Kitov Pharmaceuticals Hldgs L Sponsored ADR (KTOV)

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KITOV PHARMACEUTICALS - FULL DD
http://kitovpharma.com

INDEX
1. COMPANY OVERVIEW
2. SHARE STRUCTURE AND FINANCIALS
3. MANAGEMENT
4. PRODUCTS AND ADDRESSABLE MARKET
5. INTELLECTUAL PROPERTY
6. INSTITUTIONAL OWNERSHIP
7. RECENT DEVELOPMENT
8. UPCOMING EXPECTED CATALYSTS
9. ANALYST COVERAGE
10. SOURCES



1. COMPANY OVERVIEW

Kitov Pharmaceuticals is an innovative biopharmaceutical drug development company. Leveraging deep regulatory and clinical-trial expertise, Kitov's veteran team of healthcare professionals maintains a proven track record in streamlined end-to-end drug development and approval.
Kitov's flagship combination drug, KIT-302, aims to treat osteoarthritis pain and hypertension simultaneously. KIT-302 achieved the primary efficacy endpoint for its Phase III clinical trial. A New Drug Application (NDA) was submitted in July 2017 and the U.S. Food and Drug Administration (FDA) filed the NDA on September 29 2017, thereby accepting the NDA for a full review.
Kitov's newest drug, NT-219, which is developed by its majority-owned subsidiary, TyrNovo, is a small molecule that presents a new concept in cancer therapy. When combined with various approved oncology drugs, NT-219 demonstrated potent anti-tumor effects and increased survival in various cancer models.
By lowering development risk and cost through fast-track regulatory approval of novel therapeutics, Kitov plans to deliver a rapid ROI and long-term potential to investors, while making a meaningful impact on people's lives.

We are a development stage biopharmaceutical company currently focused on the development of:

(i) KIT-302, a combination drug for the simultaneous treatment of two clinical conditions: pain caused by osteoarthritis and hypertension (high blood pressure), which can be pre-existing or caused by the treatment for osteoarthritis; and

(ii) NT219, a small molecule that uniquely targets two pathways highly involved in cancer drug resistance.

In addition, we may consider the acquisition of therapeutic candidates at various stages of development in various therapeutic areas or currently approved drug products. We currently have no binding agreements or commitments to complete any transaction for the possible acquisition of new therapeutic candidates or approved drug products. There is no certainty that we will be able to complete any additional transactions for the possible acquisition of new therapeutic candidates or approved drug products. We may not be able to identify suitable acquisition candidates, complete acquisitions or integrate acquisitions successfully. In this regard, acquisitions involve numerous risks, including difficulties in the integration of the acquired therapeutic candidates and the diversion of management’s attention from other business concerns. Although we will endeavor to evaluate the risks inherent in any particular transaction, there can be no assurance that we will properly ascertain all such risks. In addition, acquisitions could result in the incurrence of substantial additional indebtedness and other expenses or in potentially dilutive issuances of equity securities. There can be no assurance that difficulties encountered with acquisitions will not have a material adverse effect on our business, financial condition and results of operations.

We intend to seek FDA approval for the commercialization of our therapeutic candidates, and where applicable through the Section 505(b)(2) regulatory path under the Federal Food, Drug, and Cosmetic Act of 1938, as amended. Where applicable, we also intend to seek corresponding regulatory paths for approval in other foreign jurisdictions. Our current pipeline consists of two therapeutic candidates: (i) KIT-302, which has recently successfully completed its Phase III clinical trial and which will be subject to review and approval by the FDA, upon filing a completed 505(b)(2) NDA and (ii) NT219, which is in a preclinical stage but will likely be subject to review and approval by the FDA upon filing a completed 505(b)(1) NDA, if at all. Upon and subject to receipt of the requisite approvals, we intend to commercialize our therapeutic candidates through licensing and other commercialization arrangements with pharmaceutical companies on a global and/or territorial basis. We may also evaluate, on a case by case basis, co-development and similar arrangements, as well as independent commercialization of our therapeutic candidates.

Our competitive strengths

We believe there are several advantages to the therapeutic candidates we are developing, such as:

For KIT-302:

- providing a solution to the concerns of physicians who avoid prescribing an NSAID treatment for pain caused by osteoarthritis due to its cardiovascular side effects;

- reassuring physicians who are concerned that their patients who are treated for osteoarthritis will also be treated for hypertension, which is a known side effect of NSAID treatments for pain caused by osteoarthritis. This is a particular concern, as hypertension is usually not accompanied by tangible symptoms, and therefore patients may not be aware of their condition or the need to treat it;

- using one drug that also includes an active ingredient that treats hypertension either as an existing condition or as a side effect of using other drugs, ensures that the patient receives the suitable treatment for their disease and for its side effect;

- purchasing one drug as opposed to purchasing two separate drugs may lead to financial savings for patients in the U.S. by requiring payment of just one co-payment and prescription fee as opposed to a double co-payment and prescription fee. In addition, the use of one combination drug reduces the patient’s discretion with respect to whether to purchase and use only one of the drugs and provides a comprehensive dual medical treatment in one combined drug; and

- using calcium channel blockers in our therapeutic candidates as an antihypertensive. Calcium channel blockers are not included in the FDA Safety Information Release for NSAIDs co-administered with angiotensin converting enzyme inhibitors, or ACE inhibitors, or with angiotensin II receptor antagonists.

In addition to the aforementioned medical and economic advantages of KIT-302, we believe that KIT-302 has several commercial advantages, such as reduced development time compared to the development time of new chemical entities (NCEs) and decreased risk factors in the development process. These commercial advantages derive from the fact that combination drugs are based on known materials already approved for use by the FDA. The FDA offers a shortened regulatory procedure referred to as a “505(b)(2) NDA” to approve combination drugs. This procedure may be used to file a request to approve a product that relies on the results of the safety and effectiveness trials performed for the components of the combination in the past by others and not by the submitters of the request for approval. Accordingly, the approval process in a 505(b)(2) NDA is shorter and less expensive compared to the approval process for NCEs. In addition, the use of known, proven and safe components recognized by physicians and medical organizations, and the enhanced medical effect of concurrently treating and preventing hypertension, may shorten the time and decrease the costs usually required for the acceptance of the new product in the drug marketplace.

For NT219:

NT219 is a small molecule, and small molecules typically are less expensive to develop and have less onerous CMC as compared to large proteins or antibodies. In addition, NT219 has the potentially advantageous effect of:

- overcoming drug resistance acquired by cancer; and

- working in combination with multiple approved cancer therapies.

Our strategy

Our goal is to become a significant player in the development of innovative chemical drugs with a clinical and commercial added value. Key elements of our strategy are to:

- develop our therapeutic candidates with clinical and commercial advantages and obtain approval thereof from the FDA and other foreign regulatory authorities;

- expand our line of therapeutic candidates through the acquisition or in-licensing of technologies, products and drugs intended to meet clinical needs, thereby utilizing the skills, knowledge and experience of our personnel to develop and enhance the value of additional products, and bring them to market efficiently;

- capitalize on the FDA’s 505(b)(2) regulatory pathway, or other pathways that simplify the road to an NDA submission, to obtain more timely and efficient approval of our formulations of previously approved products, when applicable;

- cooperate with third parties to both develop and commercialize therapeutic candidates in order to share costs and leverage the expertise of others; and

- enter into sub-license agreements with international companies for potential or future therapeutic candidates based on potential upfront and milestone payments, royalties and/or other marketing arrangements, depending on product and market conditions.


