Phase Ia dose escalation study of OBP-801, a cyclic depsipeptide class I histone deacetylase inhibitor, in patients with advanced solid tumors.

Background Dysregulation of histone deacetylases (HDACs) is common in cancer and is critical to the development and progression of the majority of tumors. This first-in-human Phase Ia study assessed the safety, efficacy, and pharmacokinetics (PK) of OBP-801, a cyclic depsipeptide class I HDAC inhibitor. Methods Adult patients with advanced solid tumors were treated in 3 dose cohorts (1.0 mg/m2, 2.0 mg/m2 or 2.8 mg/m2) of OBP-801 that was administered via intravenous infusion weekly. Initially, an accelerated titration design was used that was followed by a 3 + 3 dose escalation strategy. Primary objective was assessment of safety. Secondary objectives included determination of PK and objective response rate. Results Seventeen patients were enrolled, of which 8 patients were evaluable for efficacy. Drug-related ≥ Grade 3 treatment-emergent adverse events included abdominal pain, anemia, fatigue, gamma glutamyl-transferase increase, hypertriglyceridemia and vomiting. No dose-limiting toxicity was observed in the 1.0 mg/m2 cohort. The PK data showed that OBP-801 and its active metabolite OBP-801-SH exposure increased proportionally and more than proportionally, respectively. No accumulation of either agent was noticed after repeat administration. Best response was stable disease (37.5%), with one patient each in the three cohorts. Conclusion Further investigations of the OBP-801 1.0 mg/m2 dose will be needed to better understand the efficacy of the agent, either alone or in combination. Trial registration: NCT02414516 (ClinicalTrials.gov) registered on April 10, 2015.

Inhibition of C3 with pegcetacoplan results in normalization of hemolysis markers in paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disorder characterized by complement-mediated hemolysis. C5 inhibitors (eculizumab/ravulizumab) control intravascular hemolysis but do not prevent residual extravascular hemolysis. The newly approved complement inhibitor, pegcetacoplan, inhibits C3, upstream of C5, and has the potential to improve control of complement-mediated hemolysis. The PADDOCK and PALOMINO clinical trials assessed the safety and efficacy of pegcetacoplan in complement inhibitor-naïve adults (≥ 18 years) diagnosed with PNH. Patients in PADDOCK (phase 1b open-label, pilot trial) received daily subcutaneous pegcetacoplan (cohort 1: 180 mg up to day 28 [n = 3]; cohort 2: 270-360 mg up to day 365 [n = 20]). PALOMINO (phase 2a, open-label trial) used the same dosing protocol as PADDOCK cohort 2 (n = 4). Primary endpoints in both trials were mean change from baseline in hemoglobin, lactate dehydrogenase, haptoglobin, and the number and severity of treatment-emergent adverse events. Mean baseline hemoglobin levels were below the lower limit of normal in both trials (PADDOCK: 8.38 g/dL; PALOMINO: 7.73 g/dL; normal range: 11.90-18.00 g/dL), increased to within normal range by day 85, and were sustained through day 365 (PADDOCK: 12.14 g/dL; PALOMINO: 13.00 g/dL). In PADDOCK, 3 serious adverse events (SAE) led to study drug discontinuation, 1 of which was deemed likely related to pegcetacoplan and 1 SAE, not deemed related to study drug, led to death. No SAE led to discontinuation/death in PALOMINO. Pegcetacoplan was generally well tolerated and improved hematological parameters by controlling hemolysis, while also improving other clinical PNH indicators in both trials. These trials were registered at www.clinicaltrials.gov (NCT02588833 and NCT03593200).

Effect of bremelanotide on body weight of obese women: Data from two phase 1 randomized controlled trials.

AIMS: The melanocortin 4 receptor (MC4R) plays a central role in appetite regulation, and agonistic activity at this receptor promotes satiety. Results from two randomized controlled clinical trials examine the effects of bremelanotide's agonism at MC4R on caloric intake and body weight. METHODS: Premenopausal women with a body mass index >30 kg/m2 were studied in two phase 1, single-centre, randomized, double-blind, placebo-controlled trials. Study A matched subjects 1:1 to receive subcutaneous placebo or bremelanotide three times daily for days 1-15. Study B was a crossover trial with six distinct treatment sequences consisting of three 4-day treatment periods, investigating once-a-day and twice-a-day exposure to bremelanotide versus placebo. Subjects received one of the three treatments twice-daily during each period: 0 mg/0 mg, 2.5 mg/0 mg or 2.5 mg/2.0 mg bremelanotide. Body weight and food intake were recorded in detail daily. Adverse events were recorded throughout both studies. RESULTS: In Study A, 27 of 30 bremelanotide subjects (90.0%) completed the trial and exhibited a significantly greater reduction in body weight after 16 days versus placebo [least squares mean difference (95% CI), -1.3 (-1.9 to -0.8) kg; p < .0001]. Mean caloric intake in bremelanotide subjects was decreased versus placebo, with a magnitude of reduction of approximately 400 kcal/day throughout Study A (p < .01). In Study B, 15 of 27 subjects (55.6%) completed all three phases. Significantly greater reduction of mean body weight occurred in twice-daily bremelanotide subjects versus placebo (1.7 vs. 0.9 kg, respectively, p < .001). Total caloric intake reduction was significantly greater in the bremelanotide groups versus placebo (mean difference range: 398-469 kcal; p < .0001). CONCLUSIONS: Agonist activity at the MC4R may aid in reducing caloric intake and weight loss in obese women.

