Monday, 28 September 2015
Our approach to drug development always begins with the same simple question: ‘what are patients missing from current therapies?’
Few would disagree that in chronic obstructive pulmonary disease (COPD) and asthma, bronchodilators will remain central to the treatment paradigm because of the vital symptom relieving effects they offer. To further improve the lives of patients, a significant step forward would be to develop new bronchodilators that give even greater symptomatic relief than those currently available.
Bronchodilators largely fall into two categories: the long-acting beta-2 agonists (LABAs) and the long-acting muscarinic antagonists (LAMAs). Inhaled LABAs, in combination with inhaled corticosteroids (ICS), have been an essential element of asthma treatment for many years, while LAMAs have confirmed efficacy in COPD and are now being studied in uncontrolled asthma1.
Studies of separate LABA plus LAMA combinations in COPD have demonstrated significant improvements in lung function, breathlessness and symptom scores in comparison with individual drugs2. Therefore, to develop new and more effective bronchodilators, one intriguing possibility is to combine the modalities we currently have – the LABAs and LAMAs into a single product, known as an M3-antagonist beta-2 agonist(MABA).
The MABA approach
By reducing the complexity of combination inhalers and simplifying clinical development, the MABA approach also opens up the possibility of adding a fourth active agent to the LAMA/LABA/ICS combination for a more complete treatment. Additionally, there is the potential to deliver a single ‘pharmacokinetic profile’, which means distributing an optimal amount of pharmacological intervention at both beta-2 and muscarinic receptors in relevant regions of the lung, thereby maximising relief.
Although their potential to significantly help patients is great, there are some significant hurdles to overcome in designing MABAs. A key issue centres on obtaining the correct ratio of muscarinic antagonism and beta-2 agonism in the single molecule to ensure the optimal potency balance of the two parts.
One of the most important skills of the drug discovery scientist involves translating preclinical experimental data to the clinical setting so that we can create solutions to overcome hurdles such as those described above and ultimately design novel drugs. This is where lung modelling plays a central and critical role.
Lung modelling – key to unlocking the potential of MABA
We are actively working to advance the MABA approach using sophisticated mathematical modelling techniques linking drug concentrations in different lung compartments to inhibition of bronchoconstriction. This starts with building the models around pre-clinical animal data, the traditional starting point for this type of research. From the understanding gained, the mathematical description of the data is used with clinical bronchodilator efficacy information to validate the approach. From this point, outcomes in human beings treated with novel MABAs can be predicted and understood.
The modelling uses equations to describe the flow of unbound drug concentration, from the site of inhalation through different lung compartments, to distribution into the systemic blood and ultimately out of the body in excreta. By linking the unbound drug concentration in the lung to the broncho-relaxation effect driven by the beta2 and muscarinic receptors, we can deconvolute the optimal pharmacokinetics and LAMA/LABA potencies desirable for a MABA, and develop the appropriately designed novel molecule for treating patients.
Although this modelling approach is not new in the field of pharmacokinetic research, it is novel to attempt it when the drug is dosed into the target organ, the lung in this case, and unbound drug concentrations at the pharmacological receptors are unknown. Indeed, the linking of pulmonary drug concentration after inhalation of LABAs, LAMAS or MABAs presents a new way of looking at the problem and provides useful insight into potential solutions.
Making MABA a reality
Some of our recent work was presented at the European Respiratory Society International Congress in Amsterdam, Netherlands today. In it, we first show how we gained insight into the pharmacokinetic behaviour of novel inhaled bronchodilators in animal studies, and then how we link the animal work to the clinical situation in patients with asthma or COPD using the lung modelling approach to predict the effects of new compounds in patients and design new and better medicines.
Linking the animal work to human beings is essential to deliver on our promise to give patients what they need.
- Lipworth BJ. (2014). Emerging role of long acting muscarinic antagonists for asthma. Br J Clin Pharmacol 77:55-62.
- Cazzola et al. (2013). The MABA approach: a new option to improve bronchodilator therapy. Eur Respir J 42:885-7.