The holistic approach to psoriasis patients with comorbidities: the role of investigational drugs.

INTRODUCTION: Psoriasis is a high-burden syndrome characterized by cutaneous and extracutaneous manifestations that profoundly reduce patients' quality of life. The presence of concomitant comorbidities often represents a limit to the most appropriate psoriasis treatment that will be overcome by the development of drugs effective for diseases with common pathogenetic pathways. AREAS COVERED: The current review summarizes the latest findings on investigational drugs for psoriasis and their role on potentially concomitant diseases that share similar pathogenetic pathways. EXPERT OPINION: The development of novel drugs that target key-molecules in the pathogenesis of several diseases, including psoriasis, will impact on the reduction of polypharmacy and drug interaction with increased patients' compliance to treatment, wellbeing, and quality of life. Certainly, the efficacy and safety profile of each novel agent must be defined and evaluated in real-life since the performance may vary according to comorbidities and their severity. Anyway, future is now, and research must continue in this direction.

The New S7B/E14 Question and Answer Draft Guidance for Industry: Contents and Commentary.

In August 2020, the International Council on Harmonisation (ICH) released a new draft document, which for the first time combined nonclinical (S7B) and clinical (E14) Questions and Answers (Q&As) into 1 document. FDA describes the revision as a "value proposition": if the human ether-à-go-go assay and the in vivo study are performed in a standardized way, the number of dedicated thorough QT (TQT) studies can be reduced. In this article, we describe and discuss the Q&As that relate to clinical ECG evaluation. If supported by negative standardized nonclinical assays, Q&A 5.1 will obviate the need for a TQT study in the case that a >2-fold exposure margin vs high clinical scenario cannot be obtained. Q&A 6.1 addresses drugs that are poorly tolerated in healthy subjects and cannot be studied at high doses or in placebo-controlled studies; it therefore mainly applies to oncology drugs. It will enable sponsors to claim that a new drug has a "low likelihood of proarrhythmic effects" in the case that the mean corrected QT effect is <10 milliseconds at the time of market application. The E14 2015 revision allowed application of concentration-corrected QT analysis on data from routinely performed clinical pharmacology studies, for example, the first-in-human study and the proportion of dedicated TQT studies has since steadily decreased. It can be foreseen that the proposed new revision will further reduce the number of TQT studies. To achieve harmonization across regulatory regions, it seems important to reach consensus within the International Council on Harmonisation group on the new threshold proposed in 6.1. For this purpose, the Implementation Working Group has asked for public comments.

Regorafenib, an investigational agent for the treatment of cholangiocarcinoma.

INTRODUCTION: Cholangiocarcinoma is a prevalent gastrointestinal cancer with a high mortality rate. A limited number of cholangiocarcinoma patients are diagnosed with early-stage disease but unfortunately, most patients present with an advanced-stage disease which is not amenable to curative surgical resection. AREAS COVERED: We discuss regorafenib, a multi-kinase inhibitor, which has been investigated as a therapeutic agent in advanced stage biliary tract cancer patients in phase II trials. We examined the efficacy and toxicity of this agent and its potential in this patient population in the future. We also provide further insights on novel approaches to optimize the efficacy of regorafenib in cholangiocarcinoma patients. EXPERT OPINION: The recent phase II trials of single-agent regorafenib in advanced stage biliary tumors revealed a modest activity in non enriched patient population and is currently part of the national comprehensive cancer network (NCCN) guidelines (Level 2B) in the refractory setting. However, more opportunities for this agent exist in combination approaches with other therapeutics such as immune checkpoint inhibitors. It is also important to recognize that the paradigm has significantly shifted for targeted therapy to more specific and more potent tyrosine kinase inhibitors targeting specific actionable genes.

Safety, Tolerability, and Physiological Effects of AXA1665, a Novel Composition of Amino Acids, in Subjects With Child-Pugh A and B Cirrhosis.

INTRODUCTION: AXA1665 is a novel investigational amino acid (AA) composition specifically designed to impact AA imbalance, ammoniagenesis, and dysregulated anabolic activity associated with cirrhosis. METHODS: This 2-part study examined AXA1665 effects on safety, tolerability, and hepatic/muscle physiology in subjects with Child-Pugh A and B cirrhosis. Part 1 established plasma ammonia and AA concentration baselines with a standardized protein supplement. Part 2 included two 15-day domiciled periods separated by a 14-day washout. In period 1, subjects were randomly distributed to 2 groups: AXA1665 14.7 g t.i.d. (group 1) or control t.i.d. (group 2). In period 2, subjects from group 1 crossed over to control and those in group 2 crossed over to AXA1665 4.9 g t.i.d. All subjects were maintained on standard of care (standardized meals; 30-minute daily, supervised, mandatory physical activity; and daily late-evening snack). RESULTS: In parts 1 and 2, 23 and 17 participants were enrolled, respectively. Dose-dependent increases were observed in plasma concentrations of AXA1665-constituent AAs. Fasted branched-chain AA-to-aromatic AA and valine-to-phenylalanine ratios were both increased (AXA1665 14.7 g t.i.d. control-adjusted change: 44.3% ± 2.7% and 47.2% ± 3.9%, respectively; P < 0.0001). Despite provision of additional nitrogen, mean fasted plasma ammonia concentration at day 15 numerically decreased (-21.1% in AXA1665 14.7 g t.i.d. vs -3.8% in control; P > 0.05). AXA1665 14.7 g t.i.d. produced a leaner body composition and significantly decreased Liver Frailty Index at day 15 vs control (-0.70 ± 0.15 vs -0.14 ± 0.17; P < 0.05). AXA1665 was safe and well tolerated. DISCUSSION: AXA1665 has potential to mitigate core metabolic derangements associated with cirrhosis.

Practice considerations on the use of investigational anti-COVID-19 medications: Dosage, administration and monitoring.

WHAT IS KNOWN AND OBJECTIVE: Understanding investigational medications is important. Many older drugs are being investigated for repurposing against COVID-19. We comment on various drugs currently undergoing such trials to optimize their safe use. COMMENT: We describe medications used during early COVID-19 outbreaks in South Korea, focusing on practice aspects including the method of drug administration, drug formulation, patient-monitoring for adverse reactions and drug interactions informed by our experience during the 2015 outbreak of Middle East respiratory syndrome (MERS). We comment on hydroxychloroquine, chloroquine, lopinavir/ritonavir with zinc supplement, remdesivir, tocilizumab, ciclesonide, niclosamide and high-dose intravenous immunoglobulin (IVIG). WHAT IS NEW AND CONCLUSION: Effective therapies are urgently needed to manage COVID-19, and existing drugs such as antivirals and antimalarials are under investigation for repurposing to meet this need. This process requires up-to-date drug information to ensure optimum use, particularly safety and efficacy profiles of the medications, until convincing evidence is reported.

A Physiologically Based in Silico Tool to Assess the Risk of Drug-Related Crystalluria.

Drug precipitation in the nephrons of the kidney can cause drug-induced crystal nephropathy (DICN). To aid mitigation of this risk in early drug discovery, we developed a physiologically based in silico model to predict DICN in rats, dogs, and humans. At a minimum, the likelihood of DICN is determined by the level of systemic exposure to the molecule, the molecule's physicochemical properties and the unique physiology of the kidney. Accordingly, the proposed model accounts for these properties in order to predict drug exposure relative to solubility along the nephron. Key physiological parameters of the kidney were codified in a manner consistent with previous reports. Quantitative structure-activity relationship models and in vitro assays were used to estimate drug-specific physicochemical inputs to the model. The proposed model was calibrated against urinary excretion data for 42 drugs, and the utility for DICN prediction is demonstrated through application to 20 additional drugs.

GS-0976 (Firsocostat): an investigational liver-directed acetyl-CoA carboxylase (ACC) inhibitor for the treatment of non-alcoholic steatohepatitis (NASH).

Introduction: De novo lipogenesis (DNL) plays a major role in fatty acid metabolism and contributes significantly to triglyceride accumulation within the hepatocytes in patients with nonalcoholic steatohepatitis (NASH). Acetyl-CoA carboxylase (ACC) converts acetyl-CoA to malonyl CoA and is a rate-controlling step in DNL. Furthermore, malonyl-CoA is an important regulator of hepatic mitochondrial fat oxidation through its ability to inhibit carnitine palmitoyltransferase I. Therefore, inhibiting ACC pharmacologically represents an attractive approach to treating NASH.Areas covered: This article summarizes preclinical and clinical data on the efficacy and safety of the liver-targeted ACC inhibitor GS-0976 (Firsocostat) for the treatment of NASH. In a phase 2 trial that included 126 patients with NASH and fibrosis, GS-0976 20 mg daily for 12 weeks showed significant relative reduction in liver fat by 29%; however, treatment was associated with an increase in plasma triglycerides with 16 patients having levels >500 mg/dL.Expert opinion: Preclinical and preliminary clinical data support the development of GS-0976 as treatment for NASH. ACC-induced hypertriglyceridemia can be mitigated by fish oil or fibrates, but the long-term cardiovascular effects require further investigations.

MIDD0301 - A first-in-class anti-inflammatory asthma drug targets GABAA receptors without causing systemic immune suppression.

We report a 28-day repeat dose immunotoxicity evaluation of investigational drug MIDD0301, a novel oral asthma drug candidate that targets gamma amino butyric acid type A receptors (GABAA R) in the lung. The study design employed oral administration of mice twice daily throughout the study period with 100 mg/kg MIDD0301 mixed in peanut butter. Compound dosing did not reveal signs of general toxicity as determined by animal weight, organ weight or haematology. Peanut butter plus test drug (in addition to ad libitum standard rodent chow) did not affect weight gain in the adult mice, in contrast to weight loss in 5 mg/kg prednisone-treated mice. Spleen and thymus weights were unchanged in MIDD0301-treated mice, but prednisone significantly reduced the weight of those organs over the 28-day dosing. Similarly, no differences in spleen or thymus histology were observed following MIDD0301 treatment, but prednisone treatment induced morphological changes in the spleen. The number of small intestine Peyer's patches was not affected by MIDD0301 treatment, an important factor for orally administered drugs. Circulating lymphocyte, monocyte and granulocyte numbers were unchanged in the MIDD0301-treated animals, whereas differential lymphocyte numbers were reduced in prednisone-treated animals. MIDD0301 treatment did not alter IgG antibody responses to dinitrophenyl following dinitrophenyl-keyhole limpet haemocyanin immunization, indicating that systemic humoral immune function was not affected. Taken together, these studies show that repeated daily administration of MIDD0301 is safe and not associated with adverse immunotoxicological effects in mice.

The Early Preclinical Development Program for Locally Administered Investigational Medicinal Products in Ophthalmology: Preclinical Data Required for Starting a First-in-Human Clinical Trial in Europe-Basic Considerations and 2 Case Studies.

BACKGROUND: Although regulatory guidance defines which preclinical data are required in general before proceeding to first-in-human clinical trials, a certain level of flexibility exists in the actual planning, timing, and design of a drug development program. Developing an ophthalmic medicinal product adds additional challenges, since the eye is a complex organ with unique features and specialized ophthalmic guidance documents are sparse. METHODS: We analyzed the preclinical guidelines with a focus on European Union legislation and guidance documents provided by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). We elaborated the particularities specific to ophthalmic drug developments and deduced the preclinical knowledge needed to safely enter a first-in-human trial program. Two hypothetical medicinal products for ophthalmic indications were chosen and specificities for ophthalmic preclinical tests were elaborated. RESULTS AND CONCLUSION: We conclude that the preclinical program of ophthalmic medicines is flexible and differs, based on the intended use and the nature of the active substance.

WTX101 - an investigational drug for the treatment of Wilson disease.

INTRODUCTION: Wilson disease (WD) is a genetic disorder in which excess toxic copper accumulates in the liver, brain, and other tissues leading to severe and life-threatening symptoms. Copper overload can be assessed as non-ceruloplasmin-bound copper non-ceruloplasmin-bound copper (NCC) in blood. Current therapies are limited by efficacy, safety concerns, and multiple-daily dosing. Areas covered: This article reviews the literature on WTX101 (bis-choline tetrathiomolybdate), an oral first-in-class copper-protein-binding agent in development for the treatment of WD. Expert opinion: In a proof-of-concept phase II trial, once-daily WTX101 over 24 weeks rapidly lowered NCC levels and this was accompanied by improved neurological status without apparent initial drug-induced paradoxical worsening, reduced disability, stable liver function, with a favorable safety profile. WTX101 directly removes excess copper from intracellular hepatic copper stores and also forms an inert tripartite complex with copper and albumin in the circulation and promotes biliary copper excretion. These mechanisms may explain the rapid biochemical and clinical improvements observed. A phase III trial of WTX101 is ongoing and results are eagerly awaited to confirm if WTX101 can improve the treatment of this devastating disease.

Superior Glycemic Control With a Glucose-Responsive Insulin Analog: Hepatic and Nonhepatic Impacts.

