Drug Developments in
2010Implications for the
Pharmacy Purchaser
Kevin Hoehn PharmD MBA
Faxton-St. Luke’s Healthcare
Utica NY
Annual Growth in Drug Expenditures 19982009
Diamond=total expenditures
Squares=expenditures for nonfederal
hospitals
triangles=expenditures for clinics
AJHP Vol 67, 2010 e4 Figure 1
Total Numbers of Drug Shortages and Shortages Involving
Injectable Drugs in the United States 2005-2009 NEJM
June 16 2010 (ahead of print) Jensen V and Rappaport B
2010; 2010:1056
Drug Development Process

It takes 12 years on average for an
experimental drug to travel from laboratory
to medicine cabinet

Only five in 5,000 compounds that enter
preclinical testing make it to human testing
–
One of these five tested in humans is approved
Preclinical Testing

A pharmaceutical company conducts
laboratory and animal studies to show
biological activity of the compound against
the targeted disease, and the compound
is evaluated for safety. These tests take
approximately three and one-half years.
IND versus NDA

Investigational New Drug Application (IND)
–
–
–
After preclinical testing, the company files an IND with
the FDA to begin to test the drug in people
Shows results of previous experiments, chemical
structure of the compound; how thought to work in the
body; toxic effects found in the animal studies
Reviewed and approved by the Institutional Review
Board. Progress reports on clinical trials must be
submitted at least annually to the FDA
IND versus NDA

New Drug Application (NDA)
–
–
–
–
After completing all phases of clinical trials, the
company analyzes the data and files an NDA with
the FDA if the data successfully demonstrates
safety and effectiveness
Must contain all of the scientific information that
the company has gathered
Typically run 100,000 pages or more
The average NDA review time for new molecular
entities approved in 1992 was 29.9 months
Clinical Trial Phase I

These tests take about a year and involve
about 20 to 80 normal, healthy volunteers.
The tests study a drug's safety profile,
including the safe dosage range. The
studies also determine how a drug is
absorbed, distributed, metabolized and
excreted, as well as the duration of its
action.
Clinical Trial Phase II

In this phase, controlled studies of
approximately 100 to 300 volunteer
patients (people with the disease) assess
the drug's effectiveness and takes about
two years.
Clinical Trial Phase III

This phase lasts approximately three
years and usually involves 1,000 to 3,000
patients in clinics and hospitals.
Physicians monitor patients closely to
determine efficacy and identify adverse
reactions.
Approval



Once the FDA approves the NDA, the new medicine
becomes available for physicians to prescribe.
The company must continue to submit periodic
reports to the FDA, including any cases of adverse
reactions and appropriate quality-control records.
For some medicines, the FDA requires additional
studies (Phase IV) to evaluate long-term effects.
Clinical Trials
Years
Preclinical
Testing
Phase I
Phase II
Phase III
3.5
1
2
3
Lab and
animal studies
20-80 healthy
volunteers
100-300 patient
volunteers
1000-3000
patient volunteers
Purpose
Assess safety
and biological
activity
Determine
safety and
dosage
Evaluate
effectiveness,
look for side
effects
Verify effectiveness
monitor adverse
reactions from
long term use
Success
Rate
File IND
at FDA
Only 5 enter trials
Phase IV
2.5
Test
Population
5000
.compds
evaluated
FDA
Review
process /
Approval
1
approved
File NDA
at FDA
Additional
post marketing
testing required
by FDA
Cardiovascular
Cardiovascular

Ticagrelor (Brilinta®)
–
–

Dabigatran (Pradaxa®)
–
–

Astra Zeneca
Pre-registration: Launch 2010
•Fewer heart attacks and lower death
rate than Plavix arm in 18,000 patients
•Rapid onset, reversible anti-platelet
•Does not require hepatic activation
•Twice daily oral dosage
Boehringer Ingelheim
Phase III
Direct Thrombin Inhibitor
•Rapid onset, lower risk of
bleeding vs. warfarin
•Once daily, no monitoring
Rivaroxaban (Xarelto®)
–
–
Bayer/Johnson & Johnson
Phase III: Launch 2010
Factor Xa Inhibitor
•Currently approved for
prevention of post surgical
VTE in Canada and Britain
Once daily, no monitoring
Biotransformation and Mode of Action of Clopidogrel, Prasugrel, and
Ticagrelor
N Engl J Med 361:1108, September 10, 2009 Editorial
Cardiovascular

