On October 31, 2016, the Company completed an initial public offering ("IPO"), in which the Company issued and sold 7,049,230 shares of common stock at a public offering price of $13.00 per share, resulting in net proceeds of $82.8 million after deducting $6.4 million of underwriting discounts and commissions and offering costs of $2.4 million. On November 29, 2016, the Company completed the sale of an additional 1,057,385 shares of common stock to the underwriters under the underwriters’

Li, J. et al. Blockade of endothelial-mesenchymal transition by a Smad3 inhibitor delays the early development of streptozotocin-induced diabetic nephropathy. Diabetes. 59, 2612–2624 (2010).

I am wondering if CRISPR technology could improve the efficiency of the therapy and reduce off-target. Also, I am wondering if this therapy reduces mTOR levels. Maybe it could also affect some epigenetic markers.

I wonder Alan, is there much advantage in starting rapamycin early, or can you get the full benefits in terms of lifespan starting at, say, 60?

Mode-shifting or hysteresis in HCN channels has been suggested to play a key role in stabilizing firing rate and preventing arrhythmic firing in SAN cells and thalamic neurons35,36,37. Conceptually, during the hyperpolarization phase of the action potential, HCN channels do not open until very negative potentials are reached. This would prevent HCN channels from interfering with the recovery from inactivation of Nav and Cav channels. On the other hand, during the interval between action potentials, HCN channels would remain open, depolarizing the membrane potential towards threshold36. Since hysteresis is also rate dependent, it seems as though mode-shifting in HCN channels provides additional protection against bradycardia or tachycardia. As the heart rate slows, hysteresis in HCN2 and HCN4 channels would increase, leading to more HCN current, faster depolarization and thus faster heart rate. With this in consideration, we would anticipate that excessive depletion of membrane cholesterol should increase heart rate and could trigger tachycardia. This is in line with MβCD-treated SAN cells which showed a 58% faster spontaneous rhythm28. Our results may in part explain why up to 1% of patients who take statins to lower cholesterol are susceptible to tachycardia. Additionally, these changes in HCN function upon cholesterol depletion may contribute to the neuropathic pain44 reported in approximately 9% of patients being treated with statins45. Alternatively, elevated amounts of blood cholesterol have also been implicated in increasing heart rate in obese patients46. The enhanced activity we observed for HCN2 and HCN4 channels following cholesterol enrichment could also contribute to the increased heart rate in these patients.

The following description of our share capital and provisions of our Articles are summaries and do not purport to be complete and are qualified in their entirety by the complete text of the Articles, which are filed as exhibits to this annual report and incorporated by reference herein, and by Israeli law.

The results showed dose-related, but less than dose-proportional, increases in the mean Aramchol plasma concentrations, or Cmax, area under the curve, or AUC, (0-t), and AUC (inf) of 200 mg, 400 mg and 600 mg doses administered under fasting conditions or following a light meal, both at single and repeated dose administration. Cmax and AUC are metrics used to indicate the significance of a drug’s exposure. Steady-state was achieved by 144 hours (day seven). Administration of Aramchol after a high-fat, high-calorie meal afforded a 2.6 fold increase in exposure, as measured by Cmax, AUC(0-t), and AUC(inf) compared to the fasting group.

Graeff, R., Liu, Q., Kriksunov, I. A., Hao, Q. & Lee, H. C. Acidic residues at the active sites of CD38 and ADP-ribosyl cyclase determine nicotinic acid adenine dinucleotide phosphate (NAADP) synthesis and hydrolysis activities. J. Biol. Chem. 281, 28951–28957 (2006).

Ivashchenko, C. Y. et al. Regulation of the ADMA-DDAH system in endothelial cells: a novel mechanism for the sterol response element binding proteins, SREBP1c and -2. American journal of physiology. Heart and circulatory physiology 298, H251–258, doi:10.1152/ajpheart.00195.2009 (2010).

On January 1, 2018, the Company adopted ASC 606 with full retrospective application. The adoption of did not have an effect on either revenue recognized in prior periods, nor to accumulated deficit as of January 1, 2017.

Dr. Brand you are on a good track using Sulforaphane to upregulated NQO1 a more sustainable way to upregulate NAD+. Plus as you rightly pointed out it’s activates the very powerful Nrf2 which has many beneficial actions one of which is inhibiting mTOR. There is SulforaDex the only stable Sulforaphane provider I have found. I had read somewhere that it’s better than taking the broccoli sprouts powder as some issue was pointed out about that source if you Google you should land on the one I came across. Transresveratrol increases bioavailability of some nutrients it’s taken with. Another alternative is Pterostilbene which has much better stats then Resveratrol and is the one Guarante used in his NR pill to improve it’s bioavailability and efficacy.

In March 2010, President Barack Obama signed into law the Patient Protection and Affordable Care Act and the Health Care and Education Affordability Reconciliation Act of 2010, or the Affordable Care Act, a sweeping law intended to broaden access to health insurance, reduce or constrain the growth of healthcare spending, enhance remedies against fraud and abuse, add new transparency requirements for healthcare and health insurance industries, impose new taxes and fees on pharmaceutical and medical device manufacturers and impose additional health policy reforms. The Affordable Care Act expanded manufacturers’ Medicaid rebate liability to include covered drugs dispensed to individuals who are enrolled in Medicaid managed care organizations, increased the minimum rebate due for innovator drugs from 15.1% of average manufacturer price, or the AMP, to 23.1% of AMP. The rebate on innovator drugs is the greater of 23.1% of the AMP per unit or the difference between the AMP and the best price per unit and adjusted by the Consumer Price Index-Urban (CPI-U) based on a launch date and current quarter AMP. The total rebate amount for innovator drugs is capped at 100.0% of AMP. The Affordable Care Act and subsequent legislation also narrowed the definition of AMP. Furthermore, the Affordable Care Act imposes a significant annual, nondeductible fee on companies that manufacture or import certain branded prescription drug products. Substantial new provisions affecting compliance were also been enacted, which may affect our business practices with healthcare practitioners. Although it is too early to determine the effect of the Affordable Care Act, it appears likely to continue to put pressure on pharmaceutical pricing, especially under the Medicare and Medicaid programs, and may also increase our regulatory burdens and operating costs.