It’s been a tense time for AstraZeneca in recent weeks, with the company facing repeated overtures from US-based Pfizer to discuss a possible takeover. AZ remained steadfast in its opposition, however, with the potential for a megamerger eventually fizzling out this week despite a final bid of more than $100bn.
Whether justified or not, AZ’s stated reasons for rebuffing its unwanted American suitor include its “exciting, rapidly progressing pipeline”. Conversely, Pfizer is looking to bolster its relatively unpromising pipeline of medicines, but it wasn’t that long ago that AZ was looking weak on the pipeline front itself, with several major trial failures meaning the company was looking unlikely to fill the void created by patent expiries of key drugs.
However, since taking over the company in 2012, CEO Pascal Soriot has brought confidence back to AZ through a range of company acquisitions and licence agreements, as well as a planned R&D hub in Cambridge, UK, to take advantage of opportunities to collaborate with the brightest minds in life sciences.
Much of this revamp has been focused on improving AZ’s prospects in oncology, an area that the company has cited as a priority along with diabetes and respiratory disease. It’s certainly an area that AZ needs to shore up: as our Top Pharma List shows, sales of its existing oncology products fell by 10 per cent in 2013, having declined by 9 per cent the year before. But it now looks to be at something of a turning point, given new life by the determined series of deals.
So when, weeks before Pfizer’s merger ambitions were made public, I spoke with Susan Galbraith, VP of oncology and head of the oncology innovative medicine unit at AZ, she provided an unexpectedly timely look at one part of AZ’s pipeline, details of which are to be presented this week at the American Society of Clinical Oncology (ASCO) meeting in Chicago.
The company is building on its recent oncology launches of Caprelsa (vandetanib) for medullary thyroid cancer – approved in Europe in 2012 – and Iressa (gefitinib), an epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitor, which has so far been approved in non-small cell lung cancer, albeit after a much-delayed, stop-start regulatory journey.
But now hopes are high for two late-stage drugs: olaparib and selumetinib. The former is a PARP inhibitor currently under review in both the EU and the US for ovarian cancer, while AZ expects to file selumetinib for use in uveal melanoma some point during 2015, with other indications to follow.
Galbraith explained that these drugs were just some of the many reasons she was excited about the company’s cancer prospects. “We’ve got a strong portfolio of our own built up originally from our own labs together with what we have acquired,” she said.
And when AZ has made those acquisitions in oncology, they have been relevant to the company’s wider strategy, according to Galbraith: “What we have doing is looking at what we need to build on the strengths we have; what additional mechanisms we need for example.”
Fostering partnerships
Recent developments include agreements to license the WEE1 inhibitor MK-1775 from Merck & Co and a collaboration with Bind Therapeutics which puts a molecule discovered by AZ – an Aurora kinase inhibitor – into a nanoparticle formulation which has the potential to improve its therapeutic index and create a more convenient dosing regime; and the $500m acquisition of biotech Amplimmune and its portfolio of cancer antibodies.
Other deals include an alliance with the UK biotech Immunocore via AZ’s MedImmune subsidiary and an expansion of an existing personalised drug partnership with Horizon Discovery. “We’ve got a great portfolio in DNA damage response,” said Galbraith. “We’re making deals for prospects that work well with that DNA damage portfolio or complement or strengthen it. That’s the general principle. Things that build on areas of our strategic strengths or are complementary to it.”
Soriot’s ambitions for AZ include moving the company’s research efforts in the UK to a hub in Cambridge – one tip of the so-called ‘golden triangle’ of research in the UK along with Oxford and London. For Galbraith, being close to potential research partnership is a good thing for AZ.
“Drug discovery and development is a team sport,” she said. “You can’t attempt to do it really well without looking to partner with academic investigators and external biotech and diagnostics companies to bring all these things together.
“Being open and collaborative is key a part in research, and you have to understand that even if you have the best scientists in the world, the idea that not all innovative ideas will come from within your own walls is unlikely.”
Treatment combinations
Building a portfolio of oncology drugs that tackle cancer in a variety of ways mirrors AZ’s ambitions in diabetes, and is an essential part of any successful cancer R&D strategy according to Galbraith.
