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It is time for a paradigm shift in the treatment of type 2 diabetes (2)

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"It is now time for a paradigm shift in the treatment of Type 2 diabetes by assessing the individual patient’s risk by determining the inflammatory status and develop drugs that not only sustain the beta cell function but can also be evaluated as a prophylactic therapy."

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It is time for a paradigm shift in the treatment of type 2 diabetes (2)

  1. 1. 1 “Get Real and Get It Right” with Type 2 diabetes: It Is Time For A Paradigm Shift TriGlytzaÔ: A Potential Gamechanger for Type 2 diabetes Patients Ravi Kumar, Ph.D. Founder and CEO, ARKAY Therapeutics Mission Statement: Develop Clinically Superior Yet Affordable Innovative Products That Provide Sustained Glycemic Control For Type 2 diabetes Patients Worldwide. Executive Summary ARKAY Therapeutics is a privately-held clinical stage biopharmaceutical company located in East Windsor, NJ. Type 2 diabetes, a leading cause of death worldwide is an independent risk factor for a variety of diseases including: cardiovascular disease, several types of cancers and neurological disorders. Type 2 diabetes continues to be an unmet medical need because the currently marketed treatment options do not adequately treat the underlying multidimensional pathophysiology. In real-world clinical practice in the United States, the first-line of therapy, second and third add-on drugs failed in almost 50% of the newly diagnosed patients between 2006 and 2016. These drugs were approved for treating primarily the symptoms as indicated by reductions in the HbA1c levels and not for mitigating the underlying pathophysiology of progressive deterioration of pancreatic beta cell function. They are inadequate in filling one of the most important clinical gaps in the Type 2 diabetes space: sustained glycemic control with a focus on preventing pancreatic beta cell failure and decreasing insulin resistance. To fill this important gap, ARKAY Therapeutics is developing an innovative, rationalized and patient-centric product called RK-01 or TriGlytzaÔ. It is custom-designed and formulated to target multiple distinct and overlapping pro-inflammatory signaling pathways along the RAS-IL1b-Cox2-PGE2-EP3 axis that contribute to progressive deterioration of beta cell function and insulin resistance, the core defects in all patients. The scientific rationale and the product concept are supported by the results obtained from translational animal models as well as controlled clinical studies. They have been endorsed by leading experts in the diabetes and cardiovascular disease space. ARKAY is currently raising capital for an FDA-approved clinical study (ClincialTrials.gov ID: NCT03686657) to evaluate the superiority of RK-01 prototype over Metformin, the current standard of care in newly diagnosed drug naïve and obese Type 2 diabetes patients with inadequate glycemic control with Metformin monotherapy. TriGlytzaÔ represents a paradigm shift in the clinical management of Type 2 diabetes and it is a potentially disruptive product. Scientific Rationale and The Product Concept The march of diabetes has been relentless. Diabetes patient population has almost doubled between 1980 and 2014 worldwide (Statista). It is not showing any signs of slowing down. Over 90% of diabetes patients have Type 2 diabetes which is characterized by insulin resistance and pancreatic beta cell dysfunction. There are over 26 million Type 2 diabetes patients in the United States alone and it is expected to grow to over 40 million by 2040 (IDF, Facts and Figures). Over 1.3 million people are diagnosed with Type 2 diabetes every year in the United States alone. The prevalence of prediabetes is three times that of Type 2 diabetes. A Third of the U.S. population or over 86 million people have prediabetes. The Type 2 diabetes population is expected to double to over 600
