Strictly private and confidential Taking Innovations to the

Strictly private and confidential Taking Innovations to the Market – A Scientist’s Journey A V RAMA RAO Avra Laboratories Pvt. Ltd. Hyderabad, INDIA Golden Jubilee Celebrations of “Indian Drugs” Mumbai Saturday, 8 th March, 2014 1

Strictly private and confidential The need for Self Reliance • After independence, to manufacture any new drug was not possible because of prevailing system of product patents. • The Indian consumer was denied the use of several life saving drugs which were launched internationally. • Beecham introduced the semi-synthetic penicillin, Ampicillin in Europe in the early 60’s. They were unwilling to market this drug in India except on terms and conditions which were not acceptable to Indian government. • Same was also the case with the Cardiac Drug, Propranolol, introduced by ICI internationally in the mid 60 s. 2

Strictly private and confidential Indian Patent System Indian Industry fought to amend the 1911 Patent Act, resulting in the enactment of Indian Patent Act 1970, passed in September 1972. “All product patents for Drugs and Agricultural chemicals were abolished and only process patents were allowed for a period of 7 years from the date of filling or 5 years from the date of acceptance, which ever is earlier” It was a dawn of a golden age of the Indigenous Pharma Industry. 3

Strictly private and confidential Production of Diazepam Original process of HOFFMAN-LA-ROCHE: (USP. 3109843, dated 5 -11 -1963) NCL Process: Commercialized by Cipla in 1973 4

Extraction of Natural Products Strictly private and confidential Vinca Alkaloids (Vinblastine and Vincristine) VINBLASTINE: R=Me VINCRISTINE: R=CHO 5

Strictly private and confidential Ibuprofen (Anti Inflammatory, Anti Rheumatic) BOOTS Process (GB 971 700: 2. 2. 1961): Cheminor’s Approach: 6

Strictly private and confidential Vitamin B 6: NCL Process • Initiated in 1959; prevailing price $ 460/kg aimed to bring down to $ 350/kg • Based on original Folkers Route; 12 steps synthesis carried out on Pilot Scale. Completed in 1963 - Vitamine B 6 price dropped to $ 80/kg in 1960. • New Chemical Synthesis: (Kondratyers of USSR) Merck Process: NCL approach (1965 - 73) 1960, Price $80/kg 1965, Price $55/kg 1970, Price $30/kg Project failed - RM price was higher than the prevailing market price 7

Vitamin B 6: NCL Process 1980 -83 Strictly private and confidential (Based on Roche approach) Technology was implemented by Lupin in 1985 8

Strictly private and confidential AIDS and HIV AIDS (Acquired Immunodeficiency Syndrome), is caused by infection with Human Immunodeficiency Virus (HIV). Twenty years ago, an AID Diagnosis was equivalent to a death sentence. The introduction of AZT, First AIDS drug in 1987 offered hope. In 1985, Scientists at National Cancer Institute found that AZT, a molecule first synthesized in 1964 prevented HIV from multiplying in cultured human cells. US FDA approved AZT for use against AIDS in early 1987 and Burroughs Wellcome began marketing the drug under the trade name “RITROVIR”. The initial cost of AZT (A years supply) costs ~10, 000 USD per patient. Most of the under developed countries con’t afford. 9

Strictly private and confidential AZT Production of AZT Rama Rao's approach: J. C. S. Chem. Commun. , 1994, 1255 US Patent No. 5596087 (Jan 1997) 10

HIV/AIDS Drugs: Indian Contribution • HIV virus has already affected over 45 million people world over in the last 2½ decades. • It is estimated by the United Nations that 80 to 90 million Africans alone will die of AIDs by 2025 • In India HIV infected population may be more than 25 million by 2020 • Cipla marketed AZT in India in 1995 at a price of 30 cents/tablet 11 Strictly private and confidential