Characterizing New-Onset Exudation in the Randomized Phase 2 FILLY Trial of Complement Inhibitor Pegcetacoplan for Geographic Atrophy.

OBJECTIVES: To evaluate clinical characteristics of eyes in which investigator-determined new-onset exudative age-related macular degeneration (eAMD) developed during the FILLY trial. DESIGN: Post hoc analysis of the phase 2 study of intravitreal pegcetacoplan in geographic atrophy (GA). SUBJECTS: Patients with GA secondary to age-related macular degeneration (AMD), n = 246. INTERVENTION: Either 15 mg intravitreal pegcetacoplan or sham given monthly or every other month for 12 months followed by a 6-month off-treatment period. MAIN OUTCOME MEASURES: Time of new eAMD onset in the study eye, history of eAMD in the fellow eye, presence of double-layer sign (DLS) on structural OCT in the study eye, changes in retinal anatomic features by structural OCT and fluorescein angiography (FA), and changes in visual acuity. RESULTS: Exudation was reported in 26 study eyes across treatment groups over 18 months. Mean time to eAMD diagnosis was 256 days (range, 31-555 days). Overall, a higher proportion of patients with a baseline history of eAMD in the fellow eye (P = 0.016) and a DLS in the study eye (P = 0.0001) demonstrated eAMD. Among study eyes in which eAMD developed, 18 of 26 (69%) had history of fellow-eye eAMD and 19 of 26 (73.1%) had DLS at baseline, compared with 76 of 217 study eyes (35%; P = 0.0007) and 70 of 215 study eyes (32.5%; P < 0.0001), respectively, in which eAMD did not develop. All 21 patients with structural OCT imaging at the time of eAMD diagnosis demonstrated subretinal fluid, intraretinal cysts, or both consistent with exudation. Among 17 patients who underwent FA at eAMD diagnosis, 10 showed detectable macular neovascularization (MNV), all occult lesions. Development of eAMD did not have an appreciable impact on visual acuity, and all patients responded to anti-vascular endothelial growth factor (VEGF) therapy. CONCLUSIONS: Intravitreal pegcetacoplan slowed the rate of GA growth and was associated with an unexpected dose-dependent increased incidence of eAMD with no temporal clustering of onset. Exudative AMD seemed to be associated with baseline eAMD in the contralateral eye and a DLS, suggestive of nonexudative MNV, in the study eye. The safety profile of pegcetacoplan was acceptable to proceed to phase 3 studies without adjustments to enrollment criteria.

Bremelanotide: New Drug Approved for Treating Hypoactive Sexual Desire Disorder.

Objective: To review data regarding bremelanotide, a recently approved therapy for hypoactive sexual desire disorder (HSDD). Data Sources: Literature search of Medline, SCOPUS, and EMBASE was performed using the search terms bremelanotide, bremelanotide injection, Vyleesi, and melanocortin 4 receptor agonist between January 1, 1996, and December 15, 2019. Reference lists from included articles were also reviewed for pertinent citations. Study Selection/Data Extraction: We included phase 2 and 3 trials of bremelanotide. There were 2 reports of phase 3 trials and 2 reports of phase 2 trials. Additional information from supplementary analyses was also referenced. Data Synthesis: Bremelanotide demonstrates significant improvement in desire and a significant decrease in distress related to lack of desire. The most common adverse effects include nausea (39.9%), facial flushing (20.4%), and headache (11%). Relevance to Patient Care and Clinical Practice: Bremelanotide is the second Food and Drug Administration-approved medication for the treatment of HSDD. Bremelanotide's place in therapy is unknown, as the HSDD guidelines were last updated in 2017. Although the trials met statistical significance for change in sexual desire elements and distress related to sexual desire, the clinical benefit may only be modest. Conclusion: Bremelanotide is a subcutaneous injection that can be administered as needed approximately 45 minutes prior to sexual activity. Bremelanotide is safe and has limited drug-drug interactions, including no clinically significant interactions with ethanol. Prescribing guidelines recommend no more than 1 dose in 24 hours and no more than 8 doses per month. Individuals should discontinue use after 8 weeks without benefit.

Patient reported outcome data from acromegaly patients treated with injectable somatostatin receptor ligands (SRLs) in routine clinical practice.

