What changed in this filing

/stocks — the workspaceLOADING

Item 1. Business

2016-06-07 compared with 2015-06-17 · 158 added, 514 removed, 330 unchanged (67% of the section changed)

5 unchanged sentences

Except as required by applicable law, including the securities laws of the United States, we do not intend to update any of the forward-looking statements to conform these statements to actual results.

Our financial statements are stated in Canadian Dollars (CDN$) and are prepared in accordance with United States Generally Accepted Accounting Principles.

In this annual report, unless otherwise specified, all dollar amounts are expressed in Canadian dollars and all references to “common shares” refer to the common shares in our capital stock.

Our financial statements are stated in U.S.

Dollars (US$) and are prepared in accordance with United States Generally Accepted Accounting Principles.

In this annual report, unless otherwise specified, all dollar amounts are expressed in US dollars and all references to "common shares" refer to the common shares in our capital stock.

As used in this annual report, the terms "we", "us", "our" and "our company" mean Pivot Pharmaceuticals Inc., unless otherwise indicated.

General Overview

We are a development stage biopharmaceutical company.

We are a development stage pharmaceutical company.

We were incorporated in the Province of British Columbia, Canada under the name "649186 B.C.

1 unchanged sentence

On September 9, 2003, we changed our name to "Xerxes Health Corp." and on June 26, 2007, we changed our name to "Neurokine Pharmaceuticals Inc.".

Effective June 4, 2014, we filed with the British Columbia Registrar of Companies a Form 11, Notice of Alteration, wherein we have increased our authorized share capital from 500,000,000 common shares without par value to an unlimited number of common shares without par value.

Effective June 4, 2014, we filed with the British Columbia Registrar of Companies a Form 11, Notice of Alteration, wherein we increased our authorized share capital from 500,000,000 common shares without par value to an unlimited number of common shares without par value.

The increase of authorized capital was approved by our stockholders at the annual and special meeting held on June 3, 2014.

On September 26, 2014, our company held a special meeting of stockholders to approve the removal of our company's Pre-Existing Company Provisions, the cancellation of our current Articles and the adoption of new Articles and to approve a reverse stock split on the basis of up to 1:100.

Effective October 8, 2014, we filed with the British Columbia Registrar of Companies a Form 11, Notice of Alteration, wherein we have removed our Pre-Existing Company Provisions.

Effective October 8, 2014, we filed with the British Columbia Registrar of Companies a Form 11, Notice of Alteration, wherein we removed our Pre-Existing Company Provisions.

Effective April 7, 2015, we filed with the British Columbia Registrar of Companies a Form 11, Notice of Alteration, wherein we changed our name to "Pivot Pharmaceuticals Inc.".

Effective at the opening of trading on April 20, 2015, as approved by FINRA, our company effected a reverse stock split of our issued and outstanding common shares on a 10 old for 1 new share basis, and approved the change of our name from “Neurokine Pharmaceuticals Inc.”, to “Pivot Pharmaceuticals Inc.”.

Our principal executive office is located at 1275 West 6th Avenue, Vancouver, British Columbia, Canada, V6H 1A6.

Effective at the opening of trading on April 20, 2015, as approved by FINRA, our company effected a reverse stock split of our issued and outstanding common shares on the basis of 10 old common stock for 1 new common stock.

On November 20, 2015, we completed the acquisition of IndUS Pharmaceuticals, Inc.

("IndUS"), a Delaware corporation, pursuant to an Agreement and Plan of Merger and Acquisition Agreement dated as of November 4, 2015 among our company, Pivot Pharma U.S.

Inc., our wholly owned subsidiary, IndUS and Sindu Research Laboratories Pvt Ltd.

As consideration for the purchase, we issued 4,512,500 shares of common stock on November 23, 2015 and 237,500 shares of common stock on December 4, 2015.

We will also be granting 41,833 stock options pursuant to the Agreement and Plan of Merger.

As part of the acquisition, we appointed Dr.

Pravin Chaturvedi as our new Chief Executive Officer and Director.

IndUS is an emerging United States-India cross-border pharmaceutical company located in the Greater Boston area, which is engaged in conducting research and development activities for advancing novel therapeutics in the areas of oncology, infectious diseases and diabetes.

Our principal executive office is located at 1275 West 6th Avenue, Vancouver, B.C.

Canada V6H 1A6, with another office at 25 Olympia Avenue, Suite K-300, Woburn, MA 01801, USA.

Our telephone number is (978) 973-5271.

We are engaged in the development and commercialization of therapeutic pharmaceutical products with a strategic emphasis on research and development to innovate new applications for existing drugs.

This is commonly known as drug re-profiling.

Our research and development activities are focused on assessing known drugs and compounds, developing hypotheses concerning their usage for new indications (diseases), and conducting experimentation and clinical research to test those hypotheses.

Where appropriate based on our research, we intend to depart from a strict re-profiling strategy to develop new variants of, or delivery methods for, or new dosage regimens for existing drugs or compounds.

Our Current Business

We are a development stage biopharmaceutical company engaged in the development and commercialization of therapeutic pharmaceutical products, focused on the strategy of identifying new therapeutic treatments to address unmet medical needs in women's health including but not limited to urological and/or gynecological disturbances;

and advancing novel anticancer drug candidates to provide new treatment options for metastatic cancers in women that do not have adequate treatment options or have poor response to existing treatment options due to inherent or acquired mutations.

Our research and development activities are focused on i) advancing novel drug candidates for the treatment of women's cancers including, but not limited to metastatic endometrial cancer and triple-negative breast cancer, which have limited treatment options;

and ii) leveraging novel drug delivery treatment options to allow 'targeted' delivery of drugs to address women's health needs in urological and/or gynecological indications, and iii) opportunistically in-licensing later-stage drug candidates to augment our drug pipeline.

Where appropriate, we intend to depart from these strategies to opportunistically acquire additional novel treatment options to address unmet or under-served medical needs in women's health.

Our business model currently includes the following activities:

identifying new indications for approved and marketed products;

securing intellectual property rights to those products;

conducting preliminary laboratory tests and clinical trials;

establishing partnerships with large pharmaceutical, specialty pharmaceutical companies and biotechnology companies to develop and commercialize products outside of the initial market focus.

Our management believes that our strategic emphasis on drug re-profiling is superior to a strategy based exclusively on new drug development because the drugs we are seeking to re-profile have already passed a significant number of required regulatory tests.

Similarly, when compared to developing a new drug, re-profiling typically requires less research and development time and cost and offers a greater possibility of obtaining regulatory approval and ultimately achieving commercialization.

On the other hand, drug re-profiling can also pose certain challenges such as securing intellectual property rights generic drugs, the cost of which may make re-profiling prohibitive.

In spite of any advantages our strategy may provide, we will likely face a wide range of common pharmaceutical industry challenges.

For example, any products that we may develop will be required to undergo a time-consuming, costly and burdensome pre-market approval process for efficacy and we may be unable to obtain regulatory approval for them.

We may not commence clinical testing of any products that we may develop and the commercial value of any clinical study that we conduct will depend significantly upon our choice of indication and our patient population selection.

If we are unable to commence clinical testing or if we make a poor choice in terms of clinical strategy, we may never achieve revenues.

Our clinical trials may also fail to adequately demonstrate the efficacy of our product candidates for our chosen indications, which may force us to abandon our business plan.

Even if we are able to ultimately obtain regulatory approval for any products that we may develop, we may never become profitable.

To date, we have concentrated our research and development activities on innovating uses for existing drugs for the treatment of diseases mediated by acute and chronic inflammatory reactions.

Our new activities for 2015 and on will focus on repositioning drugs into the underserved markets of Women’s Health indications as well as additional targets in Neurology.

We have identified three drug classes (P-001, P-002, P-003) that can serve unmet or underserved indications in the Women’s Health market if we can demonstrate efficacy.

Through the research executed previously by Neurokine, target drugs have been identified and, where required, secured the rights necessary to develop two anti-inflammatory products, NK-001 and NK-002, that we believe hold promising prospects for the treatment of neurocognitive impairment that occurs in patients that have undergone cardiac artery bypass and Alzheimer’s disease, respectively.

P-001 is a new application of an existing generic drug class and therefore adheres to our re-profiling strategy.

We anticipate that P-001 will require minimal pre-clinical studies for the new indication in Women’s Health (including dysmenorrhea, kidney stones and urinary tract indications), but will not require preliminary safety or pharmacokinetic data (the process by which the drug is metabolized by the body) studies.

P-001 is a new application of the drug class that blocks alpha-adrenergic receptors, several of which are marketed under United States Food and Drug Administration (“FDA”) approval as a treatment for benign prostrate hyperplasia in men.

Because this class has several candidates that have already been the subject of safety studies on a patient population similar to patients targeted by P-001, we do not anticipate having to complete these additional studies before proceeding to later-stage clinical trials, such as going directly into a Phase IIa.

Although unlikely, it remains that the Regulatory Authorities may require additional studies as part of the application for marketing.

P-002 is a new application of an existing generic drug class and therefore adheres to our re-profiling strategy.

