Refractory Angina Market Size Share

1. 2020 Refractory Angina (RA) Refractory Angina (RA) Market Insights, Epidemi Market Insights, Epidemiology, and Market Forecast Forecast— — 2030 2030 ology, and Market

2. D e l v e I n s i g h t | P a g e | 1 1 Key Insights The Report contains: ` Pipeline analysis across different stages of development (Phase III and Phase II), different emerging trends and comparative analysis of pipeline products with detailed clinical profiles, key cross-competition, launch date along with product development activities Overview various diagnostic approaches and treatment algorithm detailed chapters for marketed products and emerging therapies of pathophysiology, Research Research Analysis Analysis Pipeline Pipeline Valuation Valuation including Epidemiology Epidemiology Forecast Forecast Market Market Analysis Analysis Historicalas well as forecasted epidemiology in the 7MM covering the United States, EU5 (Germany, France, Italy, Spain, and the United Kingdom) and Japan from 2017 to 2030 Market size by Market size by therapies therapies Detailed historical and forecasted market covering the United States, EU5 and Japan countries from 2017 to 2030 Detailed Market size by therapies, covering the United States, EU5 (Germany, France, Italy, Spain, and the United Kingdom), and Japan from 2017 to 2030 Strategic analysis of Treatment options & Emerging Therapies Insightful Reviews on Market Drivers & Market Barriers Healthcare Market Research DelveInsight Copyright

3. D e l v e I n s i g h t | P a g e | 2 2 DelveInsight’s “Refractory Angina (RA Refractory Angina (RA) )- - Market Insights, Epi Market Insights, Epidemiology and Market Forecast Market Forecast— provides an overview of the disease and market size of RA for the seven major pharmaceutical markets, i.e., the United States, EU5 (Germany, France, Italy, Spain, and the United Kingdom), and Japan. This report covers the various treatment practices, and RA forecasted epidemiology from 2020 to 2030, segmented by the seven major markets. Report Introduction Report Introduction demiology and —2030 2030” report The report provides an understanding of the The report provides an understanding of the epidemiology and changing market dynamics of epidemiology and changing market dynamics of Refractory Angina (RA) Refractory Angina (RA) pharmaceutical pharmaceutical marke markets for the period 2017 ts for the period 2017– –2030 understanding trends shaping and driving the global Refractory Angina (RA) market. in in the the seven seven major major 2030 ✓The report covers the descriptive overview of Refractory Angina (RA), explaining its causes and risk factors, pathophysiology, diagnosis and currently available therapies. ✓Comprehensive insight has been provided into the epidemiology of the Refractory Angina (RA) and its treatment in the 7MM. ✓Additionally, an all-inclusive account of both the current and emerging therapies for Refractory Angina (RA) is provided, along with the assessment of new therapies, which will have an impact on the current treatment landscape. ✓A detailed review of historical and forecasted Refractory Angina (RA) market is included in the report, covering drug outreach in the 7MM. ✓The report provides an edge while developing business strategies, by Key Strengths Key Strengths ❖11 11- -Year Forecast Year Forecast ❖7MM Coverage 7MM Coverage ❖Epidemiology Segmentation Epidemiology Segmentation ❖Drugs Uptake Drugs Uptake ❖Highly Analyzed Market Highly Analyzed Market ❖Key Cross Competition Key Cross Competition ❖Market Size by Country Market Size by Country ❖Market Size by Therapy Market Size by Therapy Key Assessments Key Assessments ❖Current Treatment Practices Current Treatment Practices ❖Unmet Needs Unmet Needs ❖Emerging Drug Profiles Emerging Drug Profiles ❖Market Attractiveness Market Attractiveness ❖Market Drivers and Barriers Market Drivers and Barriers Healthcare Market Research DelveInsight Copyright

4. D e l v e I n s i g h t | P a g e | 3 3 Epidemiology Insights Epidemiology Insights Refractory Angina (RA) Refractory Angina (RA) is a chronic condition where pain remain persistent for the duration of less than or equal to 3 months, characterized by angina. Angina is a type of chest pain caused by reduced blood flow to the heart. Angina has two types, chronic or stable angina and unstable angina. Around 10–15% of patients of Chronic Angina meet the measures of RA. The clinical load of RA is growing rapidly due to an ageing population and improved Coronary Artery Disease (CAD). Symptoms of RA are chest pain, shortness of breath, and easy fatigability. RA also shows neurological, psychogenic and mitochondrial dysfunctions in addition to tissue ischemia which are responsible for an insistent cardiac pain. These symptoms causes poor self-perceived health status, high incidence of depression, and burden to the health care system due to significant resource utilization. Patients with RA are a heterogeneous group that remain significantly limited by persistent debilitating chest discomfort despite optimal conventional therapy. Refractory Angina Refractory Angina— —Epidemiology by Gender Epidemiology by Gender •As per Delveinsight’s estimates, the total prevalent cases of Refractory Angina in 7 major markets ranges from 29,17,196 29,17,196 in 2017. •According to the Delveinsight’s analysts, the United States accounted for most prevalent cases of RA in 7MM with 19,05,602 19,05,602 cases in 2017. •Among EU5 countries, Germany accounted for most number of prevalent cases of RA with 5,13,896 in 2017. •Japan accounted for 27,432 27,432 cases in 2017 which are expected to grow during the study period (2017– 2030). 5,13,896 cases Healthcare Market Research DelveInsight Copyright

