Taking Innovations to the Market

1
Taking Innovations to the Market A Scientists
Journey
A V RAMA RAO
Avra Laboratories Pvt. Ltd. Hyderabad, INDIA
Golden Jubilee Celebrations of Indian
Drugs Mumbai Saturday, 8th March, 2014
2
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 60s. 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 60s.

3
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.
4
Production of Diazepam
Original process of HOFFMAN-LA-ROCHE (USP.
3109843, dated 5-11-1963)
NCL Process
Commercialized by Cipla in 1973
5
Extraction of Natural Products Vinca Alkaloids
(Vinblastine and Vincristine)
VINBLASTINE RMe VINCRISTINE RCHO
6
Ibuprofen
(Anti Inflammatory, Anti Rheumatic)
BOOTS Process (GB 971 7002.2.1961)
Cheminors Approach
7
Vitamin B6 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 B6 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
8
Vitamin B6 NCL Process 1980-83
(Based on Roche approach)
Technology was implemented by Lupin in 1985
9
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 cont afford.
10
AZT
Production of AZT
Rama Rao's approach
J. C. S. Chem. Commun., 1994, 1255 US Patent No.
5596087 (Jan 1997)
11
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

12
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 ( 1/40th 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.

13
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
  1990s, 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.

14
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.

15
Active Pharmaceutical Ingredients (APIs)

• 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. Reddys 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.

16
Avra Laboratories Pvt. Ltd., Founded on 15th
August, 1995.Mainly devoted to RD Projects,
Custom Synthesis Manufacture
17
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)
18
Avra Laboratories Pvt. Ltd.,
Pilot plant
Unit-1 (2000)
RD Centre, Nacharam, Hyderabad
19
RU 486 (Mifepristone)
For medical abortion (Avras 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 28th September, 2000.
• Avra commercialised RU 486 in 2003 and
  exclusively supplied to Zydus Cadila for
  formulating and marketing in India.

20
Avra Laboratories Pvt. Ltd.,
Unit-2 (2005) Nacharam, Hyderabad
Fine Chemical Block
21
Camptothecin and its Analogs
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.

22
Synthesis of Irinotecan from Camptothecin
Camptothecin CPT - (I)
7-Ethyl Camptothecin
IRINOTECAN yield 20 from CPT-(I)
SN-38
SAWADA.et.al., Chem. Pharm Bull. 1991, 1446.
23
Avras Final Synthesis of Irinotecan and its
Key Intermediates
AHPP
S-Trione
SN-38
Irinotecan
24
Avra Laboratories Pvt. Ltd.,
Unit-3 (2010), Visakhapatnam
25
Indian Patent Act 2005

• India joined WTO and accepted TRIPS Mandate
• Indian Patent Act 2005 was passed through an
  ordinance effective from 1st 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

26
Post 2005 I.P. Issues

• 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 AGs
  Anti-Cancer Drug, NEXAVAR.
• Recently Inidas 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.

27
Health Benefit for All

• Japans 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
• The lower income group will get the drug free.
• The middle income patients will be eligible for
  discount on the full price.
• The rich patients will be asked to pay full
  price.

• Indias 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.

28
Tuberculosis (T.B.) Major Killer in India

• 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 Worlds 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.

Bedaquiline
29
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 countrys 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.

Synriam
and
30
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 and
  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.

31

Indian Pharmaceutical Industry Current Status

• It ranks 3rd in terms of volume of products
  with 10 global share and 14th 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 worlds
  need for high quality products at
• competitive prices.

32
How Indian Economy Changed
1971 Socialist India 2011 A Flourishing
market economy
  1970-1971   1990-1991   2010-2011  
GDP (Rs. Lakh Crores)   Rs.4.7   Rs.10.8   Rs.48.8
Per Capita Income (at constant prices)   Rs.8,091   Rs.11,535   Rs.41,129
  Forex Reserves   0.97 bn   5.8   274.0
  Exports   2.1 bn   18.0   254.0
  FDI   -   0.13 bn   30.3
Number of Passenger cars   36,032   0.18 mn   2.9 mn
Pay Cheques (Cabinet secretarys monthly salary)   Rs.4,000   Rs.30,000   Rs.90,000
33
Life Expectancy at Birth
  1950 2000 2010
India 40 years 61 65
Indian Men   60 63
Indian Women   62 66
World Wide   66 68

• 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)

34
Surely, Science is not merely an individuals
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
35

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