We anticipate that P-002 will require minimal pre-clinical studies for the new indication in Women’s Health (including hot flushes in peri-menopause), but will not require preliminary safety or pharmacokinetic data (the process by which the drug is metabolized by the body) studies.

P-002 is a new application of the drug class that blocks central-adrenergic receptors, several of which are marketed under United States Food and Drug Administration (“FDA”) approval as a treatment for hypertension.

Because this class has several candidates that have already been the subject of safety studies on a patient population similar to patients targeted by P-002, we do not anticipate having to complete these additional studies before proceeding to later-stage clinical trials, such as going directly into a Phase IIa.

Although unlikely, it remains that the Regulatory Authorities may require additional studies as part of the application for marketing.

P-003 is a new application of an existing generic drug class and therefore adheres to our re-profiling strategy.

We anticipate that P-003 will require minimal pre-clinical studies for the new indication in Neurology (dementia, migraine prevention), but will not require preliminary safety or pharmacokinetic data (the process by which the drug is metabolized by the body) studies.

P-003 is a new application of the drug class that act as angiotensin-2 inhibitors, several of which are marketed under United States Food and Drug Administration (“FDA”) approval as a treatment for hypertension.

Because this class has several candidates that have already been the subject of safety studies on a patient population similar to patients targeted by P-003, we do not anticipate having to complete these additional studies before proceeding to later-stage clinical trials, such as going directly into a Phase IIa.

Although unlikely, it remains that the Regulatory Authorities may require additional studies as part of the application for marketing.

NK-001 is a new application of an existing new drug and therefore adheres to our re-profiling strategy.

We do not anticipate that NK-001 will require pre-clinical, preliminary safety or pharmacokinetic (the process by which the drug is metabolized by the body) studies.

NK-001 is a new application of the drug Etanercept, which is marketed under United States Food and Drug Administration (“FDA”) approval as a treatment for rheumatoid arthritis.

Because Etanercept has already been the subject of safety studies on a patient population similar to patients targeted by NK-001, we do not anticipate having to complete these additional studies before proceeding to later-stage clinical trials, and we have previously received approval to conduct clinical trials in South Africa on that basis.

In contrast, NK-002 is a new formulation for the delivery of an existing drug and is therefore properly classified as a new drug.

As a new drug, NK-002 will require a complete development program, including the full range of successful pre-clinical, safety and pharmacokinetic studies before advanced clinical testing will be permitted to occur.

Both of our planned products, including our leading candidate, NK-001, are in the development stage as of the date of this annual report and neither has been approved to date for sale to the public in any country.

To date, we have outsourced all other research and development work to third parties, including clinical trial planning, laboratory services, data management, statistical services and report writing.

identifying novel drug delivery technologies that will allow targeted drug delivery for drugs;

securing and developing intellectual property rights to such products;

conducting appropriate laboratory tests and clinical trials;

advancing novel drug candidates to treat women's cancers from our acquisition of IndUS to support Investigational New Drug application to allow first-in-human trials;

opportunistically acquiring later-stage drug candidates that provide new treatment options to address unmet medical needs in women's health in cancer and lower urinary tract symptoms;

establishing partnerships with large and specialty pharmaceutical companies and/or biotechnology companies to collaboratively develop and/or commercialize our products.

One of our areas of focus includes developing therapeutic applications for existing drugs using novel delivery technologies for the treatment of diseases and conditions specific to cancer and/or urological disturbances in women.

The diseases and conditions that are the subject of our research and development program include addressing resistant cancers affecting women's health and developing new treatment options using novel drugs and/or novel delivery approaches to address oncological and urological conditions such as various gynecological and breast cancers as well as lower urinary tract symptoms such as overactive bladder.

Our current pipeline addresses the therapeutic areas of cancer and lower urinary tract symptoms (LUTS):

Metastatic endometrial cancer (PVT-005)

Triple-negative breast cancer (PVT-006)

Lower urinary tract symptoms including filling and voiding issues (PVT-002)

PVT-005 and PVT-006 are novel and patented anticancer small molecule drug candidates acquired through the acquisition of IndUS.

These molecules are novel DNA damage response inhibitors and belong to the chemical class of pyrrolobenzodiazepine dimers (PBDs).

These molecules have shown preclinical activity in cancers that have mutations in their tumor suppression and/or DNA repair abilities and have shown 'synthetic lethality' when dosed as monotherapy in such resistant cancers and/or in combination with standard-of-care drugs that are used in chemotherapeutic regimens for such patients.

PVT-005 and PVT-006 have shown excellent activity in tumor cells that have genetic or epigenetic mutations in DNA mismatch repair (mlh1, MSH2), tumor suppression functions (p53, PTEN) and/or homologous recombination (HR) functions.

They have shown significant synergies with platinum-based drugs such as cisplatin, and other drugs like topoisomerase II and I inhibitors (doxorubicin and camptothecin, respectively) and receptor tyrosine kinase (RTK) inhibitors – all or some of which are part of standard-of-care chemotherapeutic regimens to treat ovarian, breast, colorectal, non-small cell lung and other cancers that affect women's health.

Our research and development strategy is focused on developing novel treatment options to address various unmet medical needs in women's health, including but not limited to 1) urological and gynecological disturbances such as lower urinary tract symptoms;

and 2) addressing unmet or under-served medical needs in women's cancers such as metastatic endometrial or triple-negative breast cancer that have inherent or acquired mutations rendering them resistant to existing treatment options and represent orphan drug designation opportunities.

Our management has prioritized the development of the two novel and patented anticancer drug candidates (PVT-005 and PVT-006) focused on the treatment of metastatic endometrial cancer and/or basal-like triple-negative breast cancers (BL-TNBC) in women.

These two indications affect approximately 50,000 and 40,000 women in the United States, respectively, and potentially represent orphan drug indications, that have limited treatment options.

PVT-005 and PVT-006 will be added to standard chemotherapeutic regimens that are used to treat these cancers and as such are intended to augment the regimen and - provide additional benefit to patients that are either refractory or have relapsed following chemotherapy.

Furthermore, due to the novel mechanism of action of these novel PBD candidates, the patients are segmented according to their DNA repair mutations, thus potentially allowing a more "personalized" medical treatment option for these patients.

We will also evaluate novel drug delivery treatment options to allow more targeted and specific delivery options for its novel anticancer drug portfolio and/or for existing drugs that may be amenable to targeted delivery, thus providing a superior benefit;

risk opportunity for these patients.

To date, we have concentrated our research and development (R&D) activities on development of our novel anticancer drug candidates (PVT-005 and PVT-006) for the treatment of metastatic endometrial and/or basal-like triple-negative breast cancers.

We have outsourced all research and development work to third parties, including clinical trial planning, laboratory services, data management, statistical services and report writing.

We anticipate that we will continue to rely on third parties to satisfy our research and development requirements until such time as it becomes cost effective to hire employees to satisfy those requirements.

We have not carried on any research and development activities since January 2009 and our ability to continue our research and development activities depends on securing additional financing.

A brief summary of the major stages of our business plan that we are seeking to complete over the next 12 months and the cost estimates to complete each step are as follows:

Screening from classes of drugs to select P-001, P-002, P-003 in specific in vitro and in vivo models either gender specific or indication specific - $1,500,000;

Reformulation and dosage regimen testing for P-001, P-002, P-003 - $1,500,000;

commence and complete planned Phase II clinical trial of NK-001 (50 patients) - $2,355,000;

complete pre-clinical studies of NK-002 - $800,000.

Our planned research and development for the next 12 months will focus on development activities for PVT-005 and PVT-006 to support the filing of an Investigational New Drug application to initiate first-in-human clinical trials as well as explore novel delivery and/or new therapeutic options for various drugs to address unmet medical needs in urological and/or gynecological disturbances in women.

We will also be required to complete additional steps in order to market and sell any of our products to the public.

1 unchanged sentence

The following table sets out the various steps we anticipate we must complete in order to carry out our business plan for our planned products.

Estimated costs and completion times have been indicated where estimable, as has any progress made to date.

Completion times have been indicated where estimable, as has any progress made to date.

Anticipated Steps

PVT-005 and PVT-006

Intellectual Property

Screening in female tissues/models, reformulation and assessment of dosage regimen ($500,000)

Follow by submission of new patent application

Screening in female tissues/models, reformulation and assessment of dosage regimen ($500,000)

Follow by submission of new patent application

Screening in female tissues/models, neurological models, reformulation and assessment of dosage regimen ($500,000)

Follow by submission of new patent application

Secure Rights to Use Re-Profiled Drugs

Not Required (generic drug)

Pre-Clinical Testing

Required to select specific drug within class ($500,000)

Secure Investigational New Drug Approval or Equivalent

Not required (Generic drug)

Phase I Clinical Trials

Phase II Clinical Trials

Phase III Clinical Trials

Submit New Drug Application or Equivalent and Obtain Marketing Approval

Finance Marketing and Manufacturing of Approved Drug or Secure Marketing and Manufacturing Partner

Anticipated Steps

Secure Intellectual Property Protection of Drug Concept

Patent Application Submitted

Secure Rights to Use Re-Profiled Drug

Not Required (Generic Drug)

Patents issued in the US and other countries on composition of matter, methods of use for treatment of cancers and process of manufacture of the drugs.

