Moti L. Kashyap Environment is partially driven by these reactive Health & Medicine︱ • Sedentary lifestyle oxygen species. Thus, Niacin prevents • Caloric excess the disease from advancing to more Normal • Saturated fats severe stages.

clinicaloptions.com • Sugar Fat Because Niacin is available without accumulation/ prescription as a vitamin, the level of High-dose Niacin is a Steatosis Niacin knowledge that we have about Niacin formulations (the form in which the medicine is given to the patient) has Inflammation/ been misunderstood by some people NASH promising treatment in the industry. For example, none of Niacin Modified from Clinical Care Options, LLC, the ‘over-the-counter’ formulations for Niacin have been fully tested for Fibrosis/ safety. And there is a known side-effect Cirrhosis for Non-Alcoholic for these particular formulations called Niacin flushing (warmth, redness, itching and tingling of the skin, especially of the face Figure 1. The progression of healthy and neck). Fatty Liver Disease liver to NAFLD-related pathologies Genes is caused by genetics as well as environmental factors. Niacin treats There is a Niacin formulation that was Non-Alcoholic Fatty Liver on-Alcoholic Fatty Liver Disease Disease progression is slow; it can all three major stages of NAFLD. developed for reducing the flushing side Disease (NAFLD) is a common (NAFLD) refers to a range of take decades for cirrhosis to develop effect and tested for safety (approved by condition worldwide. It can Nmedical conditions for which from steatosis. Since the early disease the FDA in the USA) progress to liver failure and the patient has too much fat in the liver stages (steatosis and steatohepatitis) are agencies. The that is currently being death. No drug treatment which has not been caused by excessive asymptomatic, the patient is unaware few drugs which We believe that investment in a used by physicians to in the clinic has yet shown alcohol consumption. NAFLD is common of this ‘ticking time bomb’ health risk. have reached treat hyperlipidemia sufficient efficacy to receive worldwide, affecting 20-25% of adults. This ignorance is unfortunately shared advanced clinical Phase 2 trial, if successful, could (abnormally high regulatory approval. Prof Moti This disease is more prevalent in the West, with healthcare professionals who trials have shown levels of fats in the Kashyap and co-workers at the affecting 75 million people in the USA. underdiagnose and hence underestimate insufficient efficacy generate a valuation of $5-10 billion blood) and to prevent University of California, Irvine the prevalence of this disease. and adverse side for the combination therapy. heart disease and and Aasta Pharmaceuticals For 25-30% of patients, NAFLD effects. Importantly, stroke. This is the have found that Niacin progresses from steatosis (the build- NAFLD is often seen in people who are no drug has yet been shown in the clinic content of the rat livers. Furthermore, Niacin Extended-Release formulation, reversed every stage of up of fat in the liver) to non-alcoholic overweight or obese. Patients may also to prevent the fatal consequences which the discovery that Niacin can reverse which was successfully used in a small NAFLD in preclinical studies. steatohepatitis (often called NASH), have high blood pressure, type 2 diabetes stem from liver cirrhosis. Thus, there is an fibrosis, in cells obtained from patients clinical trial alluded to earlier. Furthermore, a human clinical and is characterised by inflammation and high levels of fat and sugar in their urgent unmet clinical need. with this condition, is very promising. trial has shown that high-dose of the liver. For about a fifth of these blood. In addition, some people have a However, no Niacin formulation is Niacin reduces the build-up of patients, this disease can further progress higher risk of getting this disease because NIACIN IS A PROMISING In a small clinical trial, a Niacin oral currently approved by the FDA for fat in the liver. The research to fibrosis (scarring of the liver) and of their genetic make-up. formulation (a tablet), called Extended- the treatment of NAFLD and its team have discovered that TREATMENT cirrhosis (the scarred liver cannot function Prof Moti Kashyap and co-workers Release Niacin (the tablet dissolves complications of NASH and fibrosis, and Niacin has unique mechanisms of action, which make it correctly), manifesting clinically in stomach Healthcare professionals recommend at the University of California, Irvine more slowly so that the drug is released so trials are warranted. Yet if the trials are an excellent candidate for haemorrhage, liver failure, liver cancer lifestyle changes, such as exercise, have discovered that high-dose Niacin into the bloodstream over a prolonged successful, this Niacin formulation could combination therapy with and, ultimately, death. Indeed, NAFLD is healthy eating and weight loss, to treat (commonly known as vitamin B3), acting period of time), was found to reduce the drugs in development. estimated in a few years to become the NAFLD. However, this approach has as a drug, can reverse all the stages of liver fat content of 39 patients, who had leading cause of liver transplantation. not always been sufficiently successful NAFLD in human liver cells and in rats. excess fat in their livers, by 47% after 6 and so drug therapy, ideally in tandem months of treatment. with healthy living, may be necessary for For example, it was observed that many patients. giving Niacin to rats with steatosis Prof Kashyap has determined two not only prevented progression to mechanisms of action for Niacin which In addition, most people with NAFLD die steatohepatitis, but also reduced the fat are unique to this drug compared to the of cardiovascular disease, with NAFLD other treatments currently in the clinic and atherosclerosis (narrowing of the H O for NAFLD. Firstly, Niacin inhibits an arteries) often being observed in the same enzyme called DGAT2 (diacylglycerol patient. Thus, a drug treatment which H H acyltransferase 2). This means that Niacin prevents the build-up of fat could target O prevents the production of triglycerides both medical conditions. (fat) in the liver. Secondly, Niacin reduces the amount of oxidation in the cell Over fifty drugs, supported by billions caused by reactive oxygen species of investment dollars, are currently in H N H (molecules which can cause oxidation). development, but not one of them Now the progression of the disease from

has been approved by the regulatory Chemical structure of Niacin. fat build-up to inflammation and fibrosis Microscopic anatomy of the liver. College, OpenStax Public domain, Wikimedia via s Commons

www.researchfeatures.com www.researchfeatures.com Behind the Research Moti L. Kashyap

E: [email protected] T: +13107218552 W: http://www.aastapharma.com

Research Objectives

Prof Kashyap and his team discovered that Niacin reduces oxidative stress and inhibits a critical enzyme in liver fat formation, making it a key component for the treatment and reversal of fatty liver disease and its complications.

Excess fat in the liver can lead to fibrosis (scarring of the liver) and cirrhosis (the scarred liver cannot function correctly), manifesting clinically in Detail stomach haemorrhage, liver failure, liver cancer and, ultimately, death. Bio Institute, San Francisco. Kashyap has • Department of Veterans Affairs be used to treat multiple conditions, anticipated lucrative outcome. million patients in the US alone that are Moti Kashyap is Professor of Medicine published extensively especially on Healthcare System, such as heart disease and NAFLD, in the They have stated, “We believe that suffering from NASH.” Emeritus, University of California, niacin research, clinical and basic, and is Long Beach same patient. In addition, Prof Kashyap a relatively small investment in a Irvine. He is a physician-scientist and Fellow of several professional bodies. has noted that there is a strong possibility Phase 2 trial program of a few million Aasta Pharmaceuticals would like to Co-Founder of Aasta Pharmaceuticals. Collaborators that the past successful monotherapy dollars could generate a valuation partner with other companies who He was trained in Internal Medicine, Funding • Vaijinath Kamanna, PhD trials using Niacin in cardiovascular of $5-10 billion for the combination also have NAFLD / NASH drugs in and Lipid Metabolism at McGill • Southern California Institute for • Shobha Ganji, PhD patients included individuals with therapy (discussed in the next development for the purposes of University and Cardiovascular Research Research and Education • Naresh Nakra, PhD undiagnosed steatohepatitis (liver paragraph) if successful, based on conducting phase 2 combination drug inflammation) or NASH. industry norms.” therapy trials. References Personal Response If your pharmaceutical organisation The commercial value lies in combining a were to supply a drug candidate, Drug Kashyap, M., Ganji, S., Nakra, N. and Kamanna, V. (2019). Will a partner organisation be able to influence the Niacin formulation with another patented X, then Aasta Pharmaceuticals would Niacin for treatment of non-alcoholic fatty liver disease design of the Phase 2 clinical trial? assess interactions between your Drug X (NAFLD): novel use for an old drug? Journal of Clinical Yes. The partner and our team would jointly develop drug in development. That would create an and Niacin in a pharmacokinetics study Lipidology, 13 (6), 873-879. Available at: a detailed protocol to address safety and efficacy. The (a study which evaluates what happens https://doi.org/10.1016/j.jacl.2019.10.006 final design will have to be discussed and approved by immensely powerful drug for the treatment to the drugs that are administered to an the FDA in the USA. animal or a person). The purpose of this Kashyap, M., Ganji, S. and Kamanna, V. (2020). Pharmacologic of 20-30 million patients in the US alone. study would be to find out if giving both Therapy with Niacin for Nonalcoholic Fatty Liver Disease What inspired you to conduct this research? drugs together resulted in either of the (NAFLD): Emerging Evidence. Arch Gastroenterol Res, 1 (3), I was inspired by certain observations during my over A POWERFUL POTENTIAL DRUG COMBINING NIACIN WITH drugs not working as well as expected. 83-88. Available at: https://www.scientificarchives.com/article/ 25 years of research on Niacin. The unique mechanisms FOR THE TREATMENT OF MILLIONS A SECOND DRUG pharmacologic-therapy-with-niacin-for-nonalcoholic-fatty-liver- of action of niacin discovered by our team led me to OF PATIENTS Though Niacin has demonstrated If the pharmacokinetics study is disease-nafld-emerging-evidence conceive the idea that Niacin could be a potential Prof Kashyap and Dr Vijay Kamanna effectiveness at every stage of NAFLD, successful, a 12-month Phase 2 trial will therapy for Fatty Liver Disease for which there is no approved pharmacologic treatment. Subsequent testing are founders, and Dr Naresh Nakra is Aasta Pharmaceuticals first want to be initiated. The patients will be divided Kashyap, M. (2020). Aasta Pharmaceuticals, LLC Niacin for of this idea confirmed this in preclinical and preliminary the CEO of Aasta Pharmaceuticals LLC. conduct clinical trials to investigate the into four groups: NASH. [online] Aasta Pharmaceuticals, LLC Website. Available clinical trial data, warranting a phase 2 trial program Together, they developed Niacin as a ability of high-dose Niacin to treat NASH 1. Patients taking the placebo. at: https://aastapharma.com/ [Accessed 15 Dec. 2020]. especially with another patented drug in development to treatment for NAFLD. They have been and fibrosis. 2. Patients taking Niacin. enhance efficacy. issued with a patent by the US Patent 3. Patients taking Drug X. Office for the treatment and reversal They consider the unique mechanisms of 4. Patients taking Niacin and Drug X. of fatty liver disease by Niacin. This action of Niacin to be important because patent not only covers Niacin but also combining Niacin with another drug For each patient, the amount of fat in derivatives and analogues. Thus, there (‘Drug X’) with a different mechanism the liver, the degree of liver inflammation is ample scope to develop an even can result in enhanced efficacy. Indeed, and the extent of liver scarring will be more effective drug in the future. Prof Kashyap has said, “The commercial measured at regular intervals. value lies in combining a Niacin Aasta Pharmaceuticals are actively formulation with another patented If your company would like to partner seeking partners, including drug in development. That would be and/or invest in this opportunity, please pharmaceutical companies and more effective than either drug alone. get in touch with Aasta Pharmaceuticals financial institutions, to invest in A combination product would be a using the contact details given on their their research and to share in their powerful drug for the treatment of 20-30 company website: www.aastapharma.com

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