  2. 2. 2 million worldwide by 2045 (Figure 1). The current global economic burden is over $2.3T. Diabetes along with the cardiovascular diseases is the third leading cause of death in the United States (ADA, CDC, Biovision). The global Type 2 diabetes market is expected to grow from $20.4B to over $58.7B in 2025 (FiercePharma). The burden of Type 2 diabetes or the risk of incidence for cancers such as breast, rectum, pancreas, liver and gall bladder is over 35% because it is an independent risk factor (Zhao, X-B. et al. 2016; Ballatori, P. et al. 2017). Recent publications have highlighted the risk of developing diseases such as Alzheimer’s disease, Parkinson’s disease and depression in diabetes patients. The link between insulin resistance of the brain cells and Alzheimer’s disease is so strong that some have proposed classifying it as Type 3 diabetes (Kandimalla, R. et al. 2017). The current treatment guidelines and algorithms of AACE, ADA and EASD provide an extremely valuable tool and a roadmap for treating diabetes patients but unfortunately, they are designed to fail in real-world clinical practice due to the complex dynamic among patients, healthcare providers (HCPs) and the Health Care System (HCS) barriers. Multiple factors contribute to the clinical inertia that occurs after the failure of Metformin, the current first line of therapy as a result of the delay in the treatment intensification which prevents patients from reaching their target goals for HbA1c levels (Okemah, O. et al. 2018). HbA1c is the surrogate marker and a measure of blood glucose levels. Failure to meet patient-specific HbA1c goals put patients on a certain path to diabetes-related microvascular complications such as retinopathy, neuropathy and nephropathy, macrovascular complications such as stroke, peripheral artery disease (PAD), Coronary Artery Disease (CAD). Inadequate glycemic control is responsible for over 200,000 cases of diabetes-related complications per year in North America alone (Strain, W.D. et al. 2014). The currently marketed treatment options have focused on changing the hepatic glucose output, insulin sensitization, direct stimulation of beta cells, or reducing the glucose reabsorption in the kidneys. In real world clinical practice, a study that examined trends and intensification in the use of antidiabetes drugs in over 1,023,340 adults between 2006 and 2016 in the United States reported that the proportion of patients using Metformin as the first-line of therapy increased from 60% in 2005 to 77% in 2016 and antidiabetes drugs failed in almost 50% of the newly diagnosed patients (Montvida, O. et al. 2018). In patients prescribed Metformin as the first-line of therapy, 48% initiated a second add-on treatment at a mean HbA1c of 8.4%. Among the 78% of patients who had at least 1-year follow-up after starting a second antidiabetes medication, 52% were prescribed a third agent. The discontinuation rates in the first year were highest among SGLT2 inhibitors (25%), followed by TZDs (21%), GLP-1 receptor agonists (21%) and DPP-IV inhibitors (18%). Failure occurs because they were designed to treat and approved based primarily on their ability to treat the symptoms such as HbA1c and not for mitigating the underlying pathophysiology of progressive deterioration of pancreatic beta cell function, the core defect in all patients. Beta cells in the Pancreas have an inherent capacity for compensating for elevated blood glucose levels or hyperglycemia and insulin resistance by secreting required amount of insulin. In spite of therapy with the current treatment options, beta cell mass progressively decreases and their function continues to deteriorate compromising their ability to compensate for hyperglycemia and insulin resistance. Patients gradually reach a state of insulin dependence, a stage at which insulin therapy becomes the only treatment option and at this stage Type 2 diabetes becomes indistinguishable from Type 1 diabetes. It is important to note that the progressive nature
  3. 3. 3 of Type 2 diabetes is not due to an increase in insulin resistance but rather due to progressive decline in beta cell function. Based on the results from numerous clinical studies (Vanik, A.I. 2004), it is now time for a paradigm shift in the treatment of Type 2 diabetes by assessing the individual patient’s risk by determining the inflammatory status and develop drugs that not only sustain the beta cell function but can also be evaluated as a prophylactic therapy. Source: IDF.ORG Figure 1: Global diabetes emergency due to the unrelenting march of diabetes. Number of people with diabetes worldwide and per region, 2017 vs. 2045 (Ages 20-79 years). Source: IDF Type 2 diabetes is a progressive inflammatory disease and inflammation is central to the pathophysiology (Vinik, A.I. 2004; Skyler, J.S. et al. 2017). It has a multifactorial and multidimensional pathophysiology but the unifying pro-inflammatory signaling pathways that originate from a variety of clinically relevant tissues along the RAS-IL1b-Cox2-PGE2- EP3 axis (Figure 2) contribute to progressive deterioration of pancreatic beta cell function, the core defect or the “final common denominator” (Schwartz, S. et al. 2016). Pro- inflammatory signals originating from multiple clinically relevant cell types and tissues due to the multifactorial pathophysiology trigger apoptosis or programmed cell death of beta cells and degrade their capacity to respond adequately to the elevated blood glucose levels (Figure 3 and 4). Pro-inflammatory signals contribute to the pathophysiology of diabetes complications as well (Skyler, J.S. et al. 2017). From a clinical perspective, it is important to note that over 85% of Type 2 diabetes patients have high blood pressure (ADA, Facts and Figures) and over 47% of the adults with Type 2 diabetes also have arthritis as a coexisting condition (arthritis.org). Activation of Renin-Angiotensin System
  4. 4. 4 or RAS and Cyclooxygenase-2 or Cox-2-mediated cascade of signaling pathways contribute to high blood pressure and arthritis or degenerative joint disease, respectively. Activation of RAS in the context of pancreatic beta cells has nothing to do with high blood pressure but it is in fact pro-inflammatory. It contributes along with Cox-2 mediated elevation in PGE2 to reduction in the beta cell mass and progressive deterioration of beta cell function. The dose-dependent elevation in PGE2 levels and reduction in the beta cells ratio/islet (Oshima, H. et al. 2006) in a transgenic mouse model (Figure 5) is supported by an increased production of PGE2 isolated from islets obtained from donors with Type 2 diabetes patients compared to non-diabetic donors (Kimple, M.E. et al. 2013). Figure 2: Pro-inflammatory pathophysiology of Type 2 diabetes: RAS-IL1b-Cox2-PGE2- EP3 axis Furthermore, a cross-sectional view of an initial cohort study data revealed that PGE2 levels, a potent inhibitor of insulin secretion, predicted lack of effectiveness of GLP-1 analogs and DPP-IV inhibitors in Type 2 diabetes patients (Fenske, R. et al. 2017). The clinical significance of PGE2 is further supported by suppression of GLP-1 mediated insulin secretion by PGE2 analog Sulprostone (EP3 agonist) and it was overcome by an EP3-specific antagonist, L-798106 (Kimple, M.E. et al. 2013). Therefore, for efficient clinical management, an innovative and rationalized drug combination such as TriGlytzaÔ that can provide sustained glycemic control with a focus on preventing beta cell failure, decreasing insulin resistance, preventing or delaying insulin therapy and delaying or preventing diabetes complications in the context of comorbidities such as high blood
  5. 5. 5 pressure and a coexisting condition such as arthritis is essential and it makes perfect clinical sense. Source: Skyler, J.S. et al. 2017 Figure 3: Multidimensional and multifactorial pathophysiology of Diabetes
  6. 6. 6 Metformin is the “Gold Standard” and the current standard of care for Type 2 diabetes patients. It also is the current first line of therapy. Metformin’s efficacy is insulin dependent and it becomes ineffective as beta cell function deteriorates to a state of insulin Source: Schwartz, S. et al. 2016 Figure 4: b-cell-centric construct: Targeted therapies for preserving beta cells and decreasing insulin resistance. insufficiency in spite of therapy. It is an off-patent drug and it is highly affordable world- wide. All the drugs that have been approved for Type 2 diabetes were approved as an add-on drug to Metformin because they were evaluated in patients on Metformin background. Therefore, it makes not only the clinical sense but more importantly, an economic sense to develop a product that sustains the efficacy of Metformin and is also affordable worldwide. In real-world clinical practice, it is not just the clinical superiority that matters but what patients can afford and what they are willing to take matters more. There is no doubt that some great new drugs have reached the market in recent years such as GLP-1s e.g. Novo Nordisk’s Victoza, SGLT2 inhibitors e.g. Eli Lilly/Boehringer Ingelheim’s Jardiance and DPP4 inhibitors e.g. Merck’s Januvia. Some of these drugs have differentiated themselves by not only lowering blood glucose levels but more importantly by reducing the risk of cardiovascular disease. But unfortunately, these drugs and the mechanisms they target do not have an inherent anti-inflammatory capacity to maintain or restore beta cell function long term. They do appear to improve the beta cell function short term indirectly due to reduction in the stress on the beta cells as a consequence of lowering of the blood glucose levels. It is not sustainable as indicated by the failure of the
