Drug Developments Drug Developments in 2010in 2010Implications for the Implications for the

Pharmacy PurchaserPharmacy Purchaser

Kevin Hoehn PharmD MBAKevin Hoehn PharmD MBA

Faxton-St. Luke’s Faxton-St. Luke’s HealthcareHealthcare

Utica NYUtica NY

Annual Growth in Drug Expenditures 1998-2009Diamond=total expenditures Squares=expenditures for nonfederal hospitals triangles=expenditures for clinicsAJHP 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 Drug Development ProcessProcess

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 TestingPreclinical 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 NDAIND 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

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

IND versus NDAIND versus NDA

Clinical Trial Phase IClinical 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 IIClinical 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 IIIClinical 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.

ApprovalApproval

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.

Preclinical Phase I Phase II Phase III FDA Phase IV Testing

Years

Test Population

Purpose

Success Rate

Clinical TrialsClinical Trials

3.5 1 2 3 2.5

Lab and 20-80 healthy 100-300 patient 1000-3000 animal studies volunteers volunteers patient volunteers

Assess safety Determine Evaluate Verify effectiveness Review Additional and biological safety and effectiveness, monitor adverse process / post marketing activity dosage look for side reactions from Approval testing required effects long term use by FDA 5000 1 .compds Only 5 enter trials approved evaluated

File IND at FDA

File NDA at FDA

Cardiovascular

CardiovascularCardiovascular

Ticagrelor (Brilinta®)Ticagrelor (Brilinta®)– Astra ZenecaAstra Zeneca– Pre-registration: Launch 2010Pre-registration: Launch 2010

Dabigatran (Pradaxa®)Dabigatran (Pradaxa®)– Boehringer IngelheimBoehringer Ingelheim– Phase IIIPhase III

Rivaroxaban (Xarelto®)Rivaroxaban (Xarelto®)– Bayer/Johnson & JohnsonBayer/Johnson & Johnson– Phase III: Launch 2010Phase III: Launch 2010

Direct Thrombin InhibitorDirect Thrombin Inhibitor•Rapid onset, lower risk of Rapid onset, lower risk of

bleeding vs. warfarinbleeding vs. warfarin•Once daily, no monitoringOnce daily, no monitoring

Factor Xa InhibitorFactor Xa Inhibitor•Currently approved for Currently approved for prevention of post surgical prevention of post surgical VTE in Canada and Britain VTE in Canada and Britain

Once daily, no monitoringOnce daily, no monitoring

•Fewer heart attacks and lower Fewer heart attacks and lower death rate than Plavix arm in death rate than Plavix arm in 18,000 patients18,000 patients•Rapid onset, reversible anti-Rapid onset, reversible anti-plateletplatelet•Does not require hepatic activationDoes not require hepatic activation•Twice dailyTwice daily oral dosage oral dosage

Biotransformation and Mode of Action of Clopidogrel, Prasugrel, and TicagrelorN Engl J Med 361:1108, September 10, 2009 Editorial

CardiovascularCardiovascular

Ticagrelor (Brilinta®)Ticagrelor (Brilinta®)– Astra ZenecaAstra Zeneca– Pre-registration: Launch 2010Pre-registration: Launch 2010

Dabigatran (Pradaxa®)Dabigatran (Pradaxa®)– Boehringer IngelheimBoehringer Ingelheim– Phase IIIPhase III

Rivaroxaban (Xarelto®)Rivaroxaban (Xarelto®)– Bayer/Johnson & JohnsonBayer/Johnson & Johnson– Phase III: Launch 2010Phase III: Launch 2010

Direct Thrombin InhibitorDirect Thrombin Inhibitor•Rapid onset, lower risk of Rapid onset, lower risk of

bleeding vs. warfarinbleeding vs. warfarin•Once daily, no monitoringOnce daily, no monitoring

Factor Xa InhibitorFactor Xa Inhibitor•Currently approved for Currently approved for prevention of post surgical prevention of post surgical VTE in Canada and Britain VTE in Canada and Britain

Once daily, no monitoringOnce daily, no monitoring

•Fewer heart attacks and lower Fewer heart attacks and lower death rate than Plavix arm in death rate than Plavix arm in 18,000 patients18,000 patients•Rapid onset, reversible anti-Rapid onset, reversible anti-plateletplatelet•Does not require hepatic activationDoes not require hepatic activation•Twice dailyTwice daily oral dosage oral dosage

