Kala Pharmaceuticals (United States)

To compare postenhancement visual acuity between patients who underwent postcataract laser in situ keratomileusis (LASIK) or photorefractive keratectomy (PRK). A private, tertiary referral practice in Sioux Falls, South Dakota. 3-year, retrospective chart review. Patients who underwent postcataract extraction excimer laser enhancement surgery targeted for emmetropia (±0.50 diopter). Postenhancement uncorrected distance visual acuity (UDVA) and manifest refraction spherical equivalent (MRSE) was recorded for all available follow-ups and compared for both groups. 822 postcataract enhanced eyes (491 LASIK; 331 PRK). For patients with at least 6-month follow-up, mean UDVA was 0.05 ± 0.13 logMAR in LASIK-enhanced patients and 0.15 ± 0.20 in PRK-enhanced patients ( P < .001). Mean absolute value MRSE was 0.22 ± 0.36 and 0.48 ± 0.62 for LASIK-enhanced and PRK-enhanced patients at or beyond 6 months, respectively ( P < .001). 330 (67%) LASIK-enhanced patients achieved 20/20 or better postenhancement UDVA, compared with 142 (43%) PRK-enhanced patients ( P < .001). Controlling for pre-enhancement UDVA, LASIK-enhanced patients showed significantly better postenhancement UDVA than PRK-enhanced patients, except in those with pre-enhancement vision of 20/20 or better, or those worse than 20/50. LASIK-enhanced virgin corneas had mean postenhancement of 0.05 ± 0.14 UDVA compared with 0.13 ± 0.19 UDVA in PRK-enhanced virgin cornea patients ( P < .001). LASIK provides better and more predictable outcomes in UDVA than PRK in postcataract enhancement patients, even when controlling for pre-enhancement visual acuity and prior ocular procedures.

Single crystals of DB4HPC, a new metal–organic complex, have been grown from saturated solution for the first time. DB4HPC crystallizes in a monoclinic crystal system with noncentrosymmetric space group P21 and is thermally stable up to 240 °C.

Isunakinra, formerly known as EBI-005, is a novel interleukin (IL)-1 receptor inhibitor developed for topical treatment of patients with dry eye disease (DED). This phase 1b/2a multicenter, double-masked, randomized, vehicle controlled environmental trial assessed the safety and biological activity of isunakinra in patients with moderate to severe DED. Subjects (N=74) were randomized to vehicle (placebo) or isunakinra (5 or 20 mg/mL) 3×/daily for 6 weeks. Evaluations included safety, tolerability, biological activity for signs (corneal fluorescein staining [CFS]), symptoms (pain or sore eyes and total Ocular Surface Disease Index [OSDI]), and reduction in rescue artificial tear use. Topical administration of isunakinra (5 and 20 mg/mL) was safe and well tolerated and resulted in clinically relevant improvements in symptoms (OSDI score, painful/sore eye component of OSDI) and signs (total CFS) compared with baseline with no dose response. OSDI scores improved from baseline by 38% (18.9 points) at 6 weeks and CFS scores improved by 33% (3 points) in the isunakinra groups. These changes were not statistically significant compared with the vehicle. Use of artificial rescue tears was significantly reduced in the isunakinra treatment groups (mean=9 vials) compared with vehicle (mean=31 vials). The differences between isunakinra and vehicle treatments were more pronounced in subjects with OSDI scores less than 50 at baseline. Isunakinra was safe, well tolerated and showed clinically meaningful improvements in signs and symptoms of DED. These results encouraged the design of an adequately powered study to characterize the safety and efficacy of isunakinra in ocular surface diseases.