We evaluated the hepatic and nonhepatic responses to glucose-responsive insulin (GRI). Eight dogs received GRI or regular human insulin (HI) in random order. A primed, continuous intravenous infusion of [3-3H]glucose began at -120 min. Basal sampling (-30 to 0 min) was followed by two study periods (150 min each), clamp period 1 (P1) and clamp period 2 (P2). At 0 min, somatostatin and GRI (36 ± 3 pmol/kg/min) or HI (1.8 pmol/kg/min) were infused intravenously; basal glucagon was replaced intraportally. Glucose was infused intravenously to clamp plasma glucose at 80 mg/dL (P1) and 240 mg/dL (P2). Whole-body insulin clearance and insulin concentrations were not different in P1 versus P2 with HI, but whole-body insulin clearance was 23% higher and arterial insulin 16% lower in P1 versus P2 with GRI. Net hepatic glucose output was similar between treatments in P1. In P2, both treatments induced net hepatic glucose uptake (HGU) (HI mean ± SEM 2.1 ± 0.5 vs. 3.3 ± 0.4 GRI mg/kg/min). Nonhepatic glucose uptake in P1 and P2, respectively, differed between treatments (2.6 ± 0.3 and 7.4 ± 0.6 mg/kg/min with HI vs. 2.0 ± 0.2 and 8.1 ± 0.8 mg/kg/min with GRI). Thus, glycemia affected GRI but not HI clearance, with resultant differential effects on HGU and nonHGU. GRI holds promise for decreasing hypoglycemia risk while enhancing glucose uptake under hyperglycemic conditions.

A simple in chemico method for testing skin sensitizing potential of chemicals using small endogenous molecules.

Among many of the validated methods for testing skin sensitization, direct peptide reactivity assay (DPRA) employs no cells or animals. Although no immune cells are involved in this assay, it reliably predicts the skin sensitization potential of a chemical in chemico. Herein, a new method was developed using endogenous small-molecular-weight compounds, cysteamine and glutathione, rather than synthetic peptides, to differentiate skin sensitizers from non-sensitizers with an accuracy as high as DPRA. The percent depletion of cysteamine and glutathione by test chemicals was measured by an HPLC equipped with a PDA detector. To detect small-size molecules, such as cysteamine and glutathione, a derivatization by 4-(4-dimethylaminophenylazo) benzenesulfonyl chloride (DABS-Cl) was employed prior to the HPLC analysis. Following test method optimization, a cut-off criterion of 7.14% depletion was applied to differentiate skin sensitizers from non-sensitizers in combination of the ratio of 1:25 for cysteamine:test chemical with 1:50 for glutathione:test chemical for the best predictivity among various single or combination conditions. Although overlapping HPLC peaks could not be fully resolved for some test chemicals, high levels of sensitivity (100.0%), specificity (81.8%), and accuracy (93.3%) were obtained for 30 chemicals tested, which were comparable or better than those achieved with DPRA.

Current and Under Development Treatment Modalities of Psoriasis: A Review.

BACKGROUND AND OBJECTIVE: Psoriasis is a chronic and complex autoimmune inflammatory skin disease that affects over 125 million people worldwide. It can exhibit at any age, in spite of the fact that children are less normally influenced than adults. It is characterized by distinct erythematous plaques shielded with conspicuous silvery scales that shows up in different areas of the skin. Knowledge of pathophysiology, especially the pathogenesis of psoriasis, has significantly progressed in the recent decade. Advancement in molecular knowledge leads to better understanding of the disease, thus influencing the development of efficient treatment modalities. However, even with the availability of various options of treatment most of the efficient treatment modalities are costly. Expenses of health care bring about major financial weight to the patients as well as to health care systems. Thus, it was important to review the available current treatment options and those which are under development, in terms of efficacy, safety and cost to assist in selecting the most appropriate treatment for psoriasis patients. METHODS: Literatures were searched by using key words psoriasis, topical treatment, systemic treatment, biologics and phototherapies, on Embase, Medline, Jstor, Cochrane and Merck Index databases. RESULTS: Life-style choices such as smoking, alcohol consumption, obesity and stress are recognised as risk factors and triggers associated with psoriasis. Psoriasis poses psycho-social and economic burden on affected patients that sometimes leads to depression, reduced social interaction and suicidal tendencies in patients. Depending on the type, severity and extent of the disease, comorbidities, patient preference, efficacy and safety profile, numerous treatment modalities and therapeutic agents are available such as topical, systemic, biologic and phototherapeutic treatments. However, it was found that among all the current available treatments for psoriasis, biologic agents and phototherapeutic modalities are the most commonly employed treatment modalities for moderate to severe psoriasis. CONCLUSION: Evaluation of present-day available treatment alternatives will surely help physician to select a suitable module for each patient while keeping in mind the financial status of the patient. Future research should aim to develop therapies which are efficient, safe and cost-effective.

Evaluating the Renal Safety of Investigational New Drugs: Where Should We Be Going?

We the authors work in the US Food and Drug Administration (FDA) review division responsible for the therapeutic agents for primary renal disease. We also field consultative inquiries regarding off-target adverse renal effects of drugs intended to treat other diseases. We do neither basic science research on renal diseases nor clinical studies of new drugs, but we are professional spectators of both. We offer here our thoughts on the challenge of identifying renal safety signals in the preclinical space and in the earliest phases of clinical development.

Major achievements of evidence-based traditional Chinese medicine in treating major diseases.

A long history of use and extensive documentation of the clinical practices of traditional Chinese medicine resulted in a considerable number of classical preparations, which are still widely used. This heritage of our ancestors provides a unique resource for drug discovery. Already, a number of important drugs have been developed from traditional medicines, which in fact form the core of Western pharmacotherapy. Therefore, this article discusses the differences in drug development between traditional medicine and Western medicine. Moreover, the article uses the discovery of artemisinin as an example that illustrates the "bedside-bench-bedside" approach to drug discovery to explain that the middle way for drug development is to take advantage of the best features of these two distinct systems and compensate for certain weaknesses in each. This article also summarizes evidence-based traditional medicines and discusses quality control and quality assessment, the crucial steps in botanical drug development. Herbgenomics may provide effective tools to clarify the molecular mechanism of traditional medicines in the botanical drug development. The totality-of-the-evidence approach used by the U.S. Food and Drug Administration for botanical products provides the directions on how to perform quality control from the field throughout the entire production process.

Cancer combination therapies with artemisinin-type drugs.

Artemisia annua L. is a Chinese medicinal plant, which is used throughout Asia and Africa as tea or press juice to treat malaria. The bioactivity of its chemical constituent, artemisinin is, however, much broader. We and others found that artemisinin and its derivatives also exert profound activity against tumor cells in vitro and in vivo. Should artemisinin-type drugs be applied routinely in clinical oncology in the future, then it should probably be as part of combination therapy regimens rather than as monotherapy. In the present review, I give a comprehensive overview on synergistic and additive effects of artemisinin-type drugs in combination with different types of cytotoxic agents and treatment modalities: (a) standard chemotherapeutic drugs, (b) radiotherapy and photodynamic therapy, (c) established drugs for other indications than cancer, (d) novel synthetic compounds, (e) natural products and natural product derivatives, (f) therapeutic antibodies and recombinant proteins, and (g) RNA interference. I also summarize the activity of artemisinin-type drugs towards multidrug-resistant cells and tumor cells with other drug resistance phenomena. As synergistic interactions may not only occur in tumor cells, toxic reactions in normal cells (hepatotoxicity, drug interactions) were also considered. This review summarizes the scientific literature of more than 20years until the end of 2016.

Is there a future for andrographolide to be an anti-inflammatory drug? Deciphering its major mechanisms of action.

Andrographis paniculata has long been part of the traditional herbal medicine system in Asia and in Scandinavia. Andrographolide was isolated as a major bioactive constituent of A. paniculata in 1951, and since 1984, andrographolide and its analogs have been scrutinized with modern drug discovery approach for anti-inflammatory properties. With this accumulated wealth of pre-clinical data, it is imperative to review and consolidate different sources of information, to decipher the major anti-inflammatory mechanisms of action in inflammatory diseases, and to provide direction for future studies. Andrographolide and its analogs have been shown to provide anti-inflammatory benefits in a variety of inflammatory disease models. Among the diverse signaling pathways investigated, inhibition of NF-κB activity is the prevailing anti-inflammatory mechanism elicited by andrographolide. There is also increasing evidence supporting endogenous antioxidant defense enhancement by andrographolide through Nrf2 activation. However, the exact pathway leading to NF-κB and Nrf2 activation by andrographolide has yet to be elucidated. Validation and consensus on the major mechanistic actions of andrographolide in different inflammatory conditions are required before translating current findings into clinical settings. There are a few clinical trials conducted using andrographolide in fixed combination formulation which have shown anti-inflammatory benefits and good safety profile. A concerted effort is definitely needed to identify potent andrographolide lead compounds with improved pharmacokinetics and toxicological properties. Taken together, andrographolide and its analogs have great potential to be the next new class of anti-inflammatory agents, and more andrographolide molecules are likely moving towards clinical study stage in the near future.