On July 28, 2016, the Company entered into a license agreement ("Samil Agreement") with Samil Pharm. Co., Ltd. (the “Samil”), for an exclusive, royalty-bearing license for the commercialization of Aramchol (with an option to manufacture) for the treatment of fatty liver indications including NASH in the Republic of Korea. Additionally, following the ARREST Study, Samil has an option to extend the License to Vietnam, which, if exercised, would increase the clinical- and regulatory-based milestone payments.

NOTE: Richard Wurtman, mentioned in the articles, was also the developer of the “Fen” half of Fen-Phen, the miracle diet drug which became another disaster from unintended consequences. content.time.com /time/subscriber /article/0,33009,985187-4,00.html

We had positive cash flow from investing activities of approximately $6.4 million for the year ended December 31, 2017 as compared to a positive cash flow from investing activities of approximately $6.3 million for the year ended December 31, 2016. The positive cash flow from investing activities for the year ended December 31, 2017 was mainly due to maturity of marketable debt securities in the amount of approximately $10.3 million, offset by investment in marketable debt securities in the amount of approximately $3.9 million.

A paper by Kadowitz’s group at Tulane reported on N-nitrosodimethylamine as an arterial guanylate cyclase activator, comparing it to glyceryl trinitrate and sodium nitroprusside and found it “devoid of vasodilator activity in vivo and exerted only minimal effects on isolated arterial smooth muscle tone or on arterial guanylate cyclase activity.”

Thanks for pointing out the more recent works from Blasco. I will look at it. Regardless of its applicability to Alzheimer, I have found the mice study of 2012 convincing.

           If an emerging growth company, indicate by a check mark if the Registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ý

In the conduction system of the heart, HCN4 channels are the predominant isoform expressed, accounting for nearly 80% of Ih. The isoform which contributes most to the remaining current is species dependent, with HCN1 dominant in rabbit4 and HCN2 dominant in mouse7. In non-conduction tissue, HCN2 appears to be the dominant isoform with ubiquitous distribution in atrial and ventricular myocytes at low levels compared to the conduction system. Since cholesterol regulates a variety of ion channels important for cardiac function29,38,39,40,41, including rabbit HCN4 in which cholesterol depletion had previously been shown to modulate voltage dependence of activation and the kinetics of deactivation28, we systematically examined the role of cholesterol in regulating the 3 human cardiac isoforms of HCN channels. Intriguingly, we observed isoform specific differences in the regulation of these channels. While cholesterol depletion or enrichment had no effect on the voltage-dependence of human HCN1 and HCN2 activation, we observed a +10 mV shift to more depolarized potentials in human HCN4 channels. In HCN1 channels, cholesterol depletion slowed the slow-component of activation (τslow), but did not alter the deactivation kinetics. Cholesterol modulation did not affect the activation kinetics of HCN2 and HCN4 channels, but cholesterol enrichment slowed the rate of deactivation in these isoforms. The effect of cholesterol modulation on channel trafficking was striking (Fig. 4B). While HCN1 channel expression increased with cholesterol depletion, the slower activation kinetics and unchanged deactivation kinetics explain the unchanged current density compared to control (Fig. 1). In HCN2 channels, cholesterol enrichment caused a reduction in surface expression, however, channels at the surface deactivated more slowly, which likely recovers the current density to control levels (Fig. 2). Cholesterol depletion did not change the expression of channels at the surface, but decreased the current density despite no changes in kinetics. It is possible that cholesterol depletion in HCN2 channels causes a reduction in the unitary conductance, or generates a subpopulation of channels that are “silenced” (ie. Popen = 0), similarly to what is expected to occur in Kir2 channels upon cholesterol enrichment29,42. This could arise from altered sensitivity to tonic levels in cAMP, or sensitivities to changes in the physiochemical properties of membranes with decreased cholesterol43. However, it is not immediately clear why slowed deactivation and increased expression of HCN4 channels upon cholesterol enrichment does not lead to increased current densities at steady-state.

        As of December 31, 2018 and 2017, the Company had no unrecognized tax benefits and no accrued interest or penalties related to uncertain tax positions.

with the provisions of the approved label. The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability.

        If the scope of the patent protection we or our licensors obtain is not sufficiently broad, we may not be able to prevent others from developing and commercialize technology and products similar or identical to ours. The degree of patent protection we require to successfully compete in the marketplace may be unavailable or severely limited in some cases and may not adequately protect our rights or permit us to gain or keep any competitive advantage. We cannot provide any assurances that any of our licensed patents have, or that any of our pending licensed patent applications that mature into issued patents will include, claims with a scope sufficient to protect our proprietary platform or otherwise provide any competitive advantage, nor can we assure you that our licenses are or will remain in force. In addition, the laws of foreign countries may not protect our rights to the same extent as the laws of the U.S. Furthermore, patents have a limited lifespan. In the U.S., the natural expiration of a patent is generally twenty years after it is filed. Various extensions may be available; however, the life of a patent, and the protection it affords, is limited. Given the amount of time required for the development, testing and regulatory review of new product candidates, patents protecting such candidates might expire before or shortly after such candidates are commercialized. As a result, our

        In December 2018, Ra Pharma completed dosing in a Phase 1 ethno-bridging study in healthy subjects of Japanese and non-Japanese descent, enrolling 16 subjects in a multi-dose cohort and 20 subjects in a single-dose cohort. The Phase 1 study is designed to support development of zilucoplan in Japan.

and development services provided by us and includes milestone payments that could total up to $65.0 million ($6.0 million of which have been received to date).