5. D e l v e I n s i g h t | P a g e | 4 4 Epidemiology Epidemiology Parameters Parameters- - 7MM 7MM Total Diagnosed Population of C Total Diagnosed Population of Coronary and R and Refractory efractory A Angina in the 7MM (2017 ngina in the 7MM (2017– –2030 oronary A Artery rtery D Disease 2030) ) isease 1 Sub Sub- -type Specific Prevalence of R type Specific Prevalence of Refractory (2017 (2017– –2030) 2030) efractory A Angina in the7MM ngina in the7MM Age Specifi Age Specific Prevalent Cases c Prevalent Cases of RS of RS 2 Gender Gender- -specific Prevalent specific Prevalent Population (2017 (2017– –2030) 2030) Population of of Refractory Angina Refractory Angina in the 7MM in the 7MM 3 Diagnosed Diagnosed Population of NORDA Population of NORDA in the 7MM (2017 in the 7MM (2017– –2030) 2030) 4 Market Share 2017 [Indicative] • RA is classified on the basis of grading the pain. Among these sub-types, Class III contributes the major patient share of RA followed by Class IV angina. • Higher Prevalence of Refractory Angina is observed among males as compared to females in 7MM. United States EU-5 Japan Healthcare Market Research DelveInsight Copyright

6. D e l v e I n s i g h t | P a g e | 5 5 Graphical Representation of Graphical Representation of Refractory Angina Refractory Angina ( (RA RA) )— —Epidemiology Epidemiology Total Total Prevalent Prevalent Cases of Cases of RA RAin in the the 7MM ( 7MM (2017 2017– –2030 2030) ) 7MM Total Prevalent Patient Population of Refractory Angina Population in Number (N) 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 Year United States Germany France Italy Spain United Kingdom Japan Total Gen Total Gender der- -specific specific Prevalent Cases of RA Prevalent Cases of RAin in the the United States United States ( (2017 2017– –2030 2030) ) Gender Specific prevalence of RA Population in Number (N) 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 Year Male Female Healthcare Market Research DelveInsight Copyright

7. D e l v e I n s i g h t | P a g e | 6 6 Market Insight Market Insight Market Outlook for RA Refractory Angina ( Refractory Angina (RA with RA defined as being ‘no option’ revascularization treatment for reasons related to diffuse coronary lesions, unsuitability to chronic total occlusion mechanical revascularization, or frailty from the presence of severe comorbidities. RA) ) is a chronic disease characterized by the presence of persistent angina and patients ‘no option’ since they are not considered amenable for conventional In spite of continuous developments in Coronary Artery Disease (CAD) management, particularly in the aged population, the number of patients suffering from RA is correlated to the healthcare expenses. Currently, there are several methods to treat this disease, which involves pharmacological t approaches approaches, coronary sinus coronary sinus reducer reducer, etc. Several Several non non- -invasive methods disease, like External Enhanced Counter Pulsation (EECP), extracorporeal shockwave therapy (ESWT), neuromodulation, etc. Pragmatic rehabilitation Pragmatic rehabilitation is also an important approach to promote patients to manage their own chest pain. pharmacological treatments reatments invasive methods are also available to treat this Safety and tolerability of current anti- anginal agents is not good, so the primary focus is on improving quality of life for patients with refractory angina Market Size of RA in the 7MM is expected to grow during the study period (2017–2030) The lack of approved therapies, specifically for the treatment of RA remains the primary unmet need of the disease Owing to the launch of upcoming therapies, the market size shall increase significantly during forecast period (2020–2030) Several pharmacological, noninvasive, and invasive therapeutic techniques are under investigation, with the aim of improving care for this challenging indication. There is no significant pharmacologic approved therapy to improve quality of life in patients of RA, but a significant amount of evidence exists in the literature that supports the use of pharmacologic treatment in the stable Angina. Beta Beta- -blockers blockers and Calcium Channel Antagonists Calcium Channel Antagonists like Nicorandil (K-ATP - channel opener), Healthcare Market Research DelveInsight Copyright

