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Our manifesto for cancer drug discovery and development – focusing on innovation to tackle treatment resistance and meeting patients’ needs

30
Apr
2019

Professor Paul Workman argues that concerted action is needed to accelerate patients’ access to today’s new treatments – and incentivise creation of the innovative new medicines of tomorrow that will lead to step changes in clinical outcome.

Posted on 30 April, 2019 by Professor Paul Workman

Abiraterone tablets

Image: Abiraterone tablets 

We are making good progress against cancer – much better progress in fact than is often acknowledged.

The proportion of patients surviving 10 years from their cancer is now twice as high as it was in the 1970s. Some 50 per cent of cancer patients now survive 10 years or more and this median survival time has also doubled – in this case in less than a decade.

So when I argue that we need urgent action to fix the ecosystem for drug discovery and development this doesn’t mean that cancer patients aren’t currently benefiting from research – it’s just that I believe we could be doing so much better.

We have seen unprecedented advances in our understanding of the genetics and biology of cancer over the last two decades – accelerated by the fruits of the human genome project and the sequencing of cancer genomes – and this has led to the development of many molecularly targeted, precision cancer drugs.

However, I believe that we should be doing much more to convert our detailed knowledge of cancer into a new generation of highly innovative cancer treatments – ones that are capable of delivering step-change improvements for patients.

And equally important is that we need to make sure that all cancer patients can access these innovative treatments as early as possible.

At The Institute of Cancer Research, London, we have been thinking hard about what the key challenges are in creating, trialling and making available more effective cancer treatments – and how we can overcome these barriers.

Last week we published our new Cancer Drug Manifesto which sets out the actions we believe need to be taken across the ecosystem, both to accelerate patients’ access to today’s cancer drugs, and also to incentivise the creation of the most innovative treatments of tomorrow.

But before we get to that, I will first discuss why cancer remains such a challenge to treat today, and what the barriers are to achieving the kind of innovation that can make a real difference for patients. This is important because it forms the fundamental basis for the changes that are needed.

The scientific challenge

There is no doubt that we have already seen a paradigm shift in the way that cancer is treated today.

Where once patients mainly received standard, ‘one-size-fits-all’ treatments involving cytotoxic chemotherapy, many now benefit from modern targeted drugs, which work against specific cancer mutations and vulnerabilities.

These new molecularly targeted treatments can often be tailored very effectively for individual patients through the use of predictive biomarkers – lab tests that tell clinical doctors which patients will respond to a given drug. And because targeted drugs are hitting features that are specific to cancer, they tend to have far less severe side-effects than conventional chemotherapy.

There have been major success stories in targeted drug therapy including imatinib (Gleevec) to counteract the effects of the BCR-ABL translocation in chronic myeloid leukaemia, trastuzumb (Herceptin) for HER2-amplified breast cancer, and gefitinib and erlotinib for EGFR-mutant non small cell lung cancer.

Others include abiraterone (Zytiga) for prostate cancers driven by the androgen receptor, vemurafenib in BRAF-mutant melanoma and olaparib for BRCA mutant ovarian and breast cancer – all examples where the drug was discovered at the ICR (abiraterone) or where the discovery and application was underpinned by ICR science (vemurafenib and olaparib).

Furthermore, we are also now seeing the major benefits of a new generation of drugs – exemplified by the so-called T cell checkpoint inhibitors – that boost the host immune response. These are based on our increased basic knowledge of immunology and how the immune response is deactivated in cancer.

On the other hand, despite the progress made in treating many forms of the disease, the advent of targeted and immune therapies has not benefited all cancers. And even where the new treatments are effective they are only very rarely curative – with the cancer often responding initially only to start growing again, in some cases recurring months or years after patients have been given the all clear.

So drug resistance is the major problem we face in cancer therapy.

We now know that most cancers are extremely genetically diverse within each individual tumour, and can evolve dynamically over time to become resistant to treatment. This is a process I describe as ‘survival of the nastiest’. We are shooting at a moving target.

We need to be absolutely focused on meeting the challenge of cancer evolution and drug resistance – and at the ICR, we have placed this right at the heart of our research strategy.

We will only make step-change advances and deliver new treatments for cancers of high unmet need by creating innovative treatments that attack cancer in brand new ways to overcome cancer evolution and drug resistance.

Although we can expect improvements with new drugs used as single agents, a key part of the answer will be scientifically selected combinations of drugs which act against several different molecular targets or pathways at once. These have the potential to cut off cancer’s evolutionary ‘escape routes’ – just as we seen done successfully in combination drug treatment for HIV.

But to create these novel combinations we must expand the types of drugs we have available. We need many more truly novel cancer drugs, working through a much larger range of mechanisms of action. Only then will we be able to have molecularly targeted drugs available to treat all cancers. This will in give us the greatest flexibility to build individualised drug cocktails for each particular patient.

We currently know of at least 500 or more cancer-causing proteins but to date we have drugs available that target well under 10 per cent of them. So we need to focus more effort on discovering innovative drugs that act on currently untargeted cancer proteins.

The innovation challenge

We are going to require a huge amount of scientific innovation from both academic researchers and the pharmaceutical industry if we are going to create new drugs that attack cancer in genuinely new ways.

Our drug discovery research needs to look beyond low-hanging fruit to focus on new targets, particularly if we are going to successfully tackle cancers of unmet need and overcome drug resistance.

Working on such targets tends to carry higher risk – because they are more likely to be less well understood or validated, or they may be much more technically challenging in terms of ‘druggability’. But although the risk of failure may be higher – because we are working in uncharted territory – the benefits could be enormous. So high risk, high reward.

Nevertheless, because of the high risk, multiple pharmaceutical companies all tend to focus on the same small group of well-precedented targets from which they are more likely to see a return on their investment – even if the therapeutic value is incrementally modest. This leads to an innovation gap – often referred to as the valley of death’ – between our basic understanding of cancer and the conversion of this knowledge into benefit for patients.

This is where academic drug discovery groups, like we have at the ICR, can add major value to the ecosystem. As non-profit groups, they can take on higher-risk targets, demonstrate proof of concept and then partner with industry at the point when a given target approach is de-risked to varying degrees.

Unfortunately, despite this, the valley of death is widening, with drug discovery innovation failing to keep pace with our accelerating understanding of cancer genetics and biology.

And, I emphasise again, resistance continues to be our biggest challenge to overcome.

The patient access challenge

So exactly how are these barriers to innovation affecting patients?

Last year, the ICR published a report, titled From Patent to Patient, which examined the unmet needs in cancer and the delays in getting drugs to patients on the NHS.

As a basis for the report, we analysed all cancer drugs licenced for the first time by the European Medicines Agency from 2000 to the end of 2016. And we identified a number of areas for concern.

Although there was good news which was that more new cancer drugs are being developed than ever before, we found that the advances in drug treatment are very unevenly distributed among different cancers. In some tumour types, such as breast cancer, melanoma skin cancer and blood cancers for example, quite high numbers of new treatments have been developed and approved for patients.

But in many cancers of higher unmet need – such as brain, oesophageal, ovarian, liver and pancreatic – patients are seeing very few, if any, new treatments coming through. And just a tiny number of drugs have been licenced for use in children’s cancer.

Also of concern is that our report found that it is taking longer to get drugs to patients than it was a decade ago – apparently because of delays in taking drugs through clinical trials and getting them licensed.

Furthermore, we found – surprisingly – that highly innovative cancer drugs were less likely to have gained approval by NICE for use on the NHS than is the case for low-innovation drugs. This is especially disappointing given that it is the high-innovation drugs – with new molecular modes of action – which are essential both to open up treatments for poorly served cancers and to meet the challenge of cancer evolution and drug resistance.

To explore some of the issues of drug access in greater depth from a patient perspective, we have now surveyed 1,000 cancer patients to ask about their own experiences, and especially their perceptions of the barriers in gaining access to new treatments. The results were extremely informative and interesting.

A sixth of patients said they had faced difficulties in accessing a treatment recommended by their doctor. Although patients tended to support the role of NICE in determining which drugs are suitable for use on the NHS, only 16 per cent actually felt that NICE was carrying out its role well, with 35 per cent disagreeing.

However, patients seemed to reserve their greatest frustration for pharmaceutical companies. Only 12 per cent thought companies were doing well at delivering new medicines for patients – and 70 per cent said they saw the very high prices of cancer drugs as the biggest barrier to gaining access.

Taken together, the survey’s findings are in line with the experiences of our own researchers – that there are too many barriers to getting the most innovative treatments to patients.

We need to find creative ways of getting the most innovative cancer drugs through to patients more quickly. That’s for the benefit of patients today, of course. But in addition we also need to incentivise creation of the next generation of cancer drugs. We need to build confidence among drug companies that they are likely to be rewarded appropriately (but not excessively) for the greater risks they are prepared to take when they create genuinely innovative treatments.

The policy challenge

So the challenge for us all is – how can we create a policy environment that helps us overcome cancer evolution and drug resistance, by prioritising innovative treatments today and encouraging their creation tomorrow?

I firmly believe that the solution lies in embedding the concept of innovation throughout the whole process of bringing a drug to market – not only at the stages of discovery and clinical trials, but also during drug licensing and evaluation of cost-effectiveness.

We need a system that actively encourages companies to take on the high-risk targets which have the potential for the highest reward – and which can be incorporated into drug combinations that are more likely to tackle cancer evolution and drug resistance.

If there was confidence that health systems would prioritise and pay for (or otherwise reward) the most innovative and effective cancer treatments, then companies would be more likely to take on this risk. We need to tip the balance to incentivise innovation.

It’s not my intention to pin the blame on one party or another for our current problems of innovation and access – and it’s certainly not just the fault of pharmaceutical companies or NICE. It’s a problem of the entire ecosystem that we are all part of and we need to work together to come up with new solutions.

Meeting the challenges with a new vision

Our Cancer Drug Manifesto proposes some solutions. It takes the form of a 10-point plan laying out some of the actions we would like to see to speed up patient access to innovative cancer drugs and to incentivise future innovation.

To underpin the Manifesto we also publish a series of position statements, providing more information on:

I’m certainly not saying that the ICR has all the answers, and the manifesto is intended to encourage conversations about how to promote and make available innovative treatments.

While more interactive work is needed between the involved parties to arrive at a comprehensive list of definitive and detailed solutions, I do believe that the actions we propose in the manifesto could deliver major benefits for cancer patients, today and in the future.

We propose that drugs should be increasingly tested in smaller, smarter clinical trials to generate findings more quickly and cheaply – giving the NHS patients fast access to drugs at affordable prices.

These trials need to be guided by biomarkers to ensure that each molecularly targeted drug is directed to the patients that will respond to the treatment.

We would like to see drug companies incentivised to trial their medicines together – so we can defeat cancer through combination treatments, as we do with HIV.

To encourage early access to new drugs for patients, I believe we need to explore models of adaptive licensing, where regulators assess drugs on early evidence such as progression-free survival or quality of life, and then later review their benefits in terms of overall survival and eventually on real life-use data.

We need radical action too, as I have written before, to bring down the extremely high and unsustainable prices of modern cancer drugs. We could, for example, pilot systems that tie the price of a drug to the beneficial outcomes it achieves, or that allow price to be varied – for use in different cancer indications for example.

I also believe that NICE has an important role to play in prioritising genuinely innovative cancer treatments that attack cancer in brand new ways. We need to get these drugs to cancer patients especially quickly because they have greater potential to make a big difference.

To be fair, NICE has done well to deal with the previous backlog of cancer drugs – and has established a system for assessing cost-effectiveness that is the envy of the world. But NICE should prioritise not only activity in cancers of high unmet need – important though that is – but most especially accelerate the appraisal of those drugs with brand new mechanisms of action which have the greatest potential to help overcome drug resistance, either on their own or in combination.

Big leaps forward in cancer survival are achievable, but only if we fix the ecosystem so we can take the risks needed to create truly innovative new drugs and combination therapies.

Our Cancer Drug Manifesto is intended to encourage a debate about how we achieve this – so that all cancer patients get the benefits from innovative new treatments that they deserve.

Last week I presented the ideas in our Cancer Drug Manifesto at the Westminster Health Forum in London. This meeting was focused on tackling the twin issues of drug access and pricing, and brought together representatives from academia, the pharmaceutical industry, Government, NICE, the NHS and other stakeholders.

There was a lot of excellent debate about how to how balance 1) incentivising a thriving life-sciences industry that produces innovative drugs, 2) increasing access to these drugs for patients, and 3) ensuring affordability for the NHS. Each organisation brought a different perspective but I was heartened to see that there was a strong recognition of the shared challenges we face and of the need for change, as well as agreement on some emerging solutions that our manifesto proposes.

I was very pleased that our Cancer Drug Manifesto received extensive coverage in the mainstream media as well as in more specialist titles such as the British Medical Journal. And it also attracted a great deal of support from patients and others on social media.

I look forward to continuing the conversations we’ve started, and seeing how we can build on our manifesto to really make a difference to the landscape of innovative cancer drug discovery, clinical trials and patient access. 

Tags

abiraterone vemurafenib policy Paul Workman olaparib NICE cancer drugs drug resistance cancer evolution drug report drug access
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