BACKGROUND: Acromegaly patients managed on Somatostatin receptor ligands (SRLs), the most common first-line pharmacotherapy for acromegaly, may still experience acromegaly symptoms such as headache, sweating, fatigue, soft tissue swelling, and joint pain, even those with normal IGF-1. Additionally, treatment with SRLs may cause injection site reactions and other side effects such as gastro-intestinal (GI) symptoms. This study utilized patient-reported outcome measures to examine the burden associated with acromegaly and its treatment for patients receiving a stable dose of long-acting SRLs in routine clinical practice. METHODS: US acromegaly patients on a stable dose of SRL seen by their treating healthcare provider in the past 12 months completed a one-time online survey including the Acro-TSQ, an acromegaly-specific tool for assessing symptom burden and treatment satisfaction and convenience. RESULTS: One hundred five patients were enrolled (mean age 49.9 years, 79.1% female). Patients experienced numerous symptoms, including > 80% who experienced joint pain, acro-fog, swelling of soft tissue, and fatigue/weakness. Many symptoms occurred constantly, while some occurred at the end of the injection cycle, even among those with IGF-1 < = 1.0 ULN. Injection site reactions were common. Patients were moderately satisfied with their current treatment; symptoms and side effects often affected daily activities. On average, patients reported > 3 acromegaly provider visits/year. CONCLUSIONS: Despite receiving a stable dose of SRL and regular visits with an acromegaly healthcare provider, US acromegaly patients in routine clinical practice, and even the subgroup with normal IGF-1, report significant burden of disease and treatment.

Efficacy and safety of lanreotide in Korean patients with metastatic, well-differentiated gastroenteropancreatic-neuroendocrine tumors: a retrospective analysis.

Lanreotide autogel is a long-acting somatostatin analogue with proven efficacy and safety in patients with well-differentiated (WD) gastroenteropancreatic-neuroendocrine tumors (GEP-NETs) in a prior randomized phase III trial (CLARINET). However, the CLARINET study only enrolled patients with Ki-67 index <10%, and few patients of Asian ethnicity were included. We retrospectively analyzed the efficacy and safety of lanreotide in Korean patients with GEP-NETs in the daily practice setting. Between January 2015 and May 2018, 64 patients with metastatic WD GEP-NETs received lanreotide at Asan Medical Center, Seoul, Korea. Of them, 45 (70.3%) patients who received lanreotide as monotherapy were included in the current analysis. The most common primary tumor site was the pancreas (n = 22, 48.9%), followed by the rectum (10, 22.2%) and the small bowel (7, 15.6%). According to RECIST v1.1, a partial response was achieved in one patient (2.2%) and stable disease was achieved in 40 patients (88.9%). The median progression-free survival (PFS) was 16.4 months (95% confidence interval, 9.5-23.3 months). There were no differences in PFS according to the primary tumor site (p = 0.77). Hepatic tumor volume > 25% and prior systemic therapy were significantly associated with poorer PFS in the multivariate analysis. Lanreotide is well-tolerated and effective for Korean patients with GEP-NETs in the daily practice setting.

Balixafortide plus eribulin in HER2-negative metastatic breast cancer: a phase 1, single-arm, dose-escalation trial.

