NEW DRUGS OR NOVEL

APPROACHES FOR TREATMENT OF

RESPIRATORY DISORDERS

BY
DR. ANIMESH ARYA
CONSULTANT RESPIRATORY MEDICINE , ALLERGY ,
SLEEP AND CRITICAL CARE

SRI BALAJI ACTION MEDICAL INSTITUTE

MAX HOSPITAL PITAM PURA
Target selection & Discovery Development
validation

Target Drug Candidate

Studies of -receptor; -ion channel; -transporter; safety testing
-enzyme; - signalling molecule
Disease Mechanisms

The Drug Discovery Process

Lead Search
-Develop assays (use of automation) Human Studies
-Chemical diversity Phases I,II, III
Molecular Studies -Highly iterative process

Animal Studies
- relevant species
Drug Approval
- transgenic KO/KI mice Lead optimization and Registration
-selectivity
- conditional KOs
-efficacy in animal models
- agonists/antagonists
-tolerability: AEs mechanism-
- antibodies based or structure-based?
- antisense -pharmacokinetics
- RNAi -highly iterative process
 DEVELOPMENT
Pre-Clinical
Process R&D
Pharmacology Chem Eng. R&D
Safety Assessment Manufacturing
Toxicology
Drug Metabolism
(ADME)

Pharmaceutical R&D
Formulation Bio Process R&D

Clinical Investigator
& patient
Regulatory Affairs
Clinical Pharmacology Project Planning & Management
Clinical Research Marketing

Statistics & Epidemiology

Data Coordination
Research Information Systems
Information Services
Clinical
 Phase I Product Profile Marketing SOI
Investigational
20 - 100 healthy volunteers take
New Drug drug for about one month
application Information Learned

IND 1. Absorption and metabolism

2. Effects on organs and tissue
3. Side effects as dosage is increased

Remote data entry

CLINICAL Phase II
TRIALS Several hundred health-impaired patients Information Learned
1. Effectiveness in treating disease
Treatment Group Control Group 2. Short-term side effects in health -impaired patients
3. Dose range

Phase III Information Learned

1. Benefit/risk relationship of drug
Hundreds or thousands of health- 2. Less common and longer term side effects
impaired patients 3. Labeling information

Compassionate Use
 Clinical Advisory
Committee Regulatory
Trials Review Team
Continued
APPROVAL
Reviews,
PROCESS comments, and
(Ex. FDA)
discussions
Submit to
Regulatory Agencies
Drug Co./Regulatory
liaison activities
New Drug
Application
(NDA)
APPROVAL