2. SHARE STRUCTURE AND FINANCIALS

TOTAL ORDINARY SHARES OUTSTANDING (O/S): 11.316.716 (10,658,232 after July offering plus 658,484 American Depositary Shares or ADSs after deal with TyrNovo investors).
The number of ADSs to be outstanding after this offering excludes:
- 9,750,130 ordinary shares issuable at a weighted average exercise price of NIS 0.98 (approximately $0.28) per share issuable to holders of our options issued, as applicable, under our 2013 Option Plan, as amended, or our 2016 Equity Incentive Plan, (such number of ordinary shares would be represented by 487,506 of our ADSs);
- 142,695,863 ordinary shares underlying the ADSs issuable upon exercise of the Series A warrants and the representative's warrants issued in our initial public offering, and the Series A warrants and the placement agent warrants issued as part of our offering in July 2016 (such number of ordinary shares would be represented by 7,134,790 of our ADSs); and
- 24,317,460 ordinary shares underlying ADSs issuable upon exercise of the warrants issued in connection with the concurrent private placement and 3,404,440 ordinary shares underlying ADSs issuable upon exercise of placement agent warrants issued as part of that offering.

FULLY DILUTED CAPITAL: 20.325.107

CASH: 11 million
DEBT: NO debt


3. MANAGEMENT

John Paul Waymack, M.D., Sc.D. was one of the founders of Kitov Pharmaceuticals and has served as the chairman of Kitov Parent’s board of directors and has been responsible for the medical operations of the Company as chief medical officer since July 2013. Dr. Waymack has over 20 years of experience in the biopharma field. Dr. Waymack is a former academic transplant surgeon and a former FDA medical officer, with over twenty years of experience in drug development as a consultant to major pharmaceutical companies, including Pfizer, Roche, Pharmacia, Warner Lambert and Searle. During his 10 years of academic career, Dr. Waymack published over 100 scientific essays, mainly in the fields of prostaglandins and immunology. In addition, Dr. Waymack volunteered to the U.S. Army, where he was commissioned and served as a Major in the Medical Corp. in the position of chief of surgical studies in the U.S. Army’s Institute for Surgical Research. Dr. Waymack was also an associate professor of surgery at the University of Texas Medical Branch and at the University of Medicine and Dentistry of New Jersey. Dr. Waymack serves as a member of other boards of various healthcare corporations, both board of directors and boards of advisors, both public and private. This includes serving of the board of advisors for the publicly traded Moleculin Corporation.

Isaac Israel has served as Kitov Parent’s chief executive officer and a member of the board since October 2012. Mr. Israel was the founding chief executive officer of BeeContact Ltd. (formerly TASE:BCNT), from 2001 until 2007. Since 2008 Mr. Israel has served as founding chief executive officer of Uneri Capital Ltd., a consulting firm in the capital markets field, owned by Mr. Israel, which specializes in the healthcare sector. In providing such consulting services, Mr. Israel also serves as a member of the board of directors of various healthcare corporations, both private and public, including as chairman of the board of NextGen Biomed Ltd., which is traded on the TASE. Since 2011 Mr. Israel has also provided various consulting services to Capital Point Ltd. (TASE:CPTP).

Simcha Rock, CPA, MBA, has served as Kitov Parent’s chief financial officer and a member of the board since July 2013. Mr. Rock was a private equity manager at Edmond de Rothschild Private Equity Management, a firm specializing in the management of venture capital and other private equity investments funds, from February 2000 until January 2011, with responsibility for all financial, legal and administrative matters for several investment funds. Prior to 2000, Mr. Rock held financial management positions at Intel Electronics Ltd., The Jerusalem College of Technology, and JC Technologies Ltd. Mr. Rock holds a BA from Yeshiva University and an MBA from Cleveland State University.

Gil Ben-Menachem, Ph.D., MBA has served as our vice president business development since January 2016. He has over 15 years of experience in the pharmaceutical, biotechnology, and venture capital industries. He was most recently head of innovative products at Dexcel Pharma, the second largest Israeli pharmaceutical company. Dr. Ben-Menachem previously served as director of business development at Teva Pharmaceutical Industries, where he was responsible for business development efforts in connection with partnering and acquisition deals for late stage innovative drug candidates. Prior positions held by Dr. Ben-Menachem include serving as chief executive officer of OphthaliX, a company that developed drugs in the ophthalmology space, and serving as director of business development at Paramount Biosciences, a New York based merchant bank and biotechnology venture capital firm. Dr. Ben-Menachem received his Ph.D. from the Hebrew University, and MBA from the University of Maryland. He concluded his postdoctoral training in immunology and microbiology at the NIH.

Dr. Hadas Reuveni, Ph.D. is the founder and Chief Technology Officer of TyrNovo. Dr. Reuveni, a co-inventor of the TyrNovo technology, received her Ph.D., Summa Cum Laude, for anti-cancer drug discovery from the Hebrew University of Jerusalem. She has been engaged with the scientific projects in TyrNovo’s portfolio since 2005 and has nearly two decades of research and development experience in biotechnology. Dr. Reuveni founded NovoTyr Ltd. a biotech start-up company which a predecessor company to TyrNovo, developing small molecules for the treatment of cancer and neurodegenerative diseases, and where between 2005 and 2012 she served as the CEO. She also founded and served as a director and chief science officer of AngioB Ltd., a start-up company that developed GPCR-based agents for multiple indications (2006-2010). Prior to these roles, she was the director of research & development at Keryx Biopharmaceuticals (NASDAQ:KRX) on 2001-2004. Dr. Reuveni has served as a scientific consultant for Integra Holdings Ltd., Campus Bio Management Ltd. and BioLineRX (NASDAQ/TASE BLRX).

Avraham Ben-Tzvi, Adv., the Group’s chief legal officer, has served as the Kitov general counsel since November 2015 and was appointed as the Kitov company secretary in December 2015. Mr. Ben-Tzvi previously served as general counsel and company secretary at Medigus Ltd., a publicly traded minimally invasive endosurgical tools medical device and miniaturized imaging equipment company (NASDAQ/TASE:MDGS), from April 2014 until November 2015. Prior to that he served as an attorney at Yigal Arnon & Co. from 2009 to 2014 where, among other corporate and commercial work, he advised companies and underwriters on various offerings by Israeli companies listing in the U.S. and/or Israel and on various SEC and Israeli related securities law filings. Prior to 2009, Mr. Ben-Tzvi worked in a number of business development, corporate finance and banking roles at companies in the financial services, manufacturing and software development industries. Mr. Ben-Tzvi holds a BA in Economics from Yeshiva University in New York and an Ll.B from Sha’arei Mishpat College of Law in Hod Hasharon, Israel.


