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Drug Developments in 2010. Implications for the Pharmacy Purchaser Kevin Hoehn PharmD MBA Faxton-St. Luke’s Healthcare Utica NY.

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drug developments in 2010

Drug Developments in 2010

Implications for the Pharmacy Purchaser

Kevin Hoehn PharmD MBA

Faxton-St. Luke’s Healthcare

Utica NY

slide2

Annual Growth in Drug Expenditures 1998-2009Diamond=total expenditures Squares=expenditures for nonfederal hospitals triangles=expenditures for clinicsAJHP Vol 67, 2010 e4 Figure 1

slide3

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
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
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
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
slide8

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
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
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
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
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
Clinical Trials

Preclinical Phase I Phase II Phase III FDA Phase IV Testing

Years

Test Population

Purpose

Success Rate

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

cardiovascular16
Cardiovascular
  • Ticagrelor (Brilinta®)
    • Astra Zeneca
    • Pre-registration: Launch 2010
  • Dabigatran (Pradaxa®)
    • Boehringer Ingelheim
    • Phase III
  • Rivaroxaban (Xarelto®)
    • Bayer/Johnson & Johnson
    • Phase III: 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

Direct Thrombin Inhibitor

  • Rapid onset, lower risk of bleeding vs. warfarin
  • Once daily, no monitoring

Factor Xa Inhibitor

  • Currently approved for prevention of post surgical VTE in Canada and Britain Once daily, no monitoring
slide17
Biotransformation and Mode of Action of Clopidogrel, Prasugrel, and TicagrelorN Engl J Med 361:1108, September 10, 2009 Editorial
cardiovascular18
Cardiovascular
  • Ticagrelor (Brilinta®)
    • Astra Zeneca
    • Pre-registration: Launch 2010
  • Dabigatran (Pradaxa®)
    • Boehringer Ingelheim
    • Phase III
  • Rivaroxaban (Xarelto®)
    • Bayer/Johnson & Johnson
    • Phase III: 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

Direct Thrombin Inhibitor

  • Rapid onset, lower risk of bleeding vs. warfarin
  • Once daily, no monitoring

Factor Xa Inhibitor

  • Currently approved for prevention of post surgical VTE in Canada and Britain Once daily, no monitoring
cardiovascular20
Cardiovascular
  • PHASE III Factor Xa Inhibitors
    • Apixaban
      • Pfizer/Bristol Myers Squibb
    • Edoxaban
      • Daiichi Sankyo
  • PHASE II
    • Betrixaban
      • Merck/Portola
    • Elingrel
      • Novarits/Portola
  • Single doses cause fewer adverse bleeding events

Factor Xa Inhibitor

Adenosine Diphosphate

Receptor Antagonist

cardiovascular21
Cardiovascular
  • Rosuvastatin/Fenobiric Acid (Certriad®)
    • Astra Zeneca/Abbott
  • Darapladib
    • GlaxoSmithKline
  • SCH-530348
    • Shering Plough

Lipoprotein Associated Phospholipase

A2 Inhibitor (lp-PLA2)

Thrombin Receptor

(PAR-1) antagonist

pulmonary arterial hypertension
Pulmonary Arterial Hypertension
  • Treprostinil
    • United Therapeutics
    • Phase III
  • Sitaxsentan (Thelin®)
    • Pfizer
    • Phase III
  • Oral form of injectable Remodulin®
  • Sustained Release

Endothelin-A Antagonist

multiple sclerosis24
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 sclerosis25
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 disease27
Alzheimer’s Disease
  • Bapineuzumab
    • Wyeth/Elan
    • Phase III
  • Solanezumab
    • Lilly
  • Dimebon
    • 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
oncology
Oncology
  • Denosumab (Prolia®)
    • Amgen
    • On market June 2010
  • Sipuleucel-T (Provenge®)
    • 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
oncology31
Oncology
  • Abiraterone
    • Cougar Biotechnology/J&J
    • Phase II/III: Launch 2012
  • Enzastaurin
    • Eli Lilly
    • Phase III: Launch 2014
  • PHASE II
    • Tremelimumab - Medarex/Pfizer
    • BSI-201 - BiPar/Sanofi-Aventis
  • 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
  • Testing in prostate and bladder cancers