HIV Drugs: at Affordable Price • HIV was and is an Epidemic in South Africa. In 2001, the cost of Anti-Retroviral Drugs (ARVs) range between $ 12, 000 to 15, 000 USD per patient per year. • In that year South Africa allowed generic production of ARVs for treating HIV patients, despite the fact they were covered by patents and 40 MNCs bought litigation against South Africa for its act. • At that time Cipla offered to make them available at $ 300 per patient per year (~ 1/40 th cost) • After massive international protests in favour of public health rights, the Governments of several developed countries backed the South Africa and the case was dropped in April that year. 12 Strictly private and confidential

Strictly private and confidential New Policy Challenges of U. S. Pharma Companies • Patients with HIV / AIDS, breast cancer and other diseases protested drug prices for life saving therapies and wanted speed in regulatory reviews. • They also confronted firms about their pricing policies. These have resulted in promolgumation of “Orphan Drug Act” of 1983 and new regulations that speed regulatory approval of drugs in 1990’s, especially that those of life saving drugs such as HIV/AIDS and Cancer. • In 1984 “Drug Price Competition and Patent Terms Restorative Act” (Hatch. Waxman) authorized US FDA to approve generics without additional preclinical or clinical testing. • This has resulted in initiating generic business by large firms. They also purchased generic firms to expand their international business. • Further, developing countries such as India and China took advantage of Hatch. Waxman act and made their appearance globally by offering generic drugs at much cheaper price compared to U. S. and European companies. 13

Strictly private and confidential Indian Drug Industry – Post 1972 Patent Era • In 1972, multinational companies controlled 70% of the domestic pharmaceutical market. • Of the leading 50 pharma companies, 33 were foreign • Now, the national sector occupies the leading position with 38 Indian companies in the top 50 and controlling 80% of the market. • From Rs. 10 crores in 1947 and Rs. 360 crores in 1972, it has crossed 100, 000 crores (~1. 2% of the world pharma market) • Pharma exports crossed Rs. 60, 000 crores as against Rs. 200 crores in 1972. • All this was possible due to the efforts of the indigenous pharma companies • Indian companies built up an enviable reputation for producing good quality drugs at affordable prices. 4

Active Pharmaceutical Ingredients (APIs) Strictly private and confidential • The present API market in the world: $ 113 Billion. • It is very competitive as there are more than 2000 firms and they have 5000 manufacturing sites. • Cipla is one of the first companies to fully develop and manufacture APIs and laid foundation for the pharmaceutical industry. In India they manufacture 200 generic API and reaching more than 170 countries world wide. • Dr. Reddy’s is another leading API manufacturer (60 APIs). • Ranbaxy produces 100 APIs and present in 65 countries. • Aurobindo manufacture 200 APIs and exporting to 200 countries. • Sun Pharma manufacture 200 APIs at nine different places located in Hungary, Israel and the U. S. 15

Strictly private and confidential Avra Laboratories Pvt. Ltd. , Founded on 15 th August, 1995. Mainly devoted to R&D Projects, Custom Synthesis & Manufacture 16

Strictly private and confidential G. D. Searle Project A case study for eliminating toxic substances UREA DERIVATIVES (Anti Thrombiotic Agents) US Patent: 5484946 (1996) Filed June 1995 (Avra's first project: initiated in 1996) 17

Strictly private and confidential Avra Laboratories Pvt. Ltd. , Unit-1 (2000) R&D Centre, Nacharam, Hyderabad 18 Pilot plant

Strictly private and confidential RU 486 (Mifepristone): For medical abortion (Avra’s First Commercial Product) Sune Bergström • RU 486 is a synthetic steroid used as an abortifacient in the first two months of pregnancy and in small doses as an emergency contraceptive. • The drug was initially made available in France and other countries followed – often amid controversy • RU 486 was discovered as a progesterone receptor antagonist. • US FDA approved in 28 th September, 2000. • Avra commercialised RU 486 in 2003 and exclusively supplied to Zydus Cadila formulating and marketing in India. 19