Review of Clotting CascadeReview of Clotting Cascade

ExtrinsicExtrinsicPathwayPathway

IntrinsicIntrinsicPathwayPathway

CommonCommonPathwayPathway

XII

XI

VII

tissuetissuefactorfactor

CaCa++++

II

XIIa

XIa

IXIXa

X

CaCa++++

(prothrombin)

CaCa++++

plateletsVa

plateletsVIIIa

fibrin

(thrombin)

ThrombusThrombus(clot)(clot)

XIII

XIIIa

HMWKHMWK

KALKAL

fibrinogen

IIa

Xa

VIIa

CardiovascularCardiovascular

PHASE III PHASE III Factor Xa InhibitorsFactor Xa Inhibitors– ApixabanApixaban

Pfizer/Bristol Myers SquibbPfizer/Bristol Myers Squibb

– EdoxabanEdoxaban Daiichi SankyoDaiichi Sankyo

PHASE IIPHASE II– BetrixabanBetrixaban

Merck/PortolaMerck/Portola

– ElingrelElingrel Novarits/PortolaNovarits/Portola

•Single doses cause fewer adverse bleeding Single doses cause fewer adverse bleeding eventsevents

Factor Xa InhibitorFactor Xa Inhibitor

Adenosine Diphosphate Adenosine Diphosphate Receptor AntagonistReceptor Antagonist

CardiovascularCardiovascular

Rosuvastatin/Fenobiric Acid Rosuvastatin/Fenobiric Acid (Certriad®)(Certriad®)– Astra Zeneca/Abbott Astra Zeneca/Abbott

DarapladibDarapladib– GlaxoSmithKlineGlaxoSmithKline

SCH-530348SCH-530348– Shering PloughShering Plough

Lipoprotein Associated PhospholipaseLipoprotein Associated Phospholipase A2 Inhibitor (lp-PLA2)A2 Inhibitor (lp-PLA2)

Thrombin Receptor Thrombin Receptor (PAR-1) antagonist(PAR-1) antagonist

Pulmonary Arterial Pulmonary Arterial HypertensionHypertension

TreprostinilTreprostinil– United TherapeuticsUnited Therapeutics– Phase IIIPhase III

Sitaxsentan (Thelin®)Sitaxsentan (Thelin®)– PfizerPfizer– Phase IIIPhase III

•Oral form of injectable Oral form of injectable Remodulin® Remodulin®

•Sustained ReleaseSustained Release

Endothelin-A AntagonistEndothelin-A Antagonist

Multiple Sclerosis

Pegylated Interferon beta 1-a Pegylated Interferon beta 1-a (Avonex®)(Avonex®)– Biogen IdecBiogen Idec– Phase III: Launch 2011Phase III: Launch 2011

CladribineCladribine– EMD Serono/MerckEMD Serono/Merck– Pre-registrationPre-registration

Multiple SclerosisMultiple Sclerosis

•Longer lasting drug to be self Longer lasting drug to be self administered subcutaneously every administered subcutaneously every

other weekother week

•New formulation of anti-leukemia injectable New formulation of anti-leukemia injectable Leustatin®Leustatin®

•Reduced relapse rates Reduced relapse rates •Short treatment course of 8-20 days per yearShort treatment course of 8-20 days per year

Dalfampridine-ER (Ampyra®)Dalfampridine-ER (Ampyra®)– Acorda/ElanAcorda/Elan– Released January 2010Released January 2010

FTY-720 (Fingolimod)FTY-720 (Fingolimod)– Novartis/Mitubishi TanabeNovartis/Mitubishi Tanabe– Phase IIIPhase III– FDA panel supports June 2010FDA panel supports June 2010

Multiple SclerosisMultiple Sclerosis

•Adjunct treatment to improve walking Adjunct treatment to improve walking speed (not a disease modifying agent)speed (not a disease modifying agent)

Sphingosine 1-PhosphateSphingosine 1-PhosphateReceptor ModulatorReceptor Modulator

•Makes T cells unresponsive to stimuli Makes T cells unresponsive to stimuli leading to destruction of myelin leading to destruction of myelin