Evaluation of drug delivery technologies for 'targeted' delivery of drugs

Secure Rights to Drugs

Not required if drug selected in the delivery option is a generic drug

Pre-Clinical Testing

Pre-Clinical Trials Delayed Until Sufficient Financing is Secured Estimated Cost:

$800,000 Estimated Completion Date:

Secure Investigational New Drug Approval or Equivalent

Not Required (Generic Drug)

Significant nonclinical toxicity studies required for both drugs

Required to demonstrate pharmacological equivalence or differences

Secure Investigational New Drug ("IND") Approval or Equivalent

Targeted IND filing in the 2 nd half of 2016

Phase I Clinical Trials

Conducted in cancer patients

Bioavailability studies will need to be conducted in healthy volunteers

Phase II Clinical Trials

Clinical Trial Protocol Complete and Approved for Implementation Clinical Trials Delayed Until Sufficient Financing is Secured Estimated Cost:

$2,355,000 Estimated Completion Date:

Required in selected cancer patients

Phase III Clinical Trials

Submit New Drug Application or Equivalent and Obtain Marketing Approval

Finance Marketing and Manufacturing of Approved Drug or Secure Marketing and Manufacturing Partner

Our Current Business

We are a development stage biopharmaceutical company engaged in the development and commercialization of therapeutic pharmaceutical products, with a strategic emphasis on the innovation of new therapeutic uses for existing drugs.

This is commonly known as drug re-profiling.

Where appropriate based on our research, we intend to depart from a strict re-profiling strategy to develop new variants of, or delivery methods for, existing drugs or compounds.

Our focus on drug re-profiling, although not uncommon amongst pharmaceutical companies, differs from traditional drug development practices which focus largely on the development of new drugs.

To date, we have concentrated our research on innovating applications for existing drugs for the treatment of diseases and conditions mediated by acute and chronic inflammatory reactions in neurological indications as well as testing existing drugs in specific women’s health indications.

The diseases and conditions that have been the subject of our previous research include:

neurocognitive impairment, and specifically, neurocognitive impairment in post-coronary artery bypass graft (also known as “CABG” or “heart bypass”) surgery patients;

degenerative central nervous system diseases, and specifically, Alzheimer’s disease;

degenerative disk disease, and specifically, discogenic neck and back pain conditions.

Our planned research and development for the next 12 months will look at three well characterized, safe and broadly prescribed generic drugs.

Our Strategy:

A Focus on Drug Re-Profiling Complimented by Strategic New Drug Development

Our highly experienced management team has implemented a business-minded and cost-conscious approach to product research and development by focusing on innovating new uses for existing drugs on the market, also known as drug re-profiling, while also engaging in selective research and development regarding the innovation of new drugs.

Submit New Drug Application or

Equivalent and Obtain Marketing

Finance Marketing and

Manufacturing of Approved Drug or

Secure Marketing and Manufacturing

Our Research and Development Strategy

Our experienced management team has implemented a business-minded and cost-conscious approach to product research and development by focusing on development of novel therapies to address unmet needs in women's health.

Our research and development strategy will develop novel delivery options for new and/or existing drugs to address needs in women's health as well as advance some of its patented and proprietary novel anticancer drugs in gynecological and/or breast cancers through its recent acquisition of IndUS.

In order for a drug to be successful, it must be both efficacious and acceptably safe.

Therefore, before a drug may be commercially marketed, it must be scrutinized and approved by applicable health authorities (such as the FDA in the United States) in each country or jurisdiction where it is sought to be sold.

Before a drug may be commercially marketed, it must be scrutinized and approved by applicable health authorities (such as the Food and Drug Administration ("FDA") in the United States) in each country or jurisdiction where it is sought to be sold.

In pharmaceutical research and development, clinical trials are conducted to allow safety and efficacy data to be collected for new drugs or devices.

9 unchanged sentences

Furthermore, approval rates for new drugs at each clinical trial stage are prohibitively low, which may require the sponsor to finance additional trials or abandon the drug under development altogether.

The various phases of clinical trials and the anticipated clinical trial requirements of our planned products are described in detail in this section under the heading “Clinical Trial Phases”.

The strategy of drug re-profiling seeks to avoid the cost of repeating one or more pre-clinical, safety, pharmacokinetic or Phase I clinical tests by applying existing drug research to new indications.

In doing so, a company may reduce the time required to complete the necessary research and development activities, which can typically take in excess of 10 years, by more than half, as well as reduce the corresponding development costs.

Significantly, a re-profiled drug, if efficacious for its new indication, is also more likely to be approved by an applicable health authority because it has already been shown to meet regulated safety standards that the vast majority of developmental drugs fail to achieve.

If a re-profiled drug is no longer protected by patent, no relationship between the original owner or developer of the drug and the re-profiler of the drug need exist.

However, it may in some circumstances be beneficial for the re-profiler to obtain a license from the original owner of the drug where there exists an opportunity to receive development, manufacturing, marketing or financing assistance from such owner.

We anticipate that our re-profiling approach will result in faster, more efficient clinical trials and dramatically increase the chance of obtaining regulatory approval at each clinical trial stage.

In some cases (as in the case of NK-001, P-001, P-002 and P-003), we anticipate that we will be able to obtain a regulatory waiver and bypass certain clinical trial stages as a result of basing our products on re-profiled drugs.

Our product research will have two clear lines for Women’s Health and Neurological targets with a path of innovating existing drugs carefully selected into new indications.

The first target focus is on small molecule chemical entities that have been broadly used but not specifically tailored or personalized to women’s health indications.

To date we have identified three classes of drugs from which a specific drug candidate will be selected as the most efficacious in women including:

P-001 for the potential treatment of dysmenorrhea, lower urinary tract symptoms and kidney stones;

P-002 for the potential treatment of peri-menopausal ‘hot flushes’;

P-003 for the potential prevention and treatment of migraine headaches and the progression from mild cognitive impairment to dementia (Alzheimer’s Disease progression).

The P-001 programs are based upon a class of drugs that block the alpha adrenergic receptor.

There are several generic compounds in this drug class available for us to select from.

We plan to screen for the best female target/tissue/animal model specific compound from this class and file a patent application on our findings.

For P-001 to become profitable, we will require our patent application to be successful.

If our application is not ultimately successful, we may be forced to abandon our development of P-001.

For our patent application to succeed, we may be required to complete additional research in order to respond to enquiries from the United States Patent Office or to defend against challenges to our patent once it is published, if at all.

First P-001 Program:

Dysmenorrhea is a medical condition of pain during menstruation that interferes with daily activities.

Dysmenorrhea is often defined simply as menstrual pain, or at least menstrual pain that is excessive.

Menstrual pain is often used synonymously with menstrual cramps, but the latter may also refer to menstrual uterine contractions, which are generally of higher strength, duration and frequency than in the rest of the menstrual cycle.

Dysmenorrhea can feature different kinds of pain, including sharp, throbbing, dull, nauseating, burning, or shooting pain.

Dysmenorrhea may precede menstruation by several days or may accompany it, and it usually subsides as menstruation tapers off.

Dysmenorrhea may coexist with excessively heavy blood loss, known as menorrhagia.

Secondary dysmenorrhea is diagnosed when symptoms are attributable to an underlying disease, disorder, or structural abnormality either within or outside the uterus.

Primary dysmenorrhea is diagnosed when none of these are detected.

The main symptom of dysmenorrhea is pain concentrated in the lower abdomen, in the umbilical region or the suprapubic region of the abdomen.

It is also commonly felt in the right or left abdomen.

It may radiate to the thighs and lower back.

Symptoms often co-occurring with menstrual pain include nausea and vomiting, diarrhea or constipation, headache, dizziness, disorientation, hypersensitivity to sound, light, smell and touch, fainting, and fatigue.

Symptoms of dysmenorrhea often begin immediately following ovulation and can last until the end of menstruation.

This is because dysmenorrhea is often associated with changes in hormonal levels in the body that occur with ovulation.

The use of certain types of birth control pills can prevent the symptoms of dysmenorrhea, because the birth control pills stop ovulation from occurring.

During a woman's menstrual cycle, the endometrium thickens in preparation for potential pregnancy.

After ovulation, if the ovum is not fertilized and there is no pregnancy, the built-up uterine tissue is not needed and thus shed.

Molecular compounds called prostaglandins are released during menstruation, due to the destruction of the endometrial cells, and the resultant release of their contents.

Release of prostaglandins and other inflammatory mediators in the uterus cause the uterus to contract.

These substances are thought to be a major factor in primary dysmenorrhea.

When the uterine muscles contract, they constrict the blood supply to the tissue of the endometrium, which, in turn, breaks down and dies.

These uterine contractions continue as they squeeze the old, dead endometrial tissue through the cervix and out of the body through the vagina.

These contractions, and the resulting temporary oxygen deprivation to nearby tissues, are responsible for the pain or "cramps" experienced during menstruation.

Compared with other women, women with primary dysmenorrhea have increased activity of the uterine muscle with increased contractility and increased frequency of contractions.

The diagnosis of dysmenorrhea is usually made simply on a medical history of menstrual pain that interferes with daily activities.