BACKGROUND: The C-X-C chemokine receptor type 4 (CXCR4)-stromal cell-derived factor-1α (SDF-1α) axis regulates function and trafficking of immune cells and the tumour microenvironment. CXCR4 antagonists have been shown to enhance the activity of different anticancer treatments in preclinical models. We assessed the safety, tolerability, pharmacokinetics, and preliminary phase 1 activity of the CXCR4 antagonist, balixafortide, in combination with eribulin chemotherapy in patients with heavily pretreated, relapsed metastatic breast cancer. METHODS: This single-arm, dose-escalation, phase 1 trial enrolled patients at 11 sites in Spain and the USA. Eligible patients were women aged 18 years or older who had histologically confirmed HER2-negative metastatic breast cancer, evidence of tumour cell CXCR4 expression, an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received between one and three chemotherapy regimens for metastatic breast cancer, and at least one endocrine therapy if they had hormone receptor-positive disease, unless they were considered unsuitable for endocrine therapy. A standard 3+3 dose-escalation design was used, followed by an expanded cohort at the established maximum tolerated dose or highest dose if no dose-limiting toxicity was observed for the combination. After a treatment-related fatal adverse event in the first cohort who received 21-day cycles of treatment with eribulin and balixafortide, a protocol amendment modified the study design to be done in two parts. Patients enrolled to part 1 received an initial 28-day run-in cycle, with some cohorts receiving de-escalated doses of eribulin plus balixafortide to assess the safety and pharmacokinetics of the combination. The evaluation of part 1 did not confirm any dose-limiting toxicities or eribulin-balixafortide interactions, and therefore part 2 started enrolling patients to receive eribulin at the originally planned dose of 1·4 mg/m2 on days 2 and 9 of a 21-day cycle and balixafortide from a starting dose of 2 mg/kg with dose increments of 0·5 or 1 mg/kg on days 1-3 and 8-10 of the 21-day cycle. Both drugs were administered as intravenous infusions. All patients were to receive treatment until disease progression or unacceptable toxicity. The primary endpoints were dose-limiting toxicities and adverse events, and the establishment of a maximum tolerated dose or recommended phase 2 dose, and pharmacokinetic parameters. Safety analysis was done in all patients who received at least one dose of study treatment. Analysis of antitumour activity was done in all patients who received at least one full cycle of study treatment. The trial is registered at ClinicalTrials.gov, number NCT01837095, and is closed to accrual. FINDINGS: Between Jan 28, 2014, and Oct 4, 2016, 56 patients were enrolled into the trial. No dose-limiting toxicities were confirmed and the maximum tolerated dose was not reached. The highest dose was established as eribulin 1·4 mg/m2 on days 2 and 9, and balixafortide 5·5 mg/kg on days 1-3 and 8-10 of the 21-day cycle. Objective responses (all partial responses) were observed in 16 (30%; 95% CI 18-44) of 54 patients who were evaluable for antitumour activity. The most common treatment-emergent adverse events of any grade were fatigue (44 [79%] of 56 patients), neutropenia (32 [57%]), infusion-related reactions (27 [48%]), alopecia (26 [46%]), constipation (26 [46%]), and nausea (25 [45%]). Serious adverse events occurred in 21 (38%) of 56 patients, including febrile neutropenia in five (9%) of 56 patients, neutrophil count decrease in two (4%) patients, constipation in two (4%) patients, pneumonia in two (4%) patients, and urinary tract infection in three (5%) patients. Two (4%) of 56 patients died while receiving study treatment; one from septic shock and one from pneumonia. INTERPRETATION: The safety and tolerability of balixafortide plus eribulin seems to be similar to that of eribulin or balixafortide monotherapy, and the preliminary activity of the combination seems promising in patients with HER-negative metastatic breast cancer. The results suggest that balixafortide plus eribulin has potential to provide a new therapeutic option in heavily pretreated patients with metastatic breast cancer and warrants further investigation in randomised trials. FUNDING: Polyphor.

Pharmacokinetics and Safety of Intravenous Murepavadin Infusion in Healthy Adult Subjects Administered Single and Multiple Ascending Doses.

Murepavadin is the first in class of the outer membrane protein-targeting antibiotics (OMPTA) and a pathogen-specific peptidomimetic antibacterial with a novel, nonlytic mechanism of action targeting Pseudomonas aeruginosa Murepavadin is being developed for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP). The pharmacokinetics (PK) and safety of single and multiple doses of murepavadin were investigated in healthy male subjects. Part A of the study was a double-blind, randomized, placebo-controlled, single-ascending-dose investigation in 10 sequential cohorts where each cohort comprised 6 healthy male subjects; 4 subjects were randomized to murepavadin, and 2 subjects were randomized to placebo. Part B was a double-blind, randomized, placebo-controlled, multiple-ascending-dose investigation in 3 sequential cohorts. After a single dose of murepavadin, the geometric mean half-life (2.52 to 5.30 h), the total clearance (80.1 to 114 ml/h/kg), and the volume of distribution (415 to 724 ml/kg) were consistent across dose levels. The pharmacokinetics of the dosing regimens evaluated were dose proportional and linear. Murepavadin was well tolerated, adverse events were transient and generally mild, and no dose-limiting toxicity was identified.

Pharmacokinetics, Tolerability, and Safety of Murepavadin, a Novel Antipseudomonal Antibiotic, in Subjects with Mild, Moderate, or Severe Renal Function Impairment.

This open-label, nonrandomized, single-dose, phase 1 study evaluated the pharmacokinetics and safety of murepavadin, a novel peptide antibiotic for the treatment of serious Pseudomonas aeruginosa infections. The study was conducted in 32 subjects of either sex in 4 groups (up to 8 per group) with mild (group 1), moderate (group 2), and severe (group 3) renal function impairment or with normal renal function (group 4). The degree of renal impairment of the subjects was classified at screening according to the estimated creatinine clearance (CLCr) according to the Cockcroft-Gault equation. All subjects received a single 2.2-mg/kg of body weight intravenous infusion of murepavadin administered over 3 h. Exposure to murepavadin in plasma increased in subjects with renal function impairment, with the area under the plasma concentration-time curve from zero to infinity (AUC0-∞) increasing about 2.0- to 2.5-fold for subjects with renal function impairment compared to subjects with normal renal function, whereas the increases in maximum observed plasma concentration (Cmax) were about 1.5-fold for subjects with renal function impairment compared to subjects with normal renal function. The total clearance (CL) of murepavadin was lower in all groups of subjects with renal function impairment, with group means ranging from 2.4 liters/h to 3.8 liters/h, compared to 7.0 liters/h in subjects with normal renal function. Accordingly, the terminal elimination half-life (t1/2) prolonged up to 24 h with decreasing renal function compared to 7.7 h in subjects with normal renal function. Murepavadin was well tolerated in all renal function groups. As the elimination of murepavadin is affected by renal function, a dose adjustment is warranted in subjects with impaired renal function. (This paper has been registered at ClinicalTrials.gov under identifier NCT02110459.).

