyses demonstrated that RACK1 interacts with POE and ERK to promote ERK degradation. These results suggest that RACK1 plays a key role in polyQ pathogenesis by promoting POE-dependent degradation of ERK, and implicate RACK1/POE/ERK as potent drug targets for treatment of polyQ diseases.

Whey Peptide Alleviates Muscle Atrophy by Strongly Regulating Myocyte Differentiation in Mice.

Background and Objectives: Muscle atrophy occurs when protein degradation exceeds protein synthesis, resulting in imbalanced protein homeostasis, compromised muscle contraction, and a reduction in muscle mass. The incidence of muscle atrophy is increasingly recognized as a significant worldwide public health problem. The aim of the current study was to evaluate the effect of whey peptide (WP) on muscle atrophy induced by dexamethasone (DEX) in mice. Materials and Methods: C57BL/6 mice were divided into six groups, each consisting of nine individuals. WPs were orally administered to C57BL/6 mice for 6 weeks. DEX was administered for 5-6 weeks to induce muscle atrophy (intraperitoneal injection, i.p.). Results: Microcomputer tomography (CT) analysis confirmed that WP significantly increased calf muscle volume and surface area in mice with DEX-induced muscle atrophy, as evidenced by tissue staining. Furthermore, it increased the area of muscle fibers and facilitated greater collagen deposition. Moreover, WP significantly decreased the levels of serum biomarkers associated with muscle damage, kidney function, and inflammatory cytokines. WP increased p-mTOR and p-p70S6K levels through the IGF-1/PI3K/Akt pathway, while concurrently decreasing protein catabolism via the FOXO pathway. Furthermore, the expression of proteins associated with myocyte differentiation increased noticeably. Conclusions: These results confirm that WP reduces muscle atrophy by regulating muscle protein homeostasis. Additionally, it is believed that it helps to relieve muscle atrophy by regulating the expression of myocyte differentiation factors. Therefore, we propose that WP plays a significant role in preventing and treating muscle wasting by functioning as a supplement to counteract muscle atrophy.

Randomized Trial of Etelcalcetide for Cardiac Hypertrophy in Hemodialysis.

[Figure: see text].

Orforglipron (LY3502970), a novel, oral non-peptide glucagon-like peptide-1 receptor agonist: A Phase 1b, multicentre, blinded, placebo-controlled, randomized, multiple-ascending-dose study in people with type 2 diabetes.

AIM: To report the results of a Phase 1b trial evaluating the safety, pharmacokinetics and pharmacodynamics of orforglipron (LY3502970), an oral, non-peptide glucagon-like peptide-1 receptor agonist (GLP-1RA), in patients with type 2 diabetes (T2D). MATERIALS AND METHODS: This was a double-blind, placebo-controlled Phase 1 study evaluating five different dosing regimens. The first group established that weekly dose escalation of the daily doses of orforglipron was generally well tolerated. This enabled a parallel-arm design for the four groups following. Participants were randomized 3:1 to daily doses of orforglipron or placebo for 12 weeks. Eligible participants with T2D were aged 18 to 70 years and had glycated haemoglobin (HbA1c) levels ≥53.0 mmol/mol (7.0%) and ≤91.3 mmol/mol (10.5%). RESULTS: A total of 51 participants received orforglipron and 17 received placebo. In the placebo and orforglipron groups, respectively, baseline HbA1c was 8.1% and 8.0%, and baseline body weight was 90.3 and 88.4 kg. The most common adverse events were gastrointestinal-related, and occurred early in treatment, similar to findings with other GLP-1RAs. At Week 12, mean t1/2 ranged from 29 to 49 hours. Mean HbA1c change ranged from -1.5% to -1.8% across orforglipron doses, versus -0.4% with placebo, and body weight change was -0.24 to -5.8 kg across orforglipron doses, versus 0.5 kg with placebo. CONCLUSIONS: Orforglipron treatment resulted in meaningful reductions in HbA1c and body weight, with an adverse event profile consistent with that of other GLP-1RAs. Orforglipron may provide a safe and effective once-daily oral treatment alternative to injectable GLP-1RAs or peptide oral formulations without water and food restrictions.

Efficacy and Safety of Teduglutide in Infants and Children With Short Bowel Syndrome Dependent on Parenteral Support.