However, there is no universally accepted gold standard technique for quantifying the severity of menstrual pains.

Yet, there are quantification models, called menstrual symptometrics, that can be used to estimate the severity of menstrual pains, as well as correlate them with pain in other parts of the body, menstrual bleeding and degree of interference with daily activities.

Current treatments include non-steroidal anti-inflammatory drugs (“NSAIDs”) which are effective in relieving the pain of primary dysmenorrhea but can have side effects of nausea, dyspepsia, peptic ulcer, and diarrhea.

Women that are unable to take the more common NSAIDs may be prescribed a COX-2 inhibitor, however these have been ‘black-box’ labeled with possible significant cardiac side effects.

In addition, hormonal contraceptives are also used to treat dysmenorrhea.

Although use of hormonal contraception can improve or relieve symptoms of primary dysmenorrhea, there are no clear conclusions can be made about the efficacy of commonly used modern lower dose combined oral contraceptive pills for primary dysmenorrhea.

The prevalence of dysmenorrhea is estimated to be approximately 25% of women.

Complaints of dysmenorrhea are greatest among women in their late teens and 20s, with reports usually declining with age.

The prevalence in adolescent females is reported to be greater than 50%.

Treatment with alpha adrenergic blockers:

The uterine muscle is mainly enervated by alpha adrenergic nerve endings.

This enervation is similar to that of the bladder lower part called the trigon.

The use of effective alpha adrenergic blockers can significantly reduce or eliminate the excessive uterine contractions, the phenomenon behind the dysmenorrheal symptoms.

There are several alpha adrenergic blockers on the market with varying specificity to the sub-types of the alpha adrenergic receptor.

This selection gives us the opportunity to discover the compound with the best efficacy/risk ratio.

Currently, alpha adrenergic blockers are indicated for the treatment of hypertension (very old and non-selective alpha blockers) and Benign Prostatic Hyperplasia (BPH).

Their quick mode of action, excellent efficacy in alleviation of the BPH symptoms and almost perfect safety and tolerability profile make them the drug class of choice for BPH.

The similarity in denervation between the trigon and uterus lends to our confidence in the efficacy and safety of alpha adrenergic blockers in dysmenorrhea.

In addition, the effect of alpha blockers on dysmenorrhea lends itself to further development of a combination of formulations containing alpha adrenergic blockers and very low doses of NSAIDS reducing the side effects of NSAIDS while increasing the combined efficacy (by blocking prostaglandins).

Second P-001 Program:

Lower Urinary Tract Symptoms

Lower urinary tract symptoms (LUTS) are the name given to a group of symptoms including dysuria and incontinence.

The term was first coined to describe symptoms in men, which had previously been known as prostatitis.

An underlying cause is often not found.

LUTS come and go and will spontaneously resolve in nearly half of all cases.

Experts recommend making a specific diagnosis when possible and treating any underlying cause.

LUTS may be divided into:

Filling or irritative symptoms - eg, frequency, urgency, dysuria, nocturia, stress incontinence, urge incontinence;

Our research and development strategy includes the development of novel anticancer drugs targeting subsets of women's cancer patients that have endometrial, triple-negative breast and/or ovarian cancer, to explore the opportunity of securing an orphan drug designation (intended for patient populations <200,000 in the US).

Since our anticancer portfolio has novel drugs that will require the conduct of nonclinical and clinical studies for new molecular entities (NMEs);

we will also use targeted delivery options for approved (generic) drugs to avoid the higher cost of repeating one or more pre-clinical or clinical, safety, pharmacokinetic or other tests by applying novel drug delivery approaches to get targeted delivery of drugs and get a quicker time to market by leveraging a US regulatory pathway termed 505b2 applications.

In doing so, a company may reduce the time required to complete the necessary research and development activities, which can typically take in excess of ten years, by more than half, as well as reduce the corresponding development costs.

Our recent acquisition of Greater Boston-based IndUS has provided us with a portfolio of novel, patented and proprietary, novel anticancer drug candidates from multiple chemical classes of molecules referred to as pyrrolobenzodiazepine dimers (PBDs).

These molecules have shown excellent anticancer potential during their initial biological testing conducted at the National Cancer Institute in Bethesda, MD.

Subsequent to their initial biological evaluation, chemical scale-up and formulation studies were conducted to evaluate their pharmacokinetics in rats and two novel and patented pyrrolobenzodiazepine dimers were prioritized for advancement through preclinical studies to support first-in-human studies.

PVT-005 and PVT-006 provide novel treatment options in combination with existing chemotherapeutic regimens to address unmet medical needs in women's cancers.

Our initial focus for PVT-005 is in patients with metastatic endometrial cancer, which harbors genomic mutations in DNA replication and repair pathways that render the cancer resistant to many existing chemotherapy options.

It is estimated that approximately 50,000 women in the United States have metastatic endometrial cancer that would become eligible for new therapy options following their initial treatments and PVT-005 will be added to the standard chemotherapeutic regimen(s) that will be used to treat metastatic endometrial cancer.

Similarly, PVT-006, a novel and patented pyrrolobenzodiazepine dimer, distinct from PVT-005, has been identified as a lead candidate to address unmet medical needs of women with triple-negative breast cancer.

Triple-negative breast cancer is a very aggressive form of breast cancer that affects younger women, predominantly of African-American descent.

It is estimated that approximately 170,000 women in the United States have triple-negative breast cancer.

Five different molecular subtypes of triple-negative breast cancer have been identified and the basal-like subtype of triple-negative breast cancer (BL-TNBC) affects up to 40,000 women in the United States.

PVT-006 is more likely to be effective in combination with existing anticancer agents, in basal-like triple-negative breast cancer subtype due to their mutations in DNA repair and replication pathways, which PVT-006 targets as its mechanism of action.

Preclinical safety studies will be conducted over the next 12 months to advance at least one of these candidates to an IND-stage to allow initiation of clinical studies in these highly unmet medical needs in women's cancer.

Our product development initiatives will address two areas in women's health – oncology and urological conditions.

Lower Urinary Tract Symptoms Program

Lower urinary tract symptoms are the name given to a group of symptoms including, overactive bladder, dysuria and urinary incontinence.

Experts recommend making a specific diagnosis when possible and treating the symptoms and/or any underlying cause (if possible).

Lower urinary tract symptoms may be divided into:

Filling or irritation symptoms - eg, frequency, urgency, dysuria, nocturia, stress incontinence, urge incontinence;

Voiding or obstructive symptoms - eg, poor stream, hesitancy, terminal dribbling, incomplete voiding, overflow incontinence (due to chronic urinary retention).

Risk factors that can influence LUTS in women include:

age, postmenopausal urogenital changes, obesity, smoking, number of childbirths, poor obstetric care and abnormalities of the urogenital system, both congenital or due to pelvic organ prolapse.

Symptoms can be divided into the following groups:

Symptoms can be further divided into the following groups:

increased daytime urinary frequency, nocturia, urgency, incontinence, enuresis, continuous urinary leakage, interstitial cystitis;

9 unchanged sentences

pain may be associated with bladder filling, micturition, and postmicturition, or continuous;

Genitourinary pain syndromes and lower urinary tract dysfunction (LUTD):

symptom syndromes suggestive of LUTD may be those of an overactive bladder or of bladder outlet obstruction.

Current treatments for LUTS that do not involve administration of drugs include ‘bladder’ training with careful attention to fluid intake, reduction or avoidance of caffeine, cranberry use, pelvic floor exercises, weight loss, smoking cessation and even surgery.

Current treatments that involve medications include antibiotics, antimuscarinic drugs, botulinum toxin, antidepressants, hormone replacement therapy, and duloxetine.

Many of the drugs used have significant side effects or should be used for short term relief only.

Traditionally, focus has been on UI in women and on other LUTS, known as “prostatism”, in men.

The new term subsequently proved to be relevant since large population-based surveys in recent years have shown that bladder control symptoms are neither sex-, nor age- or disease-specific.

Urinary incontinence is, nevertheless, still the most familiar LUTS in women.

Genitourinary pain syndromes and lower urinary tract dysfunction:

symptom syndromes suggestive of lower urinary tract dysfunction may be those of an overactive bladder or of bladder outlet obstruction.

Urinary incontinence is, nevertheless, still the most familiar lower urinary tract symptom in women.

Estimates of prevalence range from a few percent to around 50% in different studies.

1 unchanged sentence

Large cross-sectional population-based samples have however concluded that the prevalence of any female urinary incontinence ranges from 20% to 40% in young and middle-aged women, and then steadily increases with age.

Approximately half of the incontinence is stress type (SUI), about 10% urge urinary incontinence (UUI) and one third mixed incontinence (MUI).

Approximately half of the incontinence is stress type, about 10% is urge urinary incontinence (UUI) and one third is mixed incontinence.

Stress leakage occurs more frequently in younger women whereas urge and mixed urinary incontinence are more prevalent in the older women.

Similarly to UI, the estimated prevalence of other LUTS varies considerably between different surveys.

In the EPIC study, which was a large European population-based survey of UI, Overactive bladder (OAB) and other LUTS, 66% of the participating women reported at least one LUTS.