β-Lactams are the most widely used class of antibiotics. Since the discovery of benzylpenicillin in the 1920s, thousands of new penicillin derivatives and related β-lactam classes of cephalosporins, cephamycins, monobactams, and carbapenems have been discovered. Each new class of β-lactam has been developed either to increase the spectrum of activity to include additional bacterial species or to address specific resistance mechanisms that have arisen in the targeted bacterial population. Resistance to β-lactams is primarily because of bacterially produced β-lactamase enzymes that hydrolyze the β-lactam ring, thereby inactivating the drug. The newest effort to circumvent resistance is the development of novel broad-spectrum β-lactamase inhibitors that work against many problematic β-lactamases, including cephalosporinases and serine-based carbapenemases, which severely limit therapeutic options. This work provides a comprehensive overview of β-lactam antibiotics that are currently in use, as well as a look ahead to several new compounds that are in the development pipeline.

Abstract AZD9150 is a gen2.5 antisense oligonucleotide (ASO) targeting STAT3. Gen2.5 ASOs exhibit enhanced drug-like properties compared to previous generations of antisense therapeutics, including increased stability and resistance to nucleases, a marked decrease in proinflammatory effects, and enhanced potency. The immune suppressive effects of STAT3 signaling are well established (Kortylewski et al.; Nat. Med. 2005 and Curr. Opin. Immunol. 2008). Preclinical experiments were carried out to determine the potential for combination of a STAT3 ASO with checkpoint inhibitor therapy, and to explore the mechanism of the antitumor activity of STAT3 ASOs observed in mouse models. The antitumor activity of STAT3 ASO treatment, as a single agent and in combination with checkpoint inhibitors, was evaluated in syngeneic mouse models, including CT-26. ASO uptake and STAT3 knockdown were evaluated by immunohistochemistry (IHC), and the pharmacodynamic effects of STAT3 ASO treatment in mice were evaluated by IHC, flow cytometry and immune gene expression profiling. In contrast to many tumor cell lines, CT26 cells take up ASOs poorly, including gen2.5 ASOs, thus as expected the tumor-associated activity of STAT3 ASOs in CT26 tumors in vivo was primarily in stromal and immune compartments (including circulating PBMCs), rather than directly in tumor cells. This was observed in several murine tumor models, as well as in clinical samples. Expression analysis of CT-26 tumor lysates taken from STAT3 ASO-treated (50 mg/kg QDx5/wk) mice using the Nanostring mouse immunology panel (561 immune related genes) identified CD163 as the gene most consistently modulated after STAT3 ASO treatment, with an average knockdown of 85% relative to control treated tumors, across 3 independent experiments. This result was confirmed by immunohistochemistry, which showed a marked reduction in the number of tumor infiltrating CD163+ cells after STAT3 ASO treatment. CD163 is a marker of M2 macrophages, and the presence of M2 macrophages in a tumor can create an immune suppressive environment which has the potential to reduce the effectiveness of checkpoint inhibitor therapy. Consistent with this hypothesis, the addition of STAT3 ASO treatment enhanced the response to a checkpoint inhibitor antibody targeting PD-L1 (clone 10F.9G2). When treatment began 2 days after tumor implant, single agent STAT3 ASO and PD-L1 antibody treatments resulted in response rates (regression or no tumor growth during the course of the experiment) of 0% and 14% respectively, while the rate was 50% with the combination. The combination remained active when treatments were delayed until established tumors were present (140 mm3 average tumor volume), with single agent and combination regression rates of 0%, and 20% respectively. These results suggest the addition of AZD9150 treatment as a promising approach to enhance the response to checkpoint inhibitor therapy Citation Format: Richard D. Woessner, Patricia McCoon, Shaun Grosskurth, Paul Lyne, Kirsten Bell, Mike Collins, Nanhua Deng, Rachel DuPont, Michele Johnstone, Youngsoo Kim, Deborah Lawson, Robert MacLeod, Lourdes Pablo, Corinne Reimer, Vasu Sah, Margaret Veldman-Jones. STAT3 antisense treatment decreases M2 macrophage infiltration and enhances the activity of checkpoint inhibitors in preclinical tumor models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A94.

Ocular drug delivery has many challenges due to the inherent physiology and natural barriers. Traditionally used eye drops are fairly inefficient with low ocular bioavailability, and drug delivery to the back of the eye currently requires invasive measures, such as implants or frequent intravitreal injections. These challenges, however, present unique opportunities for innovative drug delivery approaches. This review highlights several of these approaches, with special emphasis on those progressing in clinical development.