Medical Treatments for Acromegaly: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Acromegaly results from the hypersecretion of growth hormone. Because of the low incidence rates of this disease worldwide, few clinical trials evaluating drug treatments have been conducted. OBJECTIVES: To conduct the first network meta-analysis simultaneously comparing all available drugs used in acromegaly treatment so as to provide more robust evidence in this field. METHODS: A systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Cochrane Collaboration recommendations (PROSPERO database under the registration number CRD42017059880). The electronic searches were conducted in PubMed (MEDLINE), Scopus, and Web of Science databases. Randomized controlled trials comparing any drug for the treatment of acromegaly head-to-head or versus placebo were included. Outcomes concerning the efficacy and safety of treatments were evaluated. The statistical analyses were performed using Aggregate Data Drug Information System version 1.16.8 (drugis.org, Groningen, The Netherlands). RESULTS: The initial search retrieved 2059 articles. Of these, 10 randomized controlled trials were included in a qualitative analysis and 7 in a quantitative analysis. The network meta-analysis for the efficacy outcome (number of patients achieving insulinlike growth factor 1 control) showed that pegvisomant and lanreotide autogel were statistically superior to placebo (odds ratio [95% credible interval] 0.06 [0.00-0.55] and 0.09 [0.01-0.88]). No further differences were found. The probability rank indicated that pegvisomant and pasireotide have the highest probabilities (33% and 34%, respectively) of being the best therapeutic options. No major side effects were noted. CONCLUSIONS: Pegvisomant is still a good option for acromegaly treatment, but pasireotide seems to be a promising alternative. Nevertheless, other important key factors such as drug costs and effectiveness (real-world results) should be taken into account when selecting acromegaly treatment.

Cyclization of PLP139-151 peptide reduces its encephalitogenic potential in experimental autoimmune encephalomyelitis.

We report the novel synthesis of cyclic PLP139-151 (cPLP) and its application in SJL/J mice to study its encephalitogenic effects. Our results indicate that the cPLP analog is minimally encephalitogenic when administered to induce experimental autoimmune encephalomyelitis (low disease burden, minimal inflammatory, demyelinating and axonopathic pathology compared to its linear counterpart). Proliferation assays confirmed the low stimulatory potential of the cPLP compared to linPLP (2.5-fold lower proliferation) as well as inducing lower antibody responses. Molecular modeling showed a completely different TCR recognition profile of cPLP in regard to linPLP, where H147 replaces W144 and F151-K150 replace H147 as TCR contacts, which may explain the difference on each peptide's response.

Effect of Lanreotide on Kidney Function in Patients With Autosomal Dominant Polycystic Kidney Disease: The DIPAK 1 Randomized Clinical Trial.

Importance: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation in both kidneys and loss of renal function, eventually leading to a need for kidney replacement therapy. There are limited therapeutic management options. Objective: To examine the effect of the somatostatin analogue lanreotide on the rate of kidney function loss in patients with later-stage ADPKD. Design, Setting, and Participants: An open-label randomized clinical trial with blinded end point assessment that included 309 patients with ADPKD from July 2012 to March 2015 at 4 nephrology outpatient clinics in the Netherlands. Eligible patients were 18 to 60 years of age and had an estimated glomerular filtration rate (eGFR) of 30 to 60 mL/min/1.73 m2. Follow-up of the 2.5-year trial ended in August 2017. Interventions: Patients were randomized to receive either lanreotide (120 mg subcutaneously once every 4 weeks) in addition to standard care (n = 153) or standard care only (target blood pressure <140/90 mm Hg; n = 152). Main Outcomes and Measures: Primary outcome was annual change in eGFR assessed as slope through eGFR values during the 2.5-year treatment phase. Secondary outcomes included change in eGFR before vs after treatment, incidence of worsening kidney function (start of dialysis or 30% decrease in eGFR), change in total kidney volume and change in quality of life (range: 1 [not bothered] to 5 [extremely bothered]). Results: Among the 309 patients who were randomized (mean [SD] age, 48.4 [7.3] years; 53.4% women), 261 (85.6%) completed the trial. Annual rate of eGFR decline for the lanreotide vs the control group was -3.53 vs -3.46 mL/min/1.73 m2 per year (difference, -0.08 [95% CI, -0.71 to 0.56]; P = .81). There were no significant differences for incidence of worsening kidney function (hazard ratio, 0.87 [95% CI, 0.49 to 1.52]; P = .87), change in eGFR (-3.58 vs -3.45; difference, -0.13 mL/min/1.73 m2 per year [95% CI, -1.76 to 1.50]; P = .88), and change in quality of life (0.05 vs 0.07; difference, -0.03 units per year [95% CI, -0.13 to 0.08]; P = .67). The rate of growth in total kidney volume was lower in the lanreotide group than the control group (4.15% vs 5.56%; difference, -1.33% per year [95% CI, -2.41% to -0.24%]; P = .02). Adverse events in the lanreotide vs control group included injection site discomfort (32% vs 0.7%), injection site papule (5.9% vs 0%), loose stools (91% vs 6.6%), abdominal discomfort (79% vs 20%), and hepatic cyst infections (5.2% vs 0%). Conclusions and Relevance: Among patients with later-stage autosomal dominant polycystic kidney disease, treatment with lanreotide compared with standard care did not slow the decline in kidney function over 2.5 years of follow-up. These findings do not support the use of lanreotide for treatment of later-stage autosomal dominant polycystic kidney disease. Trial Registration: ClinicalTrials.gov Identifier: NCT01616927.

