PI3K inhibition: the pathway to next-generation respiratory medicines?

Tuesday, 29 September 2015

Matt Thomas: What is the biggest buzz at the moment in respiratory research?  For me and my colleagues at AstraZeneca, one of the most exciting areas is PI3K inhibition, which we believe could yield a major advance in treating COPD and asthma.

Our progress in this field is being accelerated through the GLAZgo Discovery Centre, our long-term partnership with the University of Glasgow.1 Together we’re pushing the science forward by unravelling immunological disease processes, and finding a way to develop new more effective, targeted treatments.

There are no shortcuts to R&D success, but I’m a true believer in pharmaceutical industry/academia collaborations. Our work with the Glasgow team led by Carl Goodyear has brought together excellence in basic scientific research and expertise in drug discovery, a combination of talents that wouldn’t be possible within one institution.

Carl Goodyear: The research in the Institute of Infection, Immunity & Inflammation at Glasgow is focused on understanding immunopathogenesis of disease in conditions such as rheumatoid arthritis, osteoarthritis and multiple myeloma, as well as respiratory diseases.  This gives us the opportunity to discover the huge commonalities across conditions – for instance some shared disease pathways – but also appreciate the disease-specific complex mechanisms that are underlying disease pathogenesis. It also allows us to thoroughly assess the current challenges we face in the generation of new drugs. Importantly, one of our current challenges is the role of PI3K isoforms in disease pathogenesis and how and which to perturb for clinical benefit.

There is currently one PI3K inhibitor on the market and it is primarily used in combination with rituximab to treat chronic lymphocytic leukaemia or as monotherapy for the treatment of adult patients with follicular lymphoma (FL) that is refractory to two prior lines of treatment.2  This oral drug only targets one isoform of PI3K, which seems fitting for oncology but our challenge is to determine whether mono-isoform inhibition is appropriate for pathologically complex respiratory conditions, and if not, define the best way forward for PI3K inhibition in respiratory medicine.

This might come across as a big ask, but it is these complexities we welcome – they’re just the sort of scientific puzzles which get our teams out of bed in the morning!

Matt Thomas: Understanding of complex pulmonary biological processes has often developed by trial and error, and major obstacles in developing drugs for the lung have to be overcome.

The biggest challenge in respiratory medicine is drug delivery. Once you’ve understood how to target the disease mechanism, the question remains: can the drug be delivered topically i.e., via inhalation?

Key mechanisms

Carl Goodyear:  Phosphoinositide-3-kinases (PI3K) are a family of enzymes involved in a huge range of cellular functions and diverse immune responses.

As Matt mentioned, applying PI3K inhibition in respiratory medicine is full of pitfalls. PI3Ks have multiple isoforms and are involved in multiple pathologies. Without greater understanding of which of these isoforms are at work, within which cell, and precisely where and when, even isoform-selective therapies might struggle to demonstrate efficacy and safety.

Both Matt and I have worked in immunology research for 20 years, and for most of that time, progress towards developing PI3K inhibitors for respiratory disease targets has been slow. But now, thanks to sharper tools and smarter working methods such as GLAZgo, we believe PI3K inhibitors’ time has come.

Understanding isoforms

Matt Thomas: There are four variants of the class 1 catalytic protein: p110 Alpha, p110 Beta p110 Gamma p110 Delta.3 For many years, researchers pursued a strategy of trying to identify which isoform had the most significant role in regulating respiratory pathophysiology. However after much trial and error, it is now clear that lung pathology is borne of co-ordinate action of multiple isoforms – particularly PI3Kgamma and delta whose expression is primarily in immune cells.

One example of this is the different stages of regulating mast cells, which play a key role in the inflammatory process in the lung, in both asthma and COPD.4

Mast cells are present in large numbers in the mucosa of the lung, and we now know that two distinct isoforms of PI3K play key roles in regulating them.  Mast cell biology is dominated by delta (survival via c-kit and degranulation via IgE) and gamma (further degranulation via adenosine and migration to sites of inflammation) isoforms.5,6

It’s clear therefore that a drug that can target these two isoforms in the lungs could be a breakthrough in controlling lung inflammation.

