Obtaining and maintaining our patent protection depends on compliance with various procedural, documentary, fee payment and other requirements imposed by governmental patent agencies, and our patent protection could be reduced or eliminated for non-compliance with these requirements.

        Net cash used in operating activities was $54.9 million for the year ended December 31, 2018 compared to $46.8 million for the year ended December 31, 2017. The increase in net cash used in operations was primarily attributable to a $10.5 million increase in our net loss as a result of higher operating expenses, primarily in connection with our pre-clinical studies and clinical trials related to our lead program zilucoplan and other research and development pipeline programs; partially offset by higher non-cash expenses, including depreciation, amortization and stock-based compensation and a net increase in operating liabilities.

Seifert, R. et al. Molecular characterization of a slowly gating human hyperpolarization-activated channel predominantly expressed in thalamus, heart, and testis. Proc Natl Acad Sci USA 96, 9391–6 (1999).

Hypoxia-sensing via HIF-1 upregulates the transcription of miR-322, which then exerts positive feedback by facilitating stabilization of HIF-1α by targeting the molecules involved in its degradation for ubiquitination and degradation23. Dysregulation of BMP signaling by increased miR-322 promotes the proliferation and migration of PASMCs.

If we are treated as a PFIC for any taxable year during the holding period of a Non-Electing U.S. Holder, we will continue to be treated as a PFIC for all succeeding years during which the Non-Electing U.S. Holder is treated as a direct or indirect Non-Electing U.S. Holder even if we are not a PFIC for such years. A U.S. Holder is encouraged to consult its tax advisor with respect to any available elections that may be applicable in such a situation, including the “deemed sale” election of Code Section 1298(b)(1) (which will be taxed under the adverse tax rules described above).

To compete effectively, we must develop and maintain a proprietary position with regard to our own technologies, intellectual property, licensing agreements, product candidates and business. Legal standards relating to the validity and scope of claims in the biotechnology and biopharmaceutical fields are still evolving. We cannot predict the scope and extent of patent protection for Aramchol because the patent positions of pharmaceutical products are complex and uncertain. Therefore, the degree of future protection for our proprietary rights in our core technologies and any product candidates or products that might be developed using these technologies is also uncertain. The risks and uncertainties that we face with respect to our patents and other proprietary rights include, but are not limited to, the following:

Even if Aramchol receives marketing approval, we or others may later identify undesirable side effects caused by the product. In such an event, regulatory authorities may:

There is growing evidence that microRNAs play important roles in cellular responses to hypoxia and in pulmonary hypertensive vascular remodeling, but the exact molecular mechanisms involved are not fully elucidated. In this study, we identified miR-322 as one of the microRNAs induced in lungs of chronically hypoxic mice and rats. The expression of miR-322 was also upregulated in primary cultured rat pulmonary arterial smooth muscle cells (PASMC) in response to hypoxia. We demonstrated that HIF-1α, but not HIF-2α, transcriptionally upregulates the expression of miR-322 in hypoxia. Furthermore, miR-322 facilitated the accumulation of HIF-1α in the nucleus and promoted hypoxia-induced cell proliferation and migration. Direct targeting BMPR1a and smad5 by miR-322 was demonstrated in PASMCs suggesting that downregulation of BMP-Smad signaling pathway may be mediating the hypoxia-induced PASMC proliferation and migration. Our study implicates miR-322 in the hypoxic proliferative response of PASMCs suggesting that it may be playing a role in pulmonary vascular remodeling associated with pulmonary hypertension.

The strongest evidence however comes from a paper on the treatment of diabetics with pioglitazone. Look up free paper ‘Pioglitazone Increases the Proportion of Small Cells in Human abdominal Subcutaneous adipose Tissue’. The diabetic subjects got fatter (without any increase of visceral fat) but healthier, according to markers of insulin resistance.

Mesenteric artery rings from model animals showed weakened endothelium-dependent vasodilator response to acetylcholine in arteries stimulated by phenylephrine compared with control mesenteric artery rings23. Mesenteric artery rings from blood stasis treated animals showed reduced endothelium-dependent vasodilator responses to acetylcholine in artery rings stimulated by phenylephrine compared to control aortic rings ACh-mediated vessel relaxation was significantly improved in β-BA (100 mg/kg/d) and β-BA (200 mg/kg/d) groups compared with blood stasis rats (Fig. 1a). β-BA prevented the blood stasis induced impairment of endothelium-dependent vasodilatation. No differences were found among all experimental groups in the aspect of concentration–contractile response induced by phenylephrine in aortic rings without endothelium (Fig. 1b). However, the vasoconstrictor response to phenylephrine in intact mesenteric artery rings was increased by β-BA (Fig. 1a).

To provide clue to understand the molecular mechanisms of each drug, we analyzed the functional distribution of these differentially expressed proteins in different groups, and the results are illustrated in Fig. 4b, wherein the proportion of each function regulated by a drug treatment is shown by the pie charts. In QSYQ, the proteins involved in energy metabolism and oxidative stress accounted for 41% and 22%, respectively, with the highest significance, indicating these two processes as the main mechanisms for the therapeutic function of QSYQ. The functional distribution of these differentially expressed proteins varied among different mono-therapies, with ASIV mainly affecting energy metabolism (41%), DLA mainly affecting oxidative stress process (44%), R1 affecting energy metabolism (37%) and DO affecting ion transport process (40%) or protein modification (40%). Interestingly, all combination treatments acted on the proteins implicated in energy metabolism and oxidative stress as their major targets.

Our ability to use net operating losses and research and development credits to offset future taxable income may be subject to certain limitations.