4. PRODUCTS AND ADDRESSABLE MARKET

KIT-302
KIT-302 is a Treatment for Hypertension and Osteoarthritis Pain. KIT-302 is a fixed dose combination drug comprised of the nonsteroidal anti-inflammatory drug (NSAID) celecoxib, and the well-known antihypertensive agent, amlodipine besylate. Celecoxib monotherapy often leads to hypertension, which if uncontrolled, can increase the risk of heart attack and stroke. KIT-302 is designed to provide a solution for physicians who avoid prescribing NSAIDs for osteoarthritis pain due to their hypertensive side effects. There is currently no single drug for the treatment of pain and hypertension, so, if approved, KIT-302 could be a unique product in the multibillion-dollar osteoarthritis market.
KIT-302 has the Potential to Increase Patient Adherence to Anti-Hypertensive Treatment. Poor patient compliance is a problem among patients with chronic diseases such as hypertension. Indeed, retrospective studies have shown that simplification of drug regimens, such as reducing the number of pills taken each day, may lead to greater adherence and improved clinical outcomes among patients. This is important since 40% of osteoarthritis patients also suffer from hypertension and would potentially benefit from a treatment that addressed both conditions. By combining celecoxib with amlodipine besylate, Kitov’s KIT-302 is effectively reducing the number of tablets patients have to ingest on a daily basis.
Positive Phase III Results for KIT-302 in Patients with Hypertension. Kitov completed a double blind, placebo controlled, Phase III clinical study evaluating the decrease of blood pressure in patients receiving KIT302. 152 subjects were enrolled in several UK sites. Subjects were randomized 1:1:1.5:1.5 to receive placebo, 200 mg celecoxib, 10 mg amlodipine, or KIT-302 once daily for two weeks. The primary endpoint of the trial was the mean reduction in daytime systolic blood pressure.
The trial met the primary endpoint. There was a significant reduction in systolic pressure in the KIT-302 combination arm, with subjects achieving a mean reduction of 10.6 mm Hg, compared to a reduction of 8.8 mm Hg for the amlodipine group. The SPA for this study required patients receiving KIT-302 to show a reduction in systolic blood pressure of at least 50% of that achieved by amlodipine treatment on its own (4.4 mm Hg). This was clearly achieved, as treatment with KIT-302 was associated with 2.4-fold reduction in blood pressure beyond the SPA requirement (p = 0.001).

Background on Osteoarthritis and Hypertension

Numerous factors influence the drug market, including the aging of the general population. As life expectancy increases, we expect that demand will increase for innovative drugs that treat diseases related to the elderly, such as osteoarthritis and hypertension.

Osteoarthritis

Arthritis means joint inflammation. The term is used to describe the pain, stiffness and/or swelling in the joints of the body where one or more bones are joined by ligaments. A normal joint provides a smooth surface enabling adjacent bones to move and glide on each other during normal motion. In contrast, an arthritic joint is one that may have varying degrees of inflammation and possibly destruction of the joint cartilage. These destructive changes preclude normal motion and cause pain.
The most common type of arthritis is called osteoarthritis and is more common with advancing age. People with osteoarthritis usually have joint pain and a decreased range of joint movement. Unlike some other forms of arthritis, osteoarthritis affects only the joints. This condition is also sometimes called degenerative joint disease. Osteoarthritis primarily affects the joint cartilage. Healthy cartilage allows bones to glide over one another and absorbs energy from the shock of physical movement. However, with osteoarthritis, the surface layer of cartilage breaks down and wears away. This allows the bony surface of the different bones under the cartilage to rub together, causing, pain, swelling, and loss of motion of the joint. Over time, affected joints may lose their normal shape. Also, bone spurs, small growths called osteophytes, may grow on the edges of the joint further impairing joint function. Thus, bits of bone or cartilage can break off and float inside the joint space, causing more pain and possible damage.
Osteoarthritis in the younger population is usually caused by traumatic injuries to the joints. In contrast, in the older population it is a more of a chronic degenerative disease process. The main symptom of osteoarthritis is pain that appears gradually, worsens with exertion, and is transiently relieved by rest.
The pain caused by osteoarthritis is described by patients as a deep pain or a burning sensation related to the joint tissues of the affected area. Osteoarthritis mainly affects the cartilage and disrupts the structural balance in the cartilage of the joint, causing the cartilage cells to increase production of new raw materials required to create cartilage, but concurrently produce enzymes that digest the cartilage.
Osteoarthritis is one of the most common diseases worldwide causing physical disabilities in adults. According to data published in the Center for Disease Control (CDC) website, an estimated 26.9 million U.S. adults in 2005 were diagnosed with osteoarthritis, of which approximately 50% suffer from hypertension. Among individuals in the U.S., it is estimated that over 40% will eventually suffer from osteoarthritis in at least one joint.
The pharmaceuticals used for treating osteoarthritis include a range of drugs. The particular choice of treatment is made according to the disease severity. These can range from acetaminophen for cases of milder severity, to diclofenac, naproxen, and celecoxib for moderate severity, up to treatment with narcotics for the most severe cases.
Various non pharmacological treatments are intended to relieve the pain caused by the disease and to preserve and improve joint function. Among these treatments are changes in the patient’s life style, namely diet, physiotherapy and exercise. The objectives of these treatments are to strengthen the muscles adjacent to the joints and increase their ranges, thereby reducing body weight, and decreasing the loads on the weight carrying joints to subsequently reduce the intensity of the pain.
In some cases, the conservative non pharmacological treatments are not sufficiently helpful. In such cases, patients typically request medical treatment. According to data published on the website of the Mayo Clinic in April 2013, the most common medical treatments are the use of analgesics, such as NSAIDs, which include enzyme inhibitors, such as COX-2. NSAIDs treat inflammation by inhibiting enzymes responsible for the initiation of the development of inflammation and subsequent pain. COX-2 enzyme inhibitors are non-steroidal drugs that treat inflammation by directly inhibiting COX-2, an enzyme responsible for the development of inflammation and subsequent pain but do not target the COX-1 enzyme. Targeting selectivity for COX-2 reduces the risk of peptic ulceration, and is the main advantage of celecoxib, rofecoxib and other members of this drug class over non COX-2 selective NSAIDs.
After several COX-2 inhibiting drugs were approved for marketing, data from clinical trials revealed that COX-2 inhibitors caused a significant increase in heart attacks and strokes, with some drugs in the class possibly having worse risks than others. See “Business - Our Therapeutic Candidates – Competitive Treatments for Pain Caused by Osteoarthritis”.
A typical osteoarthritis treatment plan with these analgesics is as follows: (i) initial treatment of minor osteoarthritis will begin with use of drugs such as acetaminophen; (ii) in the event that acetaminophen treatment is not effective, the physician will proceed to treatments using NSAIDs, which will begin using drugs such as Ibuprofen followed by naproxen and/or other NSAIDs (more than 20 types of drugs, including COX-2 enzyme inhibitors); (iii) in cases where treatment with these drugs is ineffective, the treatment will be direct injection of steroids into the affected joint; (iv) in cases where steroid injection is ineffective, treatment by injecting hyaluronic acid (HA) into the affected joint will be considered; and (v) in the event that all the aforementioned treatments fail, the patient may consider surgical replacement of the affected joint.
As noted above, NSAIDs, both over-the-counter and prescription are commonly taken to manage the pain of backache, osteoarthritis, rheumatoid arthritis, headache and other painful conditions. For example, according to a study commissioned by Kitov from IMS Health, the largest vendor of U.S. physician prescribing data, between April 2015 and March 2016 there were 2,428,176 prescriptions for celecoxib dispensed in the US.
NICOX, a pharmaceutical company, has attempted to develop NAPROXCINOD ®, a naproxen-based drug intended to treat pain and to act as an anti-hypertensive. From 2005 to 2010, NICOX completed three Phase III clinical trials following a significant investment. However, the results of the trials did not meet the FDA’s requirements. Therefore, in May 2010, an outside advisory committee to the FDA recommended against approving the drug. As a result of this recommendation, and its own internal review, the FDA rejected the request for NDA approval. According to an announcement by NICOX in April 2012, pursuant to an appeal filed by NICOX in July 2011, a meeting was held in April 2012 between representatives of NICOX and the FDA, in which NICOX was informed that in order to gain approval of its drug, it must file a new NDA, that would include results from additional clinical trials, for the purpose of approving a specific dosage of the drug.
On July 9, 2015 the FDA published a safety announcement requiring labels for prescription NSAIDs to indicate that the risk of heart attack or stroke can occur as early as the first weeks of using an NSAID and that the risk may increase with longer use of the NSAID. In effect, the current labeling, in effect since 2005, will be strengthened as a result of a review by the FDA of a variety of new safety information on prescription and over-the-counter NSAIDs, including observational studies, a large combined analysis of clinical trials, and other scientific publications. These studies were discussed at a joint meeting of the Arthritis Advisory Committee and Drug Safety and Risk Management Advisory Committee held in February 2014.