For that reason, AstraZeneca is investigating drugs that inhibit both gamma and delta PI3K isoforms in a single molecule.

Having developed initial investigative PI3K inhibitors, AstraZeneca is able to call on the University’s expertise and cutting-edge technology to test the molecules in the laboratory.

So what obstacles remain?  Well, I think it is hard to exaggerate the challenges of understanding the lung’s unique pathophysiology, as well as problem solving demanded in drug delivery.

The pathway to better drugs

Carl Goodyear:  We’re tackling these challenges through the GLAZgo partnership by building a more direct understanding of respiratory disease in humans.

Recent decades have seen a great deal of research carried out in genetically modified mouse studies to help advance understanding of human disease. However it is now clear that these often have limited relevance to humans, and so new approaches are required.

Together with AstraZeneca, GLAZgo is employing four key, cutting-edge techniques – a ‘taste’ of which will be presented in a poster at the forthcoming European Respiratory Society (ERS) meeting in Amsterdam.

Firstly, to reach a better understanding of where a target is worth inhibiting, we are using patient cells (e.g. asthma peripheral blood mononuclear cell or PBMCs) – which provide a more accurate prediction of the in vivo behaviour of a drug.

Secondly, the collaboration is able to provide a more meaningful environment for functional assays, such as matrix-chemotaxis.  This allows researchers to track the movement of immune cells in a setting much more akin to the human lung tissue environment.

Thirdly, a role for animal models comes when looking to understand drug distribution in lungs – delivered by means akin to patient dosing – and how this relates to the efficacy seen in multiple disease-relevant pathologic cell readouts.

Lastly, all these research tools allow us to link phenotypic response to pharmacodynamic action. That means pathway biomarkers such as pS6 can be used to stratify patients for likely response to PI3K inhibitor candidates. This in turn helps to accelerate the lead optimisation process of identifying the most promising molecules.

Changing the course of respiratory disease

Matt & Carl: We’re personally very excited to be involved in developing these pipeline therapies, and eventually bringing them to patients.  Single/dual PI3K inhibitors have the potential to go far beyond existing treatments, which only target the symptoms of COPD and uncontrolled/severe asthma.  PI3K inhibitors aim to actually change the course of these diseases, representing not just a breakthrough in science, but potentially making a huge difference to the daily lives of people with these conditions.

References:

  1. GLAZgo Discovery Centre. Available from http://www.astrazeneca.com/About-Us/Features/Article/20150521–glazgo-discovery-centre. Last accessed 21 September 2015.
  2. “U.S. Food and Drug Administration Approves Gilead’s Zydelig® (idelalisib) for Relapsed Chronic Lymphocytic Leukemia, Follicular Lymphoma and Small Lymphocytic Lymphoma.” Gilead. Available from http://www.gilead.com/news/press-releases/2014/7/us-food-and-drug-administration-approves-gileads-zydelig-idelalisib-for-relapsed-chronic-lymphocytic-leukemia-follicular-lymphoma-and-small-lymphocytic-lymphoma. Last accessed 21 September 2015.
  3. Zhao and Vogt.  Class I PI3K in oncogenic cellular transformation. Oncogene (2008) 27, 5486–5496.
  4. Erjefält. Mast cells in human airways: the culprit? European Respiratory Review. Available from http://err.ersjournals.com/content/23/133/299. Last accessed 21 September 2015.
  5. Kim et al. The multiple roles of phosphoinositide 3-kinase in mast cell biology. Trends Immunol. 2008 Oct; 29(10): 493–501.
  6. Medina-Tato et al. Phosphoinositide 3-kinase signalling in lung disease: leucocytes and beyond. Immunology. 2007 Aug; 121(4): 448–461.