Worldwide Marketing Authorization (WMA) in other countries

 NEW DRUG PROCESS

IT TAKES NEARLY 20 YRS FOR A NEW FEEFCTIVE

MOLECULE TO HIT THE MARKET

THE COST IS NEARLY 2 – 8 BILLION US DOLLARS

(200 T0 800 CRORES OR MORE )
 AREAS OF FOCUS

ASTHMA
COPD
LUNG FIBROSIS
PULMONARY HYPERTENSION
ANTIOBIOTICS
ALLERGY AND URTICARIA
 MODALITIES

NEW DRUGS

NEW GUIDELINES

NEWER INDICATIONS OF ALREADY EXISTING DRUGS

VARIATION IN DOSAGE AND COMBINATIONS

FOR IMPROVED OUTCOME

 ASTHMA

THE INFLAMMATORY COMOPONENT WELL

UNDERSTOOD

THE GINA GUIDELINES AND STEP WISE APPROACH

WELL ESTABLISHED

THE STEPS CORRELATED WITH CONTROL AND

PREVENTION OF EXACERBATIONS
 ASTHMA

INHALED STEROIDS LOW DOSE /OR HIGH DOSE 800-

1600

ANTI IGE –OMALIZUMAB

MORE USE OF ANTICHOLINERGIC IN ASTHMA

 COPD

NEW DRUG INDACATEROL-ULTRA LABA

24 HRS ACTION

IMPROVES IN THE FEV1 AND QUALITY OF LIFE

GLYCOPYROLIUM AS ULTRA LAMA

COMBINATION AS STAGE CD IN COPD

NACETYL CYSTEINE AS MUCOLYTIC AND ANTIOXIDANT

ROFLUMILAST – ANTI INFLAMMATORY

 PULMONARY FIBROSIS

STEROIDS NOT FOR EVERY CASE

SEPARATE IPF FROM ILD

USE PIRFENODONE 600 -2400MG

N ACETYLCYSTEINE 600 TDS

USE ADDITIONAL IMMUNOSUPPRESSIVE

 PULMONARY HYPERTENSION

SILDENAFIL AS VASODILATOR

ETRA –AMBRISENTAN , BOSENTAN

LESS DIURETIC

DIGOXIN OUT

MORE EMPHASIS ON OXYGEN THERAPY

 ALLERGIC RHINITIS

USE OF NEWER ANTIHISTAMINICS FAVOURED WITH

IMPROVED SAFETY , LESS SEDATION 2 N D OR THIRD
GENERATION

USE WITH INHALED STEROIDS

MONTELEUKAST
 URTICARIA

HIGH DOSE LORATIDINE

OMALIZUMAB ANTI IGE

LONG USE 2 YRS AND MORE

 ANTIBIOTICS

USE OF MACROLIDES MORE OFTEN

DOXY PREFERRED
LONG TERM USE OF AZITHROMYCIN
USE OF CIFRAN LONG TERM IN COPD WITH LONG
TERM SUPPURATION
NEBULISED AMIKACIN AND TOBRAMYCIN AND
COLISTIN
 INFLUENZA

FLU AND FLU LIKE ILLNESS

OSELTAMAVIR

NASAL DRUG
 VACCINES

FLU VACCINES

PNEUMO VACCINES

PNEUMO 23

PREVANAR13

 WHOOPING COUGH VACCINE

 SUMMARY

 WE HAVE NEW MOLECULES SUCH AS INDACATEROL,

GLCOPYRONIUM , ROFLUMILAST,SILDENAFIL,NAC,
PTRFENIDONE ETC AND ALSO VACCINES FOR OUR PTS.
 CONCLUSION

NEW MEDICATIONS ARE AVAILABLE FOR


IMPROVED PATIENT BENEFITS AND OUT COME

WE MUST FAMILIARIZE WITH THEIR USE



PROGNOSIS OF VARIOUS DIS HAS IMPROVED



WE HAVE MORE MOLECULES IN FUTURE TO TREAT


OUR RESP PTS. EFFECTIVELY
THANK YOU ALL
 Targets for COPD treatment based on current understanding of the inflammatory
mechanisms.

P J Barnes Thorax 2003;58:803-808

Copyright © BMJ Publishing Group Ltd & British Thoracic Society. All rights reserved.
 Pulmonary HTN sec. to lung disease
COPD
• Often mild to moderate ,slow progression
• Progression correlates with mortality and PaO2
• Exacerbations in COPD aggravate pulm. HTN
• May be latent and unmasked by exercise
• Vascular changes can be seen in mild COPD

Pathogenesis
• Chronic hypoxemia
• Inflammation HPVC
• Smoking Vascular remodeling
• Mechanical stress
 Pulmonary HTN sec. to lung disease

• Vasoconstriction
• Endothelial dysfunction eNOS, ET-1, 5 HT transporter
• Hypercoagulable state in situ thrombosis
• Smooth muscle proliferation/migration with neo vascularisation of smaller vessels
• Fibrosis of intima
• Increased synthesis of ECM
• Inflammatory cell infiltrate in wall of vessels
• Mechanical stress loss of capillary/precapillary arterioles
Apoptosis
 Treatment modalities
• Conventional therapy

• Newer therapies ?? Potential for partial reversibility

Targeting the pathogenetic mechanisms

• Smoking cessation

• LTOT

• Prevention and Rx of acute exacerbations

• Replacing deficient mediators (NO,PGI2)

• Selective pulmonary vasodilatation , ETRA, PDE Inhibitors

• Protease inhibitors
Sildenafil
• Used in recent trails as monotherapy or with prostanoids (iloprost/epoprostenol)
• Advantage of oral administration
• Selective ---- pulm > systemic vasodilatation
Supraselective --- vasodilatation in well ventilated areas

• 16 pts with severe PHTN secondary to lung fibrosis(Ghofrani et al)

NO(10-20 ppm) i v PGI2
oral Sildenafil 50 mg

NO,sildenafil ---- PVR, Pap

maintained V/Q matching
shunt (4%,3.3% vs 16%)
Pao2
• Amplifies local vasoregulatory mechanisms
 Drug Discovery—Convergence of Disciplines
Synthetic
Combinatorial Patent Law
Chemistry
Chemistry
Modelling
Novel
Intellectual Property
Molecule Physiology
Information Design Structural Biochemistry
Technology
Activity
Physiology
Metabolism Safety Pharmaco- Physiology
dynamics Pharmacology
Safety
Assessment Immunology
In Vivo activity Pharmacokinetic
Properties DMPK

Pharmacology Behavior
Pathology
Physiology Physical Physiology Enzymology
Chemistry
There is a major need to develop
new treatments for chronic
obstructive pulmonary disease
(COPD), as no currently
available drug therapy reduces
the relentless progression of the
d i s e a s e . I n p a rt i c ul a r, t h e re i s a
need to develop drugs that
control the underlying
inflammatory and destructive
processes. There have been few
therapeutic advances in the drug
treatment of COPD, in contrast to
the enormous advances made in
asthma management which reflect
a much better understanding of
the underlying disease