  7. 7. 7 second and third add-on drugs in real-world clinical practice in almost 50% of the patients in the United States (Montvida, O. et al. 2018). Source: Oshima, H. et al. 2006 Figure 5: Fluorescence immunostaining of the islets for insulin (b-cell; Green) and glucagon (a-cell;red). Shown are results of two islets from each for the wild-type (A), RIP-
  8. 8. 8 C2 (Cox2)mE(mPGES) (Tg/–) mice (B), RIP-C2mE (Tg/Tg) mice (C). Scale bars, 100 µm. Shown in the bottom panel ratio of b-cells (D) and a-cells (E) to the total islet cells (mean ±S.E.) *, p<0.05. To fill this clinically important gap, ARKAY Therapeutics is developing a uniquely formulated proprietary product, RK-01 or TriGlytzaÔ by using a dual combination of Celecoxib, a Cox-2 inhibitor and Valsartan, an Angiotensin II Type 1 receptor blocker which is also a RAS blocker as an add-on or as an adjunctive therapy to Metformin. Celecoxib or CelebrexÒ is currently approved for treating Arthritis and Valsartan or DiovanÒ is currently approved as an anti-hypertensive drug. They both are being repurposed for treating Type 2 diabetes. Results from the controlled clinical studies with Type 2 diabetes patients (El-Bahrawy, H. et al. 2017; Gonazalez-Ortiz, M. et al. 2005; Goossens, G.H. et al. 2012; Mendez del Villar, et al. 2017; Pscherer, S. et al. 2010; Ramos-Zavala, M. et al. 2011; van der Zijl, N.R. et al. 2011) as well as from appropriate animal models (Fujita, H. et al. 2007; Cole, B.K. et. Al. 2010; Kumar, R. ADA Conference 2016 and Diabetes 2016; Lu, C.H. et al. 2016) have shown that they improve beta cell function, first and second phase of insulin secretion, lower HbA1c levels, improve insulin sensitivity, inflammatory, lipid and atherogenic parameters. ARKAY has adopted a 505(b)(2) regulatory strategy for the clinical development of the commercial proprietary formulation of TriGlytzaÔ. This strategy reduces the cost and the time of development and enables competitive pricing worldwide. The cost of development is expected to be only a fraction i.e. about 20% or $200M vs. >$1B compared to the development of a new molecular entity or NCE. ARKAY has mitigated the risk to a great extent because there is already human proof-of-concept (PoC) from controlled clinical studies and the component drugs have a track record of safety for chronic use in the Type 2 diabetes space. Unlike the currently marketed treatment options which treat Type 2 diabetes in isolation, TriGlytzaÔ is custom-designed to treat the disease in the context of comorbidities and coexisting conditions. The clinical study protocol is designed with unique sets of patient populations, primary and secondary outcome measures that would help TriGlytzaÔ to differentiate from currently marketed drugs and facilitate unique labeling upon approval by the FDA (Kumar, R. 2018, ClinicalTrials.gov ID: NCT03686657). The U.S. FDA has approved or cleared the ARKAY’s IND (Investigational New Drug) application for evaluating the superiority of TriGlytzaÔ over Metformin in drug naïve newly diagnosed and obese Type 2 diabetes patients with inadequate glycemic control with Metformin monotherapy, ClinicalTrials.gov ID: NCT03686657. The U.S. patent office (USPTO) has issued ARKAY a patent, US 9,839,644 which protects the formulations and the method used for TriGlytzaÔ. ARKAY has also filed a continuation patent application which protects additional adjunctive or add-on formulations of RK-01 to drugs such as GLP-1s, SGLT2 inhibitors and DPP-IV inhibitors. The pipeline of ARKAY also includes repurposing of RK-01 for orphan diseases such as NASH (Non-alcoholic Steatohepatitis) and PCOS (Polycystic Ovarian Syndrome). ARKAY Therapeutics was recently announced as a finalist for the CARE (Clinical and Research Excellence) award. The winners will be announced at an award ceremony event on May 2nd in Boston, MA. Based on the results obtained from controlled clinical studies with the component drugs, we expect TriGlytzaÔ to prevent Metformin failure by maintaining a state of insulin sufficiency
  9. 9. 9 and mitigate the clinical inertia. Our long term goal is to replace Metformin with TriGlytzaÔ as the first line of therapy. It will also be evaluated for reducing the risk of developing Type 2 diabetes in prediabetes patients in a future clinical trial. The scientific rationale and the product concept have been endorsed by leading endocrinologists and experts in the metabolic and cardiovascular disease space; some of them have joined ARKAY’s management team, the board and the scientific advisory committee. One of them is Stan Schwartz, MD, a renowned endocrinologist, and expert in cardiometabolic syndrome and an Emeritus Associate Clinical Professor, University of Pennsylvania. Dr. Schwartz developed the pancreatic ‘beta-cell-concept’ for reclassifying diabetes as well as for efficient clinical management of diabetes by stratifying patients based on the defects and mechanisms that contribute to beta cell dysfunction. Beta cell dysfunction is the core defect or the common denominator in all patients irrespective of what the contributing or risk factors are in each individual patient. Dr. Schwartz has not only invested in ARKAY Therapeutics but also has joined the management team as the Chief Medical Advisor. Robert Busch, MD, Albany Medical College, Albany, NY, a renowned endocrinologist and a diabetes expert has graciously volunteered to be the principal Investigator (PI) on the clinical study. Dr. Busch has served as a PI in over 40 clinical trials. Ravi Kumar, Ph.D. the founder and CEO of ARKAY Therapeutics obtained M.S. and Ph.D. in Molecular and Cell Biology from New York University. He has the subject matter expertise in the metabolic, cardiovascular and chronic inflammatory disease space. Dr. Kumar has over 30 years of academic and pharmaceutical industry experience which includes The Cleveland Clinic Foundation, Pharmacia and Pfizer. He comes from a family of diabetes patients, knows first-hand the limitations of the currently marketed treatment options and the devastating consequences of diabetes-related complications. The investment community, angel investors and venture capitalist firms alike are currently focused so much on investing in the immuno-oncology space with a herd mentality and have chosen to ignore the diabetes space. There are pharma companies and VC firms who find ARKAY’s product concept “not innovative enough” because it is a combination of repurposed pre-approved drugs. In the real-word, patients don’t care if the medicine they are taking is innovative, new molecules or preapproved drugs; they just want a sustainable and an affordable solution. Large pharma companies historically have used at least $1B potential revenue threshold as a criterion to consider a new idea for a potential investment or a partnership. The choice with TriGlytzaÔ is simple and straight forward: an expensively priced innovative product developed from a NCE that can generate $1B per year revenue for short term glycemic control with a small market share or a competitively-priced patient-centric product that can provide sustained glycemic control which can also generate equivalent or better revenue stream with a larger market share with a positive impact on the lives of Type 2 diabetes patients worldwide. The 3-years exclusivity from the 505(b)(2) regulatory strategy along with exclusivity from the issued patent are expected to prevent competition from generic drugs until the patent expiration in September 2034 which makes the revenue potential of TriGlytzaÔ comparable to a drug developed from a NCE. In the prevailing environment, It has become increasingly