The most common LUTS, in both men and women, was nocturia (48.6% men, 54.5% women), which, in women, was followed by UI and urgency (13.1% and 12.8% respectively).

The overall prevalence of OAB, in the EPIC study, was 11.8%.

Other large surveys from Europe and the United States have estimated the prevalence of OAB to approximately 17% in both men and women.

Several other authors have described the bother of various LUTS and their negative impact on quality of life.

UI has been shown to have a negative effect on physical activities, confidence, self-perception and social activities, UUI and MUI being more detrimental than SUI in this respect.

In a recent study, Coyne et al.

also reported greater rates of co-morbidities and depression as well as significantly worse health-related quality of life and lower work productivity in individuals with OAB symptoms as compared to controls.

Nevertheless, several investigations have shown that only a small number of women actually seek help from the medical health care system.

Treatment with alpha adrenergic blockers:

Since there is no known gender specific characteristics of bladder function and since bladder dysfunction is at the root of both filling or obstructive types of LUTS, significant reduction in lower bladder (trigon) tension should effectively reduce LUTS symptoms.

Prostatism is composed of both obstruction and filling elements.

Alpha adrenergic blockers are the main stream treatment for benign prostrate hyperplasia (Prostatism) delivering very effective reduction of symptoms with minimal risk or side effect.

It is suggested that the use of this drug class will have similar effect on the LUTS symptoms in women with no additional risk or side effects.

This profile is significantly different from the currently used drugs that deliver partial relief with significant and often severe side effects and risk.

As with dysmenorrhea, innovative delivery systems/formulations and fixed dose combinations with low doses of existing treatments to LUTS can potentially optimize efficacy with minimal addition of side effects.

Migraine Prevention (Prophylaxis Treatment) by Angiotensin Receptor Blockers (ARB) and Angiotensin Converting Enzyme Blockers (ACE Inhibitors)

There are two intertwining theories as to the pathophysiology of migraine headache.

The classical one proposes that as a reaction to external (food, wine, smoke, etc.) or internal (hormonal fluctuations, stress, sleep deprivation etc.) triggers, susceptible patients develop severe vasoconstriction followed by vasodilatation of the meningeal vessels in the cranial cavity that cause the pain and associated symptoms (nausea, vomiting, photophobia, phonophobia and sensitivity to smell).

Another theory points out that the symptoms are a result of sterile inflammation of the meningeal vessels caused by pro-inflammatory substances (such as CGRP) released from the peri-vascular nerves The current consensus is that most probably the cause of migraine is a combination of these 2 phenomenon which influence each other in yet unknown fashion.

Angiotensin is a potent vasoconstrictor with pro-inflammatory effects.

The safety profile of the marketed ARBs and ACEI show a significant reduction in headaches compared with placebo.

Naturally, the reduction in blood pressure as a result of inhibiting Angiotensin (the main indication for these 2 classes of drugs) can reduce headache.

However, the inhibition of the vasoconstrictive effect of Angiotensin and of its pro-inflammatory effect, lends to believe that inhibitors at the level of the converting enzyme or receptor, can prevent the development of a migraine attack.

This theory has been supported by small pilot studies.

The development of fixed dose combinations of ARB or ACEI with low dose aspirin or NSAID delivered by a novel formulation can be effective, safe and patentable.

The safety/tolerability of ARB and ACEI are similar to placebo.

The Use of ARB for the Delay in the Conversion of Minimal Cognitive Impairment (MCI) to Full Blown Dementia

MCI is a state in which cognitive functions start to decline gradually with slowly increasing debilitating effect on daily function.

Due to the variable degree of MCI, people suffering of mild forms perform well at work and life outside work, but with noticeable decline in their capacities.

Full blown Dementia is a state where cognition is at such low level that daily functions are severely disrupted.

The classical approach differentiates between Vascular Dementia and Alzheimer’s disease.

In the past, these conditions were considered different in both pathophysiology and clinical aspects, a growing overlap has been lately discovered, such as the effect of high blood pressure on the development of Lewy Bodies in Alzheimer’s.

The combined effect of ARBs on reducing blood pressure and their profound anti inflammatory effect should delay the progression of MCI into Dementia.

The role of Angiotensin in the development of vascular dementia and even Alzheimer’s Disease is currently under investigation, however, there is a large body of evidence that supports the notion that reduction of blood pressure improves cognition and delays dementia.

The second target focus is on biologics (vaccines, blood and blood components), allergenics, somatic cells (cells relating to the wall of the body cavity), gene therapy, tissues, and recombinant therapeutics (drugs produced by genetic engineering) that cause cell death in tumors.

Such biologics are known as anti-tumor necrosis factors.

To date, we have identified two products as ideal candidates for development:

NK-001 for the potential treatment of neurocognitive impairment in post-coronary artery bypass graft (commonly known as “CABG” or “heart bypass”) surgery patients;

NK-002 for the potential treatment of Alzheimer’s disease.

NK-001 is a new application of the generic drug Etanercept for treating neurocognitive impairment in CABG surgery patients.

We consider NK-001 to be our flagship product as it is at a more advanced stage of development than our other planned products, and we intend to apply our resources toward its development in priority to our other planned products.

Etanercept is the generic version of the drug Enbrel, which is currently under patent protection in the United States.

While the original Amgen patent on Enbrel was set to expire in 2012, on November 2011 Amgen announced that the United States patent office has extended that patent until November 2028.

On April 18, 2008, we filed a single United States Patent Application (No.

61-046061) regarding the use of NK-001 (Etanercept) and similar TNF-Alpha targeting drugs (which can generally be described as anti-inflammatory drugs) in the treatment of post-CABG cognitive impairment.

This patent application is under examination, and a patent has not yet been granted to us or published and is currently on hold pending submission of additional data.

Also if our research and development activities are successful, we will require license and partnership with Amgen to launch NK001.

For NK-001 to become profitable, we will require our patent application to be successful.

If our application is not ultimately successful, we may be forced to abandon our development of NK-001.

TNF-Alpha Inhibitors

NK-001 is a recombinant, or an artificially created human-soluble tumor necrosis factor protein characterized by its tendency to specifically bind to and inhibit TNF-Alpha.

Tumor necrosis factor (“TNF”) is a category of protein that induces the death of tumor cells and possesses a wide range of actions that induce inflammation.

TNF-Alpha is a cytokine, a category of polypeptide (small protein) regulator that is produced widely throughout the body by cells of diverse origin.

It is involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction.

Acute phase reaction is the process where, in response to injury, the body’s inflammatory cells secrete cytokines into the bloodstream to destroy or inhibit the growth of microbes, viruses or other foreign materials.

The body’s immune cells secrete TNF-Alpha and other cytokinesto defend against infectious disease and foreign materials, and TNF-Alpha is capable of inducing inflammation and inhibiting the growth of tumors and replication of viruses.

Dysregulation and, in particular, overproduction of TNF-Alpha have been implicated in a variety of human diseases, including rheumatoid arthritis, ankylosing spondylitis (the inflammation of joints in the spine), psoriatic arthritis and psoriasis.

NK-001 has been used since 1998 to treat a number of these diseases.

CABG and Neurocognitive Impairment

We intend to apply NK-001 to the treatment of neurocognitive impairment in post-coronary artery bypass graft surgery patients.

This surgery is commonly known as CABG or heart bypass surgery.

CABG has become a standard method of treatment and has become one of the most commonly performed ‘open heart’ operations in the United States.

According to a 1999 study by Selnes, Goldsbrough, Borowicz and McKhann entitled “Neurobehavioral Sequelae of Cardiopulmonary Bypass” ( The Lancet , Vol.

353, May 8, 1999), about 800,000 patients internationally and 650,000 patients in the United States undergo heart bypass surgery every year.

Heart bypass surgery is recommended for selected groups of patients with significant narrowing and blockages of the heart arteries, or coronary artery disease.

It creates new routes around narrowed and blocked arteries, allowing sufficient blood flow to deliver oxygen and nutrients to the heart muscle.

This surgery is usually performed with the heart stopped, necessitating the usage of cardiopulmonary bypass, a technique where a pump temporarily takes over the function of the heart and lungs during surgery, maintaining the circulation of blood and the oxygen content of the body.

In addition to stroke and postoperative delirium, cognitive impairment is a recognized adverse complication of heart bypass surgery.

According to a 2009 study published in the CHEST journal of the American College of Chest Physicians, short-term post-CABG cognitive impairment has been reported as having an incidence ranging from 33% to 83%, and long-term cognitive impairment an incidence ranging of 20% to 60%.

Post-heart bypass cognitive impairment exhibits itself as impairment of memory, concentration, language comprehension and social integration.

It can present days to weeks after surgery and may remain a permanent disorder.

The cause of post-CABG cognitive impairment has been attributed to a number of factors, including obstruction of the blood vessels of the brain (cerebral microembolization), decreased blood flow through the brain (global cerebral hypoperfusion), systemic and cerebral inflammation, cerebral temperature changes, accumulation of fluid in the brain (cerebral edema), possible blood-brain barrier dysfunction and genetic susceptibility.

