Post on 20-Dec-2015
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
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
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 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
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 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/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
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 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