Ticagrelor (Brilinta®)
–
–

Dabigatran (Pradaxa®)
–
–

Astra Zeneca
Pre-registration: Launch 2010
•Fewer heart attacks and lower death
rate than Plavix arm in 18,000 patients
•Rapid onset, reversible anti-platelet
•Does not require hepatic activation
•Twice daily oral dosage
Boehringer Ingelheim
Phase III
Direct Thrombin Inhibitor
•Rapid onset, lower risk of
bleeding vs. warfarin
•Once daily, no monitoring
Rivaroxaban (Xarelto®)
–
–
Bayer/Johnson & Johnson
Phase III: Launch 2010
Factor Xa Inhibitor
•Currently approved for
prevention of post surgical
VTE in Canada and Britain
Once daily, no monitoring
Review of Clotting Cascade
tissue
factor
XIIa
HMWK
XIa
VII
XII
KAL
Ca++
XI
VIIa
IXa
IX
Ca++
VIIIa platelets
Extrinsic
Pathway
X
Intrinsic
Pathway
Xa
Va
XIII
platelets
Ca++
Common
Pathway
II
IIa
(prothrombin)
(thrombin)
fibrinogen
fibrin
XIIIa
Thrombus
(clot)
Cardiovascular

PHASE III Factor Xa Inhibitors
–
Apixaban

–
Edoxaban


Pfizer/Bristol Myers Squibb
•Single doses cause fewer adverse bleeding events
Daiichi Sankyo
PHASE II
–
Betrixaban

–
Merck/Portola
Elingrel

Factor Xa Inhibitor
Novarits/Portola
Adenosine Diphosphate
Receptor Antagonist
Cardiovascular

Rosuvastatin/Fenobiric Acid (Certriad®)
–

Darapladib
–

Astra Zeneca/Abbott
GlaxoSmithKline
SCH-530348
–
Shering Plough
Lipoprotein Associated Phospholipase
A2 Inhibitor (lp-PLA2)
Thrombin Receptor
(PAR-1) antagonist
Pulmonary Arterial Hypertension

Treprostinil
–
–

United Therapeutics
Phase III
Sitaxsentan (Thelin®)
–
–
Pfizer
Phase III
•Oral form of injectable Remodulin®
•Sustained Release
Endothelin-A Antagonist
Multiple Sclerosis
Multiple Sclerosis

Pegylated Interferon beta 1-a (Avonex®)
–
–

Biogen Idec
Phase III: Launch 2011
Cladribine
–
–
EMD Serono/Merck
Pre-registration
•Longer lasting drug to be self administered
subcutaneously every other week
•New formulation of anti-leukemia injectable Leustatin®
•Reduced relapse rates
•Short treatment course of 8-20 days per year
Multiple Sclerosis

Dalfampridine-ER (Ampyra®)
–
–

Acorda/Elan
Released January 2010
FTY-720 (Fingolimod)
–
–
–
Novartis/Mitubishi Tanabe
Phase III
FDA panel supports June 2010
•Adjunct treatment to improve walking
speed (not a disease modifying agent)
Sphingosine 1-Phosphate
Receptor Modulator
•Makes T cells unresponsive to stimuli
leading to destruction of myelin
Alzheimer’s Disease
Alzheimer’s Disease

Bapineuzumab
–
–

Solanezumab
–

Lilly
Dimebon
–

Wyeth/Elan
Phase III
Pfizer
LY450139
–
Lilly
Beta-Amyloid Antibody
• Binds to and removes accumulation
of beta-amyloid in the brain
•Binds soluble beta-amyloid
outside of the brain
•Lower risk for toxic events
•Inhibits cell death, stimulates neurite growth
•Old OTC Russian antihistamine
Gamma Secretase Inhibitor
• Inhibits beta-amyloid
producing enzyme
Chemotherapy
Monoclonal Antibodies
Oncology

Denosumab (Prolia®)
–
–

Sipuleucel-T (Provenge®)
–
–

Amgen
On market June 2010
Dendreon/Kirin
Pre-registration: Launch 2010
Ipilimumab
–
–
Medarex/BMS
Phase III: Launch 2010
Anti-Osteoporosis
Monoclonal Antibody
•Treat bone metastases related
to cancer
Prostate Cancer Vaccine
Blocks effects of negative
T-cell regulator CTLA-4
•Targets malignant melanoma, lung
cancer, lymphoma, and prostate cancer
Oncology

Abiraterone
–
–

Enzastaurin
–
–

Cougar Biotechnology/J&J
Phase II/III: Launch 2012
Eli Lilly
Phase III: Launch 2014
•Anti-tumor effect in refractory
or resistant prostate cancer
•Inhibits an enzyme necessary
for testosterone production
anywhere in the body
Phosphatidylinositol 3-Kinase
(PI3K) Inhibitor
•Results in apoptotic cell death
•Testing in non-Hodgkin’s lymphoma
PHASE II
–
–
Tremelimumab - Medarex/Pfizer
BSI-201 - BiPar/Sanofi-Aventis
•Testing in prostate and bladder cancers
Poly(ADPribiose) inhibitor
•Testing in triple-negative breast cancer
Pain Pathways
Pain Management

Oxycodone SR (Remoxy®)
–
–

Oxycodone-IR/Niacin (Acurox®)
–
–

King/Pain Therapeutics
Phase III
•ORADUR-based
•High viscosity base, when crushed
with water forms thick gel
(cannot inject or snort)
King/Acura
Phase III
•Niacin induced side effects
when taken too often
Hydromorphone ER (Exalgo®)
–
–
CominatoRx/Coridien/Neuromed
Phase III
•OROS osmotic pill pump
for controlled release
Pain Management

