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Novel hyaluronic acid-methotrexate conjugate suppresses joint inflammation in the rat knee: efficacy and safety evaluation in two rat arthritis models.

Methotrexate (MTX) is one of the most widely used medications to treat rheumatoid arthritis (RA), and recent studies have also suggested the potential benefit of the drug for the treatment of osteoarthritis (OA) of the knee. MTX is commonly administered in oral formulations, but is often associated with systemic adverse reactions. In an attempt to address this issue, we have shown previously that a conjugate of hyaluronic acid (HA) and MTX exhibits potential as a drug candidate for intra-articular treatment of inflammatory arthritis. In this study, we compare the efficacy and safety of an optimized HA-MTX conjugate, DK226, with that of MTX in inflammatory arthritis rat models.
In vitro activity of DK226 was assessed in human fibroblast-like synoviocytes (HFLS) and a synovial sarcoma cell line, SW982. Release of MTX from DK226 was investigated after incubation with rabbit synovial tissue homogenate or synovial fluid. In vivo efficacy of DK226 was evaluated in antigen-induced arthritis (AIA) and collagen-induced arthritis (CIA) in the rat knee. Pharmacokinetics and hematological toxicity after treatment with oral MTX or an intra-articular injection of DK226 were compared in AIA.
Proliferation of HFLS and SW982 cells was inhibited by DK226, and the inhibitory activity was reversed by cotreatment with excess HA or anti-CD44 antibody. MTX was released from DK226 by incubation with rabbit synovial tissue homogenate or synovial fluid at pH 4.0, but not at pH 7.4. AIA was ameliorated by intra-articular DK226, but not by HA, as potently as oral MTX. Hematological toxicity was induced by oral MTX, but not by DK226. The maximum plasma concentration of MTX after oral MTX was 40 times higher than the concentration of MTX after an intra-articular injection of DK226. Knee swelling in AIA was inhibited by intra-articular injections of DK226, but not by free MTX or a mixture of HA and MTX. In CIA, an injection of DK226 into the right knee joint significantly reduced swelling and synovial inflammation of the treated knee joint, but had no effect on the untreated contralateral knee joint.
DK226 exerted anti-arthritic effects in two different models of arthritis. The conjugate had a wider therapeutic window than oral MTX, and could be a future drug for treatment of arthritic disorders, including inflammatory OA.

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Anticholinergic medication use and falls in postmenopausal women: findings from the women’s health initiative cohort study.

Results from studies assessing the association between anticholinergic use and falls are mixed, and prior studies are limited in their ability to control for important potential confounders. Thus, we sought to examine the association between anticholinergic medication use, including over-the-counter medications, and recurrent falls in community-dwelling older women.
We analyzed data from a prospective cohort study of women aged 65 to 79 years from the Women’s Health Initiative Observational Study and Clinical Trials. Women were recruited between 1993 and 1998, and analyses included 61,451 women with complete information. Medications with moderate or strong anticholinergic effects were ascertained directly from drug containers during face-to-face interviews. The main outcome measure was recurrent falls (≥2 falls in previous year), which was determined from self-report within 1.5 years subsequent to the medication assessment.
At baseline, 11.3 % were using an anticholinergic medication, of which antihistamines (commonly available over-the-counter) were the most common medication class (received by 45.2 % of individuals on anticholinergic medication). Using multivariable GEE models and controlling for potential confounders, the adjusted odds ratio for anticholinergic medication use was 1.51 (95 % CI, 1.43-1.60) for recurrent falls. Participants using multiple anticholinergic medications had a 100 % increase in likelihood of recurrent falls (adjusted odds ratio 2.00, 95 % CI 1.73-2.32). Results were robust to sensitivity analysis.
Anticholinergic medication use was associated with increased risk for recurrent falls. Our findings reinforce judicious use of anticholinergic medications in older women. Public health efforts should emphasize educating older women regarding the risk of using over-the-counter anticholinergics, such as first-generation antihistamines.

Gilead Sciences Announces Acquisition of Nimbus Therapeutics’ Acetyl-Coa Carboxylase (ACC) Program for Nash and Other Liver Diseases

On April 4, 2016 Gilead Sciences and Nimbus Therapeutics reported that the companies have signed a definitive agreement under which Gilead will acquire Nimbus Apollo, Inc., a wholly-owned subsidiary of Nimbus Therapeutics, and its Acetyl-CoA Carboxylase (ACC) inhibitor program (Press release, Nimbus Therapeutics, APR 4, 2016, View Source [SID1234527317]). Nimbus Therapeutics will receive an upfront payment of $400 million, with the potential to receive an additional $800 million in development-related milestones over time.

The Nimbus Apollo program includes the lead candidate NDI-010976, an ACC inhibitor, and other preclinical ACC inhibitors for the treatment of non-alcoholic steatohepatitis (NASH), and for the potential treatment of hepatocellular carcinoma (HCC) and other diseases. NDI-010976 was granted Fast Track designation by the U.S. Food and Drug Administration (FDA) in February 2016 and Phase 1 data for the compound will be presented next month during an oral session at The International Liver Congress 2016, the annual meeting of the European Association for the Study of the Liver (EASL).

NASH is a serious liver disease resulting from metabolic dysfunction associated with steatosis (fat within the liver) that can lead to inflammation, hepatocellular injury, progressive fibrosis and cirrhosis. Affecting up to 15 million people in the United States, NASH is expected to become the leading indication for liver transplantation by 2020. ACC inhibitors target a central cause of the disease – reducing aberrant lipid-derived signaling that can result in steatosis, inflammation and fibrosis.

"The acquisition of Nimbus’ ACC-inhibitor program represents a timely and important opportunity to accelerate Gilead’s ongoing efforts to address unmet needs in NASH," said Norbert Bischofberger, PhD, Executive Vice President, Research and Development and Chief Scientific Officer, Gilead Sciences. "These molecules will complement and further strengthen Gilead’s pipeline and capabilities to advance a broad clinical program in NASH that includes compounds targeting multiple key pathways involved in the pathogenesis of the disease."

"Given the company’s long-standing commitment to and expertise in liver disease, we are confident that Gilead is the ideal partner to accelerate and maximize the potential of the ACC inhibitor program," said Don Nicholson, PhD, Chief Executive Officer of Nimbus Therapeutics. "This agreement underscores Nimbus’ ability to rapidly discover, design and optimize promising therapeutics in areas of unmet need, an approach we will continue to apply against other medically important targets."

Upon completion of the acquisition, Nimbus Apollo will become a wholly-owned subsidiary of Gilead. Nimbus Therapeutics will retain ownership of its other research and development subsidiaries. Gilead will be solely responsible for future development and commercialization of NDI-010976 and other ACC inhibitors.

About ACC and NDI-010976
Acetyl-CoA carboxylase (ACC) is an enzyme with two isoforms (ACC1 and ACC2) that is involved in de novo lipogenesis (the synthesis of endogenous fatty acids) and the regulation of beta-oxidation (the process by which fatty acids are broken down at a cellular level). Inhibitors of ACC therefore have the potential to prevent production of new lipids within the liver and stimulate their break down. In animal models of fatty liver, ACC inhibition reduces hepatic fat content, inflammation and fibrosis (scarring), all of which are important hallmarks of NASH progression. NDI-010976 is a potent, liver-targeted, allosteric inhibitor of both ACC isoforms.

CRT SIGNS AGREEMENT WITH CIMASS FOR THE DEVELOPMENT OF A MONOCLONAL ANTIBODY IN THE TREATMENT OF CANCER

On April 4, 2016 CRT reported that it has signed an agreement with CiMass, under which CiMass will test a proprietary monoclonal antibody in combination with natural killer cells for the treatment of cancer (Press release, Cancer Research Technology, APR 4, 2016, View Source [SID1234523501]).

CiMaas is developing cellular immunotherapy for various cancer patients, including natural killer cells for adoptive transfer to patients with breast cancer and multiple myeloma. Natural killer cells are able to efficiently kill cancer cells, but this killing can still be enhanced by addition of monoclonal antibodies. The current agreement allows CiMaas to further develop a monoclonal antibody directed against an undisclosed target to enhance the immune response mediated by natural killer cells to tumour tissue.

CiMaas will use additional technology to improve the antibody and test its efficacy in proof of concept experiments. Under the agreement CiMaas receives one year exclusivity to explore the antibody’s functionality in natural killer cell-related therapies and CRT receives a signature fee in return.

DEP cabazitaxel shows complete and sustained tumour regression in breast cancer model

On April 4, 2016 Starpharma ( ASX: SPL, OTCQX: SPHRY) reported further efficacy results of its most recent DEP candidate, DEP cabazitaxel, in a human breast cancer model (Press release, Starpharma, APR 4, 2016, View Source [SID:1234510381]). These data will be presented along with an overview of Starpharma’s DEP platform at the BioEurope Spring 2016 conference in Stockholm later this week.

DEP cabazitaxel is Starpharma’s dendrimer-enhanced, water soluble (detergent free) version of the leading cancer drug, Jevtana (cabazitaxel). Jevtana is marketed by Sanofi-Aventis with 2015 sales of ~US$430M growing at approximately 18% per annum. It is currently registered for use in advanced prostate cancer and is also under development for a number of other cancers, including breast cancer. Like docetaxel, Jevtana (cabazitaxel) is formulated with a detergent (polysorbate 80) due to its poor solubility and can be associated with anaphylaxis and neutropenia. In contrast, DEPTM cabazitaxel is completely detergent free.

Starpharma’s DEP cabazitaxel was compared with Jevtana in a human breast cancer preclinical model (xenograft). DEP cabazitaxel significantly outperformed Jevtana with respect to both level and duration of tumour regression (anticancer activity). Within four weeks of dosing, 100% of mice treated with Starpharma’s DEP cabazitaxel were tumour-free and remained so for the duration of the extended study (150 days). In contrast, the Jevtana treated group exhibited significant tumour regrowth from day 60 onwards (Figure 1). Tumour growth in both drug treated groups was significantly inhibited compared with the vehicle group (P<0.0001)[i].

DEP cabazitaxel also significantly outperformed Jevtana in terms of survival in the model. DEP cabazitaxel treated animals showed 100% survival to the end of the experiment (150 days), and survival was significantly prolonged vs Jevtana (Figure 2). The Jevtana treatment group also had a significantly better survival outcome vs. vehicle group (P<0.0001)[ii].

Starpharma Chief Executive, Dr Jackie Fairley, commented, "We are very encouraged by these results for DEP cabazitaxel, our latest development candidate. The growing body of evidence of both efficacy-enhancement and survival benefits with DEP formulations is very positive and illustrates the utility and platform nature of Starpharma’s DEP technology.

"Early indications for DEP cabazitaxel are that it also demonstrates similar safety benefits to what we have seen with DEPTM docetaxel and other DEP conjugates in terms of reduced bone marrow toxicity. Additional benefits may also be seen as the DEP formulation is polysorbate 80 (detergent) free. The results from this study clearly demonstrate sustained efficacy and survival benefits for DEP cabazitaxel compared to Jevtana, and follow recently-announced impressive sustained efficacy results with our HER2-targeted DEP conjugate."

About Jevtana
Jevtana is an oncology product marketed by Sanofi-Aventis with 2015 sales of ~US$430M growing at approximately 18% per annum. Jevtana is currently marketed for the treatment of hormone refractory metastatic prostate cancer and is also in clinical development for a variety of cancers including breast, bladder, head and neck, and others. Jevtana often works in docetaxel resistant cancer types, but is generally associated with greater toxicity than docetaxel. Jevtana has a ‘Black Box’ warning for the dose-limiting toxicity, neutropenia, and warnings due to anaphylaxis from polysorbate 80.