Strictly private and confidential Avra Laboratories Pvt. Ltd. , Unit-2 (2005) Nacharam, Hyderabad Fine Chemical Block 20

Camptothecin and its Analogs Strictly private and confidential Irinotecan [CPT-(II)] (Trade name: Camptosar) • Irinotecan is one of a number of analoges developed to circumvent the undesired properties of CPT - (I) • Irinotecan functions as the soluble prodrug for the active metabolite SN - 38. 21

Strictly private and confidential Synthesis of Irinotecan from Camptothecin CPT - (I) 7 -Ethyl Camptothecin IRINOTECAN yield 20% from CPT-(I) SN-38 SAWADA. et. al. , Chem. Pharm: Bull. 1991, 1446. 22

Avra’s Final Synthesis of Irinotecan and Strictly private and confidential its Key Intermediates AHPP S-Trione SN-38 Irinotecan 23

Strictly private and confidential Avra Laboratories Pvt. Ltd. , Unit-3 (2010), Visakhapatnam 24

Strictly private and confidential Indian Patent Act – 2005 • India joined WTO and accepted TRIPS Mandate • Indian Patent Act 2005 was passed through an ordinance effective from 1 st January 2005 • Product Patents allowed for all sectors • Patentability of Inventions • Licenses of Right Deleted • Micro organisms to be made patentable • Compulsory licenses for domestic use as well for export against third party licenses • Pre and Post-Grant opposition provisions included 25

Strictly private and confidential Post 2005 I. P. Issues 1. Drugs with Incremental changes not worthy of exclusive rights. Ex: Indian supreme court did not permit the validity of patent of Novatis Anti-Cancer drug, “GLIVEC” (Imatinib) as it has improved version and not a new invention. However this drug received patents in 38 countries. 2. Compulsory licensing for Anti-Cancer Drugs: India issued its first compulsory licensing in March 2012, when Natco Pharma won the right to manufacture Bayer AG’s Anti-Cancer Drug, “NEXAVAR”. Recently Inida’s health ministry recommended for compulsory licensing of three anti cancer drugs. Trastuzumab (Breast cancer), Ixabepilone and Dasatinib (Leukamia). If this is accepted, these products will be available at a fraction of original price. 26

Strictly private and confidential Health Benefit for All • Japan’s Eisai Pharma is expected to launch in India, its novel anti-cancer drug Eribulin, sold under the brand name of Halaven. It is used in the treatment of third line metastatic Breast Cancer. • The company has divided patients in to three catagories: a) The lower income group will get the drug free. b) The middle income patients will be eligible for discount on the full price. c) The rich patients will be asked to pay full price. • India’s Oncology market is estimated to be close to Rs. 700 crores and growing at 20%. It is estimated to touch Rs. 3000 crores by 2017. 27

Tuberculosis (T. B. ) – Major Killer in India Strictly private and confidential • WHO Global T. B. report of 2012 indicates that T. B. kills one person every two minutes in India and 750 people every day. • It is a very serious disease and annually ~ 3, 30, 000 Indian die due to the T. B. • In the world, an estimated 8. 6 million people developed T. B. 1. 3 million died. • Dr. Wadia (Hinduja Hospital) was the first to describe totally drug resistant T. B. from India, building up to a new sense of urgency. • India is the World’s largest T. B. drugs producing countries and marketing. All the four major drugs (Etambutol, Rifampicin, INH, Pyrazinamide) are manufactured by Lupin (Mumbai). • No new T. B. drug was developed for almost four decades after discovery of Rifampicin. • Recently Johnson & Johnson discovered, Bedaquiline (US FDA Approved) for MDR T. B. Drug. 28 Bedaquiline

