The latest major breakthrough in cancer is a drug called capivasertib, which has shown ‘remarkable’ results against advanced breast cancer in its first phase III trial.
Results released at the prestigious San Antonio Breast Cancer Symposium (SABCS) show that the drug can double the time before cancer returns.
But what is capivasertib? How does it work – and how was it discovered?
Here at The Institute of Cancer Research, London, we’re very proud of the major role we played in the capivasertib story – from the underpinning fundamental science, through to the drug’s discovery and then subsequent clinical development.
It’s very exciting for our researchers to see the drug succeed in such a gold standard randomised phase III trial, as new treatment options for patients with advanced breast cancer don’t come along very often.
And while capivasertib is being initially developed for oestrogen receptor positive breast cancer, it is undergoing a range of phase III trials, and it is possible that it could work in other cancers too.
How capivasertib works
Capivasertib – pronounced cap-EEVA-sertib – targets a cancer-driving protein molecule called AKT, also known as protein kinase B or PKB.
Small-molecule cancer drugs like capivasertib are designed very precisely to have the correct shape and other features to ‘lock’ into a cavity in their target protein, like a molecular key. Doing so is intended to block the protein’s cancer-driving activity.
The new CAPtello-291 trial used capivasertib alongside hormone therapy to treat patients with oestrogen receptor positive, HER2 negative breast cancer.
This very common type of breast cancer is often driven by an overactive AKT signalling pathway – and researchers were hopeful that blocking AKT could produce a strong anti-cancer effect.
How was capivasertib discovered?
The drug was ‘discovered’ – scientific parlance for its creation and synthesis – in a long-running research programme, initiated by researchers at the ICR and carried through into clinical development with our industry partners.
Here Professor Paul Workman – one of the major figures in capivasertib’s early discovery and development – explains the story, and why it’s so exciting.
“It’s a great success story for British science,” says Professor Workman. “We started here at the ICR with fundamental discovery science to understand the AKT protein molecule, and we followed this with a major drug discovery project, taking this all the way to proof of concept with our prototype drugs showing promising activity in animal models, in partnership with Astex Pharmaceuticals – a UK biotech company in Cambridge.
“We then ultimately partnered with AstraZeneca to ‘bring the project home’, if you will, and take it all the way to identify a clinical candidate and carry out the very expensive programme of clinical trials – in which colleagues at the ICR and clinical colleagues at our partner hospital, The Royal Marsden, played a leading role.
“With the presentation of these new and exciting results, we can look forward with hope that the drug will be approved by the regulatory authorities for use in cancer, not only in the UK but around the world.”
A great many scientists and clinicians have played important parts in the drug’s story, from the ICR and from partners including the pharmaceutical companies Astex and AstraZeneca, The Royal Marsden and Cancer Research UK, which alongside the ICR itself, funded the earlier work in the study of AKT.
Players in the story have included Professor David Barford, whose team carried out the fundamental research to reveal AKT’s structure and how it is activated, Professors Workman, Michelle Garrett, Ian Collins and Dr Edward McDonald, who led various aspects of the drug discovery work in partnership with Astex, and Professors Udai Banerji and Nick Turner, who respectively led early and later-phase clinical trials.
Dozens of early-career researchers, technicians and PhD students had vital parts to play too – some of whom still work at the ICR.
In praise of ‘discovery’ science
As you’ll have seen from the media coverage generated by the new trial results, the story of a new drug usually makes the biggest public impact when the results of the phase III trial are announced.
That’s to be expected, as that’s when it becomes clear that the drug has a real benefit for people with cancer.
But much of the story of a drug’s discovery and development happens long before the big trials – or even the early trials – begin. It takes years of painstaking research from scientists working in disciplines that don’t hit the headlines as often. In fact the overall timeline for the AKT project goes back some 22 years, to when the work was first initiated in 2000.
The fundamental curiosity-driven research to understand the 3D structure of AKT and how it is activated enabled the drug discovery researchers to take a structure-based design approach.
Drug discovery
The path to capivasertib involved a particular type of structure-based drug design known as ‘fragment-based’ drug design. The starting point from which the chemical structure of capivasertib evolved was a tiny molecular ‘fragment’ called 7-azaindole which was shown to bind to a particular cavity of AKT, called the ATP-binding pocket.
ICR and Astex researchers then progressively grew the fragment by expanding it into bigger chemical compounds that filled the ATP pocket and made key molecular contacts. Effectively they were creating keys that were sequentially better fits to the lock – and that bound more tightly to the ATP pocket and blocked its kinase function more effectively.
A key prototype drug compound en route to capivasertib was the so-called ‘pyrrolopyrimidine’ compound CCT128930 – which represented a vital breakthrough in targeting AKT in cancer. The ICR and Astex team found that this molecule ‘locked’ into AKT very selectively, with reduced activity on a closely related protein PKA, and was also selective compared with a number of other kinases.
