An Open-Label Phase 2 Study of Eneboparatide, a Novel PTH Receptor 1 Agonist, in Hypoparathyroidism.

CONTEXT: Hypoparathyroidism is a rare disorder characterized by a deficiency in parathyroid hormone (PTH) resulting in hypocalcemia, hyperphosphatemia, and hypercalciuria. Eneboparatide is an investigational peptide agonist of the PTH1 receptor for the treatment of chronic hypoparathyroidism (HP). OBJECTIVE: To evaluate the efficacy, safety, and tolerability of eneboparatide in HP patients. DESIGN: Open-label, phase 2 study. PARTICIPANTS: Twenty-eight patients (21 women, 7 men), mean age (range): 58 years (28-72), with HP were enrolled into 2 consecutive cohorts (C1, n = 12, and C2, n = 16). INTERVENTION: Following an optimization period, daily subcutaneous injections of eneboparatide were administered for 3 months at 20 µg/day (C1) or 10 µg/day (C2) starting dose. Conventional therapy was progressively removed and eneboparatide could be titrated up to 60 µg (C1) or 80 µg (C2). MAIN OUTCOMES: Proportion of patients achieving independence from conventional therapy, albumin-adjusted serum calcium (ADsCa), 24-h urine calcium (uCa), serum bone turnover markers (s-CTX and P1NP), bone mineral density (BMD), and adverse events (AEs). RESULTS: After 3 months, ≥ 88% patients achieved independence from conventional therapy while mean ADsCa was maintained within target range (7.8-9 mg/dL). Eneboparatide induced a rapid and sustained reduction of mean 24-hour uCa, even among patients with hypercalciuria. Bone turnover markers slightly increased and BMD remained unchanged, consistent with progressive resumption of physiologic bone turnover. Eneboparatide was well tolerated with no serious AEs. CONCLUSION: Eneboparatide allowed independence from conventional therapy and maintenance of serum calcium within a target range, while normalizing uCa excretion and producing a balanced resumption of bone turnover.

Double-Blind, Placebo-Controlled, Dose-Escalating Study Evaluating the Safety and Immunogenicity of an Epitope-Specific Chemically Defined Nanoparticle RSV Vaccine.

BACKGROUND: V-306 is a virus-like particle-based vaccine candidate displaying respiratory syncytial virus (RSV) F site II protein mimetics (FsIIm) as an antigenic epitope. METHODS: This was a randomized, placebo-controlled, double-blind, dose-escalating, first-in-human study, conducted in 60 women aged 18-45 years. Twenty subjects per cohort (15 vaccine and five placebo) received two V-306 intramuscular administrations on Days 0 and 56 at 15 µg, 50 µg, or 150 µg. Safety and immunogenicity were assessed after each vaccination and for 1 year in total. RESULTS: V-306 was safe and well tolerated at all dose levels, with no increase in reactogenicity and unsolicited adverse events between the first and second administrations. At 50 µg and 150 µg, V-306 induced an increase in FsIIm-specific immunoglobulin G (IgG) titers, which lasted at least 4 months. This did not translate into an increase in RSV-neutralizing antibody titers, which were already high at baseline. No increase in the anti-F protein-specific IgG titers was observed, which were also high in most subjects at baseline due to past natural infections. CONCLUSIONS: V-306 was safe and well-tolerated. Future modifications of the vaccine and assay conditions will likely improve the results of vaccination.

Efficacy and safety of Oleogel-S10 (birch triterpenes) for epidermolysis bullosa: results from the phase III randomized double-blind phase of the EASE study.

BACKGROUND: Epidermolysis bullosa (EB) is a heterogeneous group of rare, difficult-to-treat, inherited multisystem diseases affecting epithelial integrity. Patients with EB are affected by mechanical fragility of epithelial surfaces including the skin and, as a result, extensive recurrent blistering is a characteristic of the condition. Chronic wounds predispose patients with EB to the development of squamous cell carcinoma, which is a major cause of premature death. OBJECTIVES: EASE was a double-blind, randomized, vehicle-controlled, phase III study to determine the efficacy and safety of the topical gel Oleogel-S10 (birch triterpenes) in EB. EASE was funded by Amryt Research Limited. METHODS: Patients with dystrophic EB, junctional EB or Kindler EB and a target partial-thickness wound lasting ≥ 21 days and < 9 months that was 10-50 cm2, were enrolled and randomized via computer-generated allocation tables 1 : 1 to Oleogel-S10 or control gel - both with standard-of-care dressings. Study gel was applied to all wounds at least every 4 days. The primary endpoint was the proportion of patients with first complete closure of target wound within 45 days. RESULTS: A total of 223 patients were enrolled and treated (109 treated with Oleogel-S10, 114 with control gel). The primary endpoint was met; Oleogel-S10 resulted in 41·3% of patients with first complete target wound closure within 45 days, compared with 28·9% in the control gel arm (relative risk 1·44, 95% confidence interval (CI) 1·01-2·05; P = 0·013). Adverse events (AEs) occurred with similar frequency for Oleogel-S10 (81·7%) compared with control gel (80·7%). AEs were predominantly of mild-to-moderate intensity (4·6% were severe). CONCLUSIONS: Oleogel-S10 is the first therapy to demonstrate accelerated wound healing in EB. Oleogel-S10 was well -tolerated.