  10. 10. 10 difficult to raise capital for ARKAY’s clinical study to bring this very important patient- centric product to the Type 2 diabetes patients. TriGlytzaÔ provides not only a superior clinical solution but more importantly an affordable solution. Therefore, we are reaching out to the global investment community to raise at least $10M for the human proof-of- concept study with TriGlytzaÔ prototype. Multiple pharma companies in the diabetes space have already expressed interest in partnering with ARKAY for the commercial development after the completion of the human PoC study. Conclusions Pharmaceutical industry needs to explore Think-out-side-the-box approaches to address the challenges of the real-world clinical practice: sustained glycemic control, preventing clinical inertia, affordability and diabetes complications. It is now time for a paradigm shift in the clinical management of Type 2 diabetes. Targeting the underlying pathophysiology of multidimensional pro-inflammatory signaling cascade of events with a rationalized combination product such as TriGlytzaÔ which is custom-designed to prevent beta cell failure and decrease insulin resistance makes not only clinical sense and more importantly an economic sense for Type 2 diabetes worldwide. Please visit www.arkaytherapeutics.com for more information on the scientific rationale, the product concept, the management team, board members and the scientific advisors. Please contact ravi.kumar@arkaytherapeutics.com for the non-confidential business plan. Please feel free to share this article with your friends and family via LinkedIn and other social media. Glossary: ADA: American Diabetes Association; AACE: American Association of Clinical Endocrinologists; AngII: Angiotensin II; CARE: Clinical and Research Excellence; CDC: Center for Disease Control; Cox-2: Cyclooxygenase-2; DPP-IV: Dipeptidyl Peptidase-IV; EASD: European Association for the Study of Diabetes; FDA: Food and Drug Authority; GLP-1: Glucagon-like Peptide-1; HbA1c: Hemoglobin A1c; IDF: International Diabetes Federation; IL-1b: Interleukin-1b; NASH: Non-alcoholic Steatohepatitis; NFkB: Nuclear Factor kB; PCOS: Polycystic Ovarian Syndrome; PGE2: Prostaglandin E2; PGH2: Prostaglandin H2; PoC: Proof-of-concept; RAS: Renin-Angiotensin System; SGLT2: Sodium Glucose Transporter-2; USPTO: United States Patent and Trademark Office Key References: Ballatori, P. et al. (2017) Diabetes and risk of cancer incidence: results from a population- based cohort study in northern Italy. BMC Cancer 17(703): 1-8. Cole, B.K. et. al (2010) Valsartan protects pancreatic islets and adipose tissue from the inflammatory and metabolic consequences of a high-fat in mice. Hypertension 55: 715- 721.
  11. 11. 11 El-Bahrawy, H. et al. (2017) Targeting inflammation using celecoxib with glimepiride in the treatment of obese type 2 diabetes Egyptian patients. Int J Diabetes Dev Ctries. 37(2): 97-102. Fenske, R. et al. (2017) Prostaglandin E2 (PGE2) levels as a predictor for Type 2 diabetes control in human subjects: A cross-sectional view of initial cohort study data. FASEB J. Abstract No. 675.6 Fujita, H. et al (2007) Effect of cyclooxygenase-2 (COX-2) inhibitor treatment on glucose- stimulated insulin secretion in C57BL/6 mice. Biochem. Biophys. Res. Commun. 363(1): 37-43. Gonazalez-Ortiz, M. et al. (2005) Effect of Celecoxib, a Cyclooxygenase-2-specific inhibitor, on insulin sensitivity, C-reactive protein, homocysteine, and metabolic profile in overweight or obese subjects. Metab. Synd. Rel. Disord. 3(2): 95-101. Goossens, G.H. et al. (2012) Valsartan improves adipose tissue function in humans with impaired glucose metabolism: A randomized placebo-controlled double-blind trial. PLoS One 7(6): e39930 IDF, International Diabetes Federation (2017) Facts and Figures. www.idf.org. Accessed March 2, 2017. Kandimalla, R. (2017) Is Alzheimer’s disease a Type 3 diabetes? A critical appraisal. Biochim. Biophys. Acta. 1863(5): 1078-1089. Kimple, M.E. et al. (2013) Prostaglandin E3 receptor, EP3, is induced in diabetic islets and negatively regulated glucose and hormone-stimulated insulin secretion. Diabetes 62: 1904-1912. Kumar, R. (2016) Anti-inflammatory-centric drug combination lowers non-fasting and fasting blood glucose levels in C57BL/6 DIO mice with insulin resistance. Diabetes 65 (suppl. 1): A294. Kumar, R. (2018) Evaluation of superiority of Valsartan+Celecoxib+Metformin over Metformin alone in Type 2 diabetes patients (RESILIENCE). ClinicalTrials.gov Identifier: NCT03686657. Lu, C.H. et al. (2016) Additional Effect of Metformin and Celecoxib Against Lipid dysregulation and Adipose Tissue Inflammation in High-fat Fed Rats with Insulin Resistance and Fatty Liver. Eur. J. Pharmacol. (2016). http://dx.doi.org/10.1016/j.ejphar.2016.07.012 Mendez-del vilar, M. et al. (2017) Effect of Diacerein as an add-on to metformin in patients with type 2 diabetes mellitus and inadequate glycemic control. Arch. Endocrinol. Metab. 61(2): 188-192.
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