Post-CABG Surgery Cognitive Impairment:

An Inflammatory Phenomenon

Several reports have suggested that post-heart bypass cognitive impairment is an inflammatory phenomenon in which inflammatory mediators, such as cytokines (including the cytokines TNF-Alpha, interleukin -1, interleukin-8, and interleukin-6), are released to trigger the brain’s inflammatory response.

It has been further observed that elevated levels of inflammatory mediators, including TNF-Alpha, have been shown to be indicators of high morbidity (the presence of an abnormal condition that impairs bodily function) and mortality rates after heart bypass surgery.

While most studies have looked at peripheral levels of cytokines in response to surgical stress, it has also been reported that elevated levels of pro-inflammatory cytokines have been detected in the cerebrospinal fluid after heart bypass surgery.

Moreover, it has been shown that heart trauma leads not only to an increase in pro-inflammatory cytokine levels outside the brain, but also to a concurrent marked increase in brain cytokine levels.

Accordingly, the apparent significance of pro-inflammatory cytokines, such as TNF-Alpha, has led to the suggestion that these inflammatory mediators may be considered as targets in the inflammatory process associated with post-CABG cognitive impairment.

Current Treatment of Post-CABG Cognitive Impairment

Currently, prevention is considered to be the most effective treatment strategy for post-CABG cognitive impairment, as preventative or therapeutic interventions are limited.

It has been postulated that therapeutic interventions aimed at diminishing the inflammatory response might result in better outcomes;

for example, the use of a synthetic non-psychotropic cannabinoid (a drug having certain attributes of cannabis that does not alter brain function) to treat mild cognitive impairment, including post-surgical cognitive impairment, has been described.

The use of a protease inhibitor (a class of medication used to treat or prevent viral infection), such as aprotinin (TrasylolTM), has also been reported as having a marked protective effect on the brain in reducing the severity of cognitive deficit developing after heart bypass surgery.

Therapeutic Applications of TNF-Alpha Antagonists

The use of TNF-Alpha antagonists to treat various disorders has been described.

TNF-Alpha is an intracellular mediator, a protein that mediates the immune responses produced by a variety of cells, including both types of white blood cells (macrophages and monocytes).

The responses triggered by TNF-Alpha are initiated through its interaction with distinct TNF-Alpha cell surface receptors.

TNF-Alpha binds to these cell surface receptors and triggers an array of pro-inflammatory effects, including the release of other pro-inflammatory cytokines and chemokines (a type of cytokine);

the release of enzymes which break down proteins (metalloproteinases);

and an increase in the production of proteins that line the interior surface of blood vessels (endothelial adhesion molecules), thereby further amplifying the inflammatory and immune cascade and inducing a plethora of inflammatory and catabolic (molecule breakdown) effects.

Interference in the binding of TNF-Alpha to cell surface receptors of the target cell results in the neutralization of TNF-Alpha and the blockage of its biologic effects.

For example, TNF-Alpha receptor proteins that are naturally produced in soluble form (designated as TNF-R) inhibit TNF-Alpha action by competing with cell surface receptors for binding TNF-Alpha, thereby blocking its biologic effects.

Various TNF-Alpha targeting drugs, also known as TNF-Alpha antagonists, TNF-Alpha inhibitors and TNF-Alpha blockers, have been developed to neutralize or inhibit TNF-Alpha activity.

These drugs bind to inhibit TN F-Alpha from binding to its receptor and triggering the inflammatory response.

In this way, TNF-Alpha targeting drugs deactivate TNF-Alpha.

A human-soluble TNF-Alpha receptor protein has been shown to suppress TNF-Alpha dependent inflammatory diseases, specifically arthritis.

TNF-Alpha targeting drugs have also been shown to be effective in treating other inflammatory diseases such as Wegener’s disease, Behçet’s disease, keratoscleritis, lymphomatous tracheo-bronchitis, Cogan’s syndrome, and rapidly destructive crystal arthropathy.

Studies in rat models have also shown that TNF-Alpha targeting drugs can potentially be used to treat brain injuries.

The use of TNF-Alpha antagonists has also been described for the treatment of various neuropsychiatric and neurological disorders including multiple sclerosis, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, Bell’s palsy, PHN (shingles), influenza and HIV.

TNF-Alpha in the Treatment of Neural Disorders

While TNF-Alpha targeting drugs have been shown to be effective in treating various diseases associated with inflammation, their use in the treatment of neural disorders is hampered by the inability of most TNF-Alpha targeting drugs to cross the blood-brain barrier.

The blood-brain barrier is a cellular structure in the central nervous system that restricts the passage of certain chemical substances and microscopic objects (e.g.

bacteria) between the bloodstream and the neural tissue itself, while still allowing the passage of substances essential to metabolic function (e.g.

For example, the TNF-Alpha targeting drug Etanercept, being both hydrophilic (able to bond with water or hydrogen) and of high molecular weight, is prevented from crossing the intact blood-brain barrier.

It is also unlikely that any transport mechanism exists for TNF-Alpha targeting drugs to enter the central nervous system.

Accordingly, for brain related diseases, conventional general administration (administration into the blood stream) of TNF-Alpha targeting drugs is not effective, and they must instead be administered locally (directly into the cerebrospinal fluid) to have effect.

For example, to treat Alzheimer’s disease with a TNF-Alpha targeting drug such as Etanercept, the drug must be administered adjacent to the spinal column.

Commercially Available TNF-Alpha Inhibitors:

Etanercept is a recombinant (engineered) DNA drug made by combining two proteins (also known a fusion protein).

It binds TNF-Alpha to human immunoglobulin G1 (IgG1) in the body.

Immunoglobulins are proteins that play an essential role in the body’s immune system by attaching to foreign substances, such as bacteria, and assisting to destroy them.

In this way, Etanercept can regulate excess TNF-Alpha and decrease its role in disorders involving excess inflammation in humans and other animals, including autoimmune diseases such as ankylosing spondylitis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, and, potentially, in a variety of other disorders mediated by excess TNF-Alpha.

The most common side effects of Etanercept are mild to moderate itching, pain, swelling and redness at the site of injection.

Headache, dizziness, nasal and throat irritation also occur.

Because TNF-Alpha plays an important role in the response of the immune system to infections, blocking the action of TNF-Alpha with Etanercept may worsen or increase the occurrence of infections, and patients with serious infections should not receive the drug.

Etanercept treatment should be discontinued if a patient develops a serious infection.

Treatment using the drug is not initiated in patients with active infections or an allergy to any of its components, and children should receive their recommended immunizations before beginning any treatment involving Etanercept.

Etanercept should also be used with caution in patients prone to infection, such as those with advanced or poorly-controlled diabetes.

Some reported associated conditions may or may not be related to Etanercept.

Since Etanercept has been on the market, there have been reports of multiple sclerosis, myelitis (inflammation of the spinal cord) and optic neuritis (inflammation of the optic nerve) in patients using the drug.

Etanercept is not recommended for persons with preexisting diseases of the central nervous system (brain and/or spinal cord) or for those with multiple sclerosis, myelitis or optic neuritis.

Additionally, rare cases of seriously low blood counts (pancytopenia) have been reported in patients using the drug.

Rational and Objectives for the Application of TNF-Alpha in the Treatment of Post-CABG Neurocognitive Impairment

While it has been speculated that preventative treatment with an anti-TNF therapy might be a therapeutic approach to reducing inflammatory processes associated with heart bypass surgery, no experimental data has been provided to demonstrate the therapeutic effect of anti-TNF on post-CABG cognitive impairment.

Nevertheless, based on a review of the current medical literature, we believe that there is sufficient rationale to pursue the development of the treatment.

As the blood-brain barrier has been shown to be dysfunctional and leaky in this syndrome, it is expected that an unmodified TNF-Alpha antagonist such as NK-001 (Etanercept) will cross into the brain in sufficient amounts to diminish the inflammatory reaction.

Our research and development objectives in applying TNF-Alpha in the treatment of post-heart bypass neurocognitive impairment are:

to evaluate the effects of NK-001 in preventing cognitive side effects following CABG surgery;

to evaluate the safety and tolerability of NK-001 in patients undergoing heart bypass surgery;

to assess blood plasma levels of NK-001 in patients undergoing CABG surgery.

Blood plasma is the yellow liquid component of blood in which the blood cells are suspended.

It makes up about 55% of total blood volume and is mostly composed of water (92% by volume).

Blood plasma also contains dissolved proteins, glucose, clotting factors, mineral ions, hormones and carbon dioxide (plasma being the main medium for transporting products that are excreted by the body);

to evaluate the effects of NK-001 on serum TNF-Alpha levels in patients undergoing heart bypass surgery (the serum is a fluid component of clotted blood and it lacks clotting factors and other elements which plasma includes, instead retaining antibodies, electrolytes and soluble proteins);

to examine the relationship between markers of blood brain barrier dysfunction and cognitive outcome in patients undergoing CABG surgery.

With the assistance of Virtus Clinical Development (Pty.) Limited, a contract research organization based in South Africa, we have designed Phase II human clinical trials of NK-001 to undertake the aforementioned research and development objectives.

Virtus provides services to a wide range of international biotechnology and pharmaceutical companies, assisting them in implementing their drug development programs and specifically the design, management and monitoring of the clinical phases of such programs.