Hypertension (High Blood Pressure)

Hypertension is the most common chronic disease in the western world, affecting approximately thirty percent (30%) of the U.S. adult population, according to an article in Morbidity and Mortality Weekly Report. Untreated, hypertension can cause significant morbidity and mortality.
According to its physiological definition, “hypertension” is an excessive pressure applied by the blood on the walls of the blood vessels. The term hypertension refers to excessive arterial blood pressure, which is the pressure in the arteries that propels blood to body organs.
The blood pressure is created as a result of the contraction of the cardiac muscle propelling blood into the arteries, which possess a limited capacity to store the blood. Blood pressure is measured in units of mercury (Hg) millimeters (mm Hg). Diagnosing hypertension in adults requires at least two measures on two different occasions. There are two blood pressure values:

- Systolic pressure is the peak pressure in the arteries measured in the cardiac cycle, during the contraction of the heart’s left ventricle (systole); and

- Diastolic pressure is the lowest pressure point in the arteries measured when the heart’s left ventricle is relaxing and there is no contraction of the heart (diastole).

In the past, hypertension was generally defined as a systolic blood pressure of greater than 140 mm Hg or a diastolic blood pressure of greater than 90 mm Hg. However, as discussed below, a recently halted NIH study may result in these designated values being set lower.
The cause of hypertension in 95% of patients is unknown, and in these cases hypertension is defined as “essential hypertension”. However, some studies postulate that genetic factors and environmental factors are involved in the initial development of hypertension. These factors include high salt consumption, obesity, excessive alcohol consumption, and probably mental and behavioral factors, which may be caused by various circumstances, including working in certain professions. Extreme hypertension may lead to functional disorders, and worsening health, while the affected person does not necessarily feel it and/or is aware of it. Therefore, hypertension is often referred to as the “silent killer”.
The danger of hypertension is continuing damage to blood vessels in critical areas of the body, such as blood vessels in the heart, kidneys, eyes, and to the nerve tissue in the brain where any damage may cause a stroke. Moreover, damage to the blood vessels may cause blockage due to arteriosclerosis and lead to the tearing of the vessels. These complications may cause various diseases and even death.
Hypertension treatment methods focus on reducing the patient’s blood pressure to normal values, thereby preventing the occurrence of complications in the long term. Even a small increase in blood pressure may cause significant cardiovascular problems. For example, it has been shown that any increase in blood pressure above a systolic value of 115 mm Hg is associated with an increased risk of suffering a cardiovascular death. This finding has been repeatedly replicated and it is now established that there is no safe level of blood pressure increase above of the “normotensive baseline value” of approximately 120 systolic and 70 diastolic. The documentation of a danger of any increase in blood pressure above a value of 120/70 was recently documented in September of 2015 in a large NIH sponsored clinical trial which enrolled over 9000 patients age 50 and older. This study also documented that patients age 50 and older with systolic blood pressures greater than 120 had a greater rate of adverse cardiovascular events than did those whose systolic blood pressure was treated to levels below 120.
It has been recognized for many decades that hypertension requires treatment. This fact has been recently re-emphasized by a paper that reviewed 147 prior randomized studies of antihypertensive treatments. This meta-analysis study, concluded that the majority of the adult population with hypertension can be expected to benefit considerably from using anti-hypertension drugs.
Hypertension can be treated with many different classes of medications. These include diuretics, beta blockers, alpha blockers, calcium channel blockers, ACE inhibitors, angiotensin receptor antagonists and vasodilators. In general, these medications work by either relaxing blood vessels and thereby lowering the pressure in arteries, or by assisting the body in removing fluid and thereby decreasing the pressure inside of arteries.
Although drugs from each of the various classes of antihypertension medications are able to reduce blood pressure, there are marked differences in their side effects profiles. For example, the diuretics can result in kidney problems, while the beta blockers can slow the heart rate. It is therefore important for physicians carefully to select which antihypertension medications to prescribe for patients based upon the patient’s other medical problems, including what concomitant medications they are receiving.
Blood pressure can undergo significant alterations when subjects are placed on various medications. For example, according to a May 2010 FDA Joint Meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee report published by the FDA, an increase of about 3.5 mm Hg was diagnosed following the use of naproxen, while the use of Celebrex causes an increase of about 2.5 mm Hg. In addition, in August 2011 the FDA issued a Safety Information release stating that co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors or with angiotensin II receptor antagonists, may result in deterioration of renal function, including possible acute renal failure, and that the antihypertensive effect of ACE inhibitors may be attenuated by NSAIDs. No such Safety Information release was issued with regard to calcium channel blockers, which is the anti-hypertensive used in our therapeutic candidates.

Background on Combination Products

Numerous companies worldwide have developed in recent years successful combination products comprised of a combination of two or more drugs to treat various medical conditions, where the safety and effectiveness of each of the drugs was proven separately.
Combination products manufactured and sold, which are similar to our therapeutic candidate, include:

- Vimovo®, which was developed by Pozen Inc. and was approved by the FDA in May 2010. Vimovo® is a combination of naproxen and esomeprazole magnesium, marketed by AstraZeneca PLC worldwide (except in the U.S.) and by Horizon Pharma in the U.S., and is designed for treating both pain and preventing gastric ulcer. Vimovo’s® net sales in the U.S. reached $121 million in 2016, compared to net sales of $163 million in 2014.

- Caduet®, a combination of Lipitor® and amlodipine, was originally developed and manufactured by Pfizer and is designated for treating both cholesterol and hypertension, with global sales of $193 million in 2015.

- Janumet®, a combination of metformin and sitagliptin, manufactured by Merck & Co. Inc. and designated to treat diabetes, with sales of $2,201 million in 2016.