Strictly private and confidential Malaria: Major Threat to Developing Countries • As per the World Health Organisation, 219 Million cases of Malaria were reported, resulting in about 800, 000 deaths. 90% of which occurred in Africa. This is the main cause of death for children under five, claiming every 45 seconds. • Although Malaria is preventable and treatable, life saving drugs do not always reach the patients. • Ranbaxy had launched the country’s first indigenously developed Anti-Malarial Drug Synriam against Plasmodium Vivax, a strain responsible for almost half of Malaria infections in the World. • Synriam (3 tablets Rs. 130/- is a three day course) - It is a mixture of Arterolane Maleate and Piperaquine Phosphate. 29 Synriam and

Strictly private and confidential Affordable and Convenient Treatment for Patients (Cardiovascular Disease) Ex: Polypill: New concept development by DRL, Hyderabad. • Polypill contains Aspirin, Cholesterol lowering and Blood Pressure lowering drugs. • The recent study involving a 1000 patients from India and a 1000 from Europe (UK, Ireland Netherlands) were randomly assigned either the Polypill or their normal combination of Medicines. • The Polypill group had lower Blood Pressure and Cholesterol measurements. • Heart disease is a leading cause of premature death and disability in India and is growing at Epidemic proportions. • The Late Dr. Anji Reddy was keen to provide an affordable convenient treatment package to patients in India and elsewhere. 30

Strictly private and confidential Indian Pharmaceutical Industry – Current Status • It ranks 3 rd in terms of volume of products with 10% global share and 14 th largest by value (1. 5%). This is because drug prices are lower in India to the extent of 25 -50% compared to developed countries • The country has more then 100 manufacturing facilities approved by US FDA. The US FDA official figures indicate that 6300 active Drug Master Files (DMFs) with the regulatory body, of which 26% or 1, 700 are from Indian companies • The country has also a major share in the Abbreviated New Drug applications (ANDS) filled with US FDA for marketing generic products • Indian API manufacturing industry moves forward (average growth of 19% during the last 5 years) to meet the world’s need for high quality products at competitive prices. 31

Strictly private and confidential How Indian Economy Changed 1971 – Socialist India 2011 – A Flourishing market economy GDP: (Rs. Lakh Crores) Per Capita Income: (at constant prices) Forex Reserves: Exports: FDI Number of Passenger cars Pay Cheques: (Cabinet secretary’s monthly salary) 1970 -1971 Rs. 4. 7 Rs. 8, 091 $ 0. 97 bn $ 2. 1 bn 36, 032 Rs. 4, 000 1990 -1991 Rs. 10. 8 Rs. 11, 535 5. 8 18. 0 $ 0. 13 bn 0. 18 mn Rs. 30, 000 32 2010 -2011 Rs. 48. 8 Rs. 41, 129 274. 0 254. 0 30. 3 2. 9 mn Rs. 90, 000

Strictly private and confidential Life Expectancy at Birth India 1950 2000 2010 40 years 61 65 60 63 62 66 66 68 Indian Men Indian Women World Wide • Today India has nearly 117 Million people over 60 years • This is because of amazing progress in Medical & Biological Research • Major challenges are: New life style aliments such as Heart diseases, Hypertension, Cancers and Diabetes. These are major cause of all deaths by 2030 (75%) 33

Strictly private and confidential “Surely, Science is not merely an individual’s search for truth. It is something infinitely more than that……. It must have a social objective before it. ” Pandit Jawaharlal Nehru (1947) “My idea of better ordered world is one in which medical discoveries would be free of patents and there would no profiteering from Life or Death” Indira Gandhi At WHO, Geneva, 1981 34

Strictly private and confidential Acknowledgement Council of Scientific and Industrial Research All the three DG’s of CSIR (1985 – 95) And three directors of NCL (1960 – 85) All My Ph. D. Students and Colleagues From NCL & IICT K Venkataraman E J Corey Former Director, National Chemical Laboratory Professor of Chemistry Harvard University, USA 1990 Nobel Prize for Chemistry Dr. Y. K. Hamied Chairman, Cipla Limited 35