Global Production, Regulatory, and Trade Environment

Joseph Fortunakjfortunak@howard.edujfortunak@Comcast.net

APIs and Finished Pharmaceutical Products (FPPs)

API Synthesis

N

N N

N

NH2

OH

N

N NH

N

NH2

28

R-propylene carbonate, (2)

KOH (10 mol%, DMF)

O O

O

29

HPA, 30

DESMP (4), THF, Mg(OtBu)2

not isolated

N

N N

N

NH2

OP OEt

O

OEt

TMSCl, NaBr, DMF

TsOP OEt

O

OEt

31

N

N N

N

NH2

OP OH

O

OH

321. CMIC (6), TEA, NMP

2. fumaric acid, 2-PrOH

N

N N

N

NH2

OP O

O

O

OO

O O

O

O

HOOCCOOH

TDF, 33PMPA

2

N

OOH

NH

OF

FO

O

OOH

CH3

several steps

N

OHOBn

OH

MeO2C

3

5 steps

4 OCH3

3 additional steps

N

OOH

NH

OF

FN

O

O

H1

Dolutegravir

17

OOEtEtO2C

18

OEtHO2C

19

OOEtOO

O

NH

F

F

20

OOEt

O

NH

F

F NH

OCH3

OCH3 21

OOEt

O

NH

F

F N

OCH3

OCH3

As per Scheme 4

12

N

OXRO2C

OX

DMF acetal

15

Dolutegravir

RO2C

13

OXRO2C

N

OMe

OMeCO2Me

MeO

OO

OMe

Amine

14

OXRO2C

NH

OMe

OMe

Base

X = Cl, OCH3, OBn

N

OXHOOC

OMe

OMeCO2Me

16

Dolutegravir61% over4 steps approximately 70% Y.

API and FPP pricingAPI FPP Pricing, US FPP Pricing , LMICs API pricing/kg,

India/ChinaGeneric API pricing PPPY or per treatment

Sofosbuvir $84,000 $200 - $650 $800 $27

Daclatasvir $63,000 $45 $850 $4.25

Tenofovir disoproxil fumarate (TDF)

$15,000 $66 $140 $15.40

Efavirenz $2,600 $48 $105 $24

Lamivudine (3TC) $42 $135 $15

TLE (TDF/3TC/EFV) $95 $95 $55

Imatinib $125,000 $140 <$40

Cyclophosphamide $27,000 $270 - $310 <$20

Cholic Acid $312,000 N/A $370/kg (MP Biomedical)

$33 - $57

0

100

200

300

400

500

600

700

800

900

2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

TDF$/kg

PMPA $/kg

0.00

100.00

200.00

300.00

400.00

500.00

600.00

700.00

800.00

900.00

2008 2009 2010 2011 2012 2013 2014 2015Year

TDF raw material Cost factors ($/kg TDF) vs. API pricing, 2008-2015

Adenine

R-PC

DESMP

Mg t-buOx

CMIC

Sum

Processing (3 steps)

Model total

Drug

(indication)

Dose Pricing/dose, US Pricing /dose,

LMICs

Cefuroxime

(anti-infective)

500 mg, 20

count

$1.815 - $2.15 $0.368

Atazanavir

(AIDS)

300 mg, 30

count

$29.74 - $52.77 $0.5213

Atenolol

(cardiovascular)

50 mg/30

count

$0.133 - $0.3787 $0.0059

Atorvastatin

(lipid-lowering)

20 mg/30

count

$0.3327 - $2.933 $0.0714

Representative pricing of medicines in the US versus median pricing in LMICs.

Full Disclosure

Universal access to HIV treatment is one of the greatest success stories in medicine (>17 million treated).This should be repeated for mass treatment of Hepatitis B, C, and Cancer - and more quickly

Impact of Global Access Campaigns Upon the Indian and

Chinese Pharma Industries

Priorities in LMICs?