Alzheimer’s Disease

Alzheimer’s DiseaseAlzheimer’s Disease

BapineuzumabBapineuzumab– Wyeth/ElanWyeth/Elan– Phase IIIPhase III

SolanezumabSolanezumab– LillyLilly

DimebonDimebon– PfizerPfizer

LY450139LY450139– LillyLilly

Beta-Amyloid Antibody Beta-Amyloid Antibody

• Binds to and removes Binds to and removes accumulation of beta-amyloid in accumulation of beta-amyloid in

the brainthe brain

•Binds soluble beta-amyloid Binds soluble beta-amyloid outside of the brainoutside of the brain

•Lower risk for toxic events Lower risk for toxic events

•Inhibits cell death, stimulates neurite Inhibits cell death, stimulates neurite growthgrowth

•Old OTC Russian antihistamineOld OTC Russian antihistamine

Gamma Secretase Inhibitor Gamma Secretase Inhibitor

• Inhibits beta-amyloid Inhibits beta-amyloid producing enzymeproducing enzyme

Chemotherapy

Monoclonal Antibodies

OncologyOncology

Denosumab (Prolia®)Denosumab (Prolia®)– AmgenAmgen– On market June 2010On market June 2010

Sipuleucel-T (Provenge®)Sipuleucel-T (Provenge®)– Dendreon/KirinDendreon/Kirin– Pre-registration: Launch 2010Pre-registration: Launch 2010

IpilimumabIpilimumab– Medarex/BMSMedarex/BMS– Phase III: Launch 2010Phase III: Launch 2010

Anti-Osteoporosis Anti-Osteoporosis Monoclonal AntibodyMonoclonal Antibody

•Treat bone metastases related Treat bone metastases related to cancer to cancer

Prostate Cancer VaccineProstate Cancer Vaccine

Blocks effects of negative Blocks effects of negative T-cell regulator CTLA-4T-cell regulator CTLA-4

•Targets malignant melanoma, lung Targets malignant melanoma, lung cancer, lymphoma, and prostate cancer, lymphoma, and prostate

cancercancer

OncologyOncology

AbirateroneAbiraterone– Cougar Biotechnology/J&JCougar Biotechnology/J&J– Phase II/III: Launch 2012Phase II/III: Launch 2012

EnzastaurinEnzastaurin– Eli LillyEli Lilly– Phase III: Launch 2014Phase III: Launch 2014

PHASE IIPHASE II– TremelimumabTremelimumab - Medarex/Pfizer - Medarex/Pfizer– BSI-201BSI-201 - BiPar/Sanofi-Aventis - BiPar/Sanofi-Aventis

•Testing in prostate and bladder Testing in prostate and bladder cancerscancers

Phosphatidylinositol 3-Kinase Phosphatidylinositol 3-Kinase (PI3K) Inhibitor(PI3K) Inhibitor•Results in apoptotic cell deathResults in apoptotic cell death

•Testing in non-Hodgkin’s Testing in non-Hodgkin’s lymphomalymphoma

•Anti-tumor effect in Anti-tumor effect in refractory or resistant refractory or resistant

prostate cancerprostate cancer•Inhibits an enzyme Inhibits an enzyme

necessary for testosterone necessary for testosterone production anywhere in the production anywhere in the

bodybody

•Testing in triple-negative breast Testing in triple-negative breast cancercancer

Poly(ADPribiose) inhibitor Poly(ADPribiose) inhibitor

Pain Pathways

Pain ManagementPain Management

Oxycodone SR (Remoxy®)Oxycodone SR (Remoxy®)– King/Pain TherapeuticsKing/Pain Therapeutics– Phase IIIPhase III

Oxycodone-IR/Niacin (Acurox®)Oxycodone-IR/Niacin (Acurox®)– King/AcuraKing/Acura– Phase IIIPhase III

Hydromorphone ER (Exalgo®)Hydromorphone ER (Exalgo®)– CominatoRx/Coridien/NeuromedCominatoRx/Coridien/Neuromed– Phase IIIPhase III

•ORADUR-basedORADUR-based•High viscosity base, when crushed High viscosity base, when crushed with water forms thick gel with water forms thick gel (cannot inject or snort) (cannot inject or snort)

•OROS osmotic pill pump OROS osmotic pill pump for controlled release for controlled release

DeterDeterDiversionDiversion

•Niacin induced side effects Niacin induced side effects when taken too oftenwhen taken too often

Pain ManagementPain Management

Duloxetine (Cymbalta®)Duloxetine (Cymbalta®)– LillyLilly– Phase IIIPhase III

Nitraproxen (Naproxcinod®)Nitraproxen (Naproxcinod®)– NicOxNicOx– Phase IIIPhase III

Naproxen-EC/Esomeprazole-IR Naproxen-EC/Esomeprazole-IR (Vimovo®)(Vimovo®)– AstraZeneca/POZENAstraZeneca/POZEN– Phase IIIPhase III

•Resubmitted for treatment of Resubmitted for treatment of chronic pain indication chronic pain indication

•For patients at risk of NSAID For patients at risk of NSAID related GI ulcers related GI ulcers

•COX Inhibiting Nitric Oxide DonatorCOX Inhibiting Nitric Oxide Donator

•Relieve osteoarthritis with fewer GI Relieve osteoarthritis with fewer GI and cardiovascular side effectsand cardiovascular side effects

AnesthesiaAnesthesia

Sugammedex (Bridion®)Sugammedex (Bridion®)– Organon/Merck/Schering-PloughOrganon/Merck/Schering-Plough– Phase IIIPhase III

Timely reversal of Timely reversal of relaxant binding agents.

relaxant binding agents. Eight-nine times faster Eight-nine times faster than neostigmine.

than neostigmine.

Asthma/ COPD

Asthma/COPDAsthma/COPD

Aclidinium/FormoterolAclidinium/Formoterol– Forest/AlmirallForest/Almirall– Phase IIPhase II

QVA149 (Indacaterol/Glycopyrrolate)QVA149 (Indacaterol/Glycopyrrolate)– Novartis/SoeseiNovartis/Soesei– Phase IIPhase II

QMF149 (Indacaterol/Mometasone)QMF149 (Indacaterol/Mometasone)– NovartisNovartis– Phase IIPhase II

ONCE DAILYONCE DAILY

LABA/LAMA comboLABA/LAMA combo

LABA/ICS comboLABA/ICS combo

LAMA/LABA comboLAMA/LABA combo

LAMA: long acting muscarinic antagonistLAMA: long acting muscarinic antagonistLABA: long acting beta antagonistLABA: long acting beta antagonist

ICS: inhaled corticosteroidICS: inhaled corticosteroid

Asthma/COPDAsthma/COPD

BI-1744-CL/TiotropiumBI-1744-CL/Tiotropium– Boehringer-IngelheimBoehringer-Ingelheim– Phase IIPhase II

GW-642444/FluticasoneGW-642444/Fluticasone– GSK/TheravanceGSK/Theravance– Phase IIIPhase III

Roflumilast (Daxas®) Roflumilast (Daxas®) – Forest/NycomedForest/Nycomed– Pre-registration: Launch 2010 in EUPre-registration: Launch 2010 in EU

Phosphodiesterase-4 (PDE-4) Inhibitor Phosphodiesterase-4 (PDE-4) Inhibitor

•GI side effects and weight lossGI side effects and weight loss•Oral dosage formOral dosage form

LABA/ICS comboLABA/ICS combo

LABA/LAMA comboLABA/LAMA combo

Asthma/COPDAsthma/COPD

Mometasone/Formoterol (Dulera®)Mometasone/Formoterol (Dulera®)– MerckMerck– Approved June 2010Approved June 2010

IndacaterolIndacaterol– NovartisNovartis– Phase IIIPhase III

Fluticasone/Salmeterol (Advair®) Fluticasone/Salmeterol (Advair®) – GlaxoSmithKlineGlaxoSmithKline– Phase IIIPhase III

Ultra-LABA monotherapy for COPDUltra-LABA monotherapy for COPD

ICS/LABA comboICS/LABA combo

BID dosing for asthma in ages 12+BID dosing for asthma in ages 12+

ICS/LABA comboICS/LABA combo

Once daily dosingOnce daily dosing

Weight Loss Weight Loss Management Management

Phentermine-CR/Topiramate (Qnexa®)Phentermine-CR/Topiramate (Qnexa®)– VivusVivus– Phase III: Launch in 2010Phase III: Launch in 2010

LorcaserinLorcaserin– ArenaArena– Phase IIIPhase III

Bupropion-SR/Naltrexone-SR Bupropion-SR/Naltrexone-SR (Contrave®)(Contrave®)– OrexigenTM TherapeuticsOrexigenTM Therapeutics– Phase IIIPhase III

•Showed 10% weight loss in a Showed 10% weight loss in a large portion of patients and large portion of patients and

significantly reduced the HbA1Csignificantly reduced the HbA1C

Selective Serotonin (5HT-2C) Agonist Selective Serotonin (5HT-2C) Agonist

•No valvulopathy, depression or No valvulopathy, depression or suicidal ideationssuicidal ideations