Selective Inhibition of the Mitochondrial Permeability Transition Pore Protects against Neurodegeneration in Experimental Multiple Sclerosis.

The mitochondrial permeability transition pore is a recognized drug target for neurodegenerative conditions such as multiple sclerosis and for ischemia-reperfusion injury in the brain and heart. The peptidylprolyl isomerase, cyclophilin D (CypD, PPIF), is a positive regulator of the pore, and genetic down-regulation or knock-out improves outcomes in disease models. Current inhibitors of peptidylprolyl isomerases show no selectivity between the tightly conserved cyclophilin paralogs and exhibit significant off-target effects, immunosuppression, and toxicity. We therefore designed and synthesized a new mitochondrially targeted CypD inhibitor, JW47, using a quinolinium cation tethered to cyclosporine. X-ray analysis was used to validate the design concept, and biological evaluation revealed selective cellular inhibition of CypD and the permeability transition pore with reduced cellular toxicity compared with cyclosporine. In an experimental autoimmune encephalomyelitis disease model of neurodegeneration in multiple sclerosis, JW47 demonstrated significant protection of axons and improved motor assessments with minimal immunosuppression. These findings suggest that selective CypD inhibition may represent a viable therapeutic strategy for MS and identify quinolinium as a mitochondrial targeting group for in vivo use.

The Antiproliferative Role of Lanreotide in Controlling Growth of Neuroendocrine Tumors: A Systematic Review.

BACKGROUND: Neuroendocrine tumors (NETs) are a heterogeneous group of tumors, with >50% of cases involving the gastrointestinal system or pancreas. Somatostatin analogs (SSAs) are used for treating NET-related secretory syndromes and, more recently, for their antiproliferative effects. We conducted a systematic review of published literature on the antiproliferative efficacy and safety of the SSA lanreotide Autogel in the management of NETs to gain a fuller understanding of the evidence and identify future areas of research. METHODS: Searches were conducted in PubMed up to March 16, 2016, and in the proceedings of four congresses from 2013 to 2016. RESULTS: Screening of 1,132 publications identified in the searches found 40 relevant publications, including 27 full-length publications and 13 congress abstracts. Twenty-four of these publications reported antiproliferative efficacy data for lanreotide Autogel. The CLARINET study showed that 120 mg lanreotide Autogel every 4 weeks improves progression-free survival (PFS) in patients with gastroenteropancreatic (GEP)-NETs, with grade 1 or grade 2 (Ki-67 <10%) disease, providing class I evidence of its antiproliferative effects. The CLARINET open-label extension study reported a median PFS of 32.8 months with lanreotide Autogel. Other smaller studies generally support CLARINET. CONCLUSION: Current clinical evidence shows that lanreotide Autogel has good antiproliferative activity with favorable safety and tolerability in patients with GEP-NETs, suggesting it should be considered as an early first-line treatment in this population. Further studies are needed to assess the potential benefits of higher doses and the use of lanreotide Autogel in combination therapy and as maintenance therapy in the absence of disease progression following other therapies. The Oncologist 2017;22:272-285 IMPLICATIONS FOR PRACTICE: This review presents the current clinical evidence for the antiproliferative activity of lanreotide Autogel in patients with midgut or pancreatic neuroendocrine tumors (NETs) and shows its effectiveness, safety, and tolerability in these patient populations. By systematically presenting all the clinical evidence, the review adds to existing publications by discussing results in a broad range of settings. The review also indicates future directions for investigation of the use of lanreotide Autogel in NETs originating in other locations, in combination therapy, or as maintenance therapy in progressive disease.

Lanreotide in metastatic enteropancreatic neuroendocrine tumors.

BACKGROUND: Somatostatin analogues are commonly used to treat symptoms associated with hormone hypersecretion in neuroendocrine tumors; however, data on their antitumor effects are limited. METHODS: We conducted a randomized, double-blind, placebo-controlled, multinational study of the somatostatin analogue lanreotide in patients with advanced, well-differentiated or moderately differentiated, nonfunctioning, somatostatin receptor-positive neuroendocrine tumors of grade 1 or 2 (a tumor proliferation index [on staining for the Ki-67 antigen] of <10%) and documented disease-progression status. The tumors originated in the pancreas, midgut, or hindgut or were of unknown origin. Patients were randomly assigned to receive an extended-release aqueous-gel formulation of lanreotide (Autogel [known in the United States as Depot], Ipsen) at a dose of 120 mg (101 patients) or placebo (103 patients) once every 28 days for 96 weeks. The primary end point was progression-free survival, defined as the time to disease progression (according to the Response Evaluation Criteria in Solid Tumors, version 1.0) or death. Secondary end points included overall survival, quality of life (assessed with the European Organization for Research and Treatment of Cancer questionnaires QLQ-C30 and QLQ-GI.NET21), and safety. RESULTS: Most patients (96%) had no tumor progression in the 3 to 6 months before randomization, and 33% had hepatic tumor volumes greater than 25%. Lanreotide, as compared with placebo, was associated with significantly prolonged progression-free survival (median not reached vs. median of 18.0 months, P<0.001 by the stratified log-rank test; hazard ratio for progression or death, 0.47; 95% confidence interval [CI], 0.30 to 0.73). The estimated rates of progression-free survival at 24 months were 65.1% (95% CI, 54.0 to 74.1) in the lanreotide group and 33.0% (95% CI, 23.0 to 43.3) in the placebo group. The therapeutic effect in predefined subgroups was generally consistent with that in the overall population, with the exception of small subgroups in which confidence intervals were wide. There were no significant between-group differences in quality of life or overall survival. The most common treatment-related adverse event was diarrhea (in 26% of the patients in the lanreotide group and 9% of those in the placebo group). CONCLUSIONS: Lanreotide was associated with significantly prolonged progression-free survival among patients with metastatic enteropancreatic neuroendocrine tumors of grade 1 or 2 (Ki-67 <10%). (Funded by Ipsen; CLARINET ClinicalTrials.gov number, NCT00353496; EudraCT 2005-004904-35.).

Surotomycin versus vancomycin in adults with Clostridium difficile infection: primary clinical outcomes from the second pivotal, randomized, double-blind, Phase 3 trial.

BACKGROUND: The available treatment options for Clostridium difficile infection (CDI) are limited by high recurrence rates. Surotomycin was a novel bactericidal cyclic lipopeptide in development to treat CDI that demonstrated non-inferiority to vancomycin in a Phase 2 trial. OBJECTIVES: To assess surotomycin safety and clinical response (non-inferiority versus vancomycin) at the end of treatment (EOT) of CDI. Additionally, to assess surotomycin response over time and sustained response at 30-40 days post-EOT (superiority versus vancomycin). PATIENTS AND METHODS: Patients with CDI were randomized (1:1) to receive twice-daily oral surotomycin 250 mg alternating with twice-daily placebo or four-times-daily oral vancomycin 125 mg for 10 days in this Phase 3, double-blind, multicentre, international trial. Clinical response over time and sustained clinical response were monitored until the end of the trial, through a follow-up period of 30-40 days. Clinical Trial Registration: NCT01598311. RESULTS: A total of 285 and 292 patients with confirmed CDI were randomized to receive surotomycin and vancomycin, respectively. Surotomycin-associated clinical response at EOT was non-inferior to vancomycin (surotomycin/vancomycin: 83.4%/82.1%; difference 1.4%, 95% CI - 4.9, 7.6). Following treatment with surotomycin, both clinical response over time (stratified log-rank test, P = 0.277) and sustained clinical response (63.3%/59.0%; difference 4.3%, 95% CI - 3.6, 12.2) did not demonstrate superiority versus vancomycin at end of trial. Both treatments were generally well tolerated. CONCLUSIONS: Surotomycin demonstrated non-inferiority to vancomycin for CDI clinical response at EOT. Surotomycin did not demonstrate superiority to vancomycin for clinical response over time or sustained clinical response rate.

Enteric microbiome profiles during a randomized Phase 2 clinical trial of surotomycin versus vancomycin for the treatment of Clostridium difficile infection.