OBJECTIVES: Our objective was to evaluate the short- and long-term safety and efficacy of teduglutide treatment in infants and children with short bowel syndrome with intestinal failure (SBS-IF). METHODS: Two open-label phase 3 studies and 1 extension study investigated the short- and long-term safety and efficacy of teduglutide (0.05 mg/kg/day) in infants and children with SBS-IF: NCT03571516, 24-week study of infants who were randomized to receive teduglutide or standard of care (SoC); NCT02980666, 24-week study of infants and children who all received teduglutide; and NCT03268811, 24-week extension study of patients who completed NCT02980666 (patients could receive up to 48 weeks of total treatment). RESULTS: Twelve infants and 8 children enrolled in the core studies, and 2 infants and 7 children in the extension study. After 24 weeks of treatment, parenteral support (PS) requirements reduced by ≥20% from baseline for 4 infants (57.1%) and 4 children (66.7%) receiving teduglutide and for 2 infants receiving SoC (50.0%). One infant (50.0%) and 4 children (80.0%) receiving teduglutide maintained the ≥20% reduction in PS at 48 weeks of treatment. Two children receiving teduglutide achieved enteral autonomy, after 12 weeks and 28 weeks of treatment, respectively. All adverse events (AEs) were in line with known impacts of SBS-IF and adverse reactions to teduglutide. Only one serious AE (abdominal pain) was considered related to teduglutide. CONCLUSIONS: Short- and long-term treatment with teduglutide resulted in clinically meaningful reductions in PS requirements for infants and children with SBS-IF. Teduglutide was well tolerated, and efficacy improved with longer-term treatment.

Pacenta polypeptide injection alleviates the fibrosis and inflammation in cigarette smoke extracts-induced BEAS-2B cells by modulating MMP-9/TIMP-1 signaling.

Chronic obstructive pulmonary disease (COPD) has high morbidity and mortality. Here, we aimed to explore the roles and potential correlation of placenta polypeptide injection (PPI) and MMP-9/TIMP-1 signaling pathway in COPD. BEAS-2B cells were treated with cigarette smoke extract (CSE) to establish a COPD cell model in vitro. The cell survival and cytotoxic effect were measured by CCK-8, LDH release and flow cytometry assays. The inflammatory responses were determined by western blot and ELISA assay. Cell fibrosis was assessed by immunofluorescence and western blot assays. PPI treatment had no cytotoxic effect on BEAS-2B cells until the final concentration reached to 10%. In the range of 0%-8% final concentration, PPI treatment weakened CSE-induced the decrease of cell viability and the increase of LDH level in a concentration-dependent manner. Four percent PPI treatment enhanced cell viability and decreased cell apoptosis of CSE-treated cells in a time-dependent manner. Moreover, 4% PPI treatment significantly decreased inflammatory responses and fibrosis induced by CSE, while AMPA (MMPs agonist) had opposite effects. Notably, AMPA reversed the protective roles of PPI on CSE-induced inflammation and fibrosis. Mechanistically, 4% PPI treatment significantly suppressed MMP-1, MMP-2, MMP-3, MMP-9, MMP-13, and MMP-19 levels, but enhanced TIMP-1, TIMP-2, TIMP-3, and TIMP-4 levels. Among them, MMP-9 and TIMP-1 might be the main target of PPI. PPI effectively attenuated CSE-induced inflammation and fibrosis in vitro by regulating MMP-9/TIMP-1 signaling pathway.

New Alternative? Self-Assembling Peptide in Gastrointestinal Bleeding: A Systematic Review and Meta-Analysis.

BACKGROUND: Gastrointestinal bleeding (GIB) is a common and potentially fatal condition with all-cause mortality ranging from 3 to 10%. Endoscopic therapy traditionally involves mechanical, thermal, and injection therapies. Recently, self-assembling peptide (SAP) has become increasingly available in the United States. When applied to an affected area, this gel forms an extracellular matrix-type structure allowing for hemostasis. This is the first systematic review and meta-analysis to assess the safety and efficacy of this modality in GIB. METHODS: We performed a comprehensive literature search of major databases from inception to Nov 2022. The primary outcomes assessed were the success of hemostasis, rebleeding rates, and adverse events. The secondary outcomes assessed were successful hemostasis with monotherapy with SAP and combined therapy, which may include mechanical, injection, and thermal therapies. Pooled estimates were calculated using random-effects models with a 95% confidence interval (CI). RESULTS: The analysis included 7 studies with 427 patients. 34% of the patients were on anticoagulation or antiplatelet agents. SAP application was technically successful in all patients. The calculated pooled rate of successful hemostasis was 93.1% (95% confidence interval (CI) 84.7-97.0, I2 = 73.6), and rebleeding rates were 8.9% (95% CI 5.3-14.4, I2 = 55.8). The pooled rates of hemostasis with SAP monotherapy and combined therapy were similar. No adverse events were noted related to SAP. CONCLUSION: SAP appears to be a safe and effective treatment modality for patients with GIB. This modality provides an added advantage of improved visualization over the novel spray-based modalities. Further, prospective, or randomized controlled trials are needed to validate our findings.

A pre-market interventional, single-arm clinical investigation of a new topical lotion based on hyaluronic acid and peptides, EGYFILTM, for the treatment of pain and stiffness in soft tissues.

BACKGROUND: Muscle pain and stiffness are strictly interconnected. Injuries frequently occur during sport activities, causing muscle pain, with or without stiffness, and require effective as well as fast-acting treatments. Topical products can be ideal for the treatment of such physical alterations as they are convenient and simple to use. In this study, it was investigated the application of a novel topical formulation, EGYFIL™, for the treatment of pain and stiffness due to muscle contracture, trauma, and/or overtraining. The lotion is composed of hyaluronic acid, a well-known ingredient for the pain alleviation, mixed with skin conditioning SH-Polypeptide-6 and SH-Oligopeptide-1, embedded in it. METHODS: Twenty-six patients with pain and/or stiffness were enrolled. After a screening visit (Time 0, t0), patients were treated for the first time with the IP. The treatment consisted of topical application of the pain lotion. Level of pain and stiffness were measured with Numerical Rating Scale (NRS). Patients' pain and/or stiffness were evaluated at t0 (prior to using the product), after three hours (t1), and after three days (t2) of treatment. Participants were free to apply and re-apply the product ad libitum over the course of the study period (3 days). Potential adverse events (AE) and tolerance were evaluated during each visit. RESULTS: There was a 22% decrease in pain in the first three hours (p < 0.001), followed by an additional 20% decrease after three days (p=0.0873). Overall, there was a 42% decrease in pain over the three days of the study (p =0.001). Furthermore, a 24% reduction in stiffness in the first three hours (p=0.025) and a 38% decrease in stiffness over three days (p < 0.001) were observed. Reduction in pain and stiffness were neither age, nor sex dependent. No adverse effects were reported during the study. CONCLUSION: EGYFIL™ is safe and seems to reduce pain and stiffness in patients during the 3 days of treatment, already after 3 h from the first application. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT05711953. This trial was registered on 03/02/2023.

A Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of Single Ascending Doses of a First-in-Human Engineered Cationic Peptide, PLG0206, Intravenously Administered in Healthy Subjects.

In this first-in-human study, PLG0206, a novel engineered cationic antimicrobial peptide, was evaluated for safety, tolerability, and pharmacokinetics (PK) when intravenously (i.v.) administered as a single dose to healthy subjects. Six cohorts of 8 subjects each received escalating single i.v. infusions of PLG0206 at 0.05, 0.125, 0.25, 0.5, or 1 mg/kg dose or placebo over 1 to 4 h. Subjects were randomized to receive either PLG0206 (6 per cohort) or placebo (2 per cohort). Serial pharmacokinetic samples were taken prior to infusion and up to 48 h postinfusion. Safety and tolerability were assessed throughout the study. The demographic characteristics of subjects were comparable between those treated with PLG0206 and placebo and between dose groups. The incidence of treatment-emergent adverse events (TEAE) related to PLG0206 was low, and most events were mild in severity and were similar between the PLG0206 treatment and placebo groups. The most common adverse events reported for PLG0206 were infusion-related reactions, which were mitigated with increasing infusion time and volume. There were no severe adverse events (SAEs), life-threatening events, or deaths throughout the study. i.v. PLG0206 exhibited linear pharmacokinetics over the dose range of 0.05 to 1.0 mg/kg. The median terminal half-life (t1/2) ranged from 7.37 to 19.97 h. Following a single i.v. infusion to healthy subjects, PLG0206 was safe and well tolerated and exhibited linear PK at doses ranging from 0.05 to 1 mg/kg. These findings support the ongoing development of i.v. PLG0206 as an antimicrobial agent.

PTG-100, an Oral α4ß7 Antagonist Peptide: Preclinical Development and Phase 1 and 2a Studies in Ulcerative Colitis.

BACKGROUND & AIMS: Oral therapies targeting the integrin α4ß7 may offer unique advantages for the treatment of inflammatory bowel disease. We characterized the oral α4ß7 antagonist peptide PTG-100 in preclinical models and established safety, pharmacokinetic/pharmacodynamic relationships, and efficacy in a phase 2a trial in patients with ulcerative colitis (UC). METHODS: In vitro studies measured binding properties of PTG-100. Mouse studies measured biomarkers and drug concentrations in blood and tissues. The phase 1 study involved healthy volunteers. In phase 2a, patients with moderate to severe active UC were randomized to receive PTG-100 (150, 300, or 900 mg) or placebo once daily for 12-weeks. RESULTS: PTG-100 potently and selectively blocks α4ß7. Oral dosing of PTG-100 in mice showed high levels of target engagement and exposure in gut-associated lymphoid tissues. In healthy volunteers, PTG-100 showed dose-dependent increases in plasma exposure and blood target engagement. Although this phase 2a study initially did not meet the primary endpoint, a blinded reread of the endoscopy videos by a third party indicated clinical efficacy in conjunction with histologic remission at doses correlating with less than 100% receptor occupancy in peripheral blood. CONCLUSIONS: PTG-100 showed local gastrointestinal tissue target engagement and inhibition of memory T-cell trafficking in mice. It was safe and well tolerated in phase 1 and 2 studies. Phase 2a data are consistent with biological and clinical response and showed a dose response reflecting similar activities in preclinical models and healthy individuals. These data suggest that local gut activity of an oral α4ß7 integrin antagonist, distinct from full target engagement in blood, are important for efficacy and the treatment of UC. (ClinicalTrials.gov, Number NCT02895100; EudraCT, Number 2016-003452-75).