8. D e l v e I n s i g h t | P a g e | 7 7 Ivabradine (If current inhibitor), Trimetazidine (Reversible 3-ketoacyl-thiolase inhibitor), Ranolazine, Fasudil/hydroxyfasudil (Rho-kinase inhibitor) are few mainstay medical treatment for angina. Furthermore, the European Society of Cardiology European Society of Cardiology guidelines guidelines now consider ivabradine, nicorandil, or ranolazine with long- acting nitrates as a second-line therapy for patients with persistent angina, according to heart rate, blood pressure, and tolerance. Ivabradine Ivabradine helps to reduce the number of angina attacks in patients with chronic stable angina by blocking If channels, which regulate the intrinsic chronotropic characteristics of the sinoatrial node. It may be useful in patients with refractory angina who do not tolerate high doses of β-blockers, or when calcium-channel blockers are contraindicated. Nicorandil Nicorandil is a nicotinamide ester which contains nitrate like moiety, which helps in vasodilation of coronary arteries and also promotes the opening of the mitochondrial ATP-sensitive potassium channels (KATP), known to mimic ischemic preconditioning. This drug has shown cardioprotective effect among patients of Chronic Stable Angina. Additionally, Trimetazidine mitochondrial long-chain 3-ketoacylCoA thiolase. This is an important enzyme for the β-oxidation of fatty acids. Trimetazidine might enhance the energy efficiency of ischemic myocytes by inhibiting the βoxidation of fatty acid. This drug is also recommended as a second-line therapy, but its use is less well established. Another therapy, Ranolazine Ranolazine, affects ion channels in cardiomyocytes via inhibition of late sodium currents. The mechanism of action of ranolazine is debated but it is believed to partially inhibit the fatty acid oxidation. Ranolazine has never been tested in a specific trial of patients with refractory angina but safety is well established for RA patients as well as Acute Coronary Syndrome. The US guidelines consider ranolazine useful only when prescribed as a substitute for β-blockers for relief of symptoms in patients where the initial treatment with β-blockers was ineffective. Trimetazidine is a metabolic agent that increases glucose oxidation by blocking the Fasudil and hydroxyfasudil Fasudil and hydroxyfasudil is a Rho kinase inhibitor, which reduces calcium sensitization of vascular smooth muscle to maintain coronary vasodilatation and prevent vasospasm. Fasudil and hydoexyfasudil currently available in Japan for the prevention of central nervous system vasospasm associated with subarachnoid hemorrhage. Potentially useful for vasospastic angina. Talking about the n noninvasive therapies oninvasive therapies, these are also recommended for the treatment of RA. Enhanced external external counter pulsation counter pulsation (EECP), (EECP), has been approved by the United States Food and Drug Administration (FDA) for the management of refractory angina (Class IIb). EECP involves attachment of three sets of pneumatic cuffs around patient’s legs at the calf and lower and upper thigh, which inflate during diastole to augment coronary blood flow and deflate in systole to decrease afterload and increase venous return. The inflation of the cuffs produces a retrograde flow of blood in the aorta which helps in diastolic augmentation of blood flow. This also increases the relapse of which leads to an improved coronary perfusion pressure during diastole. EECP session involves 35 one hour session. In the year 2000, EECP has been proven to be a safe therapy by the International EECP Patient Registry (IEPR). Enhanced Extracorporeal shockwave thera Extracorporeal shockwave therapy (ESWT apply focal mechanical stress. In response to this acoustic field, naturally occurring microbubbles inside and outside of cells oscillate and collapse. These waves also promote in situ expression of chemo-attractants py (ESWT) ) is used to deliver high-amplitude acoustic pressure pulses to Healthcare Market Research DelveInsight Copyright

9. D e l v e I n s i g h t | P a g e | 8 8 (stromal cell-derived factor 1, Vascular Endothelial Growth Factor (VEGF), and nitric oxide). ESWT is a noninvasive modality that seems to be safe and warrants further study to determine the optimal dose and protocol as well as its efficacy in patients with refractory angina. In Neuromodulation Neuromodulation pain, signal is interrupted via chemically, mechanically, or electrically in the transmission pathway from the periphery to the brain. Spinal-cord modulation, subcutaneous electrical nerve stimulation, cardiac sympathectomy, and transmyocardial laser revascularization are the type of neuromodulatory methods useful for the patients with cardiac pain. Moreover, Cardiac cell Cardiac cell- -based therapy untreatable RA. According to some experimental studies, cell therapy can improve myocardial perfusion and contractile function. Cell therapy also promotes neovascularization. based therapy has emerged as a novel therapeutic option for patients dealing with A number of drugs and therapies are suggested as first and the second line of treatment, however, not all of the above-mentioned treatments were formally suggested for RA. Development of RA-specific clinical guidelines is needed. Current medical therapy has several shortcomings which include lack of proof of a direct impact of anti-ischemic therapy on clinical outcomes in the context of RA. Recent efforts have been directed toward the discovery of novel therapies. The market is expected to experience growth in the coming years as there are few drugs lined up and are expected to launch during the forecast period [2020– 2030]. Healthcare Market Research DelveInsight Copyright

10. D e l v e I n s i g h t | P a g e | 9 9 Graphical Representation of Graphical Representation of Refractory Angina (RA) Refractory Angina (RA)– –Market Size Market Size Total Market Size of Total Market Size of RA RAin the 7MM ( in the 7MM (2017 2017– –2030 2030) ) Total Market Size of RA in 7MM Market Size in USD, Million 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 Year United States Germany France Italy Spain United Kingdom Japan Market Size of Market Size of RA RAin the in the United States ( United States (2017 2017– –2030 2030) ) Total Market of RA Sales In USD, Million 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 Year US Healthcare Market Research DelveInsight Copyright

