Emerging therapies in respiratory diseases Flashcards
DRIVEs
Unmet clinical need
Scientific progress
Commercial factors
DRAGs (negative factors)
Healthcare providers
Generics
Rationing
Pricing policy
Asthma Impacts:
400M sufferers worldwide by 2025
High incidence in USA, UK, Australia, NZ
Growing incidence in BRICs
Pharmaceutical market US$22bn in
2019
Traditional hurdles to new medicine:
safety, quality, efficacy, clinical cost effectiveness, affordability + impact on services, appropriateness
Do we really need new therapies?
DRAGs and DRIVEs
Asthma:
Not a trivial disease that is well managed by inexpensive, generic medicines- much is poorly controlled
Efficacious + safe treatments
Inhaled corticosteroids (ICS)
Short-acting inhaled B2 agonists
ICS/LABA combinations
Leukotriene antagonists
Anti-IgE hMab
Anti-cytokine hMab
Current medicines for asthma+COPD
BTS + international guidelines
Mainstays:
B2 agonists (asthma + COPD)
Corticosteroids (ICS (asthma + COPD, but a significant proportion of COPD patients do not respond well to ICS)
Muscarinic antagonists (COPD > asthma)
Modern preference is to use these medicines in combination products: ‘closed doubles’ + ‘closed triples’
Therapies
Leukotriene antagonists- effective in some patients
Anti-IgE mAb- works by depleting circulating
IgE, no effect on innate immune pathways:
Expensive treatment, works only in a proportion of those who receive it
Restricted use, long-term benefits still emerging
Phosphodiesterase inhibitors- emesis is a dose-limiting side effect in many people
B2 agonists
Strengths and weaknesses of B2 agonists
Strengths- cheap, generic versions exist, once daily dosing possible, life saving in an emergency, action is mediatory-independent
Weaknesses-
Does not treat underlying disease
Mask progression of condition
Some drugs associated w cardiotoxicity
Need inhaled delivery to limit on-target side effects
Strengths and Weaknesses of corticosteroids
Strengths- generic options exist, cheap, wide-ranging action spans many cells + mediators
Weaknesses-
Metabolic effects are undesirable on-target actions
Immunosuppressant action (desirable) but is non-specific (undesirable)
Not all cells/mediators affected
Effectiveness is diminished in exacerbations (Th17/neutrophil events)
‘steroid phobia’ inhibits aggressive use
Not all patients respond (esp. in COPD, also some severe asthma)
Need inhaled delivery to limit on-target side effects
Strengths and weaknesses of muscarinic antagonists
Strengths- generic options available, cheap, once daily dosing feasible w some drugs
Weaknesses
Undesirable on-target actions require inhaled delivery
Moderate efficacy in asthma, better in COPD
New therapy criteria:
Must provide advantages over existing therapies
Must address gaps in existing treatment
Stratification? Which patients will benefit?
Requires validated high value target
Combination therapy may increase treatment potential
Strategies:
Problem for both asthma + COPD is that they are heterogenous disorders + this makes them difficult problems for new drug design if the answer has to be a molecule which works in most people
Biologicals- expensive, poor oral bioavailability, regulatory hurdles are greater
Small molecules- need tractable target, potentially cheap, constrained by ‘medicine space’
New or near-market approaches: Asthma
Various mAb therapies (e.g., anti-IL5, anti-IL receptor subunits) targeting severe allergic asthma
Immunotherapy (allergen desensitisation, Th2/Th1 deviation)
New small-molecule medicines for precendented mechanisms (once a day dosing, closed triples) or novel targets (CRTH2 antagonist, dexpramipexole)
New or near-approaches: COPD
LAMA/LABA and LAMA/LABA/ICS combinations
MABAs (muscarinic antagonist/beta agonist activity in the same molecule)
Oral + inhaled theophylline (to restore ICS responsiveness)
Anti-IL5 mAb for eosinophilic COPD
Asthma emerging therapy
Latest medicines are monoclonal antibodies
Asthma future therapies
Fevipiprant- Novartis CRTH2 antagonist
Now abandoned after recent failures in 2x Phase 2 trials
Dexpramipexole- decreases blood eosinophils by an unknown mechanism, orally active
Resurrected for possible use in asthma + other allergic conditions after Phase 3 failure in amyotrophic lateral sclerosis
Positive data obtained in Phase 2 for asthma, but much still to be proven about clinical improvement for patients
What is being treated+where?
Affects preferred route of delivery
Inhaled drug delivery
Expensive to develop
Device adds to prescription cost
Multiple inhalers not popular w patients
Cannot be used w coloured drugs or those w unpleasant taste or effects on taste perception
Oral drug delivery: Constrained by Lipinski rules
Greater off-target vulnerabilities
Compounds need clean safety profiles
Biologics- route of delivery is usually constrained by poor bioavailability
Inhaled therapy:
Inhalation requires the drug to be suspended in a respirable form in air
Several device options can do this: nebuliser, pressurised metered dose inhaler (pMDI), dry powder inhaler (DPI)
To non-experts, an easy, fast, cheap option
Nebuliser strengths and weaknesses:
Least portable; usually restricted to hospital/clinic use
Requires drug to have good aqueous solubility
Requires least pharmaceutical development
Good for prolonged delivery and do not require co-ordination skills
pMDI+DPI: strengths and weaknesses
Requires specialised devices and extensive pharmaceutical development
Convenient for patients – usable anywhere
The mainstay of asthma drug delivery
In reality, inhaled therapy is difficult, why?
Oral DMPK hurdles become other challenges- e.g., to avoid irritancy, have an acceptable physical form, potency + solubility
However, greater chemical design opportunities can exist because the Lipinski rules can sometimes be ignored- so high plasma protein binding, first pass metabolism + poor bioavailability may be virtuous
Potency must be high bc the device needs to contain many doses
For once daily dosing drugs and/or their effects must persist- this may be challenging for stability + selectivity reasons
Pharmaceutical profiling
Inhaled drug development has uncommon requirements
Pharmaceutical profile of compounds is an important decision tool in discovery, especially for drugs intended for dry powder inhalers
Profiling at an early stage mitigates later risks
Insures against unpredictable slower developability
Profiling puts early emphasis on physical properties:
- Crystallinity,
- solubility,
- low hygroscopicity
- Thermal behaviour
- Particle behaviour
- Stability w likely excipients
Late stage clinical development challengend in asthma+COPD
Clinical trials
How can disease-modifying agents be identified?
How can prophylactic agents be identified?
Which patients should be selected (patient stratification)?
What is a meaningful disease readout which can indicate success?
Lung function
Biomarkers e.g., inflammatory mediator levels + cell counts
Exacerbation rates
Equality of life questionnaire results
** plus huge issues w cost