IntroductionTopical ophthalmic formulations of corticosteroids are commonly used to treat a variety of ocular diseases and conditions that have an inflammatory component. The purpose of this study was to evaluate the effect of the mucus-penetrating particle (MPP) technology on the pharmacokinetic profile of loteprednol etabonate in the ocular tissues of rabbits.MethodsForty-eight New Zealand White rabbits were randomly assigned to two groups (n = 3 rabbits or 6 eyes per time point) and treated with either the novel loteprednol etabonate MPP suspension formulation, 0.4% (LE-MPP 0.4%), or the commercial Lotemax®-brand loteprednol etabonate ophthalmic suspension, 0.5% (Lotemax 0.5%) (Bausch & Lomb Incorporated, Inc., Rochester, NY, USA). Samples of aqueous humor, various ocular tissues, and plasma were collected from animals over a 12-h period after a single dose of the test articles. Loteprednol etabonate concentrations were assayed using liquid chromatography–tandem mass spectrometry (LC/MS/MS).ResultsLoteprednol etabonate was rapidly absorbed into ocular tissues following administration of either formulation. A higher ocular exposure was achieved using LE-MPP 0.4%, with peak concentrations of approximately threefold higher in ocular tissues and the aqueous humor than Lotemax 0.5%.ConclusionsAdministration of LE-MPP 0.4% improved loteprednol etabonate pharmacokinetic profile in ocular tissues of rabbits. The results of this study support the premise that the MPP technology can be used to enhance ocular exposure for topically applied therapeutic agents. Further studies to assess the clinical efficacy and safety of the LE-MPP formulation are warranted.Electronic supplementary materialThe online version of this article (doi:10.1007/s40123-014-0021-z) contains supplementary material, which is available to authorized users.

Abstract Benzaldehyde, C 6 H 5 CHO, is the simplest and possibly the most industrially useful member of the family of aromatic aldehydes. Benzaldehyde exists in nature, primarily in combined forms such as a glycoside in almond, apricot, cherry, and peach seeds. The characteristic benzaldehyde odor of oil of bitter almond occurs because of trace amounts of free benzaldehyde formed by hydrolysis of the glycoside amygdalin. Benzaldehyde is a versatile intermediate because of its reactive aldehyde hydrogen, its carbonyl group, and the benzene ring. The only industrially important processes for the manufacturing of synthetic benzaldehyde involve the hydrolysis of benzal chloride and the air oxidation of toluene. The hydrolysis of benzal chloride is no longer utilized in the United States. Benzaldehyde is produced in the United States by Kalama Chemical Incorporated, Kalama, Washington. Benzaldehyde is sold as technical grade or as meeting the specifications of the National Formulary (NF), the Food Chemicals Codex (FCC), or the British Pharmacopeia (BP). The oral LD 50 for benzaldehyde is reported as 1300 mg/kg in rats and as 1000 mg/kg in guinea pigs. Based upon these values, benzaldehyde is considered a moderately toxic substance when ingested. Overexposure to benzaldehyde vapors is irritating to the upper respiratory tract and produces central nervous system depression, with respiratory failure possible. The low autoignition temperature of benzaldehyde (192°) presents safety problems. Benzaldehyde may also spontaneously ignite when soaked into rags or clothing or adsorbed onto activated carbon. Bulk storage of benzaldehyde should be made under a nitrogen blanket. Benzaldehyde is a synthetic flavoring substance, sanctioned by the U.S. Food and Drug Administration (FDA) to be generally recognized as safe (GRAS) for foods. Both “pure almond extract” and “imitation almond extract” are offered for sale; each contains 2.0–2.5 wt % benzaldehyde. Benzaldehyde is also recognized as safe for use as a bee repellant in the harvesting of honey. Benzaldehyde's most important use is in organic synthesis, where it is the raw material utilized to produce various aldehydes.