Causes of Death: USA, 2014All Causes 2,626,418Cardiovascular Diseases 614,348Malignant Neoplasms 591,699Chronic Lower Respiratory Diseases 147,101

Accidents 136,053

Cerebrovascular Disease 133,103Alzheimer’s Disease 93,541Diabetes Mellitus 76.448Influenza, pneumonia 55,227Nephritis 48,146Suicide 42,773

Global Burden of Disease report, Lancet 2014, 385: 117-17132

Causes of Death - Africa

• BUT: This does not even count the incalculable burden of cardiovascular diseases and diabetes…

• (Rob Ridley) Approximately 14 million deaths per year occur in sub-Saharan Africa because of preventable or easily treatable diseases:

• Diarrheal diseases• Simple Infections• Malaria• Tuberculosis• HIV/AIDS• Hepatitis B and C

Do we compare/contrast India and China?

Local Pharmaceutical Manufacturing - Africa

29

ACADEMIA

CLASSROOMAND

LABORATORYTRAINING

INDUSTRY

Regulatory

• Pharma manufacturing requires skilled technicians, engineers, and scientists trained in pharmaceutical technology and production• “There is insufficient skilled labor to support the growing pharma industry… we spend

up to 6 months to train people but not enough people with basic skills are available

• Human resources must be developed in the areas of industrial pharmacy, production management, regulatory science, and quality control

Challenges of Pharmaceutical Manufacturing in Afreica

Foreign exchange

Availability of skilled labor force

Underdeveloped related and supporting industries

• Foreign exchange shortage causes significant challenges in importing machineries and raw materials necessary to support the pharmaceutical industry – “It can take up to 6-7 months to get approval for foreign currency and that is

discouraging... even though the pharmaceutical industry has preference, it is still one of the biggest issues facing our sector.”

• There is no production of APIs domestically; and nearly all raw materials must be imported

• Similarly, most primary packaging (e.g. PVC, bottles, vials, foils) must be imported• Bioequivalence study centers are just being established

Challenges of pharmaceutical manufacturing in Africa

Regulatory environment

• Lengthy regulatory policies for drug approvals have imposed access limitations• The current legal limitation of working with a maximum of three distributors was cited

as another regulatory barrier to the growth of the domestic pharmaceutical industry

Patents

The Patent Estate - Evergreening

• Pharmaceutical companies represent nearly every aspect of drug development and delivery as containing patentable innovation:

• Composition of matter • Method of use • Combinations with other drugs• Pharmaceutical compositions (formulations)• Processes and Intermediates (not listed in the Orange Book)• Crystalline forms (salts, polymorphs, hydrates, solvates, co-crystals,

dispersions)• Latter-day “improvements”

Tenofovir Alafenamide – Patent Applications

1998 2001 2003 (3) 2004 (3) 2006 2009 2010 2011 )2) 2012 2013 2014 (4) 2015 (3) 2016

Tenofovir, Tenofovir Disoproxil, Tenofovir Alafenamide

N

NN

N

NH2

O P

OO

O

O

O O

O

O

O

N

NN

N

NH2

O P

OHOH

O

Tenofovir disoproxil Tenofovir (API)

N

NN

N

NH2

O P

O

O

O

CO2iPr

First published by McGuigan et. al.,(1989) and appliedto hundreds of antiviral compounds

Synthesized by Antonin Holy and tested by Eric de ClerqProdrug selected by Gilead Sciences

(John Martin)

Sofosbuvir

Emerging Issues

• Alternative salts of tenofovir disoproxil fumarate (citrate, phosphate) from Indian generics have been approved by the EMA (March, 2017) and the tartrate is expected to be approved this month

• This provides a means for getting around originator patents, but it also creates new patent issues… (DTG, TDF, solvates and new crystal forms of important APIs (aripiprazole/abilify)

• Tenofovir disoproxil fumarate is presently taken by an estimated 12MM people in LMICs

• Patent coverage on the drug molecule theoretically expires in 2017/2018• Gilead Sciences seeking to extend this to 2020 in US and Europe with a 2015

application covering solid state forms of tenofovir disoproxil, preventing generic companies from