In renal fibrogenesis, matrix-producing cells integrate various fibrogenic signals and regulate ECM production and assembly. These fibrogenic factors include TGF-β1, platelet-derived growth factor, fibroblast growth factor, connective tissue growth factor and angiotensin II15. Among these cytokines, TGF-β1 is the key contributor to EMT in tubular epithelial cells29. In the kidneys of patients with IgA nephropathy, P311 protein expression correlates with TGF-β expression and proteinuria30. Thus, we next examined whether TGF-β1 was involved in EMT related to P311-mediated renal fibrogenesis. As predicted, obstructed kidneys from P311−/− mice showed impaired TGF-β1 protein expression. Interestingly, there was no difference in TGF-β1 mRNA levels between the P311−/− and P311+/+ groups. These results differ from our previous observations in human fibroblasts, which showed that P311 transfection induces TGF-β1 mRNA expression and that interfering with P311 expression in fibroblasts decreases TGF-β1 mRNA expression10. The different models (in vivo versus in vitro) and different cell types (human fibroblasts versus mouse tubular epithelial cells) might be responsible for the discrepancy. P311 binds to latency-associated proteins to regulate TGF-β1 expression31. Recently, P311 was reported to bind to eukaryotic translation initiation factor 3 subunit b to promote TGF-β translation and to be the first pan-regulator of TGF-β expression under steady-state conditions8,32. These findings may explain our results.

Additional time may be required to obtain regulatory approval for our product candidates because they are combination products.

We also rely on trade secrets to protect our proprietary know-how and technological advances, especially where we do not believe patent protection is appropriate or obtainable. However, trade secrets are difficult to protect. We rely in part on confidentiality agreements with our employees, consultants, outside scientific collaborators, sponsored researchers and other advisors to protect our trade secrets and other proprietary information. These agreements may not effectively prevent disclosure of confidential information and may not provide an adequate remedy in the event of unauthorized disclosure of confidential information. In addition, others may independently discover our trade secrets and proprietary information. Costly and time-consuming litigation could be necessary to enforce and determine the scope of our proprietary rights. Failure to obtain or maintain trade secret protection could enable competitors to use our proprietary information to develop products that compete with Aramchol or any future product candidates or cause additional material adverse effects upon our competitive business position.

        While we have not filed for protection in the U.S. or abroad for our mark, EXTREME DIVERSITY, we do use the mark and rely on common law protections for such use for goods and services.

Massague, J. How cells read TGF-beta signals. Nature reviews Molecular cell biology. 1, 169–178 (2000).

In the recently completed ARREST Study that enrolled 247 NASH patients with biopsy-proven NASH who were overweight or obese and had pre-diabetes or type II diabetes mellitus, serious adverse events were reported in 12.5%, 8.9% and 9.2% of patients in placebo, Aramchol 400mg and 600mg arms, respectively. No clustering of event type or atypical events for the studied population were reported in either Aramchol arms. Early terminations due to adverse events occurred in 4.2%, 3.0% and 4.1% in placebo, Aramchol 400mg and 600mg arms, respectively. Most frequent adverse events included headaches, UTI, pruritus, nausea, influenza, constipation and fatigue.

In September the FDA announced that retesting of all valsartan supplies had found a second carcinogenic impurity, N-nitrosodiethylamine (NDEA), in the recalled products made by ZHP in China and marketed in the U.S. under the Torrent Pharmaceuticals (India) brand.[22]

The Company also holds a wholly-owned subsidiary, Galmed Research and Development Ltd., which was incorporated in Israel.

Fujitani, M. et al. P311 accelerates nerve regeneration of the axotomized facial nerve. Journal of neurochemistry. 91, 737–744 (2004).

Oguz, A. & Uzunlulu, M. Short term fluvastatin treatment lowers serum asymmetric dimethylarginine levels in patients with metabolic syndrome. International heart journal 49, 303–311 (2008).

TCJA may cause a reduction in the economic benefit of our net operating loss carryforwards and other deferred tax assets available to us. Under the TCJA, net operating losses generated after December 31, 2017 will not be subject to expiration but may only be used to offset up to 80% of our taxable income.

We expect to expand our organization, and as a result, we may encounter difficulties in managing our growth, which could disrupt our operations.