Title and motion of NCRI 2016 conference debate 'New tricks for old drugs?'
Last evening I took part in a very interesting debate on drug repurposing — where an existing drug is used either against a new biological target mechanism or against the original target but in a new way, such as in a different disease.
Repurposing (or repositioning as it is also known) is all about teaching an old dog — or drug in this case — new tricks.
At The Institute of Cancer Research we’re in favour of drug repurposing where there is good evidence for it, and over the last few years our organisation has backed — as I have personally — the valuable campaigning led by Breast Cancer Now to look at ways we can bring off-patent and off-label drugs to patients.
But the debate wasn’t simply asking whether there was support for repurposing — the question asked was whether research into repurposing should be prioritised over research into designing and developing entirely new treatments.
In a financially constrained environment, where should the sector be putting its money? Into newly created drugs and targets or into finding ways to make better use of the drugs we already have in our repertoire?
Most people would generally agree that in an ideal world we need both approaches. But this was a debate and the audience had to decide on either one option or the other — sitting on the fence was not allowed! The two sides went head to head, chaired by the ICR’s Professor Judith Bliss, and I put the case that innovative new treatments have to be our top priority.
The other side
Speaking first, Professor Rob Coleman of the University of Sheffield and Professor David Dodwell of Leeds Teaching Hospital NHS Trust made the arguments for repurposing.
They claimed that current drug development hasn’t been working for breast cancer patients — as there has been little effect on total breast cancer deaths in the last 35 years. Their premise was that current processes for drug discovery and development are broken — and until this is fixed we won’t see the big changes needed to make a difference for patients.
The high costs of new drugs, of course, came into it. It’s a long risky road to discover and develop a new drug — and the cost needed to do this can be very high. The other side argued that although the last 10 years had seen some new breast cancer drugs make it to market, not all had been approved by NICE and so many had not made it to patients on the NHS.
The pro-repurposers said that we simply couldn’t afford to focus primarily on innovative new treatments — so the balance must shift to getting better at using what we already have.
They had some interesting ideas when it comes to existing breast cancer medicines. Tamoxifen is a good example of a failed contraceptive that was repurposed for treating cancer.
The pro-team also wanted to see a focus on increasing compliance so people take the full course of their treatments to ensure they achieve maximum effect, and on ensuring that patients can access the same drugs wherever they are in the country by getting rid of inconsistency of access. They also highlighted that we need to make sure that we follow up initial approval studies to assess the real world responses to treatments once they have been made available to patients — and that we understand and respond to the measured outcomes of these treatments when used in routine care.
And the pro-team also wished to see the use of bisphosphonates made more widely available to cancer patients. Bisphosphonates are drugs prescribed for osteoporosis and are also used to slow down or prevent bone damage which is important since some cancers can cause bone pain and weakness. But in addition there is evidence that bisphosphonates can prolong survival for women with early breast cancer who have gone through the menopause.
Arguing for innovation
With the arguments for repurposing made, it was over to myself and Dr Susan Galbraith of AstraZeneca to make the case for discovery and developing new medicines. Here are the main points we made:
1. We need to innovate to create the tools we need to defeat cancer
While our side supported drug repurposing where there is good evidence for it, this is just one tactic — whereas to meet the major challenges we face in tackling cancer we need to stand back and take a more strategic approach with a broader repertoire of approaches.
I emphasized at the outset that if we didn’t carry out innovative drug discovery on new targets, then we wouldn’t have any drugs to repurpose! And how can we hope to find cures for cancer if we don’t have a good range of tools to overcome it?
Of course we know well that drug discovery and development can be difficult, slow and expensive — and if you regularly read my blog you’ll know that I agree that we still have many things that we need to change in order to accelerate the way we bring innovative new treatments to patients and to reduce costs.
But both preclinical discovery and clinical development has got a lot faster – as I pointed out it’s now possible through new technologies to discover a first-in-class drug candidate acting in a new target in 2–3 years, and with the use of patient selection biomarkers and improved regulatory procedures we can see drug approvals within 5 years.
Furthermore the new targeted therapies are bringing transformative improvements to outcomes for patients — and dramatic effects are being seen with the new inmmune-oncology drugs.
In 2015 a total of 16 new cancer drugs were approved and so far this year a further nine have been licensed.
2. There is so much more to discover
If we are to make a real impact on cancer outcomes we need to expand the druggable cancer genome to ensure we have agents for all the key pathways and nodes that we now know are involved in cancer.
Currently only 5 per cent of known cancer genes have so far been targeted by drugs — so we’ve hardly scratched the surface when it comes to drugging the cancer genome.
I like to think of this remaining 95 per cent as the ‘dark matter’ of cancer genes. There is a huge amount of work to do to find drugs for the remaining cancer genes — and hence provide the essential therapies we need to patients whose cancers are driven by undrugged genes such as MYC, mutant RAS and mutant p53 and many others.
3. We need innovation to tackle to the challenge of cancer networks and evolution
Furthermore if we are to tackle, as we surely must, the major challenges like adaptive biochemical network responses and cancer evolution and drug resistance — which will be essential to extend survival and increase cure rates for people with cancer — then innovation is crucial.
We urgently need to devise novel strategies that hit cancer gene networks more completely and which are also able to overcome or prevent cancer evolution, tumour heterogeneity and drug resistance — which are the biggest challenges in cancer treatment today.
We need to create new drugs in the first place, and then we must discover and implement the most effective drug combinations, as well as integrating different types of treatments such as chemotherapy, targeted drugs and immuno-oncology
The value of such drug combinations is well precedented in diseases like tuberculosis and HIV, and also cytotoxic chemotherapy for cancer. So we need a huge amount of effort to create innovative drugs acting through novel mechanisms that we can reveal by basic research and reverse translation from the clinic — including especially targets involved in the fundamental processes of evolution and drug resistance — in order to achieve transformational differences to survival and cure of cancer patients.
All this involves creative new drug discovery — repurposing alone will not achieve the outcomes we urgently need.
4. Once a new drug is approved we can use it rapidly in new ways
Susan made the point that sometimes we need to wait for several years before we see the full benefits of innovation. At the time a drug is first approved it is often for late-stage cancer treatment when the benefit may be smaller — but then as the drug is used earlier in the course of treatment we can see a greater benefit, both for patients, and for the NHS as the costs for QALY gained come down
This was clearly demonstrated in breast cancer by tamoxifen — which showed only modest effects in late stage cancers and then much greater activity in the earlier, adjuvant disease setting before eventually being used for chemoprevention. Trastuzumab (Herceptin) has been a transformational new drug that has also shown greater activity when used in earlier stage disease.
In addition I argued that with greater understanding of cancer biology and genomics it is now possible to repurpose drugs so quickly that the repositioning is simply an extension of a drug’s development.
Examples are the additional use of leukaemia drug imatinib (Gleevec) to treat KIT-driven gastrointestinal stromal tumours (GIST) in addition to BCR-ABL-driven chronic myeloid leukaemia and the use of crizotinib (Xalkori) to treat non small cell lung cancers driven by ALK and ROS1 as well as the original target MET.
This is repositioning but requires innovative new drug discovery and then rapid application to other settings.
Furthermore I pointed out that where an older, off-patent, repurposed drug has to have its dose and schedule optimized to ensure maximum therapeutic effect and minimize toxicity in the new setting then, this can actually take several years at considerable cost.
5. Investing in new cancer drugs is worth it
Susan made the point that between 1988 and 2000, life expectancy after cancer increased by 3.9 years, equating to 23 million life years gained through improvements in cancer care — and providing $1.9 trillion dollars in societal value. Investing in new treatments is worth the cost as it helps patients, benefits our economy and in the long run will save the NHS money.
Optimistic about the future of drug innovation
Overall our team concluded that repurposing is a useful bonus of drug discovery, but is only a small part of the bigger picture. A tactic rather than a strategy. Innovative new drug discovery is absolutely essential in order to meet the challenges we face in cancer treatment.
At the end of the presentations and questions from the floor and via an app, the audience was asked to cast a vote one way or the other — should research priorities focus on repurposing and optimising existing drugs or developing new ones? I was pleased to see that the audience looked at the bigger picture — and chose to prioritise creative, novel drug discovery at 58 votes to 46 when the final vote came in.
The NCRI conference is the biggest cancer conference in the UK, and a great place to hear about the latest in innovative cancer research so it is only fitting that innovation and research into new treatments won the day.
I am optimistic that there is an exciting future of drug innovation based on the advances in cancer biology.
As I said in my concluding remarks, that the audience voted for innovation was a vote for hope in science being able to provide a better future for people with cancer.