Oleogel-S10 Phase 3 study "EASE" for epidermolysis bullosa: study design and rationale.

BACKGROUND: Epidermolysis bullosa (EB) is a group of rare, genetic diseases that affect the integrity of epithelial tissues, most notably the skin. Patients experience recurrent skin wounding, with severity depending on type, sub-type, and mutation. Oleogel-S10, a formulation of birch bark extract, has demonstrated efficacy in a Phase 2 trial assessing re-epithelialization of wounds in EB. EASE (NCT03068780, EudraCT 2016-002066-32) is a randomized, Phase 3, placebo-controlled study designed to determine the efficacy of Oleogel-S10 versus placebo in patients with EB. METHODS: EASE is a Phase 3, two-phase study comprising a 90-day, double-blind, randomized, placebo-controlled phase, followed by 24 months of open-label, single-arm follow-up. Patients with junctional EB, dystrophic EB, or Kindler syndrome and target wounds (10 - 50cm2) present for > 21 days and < 9 months, are randomized in a 1:1 ratio to receive wound dressings according to local standard of care with or without Oleogel-S10. Placebo is based on the Oleogel-S10 vehicle, which is sunflower oil formulated to have a consistency indistinguishable from that of the active product. The primary endpoint of the trial, directed by the US health authority according to the required study endpoints for chronic cutaneous ulcer and burn wounds, is to compare the efficacy of Oleogel-S10 versus placebo according to the proportion of patients with complete closure of the target wound within 45 ± 7 days of treatment. Additional EB-focused endpoints include wound burden, patient-reported outcomes, and safety. RESULTS: Results of the primary endpoint are anticipated to be available by H2 2019. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03068780 . EudraCT, 2016-002066-32. Registered on 3 March 2017.

Pharmacokinetics and Pharmacodynamics of Lomitapide in Japanese Subjects.

AIMS: Lomitapide is a licensed treatment for patients with homozygous familial hypercholesterolaemia in the USA, the EU, Canada, and Mexico. This study was conducted to compare the pharmacokinetics (PK), pharmacodynamics, safety, and tolerability of lomitapide between Japanese and Caucasian subjects with elevated low-density lipoprotein cholesterol (LDL-C) after single and multiple doses. METHODS: In this randomized, double-blind, placebo-controlled study, 36 Japanese and 36 Caucasian subjects with LDL-C levels ≥110 mg/dL were administered an escalating lomitapide dose range of 10-60 mg or placebo. Subjects were assessed for safety, tolerability, and lipid levels. RESULTS: Exposure to lomitapide as measured by Cmax was linear and increased over the dose range of 10-60 mg for both single- and multiple-dose administration. The correlation between AUC0-t and Ctrough demonstrated the lack of differences in the PK of lomitapide among ethnic groups. Lomitapide dose-dependent reductions in lipid parameters were observed and showed no ethnic differences. The safety assessments showed that the main treatment-related side effects identified were increases in hepatic enzymes and that the majority of treatment-related treatment-emergent AEs were gastrointestinal disorders. CONCLUSIONS: Lomitapide was effective in reducing LDL-C levels in a dose-dependent manner. Similar PK, efficacy, and safety profiles were observed in Japanese and Caucasian subjects, which suggest no differences in lomitapide activity or metabolism between the two populations compared in this study.

Evaluation of the effects of the weak CYP3A inhibitors atorvastatin and ethinyl estradiol/norgestimate on lomitapide pharmacokinetics in healthy subjects.

Lomitapide is a microsomal triglyceride transfer protein inhibitor approved as an adjunctive treatment for adult patients with homozygous familial hypercholesterolemia. Lomitapide is extensively metabolized via cytochrome P450 3A (CYP3A) and is a weak CYP3A inhibitor. Two phase 1 open-label, randomized (1:1), 2-arm drug interaction studies in healthy subjects assessed the effects of atorvastatin and ethinyl estradiol (EE)/norgestimate, both weak CYP3A inhibitors, on lomitapide pharmacokinetics with staggered (separated by 12 hours) or simultaneous administration. All subjects received a single dose of lomitapide (20 mg) in the evening on day 1. Atorvastatin (80 mg once daily, n = 32) or EE/norgestimate (0.035/0.25 mg once daily, n = 32) dosing was initiated on days 11 or 8, respectively, with evening (arm 1) or morning (arm 2) dosing; at steady state (days 15 or 22), a single lomitapide dose was administered; CYP3A inhibitor dosing continued for 6 days. Blood samples for pharmacokinetic analysis were taken until 168 hours postdose. With atorvastatin, lomitapide exposure was increased by approximately 2-fold and 1.3-fold, respectively, with simultaneous and staggered administration, respectively. Simultaneous and staggered EE/norgestimate and lomitapide administration resulted in an approximately 1.3-fold increase in lomitapide exposure. Reductions in lomitapide dose may be required for some patients when administered concomitantly with a weak CYP3A inhibitor.

Lomitapide at supratherapeutic plasma levels does not prolong the Qtc interval--results from a TQT study with moxifloxacin and ketoconazole.

BACKGROUND: The aim of this study was to assess the effect of high plasma levels of lomitapide and its main metabolite on ECG parameters. METHODS: In this randomized five-way cross-over thorough QT study, 56 healthy subjects were enrolled. Study treatments were administered orally for 3 days in five separate periods in which subjects were dosed with (1) a single dose of 75 mg lomitapide on Day 1 followed by a single dose of 200 mg on Day 3; (2) ketoconazole 200 mg BID; (3) ketoconazole with a single dose of 75 mg lomitapide on Day 3; (4) a single dose of 400 mg moxifloxacin on Day 3 and (5) placebo. RESULTS: Single doses of 75 and 200 mg lomitapide alone or in combination with ketoconazole caused minor changes in the change-from-baseline QTcI (ΔQTcI), whereas moxifloxacin and ketoconazole caused an increase of ΔQTcI with a peak effect at 1 and 3 hours postdosing, respectively. The largest mean placebo-corrected ΔQTcI (ΔΔQTcI) for lomitapide did not exceed 3 ms (upper bound of 90% CI: 4.7 ms) at any time points postdosing. Ketoconazole caused mild QT prolongation with mean ΔΔQTcI of 5.9 and 6.5 ms at 2 and 3 hours postdosing, and exposure-response analysis demonstrated a significantly positive slope of 1.3 ms per µg/mL (90% CI: 1.0-1.7). Moxifloxacin met the criteria for assay sensitivity. CONCLUSIONS: Lomitapide does not have an effect on cardiac repolarization. The study's ability to detect small QTc changes was demonstrated with both moxifloxacin and ketoconazole.

Pharmacokinetics, pharmacodynamics, and safety of clevidipine after prolonged continuous infusion in subjects with mild to moderate essential hypertension.

PURPOSE: Clevidipine is a rapidly-acting intravenous dihydropyridine antihypertensive acting via calcium channel blockade. This was a randomized, single-blind, parallel-design study of a 72-h continuous clevidipine infusion. METHOD: Doses of 2, 4, 8, or 16.0 mg/h or placebo were evaluated in 61 subjects with mild to moderate essential hypertension. IV clevidipine or placebo was initiated at 2.0 mg/h and force-titrated in doubling increments every 3 min to target dose, then maintained for 72 h. Blood pressure and heart rate were measured during infusion, and for 4, 6 and 8 h after termination of infusion, although oral therapy could be restarted at 4 h. Clevidipine blood levels were obtained during infusion and for 1 hour after termination. RESULTS: Rapid onset of drug effect occurred at all clevidipine dose levels, with consistent pharmacokinetics and rapid offset after 72-h infusion. No evidence of tolerance to the clevidipine drug effect was observed at any dose level over the 72-h infusion. No evidence of rebound hypertension was found for either 4 or 6 h after termination of the clevidipine infusion. At 8 h following cessation of clevidipine, blood pressure was not significantly higher than at baseline. Placebo-treated subjects had blood pressures lower than baseline at 8 h following infusion termination; hence, placebo-adjusted blood pressures tended to be slightly higher than baseline. CONCLUSION: This study supports the use of up to 72 h of IV clevidipine therapy for the management of blood pressure, with consistent pharmacokinetic/pharmacodynamic characteristics and context insensitive half-life across the dose ranges evaluated.