african penguin. pieter van der bijl, emeritus professor and former head of pharmacology, faculty of...

African penguin

Pieter van der Bijl, Emeritus Professor and Former Head of Pharmacology, Faculty of

Health Sciences, Stellenbosch University, Cape Town, South Africa

DD: Introduction: 1

One of the features which is thought to distinguish man from other animals is his desire to take drugs (Sir William Osler, 1849-1919)

Undeniably the practice of modern medicine is heavily dependent on drugs

E.g. one major benefit of drugs in Rx of disease has been demonstrated dramatically with the advent of antibiotic therapy

DD: Introduction: 2

In the preantibiotic era 27% of patients with lobar pneumonia succumbed to the disease

This was reduced to <8% following the discovery of the sulphonamides and, later, penicillins

Subsequently, an explosion in the development of a multitude of new drugs with antibiotic activity followed

But, drugs as we know them today have not always been available

DD: Introduction: 3

Early agents sometimes contained Hg, As and Sb compounds (inorganic)

Initially, however, many early medicines used were of botanical or zoological origin (organic)

These included fairly crude aqueous or alcoholic plant extracts usually containing one or more complex organic molecules

DD: Introduction: 4

Examples

laudanum (alcoholic extract of opium containing the alkaloid morphine)

foxgloves (containing cardiac glycosides) for Rx of “dropsy” (cardiac failure)

Although many of these mixtures can work, they may be problematical

Unpredictable efficacy/toxicity ratios

Uncertainty wrt active components

Therefore, modern pharmacology aims to deal with pure compounds

DD: Introduction: 5

What are the advantages of isolating the active ingredient(s) from mixtures?

1. Removal of biological variability (e.g. climatic or soil conditions)

2. Obtaining desirable effects without having a cocktail of unnecessary (sometimes interfering) components

3. Mode of action can be better defined with single entitiessynthesis of better drugs efficacy, side-effects ,etc.

DD: Introduction: 6

Since 1950s synthetic or semi-synthetic organic compounds have mainly been used

Recently recombinant DNA technology agents identical to those of humans, e.g.

Human insulins, epoietin (recombinant erythropoietin), interferons, interleukins, TNF- , etc.

More and more biologicals are now also available, e.g. antibodies, cytokines, etc.

In the last decade gene therapy and genomics have entered the drug development scene too

Approaches to drug discovery

Drug discovery

Synthesis and screening of new chemical entities

Synthesis of analogues of existing medicines

Synthesis of structuralanalogues of biologically active substances, precursors or antagonists

Biologics

DD: Discovery: 8

Synthesis and screening of new compounds (battery testing) – not efficient and costly, may have to screen thousands of candidate new molecular entities (NMEs)!!

Synthesis of analogues of existing medicines – often leads to only minor improvements in efficacy/toxicity

Structural analogues of biologically active substances, precursors or antagonists, e.g. desmopressin, -dopa, and H2-blockers, may also be synthesised

There is a growing interest in protein-based therapeutic agents (biologics), e.g. recombinant proteins and monoclonal antibodies

DD: Approval: 9

All drugs must pass rigorous evaluation with regard to 3 principal aspects (efficacy, safety and quality) by regulatory bodies

Food and Drug Administration (FDA) in USA

European Agency for the evaluation of Medicinal Products (EMEA)

UK Committee on Safety of Medicines (CSM)

SA Medicines Control Council (MCC)

Россия: Ministry of Health (www.regmed.ru)

Efficacy norms may vary, depending on the class of drug involved and available alternatives

Large trials are undertaken, but sometimes lack power to achive satisfactory endpoints

DD: Safety: 10 Historically, new drugs often had poor efficacy/safety ratios

(toxicity)

FDA (established in 1937) after fatal renal failure in 76 people following intake of sulfanilamide elixir containing diethylene glycol

In 1960s limb malformations (phocomelia) and cardiac defects in infants (N10 000) after anti-nausea drug thalidomide taken by mothers during pregnancy (currently used again in Tx of multiple myeloma and moderate to severe erythema nodosum leprosum) – called drug repositioning

Other example is sildenafil (Viagra®)(Tx of erectile dysfunction and pulmonary arterial hypertension)

Of the above only 5 000 adults are still alive today

Currently animal toxicity tests (predictive models) and careful monitoring during clinical studies are mandatory

DD: Quality: 11

Qaulity control is required to ensure consistency of medicines

Ther are well-defined criteria for purity – limits on content of potentially toxic impurities

Stability and sometimes sterility testing are required

Licensed formulations must contain defined, approved amount of active drug, which has to be released at a specified rate

Role of US, British and European, Russian Pharmacopoeias

Huge concerns are the so-called ‘fake’ drugs (10-15% of the ‘market’ ??) (role of the internet)

Dangerous!

0 2 4 8 –9 20Years (average) IND NDA (Patent expires

(Investigational (New Drug 20 yrs after filingNew Drug) Application) of application)

In vitroIn vitro AnimalAnimal ClinicalClinical MarketingMarketingstudiesstudies testingtesting testingtesting

BiologicBiologicproductsproducts

ChemicalChemicalsynthesissynthesis

Lead compoundLead compoundEfficacyEfficacy

selectivityselectivitymechanismmechanism

GenericsGenericsbecomebecomeavailableavailable

((PostmarketingPostmarketingsurveillance)surveillance)

(Does it work,(Does it work,double blind?)double blind?)

(Does it(Does itwork inwork in

patients?)patients?)

(Is it safe,(Is it safe,pharmacokinetics?)pharmacokinetics?)Phase 1Phase 1Phase 1Phase 1

Drug metabolism, safety assessmentDrug metabolism, safety assessment

Phase 2Phase 2Phase 2Phase 2

Phase 3Phase 3Phase 3Phase 3

Phase 4Phase 4Phase 4Phase 4

DD: Development: 12

0 105 20 yrs15

Patent expiry10 yrs of research 2-3 yrs of administrativeprocedures

Patent application

Acute toxicity

Pharmacology

Chronic toxicity

Phase I clinical tri

als

Phase II clinical tri

als

Phase III clinical tri

als

Registration and tra

nsparancy

Price

Reimbursement

Parmacovigilance

Effective patent lifeDevelopmental phase

New drug development costs over the last two decades

Cost growing by ~10% pa

0

5

10

15

20

Sale

s U

Sb

$

Leading therapeutic categories

DD: Consensus sales forecast

*Biologics

# Trade name Active Company Rx

1 Avastin Bevacizumab Roche Colon, rectal CA (anti-VEGF)

2 Humira Adalimulab Abbott RA (anti-TNF)

3 Enbrel Etanercept Pfizer RA (anti-TNF)

4 Crestor Rosuvastatin AstraZeneca Cholesterol

5 Remicade Infliximab Merck/J&J Crohn’s, RA (anti-TNF)

6 Rituxan Rituximab Roche Non-Hodgkin lymphoma (anti-CD20)

7 Lantus Long-acting isulin

Sanofi-Aventis Diabetes

8 Advair Fluticasone/ salmeterol

GlaxoSmithKline Asthma/COPD

9 Herceptin Trastuzimab Roche Metastatic breast CA

10 NovoLog Rapid-acting insulin

Novo Nordisk Diabetes

Forecast: Top ten selling drugs 2014

Biologics

Antibody-forming cells(B- cells)

Tissue culturetumour cells(Myelomas)

HybridomaHybridomas screened for antibody production

Antibody-producing hybridomas cloned

Production of unlimited quantities of a protein-specific monoclonal antibody

Biologics : Monoclonal antibody production

Protein (tumour cell) of interest

Fusion using e.g. PEG

DD: The Industry: 14

Pharmaceutical companies rated 1st or 2nd on list of most profitable business sectors over last 3 decades

They are huge, prosperous corporations, but must each produce 3 major drugs/year

WHO: inherent conflict of interest between the legitimate business goals and social/ medical/economic needs of nations

However, innovation does have a high price

DD: The Industry: 15

With these billion $ sales figures, pharmaceutical companies are among the richest legal businesses in the world

Paradox: Drug development has become more difficult and expensive than ever

Result: New drugs in the pipeline have fallen off dramatically (pipelines are not looking rich)

High risk: only ~16% making it to clinical testing

In 1987 the FDA had 60 new drug applications, but only 27 in 2012

Bottom line: New drug development is really hard (FDA and other regulatory authorities have very onerous demands)

DD: The Industry: 16

All this has led to insecurity in the international pharmaceutical industry

Stock market shares of the multinational drug companies have dropped

Contradiction between 1st and 3rd world needs and demands

Companies have their backs to the wall and BigPharma is facing challenging times

Me-too and generic drugs (good and bad ones) are fierce competitors of brand name (innovator) medicines

Some countries do not adhere to sound intellectual property (IP) principles (patent violation)!

DD: The Industry: 17

Little money is invested in orphan drugs (diseases <200 000 persons: there are 5 000 such diseases)

Governments and WHO are at loggerheads with the industry

Doha (Qatar) declaration (WTO) and there have been threats by governments to override patents

The industry forced SA to drop an amendment to their patent laws in 2001

‘Car manufacturers do not give free cars to people who do not have one! – why should drug companies give free drugs?’

DD: The Industry: 18

How are companies responding? Seriously looking at what is perceived as

excessive spending (e.g. exorbitant incomes of CEOs)

Over past two decades huge restructuring has been taking place in form of mergers (‘takeovers’), e.g.: Pfizer acquired Wyeth

Merck & Co purchased Schering-Plough

Genentech made deal with Roche

DD: The Industry: 19

Drastic in number of companies over the past 20 years and even further expected this decade

Pharmaceutical companies are very interested in biologicals now too (40% of top ten in 2008 and ? 60% in 2014!):

Recombinant proteins (growth factors), monoclonal antibodies, soluble receptors, clotting factors, replacement enzymes, vaccine components, immune system stimulants, etc.

BigPharma has vested interests in many biotech companies and they use ‘pay for delay’ tactics – keeping contender drugs (biologics) off the market

There are no clear regulatory paths for biosimilars - these are not generic alternatives per se and are generally not interchangeable

1980 2000 2010 20140

25

50

75

100

Year

No

. o

f d

rug

co

mp

anie

sNo. of major pharmaceutical companies remaining

DrugHQ

DD: The Industry: 21

Who really benefits from these mergers? None of the big mergers since 1980 have

produced the promised long-term growth No real in productivity ( if anything

efficiency ?) Almost all mergers market share They are good for the industry and shareholders They do diminish competition But, are they beneficial to consumers/patients?

DD: The Industry: 22

Companies also attempt to extend patents (>20 years) so-called (‘line extensions’) (‘patent greening’), i.e. changing formulations, combining approved medicines and developing chiral drugs (R and S forms), ‘new’ indications, all sorts of legal and regulatory manoeuvres

Regulatory authorities currently require single drug isomers and information on diagnostic biomarkers

The industry now also employs ‘racemic switching’ to produce enantomeric pure drug forms

DD: The Industry: 23

The new drug is often not much better or even different (not necessarily a value-added drug)

But chemical differences (NCE) do allow new patents

“Shark Fin” planning process () (AstraZeneca)

Patent of Losec® (omeprazole) (AstraZeneca) expired in April 2001

Sales were $26 billion over the previous 5 years

Nexiam® (esomeprazole) was brought onto the market at that time

In 2014 still one of the top drugs with billion $ sales

DD: The future : 24

Modern medicine cannot be practised and cannot progress without efficacious and safe drugs

Uses of drugs are increasing, e.g.

A decade ago peptic ulcer disease was treated surgically

Following the discovery of the bacterium Helicobacter pylori its Rx is now mainly pharmacological

DD: The future: 25

New drug development by companies is important (their lifeblood!) : drugs don’t invent themselves!!!!

The drug industry is unique - R & D must therefore be supported, by governments where necessary, particularly wrt orphan drugs (even better tax concessions and perhaps a 12-year exclusivity monopoly, etc.)

Companies must be able to recover their huge R & D expenditures in some way, i.e. there must be financial incentives for them

On the other hand, excessive profiteering must be curtailed

DD: The future : 26

Good quality generic and me-too drugs do make health care more affordable

Most major companies now have their own ‘generic’ subsidiaries

The procedural games played by drug companies must be legislatively dealt with

and

Finally some kind of balance must be achieved in order to maintain the flow of new drugs on which all of us and the rest of mankind depends