Minimally invasive micro sclerostomy (MIMS) procedure in the treatment of open-angle glaucoma.

BACKGROUND: To evaluate the safety and efficacy of the Minimally Invasive Micro Sclerotomy (MIMS) procedure in the management of uncontrolled open-angle glaucoma. METHODS: A prospective, open-label, single-arm clinical evaluation with intra-subject comparisons performed at the Ophthalmologic Center after S.V. Malayan, Yerevan, Armenia. Included were adults with primary open-angle glaucoma (OAG) (N = 114) or exfoliative glaucoma (N = 6) who were uncontrolled (IOP > 21) on tolerated topical medication. Mild (N = 7), moderate (N = 66) and severe (n = 47) cases were prospectively included without preselection. Following subconjunctival Mitomycin C, an ab-interno MIMS procedure was performed alone (N = 100) or combined with phacoemulsification (N = 20). Patients were followed for 52 weeks. Procedure-related complications and adverse events were recorded. Success criteria were defined as -5 < IOP ≤ 21mmHg OR a reduction in IOP of ≥ 20% from baseline with (qualified success) or without (complete success) hypotensive medications. RESULTS: Mean patient age was 69 ± 10.1 years. The mean duration of the procedure was 2:01 ± 0:41 min:sec. Scleral drainage channels were achieved in all cases. No device malfunctions, intraoperative complications, or serious adverse events were reported. Iris plugging of the sclerostomy site and early spikes in IOP were the most common adverse events. The only reason for failure was final IOP > 21 mmHg on tolerated medication. At 52 weeks (n = 93), mean IOP decreased by 38% from baseline (P < 0.001), from 27.9 ± 3.7 to 17.5 ± 5.3 mmHg, a difference of 10.5 mmHg (95% CI: -11.7, -9.3). One-year qualified success was documented in 82.1% (95% CI: 72.9%,89.2%) of the patients and complete success, in 70.5% (60.3-79.4%). 60% (95 CI:49.4%,69.9%) of the patients achieved maximum IOP level of 14 mmHg or at least 30% reduction in IOP. CONCLUSIONS: MIMS procedure is a relatively simple, short and safe minimally invasive bleb-forming procedure. Its efficacy, as found in this short-term evaluation, lends it suitable for mild and moderate uncontrolled open-angle glaucoma patients. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT04503590 2019-05-29.

The effect of laquinimod, a novel immuno-modulator in development to treat Huntington disease, on the pharmacokinetics of ethinylestradiol and levonorgestrel in healthy young women.

PURPOSE: Laquinimod is an orally dosed immuno-modulator currently under development for Huntington's disease (HD). Preclinical findings suggest potential teratogenicity of laquinimod, thus the reproductive ability of females with HD treated with laquinimod needs to be closely managed. Because combined oral contraceptives (COC) are often used in this context, the pharmacokinetics of COC containing ethinylestradiol (EE) and levonorgestrel (LNG) in combination with laquinimod (0.6 mg/day) was evaluated. METHODS: In this randomized, phase-1 single-center, double-blind, placebo-controlled, 2-way crossover drug-drug interaction (DDI) study in 48 healthy premenopausal women, COC were administered in a 28-day regimen of 21 days followed by 7 pill-free days for 4 cycles and laquinimod or placebo was administered for 28 days in cycle 1 and cycle 3 starting 7 days prior to COC administration. Blood samples for pharmacokinetic profiling of laquinimod, EE and LNG were collected on day 21 and day 22 of Cycles 1 and 3 pre-dose and multiple times post-dose. RESULTS: The ratio of geometric means and 90% confidence intervals for AUC0-24 and Cmax of EE and LNG with and without laquinimod were all within the bioequivalence range (80 to 125%). Laquinimod pharmacokinetics was consistent with those observed in previous studies. The adverse event profile was in line with the current knowledge on the safety profile of both drugs, with headache as the most frequently reported treatment-related adverse event. CONCLUSION: The combination of COC and laquinimod treatment was found to be safe, tolerable, and devoid of any noticeable pharmacokinetic interaction.

Direct and cytokine-mediated effects of albumin-fused growth hormone, TV-1106, on CYP enzyme expression in human hepatocytes in vitro.

Some biologics can modulate cytokines that may lead to changes in expression of drug-metabolizing enzymes and cause drug-drug interactions (DDI). DDI potential of TV-1106-an albumin-fused growth hormone (GH)-was investigated. In this study, human blood was exposed to recombinant human growth hormone (rhGH) or TV-1106, followed by isolation of the plasma and its application to human hepatocytes. While the treatment of blood with rhGH increased multiple cytokines, treatment of blood with TV-1106 had no effect on any of the nine cytokines tested. The interleukin (IL)-6 concentration was higher in the rhGH then in the TV-1106-treated plasma (P < .05). While rhGH had little or no effect on CYP1A2 or CYP2C19 mRNA but increased CYP3A4 mRNA twofold, TV-1106 had little or no effect on cytochrome P450 (CYP) mRNAs in hepatocytes. Although the plasma from rhGH-treated blood lowered CYP1A2 activity, the TV-1106 plasma had no effect on CYP activities. The CYP1A2 activity was lower in the rhGH- then in the TV-1106-plasma treated hepatocytes (P < .05). The results indicated that fusing GH with albumin made TV-1106 an unlikely participant of CYP1A2, CYP2C19 or CYP3A4-facilitated, direct or cytokine-driven DDI.

