Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

cardiovascular and respiratory diseases > New therapies > Flashcards

New therapies Flashcards

1
Q

what are the 2 things that need to happen for a new medicine to get to market and be used clinically?

A

clinically:

  1. The product needs to gain marketing authorisation from a drug regulatory authority
    - They assess the medicine based on its: safety, (reproducible, high) quality and efficacy.
    - The drug regulatory body for UK is UK medicines and health care products regulatory authority (+European medicines agency)
  2. For NHS to prescribe a medicine: a new treatment has to also be approved by NICE.
    NICE sees if it’s cost effective and if NHS will reimburse the use of the medicine.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

why is respiratory development particularly challenging?

A

Traditional hurdles:

  • safety
  • quality
  • efficacy
  • clinical cost effectiveness
  • affordability and impact on services
  • appropriateness

Does use of drug save money?
Who pays?
Can payors afford drug?

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

there are needs and constraints when making a new medicine- the drives and drags…list them

A

• Drive factors: Unmet clinical need, scientific progress, commercial factors
Need new products to take place of ones with patent-exclusivity diminishing

• DRAG factors: Healthcare providers, generics, rationing, pricing policy.
Healthcare providers want to pay as little as possible for the treatments that healthcare systems use

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

what is the impact of asthma?

A
  • 400M sufferers worldwide by 2025
  • high incidence in USA, UK, Australia, New Zealand
  • Growing incidence in BRICs
  • Pharmaceutical market; 22 billion dollars by 2019

Asthma is not a trivial disease that is well managed by inexpensive, generic medicine
• Much is poorly controlled

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

name the efficacious and safe treatments of asthma

A 
Efficacious and safe treatments:
•	Inhaled corticosteroids (ICS)
•	Short-acting inhaled B2 agonists 
•	ICS/LABA combinations 
•	Leukotriene antagonists 
•	Anti-IgE hMab 
•	Anti-cytokine hMab
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

what is the “Asthma paradox”?

A

poor control across all disease severities despite the availability of efficacious and safe treatments

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Mild-moderate asthma:
• beta agonists
• inhaled corticosteroids
• Generic medicines are cheaper (Than those with patents etc) = have lots of generic medicines

Becoming increasingly difficult to introduce new medications based on the mechanisms of actions regarding to the standard current of care

A

Severe asthma:
• inhaling steroids doesn’t help that much
• given oral steroids instead
• new approach/ proprietary therapies: a range of monoclonal antibodies and are increasingly biologic.

offers the potential of some severe asthmatics an alternative option as opposed to high dose steroids

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

describe COPD

A
  • Main causes are cigarette smoking and poor environmental air quality
  • Growing pharmaceutical market wealth
  • Huge impact on healthcare resources
  • Are medicines really the best option to deal with the problem?
  • Need a medicine-based approach to treat COPD
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

what are the current medicines for asthma and COPD?

A 
• BTS and international guidelines 
• Mainstays 
- B2 agonists (Asthma and COPD)
- Corticosteroids, ICS (asthma and COPD, but note 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’ and ‘closed triples’
i.e. different active pharmaceutical ingredients combined together in a single delivery device
o closed double= 2 medicines in a single inhaler
o closed triples= 3 medicines in single inhaler

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

what are some miscellaneous treatments for asthma and COPD?

A

• Leukotriene antagonists
– Effective in some patients
– Used to their best effect?
– Now avialble in generic form i.e. cheap i.e. maybe used more
• Anti-IgE mAb (e.g omalizumab in asthma)
– Works by binding/depleting circulating IgE; no effect on innate immune pathways (that actually drive the production of IgE)
– Expensive treatment; works in only a proportion of those who receive it
o Treatment has to be under a certain cost threshold when delivering QUALYS (Quality adjusted life years)–> NICE figures out if its worth it–> omalizumab was rejected at first but then price was discounted= can be prescribed (under stringent conditions)
– Restricted use; Long-term benefits still emerging
• Phosphodiesterase inhibitors (eg Roflumilast in severe COPD)
– Emesis is a dose-limiting side effect in many people
– Do they do anything that other drugs do not?

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

what are the strengths regarding beta-2 agonists?

