It’s a regrettably common story: a drug candidate shows great potential, only to fall at the final hurdle. After investing millions of dollars into its development, a pharma company is left with nothing to show for their efforts. Nothing, that is, except the hefty price tag associated with late-stage drug attrition.
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This could all be set to change, however, thanks to a revolutionary development by Crown Bioscience. Showcased this June at the 50th Annual ASCO Conference in Chicago, the HuTrial platform provides a low-cost substitute for a traditional phase-II trial. It could help ease the passage to market for promising oncology therapies.
HuTrials are conducted using Crown’s HuPrime patient-derived xenographs (PDX), which involve transplanting primary tumour cells directly from a patient into an immunodeficient mouse. As the new tumour develops, it retains all the key characteristics of the original. This means the surrogate truly represents the patient, and accurately determines how their cancer is likely to behave.
While patient-derived xenographs in themselves are nothing new, this is the first time the technique has been used to simulate clinical trials.
India’s strength is in generics and contract manufacturing are undeniable, but can it make the transition to full drug discovery and development?
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By GlobalData"Initially people didn’t think about it in those terms," explains Jean-Pierre Wery, president of Crown Bioscience. "But Crown has the largest collection of models for lung cancer, gastric cancer and so forth. At some point we thought, well each of these models represents a patient, so if we were to do a study in which we took hundreds of these models, it would be very similar to running a phase-II trial."
Targeting patients
Especially within oncology, phase-II clinical trials are notorious for their failure rate – an exciting preclinical candidate does not always translate into a successful drug. This is largely due to the fact that cancer is such a heterogeneous disease. Even if you take two lung cancer patients, nominally suffering the same ‘type’ of cancer, the underlying biology may be entirely different.
This means that any given drug candidate is unlikely to work well across the board. You need to pinpoint exactly which patient group will benefit, if the candidate is ever to make it past the preclinical stage.
HuTrials provides an intriguing potential solution. In essence, Crown enrols not patients but tumour models into a clinical trial. This gives a great deal of flexibility to test out treatments, discerning the different effects of each drug on any given tumour type.
"Often if you look at say 100 lung models, you will see that maybe 80 don’t respond but 20 do," says Wery. "We can go back and ask questions – what’s special about the models that do respond? Once you identify the biomarkers, you have an idea about which group of patients are going to respond to your drug. That’s absolutely wonderful information to have to maximise your chance of being successful in the clinic."
The point is not so much to pick a winning drug from a pool of candidates, but to ensure your chosen therapy goes all the way. This may mean looking within a cancer type to find a target patient population. Or it may mean looking at several cancer types – lung, liver, gastric, etc. – to discern which is most responsive to the treatment.
Cutting time and costs
Technically, the requirements are similar to those in a human trial: you need an adequate number of ‘patients’, and sufficient diversity in your tumour models. Here, though, there is an additional important factor, which is keeping the tumours alive. Typically mouse tumours would be cryopreserved until needed, but when conducting HuTrials the timelines are too short to make that a viable option. Crown therefore keeps a ready stock of mice available for trial enrolment.
"If you want a HuTrial with 50 models, and you have go back and regenerate all these models from frozen tumours, that’s very cumbersome," says Wery. "Most of your customers will say you’re going to get clinical trial information too late. So unlike many companies, Crown keeps a lot of models alive whether or not the customer’s going to use them."
If speed is one key advantage, the other is surely cost. While a typical phase-II or III trial costs millions of dollars, a pharma company can undertake a HuTrial at a fraction of the price. It’s a worthwhile investment, ensuring that only the most effective candidates make it through to the next phase of testing.
A new UCL report questioning the use of off-label drugs to save money has been criticised for propping up an unfair status quo.
"We have examples of people who spent nearly $30m on a clinical trial, and they got nothing," says Wery. "They realise after the fact there was actually a sub-population that did benefit from the treatment but it’s too late, so they come to us and ask, can you verify what we think we’ve seen in the data with a HuTrial? HuTrials cost less than half a million dollars unless they are very large."
Bridging the divide
Wery feels that HuTrials are an exciting development for the industry at large. At any given time, there are thousands of phase-II trials ongoing in cancer, meaning many different companies could benefit. And while there is still a gulf between the preclinical and clinical worlds, Crown is trying to engage organisations on both sides with a view to bridging the divide.
The idea, above all else, is to accelerate the passage of promising drugs to the clinic – ensuring that clients do not waste resources on ineffective treatments, while at the same time helping pinpoint drugs that could benefit a specific population.
"If you have an interesting candidate that has a certain mode of action, and you give it to a random selection of lung cancer patients, most of them are not going to respond to it, so that creates clinical failure," says Wery. "And the sadness is a lot of good candidates never reach the market as a result. HuTrials can enable companies to go from an interesting pre-clinical drug candidate to clinical success."