In addition, when injected into mice, this protype drug was shown to achieve promising levels in the blood plasma and tumour tissue – and using biomarker ‘assays’, or tests, developed at the ICR, it was shown to inhibit AKT in human tumours ‘xenografted’ into mice, and to block the tumour growth.
A further prototype drug developed by the ICR and Astex team was the pyrrolopyrimidine CCT129254, which has a structure very similar to capivasertib. That molecule was evaluated by AstraZeneca in studies in mice and confirmed to have promising anti-tumour activity and tolerability, before the company licensed the programme from the ICR and Astex.
Among the compounds subsequently made by AstraZeneca, the iteration from CCT129254 into capivasertib – initially referred to as AZD5363 – was especially important.
The apparently small change in structure led to the removal or reduction of two properties that would have been risky for clinical development – namely binding to an ion channel called hERG that can cause sudden effects on the heart, and binding to the kinase ROCK2 that can cause unwanted effects on blood pressure.
Based on these observations and the retention of anti-tumour activity, capivasertib was selected for clinical development.
Reaching the clinic
Much of the key work on the capivasertib project carried out at the ICR took place around the years 2000 to 2005 – covering the fundamental structural biology, understanding of AKT activation and the medicinal chemistry, development of biomarkers to show AKT inhibition, and studies in mice to demonstrate biomarker changes in vivo and anti-tumour activity.
But the ICR was involved in the trials too, in ways that demonstrate our unique ability to translate our discoveries into benefits for patients.
The first, ‘phase I’ clinical trial was led by Professor Udai Banerji, Deputy Director of Drug Development Unit at the ICR and The Royal Marsden.
Crucially, the trial was supported by teams that sit across the ICR’s drug discovery teams and our clinical research, including the Clinical Pharmacodynamic Biomarkers Group – founded by Professor Garrett in 2007.
The Clinical PD Biomarkers Group works with partners, especially in industry, to design trials very robustly, ensuring that a drug is really hitting the target suggested by the earlier science. The team also wanted to make sure clinicians chose the right dosing schedule in the phase I trial, maximising benefit while reducing the possibility of side effects.
Pharmacological ‘auditing’
The Phase I clinical trial of capivasertib utilised the Pharmacological Audit Trail approach, which was conceptualised and developed by Professor Workman and colleagues.
The PhAT, as it’s known, was created and introduced as a means to overcome the problem of too many cancer drugs failing in expensive, later-stage trials, because of a lack of understanding of the extent and duration of target modulation during clinical development.
The stories of capivasertib and other drugs in our therapeutic pipeline involve the rigorous application of the PhAT to improve the chance that new cancer drugs will prove beneficial in major trials.
The PhAT approach was specifically and explicitly used in the Phase I trial of capivasertib to show target modulation in tumour biopsies and normal tissues, and to come up with the intermittent schedule of twice a day dosing with four days on and three days off treatment. At the recommended phase II dose, capivasertib was well tolerated and achieved plasma levels and robust AKT target modulation in tumour tissue. In addition, proof-of-concept tumour responses were also seen.
Late-stage trials
And – as we’ve seen in the media – the ICR’s involvement didn’t end there, carrying on right until the present day through Professor Nick Turner’s leadership of the phase III clinical trial, funded by AstraZeneca.
Like many of the ICR’s clinical academics, Professor Turner combines his clinical research with a programme of laboratory research – in his case, leading a team in the ICR’s Breast Cancer Now Toby Robins Research Centre in Chelsea.
As Professor Turner says: “This is a fantastic finding for patients with breast cancer. Even with the best current treatments, people with this type of advanced breast cancer will eventually see their cancer stop responding to treatment. We’re delighted that this potential first-in-class drug combined with hormone therapy can slow the progression of these advanced cancers, and in almost a third of cases can shrink tumours.”
This delight is shared by many others at the ICR whose efforts have made major contributions to help discover capivasertib and progress it into the clinic, and now show its benefit in women with breast cancer in a major trial – including Professor Workman.
“This is a huge breakthrough,” says Workman. “It’s a new line of attack in cancer, it’s acting in a completely new way, slowing the development of resistance to treatment, and extending the length of time that people survive with advanced breast cancer before the cancer progresses.
“We can also expect the drug to be developed even further, and its use to be widened as well, perhaps, into other tumour types. For drug discovery researchers like myself, this is as good as it gets!”
Professor Workman is also careful to highlight the importance of partnership working, not only between many different scientific disciplines but also the many different organisations that have played a crucial role in this success story.
And now it’s crucial that the drug benefits people with cancer as soon as possible, he says.
“We now hope that capivasertib will now gain rapid marketing approval from the regulatory authorities so that patients around the world can benefit from the drug.”