A
  • Generic versions exist
  • Cheap
  • Once daily dosing possible
  • Lifesaving in emergency
  • Action (bronchodilator- i.e. antagonist of bronchoconstriction) is mediator-independent
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

what are the weaknesses regarding beta-2 agonists?

A
  • Do not treat underlying disease
  • Mask progression of condition
  • Some drugs associated with cardiotoxicity
  • Need inhaled delivery to limit on-target side-effects

To think about new approaches, we need to be aware of the strengths and limitations of existing options

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

what are the strengths regarding corticosteroids?

A

– Generic options exist
– Cheap
– Wide-ranging action spans many cells and mediators–> Broad spectrum of action is hard to beat with a single mediator intervention

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

what are the weaknesses regarding corticosteroids?

A

– Metabolic effects are undesirable on-target actions
– Immunosuppressant action (desirable) but is non-specific (undesirable):
o Medicinal chemistry has been good at separating the mineralocorticoid effect of steroids from glucocorticoid actions
o Glucocorticoid actions have been tied up as a knot of anti-inflammatory properties and metabolic effects–> better steroid if we can lose the metabolic effects

– Not all cells/mediators affected
– Effectiveness is diminished in exacerbations (Th17/neutrophil events):
o Goes from being a TH2 eosinophil mediator condition to one that has an element of TH17 based immunity + the involvement of neutrophils
o Neutrophils are insensitive to the effects of steroids

– ‘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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

what are the strengths of muscarinic antagonists

A

– Generic options available
– Cheap
– Once daily dosing feasible with some drugs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

what are the weaknesses of muscarinic antagonists?

A

– Undesirable on-target actions require inhaled delivery

– Moderate efficacy in asthma; better in COPD

17
Q

what are the key questions regarding new therapies for asthma and COPD?

A
  • Stratification? Which patient will benefit?
  • Must address gaps in existing treatment
  • Must provide advantages over existing therapies
  • Requires validated high value target
  • Combination therapy may increase treatment potential
18
Q

The problem for both asthma and COPD is that they are heterogenous disorders and this makes them difficult problems for new drug design if the answer has to be a molecule which works in most people.

A

Clinical trial design has been a stumbling block in asthma and COPD during drug development.

Development of biologics for severe asthma has been especially challenging.

Biologicals:
expensive, poor oral bioavailability, regulatory hurdles are greater

Small molecules: need tractable target, potentially cheap, constrained by “medicine space”

  • Small molecules cheaper than biologicals
  • If molecule has to be given systemically than by inhalation: molecules need an ultra-clean toxicological profile
  • Biologicals: poor bioavailability therefore may have to be given intravenously
19
Q

what are the new or near-marker approaches for asthma?

A

– Various mAb therapies (e.g. anti-IL-5, anti-IL-receptor subunits) targeting
severe allergic asthma
– Immunotherapy (allergen desensitisation; Th2/Th1 deviation)–>
o This product is sublingual immunotherapy to desensitise against house dust mite allergens

– New small-molecule medicines for precedented mechanisms (once a daydosing; closed triples) or novel targets (CRTH2 antagonist)

20
Q

what are the new or near-market approaches for COPD?

A

LAMA/LABA and LAMA/LABA/ICS combinations
– LAMA: long acting muscarinic antagonists
– LABA: Long acting beta agonists
– Laba and lama as a double combination
– We now have a triple combination: LAMA, LABA and steroid all in one device

– MABAs (muscarinic antagonist/beta agonist activity in the same molecule)
– Oral and Inhaled theophylline (to restore ICS responsiveness)
– Anti-IL-5 mAb for eosinophilic COPD – but application recently rejected by FDA

Some COPD patients respond well to steroids and some don’t

21
Q

why can anti-IL5 be used for eosinophilic COPD?