Compositional differences between Copaxone and Glatopa are reflected in altered immunomodulation ex vivo in a mouse model.

Copaxone (glatiramer acetate, GA), a structurally and compositionally complex polypeptide nonbiological drug, is an effective treatment for multiple sclerosis, with a well-established favorable safety profile. The short antigenic polypeptide sequences comprising therapeutically active epitopes in GA cannot be deciphered with state-of-the-art methods; and GA has no measurable pharmacokinetic profile and no validated pharmacodynamic markers. The study reported herein describes the use of orthogonal standard and high-resolution physicochemical and biological tests to characterize GA and a U.S. Food and Drug Administration-approved generic version of GA, Glatopa (USA-FoGA). While similarities were observed with low-resolution or destructive tests, differences between GA and USA-FoGA were measured with high-resolution methods applied to an intact mixture, including variations in surface charge and a unique, high-molecular-weight, hydrophobic polypeptide population observed only in some USA-FoGA lots. Consistent with published reports that modifications in physicochemical attributes alter immune-related processes, genome-wide expression profiles of ex vivo activated splenocytes from mice immunized with either GA or USA-FoGA showed that 7-11% of modulated genes were differentially expressed and enriched for immune-related pathways. Thus, differences between USA-FoGA and GA may include variations in antigenic epitopes that differentially activate immune responses. We propose that the assays reported herein should be considered during the regulatory assessment process for nonbiological complex drugs such as GA.

Safety and in vivo immune assessment of escalating doses of oral laquinimod in patients with RRMS.

BACKGROUND: Laquinimod is an oral immunomodulator in clinical development to treat relapsing-remitting multiple sclerosis (RRMS). Laquinimod is in clinical development for the treatment of multiple sclerosis and Huntington Disease (HD). The objective of this study is to assess the safety, tolerability, pharmacokinetics (PK) and cytoimmunologic effects following escalating doses of laquinimod in patients with RRMS. METHODS: One hundred twelve patients were randomly assigned to laquinimod/placebo in a series of separate dose-escalating cohorts starting from a daily oral dose of 0.9 mg/1.2 mg escalating to 2.7 mg, in 0.3 mg increments. RESULTS: Twenty-eight patients received placebo and 84 received laquinimod ranging from 0.9 to 2.7 mg. No deaths occurred. One serious adverse event (SAE) of perichondritis was reported, which was unrelated to laquinimod (0.9 mg). There was no increased incidence of adverse events (AEs) with escalating doses. Laquinimod-treated patients showed more abnormal laboratory levels in liver enzymes, P-amylase, C-reactive protein (CRP), and fibrinogen, but most shifts were clinically non-significant. The exposure of laquinimod was dose proportional and linear in the tested dose range. An immunological substudy showed significant dose-dependent decreases in 6-sulpho LacNAc + dendritic cell (slanDC) frequency following laquinimod compared to placebo. CONCLUSION: Laquinimod doses up to 2.7 mg were safely administered to patients with RRMS. An in vivo effect of laquinimod on the innate immune system was demonstrated. TRIAL REGISTRATION: EudraCT Number: 2009-011234-99 . Registered 23 June 2009.

Immune parameters of patients treated with laquinimod, a novel oral therapy for the treatment of multiple sclerosis: results from a double-blind placebo-controlled study.

Laquinimod is a novel orally administered drug for the treatment of relapsing remitting multiple sclerosis (RRMS). In this immunological substudy of the phase III Assessment of Oral Laquinimod in Preventing Progression of MS (ALLEGRO) trial, we performed an ex vivo and in vitro analysis of effects exerted by laquinimod on peripheral blood immune cell populations from RRMS patients with a special focus on monocyte phenotype and function. Approximately 100 patients were enrolled following a standardized protocol. Half of the patients received laquinimod and the other half received placebo. Peripheral blood samples were collected prior to commencement of therapy and after 1, 3, 6, 12, and 24 months of continuous therapy. Main lymphocytic and antigen presenting cell fractions were analyzed in peripheral blood mononuclear cells (PBMCs) ex vivo by flow cytometry. The proliferative response of PBMCs to mitogen or recall antigen was assessed in culture experiments. Untouched monocytes were sorted magnetically and cultured under pro-inflammatory conditions. PBMC analysis showed no significant differences of investigated lymphocytic and antigen presenting cell populations over time within each group, or between the two groups. However, the detailed in vitro analysis of monocytes demonstrated a lower level of CD86 expression on monocytes stimulated with LPS in laquinimod patients beginning from the 1st month of treatment. Upon pro-inflammatory stimulation, monocytes obtained from laquinimod treated patients tended to secrete lower levels of the proinflammatory chemokines CCL2 or CCL5. Taken together, in this prospective study, we demonstrate immune modulation but no immunosuppressive biological activity of laquinimod in a large group of MS patients.