11. D e l v e I n s i g h t | P a g e | 10 10 Drug Uptake Drug Uptake Emerging Therapy Analysis The dynamics of Refractory Angina market is anticipated to change in the coming years owing to the expected launch of emerging therapies during the forecast period of 2020–2030, as there is no pharmacologic treatment available to treat RA patients specifically. Several companies across the globe are thoroughly working toward the development of new treatment and devices which are expected to change the current market scenario for RA. Several emerging pharmacotherapies for RA in different stages of clinical development are Ad5FGF (Angioneti (Angionetics cs/Huapont Life Sciences /Huapont Life Sciences) ), , CLBS14 CLBS14 (Caladrius Biosciences) (Caladrius Biosciences), and several others. Ad5FGF- -4 4 Ad5FGF Ad5FGF- -4 ( precision medicine, recombinant angiogenic gene therapy product designed to stimulate the formation of functional coronary collateral vessels in patients with refractory angina due to myocardial ischemia, resulting in increased myocardial perfusion and improved patient outcomes. This product utilizes a serotype 5 adenovirus (Ad5) to deliver the FGF-4 transgene into heart cells. 4 (Angionetics/Huapont Life Sciences Angionetics/Huapont Life Sciences) ) is angiogenic gene therapy cardiac biologic product. It is a The US FDA has granted fast track designation to this product for the P Phase one-time treatment for improving exercise tolerance in patients who have angina that is refractory to standard medical therapy, and not amenable to conventional revascularization procedures. hase III III clinical investigation as a Another drug, CLBS14 refractory disabling angina (NORDA). Based on the clinical evidence from the completed studies that a single administration of CLBS14 reduces mortality, improves angina, and increases exercise capacity in patients with otherwise untreatable angina, this product received regenerative designation (RMAT) designation (RMAT) designation from the US FDA. Furthermore, the company is working closely with the US FDA, and have finalized the design of a confirmatory Phase III filed Phase I, II and III data, will be considered for the registration of CLBS14. CLBS14 by Caladrius Biosciences Caladrius Biosciences, is also in development for the treatment of no-option regenerative medicine advanced therapy medicine advanced therapy Phase III trial which, in combination with previously In August 2019, Caladrius Biosciences and Cognate BioServices entered into a manufacturing agreement for the production of CLBS14. Under the terms of the agreement, Cognate manufacture CLBS14 for Caladrius’ Phase III confirmatory pivotal clinical trial in subjects with NORDA. Under this agreement, the company has acquired the rights to data and regulatory filings for a CD34+ cell therapy program for RA that had been advanced to Phase III by a previous sponsor. In addition to aforementioned therapies in development, other therapies like IMB Pharmaceuticals), XC001 XC001 (XyloCor Therapeutics) and others are in the initial stages of development. While, some of these companies have recently shifted their focus toward this therapeutic area, yet others have completed the late stage of development. As few drugs are currently in the pipeline and in their late development stages, the market will surely experience growth in the upcoming years. IMB- -101 ( 101 (Imbria Healthcare Market Research DelveInsight Copyright

12. D e l v e I n s i g h t | P a g e | 11 11 Market Size of Refractory Angina (RA) by Therapies in the Market Size of Refractory Angina (RA) by Therapies in the United States United States ( (2017 2017– –2030 2030) ) US Drug-level Revenue ($M) Sales in USD, Million 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 Year Beta-blockers Short or Long acting nitrates ACE inhibitors Ranolazine Trimetazidine CLBS-14 (Auto-CD34+ cells) AdVEGFXC1 (XC001) Calcium antagonists Lipid-lowering agents Ivabradine Nicorandil IMB-1018972 Generx/ Alferminogene tadenovec (Ad5FGF-4) Healthcare Market Research DelveInsight Copyright

13. D e l v e I n s i g h t | P a g e | 12 12 Conjoint Analysis Scores Scores 50% 50% 20% 20% 30% 30% Weighted Weighted Score Score Safety Safety RoA RoA Treatment Treatment and and Parameters Parameters Efficacy Efficacy Drug A Drug A 3 XX 4 XX Drug B Drug B 5 XX 5 XX Drug C Drug C 7 XX 3 XX Drug D Drug D XX XX XX XX High Medium Low High Medium Low High Medium Low Legend Legend RoA and Treatment RoA and Treatment Efficacy Efficacy Safety Safety KOL Views The objective of updating DelveInsight coverage is to ensure that it represents the most up-to-date vision of the industry possible. The DelveInsight is a fully integrated solution for comprehensive intelligence on various pharmaceutical products, both in the market and in the pipeline, across the globe. Even though management of patients happen therapies, novel drug development is an ongoing opportunity for patients of this disease group. by off-label The predominant treatment for patients suffering from RA is XXXX therapy KOL B, Japan KOL A, USA XXXX therapy has provided much- needed relief to the management of patients, but many prescribers and patients are awaiting the approval of upcoming therapies KOL C, Germany Healthcare Market Research DelveInsight Copyright