We intend to begin our clinical trials of NK-001 using 50 post-CABG surgery patients.

Our trials will be conducted in four to six separate locations in and around Cape Town, South Africa.

To date, we have received approval for our proposed Phase II clinical trial protocol from the Medicines Control Council of the Department of Health (South Africa) and from the central ethics board of that country.

The protocol describes the scientific rationale, objective(s), design, methodology, statistical considerations and organization of the planned trials.

Our ability to pursue our clinical trials was subject to the approval of our research protocol by the Medicines Control Council.

In the case of NK-001, we believe that it is unnecessary to conduct pre-clinical studies and Phase I clinical trials of the drug for the following reasons:

preclinical, Phase I safety and pharmacokinetic studies have already been successfully completed on Etanercept;

Etanercept has already been tested in different patient populations (both genders, all age groups, and multiple ethnic groups);

Phase II and II studies have been completed for Etanercept as applied to a number of indications, providing additional safety information for the use of the drug on older populations who are the target population for NK-001;

there are no existing animal models for post CABG cognitive impairment by which we could conduct additional safety tests on animals.

On January 28, 2009, we submitted amendments to our clinical trial protocol that were subsequently approved by the Medicines Control Council on May 12, 2009.

As a result, we now have full authority to proceed with our Phase II clinical trial of NK-001.

Our study will involve identifying 50 otherwise healthy individuals undergoing heart bypass surgery, performing pre-surgery cognitive assessment, administering NK-001 (Etanercept) pre and post-surgery and six months of follow up.

We anticipate that we will begin our trial 6 months after the completion of the required financing estimated at $2,350,000.

Regulatory and Patent Issues

Etanercept was first released for commercial use in late 1998.

In North America, it is co-marketed by Amgen Inc.

and Pfizer Inc.

under the trade name Enbrel in two separate formulations, one in powder form and the other as a pre-mixed liquid.

is the sole marketer of Enbrel outside of North America.

In our research, we have worked with the generic form of Etanercept.

We currently have not sourced a generic form of Etanercept.

In order for us to conduct our NK-001 and NK-002 successfully, we will need to source a generic form of Etanercept.

In the United States the FDA has licensed Etanercept for the following therapeutic applications:

moderate to severe rheumatoid arthritis (November 1998);

moderate to severe polyarticular juvenile idiopathic arthritis (1999);

psoriatic arthritis (2002);

ankylosing spondylitis (July 2003);

moderate to severe plaque psoriasis (April 2004).

The United States Patent on Etanercept (Enbrel) in the United States expired in 2009.

Patent protection for Etanercept in South Africa has already lapsed, and the drug is commercially available in generic form.

On April 18, 2008, we filed a single United States Patent Application (No.

61-046061) for the use of TNF-Alpha targeting drugs (including NK-001 and similar anti-inflammatory drugs) in the treatment of post-heart bypass cognitive impairment.

The application is currently under review by the United States Patent Office and is on hold pending submission of additional data.

NK-002 is a development stage drug for the treatment of Alzheimer’s disease.

We filed a United States Patent Application for NK-002 on January 31, 2008 (No.

The application is currently under review by the United States Patent Office.

Liposome Encapsulated NK-001 for the Treatment of Alzheimer’s and Other Neurodegenerative Diseases

We are developing a novel liposome based on transferring protein.

Transferrin is a blood plasma protein for iron ion delivery.

When a transferrin protein loaded with iron encounters a transferrin receptor on the surface of a cell, it binds to it and, as a consequence, is transported into the cell in a vesicle.

By enclosing NK-001 in a transferrin-based liposome, the drug is able to cross the blood brain barrier.

As described above, the blood-brain barrier is a metabolic or cellular structure in the central nervous system that restricts the passage of various chemical substances and microscopic objects (e.g.

bacteria) between the bloodstream and the neural tissue, while still allowing the passage of substances essential to metabolic function (e.g.

In its neuroprotective role, the blood-brain barrier functions to hinder the delivery of many potentially important diagnostic and therapeutic agents to the brain.

Therapeutic molecules and genes that might otherwise be effective in diagnosis and therapy do not cross the blood-brain barrier in adequate amounts.

We anticipate that NK-002 will succeed in overcoming these limitations for the delivery of NK-001 in the treatment of Alzheimer’s disease.

Our management believes that there is currently no promising drug on the market for the treatment of Alzheimer’s disease.

Although understanding of the disease in the medical community is not conclusive, over 1,000 scientific articles on Alzheimer’s disease identify it as an autoimmune condition.

To that effect, anti-inflammatory drugs have been tested in treating Alzheimer’s disease with promising results, although a significant lack of progress in the application of anti-inflammatory drugs in the treatment of the disease has been attributed to poor brain penetration due to the blood-brain barrier.

NK-002 promises to overcome this obstacle.

NK-001 is currently used in the treatment of arthritis and psoriasis to block the actions of TNF-Alpha made by the body’s immune system.

TNF-Alpha is a protein that triggers an array of pro-inflammatory effects.

In patients with Alzheimer’s disease, NK-001 appears to have an effect that is sustained beyond six months of treatment.

In fact, a small pilot study conducted by researchers at the University of California, Los Angeles, in 15 patients administering 25-50 milligrams of NK-001 significantly improved MMS (Mini-Mental Status Examination), ADAS-Cog (Alzheimer’s Disease Assessment Skill) and SIB (Severe Impairment Battery) results (See Tobinick, Gross, Weinberger, Cohen:

“TNF-Alpha Modulation for Treatment of Alzheimer’s Disease:

A 6-Month Pilot Study ” (MedGenMed 2006, 8(2):25)).

These results show great promise, exceeding the exhibited short-lived effects of traditional cholinesterase treatment.

However, NK-001 is noted for its poor blood-brain barrier penetration.

In fact, naked protein drugs like NK-001 traverse the blood-brain barrier at a rate of approximately 0.001% to 9%.

However, if appropriately encapsulated, protein drugs traverse the blood brain barrier at a rate of between 1% and 20%.

According to a 2006 study, encapsulation increases the rate of drug uptake by 100% to 1000% (See Mishra, Mahor, Rawat, et al., “Targeted brain delivery of AZT via transferrin anchored pegylated albumin nanoparticles ” (J Drug Target 2006;

On October 2, 2007, we entered into a master service agreement with Northern Lipids pursuant to which Northern Lipids developed certain liposomal encapsulation formulas for NK-002 on our behalf.

The proprietary formulations were completed at a cost of approximately $36,000 and all intellectual property rights in the results and proceeds of the agreement were transferred to us.

In April 2008, Globe began testing three different encapsulation preparations in rodent trials on our behalf.

On January 31, 2008, we filed a United States Patent Application (No.

61-02540) for the therapeutic use of a liposome formulation for the delivery of drugs across the blood-brain barrier.

Our United States Patent Application filed on April 18, 2008 (No.

61-046061) also pertains to certain aspects of NK-001, namely the delivery of TNF-Alpha targeting drugs (including NK-001and similar anti-inflammatory drugs) across the blood-brain barrier.

We employ our own proprietary encapsulation technology developed on our behalf by Northern Lipids in accordance with our master service agreement.

Unlike NK-001, NK-002 falls under the category of a new drug and will require a complete range of successful pre-clinical and clinical trials before we can seek marketing approval.

Urinary incontinence has been shown to have a negative effect on physical activities, confidence, self-perception and social activities, urge urinary incontinence and mixed incontinence being more detrimental than stress type in this respect.

Our research and development efforts are focused on identifying novel treatments for lower urinary tract symptoms through leveraging either novel drug delivery treatment options for existing drugs and/or identifying novel biological pathways and new drugs that will address the limitations of existing treatment options for lower urinary tract symptoms in women.

Clinical Trial Phases

1 unchanged sentence

Pre-Clinical Trials

Pre-clinical trials involve in vitro (test tube) and in vivo (animal) experiments using wide-ranging doses of the study drug to obtain preliminary efficacy, toxicity and pharmacokinetic (how the body processes the drug) information.

Pre-clinical trials involve in vitro (test tube) and in vivo (animal) experiments using wide-ranging doses of the study drug to obtain preliminary efficacy, toxicity and pharmacokinetic information.

Such tests assist pharmaceutical companies in deciding whether a drug candidate possesses scientific merit for further development as an investigational new drug.

Of our current planned products, the P-001, P-002 and P-003 will require some pre-clinical work to select the best drug in class for female therapy.

In addition formulation and dosage regimen work studies may need to be conducted.

We estimate the screening studies for the three drug classes to cost approximately $500,00 per program with an aggregate cost of $1.5 M.

If formulation and dosage regimen needs to be modified for intellectual property protection, the three candidates will also require formulation work at a cost of approximately $500,00 per class with an aggregate cost of $1.5 M.

Subject to our ability to obtain adequate funding, all of these studies could be performed in a period of 18-24 months.

NK-001 will not require any additional pre-clinical testing.

NK-002 will require us to undertake pre-clinical trials.

Subject to our ability to obtain adequate financing, we anticipate completing pre-clinical trials of NK-002 at a cost of approximately $800,000 over a period of 12 months.