Combination drugs may provide improved medical treatment of patients diagnosed as suffering from two or more different diseases and also may provide convenience to patients by using a single drug instead of multiple drugs. In addition, combination drugs have significant commercial advantages deriving from maintaining and even increasing the market share of the active ingredients after their patents expire by extending the life span of the patents for the active ingredients through the use of combination drugs.

Our Therapeutic Candidate

Studies estimate that approximately 13.5 million patients in the U.S. alone may suffer concurrently from hypertension and chronic osteoarthritis pain in the joints, according to data published by the CDC. We are developing KIT-302 based on the generic drugs celecoxib and amlodipine besylate. Celecoxib is the active ingredient in the branded drug “Celebrex®”, a known and approved-for-use drug designed primarily to relieve pain caused by osteoarthritis. Our combination is designed simultaneously to relieve pain caused by osteoarthritis and treat hypertension, which is one of the side effects of using NSAIDs for treating pain caused by osteoarthritis. Our strategy in developing KIT-302 is based on our belief that the added anti-hypertensive drug will decrease the side effect of increased hypertension typically caused by the use of NSAIDs alone.
To date, no combination drug exists that offers the combined treatment of pain caused by osteoarthritis and hypertension. We therefore believe that KIT-302 potentially holds significant advantages over the currently available drugs in the market, due to the fact that the drug treatment of osteoarthritis together with hypertension eases the burden of the treatment process for patients by providing the ability to use one drug instead of multiple drugs concurrently, thereby increasing the patients’ ease of compliance with the required treatment.

KIT-302 is a fixed dosage combination product based on two known active ingredients (celecoxib and amlodipine besylate), the effectiveness and safety of which has been separately proven for each, and which is intended to enable the concurrent treatment of pain caused by osteoarthritis and hypertension.

On November 7, 2013, we filed with the FDA the final statistical plan for the Phase III clinical trial protocol for KIT-302 as part of the SPA procedures. On February 20, 2014, the FDA replied and indicated that the proposed data analysis of the trial’s results that we submitted to the FDA provides a suitable solution to achieve the primary endpoint of the Phase III clinical trial and to support the final request for approval, which will be submitted. As a result of the SPA process, the FDA approved the Phase III trial design for our clinical trial, and cleared our clinical trial to begin, and on June 18, 2014, we commenced the clinical trial, as described below under “Research and Development”. The Phase III clinical trial was performed using the Adaptive Trial Design method, or ATD, in accordance with the SPA. Based on the ATD format, in the first stage of the trial 150 patients were to be recruited. Then, the decision as to whether or not to add additional patients was to be based upon a statistical calculation of the preliminary data performed by an independent statistician appointed by the Company in accordance with the protocol of the clinical trial, and in accordance with the FDA’s requested and approved method as part of the SPA, as agreed upon between the FDA and the Company. Statistical analysis of the preliminary data collected in the Phase III clinical trial was performed by the independent statisticians in accordance with the clinical trial protocol, and showed that the study met the pre-specified criteria the FDA required for stopping patient enrollment and thus proceeding to the completion of the final statistical analyses. The final statistical analyses of the data demonstrated that the Phase III study of KIT-302 met its FDA approved primary efficacy endpoint with statistical significance based upon the efficacy endpoint of less than 0.001.
KIT-302 is based on two generic drugs (amlodipine besylate and celecoxib). Until December 2015 celecoxib was protected by patents held by Pfizer Inc. (Celebrex®). The USPTO granted Pfizer a “reissue patent” covering methods of treating osteoarthritis and other approved conditions with celecoxib, the active ingredient in Celebrex®. The reissued patent extended U.S. patent protection for Celebrex® from May 30, 2014 to Dec. 2, 2015.

We currently expect to receive approval from the FDA to market KIT-302 in 2018. As a result of this timing and because KIT-302 combines the treatment of osteoarthritis by celecoxib with amlodipine besylate, which treats the side effect of hypertension, we believe that KIT-302 may be an attractive alternative to the newly marketed generic versions of Celebrex®.

Competitive Treatments for Pain Caused by Osteoarthritis

The competition for KIT-302 is expected to come from the oral anti-arthritic market, or more specifically the traditional non-selective NSAIDs (such as naproxen and diclofenac), traditional NSAID/gastroprotective agent combination products or combination product packages (such as Vimovo®, Arthrotec®, Prevacid® and NapraPAC™) and the most common COX-2 inhibitor in the U.S. market, Celebrex® (including generic versions of Celebrex®). In 2016, global sales of branded celecoxib (Celebrex® by Pfizer, and Celecox®by Astellas) were $733 million and $423 million, respectively, out of which $116 million were in the US (by Pfizer) and $423 million in Japan (by Astellas).
Due to the voluntary withdrawal of Vioxx® by Merck & Co. in September 2004, the FDA ordered the withdrawal of Bextra® by Pfizer and issued a Public Health Advisory in April 2005, requiring manufacturers of all prescription products containing NSAIDs to provide warnings regarding potential adverse cardiovascular events as well as life-threatening gastrointestinal events associated with the use of NSAIDs. Moreover, subsequent to an FDA advisory committee meeting in February 2005 that addressed the safety of NSAIDs, and, in particular, the cardiovascular risks of COX-2 selective NSAIDs, the FDA has indicated that long-term studies evaluating cardiovascular risk will be required to approve new NSAID products that may be used on an intermittent or chronic basis. We believe that KIT-302 has a competitive advantage over other drugs in the market because, as a COX-2 inhibitor, it has limited gastrointestinal side effects, and due to the addition of amlodipine besylate it is designed to address existing hypertension and the cardiovascular side effects of NSAIDs.


NT-219
In January 2017, we acquired a majority of the shares in TyrNovo which is developing the NT219 therapeutic candidate. NT219 is a small molecule that presents what we believe is a new concept in cancer therapy by promoting the degradation of two oncology-related checkpoints, Insulin Receptor Substrates (IRS) 1 and 2 as well as the inhibition of signal transducer and activator of transcription 3 (STAT3). In pre-clinical trials, NT219, in combination with several approved cancer drugs, displayed potent anti-tumor effects and increased survival in various cancers by preventing the tumors from developing drug resistance and restoring sensitivity to the drugs after resistance is acquired. The NT219 technology has been tested in a number Patient-Derived Xenograft (PDX) models where human primary cancer cells or biopsies are taken and transplanted into mice and then used to test various cancer drugs.

Mechanism of Action

The NT219 therapeutic candidate is a small molecule that we believe presents a new concept in cancer therapy by promoting the degradation of two oncology-related checkpoints, IRS1 and IRS2 as well as the inhibition of STAT3. While targeted anti-cancer drugs inhibit the “ON” signal, NT219 activates the “OFF” switch, extensively blocking major oncogenic pathways.

Elimination of IRS proteins and blockage of STAT3 by NT219 could potentially prevent resistance to multiple anti-cancer drugs, extend the duration of effective drug treatment, and restore drug sensitivity in resistant tumors.

IRS down-regulation can be mediated by several oncogenic pathways (MAPK, mTOR, EGFR etc). Blockade of these pathways by various drugs, could inhibit serine phosphorylation of IRS, leading to the activation of IRS to AKT survival bypass. Therefore, elimination of IRS1/2 by NT219 potentially could prevent resistance and prolong the tumor’s response to various targeted drugs, as depicted below:
Preclinical results - NT219

In pre-clinical trials, NT219, in combination with several approved cancer drugs, displayed potent anti-tumor effects and increased survival in various cancers by preventing the tumors from developing drug resistance and restoring sensitivity to the drugs after resistance is acquired. The NT219 molecule has been tested in a number Patient-Derived Xenograft (PDX) models where human primary cancer cells or biopsies are taken and transplanted into mice and then used to test various cancer drugs. NT219 has shown efficacy in various PDX models originated from non-small cell lung cancer (NSCLC), sarcoma, melanoma, pancreatic, head & neck and colon cancers.

Efficacy of NT219 was demonstrated in combination with three major families of oncology drugs:

1) Antibodies such as the anti-epidermal growth factor receptor (EGFR) antibody (Erbitux®);

2) Kinase Inhibitors such as blockers of EGFR (Tagrisso®, Tarceva®), MEK (Mekinist®), Mutated BRAF (Zelboraf®), and mTOR inhibitors such as Afinitor®; and

3) Chemotherapy agents such as Gemzar®, 5FU, and Oxaliplatin.

Below are two examples of results obtained with NT219 in PDX models. In the head and neck cancer model treatment with NT219 in combination with Elrotinib (trade name Tarceva®, an anti EGFR drug approved for various oncology indications; left panel) resulted in overcoming drug resistance and lower volume of the tumor, compared to the treatment arm with Erlotinib alone. Similar results are depicted on the right panel where NT219 was tested in a pancreatic cancer PDX model where combination of NT219 with gemcitabine (a chemotherapy agent approved for pancreatic cancer) resulted in decreased tumor volume compared to those obtained with gemcitabine alone.


5. INTELLECTUAL PROPERTY

KIT-302

Kitov owns two U.S. patents and we expect to be pursuing additional international patent applications relating to our lead drug candidate, KIT-302. The following is a brief description of Kitov’s patent and trademark-related intellectual property:

On August 10, 2016, we announced that the United States Patent and Trademark Office (USPTO) issued patent #9,408,837 covering KIT-302. The patent, entitled “Ameliorating Drug-Induced Elevations In Blood Pressure By Adjunctive Use Of Antihypertensive Drugs,” was issued on August 9, 2016 and is expected to have a term that can extend to February 28, 2030. The patent includes claims covering methods of ameliorating celecoxib-induced elevation of blood pressure by administering celecoxib and amlodipine separately or in combination.

On February 1, 2017, we announced that the USPTO issued a Notice of Allowance to Kitov related to claims expanding the patent coverage for our lead drug candidate, KIT-302, to include oral dosage compositions containing both amlodipine and celecoxib. This patent is a divisional of the ’837 patent and is expected to have a similar patent term as that of patent #9,408,837.

We anticipate that in the near future, we will be filing an international patent application, in partnership with Dexcel Ltd., which is related to pharmaceutical formulations of celecoxib and amlodipine and methods of preparing the same.

We have applied to the USPTO for registered trademarks for two possible trade names for KIT-302 and have also submitted these names to the FDA for approval.

TyrNovo

TyrNovo’s patent and patent application portfolio includes five patent families, covering compounds that modulate protein kinase signaling and their use in treatment of protein kinase related disorders, including cancer and neurodegenerative disorders.

- Patent Family 1 was filed on December 4, 2007 (PCT filing date). The priority date is December 4, 2006. This family is directed to compounds modulating the insulin like growth factor receptor signaling and methods of using these compounds as chemotherapeutic agents for the treatment of protein kinase related disorders, in particular cancer. National phase counterparts exist in Europe (EP 2125712) and the United States (US 8,058,309), both of which are now granted with a maximum term of December 4, 2027 (not including any available patent term extension (PTE)). The European patent was validated in France, Germany, Switzerland and the United Kingdom.
- Patent Family 2 was filed on June 7, 2009 (PCT filing date). The priority date is June 5, 2008. This family is also directed to compounds modulating the insulin like growth factor receptor signaling, and methods of using these compounds as chemotherapeutic agents for the treatment of protein kinase related disorders, in particular cancer. This patent family specifically discloses and claims NT-219. National phase counterparts exist in Europe (EP 2285774), the United States (US 8,637,575) and Israel (IL 209638), all of which are now granted with a maximum term of June 7, 2029 (not including any available PTE). The European patent was validated in France, Germany, Italy, Netherlands, Spain, Switzerland, and the United Kingdom.
- Patent Family 3 was filed on December 27, 2011 (PCT filing date). The priority date is December 27, 2010. This family is directed to compounds having a benzo[e][1,3]thiazin-7-one core, and methods of using these compounds as chemotherapeutic agents for the treatment of protein kinase related disorders, in particular cancer. National phase counterparts exist in Europe (EP 2658847) and the United States (US 9,073,880), both of which are now granted with a maximum term of December 27, 2031 (not including any available PTE). The European patent was validated in France, Germany, Italy, Netherlands, Spain, Switzerland, and the United Kingdom.
- Patent Family 4 was filed on July 13, 2014 (PCT filing date). The priority date is July 14, 2013. This family is directed to use of the compounds disclosed in Patent Families 1-3, for the treatment of neurodegenerative diseases, including Alzheimer’s disease. National phase applications were filed in Europe (EP 3021944), the United States (US2016/0158243) and Israel (IL 243566). All of these applications are now pending. Any patent issuing from these applications will have a maximum patent term of July 13, 2034.
- Patent Family 5 was filed on February 4, 2016 (PCT filing date). The earliest priority date is February 5, 2015. This family is directed to combinations of the compounds disclosed in Patent Families 1-3, acting as dual modulators of Insulin Receptor Substrate (IRS) and signal transducer and activator of transcription 3 (STAT3), with various targeted drug families (inhibitors of Epidermal Growth Factor Receptor (EGFR), mammalian target of rapamycin (mTOR); mitogen-activated protein kinase (MEK) or mutated B-Raf), as well as chemotherapeutic agents (Gemcitabine, 5-FU, Irinotecan and Oxaliplatin), and use of such combinations for the treatment of cancer. The combinations can be used to treat tumors that have developed resistance to these anti-cancer drugs, to prevent acquired resistance of a tumor to these drugs, or to prevent tumor recurrence following cease of treatment with these drugs. The present invention further relates to the treatment of cancer using combination therapy comprising a dual modulator of IRS and STAT3, in combination with an immunotherapy agent, and can be used to sensitize a tumor to immunotherapy. The deadline to enter the national phase is August 5, 2017.


6. INSTITUTIONAL OWNERSHIP

Kitov Institutional Ownership estimation based on the recent filings.

https://www.sec.gov/Archives/edgar/data/1614744/000121390017004462/f20f2016_kitovpharma.htm

1. Goldman Hirsh Partners Ltd./Dr. Gil Pogozelich owns 11,292,508 ordinary shares (564.625 ADSs). Per TyrNovo deal, GHP accepted to be paid (half of the value) with Kitov's shares at around 3$;

2. JPW PCH LLC owns 2,184,431 ordinary shares (109.221 ADSs);

3. Dexcel Ltd owns 3,765,182 ordinary shares (188.259 ADSs). As per the agreement, the first issuance of 157,783 ordinary shares was made upon execution of the agreement, the second issuance of 597,511 ordinary shares was made upon attainment of the second milestone in May 2015, and the final issuance of 3,009,888 ordinary shares was made on June 19, 2016 in connection with the attainment of the fifth milestone;

4. Mr. Sheer Roichman / Haiku Capital Ltd. owns, as reported on the Schedules 13G filed on June 1, 2016 by Mr. Sheer Roichman and Haiku Capital Ltd., a company wholly-owned by Mr. Roichman, as of such date Haiku Capital beneficially owned 221,020 ordinary shares and held options issued by us to Haiku Capital representing the right to purchase 400,000 ordinary shares, and Mr. Sheer Roichman beneficially owned 2,473,780 ordinary shares (134.740 ADSs);

5. NEW INVESTORS (private placement) https://www.sec.gov/Archives/edgar/data/1614744/000121390017007408/f6k071117ex99i_kitovpharma.htm
Kitov issued 2,431,746 (ADSs) for some "mysterious" investors;

6. Ex-Tyrnovo investors https://www.sec.gov/Archives/edgar/data/1614744/000121390017010343/f6k100617ex99-1_kitovpharma.htm
Kitov issued 658,484 (ADSs) for ex-Tyrnovo investors;

7. Other Institutional Funds https://fintel.io/so/us/ktov
Insitutionals Funds filed 13-F for a total amount of 210,393 (ADSs);

That said, with a simplistic math, considering a total O/S of 11.316.716 (ADSs) we should have 38% of the float owned by Tutes/Investors:

1. GHP: 5%
2. JPW: 1%
3. Dexcel: 2%
4. Haiku/Roickman: 1%
5. New investors: 21%
6. Ex-Tyrnovo investors: 6%
7. Other Institutional funds: 2%

Interesting to note that both JPW (John Paul Waymack's fund), Dexcel and Haiku/Roichman (and recently GHP) has been severely diluted during these years. Interesting to note as well that GHP used to own 6.8% (now 5% after recent dilution) and it didn't have to report his stake in any form 13 to the SEC. That basically means that there could be other foreign funds owning some % in Kitov that we can not consider in this estimation.

Anyway, recent volume suggests that some Tutes entered as well increasing that percentage but this is just speculation considering we have to wait until they filed a 13-G or 13-F form filing or the 20-F filing from Kitov.


7. RECENT DEVELOPMENTS

Patents Developments
“We anticipate that in the near future, we will be filing an international patent application, in partnership with Dexcel Ltd., which is related to pharmaceutical formulations of celecoxib and amlodipine and methods of preparing the same.”
We have applied to the USPTO for registered trademarks for two possible trade names for KIT-302 and have also submitted these names to the FDA for approval (names choosen are “ENSEDAPINE and “CONSENSI”)

Europe Updates for KIT-302
In order to market or sell our KIT-302 therapeutic candidate in Europe, we must apply to an applicable European country’s regulatory authorities with a request to approve KIT-302 according to the Mutual Recognition Procedure (MRP), which is a procedure applied by European Directive No. 2001/83/EC that enables access to medicinal products (drugs) in 27 countries of the European Union. The MRP approval process requires the applicant to receive approval in one of the EU countries and then apply for recognition of the other member countries to acknowledge the approval within their territory. It is not currently known whether the European regulatory authorities will require additional studies in order to grant their approval to market KIT-302 in Europe.

The Company has engaged an external consultant to assist the Company in applying for regulatory approval of KIT-302 in Europe. As part of this process, the Company is scheduled to meet with regulatory authorities in Sweden and the UK in the second quarter of 2017. At that meeting, the applicability of the Company’s current data for obtaining marketing authorization in various EU countries will be discussed. Following this meeting, a plan will be finalized for obtaining regulatory approval for marketing in EU countries.

KIT-302 last updates (NDA)
Kitov Pharmaceuticals Holdings Ltd. (NASDAQ: KTOV, TASE: KTOV), an innovative biopharmaceutical company, today announced that the U.S. Food and Drug Administration (FDA) filed the Company’s New Drug Application (NDA) for KIT-302, its lead drug candidate, thereby accepting the NDA for a full review. KIT-302 is a patented combination of celecoxib and amlodipine, and is intended to treat osteoarthritis pain and hypertension simultaneously. In connection with its determination that Kitov’s application is sufficiently complete to permit a substantive review, the FDA, under the Prescription Drug User Fee Act (PDUFA), has set a target date of May 31, 2018 to complete its review.

Kitov Pharmaceuticals Holdings Ltd. (NASDAQ: KTOV, TASE: KTOV), an innovative biopharmaceutical company, announced today that the U.S. Food and Drug Administration (FDA) has granted Kitov a waiver related to the $2,038,100 New Drug Application (NDA 210045) filing fee for KIT-302. KIT-302 is Kitov's patented combination of Amlodipine Besylate-Celecoxib tablets, intended to treat osteoarthritis pain and hypertension simultaneously.

KIT-302 Precision Study
Additional data from the (FIRST) Phase III clinical trial of KIT-302 also suggest beneficial effects on renal (kidney) function, as compared to negative effects on renal function caused by other NSAIDS. Greater reduction in plasma levels of creatinine was observed in patients in the KIT-302’s two components arm (-3.22 umol/L) compared to creatinine reduction observed in patients in the amlodipine arm (-2.55 umol/L), suggesting better renal function. In addition, peripheral edema, a known side effect of calcium channel blockers such as amlodipine, was reported in 15.6% of patients receiving amlodipine alone, but in only 8.2% of patients receiving KIT-302’s two components, suggesting that KIT-302 may protect against the amlodipine side effect of causing fluid retention by the kidneys".
On October, 26, these beneficial effects on renal (kidney) function have been confirmed!
https://www.sec.gov/Archives/edgar/data/1614744/000121390017010999/f6k102717ex99-1_kitov.htm

"The study also demonstrated that treatment with KIT-302 led to a statistically significant reduction of serum creatinine, a marker of renal function, from its baseline value (p=0.0005). In contrast, neither amlodipine besylate nor placebo lowered creatinine to a statistically significant level".
.... Furthermore, "the peripheral edema measure in KIT-302, a known side effect of calcium channel blockers such as amlodipine, was statistically INSIGNIFICANT".

They proved that KIT-302 is the first NSAIDs with NO cardiovascular risks and NO negative effects on renal functions!

Partnerhips for KIT-302
Kitov Pharmaceuticals Holdings Ltd. (NASDAQ: KTOV; TASE: KTOV), an innovative biopharmaceutical company, announced today that the Company has signed a definitive License Agreement for its lead product candidate, KIT-302, which was developed to simultaneously treat pain caused by osteoarthritis and to treat hypertension, for the territory of South Korea with Kuhnil Pharmaceutical Co. Ltd., a leading South Korea-based pharmaceutical company. Upon receipt of marketing authorization in South Korea, Kuhnil will have the exclusive right and license to manufacture, distribute and sell KIT-302 in South Korea. Kuhnil will be responsible for seeking regulatory approval for KIT-302 in South Korea.

Under the terms of the agreement, Kitov is entitled to receive milestone payments upon achievement of certain predefined regulatory milestones, as well as double digit royalties on net sales. The initial term of the definitive agreement with Kuhnil is for ten years from the date of first commercial sale and shall automatically renew for an additional one-year term. Commercial launch in South Korea is estimated to take place in 2019.

In addition to our internal business development team, we have engaged consultants which are assisting us with finding other potential collaboration partners for KIT-302 in various markets world-wide.

Pre-clinical development for NT-219
Kitov Pharmaceuticals Holdings Ltd. (NASDAQ/TASE: KTOV), an innovative biopharmaceutical company, today announced results of a pre-clinical study demonstrating that NT-219, the lead drug candidate of its subsidiary TyrNovo Ltd., in combination with Keytruda®, converted non-responding tumors to responders and blocked tumor progression in an immune-oncology preclinical model.

The study, conducted in collaboration with researchers at Bar Ilan University and Rabin Medical Center, assessed NT-219’s ability to overcome cancer drug resistance in a patient-derived xenograft (PDX) model of immune-deficient mice, in which a tumor originated from an esophagus cancer biopsy was implanted. The mice were supplemented with immune cells from the same patient (double autologous). While no response was observed with Keytruda® alone or with NT-219 alone, and the tumors aggressively progressed, mice treated concomitantly with a combination of Keytruda® and NT-219 demonstrated complete blockage of tumor progression.

"We are excited with these initial results obtained with NT-219 in combination with pembrolizumab (Keytruda®),” stated Dr. J. Paul Waymack, Chairman of Kitov's Board and Chief Medical Officer. “Previous results obtained with NT-219 demonstrated its efficacy in overcoming drug resistance in a variety of cancers and in combination with various pharmacologic cancer therapies. We are focused on advancing this highly promising therapeutic candidate to clinical trials as quickly as possible in order to provide enhanced treatment options to cancer patients.”
Kitov Pharmaceuticals Holdings Ltd. (NASDAQ: KTOV, TASE: KTOV), (“Kitov” or “the Company”) an innovative biopharmaceutical company, announced today the acquisition of an additional 27% stake in TyrNovo Ltd., a privately- held developer of novel small molecules in the oncology therapeutic field, from unaffiliated minority shareholders. As announced on January 13, 2017, Kitov had acquired a controlling interest, which is now approximately 65% of TyrNovo. After the closing of this transaction, Kitov will hold approximately 92% of TyrNovo’s issued and outstanding ordinary shares.

Tyrnovo Ownership Updates
Following negotiations with a group of unaffiliated minority shareholders who collectively hold approximately 27%, of TyrNovo, the Company has entered into an agreement to acquire their shares based on an agreed upon TyrNovo valuation of $7 million. In exchange for these TyrNovo shares, Kitov will issue 13,169,689 new shares (equivalent to 658,484 American Depositary Shares or ADSs) of Kitov, at an agreed upon price, in excess of prevailing market prices, of $2.50 per ADS.

“Since early 2017, NT219 demonstrated impressive efficacy results including in combination with Keytruda®, where it converted non-responding tumors to responders and blocked tumor progression in an immuno-oncology preclinical model. We are pleased to have negotiated the opportunity for Kitov to increase its stake in TyrNovo. We are committed to the development of NT219, which we believe is a highly attractive asset for Kitov’s shareholders in the growing field of oncology” stated Mr. Isaac Israel, Chief Executive Officer. “We believe that expanding our ownership in TyrNovo provides a significant opportunity for further growth of Kitov and added value to our shareholders.”

“Based on the pre-clinical results generated to date, we are receiving solid preliminary interest from potential strategic partners for NT219, which presents a novel, first-in-class mechanism of action in the oncology field.”

Merger between Holding and Subsidiary
As previously announced by Kitov Pharmaceuticals Holdings Ltd. (the “Company” or the “Registrant”) on April 26, 2017, the boards of directors of each of the Company and Kitov Pharmaceuticals Ltd., the Company’s wholly owned subsidiary (the “Company Subsidiary”), approved a merger between the two entities, with the Company remaining as the surviving entity. In accordance with the Israeli Companies Law 5759-1999 (the “Companies Law”), the proposed merger between the Company and the Company Subsidiary will not require shareholder approvals.

SPECIAL MEETING (July, 12)
https://www.sec.gov/Archives/edgar/data/1614744/000121390017006251/f6k060817ex99i_kitovpharma.htm
All the proposals have been approved by shareholders https://www.sec.gov/Archives/edgar/data/1614744/000121390017007544/f6k071317_kitovpharma.htm

Private placement
Kitov Pharmaceuticals (NASDAQ/TASE: KTOV), an innovative biopharmaceutical company focused on late-stage drug development, today announced that it has entered into definitive agreements with institutional and other investors providing for the issuance of 2,431,746 American Depositary Shares (ADS) at a purchase price of $1.45 per ADS in a registered direct offering.
Kitov will issue unregistered warrants to purchase up to1,215,873 ADSs. The warrants will have a term of 5.5 years, be exercisable six months following the issuance date and have an exercise price of $1.50 per ADS. The offering is expected to result in gross proceeds of approximately $3,526,032

NOTICE OF 2017 ANNUAL GENERAL MEETING OF THE SHAREHOLDERS OF KITOV PHARMACEUTICAL
On December 4, 2017, Kitov's Shareholders will have "To vote on a proposal to a change of the Company's name to Kitov Biopharma Ltd. or such similar name containing the name “Kitov” as determined by the Company's management and approved by the Israeli Registrar of Companies, and approve the applicable amendments to the Company's Memorandum of Association and Articles of Association to reflect such name change (the change of the Company’s name will be effective only following the approval and authorization of the Israeli Registrar of Companies)".


8. UPCOMING EXPECTED CATALYSTS

1) US/EU partner for KIT-302
2) Partnership Region Ex-Eu and Ex-US
3) EU updates for KIT-302 Approval application in Europe
4) New patent filings with Dexcel for KIT-302
5) Court decision for the classaction (Kitov’s lawyers correctly asked NY Judge to toss the lawsuit considering plaintiffs didn’t find any proofs/motives)
6) NT219 partnerships/collaboration (as recently mentioned by CEO)
7) PDFUA date in May of KIT-302 approval by FDA
8) NT219 IND


9. ANALYSTS COVERAGE

Rodman & Renshaw, a unit of H.C. Wainwright & Co (Raghuram Selvaraju)
https://www.streetinsider.com/New+Coverage/Rodman+%26+Renshaw+Starts+Kitov+Pharmaceuticals+%28KTOV%29+at+Buy/11320823.html
Price Target: $10


10. SOURCES

20-F https://www.sec.gov/Archives/edgar/data/1614744/000121390017004462/f20f2016_kitovpharma.htm

Company presentation (June- 2017)
http://kitovpharma.investorroom.com/download/KitovPresentation+June+2017+FINAL.pdf

LifeSci Company update (October – 2017)
https://www.baystreet.ca/articles/research_reports/lifesci/Kitov100317.pdf

KIT-302 Study Results
https://clinicaltrials.gov/ct2/show/results/NCT02172040?term=kitov&rank=2