OBJECTIVES: The effects of surotomycin (CB-183,315, MK-4261), a bactericidal cyclic lipopeptide, and vancomycin, the current standard-of-care for Clostridium difficile infection (CDI), on intestinal pathogens and microbiota were evaluated parallel to a Phase 2 randomized, double-blind clinical trial. METHODS: The single-centre cohort included 26 patients receiving surotomycin [125 or 250 mg twice daily (n = 9 each)] or oral vancomycin [125 mg four times daily (n = 8)] for 10 days. Faecal samples were collected at days 0-42 to quantify both C. difficile by conventional culture and the major components of the microbiome by quantitative PCR. RESULTS: Surotomycin 250 mg twice daily or vancomycin 125 mg four times daily reduced faecal C. difficile counts from ∼105-107 log10 cfu/g at baseline to ≤ 102 cfu/g by days 4-10 of treatment. Day 10 counts of C. difficile in 3/9 patients receiving surotomycin 125 mg twice daily remained detectable, including one patient who failed to achieve clinical cure. Bacteroidetes and Prevotella mean counts increased 0.7 log10 or remained unchanged with surotomycin 125 and 250 mg twice daily, respectively, whereas vancomycin reduced counts by 2.5-3.2 log10 (P < 0.02). Vancomycin reduced Firmicutes counts by 2.5-2.8 log10; surotomycin moderately suppressed these microbes in a dose-dependent manner. CONCLUSIONS: In this Phase 2 trial substudy, compared with vancomycin 125 mg four times daily, surotomycin 250 mg twice daily is as active in vivo against C. difficile, but was more sparing of microbiota. Surotomycin is no longer in development due to failed Phase 3 efficacy results.

Glucose and lipid levels with lanreotide autogel 120 mg in treatment-naïve patients with acromegaly: data from the PRIMARYS study.

OBJECTIVE: Impaired glycaemic control, characteristic of acromegaly, can be exacerbated by treatment with somatostatin analogues (SSAs), particularly those with multireceptor activity. We present data from the PRIMARYS study on the impact of the SSA lanreotide, associated with tumour volume and hormonal improvements, on glucose and other metabolic parameters in acromegaly. DESIGN: PRIMARYS was a 48-week open-label single-arm phase 3b study of lanreotide autogel 120 mg/4 weeks. A priori and post hoc metabolic profile data are reported for the overall population, patients with/without diabetes and patients achieving/not achieving hormonal control. PATIENTS: Treatment-naïve adults with pituitary macroadenoma, mean growth hormone >1 µg/l and elevated insulin-like growth factor-1 levels (n = 90). MEASUREMENTS: Glycaemic parameters [glycated haemoglobin (HbA1c ) and fasting plasma glucose (FPG) levels] assessed at baseline and weeks 12, 24 and 48. Lipid-profile data (triglycerides, total cholesterol, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol) collected at baseline and study end. RESULTS: In patients with diabetes (n = 24), HbA1c showed a clinically relevant decrease during treatment [mean change from baseline to week 48, -1·44% (95% CI: -2·52, -0·36)]. In the overall population, in patients without diabetes, or in patients with/without hormonal control, HbA1c did not significantly change by week 48. Mean FPG levels showed no significant change by week 48 in all populations. Individually, increases and decreases in glycaemic parameters affected some patients in all populations. Glycaemic status as a composite measure of HbA1c and FPG (classification as normal, mild or diabetic) was stable from baseline to study end in most patients (overall, 70%; patients with diabetes, 50%; patients without diabetes, 76%), but worsened by week 48 in nine (15%) patients [seven (50%) with diabetes at baseline] and improved in nine (15%) patients (none with diabetes). Changes in lipid profiles were not considered clinically meaningful. CONCLUSIONS: Glucose and lipid levels were not detrimentally affected in most patients, while only a relatively small proportion showed deterioration in glucose control.

Phase II study of lanreotide autogel in Japanese patients with unresectable or metastatic well-differentiated neuroendocrine tumors.

Background Lanreotide is a long-acting somatostatin analog with demonstrated efficacy against enteropancreatic neuroendocrine tumor (NET) in the phase III (CLARINET) study. Materials and Methods In this single-arm study, Japanese patients with grade (G) 1/G2 NET received lanreotide (120 mg/4 weeks) for 48 weeks. Those who completed the study were enrolled in a long-term extension study. The primary endpoint was the clinical benefit rate (CBR) defined as a complete response, partial response (PR), or stable disease (SD) over 24-weeks. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), safety, and pharmacokinetics. Results Thirty-two patients were recruited at 10 sites. The full analysis set (FAS) comprised 28 patients. Primary tumors were located in pancreas (12 patients), foregut (non-pancreas, lung; 1), midgut (2), hindgut (8), and unknown (5). Four patients had gastrinoma of the functional NET, and 3 had multiple endocrine neoplasia type 1. In the FAS, 39.3% had progressive disease at baseline. The CBR at 24 weeks was 64.3% (95% confidence interval; CI: 44.1-81.4), and median PFS was 36.3 weeks (95% CI: 24.1-53.1). PR was confirmed in 1 patient at 60 weeks during the extension study (ORR: 3.6%). Frequent adverse events related to lanreotide included injection site induration (28.1%), faeces pale (18.8%), flatulence (12.5%), and diabetes mellitus (12.5%). Conclusions The efficacy and safety of lanreotide in this study indicated its usefulness as a treatment option for Japanese NET patients. TRIAL REGISTRATION: JapicCTI-132,375, JapicCTI-142,698.