Poly(ADPribiose) inhibitor

  • Testing in triple-negative breast cancer
pain management
Pain Management

Deter

Diversion

  • Oxycodone SR (Remoxy®)
    • King/Pain Therapeutics
    • Phase III
  • Oxycodone-IR/Niacin (Acurox®)
    • King/Acura
    • Phase III
  • Hydromorphone ER (Exalgo®)
    • CominatoRx/Coridien/Neuromed
    • Phase III
  • ORADUR-based
  • High viscosity base, when crushed with water forms thick gel (cannot inject or snort)
  • Niacin induced side effects when taken too often
  • OROS osmotic pill pump for controlled release
pain management34
Pain Management
  • Duloxetine (Cymbalta®)
    • Lilly
    • Phase III
  • Nitraproxen (Naproxcinod®)
    • NicOx
    • Phase III
  • Naproxen-EC/Esomeprazole-IR (Vimovo®)
    • AstraZeneca/POZEN
    • Phase III
  • Resubmitted for treatment of chronic pain indication
  • COX Inhibiting Nitric Oxide Donator
  • Relieve osteoarthritis with fewer GI and cardiovascular side effects
  • For patients at risk of NSAID related GI ulcers
anesthesia
Anesthesia
  • Sugammedex (Bridion®)
    • Organon/Merck/Schering-Plough
    • Phase III

Timely reversal of relaxant binding agents.

Eight-nine times faster than neostigmine.

asthma copd37

ONCE DAILY

Asthma/COPD
  • Aclidinium/Formoterol
    • Forest/Almirall
    • Phase II
  • QVA149 (Indacaterol/Glycopyrrolate)
    • Novartis/Soesei
    • Phase II
  • QMF149 (Indacaterol/Mometasone)
    • Novartis
    • Phase II

LAMA/LABA combo

LABA/LAMA combo

LABA/ICS combo

LAMA: long acting muscarinic antagonist

LABA: long acting beta antagonist

ICS: inhaled corticosteroid

asthma copd38
Asthma/COPD
  • BI-1744-CL/Tiotropium
    • Boehringer-Ingelheim
    • Phase II
  • GW-642444/Fluticasone
    • GSK/Theravance
    • Phase III
  • Roflumilast (Daxas®)
    • Forest/Nycomed
    • Pre-registration: Launch 2010 in EU

LABA/LAMA combo

LABA/ICS combo

Phosphodiesterase-4 (PDE-4) Inhibitor

  • GI side effects and weight loss
  • Oral dosage form
asthma copd39
Asthma/COPD
  • Mometasone/Formoterol (Dulera®)
    • Merck
    • Approved June 2010
  • Indacaterol
    • Novartis
    • Phase III
  • Fluticasone/Salmeterol (Advair®)
    • GlaxoSmithKline
    • Phase III

ICS/LABA combo

BID dosing for asthma in ages 12+

Ultra-LABA monotherapy for COPD

ICS/LABA combo

Once daily dosing

weight loss management
Weight Loss Management
  • Phentermine-CR/Topiramate (Qnexa®)
    • Vivus
    • Phase III: Launch in 2010
  • Lorcaserin
    • Arena
    • Phase III
  • Bupropion-SR/Naltrexone-SR (Contrave®)
    • OrexigenTM Therapeutics
    • 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
diabetes42
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
diabetes43
Diabetes
  • Teplizumab
    • Lilly/Macrogenics
    • Phase III
  • Inhaled Insulin (Afresa®)
    • 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 gout
Rheumatoid Arthritis/Gout
  • CP690550
    • Pfizer
    • Phase III: Launch in 2013
  • Canakinumab (Ilaris®)
    • Novartis
    • Phase II/III

Janus kinase-3 (JAK-3) Inhibitor

  • Inhibits passage of cytokines across cell membrane
  • Oral agent for rheumatoid arthritis
  • Currently indicated for cryopyrin associated periodic syndromes, testing in rheumatoid arthritis and gout
hepatitis c
Hepatitis C
  • PHASE III: Launch in 2012
    • Telapravir
      • Vertex/J&J/Mitsubishi Tanabe
    • Boceprevir
      • Schering-Plough
  • PHASE II
    • R-7128
      • Roche/Pharmasset
    • Filibuvir
      • Pfizer
  • Both attack the same HCV protease enzyme, but are based on different peptide chains

With the decrease in the incidence of new cases of HCV in the US, firms may pull the plug if the market diminishes

anti infectives

Anti-MRSA

Anti-Infectives
  • Dalbavancin
    • Pfizer
    • Phase III
  • Ceftaroline fosamil
    • 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
Conclusions
  • Very long, difficult process to bring a drug to market
  • No guarantees
  • No “blockbusters”