14. D e l v e I n s i g h t | P a g e | 13 13 Table of Content to View 1:Key Insights 1 2:Executive Summary of Refractory Angina 3 3:SWOT Analysis for Refractory Angina 5 4:Refractory Angina (RA) Market Overview at a Glance 6 4.1:Market Share (%) Distribution of Refractory Angina (RA) in 2017 6 4.2:Market Share (%) Distribution of Refractory Angina (RA) in 2030 6 5:Disease Background and Overview 14 5.1:Introduction 14 5.2:Types 16 5.3:Symptoms 17 5.4:Etiology 17 5.5:Risk Factors 19 5.6:Pathophysiology 19 5.7:Diagnosis 23 6:Epidemiology and Patient Population 27 6.1:Key Findings 27 6.2:7MM Total Prevalent Patient Population of Refractory Angina [RA] 28 7:Epidemiology Assumptions and Rationale - 7MM 29 8:Country Wise-Epidemiology of Refractory Angina (RA) 32 8.1:The United States 32 8.1.1:Total Diagnosed Population of CAD and RA in the United States 32 8.1.2:Sub-type Specific Prevalence of RA in the United States 33 8.1.3:Gender specific Prevalence of RA in the United States 34 8.1.4:Diagnosed Population of NORDA in the US 35 8.2:Germany 36 8.2.1:Total Diagnosed Population of CAD and RA in Germany 36 8.2.2:Sub-type Specific Prevalence of RA in Germany 37 8.2.3:Gender specific Prevalence of RA in Germany 38 8.2.4:Diagnosed Population of NORDA in Germany 39 8.3:France 40 8.3.1:Total Diagnosed Population of CAD and RA in France 40 8.3.2:Sub-type Specific Prevalence of RA in France 41 8.3.3:Gender specific Prevalence of RA in France 42 8.3.4:Diagnosed Population of NORDA in France 43 8.4:Italy 44 8.4.1:Total Diagnosed Population of CAD and RA in Italy 44 8.4.2:Sub-type Specific Prevalence of RA in Italy 45 8.4.3:Gender specific Prevalence of RA in Italy 46 8.4.4:Diagnosed Population of NORDA in Italy 47 8.5:Spain 48 8.5.1:Total Diagnosed Population of CAD and RA in Spain 48 8.5.2:Sub-type Specific Prevalence of RA in Spain 49 Healthcare Market Research DelveInsight Copyright

15. D e l v e I n s i g h t | P a g e | 14 14 8.5.3:Gender specific Prevalence of RA in Spain 50 8.5.4:Diagnosed Population of NORDA in Spain 51 8.6:The United Kingdom 52 8.6.1:Total Diagnosed Population of CAD and RA in the UK 52 8.6.2:Sub-type Specific Prevalence of RA in the UK 53 8.6.3:Gender specific Prevalence of RA in the United Kingdom 54 8.6.4:Diagnosed Population of NORDA in the United Kingdom 55 8.7:Japan 56 8.7.1:Total Diagnosed Population of CAD and RA in Japan 56 8.7.2:Sub-type Specific Prevalence of RA in Japan 57 8.7.3:Gender specific Prevalence of RA in Japan 58 8.7.4:Diagnosed Population of NORDA in Japan 59 9:Treatment 60 9.1:Pharmacological Therapies 62 9.2:Noninvasive Antianginal therapies 66 9.3:Invasive Antianginal therapies 70 9.4:Treatment Guidelines 74 9.4.1:European Society of Cardiology (ESC) Guidelines for Refractory Angina Patients 74 9.4.2:National Institute for Health and Clinical Excellence (NICE) guidelines: Chest pain of recent onset 76 9.4.3:Canadian Cardiovascular Society (CCS) Guidelines 78 10:Unmet Needs 82 11:Case Studies 84 11.1:A Case of Refractory Angina 84 11.2:A Case Report of Refractory Angina 85 12:Organizations related with Refractory Angina 86 13:Emerging Therapies 88 13.1:IMB-101: Imbria Pharmaceuticals 88 13.1.1:Other Developmental Activities 88 13.1.2:Clinical Development 88 13.1.3:Safety and Efficacy 89 13.2:Auto CD34+ Cells: Caladrius Biosciences, Inc. 90 13.2.1:Other Developmental Activities 90 13.2.2:Clinical Development 91 13.2.3:Safety and Efficacy 92 13.3:Generx: Angionetics Inc. 94 13.3.1:Other Developmental Activities 94 13.3.2:Clinical Development 95 13.3.3:Safety and Efficacy 98 13.4:XC001: XyloCor Therapeutics, Inc. 99 13.4.1:Other Developmental Activities 99 13.4.2:Clinical Development 99 14:Refractory Angina (RA): 7 Major Market Analysis 101 14.1:Key Findings 101 14.2:Total Market Size of RA in 7MM 102 Healthcare Market Research DelveInsight Copyright