“Having different drugs which target different segments of lung cancer means that we have got a great pipeline in lung cancer that can address some of the really important needs we still have,” she said. “The history of improvements in cancer treatment has been through working out how to put together those regimens that have high individual activity. Even with early stage breast cancer, outcomes have substantially improved over the years by working out how to put combinations together.
This also rings true for lung cancer, which now has multiple drugs that have some individual activity: “When you look at current data for EGFR therapies, data shows that the predominant resistance mechanisms for first and second generation inhibitors is the emergence of T790m, which basically switches on that same pathway again. We can start to understand the mechanisms of resistance that emerge and logically put together combinations that can address these.”
Immuno-oncology
One area of interest for many pharma companies is the potential for immunotherapies – drugs that encourage the body’s immune system to tackle a disease. The likes of Bristol-Myers Squibb and Merck Serono have made recent investments in the area, while AZ’s interests include MEDI4736, an anti-PD-L1 monoclonal antibody (mAb) in phase 2 trials for NSCLC, and tremelimumab, an anti-CTLA4 MAb in phase 2 for the rare cancer mesothelioma.
“These drugs are going to have activity in many different cancer types but there are many questions we still need to address,” said Galbraith, acknowledging struggles for some pharma companies working in the field. “There is much to be done in that space to understand better the optimal way to combine these drugs to their best effect. But I think it’s clear already that this a very important area of biology.”
And again, matching drugs that work well together will be crucial going forward: “Combination treatment will be a critical component; how best to put these drugs together with other checkpoint inhibitors, or with other agents that might affect a different part of the immune system, or with small molecules.”
Personalised medicines and diagnostics
Perhaps most critical of all for AZ, especially considering its recent launches in the field, is the continued growth of the personalised medicine market. And with the next ASCO meeting just around the corner, Galbraith is not short of things to talk about.
One of the most exciting drugs in the pipeline is selumetinib, a MEK inhibitor that has shown promise in a variety of cancer types. This includes people with NSCLC who have a mutated KRAS gene – an area where no specific treatment option exists. “What selumetinib does is potentially deliver a new targeted therapy into an area where there aren’t any targeted therapies,” says Galbraith.
Drug discovery and development is a team sport. You can’t do it really well without partnerships with academia, biotech and diagnostics companies
If approved, the drug would complement AZ’s other NSCLC drug, Iressa, which is approved in NSCLC patients with the EGFR mutation. “We can treat with Iressa – in the West – probably 15 per cent of NSCLC patients, and 30 per cent in the East,” explains Galbraith. “With selumetinib you’ve now got that plus another 20-25 per cent of NSCLC cases – people with the KRAS mutation.”
Another development is AZD9291 – a drug which addresses the T790M mutation, which is a key resistance mechanism to Iressa. This drug has recently received Breakthrough Therapy designation from the US FDA and phase 1 data will be presented at ASCO in June.
Such personalised medicines go hand-in-hand with diagnostics and Galbraith says that “understanding which are the right patients that can benefit from treatment is an important part of what we’re doing at AZ”.
Critical to that thinking is keeping track of the latest developments in technology and working with companies, such as Oxford Cancer Biomarkers, which are leading the field. This includes the analysis of tumour DNA and the increased sensitivity of machines that can track circulating DNA traces in the blood at much lower levels. Such a development that could impact oncology the way measurement of viral load in hepatitis C has benefited virologists.
“The secret to curing, or prolonging long-term outcomes of, patients with hepatitis C is depending on putting drugs together that have an ability individually to produce a two or three log viral load decrease.
“In oncology we have what you call a partial response when you’ve got a 33 per cent decrease in the diameter of tumour. With increased sensitivity in the technology of measuring circulating tumour DNA we are starting to get closer to ability to measure log cell kill. And with those kind of technological improvements, we are going to figure out ways of identifying patients who can benefit from new drugs and from new drug combinations without having to biopsy patients multiple times.”
AZ is still leaving the development of companion diagnostics to external experts, however, including a collaboration with Roche Diagnostics, and these relationships are set to get even stronger as regulatory systems adapt to a world of personalised medicines.
“Before we start [developing a cancer drug] we look at whether it’s appropriate to identify the right patient population. It’s part of the decision-making process for drugs as they go through development.”
With the distraction of a possible Pfizer takeover now over AZ can put its focus back on this process and developing an oncology pipeline that makes it an attractive proposition. And all eyes now turn to ASCO this week to see what the next developments will be.