Diabetes

DiabetesDiabetes

DapagliflozinDapagliflozin– BMS/AstraZenecaBMS/AstraZeneca– Phase III: Launch in 2011Phase III: Launch in 2011

Liraglutide (Victoza®)Liraglutide (Victoza®)– Novo NordiskNovo Nordisk– Launched January 2010Launched January 2010

Sodium Glucose Transporter Sodium Glucose Transporter Protein (SGLT2) InhibitorProtein (SGLT2) Inhibitor

•Leads to increased excretion Leads to increased excretion of glucose in the urine of glucose in the urine

•Side effects of UTI and genital Side effects of UTI and genital infectioninfection

•Daily subcutaneous injectionDaily subcutaneous injection•Approved in UK, Germany, Denmark, Approved in UK, Germany, Denmark,

EUEU

Glucagon-like Peptide-1 Glucagon-like Peptide-1 Analogue (GLP-1)Analogue (GLP-1)

Diabetes Diabetes

TeplizumabTeplizumab– Lilly/MacrogenicsLilly/Macrogenics– Phase IIIPhase III

Inhaled Insulin (Afresa®)Inhaled Insulin (Afresa®)– MannKindMannKind– Phase IIIPhase III

Oral InsulinOral Insulin– Novo NordiskNovo Nordisk– Phase IIPhase II

Anti-CD3 Monoclonal AntibodyAnti-CD3 Monoclonal Antibody

•Treatment of Type-1 DiabetesTreatment of Type-1 Diabetes

•Ultra rapid acting insulin for Ultra rapid acting insulin for treatment of Type-1 and Type-2 treatment of Type-1 and Type-2

DiabetesDiabetes

•First oral, pill form of insulinFirst oral, pill form of insulin

Rheumatoid Arthritis

Rheumatoid Rheumatoid Arthritis/GoutArthritis/Gout

CP690550CP690550– PfizerPfizer– Phase III: Launch in 2013Phase III: Launch in 2013

Canakinumab (Ilaris®)Canakinumab (Ilaris®)– NovartisNovartis– Phase II/IIIPhase II/III

Janus kinase-3 (JAK-3) InhibitorJanus kinase-3 (JAK-3) Inhibitor

•Inhibits passage of cytokines Inhibits passage of cytokines across cell membraneacross cell membrane

•Oral agent for rheumatoid arthritisOral agent for rheumatoid arthritis

•Currently indicated for cryopyrin Currently indicated for cryopyrin associated periodic syndromes, associated periodic syndromes,

testing in rheumatoid arthritis and testing in rheumatoid arthritis and goutgout

Hepatitis CHepatitis C

PHASE III: Launch in 2012PHASE III: Launch in 2012– TelapravirTelapravir

Vertex/J&J/Mitsubishi TanabeVertex/J&J/Mitsubishi Tanabe

– BoceprevirBoceprevir Schering-PloughSchering-Plough

PHASE IIPHASE II– R-7128R-7128

Roche/PharmassetRoche/Pharmasset

– FilibuvirFilibuvir PfizerPfizer

With the decrease in With the decrease in the incidence of new the incidence of new cases of HCV in the US,

cases of HCV in the US, firms may pull the plug firms may pull the plug if the market

if the market diminishes diminishes

•Both attack the Both attack the same HCV protease same HCV protease

enzyme, but are enzyme, but are based on different based on different

peptide chainspeptide chains

Anti-InfectivesAnti-Infectives

DalbavancinDalbavancin– PfizerPfizer– Phase IIIPhase III

Ceftaroline fosamilCeftaroline fosamil– Takedea/Forest LabsTakedea/Forest Labs– Phase IIIPhase III

CeftobiproleCeftobiprole– Phase IIIPhase III

CephalosporinCephalosporin

GlycopeptideGlycopeptide

•For MRSA related skin infectionsFor MRSA related skin infections•Once-a-week IV dosingOnce-a-week IV dosing

•Kills gram positive bacteria like Kills gram positive bacteria like MRSA but also gram negative MRSA but also gram negative

organismsorganisms•Pro-drug to increase its water Pro-drug to increase its water

solubilitysolubility

Anti-MRSAAnti-MRSA

Conclusions

Very long, difficult process to bring a drug to market

No guarantees No “blockbusters”