16. D e l v e I n s i g h t | P a g e | 15 15 14.3:Market Outlook: 7MM 103 15:United States 107 15.1:Total Market size of RA 107 15.2:RA Market Size by Therapies 108 16:EU5 Countries 109 16.1:Germany 109 16.1.1:Total Market size of RA 109 16.1.2:RA Market Size by Therapies 110 16.2:France 111 16.2.1:Total Market size of RA 111 16.2.2:RA Market Size by Therapies 112 16.3:Italy 113 16.3.1:Total Market size of RA 113 16.3.2:RA Market Size by Therapies 114 16.4:Spain 115 16.4.1:Total Market size of RA 115 16.4.2:RA Market Size by Therapies 116 16.5:United Kingdom 117 16.5.1:Total Market size of RA 117 16.5.2:RA Market Size by Therapies 118 17:Japan 119 17.1:Total Market size of RA 119 17.2:RA Market Size by Therapies 120 18:Market Drivers 121 19:Market Barriers 123 20:Appendix 124 20.1:Bibliography 124 20.2:Report Methodology 126 21:DelveInsight Capabilities 128 22:Disclaimer 129 23:About DelveInsight *The table of contents is not exhaustive *The table of contents is not exhaustive; will be provided in the final report 129 ; will be provided in the final report Healthcare Market Research DelveInsight Copyright

17. D e l v e I n s i g h t | P a g e | 16 16 List of Tables Table 1: Summary of Refractory Angina (RA) Market, Epidemiology, and Key Events (2017–2030) 4 Table 2: Difference between Stable and Unstable Angina 18 Table 3: Probability of Coronary Artery Diseases and Associated Diagnostic Strategies 23 Table 4: Total Prevalent Patient Population of RA in 7MM (2017–2030) 28 Table 5: Diagnosed Population of CAD and RA in the United States (2017–2030) 32 Table 6: Sub-type Specific Prevalence of RA in the United States (2017–2030) 33 Table 7: Gender specific Prevalence of RA in the United States (2017–2030) 34 Table 8: Diagnosed Population of NORDA in the US (2017–2030) 35 Table 9: Total Prevalent Population of RA in Germany (2017–2030) 36 Table 10: Sub-type Specific Prevalence of RA in Germany (2017–2030) 37 Table 11: Gender specific Prevalence of RA in Germany (2017–2030) 38 Table 12: Diagnosed Population of NORDA in Germany (2017–2030) 39 Table 13: Diagnosed Population of CAD and RA in France (2017–2030) 40 Table 14: Sub-type Specific Prevalence of RA in France (2017–2030) 41 Table 15: Gender specific Prevalence of RA in France (2017–2030) 42 Table 16: Diagnosed Population of NORDA in France (2017–2030) 43 Table 17: Diagnosed Population of CAD and RA in Italy (2017–2030) 44 Table 18: Sub-type Specific Prevalence of RA in Italy (2017–2030) 45 Table 19: Gender specific Prevalence of RA in Italy (2017–2030) 46 Table 20: Diagnosed Population of NORDA in Italy (2017–2030) 47 Table 21: Diagnosed Population of CAD and RA in Spain (2017–2030) 48 Table 22: Sub-type Specific Prevalence of RA in Italy (2017–2030) 49 Table 23: Gender specific Prevalence of RA in Spain (2017–2030) 50 Table 24: Diagnosed Population of NORDA in Spain (2017–2030) 51 Table 25: Diagnosed Population of CAD and RA in the UK (2017–2030) 52 Table 26: Sub-type Specific Prevalence of RA in the UK (2017–2030) 53 Table 27: Gender specific Prevalence of RA in the United Kingdom (2017–2030) 54 Table 28: Diagnosed Population of NORDA in the UK (2017–2030) 55 Table 29: Diagnosed Population of CAD and RA in Japan (2017–2030) 56 Table 30: Sub-type Specific Prevalence of RA in Japan (2017–2030) 57 Table 31: Gender specific Prevalence of RA in Japan (2017–2030) 58 Table 32: Diagnosed Population of NORDA in Japan (2017–2030) 59 Table 33: Grading of Angina Pectoris 78 Table 34: Organizations contributing toward Refractory Angina 86 Table 35: IMB-101, Clinical Trial Description, 2020 89 Table 36: Auto CD34+ cells, Clinical Trial Description, 2020 91 Table 37: Generx, Clinical Trial Description, 2020 96 Table 38: XC001, Clinical Trial Description, 2020 100 Table 39: 7 Major Market Size of RA in USD Million (2017–2030) 102 Table 40: The US Market size of RA in USD Million (2017–2030) 107 Table 41: The US market size of RA by Therapies in USD Million (2017–2030) 108 Healthcare Market Research DelveInsight Copyright

18. D e l v e I n s i g h t | P a g e | 17 17 Table 42: Germany Market size of RA in USD Million (2017–2030) 109 Table 43: Germany market size of RA by Therapies in USD Million (2017–2030) 110 Table 44: France Market size of RA in USD Million (2017–2030) 111 Table 45: France market size of RA by Therapies in USD Million (2017–2030) 112 Table 46: Italy Market size of RA in USD Million (2017–2030) 113 Table 47: Italy market size of RA by Therapies in USD Million (2017–2030) 114 Table 48: Spain Market size of RA in USD Million (2017–2030) 115 Table 49: Spain market size of RA by Therapies in USD Million (2017–2030) 116 Table 50: The UK Market size of RA in USD Million (2017–2030) 117 Table 51: The UK market size of RA by Therapies in USD Million (2017–2030) 118 Table 52: Japan Market size of RA in USD Million (2017–2030) 119 Table 53: Japan market size of RA by Therapies in USD Million (2017–2030) *The list of tables is not exhaustive *The list of tables is not exhaustive; will be ; will be provided in the final report 120 provided in the final report Healthcare Market Research DelveInsight Copyright

19. D e l v e I n s i g h t | P a g e | 18 18 List of Figures Figure 1: SWOT Analysis 5 Figure 2: Normal and Plaque Buildup Artery 14 Figure 3: Pictorial Representation of Different Types of Angina 16 Figure 4: Few of the causes of Chest Pain 18 Figure 5: Mechanisms and Pathways involved in Cardiac Chest Pain 20 Figure 6: The Heart-Brain Axis Model of Angina Physiopathology and Related Therapeutic Targets 22 Figure 7: Diagnosis of Chest Pain Symptoms according to Anginal Symptoms 24 Figure 8: Diagnostic Interventions 25 Figure 9: Definite Diagnosis 26 Figure 10: Total Prevalent Patient Population of RA in 7MM (2017–2030) 28 Figure 11: Diagnosed Population of CAD and RA in the United States (2017–2030) 32 Figure 12: Sub-type Specific Prevalence of RA in the United States (2017–2030) 33 Figure 13: Gender specific Prevalence of RA in the United States (2017–2030) 34 Figure 14: Diagnosed Population of NORDA in the US (2017–2030) 35 Figure 15: Diagnosed Population of CAD and RA in Germany (2017–2030) 36 Figure 16: Sub-type Specific Prevalence of RA in Germany (2017–2030) 37 Figure 17: Gender specific Prevalence of RA in Germany (2017–2030) 38 Figure 18: Diagnosed Population of NORDA in Germany (2017–2030) 39 Figure 19: Diagnosed Population of CAD and RA in France (2017–2030) 40 Figure 20: Sub-type Specific Prevalence of RA in France (2017–2030) 41 Figure 21: Gender specific Prevalence of RA in France (2017–2030) 42 Figure 22: Diagnosed Population of NORDA in France (2017–2030) 43 Figure 23: Diagnosed Population of CAD and RA in Italy (2017–2030) 44 Figure 24: Sub-type Specific Prevalence of RA in Italy (2017–2030) 45 Figure 25: Gender specific Prevalence of RA in Italy (2017–2030) 46 Figure 26: Diagnosed Population of NORDA in Italy (2017–2030) 47 Figure 27: Diagnosed Population of CAD and RA in Spain (2017–2030) 48 Figure 28: Sub-type Specific Prevalence of RA in Spain (2017–2030) 49 Figure 29: Gender specific Prevalence of RA in Spain (2017–2030) 50 Figure 30: Diagnosed Population of NORDA in Spain (2017–2030) 51 Figure 31: Diagnosed Population of CAD and RA in the UK (2017–2030) 52 Figure 32: Sub-type Specific Prevalence of RA in the UK (2017–2030) 53 Figure 33: Gender specific Prevalence of RA in the United Kingdom (2017–2030) 54 Figure 34: Diagnosed Population of NORDA in the UK (2017–2030) 55 Figure 35: Diagnosed Population of CAD and RA in Japan (2017–2030) 56 Figure 36: Sub-type Specific Prevalence of RA in Japan (2017–2030) 57 Figure 37: Gender specific Prevalence of RA in Japan (2017–2030) 58 Figure 38: Diagnosed Population of NORDA in Japan (2017–2030) 59 Figure 39: Treatments Addressing Myocardial Perfusion 60 Figure 40: Treatments Addressing Neural Processing 61 Figure 41: Treatment Landscape of Refractory Angina 61 Figure 42: Possible Combinations of Anti-anginal Drugs 65 Healthcare Market Research DelveInsight Copyright

