Ahmed Abouelnour

Asthma Drug DevelopmentsFrom Generalized to Personalized

Ahmed Abouelnour

Topics

1. Asthma overview & Pathophysiology.2. Generalized Targets.3. Generalized Targets Developments Strategies.4. Limitations to Generalized Targets.5. Asthma Pathophysiology Development (TH2).6. First Degree Personalization.7. Second Degree Personalization8. Conclusion.

Ahmed Abouelnour

1-Asthma Overview & Pathophysiology.

• Chronic inflammatory disorder of the causes symptoms which are usually associated with widespread, but variable, airflow obstruction that is often reversible either spontaneously or with treatment. causes wheeze, cough, chest tightness, and breathlessness (dyspnoea) (1)

• Affected about 235 m people around the world.

• Intrinsic (Non Allergic) or Extrinsic (Allergic).

• Pathophysiological Pathway discovery developed over last decades advancing the targets and strategies of drug discovery.

Ahmed Abouelnour

2- Generalized Targets• Based on simple asthma pathophysiological mechanism of mast

cells degranulation.

Binds to DegranulationHistamine & Arachedonic Acid

Lipoxyginase

LeukotrienesBronchoconstriction

1- Mast cell Stabilizers (Cromoglycate).2-Anti Histaminic.(Loratidine)3- (5) Lipoxiginase inhibitors.(Zeluton)4-Leukotrienes Receptors Antagonists.(Motelukast)5-Bronchodilators.(B Agonists-Methylxanthine Der.-Anticholinergics) 6-Glucocorticoids (Bechlomethasone-Fluticasone)

Ahmed Abouelnour

2- Generalized TargetsBronchodilators

Muscarinic Antagonists B2 Agonists Methylxanthine

derivatives

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2- Generalized Targets6-Glucocorticoids (Bechlomethasone-Fluticasone)

Ahmed Abouelnour

3- Generalized Targets Developments Strategies

No Strategy Example

1 Increase duration of action for the same target

-B2 Agonists from short acting to long acting.(Bambuterol-Salmetrol-Fenoterol)

2 Increase Selectivity to receptor

-Muscarinic M3 antagonists (Ipratropium to Tiotropium)

3 Targeted Formulations (decrease side effects)

-Inhaled Glucocorticoids.-B2 Agonists Inhalations

4 Combinations products B2 Agonists & Glucocorticoids (Salmetrol+Fluticasone)

Ahmed Abouelnour

4-Limitations to Generalized Targets

FCMR734 Researching Contemporary Issues in Complementary Medicine

• Possible Side effects (Corticosteroid)• Response Variability &Heterogeneity. (Genetic Environmental&

Character).• Pathophysiology Mechanism Developments.

Ahmed Abouelnour

5-Asthma Pathophysiology Development (TH2).

1- What’s developed?

2-Where to target?

3-Heterogenity?

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6-First Degree PersonalizationOmalizumab (Xolair®) : 1-IgE monoclonal antibody.2- ↓ Asthma exacerbations greater when subanalyzed by type 2–high phenotypes (↑ FENO levels, blood eosinophil counts, or serum periostin levels)-Biomarker.

Ahmed Abouelnour

7-Second Degree PersonalizationLebrikizumab : 1-IL 13 monoclonal antibody.2- ↑ FEV1; greatest clinical benefit when subanalyzed by type 2–high phenotypes (↑ periostin and sputum IL-131).

Ahmed Abouelnour

7-Second Degree Personalization• Other monoclonal Ab are being developed targeting:

1. IL-5 (mepolizumab) .2. IL-4 (pitrakinra) 3. Thymic stromal lymphopoietin.

• Biomarker Identification & Regulatory Challenges for IVD and product approval.

Ahmed Abouelnour

8-Conclusion

• Generalized ttt of Asthma is moving to personalized.

• Heterogeneous concept of Asthma is widely being recognized.

• Th2 cycle targets is under vigorous investigation via many Monoclonal Ab.

• Biomarkers identification & Validation remain a challenge.

• Companies Strategies.

Ahmed Abouelnour

Thank You.Q&A

Ahmed Abouelnour

References1. National Heart Lung, and Blood Institute. Guidelines for the diagnosis and management of asthma. National asthma education and

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8. Humbert M, Menz G, Ying S, Corrigan CJ, Robinson DS, Durham SR, et al. The immunopathology of extrinsic (atopic) and intrinsic (non-atopic) asthma: more similarities than differences. Immunol Today 1999;20(11):528–33

9. Litonjua AA, Lasky-Su J, Schneiter K, Tantisira KG, Lazarus R, Klanderman B, et al. ARG1 is a novel bronchodilator response gene: screening and replication in four asthma cohorts. Am J Respir Crit Care Med 2008;178(7):688–94 [Epub 2008/07/12]

10. Wenzel S, Wilbraham D, Fuller R, Getz EB, Longphre M. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet 2007;370(9596):1422–31 [Epub 2007/10/24]

   

Ahmed Abouelnour

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