UAEM Introductory Seminars Neglected Diseases and the Research

UAEM Introductory Seminars Neglected Diseases and the Research Gap October 17, 2009

Canadian Patient: High Blood Pressure (Hypertension) Treatment Options • 50+ Cost • $20 -100/year Availability • High (need prescription) Side Effects Low blood pressure (dizziness, lightheadedness, headache, change in vision, and fatigue)

Alpha Blockers / Inhibitors Cardura (Doxazosin)Catapres (Clonidine)Dibenzyline (Phenoxybenzamine)Hytrin (Terazosin)Micardis (Telmisartan)Minipress, Minizide (Prazosin) Beta Blockers Blocadren, Timolide (Timolol)Cartrol (Carteolol)Cibenzyline (Phenoxybenzamine)Coreg (Carvedilol)Corgard, Corzide (Nadolol)Inderal, Inderide, Innopran (Propranolol)Kerlone (Betaxolol)Levatol (Penbutolol)Lopressor, Toprol (Metoprolol)Normodyne, Trandate (Labetalol)Sectral (Acebutolol)Tenormin, Tenoretic (Atenolol)Visken (Pindolol)Zebeta, Ziac (Bisoprolol) Calcium Channel Blockers Adalat, Procardia (Nifedipine)Caduet (Amlodipine Besylate + Atorvastatin Calcium)Cardizem, Dilacor, Tiazac (Diltiazem)Cardene (Nicardipine)Calan, Covera, Isoptin, Veralan, Tarka (Verapamil)Dyna. Circ (Isradipine)Norvasc, Lotrel (Amlodipine)Plendil, Lexxel (Felodipine)Posicor (Mibefradil)Sular (Nisoldipine) Angiotensin Converting Enzyme (ACE) Inhibitors Aceon (Perindopril Erbumine)Accupril (Quinapril)Altace (Ramipril)Capoten, Capozide (Captopril)Lotensin (Benazepril)Mavik (Trandolapril)Monopril (Fosinopril)Prinivil, Prinzide, Zestril, Zestoretic (Lisinopril)Univasc, Unitrec (Moexipril)Vasotec, Vaseretic (Enalapril) Angiotensin II Receptor Antagonists Atacand (Candesartan)Avapro, Avalide (Irbesartan)Benicar (Olmesartan Medoxomil)Benicar HCT (Olmesartan Medoxomil + Hydrochlorothiazide)Cozaar, Hyzaar (Losartan)Diovan (Valsartan)Micardis (Telmisartan) Diuretics Aldactone, Aldactazide (Spironolactone)Bumex (Bumetanide)Camadex, Demadex (Torsemide)Diuril, Hydrochlorothiazide, HCTZ, Hydrodiuril, Oretic, Enduron (Thiazides)Dyazide, Maxzide, Moduretic (Combinations)Dyrenium (Triamterene)Lasix (Furosemide)Lozol (Indapamide)Mykrox (Metolazone)Zaroxolyn, Mykrox (Metolazone) More than 50!!!

South Asian Patient: • Leishmaniasis • Treatment Options • 5 • Cost • $50 -500/treatment of 20 -30 days • Side Effects • Toxicities to major organs (renal, hepatic, cardiac, pancreatic) • GI problems, fever, fatigue, rash, hypo/hypertension, Diabetes Mellitus • Availability • Due to limited health care access and funding

Paromomycin Interferon-gamma-1 b Pentamidine Only 5!!! Sodium antimony gluconate Amphotericin B

Question: Why is the treatment so different for these two diseases? Answer: It’s all about the pipeline… the drug pipeline

1. Discovery: - basic research - discover therapeutic targets - possible candidate molecules 2. Development: - formulation - assessment via clinical trial($$$) - mass production processes 3. Delivery: Time: 8 - 15 years - registration manufacturing sale distribution Cost: $200 million - $1 billion Pecoul, PLo. S Med. 2004

1. Discovery: - Produces useful knowledge, but not marketable technologies - Requires creativity and relatively modest investment - Carried out by academic researchers with grants from governments/charities 2. Development: - Produces marketable technologies - Requires big investments: testing is expensive and most candidates will fail - Carried out by private biotech and pharmaceutical industries who expect to make a profit 3. Delivery: - Requires infrastructure -Relatively inexpensive compared to drug development - Problems with intellectual property (patents) - Also carried out by mainly by industry, for profit

Cancer Cardiovascular disease HIV/AIDS TB Malaria Tropical diseases

Cancer Cardiovascular disease HIV/AIDS TB Malaria Tropical diseases

Advocacy groups/charities Government Patients Industry

Advocacy groups/charities Industry Government Patients

10/90 Gap • 10% of Total funding for R&D • Poorest 90% of the world’s population’s health problems • Needs present – but no resources available • Disconnect with needs and invested interest What former MSF-USA director Nicolas De Torrente called "a fundamental mismatch, expressed as millions of lives lost each year, between human needs and scientific innovation. "

Neglected Diseases Limited or no basic health care Life-long disabilities Many cause mortality Economic and social costs A neglected disease… Predominantly affects people who are too poor to constitute a market attractive to R&D investment

Malaria Major health burden: 250, 000 cases and 900, 000 deaths/year, mostly children Major economic burden: reduced African GNP by 50% from 1965 to 1990

Malaria • Present in more than 100 countries and threatens half of the world’s population • Widespread resistance to old treatments • Only one major new class of drugs in last decade (artemisinin derivatives) – • Difficult to synthesize; frequent shortages No vaccine

Malaria

Tuberculosis 2, 000, 000 people (1 in 3 worldwide) are currently infected – mostly dormant #1 killer of HIV/AIDS patients worldwide Curative therapy requires months or years to complete Drug resistance is a major problem – XDR-TB: virtually untreatable

Tuberculosis

Leishmaniasis A major parasitic killer on a worldwide scale Superficial infections cause disfiguring skin lesions, and destroy the mouth and nose (non-fatal), visceral infections damage organs and bone (fatal) Once clinical symptoms show, fatal within months if untreated TDR Poster 2001

Leishmaniasis Spread and fatality are correlated to environmental conditions, malnutrition, complex emergencies and large population movements Treatments are limited by the same factors, in addition: Difficult administration (IV, IM ) Lengthy treatment time (20 -30 d) Toxicity (cardiac, pancreatic, nephritic, hepatic, otic, GI, teratogenicity) Cost Resistance

Leishmaniasis

Onchocerciasis river blindness Parasitic worm Onchocerca volvulus invades the skin and eyes, causes lifelong blindness and lesions Affects the most fertile agricultural areas in tropical Africa

Onchocerciasis river blindness • – Only one treatment (ivermectin) Not curative, but controls the symptoms of infection and suppresses its spread – A single dose every 6 -12 months until asymptomatic – Manufacturer donates it for free and onchocerciasis has been eliminated from several African countries – However, resistance is beginning to emerge

Onchocerciasis river blindness

The neglected diseases The “big three”: HIV/AIDS Malaria Tuberculosis >6 million deaths annually 10% of global disease burden “Most neglected” diseases: Dengue fever Leishmaniasis Schistosomiasis African trypanosomiasis Chagas disease Trachoma Buruli ulcer Leprosy Yaws Lymphatic filariasis Onchocerciasis

Neglected needs Diagnostic tests Different populations Need for simple, easy to administer tests in areas with limited health care facilities Need for pediatric formulations of drugs Different settings Need for portability and heat-stability

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