20. D e l v e I n s i g h t | P a g e | 19 19 Figure 43: Technique of enhanced external counterpulsation 66 Figure 44: Possible mechanisms responsible for the clinical benefit associated with EECP therapy 67 Figure 45: Pictorial Representation of Neuromodulation Targets 69 Figure 46: Pictorial Representation of Coronary Sinus Reducer 72 Figure 47: Clinical Assessment of Angina 73 Figure 48: Clinical assessment and the typicality of anginal pain 76 Figure 49: Unmet Needs of RA 82 Figure 50: 7 Major Market Size of RA in USD Million (2017–2030) 102 Figure 51: Market Size of RA in the United States, USD Millions (2017–2030) 107 Figure 52: The U.S. market size of RA by therapies in USD Million (2017–2030) 108 Figure 53: Market Size of RA in Germany, USD Millions (2017–2030) 109 Figure 54: Germany market size of RA by therapies in USD Million (2017–2030) 110 Figure 55: Market Size of RA in France, USD Millions (2017–2030) 111 Figure 56: France market size of RA by therapies in USD Million (2017–2030) 112 Figure 57: Market Size of RA in Italy, USD Millions (2017–2030) 113 Figure 58: Italy market size of RA by therapies in USD Million (2017–2030) 114 Figure 59: Market Size of RA in Spain, USD Millions (2017–2030) 115 Figure 60: Spain market size of RA by therapies in USD Million (2017–2030) 116 Figure 61: Market Size of RA in the UK, USD Millions (2017–2030) 117 Figure 62: The UK market size of RA by therapies in USD Million (2017–2030) 118 Figure 63: Market Size of RA in Japan, USD Millions (2017–2030) 119 Figure 64: Japan market size of RA by therapies in USD Million (2017–2030) 120 Figure 65: Market Drivers 121 Figure 66:Market Barriers *The list of figures is not exhaustive *The list of figures is not exhaustive; will be provided in the final report 123 ; will be provided in the final report Healthcare Market Research DelveInsight Copyright

21. D e l v e I n s i g h t | P a g e | 20 20 Appendix Report Methodology Report Methodology Epidemiology Segmentation Methodology Epidemiology Segmentation Methodology Country/Regional Country/Regional population population Model Flow Model Flow Prevalence rate Prevalence rate Sub-segmented by Prevalent pool Prevalent pool Gender, diagnosed patients CAD and RA, NORDA etc. Diagnosis rate Diagnosis rate Patient pool Patient pool Diagnosed patient pool Diagnosed patient pool Current Treatment Therapies: Current Treatment Therapies: • Approved Therapies Approved Therapies • Beta-blockers • Calcium-channel blockers • Others • Supportive Therapies Supportive Therapies Treatment rate Treatment rate Treated Cases Treated Cases Focused group patient pool Focused group patient pool Existing market Existing market Treatment eligible or Treatment eligible or potential patient pool potential patient pool Uptake / Patient Uptake / Patient share share Pipeline product share: Pipeline product share: - IMB IMB- -101 - Generx Generx - Auto CD34 Auto CD34+ + cells 101 ACoT, compliance rate, ACoT, compliance rate, market access and market access and reimbursement reimbursement cells Conversion factors Conversion factors • ACoT ACoT • Compliance rate Compliance rate • Market access and Market access and Reimbursement Reimbursement Revenue Revenue estimation estimation Revenue by Revenue by therapies therapies MARKET SIZE MARKET SIZE Healthcare Market Research DelveInsight Copyright

22. D e l v e I n s i g h t | P a g e | 21 21 DelveInsight is a premier source for pharmaceutical and biotechnology sector analysis, delivering exclusive, trusted commercial insight into industry performance through its proprietary platform. DelveInsight’s reports are continuously updated and revised. The following research methodology is followed for all databases and reports. Coverage Coverage The objective of updating DelveInsight coverage is to ensure that it represents the most up-to-date vision of the industry possible. The DelveInsight is a fully integrated solution for comprehensive intelligence on various pharmaceutical products, both in the market and in the pipeline, across the globe. Research Design Research Design Secondary Research Secondary Research The secondary research on internal and external sources is being carried out to source qualitative and quantitative information relating to each market. The secondary research sources that are typically referred to include, but are not limited to: •Company websites, annual reports, financial reports, broker reports, investor presentations, and SEC Filings Industry trade journals and other literature. •Internal and external proprietary databases. •National government documents, statistical databases, and market reports. •News articles, press releases, and web-casts specific to the companies operating in the market. Primary Research Primary Research DelveInsight conducts primary research by interacting with the healthcare professionals, doctors, industry’s experts, and industry participants and commentators in order to validate its data and analysis. The discussion provides first-hand information on the market size, market trends, growth trends, competitive landscape, and future outlook, for example. •It helps in validating and strengthening the secondary research findings. •It further develops the Analysis Team’s expertise and market understanding. •An interactive one-stop, fully integrated business intelligence (BI) platform, catering the need of the global pharmaceuticals market, across all the value chains. •The comprehensive integration allows for the seamless comparison of the market dynamics, helps strategic planning, and decision making to stay competitive in the global pharmaceuticals industry. •We help our clients to find answers relevant to business decision-making, including potential market opportunities, competitor assessments, and business environmental dynamics enhances companies to plan development, trials or process-based research on their competitor focus. Healthcare Market Research DelveInsight Copyright

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26. D e l v e I n s i g h t | P a g e | 25 25 REPORT PRICE Refractory Angina (RA) Refractory Angina (RA) 30 Market Insights, Epidemiology, and Market Forecast Market Insights, Epidemiology, and Market Forecast— —20 2030 USD 6,950 Single User License USD 10,450 2-3 Users License USD 13,900 Site License USD 20,850 Corporate License Healthcare Market Research DelveInsight Copyright