It is our goal to begin pre-clinical trials of NK-002 4 months after the completion of the required financing;

however we will not establish a firm start date until we raise sufficient financing, which there is no guarantee that we will be able to do.

Phase 0 is a recent designation for exploratory, first-in-human trials conducted in accordance with the FDA’s 2006 Guidance on Exploratory Investigational New Drug (IND)

Distinctive features of Phase 0 trials include the administration of single subtherapeutic doses (doses not intended to treat diseases) of the study drug to a small number of subjects (10-15) to gather preliminary data on the agent’s pharmacokinetics (how the body processes the drug) and pharmacodynamics (how the drug works in the body).

Of our current planned products, only NK-002 will require us to undertake Phase 0 clinical trials.

Subject to our ability to obtain adequate financing, we anticipate completing combined Phase 0 and Phase I clinical trials of NK-002 at a cost of approximately $1,100,000.

We have not scheduled or completed trial protocols for these trials although we anticipate that they will require 12 to 24 months to complete.

In addition, formulation and dosage regimen work studies will need to be conducted.

Phase 0 is a recent designation for exploratory, first-in-human trials conducted in accordance with the FDA's 2006 Guidance on Exploratory Investigational New Drug.

These trials are generally used for novel anticancer drugs.

Phase I trials are the first stage of drug testing in human subjects.

10 unchanged sentences

Pay ranges from a small amount of money for a short period of residence to a larger amount of up to approximately $6,000 depending on the length of the volunteer's participation in the trial.

Of our current planned products, we believe that only NK-002 will require us to undertake Phase I clinical trials.

Subject to our ability to obtain adequate financing, we anticipate completing combined Phase 0 and Phase I clinical trials of NK-002 at a cost of approximately $1,100,000.

We have not scheduled or completed trial protocols for these trials although we anticipate that they will require 12 to 24 months to complete.

We do not anticipate requiring Phase I trials of NK-001 because equivalent trials of Etanercept, the drug underlying NK-001, have already been successfully completed by third parties.

Once the initial safety of a study drug has been confirmed in Phase I trials, Phase II trials are performed on larger groups (20-300) and are designed to assess how well the drug works, as well as to continue Phase I safety assessments using a larger group of volunteers and patients.

3 unchanged sentences

Some trials combine Phase I and Phase II, and test both efficacy and toxicity.

All of our planned products must undergo Phase II clinical trials.

All of our planned anticancer products will need to undergo Phase II clinical trials.

Completion of these trials is subject to our ability to obtain adequate financing.

We anticipate completing our Phase II trial of NK-001 at a cost of approximately $2,355,000 over a 12 month period.

It is our goal to begin our trial 6 months after the completion of the required financing;

We anticipate initiating and completing at least one Phase II trial of either PVT-005 or PVT-006 at a cost of approximately $8.6 million over a 12 month period.

It is our goal to begin our trial six months after the completion of the required financing;

however, we will not establish a firm start date until we raise sufficient financing, which there is no guarantee that we will be able to do.

The trial protocol for our Phase II trial is complete and has received full regulatory approval.

We have not completed a prospective budget or timetable for completing Phase II trials of P-001, P-002, P-003 or NK-002.

Our ability to pursue Phase II trials for these programs is subject to our ability to obtain adequate financing and to successfully complete pre-clinical and Phase I trials on the drugs.

The trial protocol for our Phase II trial has been developed with input from our clinical advisors.

Phase III studies are randomized controlled multi-center trials on large patient groups (300-3,000 or more, depending upon the disease or medical condition studied), and are intended to definitively assess the effectiveness of the drug as compared to the current "gold standard" treatment.

4 unchanged sentences

Studies in this phase are categorized by some companies as "Phase IIIB studies".

While not required in all cases, it is typically expected that at least two successful Phase III trials will be necessary to demonstrate a drug’s safety and efficacy in order to obtain approval from appropriate regulatory agencies, such as the FDA (United States), the Therapeutic Goods Administration (Australia) or the European Medicines Agency (European Union), for example.

While not required in all cases, it is typically expected that at least two successful Phase III trials will be necessary to demonstrate a drug's safety and efficacy in order to obtain approval from appropriate regulatory agencies, such as the FDA in the United States, the Therapeutic Goods Administration in Australia or the European Medicines Agency in the European Union, for example.

Once a drug has proved satisfactory after Phase III trials, the trial results are usually combined into a large document containing a comprehensive description of the methods and results of human and animal studies, manufacturing procedures, formulation details and shelf life.

3 unchanged sentences

While most pharmaceutical companies refrain from this practice, it is not abnormal to see many drugs undergoing Phase III clinical trials in the market.

We anticipate that all of our current planned products will require us to undertake Phase III clinical trials;

We anticipate that all of our current planned products will require us to undertake the conduct of Phase III clinical trials;

however, we lack sufficient information to estimate the costs or timeframe required to complete any Phase III clinical trials at this time.

2 unchanged sentences

Phase IV trials involve safety surveillance (pharmacovigilance) and ongoing technical support of a drug after it receives permission to be sold.

Phase IV studies may be required by regulatory authorities or may be undertaken by a sponsoring company for competitive (to find a new market for the drug) or other reasons (for example, the drug may not have been tested for interactions with other drugs, or on certain population groups such as pregnant women, who are unlikely to subject themselves to trials).

Phase IV studies may be required by regulatory authorities or may be undertaken by a sponsoring company for competitive or other reasons (for example, the drug may not have been tested for interactions with other drugs, or on certain population groups such as pregnant women, who are unlikely to subject themselves to trials).

The safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the Phase I through III clinical trials.

4 unchanged sentences

Markets for Our Planned Products

Women’s Health

Female Lower Urinary Tract Symptoms

Kidney Stones

Sales are very conservatively estimated for US only, incidence of indication, modest pricing and market penetration.

Therapeutic Area

Potential Sales (USD)

Women’s Health

Peri-Menopausal Symptoms

Sales are very conservatively estimated for US only, incidence of indication, modest pricing and market penetration.

Therapeutic Area

Potential Sales (USD)

Sales are very conservatively estimated for US only, incidence of indication, modest pricing and market penetration.

We anticipate that our study of NK-001 in post-CABG patients will, if successful, generate a market for the drug as well as provide data that may lead to applying the drug in the treatment of other diseases such as Alzheimer’s disease.

Heart bypass surgery has become a standard method of treatment and has become one of the most commonly performed “open heart” operations in the United States.

An estimated 800,000 patients throughout the world undergo heart bypass surgery every year and about 650,000 of those patients are located in the United States (Selnes, Goldsbrough, Borowicz and McKhann:

Neurobehavioral Sequelae of Cardiopulmonary Bypass ( The Lancet, Vol.

353, May 8, 1999)).

Heart bypass surgery is recommended for selected groups of patients with significant narrowing and blockage of the heart arteries.

We envision that NK-001 will be used at the time of surgery to prevent cognitive impairment from occurring.

We will test our hypothesis as part of our planned Phase II clinical trial of NK-001, in which trial participants will receive NK-001 (or a placebo) before undergoing CABG surgery.

There is currently no effective therapy for post-CABG cognitive impairment, so if we are successful, we anticipate that all heart bypass patients will be prescribed NK-001.

Accordingly, based on the annual number of worldwide heart bypass surgery patients and an estimated average treatment cost of approximately USD$1,000 per patient, we anticipate that the potential annual worldwide market for NK-001 will be approximately USD$800 million and USD$650 million in the United States alone.

According to the United States Alzheimer’s Association, approximately 5.3 million Americans suffered from Alzheimer’s disease in 2009.

According to Alzheimer’s Disease International, there are an estimated 30 million people with dementia worldwide.

By 2050, it is projected that this figure will have increased to over 100 million, with much of the increase occurring in developing countries.

Already more than 60% of people with dementia live in developing countries, but by 2040 this is estimated to rise to 71%.

The fastest growth in the elderly population is taking place in China, India and their south Asian and western Pacific neighbors.

Alzheimer’s disease accounts for more than 50% of cases of dementia in Caucasian populations, but this may not apply to other national or ethnic groups, as more research is needed in this area.

We cannot yet anticipate what share of the market of Alzheimer’s medication NK-002 is likely to assume if it is proven safe and effective.

Estimated Sales

Metastatic Endometrial Cancer (PVT-005)

Triple-negative breast cancer (PVT-006)

Female Lower Urinary Tract Symptoms (PVT-002)

Sales are conservatively estimated for US only, incidence of indication, modest pricing and market penetration.

Research and Development

We have spent $nil on research and development expenses for the last two fiscal years.

We have not spent any amount on research and development expenses for the last two fiscal years.

From our inception on June 10, 2002 to January 31, 2016 we spent $282,715 on research and development activities.

2 unchanged sentences

Intellectual Property

We own the common law trademark rights in our corporate name and logo.

We have not registered any of our trademark rights for protection.

We also own 100% of all right and title in and to the following patents:

We own the common law trademark rights in our corporate name and logo as well as the trademark for "INDUS PHARMACEUTICALS".

With the exception of the trademark for IndUS, we have not registered any of our trademark rights for protection.

We have also secured exclusive worldwide licensing rights and title in and to the following patents through our acquisition of IndUS Pharmaceuticals: