Provisions of Israeli law and our articles of association, or Articles, may delay, prevent or otherwise impede a merger with, or an acquisition of, our company, which could prevent a change of control, even when the terms of such a transaction are favorable to us and our shareholders.

Even the Chinese manufacturing process for acetaminophen (a.k.a. paracetamol) is a point of concern, says André, since one of the early intermediates is the probable carcinogen, 1-chloro-4-nitrobenzene. “We have audited most of the major Chinese manufacturing plants of acetaminophen, and found no evaluation of and no testing for 1-chloro-4-nitrobenzene at any of them,” he says. André sees a need for manufacturers and regulators to pay much closer attention to potential risks in the manufacturing process. “In the valsartan case, the focus was on control of the related substances of synthesis and other impurities above the reporting threshold (0.05% in the case of valsartan), rather than on the safety of the chemical synthesis processes.

        Zilucoplan is a novel therapeutic compound and its potential therapeutic benefit is unproven. Our product candidates may not demonstrate in patients any or all of the pharmacological benefits we believe they may possess or compare favorably to the approved C5 inhibitor therapy. We have not yet succeeded and may never succeed in demonstrating efficacy and safety for these or any other product candidates in clinical trials or in obtaining marketing approval thereafter. For example, although we have evaluated zilucoplan in pre-clinical studies and have evaluated zilucoplan in early-stage clinical trials and in two Phase 2 clinical trials, we have not yet advanced zilucoplan into Phase 3 clinical development, nor have we obtained regulatory approval to sell any product based on our therapeutic approaches.

The FDA announced recalls of valsartan in July 2018 due to the presence of NDMA in API supplied by ZHP. Since the initial recall, international investigations have expanded to include all manufacturers of API and finished drugs in the angiotensin II receptor blocker (ARB) class. Additional recalls were issued for valsartan, irbesartan, and losartan-containing products found to contain NDMA and N-Nitrosodiethylamine (NDEA), both known animal and suspected human carcinogens.  

Lane, K. B. et al. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat. Genet. 26, 81–84 (2000).

So virtually all of their protection is secondary to their exercise regimen and adiponectins. Once they retire, it’s rapidly down hill.

The board of directors must make the determination as to the financial and accounting expertise, and as to the professional qualifications, of a director taking into consideration those criteria and matters set forth in the regulations. A director with financial and accounting expertise is a director who by virtue of his or her education, professional experience and skill, has a high level of proficiency in and understanding of business accounting matters and financial statements so that he or she is able to fully understand our financial statements and initiate debate regarding the manner in which the financial information is presented. In addition, the board of directors of a public company is required to make a determination as to the minimum number of directors who must have such financial and accounting expertise based on, among other things, the type of company, its size, the volume and complexity of the company’s activities and the number of directors. Our Board has determined that the minimum number of directors with financial and accounting expertise, in addition to the external director or directors who have such expertise, will be one, and that Mr. Marth qualifies as such. The external director who qualifies to have such expertise is Ms. Yaron-Eldar. In addition, our Board has determined that Ms. Yaron-Eldar qualifies as an audit committee financial expert pursuant to the applicable SEC rules, and accordingly as having the necessary financial sophistication as required by the Nasdaq Capital Market rules.

        Any of our product candidates for which we, or any future collaborators, obtain marketing approval, as well as the manufacturing processes, post-approval studies and measures, labeling, advertising and promotional activities for such product, among other things, will be subject to ongoing requirements of and review by the FDA, the EMA and other regulatory authorities. These requirements include submissions of safety and other post-marketing information and reports, registration and listing requirements, requirements relating to manufacturing, quality control, quality assurance and corresponding maintenance of records and documents, requirements regarding the distribution of samples to physicians and recordkeeping. Even if marketing approval of a product candidate is granted, the approval may be subject to limitations on the indicated uses for which the product may be marketed or to the conditions of approval, including the requirement to implement a Risk Evaluation and Mitigation Strategy.

I’ve been filming scientists on aging research for 11 years, during which, its wide implications have gripped me. I homed in on something G B Shaw touched on in his play “back to Methuselah,” where in the Barnabas Brothers, one an ex-clergyman, the other a biologist, posited “that the duration human life must be extended to 300 years; not because people would profit by a longer experience, but because it was not worth their time to make any serious attempt to better the world or their own condition, when they only had 30 or 40 years before they doddered away to decay and death.” according to Shaw, “its is our expectation of life and not our experience of it that determines our conduct and character. Consequently, the very vulgar notion that you cannot change human nature is valid only on the assumption that you cannot change the duration of human life. If you can change that, then you can change political conduct.” Thus spoke G B 100 years ago. I’ve devised a series incorporating this idea as a springboard to tackle the evolving psychological and political impacts. Indeed I see this new science as providing an end run around the status quo of the way we practice politics and business. I am hopeful.

        The trading market for our common stock may be influenced, in part, by the research and reports that industry or securities analysts publish about us or our business. If no or few securities or industry analysts maintain coverage of us, or one or more of the analysts who cover us issues an adverse opinion about our company, our stock price would likely decline. If one or more of these analysts ceases research coverage of us or fails to regularly publish reports on us, we could lose visibility in the financial markets, which in turn could cause our stock price or trading volume to decline.

But then the FDA found, while testing material from all over, that valsartan manufactured by Hetero Labs of India (and sold as Camber Pharmaceuticals tablets) also had NMDA contamination, so the problem wasn’t just that one manufacturing source in China. This takes us up to late October, and that’s then things really started getting messy. Another drug in the same angiotensin II antagonist class as valsartan (irbesartan) was found to be contaminated, but this time with the N-nitrosodiethylamine (NDEA) instead of the dimethyl compound. This was made by ScieGen, and again was repackaged under still more names. The API manufacturer for the ScieGen material was Aurobindo (of India), and they recalled material. Yet another compound in this class, losartan, turned out to have contaminated material also produced by ZHP, but since ZHP themselves had by that time already been placed on the FDA’s import restriction list, no more of that API was coming in.

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.