A

o Subset of COPD patients who have a large influx of neutrophils in their lung as well as eosinophils
o IL-5 is a vital driver of eosinophil production in the body  successful target of mAB in asthma thus wanted to use same product in eosinophilic COPD patients
o 2 clinical trials occurred: 1 had more success application to FDA FDA declined as the company didn’t characteristics the nature of the patients who were treated

22
Q

Asthma- Emerging therapy
• Latest medicines are monoclonal antibodies
– Targeting Anti-IL-5 (mepolizumab [Nucala]; reslizumab [Cinqair]) and anti-IL5Rα (benralizumab [Fasenra]); Anti-IL-13; Anti-IL-4Rα (dupilumab [Dupixent])
o Dupilmuab targets the alpha subunit which is shared by the receptor for the 2 cytokines (IL4 and IL13) thus targets both cytokines
• Target Th2 cytokines or their receptors
• Impressive clinical trial results – but only if participants are highly stratified. More than one mAb may be required for some patients

A

– Intended patient population is severe asthma (~10% of all asthma); BUT these approaches only work well in people with eosinophilic asthma so the patients to benefit will be fewer because of stratification
– How can patients be stratified?
• Eosinophil counts; plasma biomarkers; IgE are possibilities. But what is reliable?
– Must be given sub-cutaneously or iv because of bioavailability problems
– Lots of interventions (based around single mediators/small molecules) have largely failed to knock out inhaled corticosteroids off their “perch”

These medications are very expensive so really specific on who gets prescribed it i.e. severe asthmatics

23
Q

what is the future therapy for asthma?

A

, not all anti-Th2 cytokine antibodies are efficacious (anti-IL-13 mAbs are a notable failure)
• Other targets e.g. TSLP, IL-33 may be more interesting and are in clinical trial (involved in innate immune perspectives)
• Future challenges are to make these treatments easier to use (increase duration of action) or to give greater power by engineering bispecific antibodies or nanobodies
- Nanobodies: take parts of an antibody molecule and combine them with parts of another antibody molecule= producing a binding entity
• Small molecules may still have a role in certain sub-groups of patients (e.g. CRTh2 antagonists) or as bifunctional agents (beta agonist and muscarinic antagonist in a single molecule)
• Longer term future – mRNA therapeutics? Powerful potential, but many technical hurdles to overcome

24
Q

what is the future therapy for COPD?

A
  • Far horizon therapeutic challenge is to repair lung damage
  • Meantime, focus is on dampening down inflammation e.g. anti-chemokine biologics. Not much success to date
  • Alternatively, prevent exacerbations by targeting infections e.g. interferon-b. Not much success to date
  • MABAs – Allow creation of new intellectual property and may offer formulation advantages with patient convenience, but are they greater than the sum of their orthosteres? Yet to see the light of day – numerous projects abandoned

Example of MABA: muscarinic bit on left hand side and beta agonist on right hand side. Can see a catechol ring that has been modified and adrenergic. In the middle: linker.

25
Q

New mAb therapy in asthma presents interesting opportunities and many challenges.

The mAb approach recognises that asthma and COPD are not single disorders and that patient stratification is both justifiable and desirable.

A

Considerable doubt must exist about the high cost of treatment and the willingness of payors to reimburse treatment costs, even if other healthcare costs are reduced as a result of better disease control.

Will the market tolerate all of these expensive products?

Little prospect of immediate improvements in treatment of 90% of the asthma or COPD patient population

So the search for new approaches must continue!

26
Q

what are the problems with developing inhaled drug delivery treatments?

A 
–	Expensive to develop
–	Device adds to prescription cost
–	Multiple inhalers not popular with patients
–	Cannot be used with coloured drugs or those with unpleasant taste or effects on taste perception
–	Oral drug delivery
–	Constrained by Lipinski rules
–	Greater off-target vulnerabilities
–	Compounds need clean safety profile
27
Q

What are problems with biologics?

A

route of delivery is usually constrained by poor bioavailability

28
Q

give an overview on inhaled therapy

A

• 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)
– Nebuliser
– 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 and DPI
– Requires specialised devices and extensive pharmaceutical development
– Convenient for patients – usable anywhere
– The mainstay of asthma drug delivery

29
Q

describe the pharmaceutical profiling of inhaled therapy

A

• 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 with likely excipients
Compounds lacking appropriate physical properties are not developable assets for inhalation from dry powder devices but may be ok for use in nebulisers

30
Q

what are are the late-stage clinical development challenges in asthma and COPD?

A

How do we know if an experimental treatment works?
• 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 (eg inflammatory mediator levels and cell counts)
• Exacerbation rates
• Quality of life questionnaire results

Note that the linkage between these readouts is complex and not all may be affected equally, if at all. How do we interpret ‘complicated’ results?
– Huge issues with huge costs! (and no easy answers)

cardiovascular and respiratory diseases (13 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions