Strictly private and confidential Taking Innovations to the Market – A Scientist’s Journey 1 Avra Laboratories Pvt. Ltd. Hyderabad, INDIA Golden Jubilee

Strictly private and confidential

Taking Innovations to the Market – A Scientist’s Journey

1

Avra Laboratories Pvt. Ltd.

Hyderabad, INDIA

Golden Jubilee Celebrations of “Indian Drugs”Mumbai

Saturday, 8th March, 2014

A V RAMA RAO


The need for Self Reliance

2

• 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 60s.


Indian Patent System

3

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.


Production of Diazepam

Commercialized by Cipla in 1973

Original process of HOFFMAN-LA-ROCHE: (USP. 3109843, dated 5-11-1963)

NCL Process:

1. BzCl

ZnCl2,2.Hydrolysis

Cl

HN SO2 CH3

O

MeI

Base, HydrolysisCl

NH

Me

O1. ClCH2COCl

2. HexamineN

NMe

O

DIAZEPAM

PTS - Cl

Base

NO2

Cl

PhCH2CN

NaOH

ON

Fe,HCl

NH

O

Me

DIAZEPAM

Me2SO4

Cl

N

NMe

O

Cl

( 40% )

Cl

Cl

NH2Cl

NH2

O

4


Extraction of Natural Products

Vinca Alkaloids

5

(Vinblastine and Vincristine)

Avra

VINBLASTINE: R=Me

VINCRISTINE: R=CHO

N

NH

N

OH

CH3

N

H

O

CH3CH3

OOCH3O

O

CH3

OOCH3

HHO

H

R


Ibuprofen

6

BOOTS Process (GB 971 700:2.2.1961):

(Anti Inflammatory, Anti Rheumatic)

Cheminor’s Approach:

CH3COCl

AlCl3

O

Cl CH2CO2Et

NaOEt,EtOH

OH3C1.NaOH

2. H

CH3

CHO

NH2OH 1/2 H2SO4

CH3

NOH

CH3

CN NaOH

CH3

CO2H

O

CH3

H2,Raney-Ni

CH3

OH SOCl2

CH3

Cl

NaCN

( B ) ( C )

( D )

( A )( B )

O

OEt


Vitamin B6: NCL Process

7

N

OX O

O

ON

X

HO

CO2H

CO2H

CH3H2N

CO2H

EtOH

HCl

CH3H2N

CO2Et.HCl

H2N CHO CH3

HN

CO2Et

OHC

P2o5

O

N CH3

OEt

O

O

N

CH2OH

H3C

HO

CH2OH

.HCl1. 180 °C2. HCl

Substituted Pyridines

• 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)

1960, Price $80/kg1965, Price $55/kg1970, Price $30/kg

Project failed - RM price was higher than the prevailing market price

Merck Process: NCL approach (1965 - 73)


Vitamin B6: NCL Process 1980-83

8

(Based on Roche approach)

SO2Cl2 H2N CHO

O

NCH3

CO2Et

NH3 O

NCH3

CO2NH2

P2O5 O

NCH3

CN

O

O

180 °CN

OO

HO

H3C

HCl

N

CH2OH

HO

H3C

CH2OH

.HCl

CH3COCHClCO2EtCH3COCH2CO2Et

Technology was implemented by Lupin in 1985


AIDS and HIV

9

HN

N

O

OO

N3

HO

AZT

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.


10

Avra

O

HO OH

HO

N

HN

O

O

O

HO

HO

N

N

O

OO

HO

HO

N

HN

O

O1. PhOCO2Ph2. NaHCO3

3. DMF

1. Br2

2. H2, Pd/C

HN

N

O

OO

N3

HO

1. LiN32. H+

O

HO

HO

N

N

O

O

1. PhOCO2Ph2. NaHCO3

3. DMF, 150o CO

OH

HO OH

N

HN

O

O 1. Ac2O, Py

2. HBr OAcO

N

HN

O

O

OAc

Beta-Thymidine

1. Raney Ni, H22. NaOMe, MeOH

AZT

Br

J. C. S. Chem. Commun., 1994, 1255US Patent No. 5596087 (Jan 1997)

Production of AZT

AZT

Rama Rao's approach:


HIV/AIDS Drugs: Indian Contribution

11

• 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


HIV Drugs: at Affordable Price

12

• 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.


New Policy Challenges of U.S. Pharma Companies

13

• 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.


Indian Drug Industry – Post 1972 Patent Era

4

• 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.


Active Pharmaceutical Ingredients (APIs)

15

• 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.


Avra Laboratories Pvt. Ltd.,

Founded on 15th August, 1995.Mainly devoted to R&D Projects, Custom Synthesis & Manufacture

16


(Avra's first project: initiated in 1996)

N

CN

NH2

O

N-(4-Cyanophenyl)-3(S)-aminopyrrolidone

UREA DERIVATIVES

(Anti Thrombiotic Agents)US Patent: 5484946 (1996)

Filed June 1995

A case study for eliminating toxic substances

G.D. Searle Project

17



18

Unit-1 (2000) Pilot plant

R&D Centre, Nacharam, Hyderabad


RU 486 (Mifepristone):

19

For medical abortion (Avra’s First Commercial Product)

• 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.

O

H

Me OH

H

RU-486

Me2N

Sune Bergström



20

Unit-2 (2005)Nacharam, Hyderabad

Fine Chemical Block


Camptothecin and its Analogs

21

• 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.

Irinotecan [CPT-(II)](Trade name: Camptosar)

N O

NO

O

OHO

AB

C D E

NO

N


Synthesis of Irinotecan from Camptothecin

22

SAWADA.et.al., Chem. Pharm: Bull. 1991, 1446.

H2O2, FeSO4

C2H5CHOaq.H2SO4 (70%)

N

N

O

O

OHO

1. H2O2, AcOH

2. hv, dioxane, H2SO4 N

N

O

O

OHO

HO

N N COCl

Pyridine (~ 40%)

N

ON

O

OHO

A BC

DE

CamptothecinCPT - (I)

7-Ethyl Camptothecin

SN-38

IRINOTECAN

yield 20% from CPT-(I)


Avra’s Final Synthesis of Irinotecan and

its Key Intermediates

23

N O

NO

O

OHO

AB

C D E

NO

N

N

N O

O

OHO

HO

HO

NH2

ON O

O

O

OOH

AHPP S-Trione SN-38

Irinotecan



24

Unit-3 (2010), Visakhapatnam


Indian Patent Act – 2005

25

• 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


Post 2005 I.P. Issues

26

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.


Health Benefit for All

27

• 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.


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

28

• 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.

O

NOH

N

Br

• 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. 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 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.

Synriam

and


Affordable and Convenient Treatment for Patients

(Cardiovascular Disease)

30

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

Avra

• It ranks 3rd 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.

Indian Pharmaceutical Industry – Current Status


32

How Indian Economy Changed

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 secretary’s monthly salary)

Rs.4,000

Rs.30,000

Rs.90,000

1971 – Socialist India2011 – A Flourishing market economy


33

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%)

Life Expectancy at Birth


34

“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 GandhiAt WHO, Geneva, 1981

“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)


35

K VenkataramanFormer Director,

National Chemical Laboratory

E J CoreyProfessor of ChemistryHarvard University, USA

1990 Nobel Prize for Chemistry

Dr. Y. K. HamiedChairman, Cipla Limited

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 ColleaguesFrom NCL & IICT

Documents

Strictly private and confidential Taking Innovations to the Market – A Scientist’s Journey 1 Avra Laboratories Pvt. Ltd. Hyderabad, INDIA Golden Jubilee