Duloxetine (Cymbalta®)
–
–

–

Lilly
Phase III
Nitraproxen (Naproxcinod®)
–
•Resubmitted for treatment of
chronic pain indication
NicOx
Phase III
•COX Inhibiting Nitric Oxide Donator
•Relieve osteoarthritis with fewer GI
and cardiovascular side effects
Naproxen-EC/Esomeprazole-IR (Vimovo®)
–
–
AstraZeneca/POZEN
Phase III
•For patients at risk of NSAID
related GI ulcers
Anesthesia

Sugammedex (Bridion®)
–
–
Organon/Merck/Schering-Plough
Phase III
Asthma/ COPD
Asthma/COPD

Aclidinium/Formoterol
–
–

Forest/Almirall
Phase II
QVA149 (Indacaterol/Glycopyrrolate)
–
–

LAMA/LABA combo
Novartis/Soesei
Phase II
QMF149 (Indacaterol/Mometasone)
–
–
LABA/LAMA combo
Novartis
Phase II
LABA/ICS combo
LAMA: long acting muscarinic antagonist
LABA: long acting beta antagonist
ICS: inhaled corticosteroid
Asthma/COPD

BI-1744-CL/Tiotropium
–
–

–

Boehringer-Ingelheim
Phase II
GW-642444/Fluticasone
–
–
LABA/ICS combo
GSK/Theravance
Phase III
Roflumilast (Daxas®)
–
LABA/LAMA combo
Phosphodiesterase-4 (PDE-4) Inhibitor
Forest/Nycomed
•GI side effects and weight loss
Pre-registration: Launch 2010 in EU •Oral dosage form
Asthma/COPD

Mometasone/Formoterol (Dulera®)
–
–

Indacaterol
–
–

Merck
Approved June 2010
ICS/LABA combo
BID dosing for asthma in ages 12+
Ultra-LABA monotherapy for COPD
Novartis
Phase III
Fluticasone/Salmeterol (Advair®)
–
–
GlaxoSmithKline
Phase III
ICS/LABA combo
Once daily dosing
Weight Loss Management

Phentermine-CR/Topiramate (Qnexa®)
–
–

Lorcaserin
–
–

Vivus
Phase III: Launch in 2010
Arena
Phase III
•Showed 10% weight loss in a
large portion of patients and
significantly reduced the HbA1C
Selective Serotonin (5HT-2C) Agonist
•No valvulopathy, depression or
suicidal ideations
Bupropion-SR/Naltrexone-SR (Contrave®)
–
–
OrexigenTM Therapeutics
Phase III
Diabetes
Diabetes

Dapagliflozin
–
–

BMS/AstraZeneca
Phase III: Launch in 2011
Liraglutide (Victoza®)
–
–
Novo Nordisk
Launched January 2010
Sodium Glucose Transporter
Protein (SGLT2) Inhibitor
•Leads to increased excretion
of glucose in the urine
•Side effects of UTI and genital infection
Glucagon-like Peptide-1
Analogue (GLP-1)
•Daily subcutaneous injection
•Approved in UK, Germany, Denmark, EU
Diabetes

Teplizumab
–
–

Inhaled Insulin (Afresa®)
–
–

Lilly/Macrogenics
Phase III
MannKind
Phase III
Oral Insulin
–
–
Novo Nordisk
Phase II
Anti-CD3 Monoclonal Antibody
•Treatment of Type-1 Diabetes
•Ultra rapid acting insulin for treatment
of Type-1 and Type-2 Diabetes
•First oral, pill form of insulin
Rheumatoid Arthritis
Rheumatoid Arthritis/Gout

CP690550
–
–

Pfizer
Phase III: Launch in 2013
Janus kinase-3 (JAK-3) Inhibitor
•Inhibits passage of cytokines
across cell membrane
•Oral agent for rheumatoid arthritis
Canakinumab (Ilaris®)
–
–
Novartis
Phase II/III
•Currently indicated for cryopyrin
associated periodic syndromes, testing
in rheumatoid arthritis and gout
Hepatitis C

PHASE III: Launch in 2012
–
Telapravir

–
Boceprevir


Vertex/J&J/Mitsubishi Tanabe
Schering-Plough
PHASE II
–
R-7128

–
Roche/Pharmasset
Filibuvir

Pfizer
•Both attack the same
HCV protease enzyme,
but are based on
different peptide chains
Anti-Infectives

Dalbavancin
–
–

Ceftaroline fosamil
–
–

Pfizer
Phase III
Takedea/Forest Labs
Phase III
Ceftobiprole
–
Phase III
Glycopeptide
•For MRSA related skin infections
•Once-a-week IV dosing
Cephalosporin
•Kills gram positive bacteria like
MRSA but also gram negative organisms
•Pro-drug to increase its water solubility
Conclusions



Very long, difficult process to bring a drug to
market
No guarantees
No “blockbusters”